Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast Cancer Outcomes

*Donovan McGrowder, Fabian Miller, Chukwuemeka Nwokocha, Cameil Wilson-Clarke, Melisa Anderson, Lennox Anderson-Jackson and Lowen Williams*

## **Abstract**

Breast cancer remains one of the most frequent cancers affecting women globally. The incidence of breast cancer is rising due to improved screening and awareness, and there is epidemiological data signifying an interaction among environmental and biological risk factors in the development and progress of breast cancer. There is substantial experimental data of the protective effect of micronutrient antioxidants for breast cancer via alteration of many signaling pathways and molecular events including inducing apoptosis, and inhibition of breast cancer cell proliferation and invasion. The main focus of this review is to examine past and current epidemiological evidence that suggests that nutritional micronutrients with antioxidant properties in dietary or supplemental form may be beneficial in protecting women against breast cancer and affect outcomes.

**Keywords:** breast cancer, risk, antioxidants, micronutrients, mortality, recurrence, dietary, intake

## **1. Introduction: breast cancer**

## **1.1 Etiology of breast cancer and role of oxidative stress**

Breast cancer remains one of the most frequent cancers affecting women globally. In 2018, 2.1 million new cases were reported, accounting for approximately one in every four cases of cancer among women [1]. Breast cancer accounted for almost 15% of cancer-related deaths in women in 2018 [2]. It is more common in the developed world, with highest incidence in regions such as Europe and Northern America [1]. However, mortality rates are higher in developing regions such as Africa [1]. Breast cancer is linked to numerous risk factors including family history, gene mutations, obesity, hormonal therapy, and alcohol consumption [3] but a recognizable risk profile is not usually present in most women who develop the disease [4]. Even though

curative therapy is promising following early detection, approximately 30% of cases diagnosed at early stages will progress to metastatic disease [5]. Furthermore, cases of disseminated disease are almost always untreatable and radical prophylactic mastectomy remains the only primary preventative measure [6]. These challenges have spawned a shift in the treatment paradigm of the disease, which has led to major treatment advancements and improved palliative care. However, drug resistance and adverse side effects are common nuisances of current therapy [7]. Therefore, new approaches to breast cancer management with treatments that have minimal harmful effects and can retard tumor progression are required.

To determine effective treatment approaches for breast cancer, it may be worthwhile to elucidate the complexity of the tumor microenvironment. It has been suggested that impaired mitochondrial metabolism may be a feature of tumor progression [8]. Additionally, it has been reported that a hallmark feature of mitochondrial dysfunction is the generation of reactive oxygen species (ROS) which may cause pro-tumorigenic outcomes such as DNA damage and genomic instability [8]. Reactive oxygen species include molecules such as superoxide anion, hydrogen peroxide, hydroxyl radical and singlet oxygen. They are involved in cell signaling through second messenger pathways in both cancer cells and their normal counterparts [9]. It was reported that various cancers are characterized by overproduction of ROS that can increase pro-tumorigenic signaling, cell survival and DNA aberrations [10]. Similarly, another study reported that elevated ROS levels is necessary to support and sustain metastasis [11].

Oxidative stress is widely considered to play a major role in the initiation and pathogenesis of breast cancer [12]. It refers to the imbalance between ROS production and clearance favoring decreased clearance and a pro-oxidant environment caused by either an overproduction of ROS or decreased antioxidant activity [13]. In breast cancer, a vast majority of stromal fibroblasts becomes activated following exposure to oxidative stress resulting in hydrogen peroxide production which triggers tumorigenic changes in breast epithelial cells [12]. A plethora of high energy nutrients and growth factors are also produced which fuels metastasis [12]. Congruently, it was reported that higher levels of oxidative stress biomarkers such as malondialdehyde and oxidized glutathione were found in breast cancer patients compared to control subjects [14]. The human body comprises an antioxidant defense system which exerts its function by generating antioxidants including the catalases, glutathione peroxidases and superoxide dismutase which offer protective effects by metabolizing and scavenging free radicals to inhibit and minimize tissue damage [15]. It is important to note that despite the presence of an endogenous antioxidant system, DNA damage ensues and accumulates throughout life and could considerably contribute to the initiation and progression of cancers [16]. Given the accumulation of evidence supporting the role of ROS in the pathogenesis of breast cancer, there is a possibility that dietary micronutrient antioxidants may be useful to counteract oxidative stress induced cancer. Moreover, it was reported that antioxidant supplement use among breast cancer patients was 45–80% [17].

This paper will review information in the literature on the relationship between dietary and supplement micronutrient antioxidants including vitamins C and E and their association with the risk of breast cancer as well as outcomes such as disease recurrence and mortality.

## **2. Method of article selection**

A literature search was conducted for all English language literature published before December 2020. The search was conducted using the electronic databases,

**19**

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

including PubMed, Embase, Web of Science, and Cochrane Library. The search strategy included keywords such as breast cancer, epidemiology, incidence, risk, recurrence, mortality, vitamin E, vitamin C, carotenoids, flavonoids and green tea. The authors include many interventional and observational studies that have reported findings of dietary and supplemental micronutrient antioxidants, breast cancer incidence, and progression. The majority of these studies focused on vitamins E and C, carotenoids, specifically beta- and alpha-carotene, lycopene as well

Vitamin C is a naturally occurring essential micronutrient that is soluble in water and its antioxidant properties involve neutralizing reactive oxygen species as well as other free radicals [18]. Investigational experiments and epidemiologic findings on vitamin C and breast cancer risk are still inconclusive and reviews of data have suggested both detrimental and protective effects on overall risk of breast cancer [19]. Prospective studies on vitamin C intake and breast cancer risk have yielded diverse findings [20–23]. A recent meta-analysis reported that dietary vitamin C but not supplements was associated with a lesser risk of breast cancer incidence (RR = 0.89; 95% CI: 0.82–0.96) [20]. In the European Prospective Investigation into Cancer and Nutrition Study of 7,502 primary invasive breast cancer cases with a median followup time of approximately 9 years, multivariate analyses showed that vitamin E and C were not related with breast cancer risk in postmenopausal and premenopausal women. However, high intake of vitamin C was associated with decreased breast cancer risk in postmenopausal women utilizing exogenous hormones [21]. Earlier, in the Netherlands Cohort Study comprising of 62,573 women with 650 incident breast cancer cases identified after a follow-up of 4.3 years, dietary Vitamin E and vitamin C supplement use did not influence breast cancer risk, but there a small reduction in risk with increasing dietary intake of vitamin C particularly at the highest quintile [22]. Correspondingly, findings from the Women's Health Initiative Observational Study which followed 84,805 women for approximately 8 years with 2,879 incident invasive cancer cases ascertained, showed a weak positive association of breast cancer risk with total and supplemental vitamin C particularly among

Other prospective studies showed increased breast cancer risk with dietary or supplemental vitamin C. Using a large cohort of 2,482 invasive breast cancer cases in 57,403 postmenopausal Women, Cadeau et al. examine the association between vitamin C supplement use and breast cancer risk while bearing in mind dietary vitamin C intake, and found no relation with the overall risk, but females in the fourth quartile of vitamin C intake from foods had a 32% increase in breast cancer risk [24]. Published in 2011, a meta-analysis of 51 studies comparing highest with the lowest vitamin C intake from supplements may be associated with higher breast cancer risk [25], but it was noted that the overall result was influenced by a single large study [23]. In this same meta-analysis, dietary and total vitamin E, and dietary vitamin A significantly decreased breast cancer risk for cohort studies, but the results became nonsignificant when case–controlled studies were pooled [25]. Notably, Sharhar et al. examined relations between oxidative stress and antioxidant status in 57 newly diagnosed breast cancer cases and found poor antioxidant status

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

as the flavonoids, flavonols and isoflavones.

*3.1.1 Vitamin C and breast cancer risk*

postmenopausal women (**Table 1**) [23].

**3.1 Vitamin C**

**3. Epidemiological evidence of vitamins as antioxidants**

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

including PubMed, Embase, Web of Science, and Cochrane Library. The search strategy included keywords such as breast cancer, epidemiology, incidence, risk, recurrence, mortality, vitamin E, vitamin C, carotenoids, flavonoids and green tea. The authors include many interventional and observational studies that have reported findings of dietary and supplemental micronutrient antioxidants, breast cancer incidence, and progression. The majority of these studies focused on vitamins E and C, carotenoids, specifically beta- and alpha-carotene, lycopene as well as the flavonoids, flavonols and isoflavones.

## **3. Epidemiological evidence of vitamins as antioxidants**

#### **3.1 Vitamin C**

*Antioxidants - Benefits, Sources, Mechanisms of Action*

effects and can retard tumor progression are required.

support and sustain metastasis [11].

curative therapy is promising following early detection, approximately 30% of cases diagnosed at early stages will progress to metastatic disease [5]. Furthermore, cases of disseminated disease are almost always untreatable and radical prophylactic mastectomy remains the only primary preventative measure [6]. These challenges have spawned a shift in the treatment paradigm of the disease, which has led to major treatment advancements and improved palliative care. However, drug resistance and adverse side effects are common nuisances of current therapy [7]. Therefore, new approaches to breast cancer management with treatments that have minimal harmful

To determine effective treatment approaches for breast cancer, it may be worthwhile to elucidate the complexity of the tumor microenvironment. It has been suggested that impaired mitochondrial metabolism may be a feature of tumor progression [8]. Additionally, it has been reported that a hallmark feature of mitochondrial dysfunction is the generation of reactive oxygen species (ROS) which may cause pro-tumorigenic outcomes such as DNA damage and genomic instability [8]. Reactive oxygen species include molecules such as superoxide anion, hydrogen peroxide, hydroxyl radical and singlet oxygen. They are involved in cell signaling through second messenger pathways in both cancer cells and their normal counterparts [9]. It was reported that various cancers are characterized by overproduction of ROS that can increase pro-tumorigenic signaling, cell survival and DNA aberrations [10]. Similarly, another study reported that elevated ROS levels is necessary to

Oxidative stress is widely considered to play a major role in the initiation and pathogenesis of breast cancer [12]. It refers to the imbalance between ROS production and clearance favoring decreased clearance and a pro-oxidant environment caused by either an overproduction of ROS or decreased antioxidant activity [13]. In breast cancer, a vast majority of stromal fibroblasts becomes activated following exposure to oxidative stress resulting in hydrogen peroxide production which triggers tumorigenic changes in breast epithelial cells [12]. A plethora of high energy nutrients and growth factors are also produced which fuels metastasis [12]. Congruently, it was reported that higher levels of oxidative stress biomarkers such as malondialdehyde and oxidized glutathione were found in breast cancer patients compared to control subjects [14]. The human body comprises an antioxidant defense system which exerts its function by generating antioxidants including the catalases, glutathione peroxidases and superoxide dismutase which offer protective effects by metabolizing and scavenging free radicals to inhibit and minimize tissue damage [15]. It is important to note that despite the presence of an endogenous antioxidant system, DNA damage ensues and accumulates throughout life and could considerably contribute to the initiation and progression of cancers [16]. Given the accumulation of evidence supporting the role of ROS in the pathogenesis of breast cancer, there is a possibility that dietary micronutrient antioxidants may be useful to counteract oxidative stress induced cancer. Moreover, it was reported that

antioxidant supplement use among breast cancer patients was 45–80% [17].

This paper will review information in the literature on the relationship between dietary and supplement micronutrient antioxidants including vitamins C and E and their association with the risk of breast cancer as well as outcomes such as disease

A literature search was conducted for all English language literature published before December 2020. The search was conducted using the electronic databases,

**18**

recurrence and mortality.

**2. Method of article selection**

#### *3.1.1 Vitamin C and breast cancer risk*

Vitamin C is a naturally occurring essential micronutrient that is soluble in water and its antioxidant properties involve neutralizing reactive oxygen species as well as other free radicals [18]. Investigational experiments and epidemiologic findings on vitamin C and breast cancer risk are still inconclusive and reviews of data have suggested both detrimental and protective effects on overall risk of breast cancer [19]. Prospective studies on vitamin C intake and breast cancer risk have yielded diverse findings [20–23]. A recent meta-analysis reported that dietary vitamin C but not supplements was associated with a lesser risk of breast cancer incidence (RR = 0.89; 95% CI: 0.82–0.96) [20]. In the European Prospective Investigation into Cancer and Nutrition Study of 7,502 primary invasive breast cancer cases with a median followup time of approximately 9 years, multivariate analyses showed that vitamin E and C were not related with breast cancer risk in postmenopausal and premenopausal women. However, high intake of vitamin C was associated with decreased breast cancer risk in postmenopausal women utilizing exogenous hormones [21]. Earlier, in the Netherlands Cohort Study comprising of 62,573 women with 650 incident breast cancer cases identified after a follow-up of 4.3 years, dietary Vitamin E and vitamin C supplement use did not influence breast cancer risk, but there a small reduction in risk with increasing dietary intake of vitamin C particularly at the highest quintile [22]. Correspondingly, findings from the Women's Health Initiative Observational Study which followed 84,805 women for approximately 8 years with 2,879 incident invasive cancer cases ascertained, showed a weak positive association of breast cancer risk with total and supplemental vitamin C particularly among postmenopausal women (**Table 1**) [23].

Other prospective studies showed increased breast cancer risk with dietary or supplemental vitamin C. Using a large cohort of 2,482 invasive breast cancer cases in 57,403 postmenopausal Women, Cadeau et al. examine the association between vitamin C supplement use and breast cancer risk while bearing in mind dietary vitamin C intake, and found no relation with the overall risk, but females in the fourth quartile of vitamin C intake from foods had a 32% increase in breast cancer risk [24]. Published in 2011, a meta-analysis of 51 studies comparing highest with the lowest vitamin C intake from supplements may be associated with higher breast cancer risk [25], but it was noted that the overall result was influenced by a single large study [23]. In this same meta-analysis, dietary and total vitamin E, and dietary vitamin A significantly decreased breast cancer risk for cohort studies, but the results became nonsignificant when case–controlled studies were pooled [25]. Notably, Sharhar et al. examined relations between oxidative stress and antioxidant status in 57 newly diagnosed breast cancer cases and found poor antioxidant status


**21**

**Vitamin/ Micro-nutrient (antioxidant)** Total flavonoids and flavonols

Flavones and flavonols Soy isoflavones

Lycopene and

93

Case–control

beta-carotene

**Table 1.**

*Summary of selected studies that provide risk estimates of the associations between dietary and supplemental vitamins and micronutrients (antioxidants) and breast cancer risk.*

129

The Shanghai Breast Cancer Survival Study (prospective)

4,139 stage 0 –III breast cancer patients and 1987 pre−/

Dietary soy

HR = 0.22,

Reduction by 78% in

premenopausal women

(high intake)

(0.09–0.53)

isoflavones

perimenopausal and 2152

postmenopausal patients

122 breast cancer cases and 632

Dietary lycopene and

Lycopene:

Reduction by 74%

Reduction by 57%

Adjusted OR = 0.26,

(0.14–0.46)

Beta-carotene:

Adjusted OR =

0.43 (0.23–0.82)

beta-carotene

healthy controls

112

Case–control

1,434 breast cancer cases and 1,440 controls

Dietary flavones and flavonols

Flavones: OR = 0.61, (0.45–0.83) Flavonols: OR = 0.54 (0.40–0.73)

Reduction by 39%

Reduction by 46%

110

Case–control

1522 breast cancer cases and 1547 controls

Dietary total flavonoids and flavonols

Total flavonoids: OR = 0.66 (0.54–0.82) Flavonols: OR = 0.51

Reduction by 34%

Reduction by 49%

(0.41–0.63)

**Reference**

**Study design**

**Population (Case, participants)**

**Exposure**

**Risk estimates (95% CI)**

**Outcome**

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

*Antioxidants - Benefits, Sources, Mechanisms of Action*


*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

**20**

**Vitamin/**

**Reference**

**Study design**

**Population (Case, participants)**

**Exposure**

**Risk estimates** 

**Outcome**

**(95% CI)**

**Micro-nutrient** 

**(antioxidant)**

Vitamin C and E

Lycopene Vitamin E Vitamin E Alpha-carotene

90

Population-based

case–control

and beta-carotene

Alpha-carotene

23

Women's Health

84,805 women followed for average

Alpha-carotene

and beta-carotene

(supplement)

7.6 yrs.

Initiative Observational

Study

and beta-carotene

53

Population-based

case–control

29

Case–control

297 breast cancer cases and 311

controls

2,362 breast cancer cases and 2,462

Vitamin E

(supplement)

Alpha-carotene

and beta-carotene

(supplement)

controls

5,707 women with incident invasive

breast cancer

150

Case–control

46 breast cancer cases and 63 controls

Lycopene in adipose

tissue

Dietary vitamin E

29

Case–control

297 breast cancer cases and 311

Dietary vitamin C

Vitamin C:

Reduction by 47% (mainly

in premenopausal women)

Reduction by 45%

OR = 0.53

(0.33–0.86)

Vitamin E:

OR = 0.55

(0.34–0.88)

OR = 0.32

Reduction by 68%

(0.11–0.94)

OR = 0.55

Reduction by 45%

(0.34–0.88)

OR = 0.75

Reduction by 25%

(0.58–0.97)

Alpha-carotene

Reduction by 18% for

premenopausal women

Reduction by 19% for

premenopausal women

OR = 0.82

(0.68–0.98;

Ptrend = 0.07)

Beta-carotene

OR = 0.81

(0.68–0.98;

Ptrend = 0.009)

Alpha-carotene

Reduction by 17% (highest

vs. lowest quintile)

Reduction by 22% (highest

vs. lowest quintile)

RR = 0.83

(0.70–0.99,

Ptrend = 0.019).

Beta-carotene

RR = 0.78

(0.66–0.94,

Ptrend = 0.021)

controls

as indicated by low plasma vitamin C which elevated by two to three times the breast cancer risk [26].

The findings of reduced breast cancer incidence with vitamin C consumption was more evident in case–control studies. In Nurses' Health Study involving a large cohort of 83,234 women where 2,697 incident cases of invasive breast cancer was identified after 14 years, the associations between vitamins A, C and E, fruit and vegetables, and specific carotenoids and breast cancer risk were examined. There was a weakly inverse association between dietary vitamin A and breast cancer risk in premenopausal women and strong inverse association with increasing quartiles of dietary vitamin C, alpha-carotene and beta-carotene among premenopausal women who had a positive family history of breast cancer [27]. Likewise, a case–control study conducted in Korea comprising 224 incident breast cancer cases and 250 matched controls establish that vitamin C and betacarotene intake were associated with decreased breast cancer risk, thus possibly lowered incidence in Korean women [28]. Moreover, in an earlier case–control study of 297 breast cancer cases matched with 311 control subjects, there was a significant reduction in breast cancer risk with beta-carotene, alpha-tocopherol and vitamin C when the lowest quartile was used as reference and odds ratios adjusted for the highest quartile [29] (**Table 1**). Conversely, no evidence of association between dietary or total vitamin C intake and breast cancer risk in the UK Dietary Cohort Consortium pooled analysis involving a nested case–control study [30], nor between dietary and supplement vitamin C intake and breast cancer risk in a large prospective study of 89,494 women during eight years of follow-up [31].

#### *3.1.2 Vitamin C and survival outcomes*

Cancer chemoprevention in vitro studies have demonstrated that vitamin C in pharmacological concentrations is cytotoxic to numerous type of cancer cells including ovarian and pancreatic while not affecting normal cells [32].

Globally, there is increasing use of vitamins among cancer patients and in the UK Women's Cohort Study comprising 12,453 females, there was self-reported frequently high dose vitamin C supplement intake use among breast cancer patients [33]. Furthermore, a number of epidemiologic studies have investigated the association between dietary vitamin C, vitamin C supplements and survival outcomes subsequent to breast cancer diagnosis. In a meta-analysis of prospective studies, post-diagnosis vitamin C supplement use was associated with decreased risk for breast cancer-specific (RR = 0.85, 95%CI: 0.74–0.99) and total mortality (RR = 0.81, 95%CI: 0.72–0.91) while dietary intake was also statistically significant for these two survival outcomes [34]. It was noted that in the Swedish Mammography Cohort Study comprising of 3,405 females with invasive breast cancer there was a marginal significant association between dietary vitamin C intake and all-cause mortality, but no association between supplement use subsequent to diagnosis and breast cancer-specific mortality [35].

Nevertheless, the findings are not consistent with intake of dietary vitamin C stated to decrease mortality risk in some studies [36, 37], while no relation in other epidemiologic studies [38–40]. There are also other prospective studies, which have investigated the relationship between vitamin C supplement use and breast cancer survival [17, 41, 42], and recently there is a published meta-analysis of observational studies [20]. In this meta-analysis, pooled results from 69 studies, the hazard risk for all-cause mortality was 0.82 (95% CI: 0.74–0.91), breast cancer recurrence 0.81 (95% CI: 0.67–0.99) and breast cancer-specific mortality 0.78 (95% CI: 0.69–0.88) [20].

**23**

comprising Greek women [56].

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

There are apprehensions that supplement use, mainly antioxidants might decrease the cytotoxicity of chemotherapy and make it less operative [43]. Dietary antioxidant supplementation with radiation treatment and conventional chemotherapy have yielded conflicting results and many randomized clinical trials have reported deceased therapy-related side effects [44, 45]. There is data that attest to the protective effect of tumor cells as well as healthy cells by antioxidants since they neutralize reactive oxygen species and other free radical generated by some forms of chemotherapy and radiotherapy, thus reducing efficacy and ultimately survival [46, 47]. In the Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221), Ambrosone et al. assessed associations between dietary antioxidant supplement (vitamins C, E and A as well as coenzyme Q and carotenoids) before and during chemotherapy (doxorubicin, paclitaxel and cyclophosphamide) treatment and survival outcomes. The use of any of the dietary supplements such as vitamin C resulted in a 41% higher hazard of recurrence of marginal significance, with a comparative but lesser association with mortality [48]. The authors suggested that patients should exercise caution when contemplating the use of

Conversely, epidemiologic studies have demonstrated improved usefulness of numerous cancer therapeutic agents with less adverse side effects when administered concomitantly with antioxidants [49]. Interesting, in a recent study it was found that vitamin C increased the therapeutic window of bromodomain and extra-terminal inhibitors thereby improving their efficacy for treating patients with

The role of dietary and vitamin E supplements in preventing breast cancer still remains unclear [51]. Previous research have demonstrated that there is a lack of any consistent association between vitamin E and the risk of breast cancer [52]. In a large population-based case–control study conducted in Canada that examined antioxidants intakes from diet and supplements and their potential breast cancer risk, 10 years or more supplementation with vitamin E was associated with reduced breast cancer risk (OR = 0.75, 95% CI: 0.58–0.97). However, no significant effect of dietary vitamin E intake or from supplementation less than 10 years was observed [53] (**Table 1**). Likewise, Fulan et al. conducted a meta-analysis of 51 studies on vitamin E intake and found that dietary vitamin E significantly decreased breast cancer risk, but there was no significant dose–response relationship in the higher intake of vitamin E [25]. An earlier case–control study comprising 297 breast cancer cases and 311 control subjects conducted in the United States found a significant reduction in breast cancer risk associated with high intake of dietary vitamin E (OR = 0.55; 95% CI: 0.34–0.88). However, no association was observed between vitamin E supplement intake and breast cancer risk [29]. Notably, findings from the Shanghai Breast Cancer Study suggests that vitamin E supplements may confer safeguard against breast cancer (OR = 0.80; 95%CI, 0.60–1.00) among Chinese women who had low dietary intake [54]. In addition, there were other studies that corroborated these finding including an inverse association of dietary vitamin E with breast cancer risk in a hospital-based case–control study of Chinese women [55] and vitamin E significantly decreased breast cancer risk in a case–control study

*3.1.3 Vitamin C use during chemotherapy and radiation therapy*

supplement vitamin C during chemotherapy [48].

aggressive triple negative breast cancer [50].

*3.2.1 Vitamin E and breast cancer risk*

**3.2 Vitamin E**

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

## *3.1.3 Vitamin C use during chemotherapy and radiation therapy*

There are apprehensions that supplement use, mainly antioxidants might decrease the cytotoxicity of chemotherapy and make it less operative [43]. Dietary antioxidant supplementation with radiation treatment and conventional chemotherapy have yielded conflicting results and many randomized clinical trials have reported deceased therapy-related side effects [44, 45]. There is data that attest to the protective effect of tumor cells as well as healthy cells by antioxidants since they neutralize reactive oxygen species and other free radical generated by some forms of chemotherapy and radiotherapy, thus reducing efficacy and ultimately survival [46, 47]. In the Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221), Ambrosone et al. assessed associations between dietary antioxidant supplement (vitamins C, E and A as well as coenzyme Q and carotenoids) before and during chemotherapy (doxorubicin, paclitaxel and cyclophosphamide) treatment and survival outcomes. The use of any of the dietary supplements such as vitamin C resulted in a 41% higher hazard of recurrence of marginal significance, with a comparative but lesser association with mortality [48]. The authors suggested that patients should exercise caution when contemplating the use of supplement vitamin C during chemotherapy [48].

Conversely, epidemiologic studies have demonstrated improved usefulness of numerous cancer therapeutic agents with less adverse side effects when administered concomitantly with antioxidants [49]. Interesting, in a recent study it was found that vitamin C increased the therapeutic window of bromodomain and extra-terminal inhibitors thereby improving their efficacy for treating patients with aggressive triple negative breast cancer [50].

#### **3.2 Vitamin E**

*Antioxidants - Benefits, Sources, Mechanisms of Action*

breast cancer risk [26].

follow-up [31].

*3.1.2 Vitamin C and survival outcomes*

as indicated by low plasma vitamin C which elevated by two to three times the

was more evident in case–control studies. In Nurses' Health Study involving a large cohort of 83,234 women where 2,697 incident cases of invasive breast cancer was identified after 14 years, the associations between vitamins A, C and E, fruit and vegetables, and specific carotenoids and breast cancer risk were examined. There was a weakly inverse association between dietary vitamin A and breast cancer risk in premenopausal women and strong inverse association with increasing quartiles of dietary vitamin C, alpha-carotene and beta-carotene among premenopausal women who had a positive family history of breast cancer [27]. Likewise, a case–control study conducted in Korea comprising 224 incident breast cancer cases and 250 matched controls establish that vitamin C and betacarotene intake were associated with decreased breast cancer risk, thus possibly lowered incidence in Korean women [28]. Moreover, in an earlier case–control study of 297 breast cancer cases matched with 311 control subjects, there was a significant reduction in breast cancer risk with beta-carotene, alpha-tocopherol and vitamin C when the lowest quartile was used as reference and odds ratios adjusted for the highest quartile [29] (**Table 1**). Conversely, no evidence of association between dietary or total vitamin C intake and breast cancer risk in the UK Dietary Cohort Consortium pooled analysis involving a nested case–control study [30], nor between dietary and supplement vitamin C intake and breast cancer risk in a large prospective study of 89,494 women during eight years of

Cancer chemoprevention in vitro studies have demonstrated that vitamin C in pharmacological concentrations is cytotoxic to numerous type of cancer cells

Globally, there is increasing use of vitamins among cancer patients and in the UK Women's Cohort Study comprising 12,453 females, there was self-reported frequently high dose vitamin C supplement intake use among breast cancer patients [33]. Furthermore, a number of epidemiologic studies have investigated the association between dietary vitamin C, vitamin C supplements and survival outcomes subsequent to breast cancer diagnosis. In a meta-analysis of prospective studies, post-diagnosis vitamin C supplement use was associated with decreased risk for breast cancer-specific (RR = 0.85, 95%CI: 0.74–0.99) and total mortality (RR = 0.81, 95%CI: 0.72–0.91) while dietary intake was also statistically significant for these two survival outcomes [34]. It was noted that in the Swedish Mammography Cohort Study comprising of 3,405 females with invasive breast cancer there was a marginal significant association between dietary vitamin C intake and all-cause mortality, but no association between supplement use subsequent to

Nevertheless, the findings are not consistent with intake of dietary vitamin C stated to decrease mortality risk in some studies [36, 37], while no relation in other epidemiologic studies [38–40]. There are also other prospective studies, which have investigated the relationship between vitamin C supplement use and breast cancer survival [17, 41, 42], and recently there is a published meta-analysis of observational studies [20]. In this meta-analysis, pooled results from 69 studies, the hazard risk for all-cause mortality was 0.82 (95% CI: 0.74–0.91), breast cancer recurrence 0.81 (95% CI: 0.67–0.99) and breast cancer-specific mortality 0.78 (95%

including ovarian and pancreatic while not affecting normal cells [32].

diagnosis and breast cancer-specific mortality [35].

The findings of reduced breast cancer incidence with vitamin C consumption

**22**

CI: 0.69–0.88) [20].

#### *3.2.1 Vitamin E and breast cancer risk*

The role of dietary and vitamin E supplements in preventing breast cancer still remains unclear [51]. Previous research have demonstrated that there is a lack of any consistent association between vitamin E and the risk of breast cancer [52]. In a large population-based case–control study conducted in Canada that examined antioxidants intakes from diet and supplements and their potential breast cancer risk, 10 years or more supplementation with vitamin E was associated with reduced breast cancer risk (OR = 0.75, 95% CI: 0.58–0.97). However, no significant effect of dietary vitamin E intake or from supplementation less than 10 years was observed [53] (**Table 1**). Likewise, Fulan et al. conducted a meta-analysis of 51 studies on vitamin E intake and found that dietary vitamin E significantly decreased breast cancer risk, but there was no significant dose–response relationship in the higher intake of vitamin E [25]. An earlier case–control study comprising 297 breast cancer cases and 311 control subjects conducted in the United States found a significant reduction in breast cancer risk associated with high intake of dietary vitamin E (OR = 0.55; 95% CI: 0.34–0.88). However, no association was observed between vitamin E supplement intake and breast cancer risk [29]. Notably, findings from the Shanghai Breast Cancer Study suggests that vitamin E supplements may confer safeguard against breast cancer (OR = 0.80; 95%CI, 0.60–1.00) among Chinese women who had low dietary intake [54]. In addition, there were other studies that corroborated these finding including an inverse association of dietary vitamin E with breast cancer risk in a hospital-based case–control study of Chinese women [55] and vitamin E significantly decreased breast cancer risk in a case–control study comprising Greek women [56].

However, there are a number of prospective and case–control studies that reported no association between dietary and/or supplement vitamin E intake and breast cancer risk [22, 31, 57]. Verhoeven et al. reported findings from the Netherlands Cohort Study, a large prospective cohort research that examined the relationships between various vitamins, vegetables and fruits with breast cancer risk and found no strong evidence of dietary vitamin E intake in the etiology of breast cancer [22]. An earlier large prospective study found that large intake of dietary vitamin E did not protect from breast cancer (OR = 0.99, 95%CI: 0.83–1.19) [31]. Results from other studies on dietary or supplemental vitamin E intake demonstrated similar null association [58, 59]. These include: a case–control by Wang et al. that did not find any meaningful association of dietary vitamin E intake with breast cancer risk [60], no association of higher dietary intake of vitamin E (in early adult life) among postmenopausal women in the Nurses' Health Study II [57], and meta-analysis of 26 studies that found no effect of vitamin E supplementation on breast cancer risk on reviewing data from five cohort and four case–control studies [61].

#### *3.2.2 Vitamin E use during chemotherapy and radiation therapy*

Over the last decade the use of antioxidant supplements after breast cancer diagnosis and during treatment significantly increased and has become quite common among survivors [53, 61]. In a review of the literature on non-herbal nutrition supplements use in relieving symptoms induced by chemotherapy or radiation treatment, Samuels et al. showed that a number of studies suggest that antioxidant supplements use comprising glutamine, vitamin E and acetyl-L-carnithine possibly might decrease the occurrence and severity of paclitaxel-induced neuropathy [62]. In a comprehensive review of the 22 prospective studies by Greenlee et al. in 2009 that examined the association between use of antioxidant supplements (vitamin E as well as multivitamins, vitamin C, antioxidant combinations, soy isoflavones, melatonin, glutathione, or glutamine) and patient outcomes, there were no single antioxidant supplement during conventional breast cancer therapy that had a significant effect on recurrence, tumor response, toxicities, or survival. The authors indicated that findings from limited studies proposed that vitamin E decrease the hot flashes in patients treated with hormonal therapy and glutamine for oral mucositis [17]. In a more recent study, Huang et al. assessed the associations of dietary intake of fish, fruit and vegetable supplemented with vitamins E and B, and post-therapy cognitive recovery in 1,047 patients with breast cancer enrolled in the Shanghai Breast Cancer Survival Study. Higher dietary intake and supplement use were associated with greater cognitive scores at 36 months post-diagnosis thus improvement in post-therapy mental recovery [63].

#### *3.2.3 Vitamin E and survival outcomes*

Globally, the consumption of dietary supplements including vitamins and multivitamins/multi-minerals is increasing more so among females than males [64, 65]. However, there are only few studies that have examined vitamin E supplementation and survival outcomes in breast cancer patients. A well-designed prospective population-based prospective cohort study comprised of 4,877 females diagnosed with invasive breast cancer in China reported that vitamin E as well as multivitamin use were beneficial in improving survival and mortality rates. There was a 22% decreased recurrence risk and 18% lower mortality risk in females who use vitamin E supplement within 6 months after breast cancer diagnosis [42] (**Table 2**). Likewise, in the Life After Cancer Epidemiology (LACE) Study

**25**

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

comprising of 2,264 females with early-stage breast cancer, 81% use antioxidants post-diagnosis. The regular use of vitamin E was concomitant with reduced risk of disease recurrence (HR = 0.71, 95%CI: 0.54–0.94) and diminished risk for all-cause mortality (HR = 0.76, 95%CI: 0.58–1.00) [41] (**Table 2**). Similarly, data from the After Breast Cancer Pooling Project showed that vitamin E was associated with reduced risk of breast cancer recurrence (RR = 0.88; 95%CI 0.79–0.99) [66]. The findings of a case–control study comprising 385 post-menopausal breast cancer patients performed in the United States corroborated previous reports as the use of antioxidant supplement (vitamins E or C, selenium or β-carotene) was associated with decreased breast cancer-specific death [37]. While these results suggest that antioxidants supplement use may have a protective effect and improve breast cancer survival, there were concerns of recall bias and the legitimacy of the exposure assessment. Furthermore, a recent systematic review and meta-analysis comprising randomized clinical trials and observational studies showed that vitamin E significantly reduced total mortality (RR = 0.76, 95% CI: 0.64–0.90) and breast cancer

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

recurrence (RR = 0.69, 95% CI: 0.55–0.85) [67] (**Table 3**).

chemotherapeutic agents and radiation treatment [71, 72].

*3.3.2 Multivitamins and survival outcomes*

*3.3.1 Multivitamins use during chemotherapy and radiation therapy*

Despite over thirty years of research examining dietary antioxidant supplement use during radiation therapy and conservative chemotherapy, there are significant disagreements regarding the effectiveness of this complementary therapy [68, 69]. Encouraging results from many randomized control trials confirmed that the concomitant administration of supplementation antioxidants with radiation therapy and chemotherapy decreases side effects related to treatment [70]. However, some studies have suggested that antioxidant supplementation may guard malignant tumor cells from the pro-oxidant effects such as oxidative injury produced by

The quality of life and performance of normal daily activities can be negatively impacted by chemotherapy-induced peripheral neuropathy [73]. Using data from the Diet, Exercise, Lifestyle, and Cancer Prognosis (DELCaP) study, Zirpoli et al. reported that the use of multivitamins prior to diagnosis was associated with decreased symptoms of chemotherapy-induced peripheral neuropathy while use during therapy was slightly related with this outcome [74]. However, in a recent study, Jung et al. reported findings from the population-based Mamma Carcinoma Risk Factor Investigation (MARIE) study and noted that pre and post-diagnosis supplement use among of 2,223 postmenopausal women diagnosed with non-metastatic breast cancer was 36% and 45% respectively. The use of antioxidants throughout radiation therapy and chemotherapy was associated with higher total mortality risk (HR = 1.64; 95% CI: 1.01–2.66) and exacerbated recurrence-free survival (HR = 1.84; 95% CI: 1.26–2.68) [75]. The was also no relations between post-diagnosis use of supplement and disease prognosis, and the authors suggests that breast cancer patients should not use antioxidants during radiation therapy and chemotherapy [75].

The natural activity of dietary and supplement antioxidants is due to a number of factors comprising the existing level of oxidative stress, collaborations of antioxidants, and the level of antioxidants present in cells [45]. The consumption of vitamin supplements among breast cancer patients post-diagnosis is quite common [76]. There are prospective studies that have demonstrated that multivitamin

**3.3 Multivitamins**

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

comprising of 2,264 females with early-stage breast cancer, 81% use antioxidants post-diagnosis. The regular use of vitamin E was concomitant with reduced risk of disease recurrence (HR = 0.71, 95%CI: 0.54–0.94) and diminished risk for all-cause mortality (HR = 0.76, 95%CI: 0.58–1.00) [41] (**Table 2**). Similarly, data from the After Breast Cancer Pooling Project showed that vitamin E was associated with reduced risk of breast cancer recurrence (RR = 0.88; 95%CI 0.79–0.99) [66]. The findings of a case–control study comprising 385 post-menopausal breast cancer patients performed in the United States corroborated previous reports as the use of antioxidant supplement (vitamins E or C, selenium or β-carotene) was associated with decreased breast cancer-specific death [37]. While these results suggest that antioxidants supplement use may have a protective effect and improve breast cancer survival, there were concerns of recall bias and the legitimacy of the exposure assessment. Furthermore, a recent systematic review and meta-analysis comprising randomized clinical trials and observational studies showed that vitamin E significantly reduced total mortality (RR = 0.76, 95% CI: 0.64–0.90) and breast cancer recurrence (RR = 0.69, 95% CI: 0.55–0.85) [67] (**Table 3**).

### **3.3 Multivitamins**

*Antioxidants - Benefits, Sources, Mechanisms of Action*

*3.2.2 Vitamin E use during chemotherapy and radiation therapy*

improvement in post-therapy mental recovery [63].

*3.2.3 Vitamin E and survival outcomes*

studies [61].

However, there are a number of prospective and case–control studies that reported no association between dietary and/or supplement vitamin E intake and breast cancer risk [22, 31, 57]. Verhoeven et al. reported findings from the Netherlands Cohort Study, a large prospective cohort research that examined the relationships between various vitamins, vegetables and fruits with breast cancer risk and found no strong evidence of dietary vitamin E intake in the etiology of breast cancer [22]. An earlier large prospective study found that large intake of dietary vitamin E did not protect from breast cancer (OR = 0.99, 95%CI: 0.83–1.19) [31]. Results from other studies on dietary or supplemental vitamin E intake demonstrated similar null association [58, 59]. These include: a case–control by Wang et al. that did not find any meaningful association of dietary vitamin E intake with breast cancer risk [60], no association of higher dietary intake of vitamin E (in early adult life) among postmenopausal women in the Nurses' Health Study II [57], and meta-analysis of 26 studies that found no effect of vitamin E supplementation on breast cancer risk on reviewing data from five cohort and four case–control

Over the last decade the use of antioxidant supplements after breast cancer diagnosis and during treatment significantly increased and has become quite common among survivors [53, 61]. In a review of the literature on non-herbal nutrition supplements use in relieving symptoms induced by chemotherapy or radiation treatment, Samuels et al. showed that a number of studies suggest that antioxidant supplements use comprising glutamine, vitamin E and acetyl-L-carnithine possibly might decrease the occurrence and severity of paclitaxel-induced neuropathy [62]. In a comprehensive review of the 22 prospective studies by Greenlee et al. in 2009 that examined the association between use of antioxidant supplements (vitamin E as well as multivitamins, vitamin C, antioxidant combinations, soy isoflavones, melatonin, glutathione, or glutamine) and patient outcomes, there were no single antioxidant supplement during conventional breast cancer therapy that had a significant effect on recurrence, tumor response, toxicities, or survival. The authors indicated that findings from limited studies proposed that vitamin E decrease the hot flashes in patients treated with hormonal therapy and glutamine for oral mucositis [17]. In a more recent study, Huang et al. assessed the associations of dietary intake of fish, fruit and vegetable supplemented with vitamins E and B, and post-therapy cognitive recovery in 1,047 patients with breast cancer enrolled in the Shanghai Breast Cancer Survival Study. Higher dietary intake and supplement use were associated with greater cognitive scores at 36 months post-diagnosis thus

Globally, the consumption of dietary supplements including vitamins and multivitamins/multi-minerals is increasing more so among females than males [64, 65]. However, there are only few studies that have examined vitamin E supplementation and survival outcomes in breast cancer patients. A well-designed prospective population-based prospective cohort study comprised of 4,877 females diagnosed with invasive breast cancer in China reported that vitamin E as well as multivitamin use were beneficial in improving survival and mortality rates. There was a 22% decreased recurrence risk and 18% lower mortality risk in females who use vitamin E supplement within 6 months after breast cancer diagnosis [42] (**Table 2**). Likewise, in the Life After Cancer Epidemiology (LACE) Study

**24**

#### *3.3.1 Multivitamins use during chemotherapy and radiation therapy*

Despite over thirty years of research examining dietary antioxidant supplement use during radiation therapy and conservative chemotherapy, there are significant disagreements regarding the effectiveness of this complementary therapy [68, 69]. Encouraging results from many randomized control trials confirmed that the concomitant administration of supplementation antioxidants with radiation therapy and chemotherapy decreases side effects related to treatment [70]. However, some studies have suggested that antioxidant supplementation may guard malignant tumor cells from the pro-oxidant effects such as oxidative injury produced by chemotherapeutic agents and radiation treatment [71, 72].

The quality of life and performance of normal daily activities can be negatively impacted by chemotherapy-induced peripheral neuropathy [73]. Using data from the Diet, Exercise, Lifestyle, and Cancer Prognosis (DELCaP) study, Zirpoli et al. reported that the use of multivitamins prior to diagnosis was associated with decreased symptoms of chemotherapy-induced peripheral neuropathy while use during therapy was slightly related with this outcome [74]. However, in a recent study, Jung et al. reported findings from the population-based Mamma Carcinoma Risk Factor Investigation (MARIE) study and noted that pre and post-diagnosis supplement use among of 2,223 postmenopausal women diagnosed with non-metastatic breast cancer was 36% and 45% respectively. The use of antioxidants throughout radiation therapy and chemotherapy was associated with higher total mortality risk (HR = 1.64; 95% CI: 1.01–2.66) and exacerbated recurrence-free survival (HR = 1.84; 95% CI: 1.26–2.68) [75]. The was also no relations between post-diagnosis use of supplement and disease prognosis, and the authors suggests that breast cancer patients should not use antioxidants during radiation therapy and chemotherapy [75].

#### *3.3.2 Multivitamins and survival outcomes*

The natural activity of dietary and supplement antioxidants is due to a number of factors comprising the existing level of oxidative stress, collaborations of antioxidants, and the level of antioxidants present in cells [45]. The consumption of vitamin supplements among breast cancer patients post-diagnosis is quite common [76]. There are prospective studies that have demonstrated that multivitamin


*Summary of selected studies that provide risk estimates of the associations between dietary and supplemental vitamins and micronutrients (antioxidants) and breast cancer outcomes such as* 

*recurrence and mortality.*

**27**

**Vitamin/ Micro-nutrient (antioxidant)**

Vitamin C Vitamin C Vitamin C and E

Alpha carotene and

91

Metaanalysis

33 observational studies

Dietary alpha carotene and

beta-carotene

beta-carotene

Soy isoflavones

Soy isoflavones

146

Metaanalysis

18 studies

Soy isoflavones intake

135

Metaanalysis

35

Soy flavones intake

67

Metaanalysis

Observational studies and randomized clinical trials

Vitamin C and E (supplement)

34

Meta- analysis

10 studies

Supplement vitamin

C

20

Meta- analysis

69 studies relevant to breast cancer risk (54 studies) and survival (15 studies)

Dietary vitamin C

RR = 0.78 (0.69–0.88) for breast cancer-

specific mortality;

RR = 0.81 (0.67–0.99) for risk of breast cancer recurrence

RR = 0.81 (0.72–0.91) for total mortality

& RR = 0.85 (0.74–0.99) for risk of breast

cancer-specific mortality

Vitamin C: RR = 0.79 (0.68–0.92) for total mortality and RR = 0.76 (0.64–0.91) for risk

of breast cancer recurrence

Vitamin E: RR = 0.76 (0.64–0.90) for total

mortality and RR = 0.69 (0.55–0.85) for risk

of breast cancer recurrence

Alpha-carotene:

Reduction by 9%

Reduction by 6%

RRpooled = 0.91

(0.85–0.8, P = 0.01) for breast cancer risk

Beta-carotene RRpooled = 0.94

(0.88–1.00, P = 0.05)for breast cancer risk

Premenopausal: OR = 0.59 (0.48–0.69) for breast cancer risk

Reduction by 41%

Reduction by 41%

Postmenopausal women:

OR = 0.59, (0.44–0.74) for breast cancer risk

particularly in Asian women

RR = 0.89 (0.79–0.99) for risk of breast cancer

Reduction by 11%

Reduction by 16%

incidence

RR = 0.84

(0.70–0. 99) for risk of breast cancer

recurrence

Reduction by 22% and 19% respectively

**Reference**

**Study design**

**Population (Case, participants)**

**Exposure**

**Risk estimates (95% CI)**

**Outcome**

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

Reduction by 19%

and 15% respectively

Reduction by

21% and 24%

respectively

Reduction by 24%

and 31% respectively

*Antioxidants - Benefits, Sources, Mechanisms of Action*

**26**


#### *Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

**26**

**Vitamin/**

**Reference**

**Study design**

**Population (Case,** 

**Exposure**

**Risk estimates (95% CI)**

**Outcome**

**participants)**

**Micro-nutrient** 

**(antioxidant)**

Vitamin E, C and

42

Population-based

4,877 women diagnosed

Vitamin E, C and

HR = 0.82 (0.65–1.02) for

Reduction by 18% and

22% respectively

mortality

HR = 0.78 (0.63–0.95) for risk of

breast recurrence

(i) Vitamin E: HR = 0.71

Reduction by 29% and

24% respectively

Reduction by 27%

(0.54–0.94) for breast cancer

recurrence

and

HR = 0.76 (0.58–1.00) for allcause mortality

Vitamin C:

HR = 0.73 (0.55–0.97) for risk of

breast cancer recurrence

Vitamin C: RR = 0.81 (0.55–0.97)

Reduction by 19%

Reduction by 12%

for all-cause mortality

Vitamin E: RR = 0.88 (0.79–0.99)

for risk of breast cancer

recurrence

HR = 0.68

Reduction by 32%

Reduction by 29%

(0.64–0.87) for risk of breast

cancer recurrence

(HR = 0.71 (0.54–0.92) for allcause mortality

(ER+ or ER- women)

Soy isoflavones: OR = 0.25

Reduction by 75%

(0.09–0.54) for breast cancer

mortality

multivitamins

with breast cancer (aged

20–75 yrs)

prospective cohort

multivitamins

Vitamin E and C

Vitamin C and E

Soy isoflavones or

143

The Shanghai Breast

5,042 female breast cancer

Soy isoflavones or

soy protein intake

survivors

Cancer Survival Study

(a large, populationbased cohort

soy protein

Soy isoflavonones

**Table 2.**

*recurrence and mortality.*

144

Prospective

256 Chines women

*Summary of selected studies that provide risk estimates of the associations between dietary and supplemental vitamins and micronutrients (antioxidants) and breast cancer outcomes such as* 

66

After Breast Cancer

Four cohorts of 12,019

Vitamin C and E

(supplement)

breast cancer survivors

Pooling Project

41

Life After Cancer

2,264 women with early

Vitamin E and C

(supplement)

stage breast cancer

Epidemiology (LACE)

cohort


**Table 3.** *Summary of selected meta-analysis and systematic reviews that provide risk estimates of the associations between dietary and supplemental vitamins and micronutrients (antioxidants) and breast* 

*cancer risk.*

**29**

**4.2 Carotenoids**

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

consumption improve survival rates in breast cancer patients [66, 77]. In the After Breast Cancer Pooling Project, Poole et al. examined the associations between post-diagnosis supplement use (multivitamins, vitamin E, D, C and B) and survival outcomes such as breast cancer-specific mortality, total disease mortality and risk of breast cancer recurrence in four cohorts of 12,019 patients in China and the United States. Using multivariate models, antioxidant supplement use (multivitamins, vitamin E or, C) was associated with improved survival as there was a 16% reduced risk of total mortality but not related with disease recurrence [66]. The findings of the Life After Cancer Epidemiology study that comprised of 2,236 women diagnosed with early-stage breast cancer indicate that multivitamin use may be valuable in improving breast cancer outcomes as frequent use prior to and after diagnosis was associated with non-significant reduced death from any cause and disease recurrence. In addition, the protective effect was for only breast cancer survivors treated by both radiation and chemotherapy, and radiation only and those who ate more fruits and vegetable and engaged in physical exercise had improved overall survival [77]. Notably, a recent systematic review and meta-analysis comprising randomized clinical trials and observational studies reported that multivitamin use lower breast cancer recurrence, and these findings were mostly based on observational studies while more randomized clinical trials are required to justify

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

any recommendation for the dietary supplement use [67].

**4. Epidemiological evidence of carotenoids as antioxidants**

*4.2.1 Alpha-carotene, beta-carotene intake and breast cancer risk*

Epidemiologic studies have suggested that increased fruit and vegetable intake is associated with lower risk of breast cancer [79]. Supporting evidence is provided by findings from a pooled analysis of eight prospective cohort studies where total fruit and vegetable intake was associated with decreased breast cancer risk (RR = 0.93, 95% CI: 0.86–1.00; Ptrend = 0.12) when comparing the highest with the lowest quartiles [80]. Recent systemic review and meta-analysis indicated that high intakes of vegetables and fruits were associated with lower risks of breast cancer [81, 82], while a large-scale study demonstrated that the same may be related with improved overall survival among primary breast cancer patients [83]. However, a large prospective study such as the European Prospective Investigation into Cancer and Nutrition did not find a relationship between fruit and vegetable intake, and breast cancer risk [84].

Carotenoids such as alpha-carotene, beta-carotene, lycopene and beta-cryptoxanthin are found in fruits and in dark green leafy vegetables as well as in yellow

**4.1 Fruit, vegetables and breast cancer risk**

Conversely, in a large retrospective cohort study of breast cancer patients belonging to the British Columbia Cancer Agency followed for 68 months, an administered regimen mega-dose vitamin/mineral supplements non-significantly increase the hazard ratios for disease-free survival and breast cancer-specific mortality. However, limitations include absence of critical information on use of over-the-counter vitamins, treatment compliance and possible selection bias [78]. Moreover, in a multicenter study of 3,081 early-stage breast cancer patients, although dietary supplement users had acceptable intakes of micronutrients, vitamin use and mineral intake was not concomitant with all-cause mortality.

## *Antioxidants - Benefits, Sources, Mechanisms of Action*

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

consumption improve survival rates in breast cancer patients [66, 77]. In the After Breast Cancer Pooling Project, Poole et al. examined the associations between post-diagnosis supplement use (multivitamins, vitamin E, D, C and B) and survival outcomes such as breast cancer-specific mortality, total disease mortality and risk of breast cancer recurrence in four cohorts of 12,019 patients in China and the United States. Using multivariate models, antioxidant supplement use (multivitamins, vitamin E or, C) was associated with improved survival as there was a 16% reduced risk of total mortality but not related with disease recurrence [66]. The findings of the Life After Cancer Epidemiology study that comprised of 2,236 women diagnosed with early-stage breast cancer indicate that multivitamin use may be valuable in improving breast cancer outcomes as frequent use prior to and after diagnosis was associated with non-significant reduced death from any cause and disease recurrence. In addition, the protective effect was for only breast cancer survivors treated by both radiation and chemotherapy, and radiation only and those who ate more fruits and vegetable and engaged in physical exercise had improved overall survival [77]. Notably, a recent systematic review and meta-analysis comprising randomized clinical trials and observational studies reported that multivitamin use lower breast cancer recurrence, and these findings were mostly based on observational studies while more randomized clinical trials are required to justify any recommendation for the dietary supplement use [67].

Conversely, in a large retrospective cohort study of breast cancer patients belonging to the British Columbia Cancer Agency followed for 68 months, an administered regimen mega-dose vitamin/mineral supplements non-significantly increase the hazard ratios for disease-free survival and breast cancer-specific mortality. However, limitations include absence of critical information on use of over-the-counter vitamins, treatment compliance and possible selection bias [78]. Moreover, in a multicenter study of 3,081 early-stage breast cancer patients, although dietary supplement users had acceptable intakes of micronutrients, vitamin use and mineral intake was not concomitant with all-cause mortality.

## **4. Epidemiological evidence of carotenoids as antioxidants**

#### **4.1 Fruit, vegetables and breast cancer risk**

Epidemiologic studies have suggested that increased fruit and vegetable intake is associated with lower risk of breast cancer [79]. Supporting evidence is provided by findings from a pooled analysis of eight prospective cohort studies where total fruit and vegetable intake was associated with decreased breast cancer risk (RR = 0.93, 95% CI: 0.86–1.00; Ptrend = 0.12) when comparing the highest with the lowest quartiles [80]. Recent systemic review and meta-analysis indicated that high intakes of vegetables and fruits were associated with lower risks of breast cancer [81, 82], while a large-scale study demonstrated that the same may be related with improved overall survival among primary breast cancer patients [83]. However, a large prospective study such as the European Prospective Investigation into Cancer and Nutrition did not find a relationship between fruit and vegetable intake, and breast cancer risk [84].

#### **4.2 Carotenoids**

#### *4.2.1 Alpha-carotene, beta-carotene intake and breast cancer risk*

Carotenoids such as alpha-carotene, beta-carotene, lycopene and beta-cryptoxanthin are found in fruits and in dark green leafy vegetables as well as in yellow

*Antioxidants - Benefits, Sources, Mechanisms of Action*

**28**

**Vitamin/**

**Reference**

**Study** 

**Population**

**Exposure**

**Risk estimates (95% CI)**

**Outcome**

**(Case, participants)**

**design**

**Micro-nutrient** 

**(antioxidant)**

Lutein/zeaxanthin

Quercetin

**Table 3.**

*cancer risk.*

116

Metaanalysis

12 studies (6 prospective cohort and 6 case controls)

Quercetin intake

*Summary of selected meta-analysis and systematic reviews that provide risk estimates of the associations between dietary and supplemental vitamins and micronutrients (antioxidants) and breast* 

151

Metaanalysis

8 cohort studies

Lutein/zeaxanthin

RR = 0.84 (0.70–1.01, Ptrend = 0.05)

Reduction by 16%

RR = 0.88 (0.80–0.98)

Reduction by 12%

and orange vegetables [85]. The chemo-prevention and protective potential of carotenoids lies in their antioxidant, retinoic and anti-proliferative activities and obstructing estrogen signaling of 17β-estradiol, with subsequent weakening of the properties of malignancies such as breast cancer that are hormone-dependent [86]. There are a number of studies that have examined the relation of breast cancer risk with dietary and/or supplemental consumption of carotenoids [87–89]. In a large population-based case–control study consisting of 5,707 women with incident invasive breast cancer (3,516 postmenopausal women and 2,363 premenopausal women), there were inverse associations observed among premenopausal women for high levels of alpha-carotene (OR = 0.82, 95% CI: 0.68–0.98) and beta-carotene (OR = 0.81, 95% CI: 0.68–0.98) but not for postmenopausal women [90] (**Table 1**). Likewise, in the Women's Health Initiative Observational Study, high dietary betacarotene intake (RR = 0.78; 95% CI: 0.66–0.94; Ptrend = 0.021) and elevated alphacarotene (RR = 0.83; 95% CI: = 0.70–0.99; Ptrend = 0.019) were inversely related to risk of estrogen receptor (ER)-positive and progesterone receptor (PR)-positive breast cancer. However, supplemental or total beta-carotene were not related to breast cancers demarcated by PR and ER status [23]. In an earlier population-based case–control study conducted in Canada, Nkondjock et al. found decreased risk for beta-carotene for those who never used hormone replacement therapy [89] but increased breast cancer risk associated with significantly high serum levels of alphacarotene (OR = 2.40; 95% CI: 0.90–6.41) in premenopausal women.

These findings were corroborated by a review study that systematically summarized the associations between beta-carotene and alpha-carotene, and breast cancer risk. In the meta-analysis that comprehensively review the associations between carotenoids and breast cancer, higher intakes of dietary beta-carotene significantly decreased breast cancer risk by 6.0% (RRpooled = 0.94; 95% CI: 0.88–1.00) and dietary alpha-carotene lower the risk by 9.0% when the cohort studies were pooled. Furthermore, significant dose–response associations were seen in both the higher intake of dietary and total beta-carotene with decreased breast cancer risk when considering cohort studies and case–control studies [91] (**Table 3**). There are other observational studies that have confirmed an inverse relationship of dietary or supplemental alpha-carotene or beta-carotene with risk of breast cancer [27, 87, 92, 93].

However, there are few studies that have reported null association between the carotenoids and breast cancer risk [84, 88, 94]. Terry et al. found no clear association between alpha-carotene and beta-carotene, and breast cancer risk in a large cohort of women who were registered in the Canadian National Breast Screening Study [88]. In subsequently large prospective study of women enrolled in the European Prospective Investigation Into Cancer and Nutrition there was no association of dietary beta-carotene with breast cancer risk, although betacarotene supplement demonstrated a protective effect against lobular breast cancer (IRR = 0.72; 95%CI: 0.57–0.91] [84]. This study also found no association between overall breast cancer and any micronutrients, while some effects were shown when stratifying by breast cancer subtypes [84]. Finally, there is another study that have reported null association between the carotenoids and breast cancer risk [95].

## *4.2.2 Serum and plasma levels of carotenoids (alpha-carotene, beta-carotene) and breast cancer risk*

Blood vitamin intakes are regarded as biomarkers of the consumption of vegetables and fruits [96]. Plasma or serum levels of antioxidants such as vitamin E are thought to be related to breast cancer risk but results from prospective and case control studies remain inconclusive [97]. In a nested case–control study comprising

**31**

humans [109].

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

Prospective Investigation into Cancer and Nutrition cohort, plasma vitamin E level was not statistically associated with ER negative or ER positive breast cancer [98]. Epplein et al. earlier published a nested case–control study, a sub-cohort of the Multiethnic Cohort Study which demonstrated that multiethnic women with breast cancer were more likely to have lower levels of vitamin E than matched controls [99]. Notably, a meta-analysis of 40 studies by Hu et al. summarize the associations between plasma levels of vitamins A, C and E, and breast cancer risk and observed significant relationship between plasma vitamin E levels and breast cancer incidence (ORpooled = 0.42, 95% CI: 0.25–0.72, p = 0.001). The authors suggested that severe vitamin E could increase breast cancer risk [100]. Furthermore, even though there was an association between serum vitamin E [biomarker of fruit and vegetable intake, (OR = 0.68, 95% CI: 0.41–1.10)] in the E3N-EPIC Study, it was not

However, there are findings from studies that do not support plasma or serum levels of vitamin E being associated with reduced risk of breast cancer [54, 102]. In a nested case–control comprising of 365 incident breast cancer cases and 726 individually matched control women within the prospective population-based Shanghai Women's Health Study, there was no association between plasma levels of vitamin E and reduced breast cancer risk, although the authors noted that there may be protective effects among sub-groups of women [54]. Likewise, in an earlier case–control study nested in a prospective cohort from the Breast Cancer Serum Bank in Missouri, United States no evidence of the protective effect of vitamin E was observed for breast cancer, although carotenoids such as lycopene and betacryptoxanthin may protect against breast cancer [103]. There are other studies that have reported null findings in the relationship between serum or plasma levels of vitamin E and breast cancer risk [102, 104]. These include: no association between plasma vitamin E levels and breast cancer risk in the Nurses' Health Study [105] and no significant association of plasma vitamin E levels in a nested case-referent study

**5. Epidemiological evidence of flavonoids as antioxidants**

Flavonoids are an assembly of naturally occurring phenolic compounds located

There is epidemiological evidence determined by prospective cohort study and case-study designs that have suggested an associations between dietary and supplemental flavonoids intake and breast cancer risk [110, 111]. In a recent case–control study that examined the relationship between breast cancer risk and total and subclasses of flavonoids, higher dietary intakes of total flavonoids (OR = 0.66, 95% CI: 0.54–0.82), flavonols (OR = 0.51, 95% CI: 0.41–0.63) were inversely associated with breast cancer risk [110] (**Table 1**). No significant relationship was observed

in vegetables and fruits and are classified into 6 main sub-classes based on the complexity of their structure. They include flavanones, flavones, flavonols, flavan-3-ols, isoflavanones and anthocyanins [107]. Investigational studies have suggested that flavonoids such as flavonols, flavones and flavanones possess preventative biological activity on breast carcinogenesis and is protective against commencement and development of tumor [108]. Nevertheless, epidemiological data regarding the associations between these flavonoid biomarkers and risk of breast cancer is inadequate and is very much needed to evaluate the definite effects of flavonoids in

1,502 incident breast cancer cases and 1,502 controls within the European

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

statistically significant (Ptrend = 0.26) [101].

conducted in Sweden [106].

**5.1 Flavonols and breast cancer risk**

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

1,502 incident breast cancer cases and 1,502 controls within the European Prospective Investigation into Cancer and Nutrition cohort, plasma vitamin E level was not statistically associated with ER negative or ER positive breast cancer [98]. Epplein et al. earlier published a nested case–control study, a sub-cohort of the Multiethnic Cohort Study which demonstrated that multiethnic women with breast cancer were more likely to have lower levels of vitamin E than matched controls [99]. Notably, a meta-analysis of 40 studies by Hu et al. summarize the associations between plasma levels of vitamins A, C and E, and breast cancer risk and observed significant relationship between plasma vitamin E levels and breast cancer incidence (ORpooled = 0.42, 95% CI: 0.25–0.72, p = 0.001). The authors suggested that severe vitamin E could increase breast cancer risk [100]. Furthermore, even though there was an association between serum vitamin E [biomarker of fruit and vegetable intake, (OR = 0.68, 95% CI: 0.41–1.10)] in the E3N-EPIC Study, it was not statistically significant (Ptrend = 0.26) [101].

However, there are findings from studies that do not support plasma or serum levels of vitamin E being associated with reduced risk of breast cancer [54, 102]. In a nested case–control comprising of 365 incident breast cancer cases and 726 individually matched control women within the prospective population-based Shanghai Women's Health Study, there was no association between plasma levels of vitamin E and reduced breast cancer risk, although the authors noted that there may be protective effects among sub-groups of women [54]. Likewise, in an earlier case–control study nested in a prospective cohort from the Breast Cancer Serum Bank in Missouri, United States no evidence of the protective effect of vitamin E was observed for breast cancer, although carotenoids such as lycopene and betacryptoxanthin may protect against breast cancer [103]. There are other studies that have reported null findings in the relationship between serum or plasma levels of vitamin E and breast cancer risk [102, 104]. These include: no association between plasma vitamin E levels and breast cancer risk in the Nurses' Health Study [105] and no significant association of plasma vitamin E levels in a nested case-referent study conducted in Sweden [106].

## **5. Epidemiological evidence of flavonoids as antioxidants**

#### **5.1 Flavonols and breast cancer risk**

Flavonoids are an assembly of naturally occurring phenolic compounds located in vegetables and fruits and are classified into 6 main sub-classes based on the complexity of their structure. They include flavanones, flavones, flavonols, flavan-3-ols, isoflavanones and anthocyanins [107]. Investigational studies have suggested that flavonoids such as flavonols, flavones and flavanones possess preventative biological activity on breast carcinogenesis and is protective against commencement and development of tumor [108]. Nevertheless, epidemiological data regarding the associations between these flavonoid biomarkers and risk of breast cancer is inadequate and is very much needed to evaluate the definite effects of flavonoids in humans [109].

There is epidemiological evidence determined by prospective cohort study and case-study designs that have suggested an associations between dietary and supplemental flavonoids intake and breast cancer risk [110, 111]. In a recent case–control study that examined the relationship between breast cancer risk and total and subclasses of flavonoids, higher dietary intakes of total flavonoids (OR = 0.66, 95% CI: 0.54–0.82), flavonols (OR = 0.51, 95% CI: 0.41–0.63) were inversely associated with breast cancer risk [110] (**Table 1**). No significant relationship was observed

*Antioxidants - Benefits, Sources, Mechanisms of Action*

and orange vegetables [85]. The chemo-prevention and protective potential of carotenoids lies in their antioxidant, retinoic and anti-proliferative activities and obstructing estrogen signaling of 17β-estradiol, with subsequent weakening of the properties of malignancies such as breast cancer that are hormone-dependent [86]. There are a number of studies that have examined the relation of breast cancer risk with dietary and/or supplemental consumption of carotenoids [87–89]. In a large population-based case–control study consisting of 5,707 women with incident invasive breast cancer (3,516 postmenopausal women and 2,363 premenopausal women), there were inverse associations observed among premenopausal women for high levels of alpha-carotene (OR = 0.82, 95% CI: 0.68–0.98) and beta-carotene (OR = 0.81, 95% CI: 0.68–0.98) but not for postmenopausal women [90] (**Table 1**). Likewise, in the Women's Health Initiative Observational Study, high dietary betacarotene intake (RR = 0.78; 95% CI: 0.66–0.94; Ptrend = 0.021) and elevated alphacarotene (RR = 0.83; 95% CI: = 0.70–0.99; Ptrend = 0.019) were inversely related to risk of estrogen receptor (ER)-positive and progesterone receptor (PR)-positive breast cancer. However, supplemental or total beta-carotene were not related to breast cancers demarcated by PR and ER status [23]. In an earlier population-based case–control study conducted in Canada, Nkondjock et al. found decreased risk for beta-carotene for those who never used hormone replacement therapy [89] but increased breast cancer risk associated with significantly high serum levels of alpha-

carotene (OR = 2.40; 95% CI: 0.90–6.41) in premenopausal women.

of breast cancer [27, 87, 92, 93].

*breast cancer risk*

These findings were corroborated by a review study that systematically summarized the associations between beta-carotene and alpha-carotene, and breast cancer risk. In the meta-analysis that comprehensively review the associations between carotenoids and breast cancer, higher intakes of dietary beta-carotene significantly decreased breast cancer risk by 6.0% (RRpooled = 0.94; 95% CI: 0.88–1.00) and dietary alpha-carotene lower the risk by 9.0% when the cohort studies were pooled. Furthermore, significant dose–response associations were seen in both the higher intake of dietary and total beta-carotene with decreased breast cancer risk when considering cohort studies and case–control studies [91] (**Table 3**). There are other observational studies that have confirmed an inverse relationship of dietary or supplemental alpha-carotene or beta-carotene with risk

However, there are few studies that have reported null association between the carotenoids and breast cancer risk [84, 88, 94]. Terry et al. found no clear association between alpha-carotene and beta-carotene, and breast cancer risk in a large cohort of women who were registered in the Canadian National Breast Screening Study [88]. In subsequently large prospective study of women enrolled in the European Prospective Investigation Into Cancer and Nutrition there was no association of dietary beta-carotene with breast cancer risk, although betacarotene supplement demonstrated a protective effect against lobular breast cancer (IRR = 0.72; 95%CI: 0.57–0.91] [84]. This study also found no association between overall breast cancer and any micronutrients, while some effects were shown when stratifying by breast cancer subtypes [84]. Finally, there is another study that have reported null association between the carotenoids and breast cancer risk [95].

*4.2.2 Serum and plasma levels of carotenoids (alpha-carotene, beta-carotene) and* 

Blood vitamin intakes are regarded as biomarkers of the consumption of vegetables and fruits [96]. Plasma or serum levels of antioxidants such as vitamin E are thought to be related to breast cancer risk but results from prospective and case control studies remain inconclusive [97]. In a nested case–control study comprising

**30**

between the flavins, flavan-3-ol monomers and flavanols, and breast cancer risk [110]. These findings are compatible with those of a large case–control study conducted in Italy, where decreased breast cancer risk was found for flavonols (OR = 0.80, Ptrend 0.06) and flavones (OR = 0.81, Ptrend = 0.02), but not for flavan-3-ols, flavanones, isoflavones and anthocyanidins [111]. Similarly, in a subsequent case–control study of United States women reduced breast cancer risk was related with high dietary uptake of flavones (OR = 0.61, 95% CI: 0.45, 0.83), flavonols (OR = 0.54, 95% CI: 0.40–0.73) and flavan-3-ols in postmenopausal women. The authors suggested that consuming sufficient amount of these flavonoids could be beneficial to these women in the chemoprevention of breast cancer [112] (**Table 1**). Notably, in a recent hospital-based case–control, higher levels of serum flavonols (OR = 0.52, 95% CI 0.38–0.70) and flavanone (OR = 0.45, 95% CI: 0.34–0.60) were significantly associated with decreased breast cancer risk [113]. The outcomes of these studies corroborated those of other case–control studies [114, 115] which supported the protective influence of high dietary intake of flavonols and flavones against breast cancer particularly among postmenopausal females.

The findings from prospective cohort studies are not so favorable regarding the chemo-preventative actions of flavonoids. In a meta-analysis of epidemiologic studies comprising 6 prospective cohort and 6 case–control studies, higher dietary intake of flavones (RR = 0.83, 95% CI: 0.76–0.91), flavonols (RR = 0.88, 95% CI: 0.80–0.98) decreased breast cancer risk although there were no significant relation of flavanones, flavan-3-ols and anthocyanins particularly in post-menopausal women [116] (**Table 3**). However, The Nurses' Health Study II investigated the effect of dietary flavonols on breast cancer risk, and found a non-significant null association with a risk ratio of 0.94 (95% CI: 0.72–1.22, Ptrend = 0.54) that was reported for flavonol-rich foods. Furthermore, dietary intakes of flavonol containing foods such as beans and lentils were inversely associated with breast cancer risk but this was not observed for onions, apples, blueberries tea, green pepper and broccoli [117]. There was also no association and thus no protective effects against breast cancer risk for increased intake of flavanones [118–120], flavanols [118, 119], flavonols [118–120], flavones [118], anthocyanidins [118] as well as total flavonoids [118–122].

#### **5.2 Soy isoflavones and breast cancer risk**

Isoflavones are a subclass of flavonoids and are found in legumes such as soybeans and soy products. These polyphenolic compounds are derived from plants and the three main isoflavones are daidzin, glycitin and genistin [123]. Globally the consumption of soy and soy products is increasing as the health benefits due to their biological actions including estrogenic and anti-estrogenic properties, inhibition of tumor proliferation, antioxidant, anti-inflammatory and lower risk for cardiovascular disease [124, 125]. Notwithstanding potential mechanisms from experimental studies, epidemiological evidence from case–control and prospective cohort studies regarding association of soy food and isoflavone, and breast cancer risk provide unreliable results [126–128].

In The Shanghai Breast Cancer Survival Study that assessed bone fracture incidence and its relationship with soy food consumption among breast cancer patients, high soy isoflavone intake was concomitant with decreased risk among both peri- and premenopausal subjects (HR = 0.22, 95% CI: 0.09–0.53) but no association for postmenopausal subjects [129] (**Table 1**). Similarly, a recent study that examined the relationship between isoflavone intake and hereditary breast cancer risk, reported that high intake of this flavonoid was inversely related with luminal A breast cancer hazard in women who are BRCA2 mutation carriers [130]. Conversely,

**33**

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

in a large prospective study comprising women from the Epidemiologique aupres de Femmes de la Mutuelle Generale de l'Education Nationale (E3N) cohort, there was no relation between past consumption of soy isoflavones supplement and breast cancer risk (HR = 1.36, 95% CI: 0.95–1.93) particularly among premenopausal patients [131]. Furthermore, in this study, there were contrasting associations of soy supplements with estrogen receptor-positive (HR = 0.78, 95%CI: 0.60–0.99) and estrogen receptor-negative (HR = 2.01, 95%CI: 1.41–2.86) breast cancer risk [131]. In another contemporary study, null association was observed between breast cancer risk and soy products containing isoflavones in a large cohort study of North American women although greater dairy milk intakes were associated with increased breast cancer risk, after adjusted for consumption [132]. The authors suggested that caution should be exercised when viewing existing guidelines for dairy

There are meta-analyses that have indicated that higher levels of soy products and isoflavones with lower incident breast cancer risk [133, 134]. In a meta-analysis of 35 studies soy isoflavone intake has a protective effect in that it is inversely associated with breast cancer for both pre- (OR = 0.59, 95%CI: 0.48–0.69 and postmenopausal women (OR = 0.59, 95%CI: 0.44–0.74) particularly in Asian women while no evidence of a relationship in Western women [135] (**Table 3**). Nonetheless, in a previous meta-analysis of prospective cohort studies, there was no significant association between high (versus low) intake of isoflavones (RR = 0.99, 95% CI: 0.91–1.09) and moderate (versus low) intake of isoflavones (RR = 0.99, 95% CI = 0.92–1.05) and breast cancer risk, indicating that women with high dietary intake of soy isoflavones may experience decreased breast cancer incidence [136]. Support for the null finding was observed in a large Multiethnic Cohort study of women with a wide range of soya intake level and who were followed for 13 years, where no statistically association was detected between overall breast cancer risk and high dietary isoflavone intake (HR = 0.96, 95% CI: 0.85–1.08). The authors posited that higher consumption may be protective for Japanese American, Latina and African American women [137]. Notably, a recent publication of the China Kadoorie Biobank (CKB) study which involved a dose–response meta-analysis of dietary data of soy intake over a follow-up period of 10 years, the relative risk for high soy isoflavones consumption was 1.00 (95% CI: 0.81–1.22) [138]. A 3% decreased breast cancer risk for each 10 mg/day increment of soy isoflavones was observed. The results suggests that soy isoflavone was not related with breast cancer risk though increased intake may be beneficial in preventing breast cancer [138]. There are not many case–control studies that investigated the relation between soy isoflavone intake and breast cancer risk. In a case–control study conducted in Japan, increasing intake of isoflavone significantly reduced breast cancer risk in premenopausal women (OR = 0.44; 95% CI: 0.22–0.89), while no significant association was observed among postmenopausal women [139]. This shows the need to conduct more case–control studies in order to afford a clearer picture on the

relationship between soy products and breast cancer incidence.

**5.3 Soy proteins and soy isoflavones and breast cancer outcomes**

There are studies that have examined the association between soy products and isoflavones intake and breast cancer survival, however the results are not definitive [140–142]. There are prospective cohort and meta-analyses studies that have reported significant inversely association between soy protein and soy isoflavones and breast cancer survival outcomes. In looking at prospective studies, The Shanghai Breast Cancer Survival Study comprised of 5,033 surgically treated breast cancer patients that were followed for 3.9 years. High soy protein

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

milk intake [132].

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

in a large prospective study comprising women from the Epidemiologique aupres de Femmes de la Mutuelle Generale de l'Education Nationale (E3N) cohort, there was no relation between past consumption of soy isoflavones supplement and breast cancer risk (HR = 1.36, 95% CI: 0.95–1.93) particularly among premenopausal patients [131]. Furthermore, in this study, there were contrasting associations of soy supplements with estrogen receptor-positive (HR = 0.78, 95%CI: 0.60–0.99) and estrogen receptor-negative (HR = 2.01, 95%CI: 1.41–2.86) breast cancer risk [131]. In another contemporary study, null association was observed between breast cancer risk and soy products containing isoflavones in a large cohort study of North American women although greater dairy milk intakes were associated with increased breast cancer risk, after adjusted for consumption [132]. The authors suggested that caution should be exercised when viewing existing guidelines for dairy milk intake [132].

There are meta-analyses that have indicated that higher levels of soy products and isoflavones with lower incident breast cancer risk [133, 134]. In a meta-analysis of 35 studies soy isoflavone intake has a protective effect in that it is inversely associated with breast cancer for both pre- (OR = 0.59, 95%CI: 0.48–0.69 and postmenopausal women (OR = 0.59, 95%CI: 0.44–0.74) particularly in Asian women while no evidence of a relationship in Western women [135] (**Table 3**). Nonetheless, in a previous meta-analysis of prospective cohort studies, there was no significant association between high (versus low) intake of isoflavones (RR = 0.99, 95% CI: 0.91–1.09) and moderate (versus low) intake of isoflavones (RR = 0.99, 95% CI = 0.92–1.05) and breast cancer risk, indicating that women with high dietary intake of soy isoflavones may experience decreased breast cancer incidence [136]. Support for the null finding was observed in a large Multiethnic Cohort study of women with a wide range of soya intake level and who were followed for 13 years, where no statistically association was detected between overall breast cancer risk and high dietary isoflavone intake (HR = 0.96, 95% CI: 0.85–1.08). The authors posited that higher consumption may be protective for Japanese American, Latina and African American women [137]. Notably, a recent publication of the China Kadoorie Biobank (CKB) study which involved a dose–response meta-analysis of dietary data of soy intake over a follow-up period of 10 years, the relative risk for high soy isoflavones consumption was 1.00 (95% CI: 0.81–1.22) [138]. A 3% decreased breast cancer risk for each 10 mg/day increment of soy isoflavones was observed. The results suggests that soy isoflavone was not related with breast cancer risk though increased intake may be beneficial in preventing breast cancer [138].

There are not many case–control studies that investigated the relation between soy isoflavone intake and breast cancer risk. In a case–control study conducted in Japan, increasing intake of isoflavone significantly reduced breast cancer risk in premenopausal women (OR = 0.44; 95% CI: 0.22–0.89), while no significant association was observed among postmenopausal women [139]. This shows the need to conduct more case–control studies in order to afford a clearer picture on the relationship between soy products and breast cancer incidence.

#### **5.3 Soy proteins and soy isoflavones and breast cancer outcomes**

There are studies that have examined the association between soy products and isoflavones intake and breast cancer survival, however the results are not definitive [140–142]. There are prospective cohort and meta-analyses studies that have reported significant inversely association between soy protein and soy isoflavones and breast cancer survival outcomes. In looking at prospective studies, The Shanghai Breast Cancer Survival Study comprised of 5,033 surgically treated breast cancer patients that were followed for 3.9 years. High soy protein

*Antioxidants - Benefits, Sources, Mechanisms of Action*

between the flavins, flavan-3-ol monomers and flavanols, and breast cancer risk [110]. These findings are compatible with those of a large case–control study conducted in Italy, where decreased breast cancer risk was found for flavonols (OR = 0.80, Ptrend 0.06) and flavones (OR = 0.81, Ptrend = 0.02), but not for flavan-3-ols, flavanones, isoflavones and anthocyanidins [111]. Similarly, in a subsequent case–control study of United States women reduced breast cancer risk was related with high dietary uptake of flavones (OR = 0.61, 95% CI: 0.45, 0.83), flavonols (OR = 0.54, 95% CI: 0.40–0.73) and flavan-3-ols in postmenopausal women. The authors suggested that consuming sufficient amount of these flavonoids could be beneficial to these women in the chemoprevention of breast cancer [112] (**Table 1**). Notably, in a recent hospital-based case–control, higher levels of serum flavonols (OR = 0.52, 95% CI 0.38–0.70) and flavanone (OR = 0.45, 95% CI: 0.34–0.60) were significantly associated with decreased breast cancer risk [113]. The outcomes of these studies corroborated those of other case–control studies [114, 115] which supported the protective influence of high dietary intake of flavonols and flavones

against breast cancer particularly among postmenopausal females.

The findings from prospective cohort studies are not so favorable regarding the chemo-preventative actions of flavonoids. In a meta-analysis of epidemiologic studies comprising 6 prospective cohort and 6 case–control studies, higher dietary intake of flavones (RR = 0.83, 95% CI: 0.76–0.91), flavonols (RR = 0.88, 95% CI: 0.80–0.98) decreased breast cancer risk although there were no significant relation of flavanones, flavan-3-ols and anthocyanins particularly in post-menopausal women [116] (**Table 3**). However, The Nurses' Health Study II investigated the effect of dietary flavonols on breast cancer risk, and found a non-significant null association with a risk ratio of 0.94 (95% CI: 0.72–1.22, Ptrend = 0.54) that was reported for flavonol-rich foods. Furthermore, dietary intakes of flavonol containing foods such as beans and lentils were inversely associated with breast cancer risk but this was not observed for onions, apples, blueberries tea, green pepper and broccoli [117]. There was also no association and thus no protective effects against breast cancer risk for increased intake of flavanones [118–120], flavanols [118, 119], flavonols [118–120], flavones [118], anthocyanidins [118] as well as

Isoflavones are a subclass of flavonoids and are found in legumes such as soybeans and soy products. These polyphenolic compounds are derived from plants and the three main isoflavones are daidzin, glycitin and genistin [123]. Globally the consumption of soy and soy products is increasing as the health benefits due to their biological actions including estrogenic and anti-estrogenic properties, inhibition of tumor proliferation, antioxidant, anti-inflammatory and lower risk for cardiovascular disease [124, 125]. Notwithstanding potential mechanisms from experimental studies, epidemiological evidence from case–control and prospective cohort studies regarding association of soy food and isoflavone, and breast cancer risk provide unreliable

In The Shanghai Breast Cancer Survival Study that assessed bone fracture incidence and its relationship with soy food consumption among breast cancer patients, high soy isoflavone intake was concomitant with decreased risk among both peri- and premenopausal subjects (HR = 0.22, 95% CI: 0.09–0.53) but no association for postmenopausal subjects [129] (**Table 1**). Similarly, a recent study that examined the relationship between isoflavone intake and hereditary breast cancer risk, reported that high intake of this flavonoid was inversely related with luminal A breast cancer hazard in women who are BRCA2 mutation carriers [130]. Conversely,

**32**

total flavonoids [118–122].

results [126–128].

**5.2 Soy isoflavones and breast cancer risk**

intake was inversely associated with breast cancer recurrence (HR = 0.68, 95%CI: 0.64–0.87) and all-cause mortality (HR = 0.71, 95%CI: 0.54–0.92) among women with either estrogen receptor-positive or -negative breast cancer [143] (**Table 2**). In an earlier prospective study of 256 Chinese women, elevated soy isoflavones intake was associated with reduced risk of breast cancer mortality (OR = 0.25, 95% CI: 0.09–0.54) and high soy protein was also concomitant with significant decreased breast cancer risk (OR = 0.38, 95% CI: 0.17–0.86) [144] (**Table 2**). In another study published in the same year involving 339 Korean women, dietary soy isoflavones was inversely related with breast cancer recurrence in HER2-positive breast cancer patients (HR = 0.23, 95%CI: 0.06–0.89) while no effect was observed with total soy intake [145].

The findings from systematic and meta-analysis of prospective cohort and case–control studies are also inconsistent. In a meta-analysis of protective studies, soy isoflavones intake was inversely linked with risk of breast cancer incidence (RR = 0.89, 95% CI: 0.79–0.99) and also inversely concomitant with risk of breast cancer recurrence (RR = 0.84, 95% CI: 0.70–0.99) [146] (**Table 3**). Likewise, Nachvak et al. conducted a systematic review and dose–response meta-analysis of 23 prospective cohort studies and reported that a 9% reduced risk of breast cancerspecific mortality for each 10 mg/day increase in soy isoflavones intake and a 12% decrease in the same survival outcome for each 5-g/day elevation of soy protein intake [147]. On the other hand, Qiu and Jiang conducted a systematic review and meta-analysis of 12 studies that explored the relationship between soy and isoflavones intake and breast cancer survival and recurrence. Pre- and post-diagnosis of soy and isoflavones intake were associated with minor reduction in risk of breast cancer recurrence (HR = 0.84 95% CI: 0.71–0.98) and breast cancer specific survival (HR = 0.89 95% CI: 0.74–1.07). Stratified analyses revealed no significant relationship between post-diagnosis soy and isoflavones consumption with overall survival (HR = 0.80, 95% CI: 0.62–1.04), and breast cancer specific survival (HR = 0.83, 95%CI: 0.64–1.07) [141].

### **5.4 Lycopene and breast cancer risk**

The consumption of fruits and vegetables particularly those containing lycopene may offer protection against different types of cancers including breast cancer. There are a number of prospective and case–control studies that examined the relationship between dietary lycopene and breast cancer risk. In a case–control study conducted among Chinese women comprising of 122 primary breast cancer cases and 632 age-matched healthy females, high intake of dietary lycopene was statistically strongly associated with lower breast cancer risk (adjusted OR = 0.26, 95% CI: 0.14–0.46) [93] (**Table 1**). In the Women's Health Initiative Observational Study comprising 84 805 women with reported 2,879 incident breast cancer cases during a follow-up period of 7.6 years, high intake of dietary lycopene non-significantly reduced breast cancer risk by 15% (RR = 0.85; 95% CI: 0.73–1.00; Ptrend = 0.064) in ER+ and PR+ breast cancer among post-menopausal women [23]. Also, a Swiss case–control study comprising 289 incident breast cancer cases and 442 controls reported a significant inverse association for lycopene with breast cancer risk (OR = 0.64) [148].

However, there are both prospective and case–control studies that have found null association between dietary lycopene and breast cancer risk. In a case–control study of Chinese women involving of 561 cases and 561 age-matched control high intake of lycopene was not associated with breast cancer risk (0.89, 95% CI: 0·61–1·30) [118]. Likewise, in another case–control study of non-Hispanic White and Hispanic women there was no association and therefore no protective effect of

**35**

with breast cancer risk [91].

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

dietary lycopene on breast cancer risk [60]. Furthermore, there are other studies of dietary lycopene intake including prospective cohort [57, 88, 105, 146], case–control [149] and meta-analysis [91] that have found no association of lycopene with

Epidemiologic studies evaluating whether circulating lycopene is associated with breast cancer risk have yielded equivocal answers. A nested case–control study conducted comprising 295 breast cancer cases and 295 age- and race-matched controls demonstrated significantly strong inverse association of high levels of lycopene with the risk of developing breast cancer [97]. In another case–control study among women in the United States (46 breast cancer cases and 63 controls), there was a strong inverse association of lycopene (OR = 0.32, 95% CI: 0.11 -, 0.94) in breast adipose tissue and risk of breast cancer [150] (**Table 1**). Likewise, a pilot case–control study of Caucasian and African American women found a weak inverse relation between plasma lycopene concentration and risk of breast cancer (Simon et al., 2000). The findings of these study were in agreement with that of a comprehensive pooled analysis of 8 prospective cohort studies conducted by Eliassen and colleagues. They found serum or plasma levels of lycopene significantly lower the risk of breast cancer patients by 22% (RR = 0.78, 95% CI: 0.62–0.99, Ptrend = 0.02) [151]

Others studies with findings in consonant with an inverse association between serum or plasma levels of lycopene and breast cancer risk include two case–control studies that showed deceased risk among females with elevated mammographic density [152] and blood donors [103] and a nested case–case control in the Nurses' Health Study [153]. Likewise, in a nested case–control study, stepwise increase in plasma lycopene levels were not associated (RR = 0.95, 1.15, 0.93, 1.00 (reference, P trend = 0.86) with decreased breast cancer risk in older and middle-aged

There are a few epidemiologic studies that have investigate the protective effect of dietary lutein and zeaxanthin on breast cancer incidence [90, 119, 155]. A case–control study of Chinese women found that lutein/zeaxanthin reduced breast cancer risk by 51% (OR = 0·49, 95% CI: 0·34–0·71) particularly among premenopausal women and those exposed to second-hand smoke [119]. In an earlier large population-based case–control study of United States residents, an inverse association was shown for higher consumption of lutein/zeaxanthin (OR = 0.83, 95% CI 0.68–0.99, Ptrend = 0.02) and breast cancer risk among postmenopausal women [90]. Likewise, Bae conducted a pooled analysis of eighteen prospective cohort studies and reported that lutein/zeaxanthin demonstrated protective effect

However, a case–control study of Chinese women demonstrated that high dietary lutein/zeaxanthin were not inversely associated with breast cancer risk [93]. Similarly, in a large cohort study of Canadian women Terry et al. reported no clear association between dietary intake of lutein/zeaxanthin and risk of breast cancer [88]. In a later meta-analysis involving 33 studies, high dietary intake of lutein/+zeaxanthin offered no protective effect and thus no significant association

In addition to epidemiological studies that have discovered the anti-cancer potential of dietary lutein/zeaxanthin, there are a few research that investigated the protective role of this circulating antioxidant. Serum or plasma levels of lutein/ zeaxanthin are more suitable biological indicators of the amount of these flavonol available for chemo-preventative action [156]. In a case–control study conducted

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

breast cancer risk.

(**Table 3**).

females [154].

**5.5 Lutein and zeaxanthin and breast cancer risk**

on ER- and PR+ as well as ER-/PR- breast cancer [155].

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

dietary lycopene on breast cancer risk [60]. Furthermore, there are other studies of dietary lycopene intake including prospective cohort [57, 88, 105, 146], case–control [149] and meta-analysis [91] that have found no association of lycopene with breast cancer risk.

Epidemiologic studies evaluating whether circulating lycopene is associated with breast cancer risk have yielded equivocal answers. A nested case–control study conducted comprising 295 breast cancer cases and 295 age- and race-matched controls demonstrated significantly strong inverse association of high levels of lycopene with the risk of developing breast cancer [97]. In another case–control study among women in the United States (46 breast cancer cases and 63 controls), there was a strong inverse association of lycopene (OR = 0.32, 95% CI: 0.11 -, 0.94) in breast adipose tissue and risk of breast cancer [150] (**Table 1**). Likewise, a pilot case–control study of Caucasian and African American women found a weak inverse relation between plasma lycopene concentration and risk of breast cancer (Simon et al., 2000). The findings of these study were in agreement with that of a comprehensive pooled analysis of 8 prospective cohort studies conducted by Eliassen and colleagues. They found serum or plasma levels of lycopene significantly lower the risk of breast cancer patients by 22% (RR = 0.78, 95% CI: 0.62–0.99, Ptrend = 0.02) [151] (**Table 3**).

Others studies with findings in consonant with an inverse association between serum or plasma levels of lycopene and breast cancer risk include two case–control studies that showed deceased risk among females with elevated mammographic density [152] and blood donors [103] and a nested case–case control in the Nurses' Health Study [153]. Likewise, in a nested case–control study, stepwise increase in plasma lycopene levels were not associated (RR = 0.95, 1.15, 0.93, 1.00 (reference, P trend = 0.86) with decreased breast cancer risk in older and middle-aged females [154].

#### **5.5 Lutein and zeaxanthin and breast cancer risk**

There are a few epidemiologic studies that have investigate the protective effect of dietary lutein and zeaxanthin on breast cancer incidence [90, 119, 155]. A case–control study of Chinese women found that lutein/zeaxanthin reduced breast cancer risk by 51% (OR = 0·49, 95% CI: 0·34–0·71) particularly among premenopausal women and those exposed to second-hand smoke [119]. In an earlier large population-based case–control study of United States residents, an inverse association was shown for higher consumption of lutein/zeaxanthin (OR = 0.83, 95% CI 0.68–0.99, Ptrend = 0.02) and breast cancer risk among postmenopausal women [90]. Likewise, Bae conducted a pooled analysis of eighteen prospective cohort studies and reported that lutein/zeaxanthin demonstrated protective effect on ER- and PR+ as well as ER-/PR- breast cancer [155].

However, a case–control study of Chinese women demonstrated that high dietary lutein/zeaxanthin were not inversely associated with breast cancer risk [93]. Similarly, in a large cohort study of Canadian women Terry et al. reported no clear association between dietary intake of lutein/zeaxanthin and risk of breast cancer [88]. In a later meta-analysis involving 33 studies, high dietary intake of lutein/+zeaxanthin offered no protective effect and thus no significant association with breast cancer risk [91].

In addition to epidemiological studies that have discovered the anti-cancer potential of dietary lutein/zeaxanthin, there are a few research that investigated the protective role of this circulating antioxidant. Serum or plasma levels of lutein/ zeaxanthin are more suitable biological indicators of the amount of these flavonol available for chemo-preventative action [156]. In a case–control study conducted

*Antioxidants - Benefits, Sources, Mechanisms of Action*

(HR = 0.83, 95%CI: 0.64–1.07) [141].

**5.4 Lycopene and breast cancer risk**

intake [145].

intake was inversely associated with breast cancer recurrence (HR = 0.68, 95%CI: 0.64–0.87) and all-cause mortality (HR = 0.71, 95%CI: 0.54–0.92) among women with either estrogen receptor-positive or -negative breast cancer [143] (**Table 2**). In an earlier prospective study of 256 Chinese women, elevated soy isoflavones intake was associated with reduced risk of breast cancer mortality (OR = 0.25, 95% CI: 0.09–0.54) and high soy protein was also concomitant with significant decreased breast cancer risk (OR = 0.38, 95% CI: 0.17–0.86) [144] (**Table 2**). In another study published in the same year involving 339 Korean women, dietary soy isoflavones was inversely related with breast cancer recurrence in HER2-positive breast cancer patients (HR = 0.23, 95%CI: 0.06–0.89) while no effect was observed with total soy

The findings from systematic and meta-analysis of prospective cohort and case–control studies are also inconsistent. In a meta-analysis of protective studies, soy isoflavones intake was inversely linked with risk of breast cancer incidence (RR = 0.89, 95% CI: 0.79–0.99) and also inversely concomitant with risk of breast cancer recurrence (RR = 0.84, 95% CI: 0.70–0.99) [146] (**Table 3**). Likewise, Nachvak et al. conducted a systematic review and dose–response meta-analysis of 23 prospective cohort studies and reported that a 9% reduced risk of breast cancerspecific mortality for each 10 mg/day increase in soy isoflavones intake and a 12% decrease in the same survival outcome for each 5-g/day elevation of soy protein intake [147]. On the other hand, Qiu and Jiang conducted a systematic review and meta-analysis of 12 studies that explored the relationship between soy and isoflavones intake and breast cancer survival and recurrence. Pre- and post-diagnosis of soy and isoflavones intake were associated with minor reduction in risk of breast cancer recurrence (HR = 0.84 95% CI: 0.71–0.98) and breast cancer specific survival (HR = 0.89 95% CI: 0.74–1.07). Stratified analyses revealed no significant relationship between post-diagnosis soy and isoflavones consumption with overall survival (HR = 0.80, 95% CI: 0.62–1.04), and breast cancer specific survival

The consumption of fruits and vegetables particularly those containing lycopene

However, there are both prospective and case–control studies that have found null association between dietary lycopene and breast cancer risk. In a case–control study of Chinese women involving of 561 cases and 561 age-matched control high intake of lycopene was not associated with breast cancer risk (0.89, 95% CI: 0·61–1·30) [118]. Likewise, in another case–control study of non-Hispanic White and Hispanic women there was no association and therefore no protective effect of

may offer protection against different types of cancers including breast cancer. There are a number of prospective and case–control studies that examined the relationship between dietary lycopene and breast cancer risk. In a case–control study conducted among Chinese women comprising of 122 primary breast cancer cases and 632 age-matched healthy females, high intake of dietary lycopene was statistically strongly associated with lower breast cancer risk (adjusted OR = 0.26, 95% CI: 0.14–0.46) [93] (**Table 1**). In the Women's Health Initiative Observational Study comprising 84 805 women with reported 2,879 incident breast cancer cases during a follow-up period of 7.6 years, high intake of dietary lycopene non-significantly reduced breast cancer risk by 15% (RR = 0.85; 95% CI: 0.73–1.00; Ptrend = 0.064) in ER+ and PR+ breast cancer among post-menopausal women [23]. Also, a Swiss case–control study comprising 289 incident breast cancer cases and 442 controls reported a significant inverse association for lycopene with breast cancer risk

**34**

(OR = 0.64) [148].

among Chinese women, there was a significantly strong inverse association of high serum levels of lutein/zeaxanthin with breast cancer risk (OR = 0·26, 95% CI: 0·17–0·38) [157]. Likewise, a nested case–control study comprising 604 incident breast cancer cases and 626 controls in the Nurses' Health Study found that circulating lycopene, alpha-carotene and beta-cryptoxanthin were concomitant with a significant 40% - 50% decrease in the risk of breast cancer (Ptrend < 0.05) [152]. These findings were corroborated by a comprehensive analysis of 8 cohort studies where lutein/zeaxanthin was significantly inversely associated with breast cancer risk (RR = 0.84, 95% CI: 0.70–1.01, Ptrend = 0.05) [151]. Interestingly, in a nested case–control study (270 breast cancer cases, 270 matched controls) the risk of breast cancer increased due to low blood levels (OR = 2.08, 95% CI: 1.11–3.90) [158].

However, In a nested case–control study (1502 breast cancer cases and 1502 individually matched controls) conducted within the European Prospective Investigation into Cancer and Nutrition cohort, there was no statistical association of plasma levels of lutein with of ER- breast tumors [98]. Supporting evidence was also observed in a case–control cohort (201 breast cancer cases and 290 referents) where plasma concentrations of lutein was significantly inversely related with breast cancer risk in premenopausal women [106].

#### **5.6 Quercetin and breast cancer risk**

The number of epidemiological research involving quercetin and potential relationship with breast cancer risk is lacking. In a linkage of multi-centered case– control studies conducted in Italy (comprising 10,000 incident breast cancer cases and 16,000 controls) high intake of flavonols including quercetin was inversely associated with breast cancer risk (OR = 0.80) [158]. Similarly, in an earlier largecase control study also conducted in Italy (2,569 incident breast cancer cases and 2,588 controls), increasing consumption of flavonols decreased breast cancer risk by 20% (OR = 0.80; Ptrend, 0.06) [111]. The findings of another large case–control study comprising Greek women was consistent with these two previous results where a strong significant inverse relationship of daily flavonols in fruit comprising quercetin with breast cancer risk [114]. Higher intake of quercetin reduced breast cancer risk by 38% (RR = 0.62, 95%CI: 0.37–1.03, P = 0.25) and the relation was stronger when modification was made in lieu of other dietary sources with a lower risk of 46% (RR = 0.54, 95%CI: 0.30–0.95, P = 0.14) [120]. Lastly, in a metaanalyses of 6 case–controls and 6 prospective cohort studies, breast cancer risk due to high intake (compared with low consumption) of flavonols such as quercetin declined by 12% in females (RR = 0.88, 95% CI: 0.80–0.98). It was also observed that further analyses of 3 case–control studies, high flavonol intake (compared with low consumption) was associated with decreased breast cancer risk in postmenopausal women [116].

#### **6. Green tea**

#### **6.1 Green tea intake and breast cancer risk**

Green tea is a product of dry tea leaves of the plant *Camellia sinensis*, and numerous pre-clinical and epidemiologic studies have been conducted examining the possible protective effect of green tea from various types of human cancers including breast carcinoma [159]. Epidemiologic studies have described a protecting effect of green tea consumption against the initiation and progression of breast cancer, although the results has not being conclusive. A case–control study (1009 incident

**37**

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

breast cancer cases and 1009 age-matched controls) of regular green tea (dried green tea leaves per annum) consumption in a dose-dependent manner significantly reduced breast cancer risk [(OR = 0.87, 95% CI: 0.73–1.04) for 1–249 g; (OR = 0.68, 95% CI: 0.54–0.86) for 250–499 g and (OR = 0.59, 95 CI: 0.45–0.77) for 500–749 g, Ptrend < 0.001) [160]. Likewise, in a population-based, case–control study of Asian women with breast cancer (501 breast cancer patients and 594 controls), there was a significant trend of reducing risk with cumulative amount of green tea consumption ([OR = 0.71, 95% CI: 0.51–0.99) and (OR = 0.53, 95% CI: 0.35–0.78) for

0–85.7 ml and > 85.7 ml of green tea per day respectively] [161]. These findings were corroborated by a population-based case–control study of Chinese women in which regular green tea mildly decreased breast cancer risk by 18% (OR = 0.88; 95% CI: 0.79–0.98). It was observed that a dose-dependent association existed with the quantity of green tea intake per month and catechol-O-methyltransferase rs4680

Two other nested case–control studies are consistent with the protective effect of green tea consumption. Yuan et al. piloted a nested case–control study (297 incident breast cancer cases and 665 controls) inside the Singapore Chinese Health Study and found that frequent green tea consumption significantly decreases breast cancer risk in women with high angiotensin-converting enzyme activity (OR = 0.33, 95%CI: 0.13–0.82, Ptrend = 0.039) [163]. In an earlier nested case–control study (380 incident breast cancer cases and 662 controls) also within the Singapore Chinese Health Study, women with low folate intake and daily or weekly green tea consumption had a 55% reduced breast cancer risk (OR = 0.45, 95% CI: 0.26–0.79, Pinteraction = 0.02). Green tea consumption was not associated with breast cancer risk at high folate intake and the authors suggested that inhibition of the folate intake may be a possible mechanism which account for the protective effect of green tea

There are two meta-analyses that support the reduction of breast cancer incidence and recurrence due to green tea consumption. A meta-analysis of studies by Ogunleye et al. of breast cancer recurrence and risk comprising 5,617 cases showed that increased green tea intake (greater than 3 cups/day) was inversely related with breast cancer recurrence (RRpooled = 0.73, 95%CI: 0.56–0.96 [165] (Ogunleye et al., 2010). An analysis of only case–control studies showed that the inverse relationship was preserved (RRpooled = 0.81, 95%CI: 0.75–0.88) while there was no protective effect and therefore null association of breast cancer risk among prospective cohort studies [165]. There was additional supportive evidence in a more recent meta-analysis of 13 studies (5 case–control and 8 cohort studies comprising of 63,810 women) where a statistically significant inverse association existed between green tea consumption and breast cancer incidence with a 15% risk reduction (ORpooled = 0.85, 95% CI: 0.80–0.92, p = 0.0001) [166]. Analysis of only case–control studies also showed a significant inverse relationship with a 19% decrease in the

risk of breast cancer (ORpooled = 0.81, 95%CI: 0.74–0.88, p = 0.000) [166]. The results of prospective cohort studies demonstrating a protective effects against breast cancer were less conclusive with some of the studies reporting null association. In a prospective cohort study of the Hospital-based Epidemiologic Research Program in Japan, there was reduced breast cancer recurrence among subjects who consumed 3 or more cups of green tea (HR = 0.69, 95%CI: 0.47–1.00), particularly in stage I disease (HR = 0.43, 95%CI: 0.22–0.84) [167]. In the Shanghai Women's Health Study, a large population based study comprising 74,942 Chinese females, subjects who began drinking green tea less than or at 25 years of age were less likely to develop breast cancer (HR = 0.69, 95% CI: 0.41–1.17) [168]. However, in a later population-based prospective cohort study also conducted in Japan, there was no association of breast cancer risk and green tea consumption (> 5 or more

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

genotypes did not modify the relationship [162].

against breast carcinoma [164].

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

breast cancer cases and 1009 age-matched controls) of regular green tea (dried green tea leaves per annum) consumption in a dose-dependent manner significantly reduced breast cancer risk [(OR = 0.87, 95% CI: 0.73–1.04) for 1–249 g; (OR = 0.68, 95% CI: 0.54–0.86) for 250–499 g and (OR = 0.59, 95 CI: 0.45–0.77) for 500–749 g, Ptrend < 0.001) [160]. Likewise, in a population-based, case–control study of Asian women with breast cancer (501 breast cancer patients and 594 controls), there was a significant trend of reducing risk with cumulative amount of green tea consumption ([OR = 0.71, 95% CI: 0.51–0.99) and (OR = 0.53, 95% CI: 0.35–0.78) for 0–85.7 ml and > 85.7 ml of green tea per day respectively] [161]. These findings were corroborated by a population-based case–control study of Chinese women in which regular green tea mildly decreased breast cancer risk by 18% (OR = 0.88; 95% CI: 0.79–0.98). It was observed that a dose-dependent association existed with the quantity of green tea intake per month and catechol-O-methyltransferase rs4680 genotypes did not modify the relationship [162].

Two other nested case–control studies are consistent with the protective effect of green tea consumption. Yuan et al. piloted a nested case–control study (297 incident breast cancer cases and 665 controls) inside the Singapore Chinese Health Study and found that frequent green tea consumption significantly decreases breast cancer risk in women with high angiotensin-converting enzyme activity (OR = 0.33, 95%CI: 0.13–0.82, Ptrend = 0.039) [163]. In an earlier nested case–control study (380 incident breast cancer cases and 662 controls) also within the Singapore Chinese Health Study, women with low folate intake and daily or weekly green tea consumption had a 55% reduced breast cancer risk (OR = 0.45, 95% CI: 0.26–0.79, Pinteraction = 0.02). Green tea consumption was not associated with breast cancer risk at high folate intake and the authors suggested that inhibition of the folate intake may be a possible mechanism which account for the protective effect of green tea against breast carcinoma [164].

There are two meta-analyses that support the reduction of breast cancer incidence and recurrence due to green tea consumption. A meta-analysis of studies by Ogunleye et al. of breast cancer recurrence and risk comprising 5,617 cases showed that increased green tea intake (greater than 3 cups/day) was inversely related with breast cancer recurrence (RRpooled = 0.73, 95%CI: 0.56–0.96 [165] (Ogunleye et al., 2010). An analysis of only case–control studies showed that the inverse relationship was preserved (RRpooled = 0.81, 95%CI: 0.75–0.88) while there was no protective effect and therefore null association of breast cancer risk among prospective cohort studies [165]. There was additional supportive evidence in a more recent meta-analysis of 13 studies (5 case–control and 8 cohort studies comprising of 63,810 women) where a statistically significant inverse association existed between green tea consumption and breast cancer incidence with a 15% risk reduction (ORpooled = 0.85, 95% CI: 0.80–0.92, p = 0.0001) [166]. Analysis of only case–control studies also showed a significant inverse relationship with a 19% decrease in the risk of breast cancer (ORpooled = 0.81, 95%CI: 0.74–0.88, p = 0.000) [166].

The results of prospective cohort studies demonstrating a protective effects against breast cancer were less conclusive with some of the studies reporting null association. In a prospective cohort study of the Hospital-based Epidemiologic Research Program in Japan, there was reduced breast cancer recurrence among subjects who consumed 3 or more cups of green tea (HR = 0.69, 95%CI: 0.47–1.00), particularly in stage I disease (HR = 0.43, 95%CI: 0.22–0.84) [167]. In the Shanghai Women's Health Study, a large population based study comprising 74,942 Chinese females, subjects who began drinking green tea less than or at 25 years of age were less likely to develop breast cancer (HR = 0.69, 95% CI: 0.41–1.17) [168]. However, in a later population-based prospective cohort study also conducted in Japan, there was no association of breast cancer risk and green tea consumption (> 5 or more

*Antioxidants - Benefits, Sources, Mechanisms of Action*

breast cancer risk in premenopausal women [106].

**5.6 Quercetin and breast cancer risk**

menopausal women [116].

**6.1 Green tea intake and breast cancer risk**

**6. Green tea**

among Chinese women, there was a significantly strong inverse association of high serum levels of lutein/zeaxanthin with breast cancer risk (OR = 0·26, 95% CI: 0·17–0·38) [157]. Likewise, a nested case–control study comprising 604 incident breast cancer cases and 626 controls in the Nurses' Health Study found that circulating lycopene, alpha-carotene and beta-cryptoxanthin were concomitant with a significant 40% - 50% decrease in the risk of breast cancer (Ptrend < 0.05) [152]. These findings were corroborated by a comprehensive analysis of 8 cohort studies where lutein/zeaxanthin was significantly inversely associated with breast cancer risk (RR = 0.84, 95% CI: 0.70–1.01, Ptrend = 0.05) [151]. Interestingly, in a nested case–control study (270 breast cancer cases, 270 matched controls) the risk of breast cancer increased due to low blood levels (OR = 2.08, 95% CI: 1.11–3.90) [158]. However, In a nested case–control study (1502 breast cancer cases and 1502 individually matched controls) conducted within the European Prospective Investigation into Cancer and Nutrition cohort, there was no statistical association of plasma levels of lutein with of ER- breast tumors [98]. Supporting evidence was also observed in a case–control cohort (201 breast cancer cases and 290 referents) where plasma concentrations of lutein was significantly inversely related with

The number of epidemiological research involving quercetin and potential relationship with breast cancer risk is lacking. In a linkage of multi-centered case– control studies conducted in Italy (comprising 10,000 incident breast cancer cases and 16,000 controls) high intake of flavonols including quercetin was inversely associated with breast cancer risk (OR = 0.80) [158]. Similarly, in an earlier largecase control study also conducted in Italy (2,569 incident breast cancer cases and 2,588 controls), increasing consumption of flavonols decreased breast cancer risk by 20% (OR = 0.80; Ptrend, 0.06) [111]. The findings of another large case–control study comprising Greek women was consistent with these two previous results where a strong significant inverse relationship of daily flavonols in fruit comprising quercetin with breast cancer risk [114]. Higher intake of quercetin reduced breast cancer risk by 38% (RR = 0.62, 95%CI: 0.37–1.03, P = 0.25) and the relation was stronger when modification was made in lieu of other dietary sources with a lower risk of 46% (RR = 0.54, 95%CI: 0.30–0.95, P = 0.14) [120]. Lastly, in a metaanalyses of 6 case–controls and 6 prospective cohort studies, breast cancer risk due to high intake (compared with low consumption) of flavonols such as quercetin declined by 12% in females (RR = 0.88, 95% CI: 0.80–0.98). It was also observed that further analyses of 3 case–control studies, high flavonol intake (compared with low consumption) was associated with decreased breast cancer risk in post-

Green tea is a product of dry tea leaves of the plant *Camellia sinensis*, and numer-

ous pre-clinical and epidemiologic studies have been conducted examining the possible protective effect of green tea from various types of human cancers including breast carcinoma [159]. Epidemiologic studies have described a protecting effect of green tea consumption against the initiation and progression of breast cancer, although the results has not being conclusive. A case–control study (1009 incident

**36**

cups/day; HR = 1.12, 95%CI: 0.81–1.56; Ptrend = 0.60) [169]. Green tea intake was not associated with a reduced breast cancer risk in another prospective study conducted in Japan [170] and in 2 prospective studies piloted among 35,004 Japanese women (RR = 0.84, 95%CI: 0.57–1.24; > 5 cups/day) [171].

## *6.1.1 Epigallocatechin-3-gallate intake and breast cancer risk*

Epigallocatechin-3-gallate is a natural antioxidant and it has been reported to be more efficient at arresting reactive oxygen species and other radical than vitamin C and E [172]. Experimental studies have demonstrated that epigallocatechin-3-gallate, the biologically active and most abundant tea catechins displays anticancer and chemotherapeutic effects against breast cancer [173]. Epidemiologic studies relating to epigallocatechin-3-gallate are lacking. In a nested case–control study (144 incident breast cancer cases and 288 age-matched controls) in the Japan Public Health Center-based Prospective Study, elevated plasma levels of epigallocatechin-3-gallate along with epicatechin-3-gallate, epicatechin and epigallocatechin were not associated with reduced breast cancer risk [epigallocatechin-3-gallate (OR = 1.21, 95%CI: 0.52–2.80; Ptrend = 0.53)] [169]. In another study published three years ago, green tea extract capsules comprising 843 mg epigallocatechin-3-gallate administered for 1 year decreased mammographic density in healthy postmenopausal women [174]. Interesting, epigallocatechin-3-gallate (400 mg capsules, 3 times/day for 2–8 weeks) orally administered to breast cancer subjects undergoing radiotherapy potentiate the effectiveness of the treatment as evident by decreased metalloproteinase-9 and metalloproteinase-2 activities and elevated serum concentration of vascular endothelial growth factor [175].

The few reports of epidemiologic evidence of epigallocatechin-3-gallate and inconclusive findings in prospective studies suggests that further exploration of its probable chemo-preventative.

## **7. Discussion and conclusion**

The epidemiological evidence shown by a number of case–control, prospective cohort studies as well as meta-analysis and systematic reviews presented does support the view that nutritional micronutrients with antioxidant properties in dietary or supplemental form may be beneficial in protecting women against breast cancer. However, there are studies that have demonstrated null association between the dietary and supplemental micronutrients, and the risk or survival outcomes of breast cancer. Thus overall the findings are inconsistent and epidemiological data on some of the antioxidants as it relates to breast cancer outcomes such as recurrence, and breast cancer-specific and all-cause mortality is inadequate.

Notably, there is substantial evidence which is well documented in the literature of the protective action and modification of many signaling pathways and molecular events by these antioxidants inducing apoptosis, inhibition of breast cancer cell proliferation and invasion, and preventing angiogenesis and metastasis. However, the findings of epidemiological results are somewhat disappointing and are not concurrent with experimental results for most of these natural antioxidants. There are limiting factors which negatively impact epidemiological association studies such as genetic, confounding lifestyle, samples sizes, possible selection bias in case–control studies, the length of intervention, possible recall bias in retrospective studies, not accurately measuring dietary intake in prospective studies, interaction among different micronutrients which may nullify individual effect among others.

**39**

**Author details**

Donovan McGrowder1

prevention of breast cancer.

tea intake on breast cancer development.

Cameil Wilson-Clarke3

Indies, Jamaica, West Indies

College, Jamaica, West Indies

Technology, Jamaica, West Indies

of the West Indies, Jamaica, West Indies

provided the original work is properly cited.

and Lowen Williams5

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

Nevertheless, despite the inconsistencies, the findings of the chemo-preventative effects of vitamins, flavonoids and green tea presented in this review are encouraging. There need to be more large-scale and randomized controlled studies to investigate the association of these antioxidants and outcomes such as breast cancer recurrence, and breast cancer-specific mortality. More studies investigating the dietary intake of these antioxidants with sub-types of breast cancer, namely ER and PR status among both premenopausal and postmenopausal women is warranted. The elucidation of the mechanism of action by which these antioxidants decrease breast cancer risk may be helpful in recognizing sub-groups who could benefit from the consumption of these antioxidants with better dietary endorsements for the

Furthermore, the finding that the inhibition of folate intake may be a possible mechanism which account for the protective effect of green tea against breast cancer is noted. Large prospective randomized control trials are warranted as they could provide definitive information on the beneficial or harmful effects of green

\*, Fabian Miller2,5, Chukwuemeka Nwokocha3

1 Department of Pathology, Faculty of Medical Sciences, The University of the West

2 Department of Physical Education, Faculty of Education, The Mico University

4 School of Allied Health and Wellness, College of Health Sciences, University of

5 Department of Biotechnology, Faculty of Science and Technology, The University

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

3 Department of Basic Medical Sciences, Faculty of Medical Sciences, The

University of the West Indies, Jamaica, West Indies

\*Address all correspondence to: dmcgrowd@yahoo.com

, Lennox Anderson-Jackson1

, Melisa Anderson4

,

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

Nevertheless, despite the inconsistencies, the findings of the chemo-preventative effects of vitamins, flavonoids and green tea presented in this review are encouraging. There need to be more large-scale and randomized controlled studies to investigate the association of these antioxidants and outcomes such as breast cancer recurrence, and breast cancer-specific mortality. More studies investigating the dietary intake of these antioxidants with sub-types of breast cancer, namely ER and PR status among both premenopausal and postmenopausal women is warranted. The elucidation of the mechanism of action by which these antioxidants decrease breast cancer risk may be helpful in recognizing sub-groups who could benefit from the consumption of these antioxidants with better dietary endorsements for the prevention of breast cancer.

Furthermore, the finding that the inhibition of folate intake may be a possible mechanism which account for the protective effect of green tea against breast cancer is noted. Large prospective randomized control trials are warranted as they could provide definitive information on the beneficial or harmful effects of green tea intake on breast cancer development.

## **Author details**

*Antioxidants - Benefits, Sources, Mechanisms of Action*

(RR = 0.84, 95%CI: 0.57–1.24; > 5 cups/day) [171].

tration of vascular endothelial growth factor [175].

probable chemo-preventative.

**7. Discussion and conclusion**

individual effect among others.

*6.1.1 Epigallocatechin-3-gallate intake and breast cancer risk*

cups/day; HR = 1.12, 95%CI: 0.81–1.56; Ptrend = 0.60) [169]. Green tea intake was not associated with a reduced breast cancer risk in another prospective study conducted in Japan [170] and in 2 prospective studies piloted among 35,004 Japanese women

Epigallocatechin-3-gallate is a natural antioxidant and it has been reported to be more efficient at arresting reactive oxygen species and other radical than vitamin C and E [172]. Experimental studies have demonstrated that epigallocatechin-3-gallate, the biologically active and most abundant tea catechins displays anticancer and chemotherapeutic effects against breast cancer [173]. Epidemiologic studies relating to epigallocatechin-3-gallate are lacking. In a nested case–control study (144 incident breast cancer cases and 288 age-matched controls) in the Japan Public Health Center-based Prospective Study, elevated plasma levels of epigallocatechin-3-gallate along with epicatechin-3-gallate, epicatechin and epigallocatechin were not associated with reduced breast cancer risk [epigallocatechin-3-gallate (OR = 1.21, 95%CI: 0.52–2.80; Ptrend = 0.53)] [169]. In another study published three years ago, green tea extract capsules comprising 843 mg epigallocatechin-3-gallate administered for 1 year decreased mammographic density in healthy postmenopausal women [174]. Interesting, epigallocatechin-3-gallate (400 mg capsules, 3 times/day for 2–8 weeks) orally administered to breast cancer subjects undergoing radiotherapy potentiate the effectiveness of the treatment as evident by decreased metalloproteinase-9 and metalloproteinase-2 activities and elevated serum concen-

The few reports of epidemiologic evidence of epigallocatechin-3-gallate and inconclusive findings in prospective studies suggests that further exploration of its

The epidemiological evidence shown by a number of case–control, prospective cohort studies as well as meta-analysis and systematic reviews presented does support the view that nutritional micronutrients with antioxidant properties in dietary or supplemental form may be beneficial in protecting women against breast cancer. However, there are studies that have demonstrated null association between the dietary and supplemental micronutrients, and the risk or survival outcomes of breast cancer. Thus overall the findings are inconsistent and epidemiological data on some of the antioxidants as it relates to breast cancer outcomes such as recur-

Notably, there is substantial evidence which is well documented in the literature of the protective action and modification of many signaling pathways and molecular events by these antioxidants inducing apoptosis, inhibition of breast cancer cell proliferation and invasion, and preventing angiogenesis and metastasis. However, the findings of epidemiological results are somewhat disappointing and are not concurrent with experimental results for most of these natural antioxidants. There are limiting factors which negatively impact epidemiological association studies such as genetic, confounding lifestyle, samples sizes, possible selection bias in case–control studies, the length of intervention, possible recall bias in retrospective studies, not accurately measuring dietary intake in prospective studies, interaction among different micronutrients which may nullify

rence, and breast cancer-specific and all-cause mortality is inadequate.

**38**

Donovan McGrowder1 \*, Fabian Miller2,5, Chukwuemeka Nwokocha3 , Cameil Wilson-Clarke3 , Melisa Anderson4 , Lennox Anderson-Jackson1 and Lowen Williams<sup>5</sup>

1 Department of Pathology, Faculty of Medical Sciences, The University of the West Indies, Jamaica, West Indies

2 Department of Physical Education, Faculty of Education, The Mico University College, Jamaica, West Indies

3 Department of Basic Medical Sciences, Faculty of Medical Sciences, The University of the West Indies, Jamaica, West Indies

4 School of Allied Health and Wellness, College of Health Sciences, University of Technology, Jamaica, West Indies

5 Department of Biotechnology, Faculty of Science and Technology, The University of the West Indies, Jamaica, West Indies

\*Address all correspondence to: dmcgrowd@yahoo.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2018;**68**(6):394-424

[2] World Health Organization. Breast Cancer. 2020. https://www.who.int/ cancer/prevention/diagnosis-screening/ breast-cancer/en/

[3] Majeed W, Aslam B, Javed I, Khaliq T, Muhammaf F, Ali A, Raza A. Breast Cancer: Major risk factors and recent developments in treatment. Asian Pacific Journal Cancer Prevention. 2014;**15**(8):3353-3358

[4] Ben-Chioma A, Obunwo C, Ebirien– Agana B, Ndokiari B. Evaluation of heavy metal levels in the serum of breast cancer patients in Port Harcourt, Nigeria. International Journal of Contemporary Medical Research. 2018;**4**(12):1-5

[5] Lee C. Delay in breast cancer: Implications for stage at diagnosis and survival. Frontiers in Public Health. 2014;**2**:87. doi: 10.3389/ fpubh.2014.00087

[6] Kennecke H, Yerushalmi RR, Woods, et al. Metastatic behavior of breast cancer subtypes. Journal of Clinical Oncology. 2010;**28**(20):3271-3277

[7] Cherny NI, Paluch-Shimon S, Berner-Wygoda Y. Palliative care: Needs of advanced breast cancer patients. Breast Cancer (Dove Medical Press), 2018;**10**, 231-243. doi.org/10.2147/BCTT. S160462

[8] Sarmiento-Salinas LF, Delgado-Magallón A, Montes-Alvarado JB, Ramírez-Ramírez D, Flores-Alonso J, Cortés-Hernández P, Reyes-Leyva J,

Herrera-Camacho I, et al. Breast cancer subtypes present a differential production of reactive oxygen species (ROS) and susceptibility to antioxidant treatment. Frontiers in Oncology. 2019;**9**:480. doi: 10.3389/ fonc.2019.00480

[9] Chio IIC, Tuveson DA. ROS in cancer: the burning question. Trends in Molecular Medicine. 2017;**23**:411-429

[10] Moloney JN, Cotter TG. ROS signalling in the biology of cancer. Seminars in Cell and Developmental Biology. 2018;**80**:50-64. doi: 10.1016/j. semcdb.2017.05.023

[11] Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE, Zhao Z, Leitch AM, Johnson TM, DeBerardinis RJ, Morrison SJ. Oxidative stress inhibits distant metastasis by human melanoma cells Nature. 2015;**527**:186-191

[12] Jezierska-Drutel A, Rosenzweig SA, Neumann CA. A Role of oxidative stress and the microenvironment in breast cancer development and progression. Advance Cancer Research. 2013;**119**:107-125. doi: 10.1016/ B978-0-12-407190-2.00003-4

[13] Hecht F, Pessoa CF, Gentile LB, Rosenthal D, Carvalho DP, Fortunato RS. The role of oxidative stress on breast cancer development and therapy. Tumor Biology. 2016;**37**(4):4281-4291

[14] Hewala TI, Ramadan Abo El-soud. The clinical significance of serum oxidative stress biomarkers in breast cancer females. Medical Research Journal 2019;**4**(1):1-7

[15] Adwas AA, Elsayed ASI, Azab AE, Quwaydir FA. Oxidative stress and antioxidant mechanisms in human

**41**

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

[23] Cui Y, Shikany JM, Liu S, Shagufta Y, Rohan TE. Selected antioxidants and risk of hormone receptor-defined invasive breast cancers among postmenopausal women

in the Women's Health Initiative Observational Study. Am J Clin Nutr.

2008;**87**(4):1009-1018

[24] Cadeau C, Fournier A, Mesrine S, Clavel-Chapelon F, Fagherazzi G, Boutron-Ruault MC. Vitamin C supplement intake and postmenopausal breast cancer risk: interaction with dietary vitamin C. Am J

Clin Nutr. 2016;**104**(1):228-234

Baina WY, Wencui Z, Chunqing L, Fan W, Dandan L, Dianjun S, Tong W, Da P, et al. Retinol, vitamins A, C, and E and breast cancer risk: a meta-analysis and meta-regression. Cancer Causes

[27] Zhang S, Hunter DJ, Forman MR, Rosner BA, Speizer FE, Colditz GA, Manson JE, Hankinson SE, Willett WC. Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. J Natl Cancer Inst. 1999;**91**(6):547-556

[28] Do MH, Lee SS, Jung PJ, Lee MH. Intake of dietary fat and vitamin in relation to breast cancer risk in Korean women: a case-control study. Journal of Korean Medical Science.

[29] Freudenheim JL, Marshall JR, Vena JE, Laughlin R, Brasure JR, Swanson MK, Nemoto T, Graham S. Premenopausal breast cancer risk and

[25] Fulan H, Changxing J,

Control. 2011;**22**:1383-1396

[26] Sharhar S, Normah H, Fatimah A, Fadilah RN, Rohi GA, Amin I, Cham BG, Rizal RM, Fairulnizal MN. Antioxidant intake and status, and oxidative stress in relation to breast cancer risk: a casecontrol study. Asian Pac J Cancer Prev.

2008;**9**(2):343-349

2003;**18**(4):534-540

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

body. Journal of Applied Biotechnology & Bioengineering. 2019;**6**(1):43-47. doiI:

[16] Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. International Journal of Biomedical Science. 2008;**4**(2):89-96

[18] Willcox JK, Ash SL, Catignani GL. Antioxidants and prevention of chronic disease. Critical Reviews in Food Science and Nutrition. 2004;**44**(4):275-295

[19] Traber MG, Stevens JF. Vitamins C and E: beneficial effects from a mechanistic perspective. Free Radic Biol

[20] Zhang D, Xu P, Li Y, Wei B, Yang S, Zheng Y, Lyu L, Deng Y, Zhai Z, Li N, Wang N, Lyu J, Dai Z. Association of vitamin C intake with breast cancer risk and mortality: a meta-analysis of observational studies. Aging (Albany NY). 2020;**12**(18):18415-18435

[21] Nagel G, Linseisen J, van Gils CH, Peeters PH, Boutron-Ruault MC, Clavel-Chapelon F, Romieu I, Tjønneland A, Olsen A et al. Dietary beta-carotene, vitamin C and E intake and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Breast Cancer Res Treat. 2010;**119**(3):753-765

[22] Verhoeven DT, Assen N, Goldbohm RA, Dorant E, van 't Veer P, Sturmans F, Hermus RJ, van den Brandt PA. Vitamins C and E, retinol, beta-carotene and dietary fibre in relation to breast cancer risk: a prospective cohort study. Br J Cancer.

1997;**75**(1):149-155

10.15406/jabb.2019.06.00173

[17] Greenlee H, Hershman DL, Jacobson JS. Use of antioxidant supplements during breast cancer treatment: a comprehensive review. Breast Cancer Res. Treat.

2009;**115**(3):437-452

Med. 2011;**51**:1000-1013

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

body. Journal of Applied Biotechnology & Bioengineering. 2019;**6**(1):43-47. doiI: 10.15406/jabb.2019.06.00173

[16] Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. International Journal of Biomedical Science. 2008;**4**(2):89-96

[17] Greenlee H, Hershman DL, Jacobson JS. Use of antioxidant supplements during breast cancer treatment: a comprehensive review. Breast Cancer Res. Treat. 2009;**115**(3):437-452

[18] Willcox JK, Ash SL, Catignani GL. Antioxidants and prevention of chronic disease. Critical Reviews in Food Science and Nutrition. 2004;**44**(4):275-295

[19] Traber MG, Stevens JF. Vitamins C and E: beneficial effects from a mechanistic perspective. Free Radic Biol Med. 2011;**51**:1000-1013

[20] Zhang D, Xu P, Li Y, Wei B, Yang S, Zheng Y, Lyu L, Deng Y, Zhai Z, Li N, Wang N, Lyu J, Dai Z. Association of vitamin C intake with breast cancer risk and mortality: a meta-analysis of observational studies. Aging (Albany NY). 2020;**12**(18):18415-18435

[21] Nagel G, Linseisen J, van Gils CH, Peeters PH, Boutron-Ruault MC, Clavel-Chapelon F, Romieu I, Tjønneland A, Olsen A et al. Dietary beta-carotene, vitamin C and E intake and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Breast Cancer Res Treat. 2010;**119**(3):753-765

[22] Verhoeven DT, Assen N, Goldbohm RA, Dorant E, van 't Veer P, Sturmans F, Hermus RJ, van den Brandt PA. Vitamins C and E, retinol, beta-carotene and dietary fibre in relation to breast cancer risk: a prospective cohort study. Br J Cancer. 1997;**75**(1):149-155

[23] Cui Y, Shikany JM, Liu S, Shagufta Y, Rohan TE. Selected antioxidants and risk of hormone receptor-defined invasive breast cancers among postmenopausal women in the Women's Health Initiative Observational Study. Am J Clin Nutr. 2008;**87**(4):1009-1018

[24] Cadeau C, Fournier A, Mesrine S, Clavel-Chapelon F, Fagherazzi G, Boutron-Ruault MC. Vitamin C supplement intake and postmenopausal breast cancer risk: interaction with dietary vitamin C. Am J Clin Nutr. 2016;**104**(1):228-234

[25] Fulan H, Changxing J, Baina WY, Wencui Z, Chunqing L, Fan W, Dandan L, Dianjun S, Tong W, Da P, et al. Retinol, vitamins A, C, and E and breast cancer risk: a meta-analysis and meta-regression. Cancer Causes Control. 2011;**22**:1383-1396

[26] Sharhar S, Normah H, Fatimah A, Fadilah RN, Rohi GA, Amin I, Cham BG, Rizal RM, Fairulnizal MN. Antioxidant intake and status, and oxidative stress in relation to breast cancer risk: a casecontrol study. Asian Pac J Cancer Prev. 2008;**9**(2):343-349

[27] Zhang S, Hunter DJ, Forman MR, Rosner BA, Speizer FE, Colditz GA, Manson JE, Hankinson SE, Willett WC. Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. J Natl Cancer Inst. 1999;**91**(6):547-556

[28] Do MH, Lee SS, Jung PJ, Lee MH. Intake of dietary fat and vitamin in relation to breast cancer risk in Korean women: a case-control study. Journal of Korean Medical Science. 2003;**18**(4):534-540

[29] Freudenheim JL, Marshall JR, Vena JE, Laughlin R, Brasure JR, Swanson MK, Nemoto T, Graham S. Premenopausal breast cancer risk and

**40**

S160462

*Antioxidants - Benefits, Sources, Mechanisms of Action*

Herrera-Camacho I, et al. Breast cancer

subtypes present a differential production of reactive oxygen species (ROS) and susceptibility to antioxidant treatment. Frontiers in Oncology. 2019;**9**:480. doi: 10.3389/

[9] Chio IIC, Tuveson DA. ROS in cancer: the burning question. Trends in Molecular Medicine. 2017;**23**:411-429

[10] Moloney JN, Cotter TG. ROS signalling in the biology of cancer. Seminars in Cell and Developmental Biology. 2018;**80**:50-64. doi: 10.1016/j.

[11] Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE, Zhao Z, Leitch AM, Johnson TM, DeBerardinis RJ, Morrison SJ. Oxidative

stress inhibits distant metastasis by human melanoma cells Nature.

2013;**119**:107-125. doi: 10.1016/ B978-0-12-407190-2.00003-4

[13] Hecht F, Pessoa CF,

Journal 2019;**4**(1):1-7

[12] Jezierska-Drutel A, Rosenzweig SA, Neumann CA. A Role of oxidative stress and the microenvironment in breast cancer development and progression. Advance Cancer Research.

Gentile LB, Rosenthal D, Carvalho DP, Fortunato RS. The role of oxidative stress on breast cancer development and therapy. Tumor Biology. 2016;**37**(4):4281-4291

[14] Hewala TI, Ramadan Abo El-soud. The clinical significance of serum oxidative stress biomarkers in breast cancer females. Medical Research

[15] Adwas AA, Elsayed ASI, Azab AE, Quwaydir FA. Oxidative stress and antioxidant mechanisms in human

fonc.2019.00480

semcdb.2017.05.023

2015;**527**:186-191

[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2018;**68**(6):394-424

[2] World Health Organization. Breast Cancer. 2020. https://www.who.int/ cancer/prevention/diagnosis-screening/

[3] Majeed W, Aslam B, Javed I, Khaliq T, Muhammaf F, Ali A, Raza A. Breast Cancer: Major risk factors and recent developments in treatment. Asian Pacific Journal Cancer Prevention.

[4] Ben-Chioma A, Obunwo C, Ebirien– Agana B, Ndokiari B. Evaluation of heavy metal levels in the serum of breast cancer patients in Port Harcourt, Nigeria. International Journal of Contemporary Medical Research.

[5] Lee C. Delay in breast cancer: Implications for stage at diagnosis and survival. Frontiers in Public Health. 2014;**2**:87. doi: 10.3389/

[7] Cherny NI, Paluch-Shimon S, Berner-Wygoda Y. Palliative care: Needs of advanced breast cancer patients. Breast Cancer (Dove Medical Press), 2018;**10**, 231-243. doi.org/10.2147/BCTT.

[8] Sarmiento-Salinas LF, Delgado-Magallón A, Montes-Alvarado JB, Ramírez-Ramírez D, Flores-Alonso J, Cortés-Hernández P, Reyes-Leyva J,

[6] Kennecke H, Yerushalmi RR, Woods, et al. Metastatic behavior of breast cancer subtypes. Journal of Clinical Oncology. 2010;**28**(20):3271-3277

breast-cancer/en/

**References**

2014;**15**(8):3353-3358

2018;**4**(12):1-5

fpubh.2014.00087

intake of vegetables, fruits, and related nutrients. J Natl Cancer Inst. 1996;**88**(6):340-348

[30] Hutchinson J, Lentjes MA, Greenwood DC, Burley VJ, Cade JE, Cleghorn CL, Threapleton DE, Key TJ, Cairns BJ, Keogh RH, et al. Vitamin C intake from diary recordings and risk of breast cancer in the UK Dietary Cohort Consortium. Eur J Clin Nutr. 2012;**66**(5):561-568

[31] Hunter DJ, Manson JE, Colditz GA, Stampfer MJ, Rosner B, Hennekens CH, Speizer FE, Willett WC. A prospective study of the intake of vitamins C, E, and A and the risk of breast cancer. N Engl J Med. 1993;**329**(4):234-240

[32] Ullah M, Khan H, Zubair H, Shamim U, Hadi S. The antioxidant ascorbic acid mobilizes nuclear copper leading to a prooxidant breakage of cellular DNA: implications for chemotherapeutic action against cancer. Cancer Chemother Pharmacol. 2011;**67**(1):103-110

[33] Hutchinson J, Burley VJ, Greenwood DC, Thomas JD, Cade JE. High-dose vitamin C supplement use is associated with self-reported histories of breast cancer and other illnesses in the UK Women's Cohort Study. Public Health Nutr. 2011;**14**(5):768-777

[34] Harris HR, Orsini N, Wolk A. Vitamin C and survival among women with breast cancer: a meta-analysis. Eur J Cancer. 2014;**50**(7):1223-1231

[35] Harris HR, Bergkvist L, Wolk A. Vitamin C intake and breast cancer mortality in a cohort of Swedish women. Br J Cancer. 2013;**109**(1):257-264

[36] McEligot A, Largent J, Ziogas A, Peel D, Anton-Culver H. Dietary fat, fiber, vegetable, and micronutrients are associated with overall survival in postmenopausal women diagnosed

with breast cancer. Nutr Cancer. 2006;**55**(2):132-140

[37] Fleischauer AT, Simonsen N, Arab L. Antioxidant supplements and risk of breast cancer recurrence and breast cancer-related mortality among postmenopausal women. Nutr Cancer. 2003;**46**(1):15-22

[38] Saquib J, Rock CL, Natarajan L, Saquib N, Newman VA, Patterson RE, Thomson CA, Al-Delaimy WK, Pierce JP. Dietary intake, supplement use, and survival among women diagnosed with early-stage breast cancer. Nutr Cancer. 2011;**63**(3):327-333

[39] Holmes MD, Stampfer MJ, Colditz GA, Rosner B, Hunter DJ, Willett WC. Dietary factors and the survival of women with breast carcinoma. Cancer. 1999;**86**(5):826-835

[40] Saxe GA, Rock CL, Wicha MS, Schottenfeld D. Diet and risk for breast cancer recurrence and survival. Breast Cancer Res Treat. 1999;**53**(3):241-253

[41] Greenlee H, Kwan ML, Kushi LH, Song J, Castillo A, Weltzien E, Quesenberry CP Jr, Caan BJ. Antioxidant supplement use after breast cancer diagnosis and mortality in the Life After Cancer Epidemiology (LACE) cohort. Cancer. 2012;**118**(8):2048-2058

[42] Nechuta S, Lu W, Chen Z, Zheng Y, Gu K, Cai H, Zheng W, Shu XO. Vitamin supplement use during breast cancer treatment and survival: a prospective cohort study. Cancer Epidemiol Biomarkers Prev. 2011;**20**(2):262-271

[43] Zirpoli GR, Brennan PM, Hong CC, McCann SE, Ciupak G, Davis W, Unger JM, Budd GT et al. Supplement use during an intergroup clinical trial for breast cancer (S0221). Breast Cancer Res Treat. 2013;**137**(3):903-913

[44] Lamson DW, Brignall MS. Antioxidants in cancer therapy; their

**43**

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

[52] Ronco AL, Stefani ED, Mendoza B, Vazquez A, Abbona E, Sanchez G, Rosa AD. Mate and tea intake, Dietary antioxidants and risk of breast cancer: a case-control study. Asian Pac J Cancer

Morrison H, Wen SW; Canadian Cancer Registries Epidemiology Research Group [CCRERG]. Antioxidants and breast cancer risk- a populationbased case-control study in Canada. BMC Cancer. 2011;**24**(11):372. doi:

Prev. 2016;**17**(6):2923-2933

10.1186/1471-2407-11-372

2008;**111**(2):269-278

[54] Dorjgochoo T, Shrubsole MJ, Shu XO, Lu W, Ruan Z, Zheng Y, Cai H, Dai Q, Gu K, Gao YT, Zheng W. Vitamin supplement use and risk for breast cancer: the Shanghai Breast Cancer Study. Breast Cancer Res Treat.

[55] Zhang C, Ho SC, Lin F, Cheng S, Fu J, Chen Y. Soy product and isoflavone intake and breast cancer risk defined by hormone receptor status. Cancer Science. 2010;**101**(2):501-507

[56] Bohlke K, Spiegelman D, Trichopoulou A,

[57] Cho E, Spiegelman D, Hunter DJ, Chen WY, Zhang SM, Colditz GA, Willett WC. Premenopausal intakes of vitamins A, C, and E, folate, and carotenoids, and risk of breast cancer. Cancer Epidemiol Biomarkers Prev.

[58] Rohan TE, Hiller JE, McMichael AJ. Dietary factors and survival from breast cancer. Nutr Cancer. 1993;**20**:167-177

[59] Shibata A, Paganini-Hill A, Ross RK, Henderson BE. Intake of vegetables, fruits, beta-carotene, vitamin C and vitamin supplements

Katsouyanni K, Trichopoulos D. Vitamins A, C and E and the risk of breast cancer: results from a casecontrol study in Greece. British Journal

of Cancer. 1999;**79**(1):23-29

2003;**12**(8):713-720

[53] Pan SY, Zhou J, Gibbons L,

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

actions and interactions with oncologic

therapies. Altern Med Rev.

[45] Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst.

1999;**4**(5):304-329

2008;**100**(11):773-783

[46] Fuchs-Tarlovsky V. Role of antioxidants in cancer therapy. Nutrition. 2013;**29**(1):15-21

[47] Salganik, RI. The benefits and hazards of antioxidants: controlling apoptosis and other protective

2001;**20**(5 Suppl.) 464S–467S.

[48] Ambrosone CB, Zirpoli GR, Hutson AD, McCann WE, McCann SE, Barlow WE, Kelly KM, Cannioto R, et al. Dietary supplement use during chemotherapy and survival outcomes of patients with breast cancer enrolled in a Cooperative Group Clinical Trial (SWOG S0221). J Clin Oncol.

[49] Singh K, Bhori M, Kasu YA, Bhat G, Marar, T. Antioxidants as precision weapons in war against cancer chemotherapy induced toxicity - Exploring the armoury of obscurity. Saudi Pharmaceutical Journal,

[50] Roa FJ, Peña E, Gatica M, Escobar-Acuña K, Saavedra P,

use of vitamin C in cancer:

Maldonado M, Cuevas ME, Moraga-Cid G, Rivas CI, Muñoz-Montesino C. Therapeutic

Physiological considerations. Front Pharmacol. 2020;**11**:211. doi: 10.3389/

[51] Kimmick GG, Bell RA, Bostick RM. Vitamin E and breast cancer: a review. Nutr Cancer. 1997;**27**(2):109-117.

2020;**38**(8):804-814

2018;**26**(2);177-190

fphar.2020.00211

mechanisms in cancer patients and the human population. J Am Coll Nutrition *Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

actions and interactions with oncologic therapies. Altern Med Rev. 1999;**4**(5):304-329

*Antioxidants - Benefits, Sources, Mechanisms of Action*

with breast cancer. Nutr Cancer.

[37] Fleischauer AT, Simonsen N, Arab L. Antioxidant supplements and risk of breast cancer recurrence and breast cancer-related mortality among postmenopausal women. Nutr Cancer.

[38] Saquib J, Rock CL, Natarajan L, Saquib N, Newman VA, Patterson RE, Thomson CA, Al-Delaimy WK, Pierce JP. Dietary intake, supplement use, and survival among women diagnosed with early-stage breast cancer. Nutr Cancer.

2006;**55**(2):132-140

2003;**46**(1):15-22

2011;**63**(3):327-333

[39] Holmes MD, Stampfer MJ, Colditz GA, Rosner B, Hunter DJ, Willett WC. Dietary factors and the survival of women with breast carcinoma. Cancer. 1999;**86**(5):826-835

[40] Saxe GA, Rock CL, Wicha MS, Schottenfeld D. Diet and risk for breast cancer recurrence and survival. Breast Cancer Res Treat. 1999;**53**(3):241-253

Weltzien E, Quesenberry CP Jr, Caan BJ. Antioxidant supplement use after breast cancer diagnosis and mortality in the Life After Cancer Epidemiology (LACE) cohort. Cancer. 2012;**118**(8):2048-2058

[42] Nechuta S, Lu W, Chen Z, Zheng Y, Gu K, Cai H, Zheng W, Shu XO. Vitamin supplement use during breast cancer treatment and survival: a prospective cohort study. Cancer Epidemiol Biomarkers Prev. 2011;**20**(2):262-271

[43] Zirpoli GR, Brennan PM, Hong CC, McCann SE, Ciupak G, Davis W, Unger JM, Budd GT et al. Supplement use during an intergroup clinical trial for breast cancer (S0221). Breast Cancer

Res Treat. 2013;**137**(3):903-913

[44] Lamson DW, Brignall MS. Antioxidants in cancer therapy; their

[41] Greenlee H, Kwan ML, Kushi LH, Song J, Castillo A,

intake of vegetables, fruits, and related

[31] Hunter DJ, Manson JE, Colditz GA, Stampfer MJ, Rosner B, Hennekens CH, Speizer FE, Willett WC. A prospective study of the intake of vitamins C, E, and A and the risk of breast cancer. N Engl J

nutrients. J Natl Cancer Inst.

[30] Hutchinson J, Lentjes MA, Greenwood DC, Burley VJ, Cade JE, Cleghorn CL, Threapleton DE, Key TJ, Cairns BJ, Keogh RH, et al. Vitamin C intake from diary recordings and risk of breast cancer in the UK Dietary Cohort Consortium. Eur J Clin Nutr.

1996;**88**(6):340-348

2012;**66**(5):561-568

Med. 1993;**329**(4):234-240

2011;**67**(1):103-110

2011;**14**(5):768-777

[32] Ullah M, Khan H, Zubair H, Shamim U, Hadi S. The antioxidant ascorbic acid mobilizes nuclear copper leading to a prooxidant breakage of cellular DNA: implications for chemotherapeutic action against cancer. Cancer Chemother Pharmacol.

[33] Hutchinson J, Burley VJ,

Greenwood DC, Thomas JD, Cade JE. High-dose vitamin C supplement use is associated with self-reported histories of breast cancer and other illnesses in the UK Women's Cohort Study. Public Health Nutr.

[34] Harris HR, Orsini N, Wolk A. Vitamin C and survival among women with breast cancer: a meta-analysis. Eur

J Cancer. 2014;**50**(7):1223-1231

[35] Harris HR, Bergkvist L, Wolk A. Vitamin C intake and breast cancer mortality in a cohort of Swedish women.

[36] McEligot A, Largent J, Ziogas A, Peel D, Anton-Culver H. Dietary fat, fiber, vegetable, and micronutrients are associated with overall survival in postmenopausal women diagnosed

Br J Cancer. 2013;**109**(1):257-264

**42**

[45] Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst. 2008;**100**(11):773-783

[46] Fuchs-Tarlovsky V. Role of antioxidants in cancer therapy. Nutrition. 2013;**29**(1):15-21

[47] Salganik, RI. The benefits and hazards of antioxidants: controlling apoptosis and other protective mechanisms in cancer patients and the human population. J Am Coll Nutrition 2001;**20**(5 Suppl.) 464S–467S.

[48] Ambrosone CB, Zirpoli GR, Hutson AD, McCann WE, McCann SE, Barlow WE, Kelly KM, Cannioto R, et al. Dietary supplement use during chemotherapy and survival outcomes of patients with breast cancer enrolled in a Cooperative Group Clinical Trial (SWOG S0221). J Clin Oncol. 2020;**38**(8):804-814

[49] Singh K, Bhori M, Kasu YA, Bhat G, Marar, T. Antioxidants as precision weapons in war against cancer chemotherapy induced toxicity - Exploring the armoury of obscurity. Saudi Pharmaceutical Journal, 2018;**26**(2);177-190

[50] Roa FJ, Peña E, Gatica M, Escobar-Acuña K, Saavedra P, Maldonado M, Cuevas ME, Moraga-Cid G, Rivas CI, Muñoz-Montesino C. Therapeutic use of vitamin C in cancer: Physiological considerations. Front Pharmacol. 2020;**11**:211. doi: 10.3389/ fphar.2020.00211

[51] Kimmick GG, Bell RA, Bostick RM. Vitamin E and breast cancer: a review. Nutr Cancer. 1997;**27**(2):109-117.

[52] Ronco AL, Stefani ED, Mendoza B, Vazquez A, Abbona E, Sanchez G, Rosa AD. Mate and tea intake, Dietary antioxidants and risk of breast cancer: a case-control study. Asian Pac J Cancer Prev. 2016;**17**(6):2923-2933

[53] Pan SY, Zhou J, Gibbons L, Morrison H, Wen SW; Canadian Cancer Registries Epidemiology Research Group [CCRERG]. Antioxidants and breast cancer risk- a populationbased case-control study in Canada. BMC Cancer. 2011;**24**(11):372. doi: 10.1186/1471-2407-11-372

[54] Dorjgochoo T, Shrubsole MJ, Shu XO, Lu W, Ruan Z, Zheng Y, Cai H, Dai Q, Gu K, Gao YT, Zheng W. Vitamin supplement use and risk for breast cancer: the Shanghai Breast Cancer Study. Breast Cancer Res Treat. 2008;**111**(2):269-278

[55] Zhang C, Ho SC, Lin F, Cheng S, Fu J, Chen Y. Soy product and isoflavone intake and breast cancer risk defined by hormone receptor status. Cancer Science. 2010;**101**(2):501-507

[56] Bohlke K, Spiegelman D, Trichopoulou A, Katsouyanni K, Trichopoulos D. Vitamins A, C and E and the risk of breast cancer: results from a casecontrol study in Greece. British Journal of Cancer. 1999;**79**(1):23-29

[57] Cho E, Spiegelman D, Hunter DJ, Chen WY, Zhang SM, Colditz GA, Willett WC. Premenopausal intakes of vitamins A, C, and E, folate, and carotenoids, and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2003;**12**(8):713-720

[58] Rohan TE, Hiller JE, McMichael AJ. Dietary factors and survival from breast cancer. Nutr Cancer. 1993;**20**:167-177

[59] Shibata A, Paganini-Hill A, Ross RK, Henderson BE. Intake of vegetables, fruits, beta-carotene, vitamin C and vitamin supplements and cancer incidence among the elderly: a prospective study. Br J Cancer. 1992;**66**:673-679

[60] Wang C, Baumgartner RN, Yang D, Slattery ML, Murtaugh MA, Byers T, Hines LM, Giuliano AR, Baumgartner KB. No evidence of association between breast cancer risk and dietary carotenoids, retinols, vitamin C and tocopherols in Southwestern Hispanic and non-Hispanic White women. Breast Cancer Res Treat. 2009;**114**(1):1371-45

[61] Misotti AM, Gnagnarella P. Vitamin supplement consumption and breast cancer risk: a review. Ecancer Medical Science. 2013;**7**:365. doi: 10.3332/ ecancer.2013.365

[62] Samuels N, Schiff E, Ben-Arye E. Non-herbal nutritional supplements for symptom relief in adjuvant breast cancer: creating a doctor-patient dialogue. BMJ Support Palliat Care. 2014;**4**(3):e1. doi: 10.1136/ bmjspcare-2013-000463

[63] Huang Z, Shi Y, Bao P, Cai H, Hong Z, Ding D, Jackson J, Shu XO, Dai Q. Associations of dietary intake and supplement use with post-therapy cognitive recovery in breast cancer survivors. Breast Cancer Res Treat. 2018;**171**(1):189-198

[64] Meulepas JM, Newcombe PA, Burnett-Hartman AN, Hampton JM, Trentham-Dietz A. Multivitamin supplement use and risk of invasive breast cancer. Public Health Nutr. 2010;**13**(10):1540-1545

[65] Gahche J, Bailey R, Burt V, Hughes J, Yetley E, Dwyer J, Picciano MF, McDowell M, Sempos C. Dietary supplement use among U.S. adults has increased since NHANES III (1988-1994) NCHS Data Brief. 2011;**61**:1-8

[66] Poole EM, Shu X, Caan BJ, Flatt SW, Holmes MD, Lu W, Kwan ML, Nechuta SJ, Pierce JP, Chen WY. Postdiagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project. Breast Cancer Res Treat. 2013;**139**(2):529-537

[67] Kanellopoulou A, Riza E, Samoli E, Benetou V. Dietary supplement use after cancer diagnosis in relation to total mortality, cancer mortality and recurrence: A systematic review and meta-analysis. Nutr Cancer. 2020;**9**:1-15

[68] Simone CB 2nd, Simone NL, Simone V, Simone CB. Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, part 1. Altern Ther Health Med. 2007;**13**(1):22-28

[69] Moss RW. Should patients undergoing chemotherapy and radiotherapy be prescribed antioxidants? Integr Cancer Ther. 2006;**5**(1):63-82

[70] Yasueda, A, Urushima, H, Ito, T. Efficacy and interaction of antioxidant supplements as adjuvant therapy in cancer treatment: A systematic review. Integrative Cancer Therapies. 2016;**15**(1):17-39

[71] Conklin KA. Dietary antioxidants during cancer chemotherapy: impact on chemotherapeutic effectiveness and development of side effects. Nutr Cancer. 2000;**37**(1):1-18

[72] Block K, Koch A, Mead M, Newman RA, Gyllenhaal C. Re: Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst. 2009;**101**(2):124-125

[73] Beijers A, Mols F, Dercksen W, Driessen C, Vreugdenhil G. Chemotherapy-induced peripheral neuropathy and impact on quality of life 6 months after treatment with

**45**

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

[80] Smith-Warner SA, Spiegelman D, Yaun SS, Adami HO, Beeson WL, van den Brandt PA, Folsom AR, Fraser GE, et al. Intake of fruits and vegetables and risk of breast cancer: a pooled analysis of cohort studies. JAMA.

2001;**285**(6):769-776

advances/nmaa147

2020; **80**(22):5134-5143.

ijerph17134731

293(2):183-193

1991;**2**:427-442

2007;**104**:221-230

[83] Buja A, Pierbon M, Lago L,

Grotto G, Baldo V. Breast cancer primary prevention and diet: An umbrella review. Int J Environ Res Public Health. 2020;17(13):4731. doi: 10.3390/

[84] van Gils CH, Peeters PH, Buenode-Mesquita HB, Boshuizen HC, Lahmann PH, Clavel-Chapelon F, Thiébaut A, Kesse E et al. Consumption

of vegetables and fruits and risk of breast cancer. JAMA. 2005

[85] Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. II. Mechanisms. Cancer Causes Control.

[86] Hirsch K, Atzmon A, Danilenko M, Levy J, Sharoni Y. Lycopene and other carotenoids inhibit estrogenic activity of 17beta-estradiol and genistein in cancer cells. Breast Cancer Res Treat.

[81] Kazemi A, Barati-Boldaji R, Soltani S, Mohammadipoor N, Esmaeilinezhad Z, Clark CCT,

studies. Advances in Nutrition (Bethesda, Md.). 2020. doi: 10.1093/

Babajafari S, Akbarzadeh M. Intake of various food groups and risk of breast cancer: A systematic review and doseresponse meta-analysis of prospective

[82] Farvid MS, Holmes MD, Chen WY, Rosner BA, Tamimi RM, Willett WC, Eliassen AH. Post-diagnostic fruit and vegetable consumption and breast cancer survival: Prospective analyses in the Nurses' Health Studies. Cancer Res.

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

chemotherapy. J Community Support

Oncol. 2014;**12**(11):401-406

[74] Zirpoli GR, McCann SE, Sucheston-Campbell LE, et al. Supplement use and chemotherapyinduced peripheral neuropathy in a cooperative group trial (S0221): The DELCaP study. J Natl Cancer Inst. 2017;**109**:djx098. doi: 10.1093/jnci/

[75] Jung AY, Cai X, Thoene K, Obi N, Jaskulski S, Behrens S, Flesch-Janys D, Chang-Claude J.

2019;**109**(1):69-78

Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy. Am J Clin Nutr.

[76] Greenlee, H., Kwan, M.L., Ergas, I.J. et al. Changes in vitamin and mineral supplement use after breast cancer diagnosis in the Pathways Study: a prospective cohort study. BMC Cancer 2014;**14**:382. doi. org/10.1186/1471-2407-14-382

[77] Kwan ML, Greenlee H, Lee VS, Castillo A, Gunderson EP, Habel LA, Kushi LH, Sweeney C, Tam EK, Caan BJ. Multivitamin use and breast cancer outcomes in women with early-stage breast cancer: the Life After Cancer Epidemiology study. Breast Cancer Res

Treat. 2011;**130**(1):195-205

2002;**76**(2):137-143

2016;**8**(9):3011-3014.

[78] Lesperance ML, Olivotto IA, Forde N, Zhao Y, Speers C, Foster H, Tsao M, MacPherson N, Hoffer A. Mega-dose vitamins and minerals in the treatment of non-metastatic breast cancer: an historical cohort study. Breast Cancer Res Treat.

[79] Kooshki A, Moghaddam M Y, Akbarzadeh R. Study of fruit and vegetable intake in breast cancer patients in the city of Sabzevar. Electronic Physician.

djx098

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

chemotherapy. J Community Support Oncol. 2014;**12**(11):401-406

*Antioxidants - Benefits, Sources, Mechanisms of Action*

Nechuta SJ, Pierce JP, Chen WY. Postdiagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project. Breast Cancer

[67] Kanellopoulou A, Riza E, Samoli E, Benetou V. Dietary supplement use after cancer diagnosis in relation to total mortality, cancer mortality and recurrence: A systematic review and meta-analysis. Nutr Cancer.

Res Treat. 2013;**139**(2):529-537

[68] Simone CB 2nd, Simone NL, Simone V, Simone CB. Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, part 1. Altern Ther Health Med.

[69] Moss RW. Should patients undergoing chemotherapy and radiotherapy be prescribed antioxidants? Integr Cancer Ther.

[70] Yasueda, A, Urushima, H, Ito, T. Efficacy and interaction of antioxidant supplements as adjuvant therapy in cancer treatment: A systematic review. Integrative Cancer Therapies.

[71] Conklin KA. Dietary antioxidants during cancer chemotherapy: impact on chemotherapeutic effectiveness and development of side effects. Nutr

2020;**9**:1-15

2007;**13**(1):22-28

2006;**5**(1):63-82

2016;**15**(1):17-39

Cancer. 2000;**37**(1):1-18

[72] Block K, Koch A, Mead M, Newman RA, Gyllenhaal C. Re: Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst. 2009;**101**(2):124-125

[73] Beijers A, Mols F, Dercksen W, Driessen C, Vreugdenhil G.

Chemotherapy-induced peripheral neuropathy and impact on quality of life 6 months after treatment with

and cancer incidence among the

[60] Wang C, Baumgartner RN, Yang D, Slattery ML, Murtaugh MA, Byers T, Hines LM, Giuliano AR, Baumgartner KB. No evidence of association between breast cancer risk and dietary carotenoids, retinols, vitamin C and tocopherols in Southwestern Hispanic and non-Hispanic White women. Breast Cancer

Res Treat. 2009;**114**(1):1371-45

[61] Misotti AM, Gnagnarella P. Vitamin supplement consumption and breast cancer risk: a review. Ecancer Medical Science. 2013;**7**:365. doi: 10.3332/

[62] Samuels N, Schiff E, Ben-Arye E. Non-herbal nutritional supplements for symptom relief in adjuvant breast cancer: creating a doctor-patient dialogue. BMJ Support Palliat Care. 2014;**4**(3):e1. doi: 10.1136/

1992;**66**:673-679

ecancer.2013.365

bmjspcare-2013-000463

2018;**171**(1):189-198

2010;**13**(10):1540-1545

[65] Gahche J, Bailey R, Burt V, Hughes J, Yetley E, Dwyer J,

[66] Poole EM, Shu X, Caan BJ,

Picciano MF, McDowell M, Sempos C. Dietary supplement use among U.S. adults has increased since NHANES III (1988-1994) NCHS Data Brief.

Flatt SW, Holmes MD, Lu W, Kwan ML,

[63] Huang Z, Shi Y, Bao P, Cai H, Hong Z, Ding D, Jackson J, Shu XO, Dai Q. Associations of dietary intake and supplement use with post-therapy cognitive recovery in breast cancer survivors. Breast Cancer Res Treat.

[64] Meulepas JM, Newcombe PA, Burnett-Hartman AN, Hampton JM, Trentham-Dietz A. Multivitamin supplement use and risk of invasive breast cancer. Public Health Nutr.

elderly: a prospective study. Br J Cancer.

**44**

2011;**61**:1-8

[74] Zirpoli GR, McCann SE, Sucheston-Campbell LE, et al. Supplement use and chemotherapyinduced peripheral neuropathy in a cooperative group trial (S0221): The DELCaP study. J Natl Cancer Inst. 2017;**109**:djx098. doi: 10.1093/jnci/ djx098

[75] Jung AY, Cai X, Thoene K, Obi N, Jaskulski S, Behrens S, Flesch-Janys D, Chang-Claude J. Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy. Am J Clin Nutr. 2019;**109**(1):69-78

[76] Greenlee, H., Kwan, M.L., Ergas, I.J. et al. Changes in vitamin and mineral supplement use after breast cancer diagnosis in the Pathways Study: a prospective cohort study. BMC Cancer 2014;**14**:382. doi. org/10.1186/1471-2407-14-382

[77] Kwan ML, Greenlee H, Lee VS, Castillo A, Gunderson EP, Habel LA, Kushi LH, Sweeney C, Tam EK, Caan BJ. Multivitamin use and breast cancer outcomes in women with early-stage breast cancer: the Life After Cancer Epidemiology study. Breast Cancer Res Treat. 2011;**130**(1):195-205

[78] Lesperance ML, Olivotto IA, Forde N, Zhao Y, Speers C, Foster H, Tsao M, MacPherson N, Hoffer A. Mega-dose vitamins and minerals in the treatment of non-metastatic breast cancer: an historical cohort study. Breast Cancer Res Treat. 2002;**76**(2):137-143

[79] Kooshki A, Moghaddam M Y, Akbarzadeh R. Study of fruit and vegetable intake in breast cancer patients in the city of Sabzevar. Electronic Physician. 2016;**8**(9):3011-3014.

[80] Smith-Warner SA, Spiegelman D, Yaun SS, Adami HO, Beeson WL, van den Brandt PA, Folsom AR, Fraser GE, et al. Intake of fruits and vegetables and risk of breast cancer: a pooled analysis of cohort studies. JAMA. 2001;**285**(6):769-776

[81] Kazemi A, Barati-Boldaji R, Soltani S, Mohammadipoor N, Esmaeilinezhad Z, Clark CCT, Babajafari S, Akbarzadeh M. Intake of various food groups and risk of breast cancer: A systematic review and doseresponse meta-analysis of prospective studies. Advances in Nutrition (Bethesda, Md.). 2020. doi: 10.1093/ advances/nmaa147

[82] Farvid MS, Holmes MD, Chen WY, Rosner BA, Tamimi RM, Willett WC, Eliassen AH. Post-diagnostic fruit and vegetable consumption and breast cancer survival: Prospective analyses in the Nurses' Health Studies. Cancer Res. 2020; **80**(22):5134-5143.

[83] Buja A, Pierbon M, Lago L, Grotto G, Baldo V. Breast cancer primary prevention and diet: An umbrella review. Int J Environ Res Public Health. 2020;17(13):4731. doi: 10.3390/ ijerph17134731

[84] van Gils CH, Peeters PH, Buenode-Mesquita HB, Boshuizen HC, Lahmann PH, Clavel-Chapelon F, Thiébaut A, Kesse E et al. Consumption of vegetables and fruits and risk of breast cancer. JAMA. 2005 293(2):183-193

[85] Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. II. Mechanisms. Cancer Causes Control. 1991;**2**:427-442

[86] Hirsch K, Atzmon A, Danilenko M, Levy J, Sharoni Y. Lycopene and other carotenoids inhibit estrogenic activity of 17beta-estradiol and genistein in cancer cells. Breast Cancer Res Treat. 2007;**104**:221-230

[87] Gaudet MM, Britton JA, Kabat GC, Steck-Scott S, Eng SM, Teitelbaum SL, Terry MB, Neugut AI, Gammon MD. Fruits, vegetables, and micronutrients in relation to breast cancer modified by menopause and hormone receptor status. Cancer Epidemiol Biomarkers Prev. 2004;**13**:1485-1494

[88] Terry P, Jain M, Miller AB, Howe GR, Rohan TE. Dietary carotenoids and risk of breast cancer. Am J Clin Nutr. 2002;**76**:883-888

[89] Nkondjock A, Ghadirian P. Intake of specific carotenoids and essential fatty acids and breast cancer risk in Montreal, Canada. Am J Clin Nutr. 2004;**79**(5):857-864

[90] Mignone L I, Giovannucci E, Newcomb P A, Titus-Ernstoff L, Trentham-Dietz A, Hampton J. M, Willett W C, Egan K M. Dietary carotenoids and the risk of invasive breast cancer. International Journal of Cancer. 2009;**124**(12):2929-2937

[91] Hu F, Wang Yi B, Zhang W, Liang J, Lin C, Li D, Wang F, Pang D, Zhao Y. Carotenoids and breast cancer risk: a meta-analysis and metaregression. Breast Cancer Res Treat. 2012;**131**(1):239-253

[92] Larsson SC, Bergkvist L, Wolk A. Dietary carotenoids and risk of hormone receptor-defined breast cancer in a prospective cohort of Swedish women. Eur J Cancer. 2010;**46**(6):1079-1085

[93] Huang JP, Zhang M, Holman CD, Xie X. Dietary carotenoids and risk of breast cancer in Chinese women. Asia Pac J Clin Nutr. 2007;16(Suppl 1):437-442

[94] Baena Ruiz R, Salinas Hernández P. Cancer chemoprevention by dietary phytochemicals: Epidemiological evidence. Maturitas. 2016;**94**:13-19.

[95] Rohan TE, Jain M, Howe GR, Miller AB. A cohort study of dietary carotenoids and lung cancer risk in women (Canada). Cancer Causes Control. 2002;**13**(3):231-237.

[96] Duthie S J, Duthie G G, Russell W R, Kyle J, Macdiarmid J I, Rungapamestry V, Stephen S, Megias-Baeza C, et al. Effect of increasing fruit and vegetable intake by dietary intervention on nutritional biomarkers and attitudes to dietary change: a randomized trial. European Journal of Nutrition. 2018;**57**(5):1855-1872

[97] Sato R, Helzlsouer KJ, Alberg AJ, Hoffman SC, Norkus EP, Comstock GW. Prospective study of carotenoids, tocopherols, and retinoid concentrations and the risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2002;**11**(5):451-457

[98] Bakker MF, Peeters PH, Klaasen VM, Bueno-de-Mesquita HB, Jansen EH, Ros MM, Travier N, Olsen A, Tjønneland A et al. Plasma carotenoids, vitamin C, tocopherols, and retinol and the risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition cohort. Am J Clin Nutr. 2016; **103**(2):454-464

[99] Epplein M, Shvetsov YB, Wilkens LR, Franke AA, Cooney RV, Le Marchand L, Henderson BE, Kolonel LN, Goodman MT. Plasma carotenoids, retinol, and tocopherols and postmenopausal breast cancer risk in the Multiethnic Cohort Study: a nested case-control study. Breast Cancer Res. 2009;**11**(4):R49. doi:10.1186/bcr2338

[100] Hu F, Wu Z, Li G, Teng C, Liu Y, Wang F, Zhao Y, Pang D. The plasma level of retinol, vitamins A, C and α-tocopherol could reduce breast cancer risk? A meta-analysis and metaregression. J Cancer Res Clin Oncol. 2015;**141**(4):601-614

**47**

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

[108] Batra P, Sharma AK. Anti-cancer potential of flavonoids: recent trends and future perspectives. Biotech.

[109] Sak K. Epidemiological evidences on dietary flavonoids and breast cancer risk: A narrative review. Asian Pacific Journal of Cancer Prevention.

[110] Feng XL, Ho SC, Mo XF, Lin FY, Zhang NQ, Luo H, Zhang X, Zhang CX.

Parpinel M, Gnagnarella P, Lagiou P, Negri E, Franceschi S, Montella M, Peterson J, Dwyer J, Giacosa A, La Vecchia C. Flavonoids and breast cancer risk in Italy. Cancer Epidemiol Biomarkers Prev. 2005, **14**(4):805-808

[112] Fink BN, Steck SE, Wolff MS, et al. Dietary flavonoid intake and breast cancer risk among women on Long Island. Am J Epidemiol.

[113] Feng XL, Zhan XX, Zuo LS, Mo XF, Zhang X, Liu KY, Li L,

concentration of flavonoids and breast cancer risk among Chinese women. Eur J Nutr. 2020. doi: 10.1007/

Zhang CX. Associations between serum

[114] Peterson J, Lagiou P, Samoli E, et al. Flavonoid intake and breast cancer risk: a case-control study in Greece. Br J

Lopez-Carrillo L. Dietary consumption of phytochemicals and breast cancer risk in Mexican women. Public Health

Association between flavonoids, flavonoid subclasses intake and breast cancer risk: a case-control study in China. Eur J Cancer Prev. 2020

[111] Bosetti C, Spertini L,

2013;**3**:439-459

**29**(6):493-500

2007;**165**:514-523

s00394-020-02331-z

Cancer. 2003;**89**:1255-1229

[115] Torres-Sanchez L, Galvan-Portillo M, Wolff MS,

Nutr. 2009;**12**:825-831

2017;**18**(9):2309-2328.

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

[101] Maillard V et al. Serum carotenoid, tocopherol and retinol concentrations and breast cancer risk in the E3N-EPIC study. Int J Cancer. 2009;**127**:1188-1196

Campbell LL, Caan BJ, Chlebowski RT, Neuhouser ML, Shikany JM, Rohan TE; WHI Investigators. Longitudinal study of serum carotenoid, retinol, and tocopherol concentrations in relation to breast cancer risk among postmenopausal women. Am J Clin

[103] Dorgan JF, Sowell A, Swanson CA, Potischman N, Miller R, Schussler N, Stephenson HE Jr. Relationships of serum carotenoids, retinol, alphatocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States). Cancer Causes Control.

[104] Riboli E, van Gils CH. Plasma carotenoids, vitamin C, tocopherols, and retinol and the risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition cohort. Am J Clin Nutr.

[105] Tamimi RM, Hankinson SE, Campos H, Spiegelman D,

Zhang S, Colditz GA, Willett WC, Hunter DJ. Plasma carotenoids, retinol, and tocopherols and risk of breast cancer. Am J Epidemiol.

[106] Hultén K, Van Kappel AL, Winkvist A, Kaaks R, Hallmans G, Lenner P, Riboli E. Carotenoids, alphatocopherols, and retinol in plasma and breast cancer risk in northern Sweden. Cancer Causes Control.

[107] Panche A N, Diwan A D,

doi.org/10.1017/jns.2016.41

Chandra SR. Flavonoids: an overview. Journal of Nutritional Science, 5, e47.

[102] Kabat GC, Kim M, Adams-

Nutr. 2009; **90**(1):162-169

1998;**9**(1):89-97

2016;**103**(2):454-464

2005;**161**(2):153-160

2001;**12**(6):529-537

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

[101] Maillard V et al. Serum carotenoid, tocopherol and retinol concentrations and breast cancer risk in the E3N-EPIC study. Int J Cancer. 2009;**127**:1188-1196

*Antioxidants - Benefits, Sources, Mechanisms of Action*

[95] Rohan TE, Jain M, Howe GR, Miller AB. A cohort study of dietary carotenoids and lung cancer risk in women (Canada). Cancer Causes Control. 2002;**13**(3):231-237.

Stephen S, Megias-Baeza C, et al. Effect of increasing fruit and vegetable intake by dietary intervention on nutritional biomarkers and attitudes to dietary change: a randomized trial. European Journal of Nutrition.

[97] Sato R, Helzlsouer KJ, Alberg AJ,

Comstock GW. Prospective study of carotenoids, tocopherols, and retinoid concentrations and the risk of breast cancer. Cancer Epidemiol Biomarkers

Klaasen VM, Bueno-de-Mesquita HB, Jansen EH, Ros MM, Travier N, Olsen A, Tjønneland A et al. Plasma carotenoids, vitamin C, tocopherols, and retinol and the risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition cohort. Am J Clin Nutr.

2018;**57**(5):1855-1872

Hoffman SC, Norkus EP,

Prev. 2002;**11**(5):451-457

2016; **103**(2):454-464

doi:10.1186/bcr2338

2015;**141**(4):601-614

[99] Epplein M, Shvetsov YB,

Wilkens LR, Franke AA, Cooney RV, Le Marchand L, Henderson BE, Kolonel LN, Goodman MT. Plasma carotenoids, retinol, and tocopherols and postmenopausal breast cancer risk in the Multiethnic Cohort Study: a nested case-control study. Breast Cancer Res. 2009;**11**(4):R49.

[100] Hu F, Wu Z, Li G, Teng C, Liu Y, Wang F, Zhao Y, Pang D. The plasma level of retinol, vitamins A, C and α-tocopherol could reduce breast cancer

risk? A meta-analysis and metaregression. J Cancer Res Clin Oncol.

[98] Bakker MF, Peeters PH,

[96] Duthie S J, Duthie G G, Russell W R, Kyle J, Macdiarmid J I, Rungapamestry V,

[87] Gaudet MM, Britton JA, Kabat GC, Steck-Scott S, Eng SM, Teitelbaum SL, Terry MB, Neugut AI, Gammon MD. Fruits, vegetables, and micronutrients in relation to breast cancer modified by menopause and hormone receptor status. Cancer Epidemiol Biomarkers

Prev. 2004;**13**:1485-1494

2004;**79**(5):857-864

[88] Terry P, Jain M, Miller AB, Howe GR, Rohan TE. Dietary

carotenoids and risk of breast cancer. Am J Clin Nutr. 2002;**76**:883-888

[89] Nkondjock A, Ghadirian P. Intake of specific carotenoids and essential fatty acids and breast cancer risk in Montreal, Canada. Am J Clin Nutr.

[90] Mignone L I, Giovannucci E, Newcomb P A, Titus-Ernstoff L, Trentham-Dietz A, Hampton J. M, Willett W C, Egan K M. Dietary carotenoids and the risk of invasive breast cancer. International Journal of Cancer. 2009;**124**(12):2929-2937

[91] Hu F, Wang Yi B, Zhang W, Liang J, Lin C, Li D, Wang F, Pang D, Zhao Y. Carotenoids and breast cancer

risk: a meta-analysis and metaregression. Breast Cancer Res Treat.

[92] Larsson SC, Bergkvist L,

Wolk A. Dietary carotenoids and risk of hormone receptor-defined breast cancer in a prospective cohort of Swedish women. Eur J Cancer.

[93] Huang JP, Zhang M, Holman CD, Xie X. Dietary carotenoids and risk of breast cancer in Chinese women. Asia Pac J Clin Nutr. 2007;16(Suppl

[94] Baena Ruiz R, Salinas Hernández P. Cancer chemoprevention by dietary phytochemicals: Epidemiological evidence. Maturitas. 2016;**94**:13-19.

2012;**131**(1):239-253

2010;**46**(6):1079-1085

**46**

1):437-442

[102] Kabat GC, Kim M, Adams-Campbell LL, Caan BJ, Chlebowski RT, Neuhouser ML, Shikany JM, Rohan TE; WHI Investigators. Longitudinal study of serum carotenoid, retinol, and tocopherol concentrations in relation to breast cancer risk among postmenopausal women. Am J Clin Nutr. 2009; **90**(1):162-169

[103] Dorgan JF, Sowell A, Swanson CA, Potischman N, Miller R, Schussler N, Stephenson HE Jr. Relationships of serum carotenoids, retinol, alphatocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States). Cancer Causes Control. 1998;**9**(1):89-97

[104] Riboli E, van Gils CH. Plasma carotenoids, vitamin C, tocopherols, and retinol and the risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition cohort. Am J Clin Nutr. 2016;**103**(2):454-464

[105] Tamimi RM, Hankinson SE, Campos H, Spiegelman D, Zhang S, Colditz GA, Willett WC, Hunter DJ. Plasma carotenoids, retinol, and tocopherols and risk of breast cancer. Am J Epidemiol. 2005;**161**(2):153-160

[106] Hultén K, Van Kappel AL, Winkvist A, Kaaks R, Hallmans G, Lenner P, Riboli E. Carotenoids, alphatocopherols, and retinol in plasma and breast cancer risk in northern Sweden. Cancer Causes Control. 2001;**12**(6):529-537

[107] Panche A N, Diwan A D, Chandra SR. Flavonoids: an overview. Journal of Nutritional Science, 5, e47. doi.org/10.1017/jns.2016.41

[108] Batra P, Sharma AK. Anti-cancer potential of flavonoids: recent trends and future perspectives. Biotech. 2013;**3**:439-459

[109] Sak K. Epidemiological evidences on dietary flavonoids and breast cancer risk: A narrative review. Asian Pacific Journal of Cancer Prevention. 2017;**18**(9):2309-2328.

[110] Feng XL, Ho SC, Mo XF, Lin FY, Zhang NQ, Luo H, Zhang X, Zhang CX. Association between flavonoids, flavonoid subclasses intake and breast cancer risk: a case-control study in China. Eur J Cancer Prev. 2020 **29**(6):493-500

[111] Bosetti C, Spertini L, Parpinel M, Gnagnarella P, Lagiou P, Negri E, Franceschi S, Montella M, Peterson J, Dwyer J, Giacosa A, La Vecchia C. Flavonoids and breast cancer risk in Italy. Cancer Epidemiol Biomarkers Prev. 2005, **14**(4):805-808

[112] Fink BN, Steck SE, Wolff MS, et al. Dietary flavonoid intake and breast cancer risk among women on Long Island. Am J Epidemiol. 2007;**165**:514-523

[113] Feng XL, Zhan XX, Zuo LS, Mo XF, Zhang X, Liu KY, Li L, Zhang CX. Associations between serum concentration of flavonoids and breast cancer risk among Chinese women. Eur J Nutr. 2020. doi: 10.1007/ s00394-020-02331-z

[114] Peterson J, Lagiou P, Samoli E, et al. Flavonoid intake and breast cancer risk: a case-control study in Greece. Br J Cancer. 2003;**89**:1255-1229

[115] Torres-Sanchez L, Galvan-Portillo M, Wolff MS, Lopez-Carrillo L. Dietary consumption of phytochemicals and breast cancer risk in Mexican women. Public Health Nutr. 2009;**12**:825-831

[116] Hui C, Qi X, Qianyong Z, Xiaoli P, Jundong Z, Mantian M. Flavonoids, flavonoid subclasses and breast cancer risk: a meta-analysis of epidemiologic studies. PLoS One. 2013;**8**(1):e54318. doi: 10.1371/journal.pone.0054318

[117] Adebamowo CA, Cho E, Sampson L, Katan MB, Spiegelman D, Willett WC, Holmes MD. Dietary flavonols and flavonol-rich foods intake and the risk of breast cancer. Int J Cancer. 2005;**114**:628-633

[118] Zamora-Ros R, Ferrari P, Gonzalez CA, et al. Dietary flavonoid and lignan intake and breast cancer risk according to menopause and hormone receptor status in the European prospective investigation into cancer and nutrition (EPIC) Study. Breast Cancer Res Treat. 2013;**139**:163-176

[119] Wang Y, Gapstur SM, Gaudet MM, et al. Evidence for an association of dietary flavonoid intake with breast cancer risk by estrogen receptor status is limited. J Nutr. 2014;**144**:1603-1611

[120] Knekt P, Kumpulainen J, Järvinen R, et al. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr. 2002;**76**:560-568

[121] Pantavos A, Ruiter R, Feskens EF, et al. Total dietary antioxidant capacity, individual antioxidant intake and breast cancer risk: the Rotterdam study. Int J Cancer. 2015;**136**:2178-2186

[122] Goldbohm RA, Hertog MG, Brants HA, van Poppel G, van den Brandt PA. Intake of flavonoids and cancer risk:a prospective cohort study. In: Armado R, Andersson H, Bardocz S, Serra F, editors. In 'Polyphenols in food'. Luxembourg: Office for Official Publications of the European Communities; 1998;159-166

[123] Křížová L, Dadáková K, Kašparovská J, Kašparovský T. Isoflavones. Molecules (Basel, Switzerland),

2019;**24**(6):1076. doi.org/10.3390/ molecules24061076

[124] Sacks FM, Lichtenstein A, Van Horn L, et al. Soy protein, isoflavones, and cardiovascular health - An American heart association science advisory for professionals from the nutrition committee. Circulation. 2006;**113**:10341044

[125] Xiao CW. Health effects of soy protein and isoflavones in humans. J Nutrition. 2008;138:1244S–1249S.

[126] Wu Y.C. Meta-analysis of studies on breast cancer risk and diet in Chinese women. Int J Clin Exp Med. 2015;**8**(1):73-85

[127] Nechuta S.J. Soy food intake after diagnosis of breast cancer and survival: an in-depth analysis of combined evidence from cohort studies of US and Chinese women. Am J Clin Nutr 2012;**96**(1):123-132

[128] Zhong X., Zhang C. Soy food intake and breast cancer risk: a meta-analysis. Wei Sheng Yan Jiu. 2012;**41**(4):670-676

[129] Zheng N, Hsieh E, Cai H, Shi L, Gu K, Zheng Y, Bao PP, Shu XO. Soy food consumption, exercise, and body mass index and osteoporotic fracture risk among breast cancer survivors: The Shanghai Breast Cancer Survival Study. JNCI Cancer Spectr. 2019;**3**(2):pkz017. doi: 10.1093/jncics/pkz017

[130] Sim EJ, Ko KP, Ahn C, Park SM, Surh YJ, An S, Kim SW, Lee MH, Lee JW, Lee JE, Kim KS, Yom CK, Kim HA, Park SK. Isoflavone intake on the risk of overall breast cancer and molecular subtypes in women at high risk for hereditary breast cancer. Breast Cancer Res Treat. 2020;**184**(2):615-626.

[131] Touillaud M, Gelot A, Mesrine S, Bennetau-Pelissero C, Clavel-Chapelon F, Arveux P, Bonnet F, Gunter M,

**49**

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

[138] Wei Y, Lv J, Guo Y,

[139] Hirose K, Imaeda N, Tokudome Y, Goto C, Wakai K, Matsuo K, Ito H, Toyama T,

Cancer. 2005;**93**(1):15-22

nu8120754

[140] Messina M. Soy and health update: Evaluation of the clinical and epidemiologic literature. Nutrients. 2016;**8**(12):754. doi.org/10.3390/

consumption and breast cancer survival and recurrence: a systematic review and meta-analysis. Eur J Nutr.

2019;**58**(8):3079-3090

Treat. 2009;**118**(2):395-405

[143] Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, Lu W. Soy food intake and breast cancer survival. JAMA. 2009;**302**(22):2437-2443

[144] Kang HB, Zhang YF, Yang JD, Lu KL. Study on soy isoflavone

[145] Woo HD, Park KS, Ro J, Kim J. Differential influence of dietary soy intake on the risk of breast cancer

2012;**13**(3):995-998

consumption and risk of breast cancer and survival. Asian Pac J Cancer Prev.

Bian Z, Gao M, Du H, Yang L, Chen Y, Zhang X, Wang T, Chen J, Chen Z, Yu C, Huo D, Li L; China Kadoorie Biobank Collaborative Group. Soy intake and breast cancer risk: a prospective study of 300,000 Chinese women and a dose-response meta-analysis. Eur J Epidemiol. 2020;**35**(6):567-578

Iwata H, Tokudome S, Tajima K. Soybean products and reduction of breast cancer risk: a case-control study in Japan. Br J

[141] Qiu S, Jiang C. Soy and isoflavones

[142] Guha N, Kwan ML, Quesenberry CP Jr, Weltzien EK, Castillo AL, Caan BJ. Soy isoflavones and risk of cancer recurrence in a cohort of breast cancer survivors: the Life After Cancer Epidemiology study. Breast Cancer Res

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

Boutron-Ruault MC, Fournier A. Use of dietary supplements containing soy isoflavones and breast cancer risk among women aged >50 y: a prospective study. Am J Clin Nutr.

[132] Fraser GE, Jaceldo-Siegl K, Orlich M, Mashchak A, Sirirat R, Knutsen S. Dairy, soy, and risk of breast cancer: those confounded milks. Int J Epidemiol. 2020. dyaa007. doi: 10.1093/

[133] Dong JY, Qin LQ. Soy isoflavones consumption and risk of breast cancer incidence or recurrence: a meta-analysis of prospective studies. Breast Cancer Res Treat. 2011;**125**(2):315-323.

[134] Xie Q, Chen ML, Qin Y, Zhang QY,

Xu HX, Zhou Y, et al. Isoflavone consumption and risk of breast cancer: a dose-response meta-analysis of observational studies. Asia Pac J Clin

Nutr. 2013;**22**(1):118-127.

pone.0089288

2019;**38**(1):136-145

[135] Chen M, Rao Y, Zheng Y, Wei S, Li Y, Guo T, et al. Association between soy isoflavone intake and breast cancer risk for pre- and postmenopausal women: a meta-analysis of epidemiological studies. PLoS ONE. 2014;**9**(2):e89288. doi: 10.1371/journal.

[136] Zhao TT, Jin F, Li JG, Xu YY, Dong HT, Liu Q, Xing P, Zhu GL, Xu H, Miao ZF. Dietary isoflavones or isoflavone-rich food intake and breast cancer risk: A meta-analysis of prospective cohort studies. Clin Nutr.

[137] Morimoto Y, Maskarinec G, Park SY, Ettienne R, Matsuno RK, Long C, Steffen AD, Henderson BE, Kolonel LN, Le Marchand L, Wilkens LR. Dietary isoflavone intake is not statistically significantly associated with breast cancer risk in the Multiethnic Cohort.

Br J Nutr. 2014;**112**(6):976-983

2019;**109**(3):597-605

ije/dyaa007

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

Boutron-Ruault MC, Fournier A. Use of dietary supplements containing soy isoflavones and breast cancer risk among women aged >50 y: a prospective study. Am J Clin Nutr. 2019;**109**(3):597-605

*Antioxidants - Benefits, Sources, Mechanisms of Action*

2019;**24**(6):1076. doi.org/10.3390/

[124] Sacks FM, Lichtenstein A, Van Horn L, et al. Soy protein, isoflavones,

[125] Xiao CW. Health effects of soy protein and isoflavones in humans. J Nutrition. 2008;138:1244S–1249S.

[126] Wu Y.C. Meta-analysis of studies on breast cancer risk and diet in Chinese women. Int J Clin Exp Med.

[127] Nechuta S.J. Soy food intake after diagnosis of breast cancer and survival: an in-depth analysis of combined evidence from cohort studies of US and Chinese women. Am J Clin Nutr

[128] Zhong X., Zhang C. Soy food intake and breast cancer risk: a meta-analysis. Wei Sheng Yan Jiu.

[129] Zheng N, Hsieh E, Cai H, Shi L, Gu K, Zheng Y, Bao PP, Shu XO. Soy food consumption, exercise, and body mass index and osteoporotic fracture risk among breast cancer survivors: The Shanghai Breast Cancer Survival Study. JNCI Cancer Spectr. 2019;**3**(2):pkz017.

[130] Sim EJ, Ko KP, Ahn C, Park SM, Surh YJ, An S, Kim SW, Lee MH, Lee JW, Lee JE, Kim KS, Yom CK, Kim HA, Park SK. Isoflavone intake on the risk of overall breast cancer and molecular subtypes in women at high risk for hereditary breast cancer. Breast Cancer Res Treat. 2020;**184**(2):615-626.

[131] Touillaud M, Gelot A, Mesrine S, Bennetau-Pelissero C, Clavel-Chapelon F,

Arveux P, Bonnet F, Gunter M,

and cardiovascular health - An American heart association science advisory for professionals from the nutrition committee. Circulation.

molecules24061076

2006;**113**:10341044

2015;**8**(1):73-85

2012;**96**(1):123-132

2012;**41**(4):670-676

doi: 10.1093/jncics/pkz017

[116] Hui C, Qi X, Qianyong Z, Xiaoli P, Jundong Z, Mantian M. Flavonoids, flavonoid subclasses and breast cancer risk: a meta-analysis of epidemiologic studies. PLoS One. 2013;**8**(1):e54318. doi: 10.1371/journal.pone.0054318

[117] Adebamowo CA, Cho E,

Cancer. 2005;**114**:628-633

[118] Zamora-Ros R, Ferrari P,

Sampson L, Katan MB, Spiegelman D, Willett WC, Holmes MD. Dietary flavonols and flavonol-rich foods intake and the risk of breast cancer. Int J

Gonzalez CA, et al. Dietary flavonoid and lignan intake and breast cancer risk according to menopause and hormone receptor status in the European prospective investigation into cancer and nutrition (EPIC) Study. Breast Cancer Res Treat. 2013;**139**:163-176

[119] Wang Y, Gapstur SM, Gaudet MM, et al. Evidence for an association of dietary flavonoid intake with breast cancer risk by estrogen receptor status is limited. J Nutr. 2014;**144**:1603-1611

Järvinen R, et al. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr.

[121] Pantavos A, Ruiter R, Feskens EF, et al. Total dietary antioxidant capacity, individual antioxidant intake and breast cancer risk: the Rotterdam study. Int J

[120] Knekt P, Kumpulainen J,

Cancer. 2015;**136**:2178-2186

[122] Goldbohm RA, Hertog MG, Brants HA, van Poppel G, van den Brandt PA. Intake of flavonoids and cancer risk:a prospective cohort study. In: Armado R, Andersson H, Bardocz S, Serra F, editors. In 'Polyphenols in food'.

Luxembourg: Office for Official Publications of the European Communities; 1998;159-166

[123] Křížová L, Dadáková K,

Molecules (Basel, Switzerland),

Kašparovská J, Kašparovský T. Isoflavones.

2002;**76**:560-568

**48**

[132] Fraser GE, Jaceldo-Siegl K, Orlich M, Mashchak A, Sirirat R, Knutsen S. Dairy, soy, and risk of breast cancer: those confounded milks. Int J Epidemiol. 2020. dyaa007. doi: 10.1093/ ije/dyaa007

[133] Dong JY, Qin LQ. Soy isoflavones consumption and risk of breast cancer incidence or recurrence: a meta-analysis of prospective studies. Breast Cancer Res Treat. 2011;**125**(2):315-323.

[134] Xie Q, Chen ML, Qin Y, Zhang QY, Xu HX, Zhou Y, et al. Isoflavone consumption and risk of breast cancer: a dose-response meta-analysis of observational studies. Asia Pac J Clin Nutr. 2013;**22**(1):118-127.

[135] Chen M, Rao Y, Zheng Y, Wei S, Li Y, Guo T, et al. Association between soy isoflavone intake and breast cancer risk for pre- and postmenopausal women: a meta-analysis of epidemiological studies. PLoS ONE. 2014;**9**(2):e89288. doi: 10.1371/journal. pone.0089288

[136] Zhao TT, Jin F, Li JG, Xu YY, Dong HT, Liu Q, Xing P, Zhu GL, Xu H, Miao ZF. Dietary isoflavones or isoflavone-rich food intake and breast cancer risk: A meta-analysis of prospective cohort studies. Clin Nutr. 2019;**38**(1):136-145

[137] Morimoto Y, Maskarinec G, Park SY, Ettienne R, Matsuno RK, Long C, Steffen AD, Henderson BE, Kolonel LN, Le Marchand L, Wilkens LR. Dietary isoflavone intake is not statistically significantly associated with breast cancer risk in the Multiethnic Cohort. Br J Nutr. 2014;**112**(6):976-983

[138] Wei Y, Lv J, Guo Y, Bian Z, Gao M, Du H, Yang L, Chen Y, Zhang X, Wang T, Chen J, Chen Z, Yu C, Huo D, Li L; China Kadoorie Biobank Collaborative Group. Soy intake and breast cancer risk: a prospective study of 300,000 Chinese women and a dose-response meta-analysis. Eur J Epidemiol. 2020;**35**(6):567-578

[139] Hirose K, Imaeda N, Tokudome Y, Goto C, Wakai K, Matsuo K, Ito H, Toyama T, Iwata H, Tokudome S, Tajima K. Soybean products and reduction of breast cancer risk: a case-control study in Japan. Br J Cancer. 2005;**93**(1):15-22

[140] Messina M. Soy and health update: Evaluation of the clinical and epidemiologic literature. Nutrients. 2016;**8**(12):754. doi.org/10.3390/ nu8120754

[141] Qiu S, Jiang C. Soy and isoflavones consumption and breast cancer survival and recurrence: a systematic review and meta-analysis. Eur J Nutr. 2019;**58**(8):3079-3090

[142] Guha N, Kwan ML, Quesenberry CP Jr, Weltzien EK, Castillo AL, Caan BJ. Soy isoflavones and risk of cancer recurrence in a cohort of breast cancer survivors: the Life After Cancer Epidemiology study. Breast Cancer Res Treat. 2009;**118**(2):395-405

[143] Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, Lu W. Soy food intake and breast cancer survival. JAMA. 2009;**302**(22):2437-2443

[144] Kang HB, Zhang YF, Yang JD, Lu KL. Study on soy isoflavone consumption and risk of breast cancer and survival. Asian Pac J Cancer Prev. 2012;**13**(3):995-998

[145] Woo HD, Park KS, Ro J, Kim J. Differential influence of dietary soy intake on the risk of breast cancer

recurrence related to HER2 status. Nutr Cancer. 2012;**64**(2):198-205

[146] Dong JY, Qin LQ. Soy isoflavones consumption and risk of breast cancer incidence or recurrence: a meta-analysis of prospective studies. Breast Cancer Res Treat. 2011;**125**(2):315-323

[147] Nachvak SM, Moradi S, Anjom-Shoae J, Rahmani J, Nasiri M, Maleki V, Sadeghi O. Soy, Soy isoflavones, and protein intake in relation to mortality from all causes, cancers, and cardiovascular diseases: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies. J Acad Nutr Diet. 2019;**119**(9):1483-1500

[148] Levi F, Pasche C, Lucchini F, La Vecchia C. Dietary intake of selected micronutrients and breast-cancer risk. Int J Cancer. 2001;**15**;91(2):260-263

[149] Freudenheim JL, Marshall JR, Vena JE, Laughlin R, Brasure JR, Swanson MK, Nemoto T, Graham S. Premenopausal breast cancer risk and intake of vegetables, fruits, and related nutrients. J Natl Cancer Inst. 1996;**88**(6):340-348

[150] Zhang S, Tang G, Russell RM, Mayzel KA, Stampfer MJ, Willett WC, Hunter DJ. Measurement of retinoids and carotenoids in breast adipose tissue and a comparison of concentrations in breast cancer cases and control subjects. Am J Clin Nutr. 1997;**66**(3):626-632

[151] Eliassen AH, Hendrickson SJ, Brinton LA, Buring JE, Campos H, Dai Q, Dorgan JF, Franke AA et al. Circulating carotenoids and risk of breast cancer: pooled analysis of eight prospective studies. J Natl Cancer Inst. 2012;**104**(24):1905-1916

[152] Tamimi RM, Colditz GA, Hankinson SE. Circulating carotenoids, mammographic density, and subsequent risk of breast cancer. Cancer Res. 2009;**69**(24):9323-9329

[153] Eliassen AH, Liao X, Rosner B, Tamimi RM, Tworoger SS, Hankinson SE. Plasma carotenoids and risk of breast cancer over 20 y of follow-up. Am J Clin Nutr. 2015;**101**(6):1197-1205

[154] Sesso HD, Buring JE, Zhang SM, Norkus EP, Gaziano JM. Dietary and plasma lycopene and the risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2005;**14**(5):1074-1081

[155] Bae JM, Kim EH. Breast density and risk of breast cancer in Asian Women: A Meta-analysis of observational studies. J Prev Med Public Health. 2016;**49**(6):367-375

[156] Ribaya-Mercado JD, Blumberg JB. Lutein and zeaxanthin and their potential roles in disease prevention. J Am Coll Nutr. 2004;**23**(6 Suppl):567S–587S

[157] Yan B, Lu MS, Wang L, Mo XF, Luo WP, Du YF, Zhang CX. Specific serum carotenoids are inversely associated with breast cancer risk among Chinese women: a case-control study. Br J Nutr. 2016;115(1):129-137.

[158] Toniolo P, Van Kappel AL, Akhmedkhanov A, et al. Serum carotenoids and breast cancer. Am J Epidemiol. 2001;**153**:1142-1147

[159] Rossi M, Bosetti C, Negri E, Lagiou P, La Vecchia C. Flavonoids, proanthocyanidins, and cancer risk: A network of case-control studies from Italy. Nutr Cancer. 2010;**62**(7):871-877

[160] Zhang M, Holman CD, Huang JP, Xie X. Green tea and the prevention of breast cancer: a case-control study in Southeast China. Carcinogenesis. 2007;**28**:1074-1078

[161] Wu AH, Yu MC, Tseng CC, Hankin J, Pike MC. Green tea and risk of

**51**

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast…*

population to based cohort of Japanese women. Breast Cancer Res. 2010;12:R88.

[170] Nagano J, Kono S, Preston DL, Mabuchi K. A prospective study of green tea consumption and cancer incidence, Hiroshima and Nagasaki (Japan) Cancer Causes Control.

[171] Suzuki Y, Tsubono Y, Nakaya N, Koizumi Y, Tsuji I. Green tea and the risk of breast cancer: pooled analysis of two prospective studies in Japan. Br J

[172] Musial, C., Kuban-Jankowska, A., & Gorska-Ponikowska, M. (2020). Beneficial Properties of Green Tea Catechins. International Journal of Molecular Sciences, 2020;**21**(5):1744. https://doi.org/10.3390/ijms21051744

Cancer. 2004;90:1361-1363

[173] Singh, BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochemical Pharmacology, 2001;**82(**12): 1807- 1821. https://doi.org/10.1016/j.

[174] Samavat H, Ursin G, Emory TH, Lee E, Wang R,

Torkelson CJ, Dostal AM, Swenson K, Le CT, Yang CS, Yu MC, Yee D, Wu AH, Yuan JM, Kurzer MS. A randomized controlled trial of green tea extract supplementation and mammographic density in postmenopausal women at increased risk of breast cancer. Cancer Prev Res (Phila). 2017;**10**(12):710-718

[175] Zhang G, Wang Y, Zhang Y, Wan X, Li J, Liu K, Wang F, Liu K, Liu Q, Yang C, Yu P, Huang Y, Wang S, Jiang P, Qu Z, Luan J, Duan H, Zhang L, Hou A, Jin S, Hsieh TC, Wu E. Anticancer activities of tea epigallocatechin-3-gallate in breast cancer patients under radiotherapy. Curr Mol Med.

2012;**12**(2):163-176

bcp.2011.07.093

doi: 10.1186/bcr2756

2001;**12**:501-508

*DOI: http://dx.doi.org/10.5772/intechopen.95886*

breast cancer in Asian Americans. Int J

Chen Z, Shu XO, et al. Drinking green tea modestly reduces breast cancer risk.

[163] Yuan JM, Koh WP, Sun CL, Lee HP, Yu MC. Green tea intake, ACE gene polymorphism and breast cancer risk among Chinese women in Singapore. Carcinogenesis. 2005;**26**:1389-1394

[164] Inoue M, Robien K, Wang R, Van Den Berg DJ, et al. Green tea intake, MTHFR/TYMS genotype and breast cancer risk: the Singapore Chinese Health Study. Carcinogenesis.

[165] Ogunleye AA, Xue F, Michels KB. Green tea consumption and breast cancer risk or recurrence: a metaanalysis. Breast Cancer Res Treat.

Cancer. 2003;**106**:574-579

[162] Shrubsole MJ, Lu W,

J Nutr. 2009;**139**:310-316

2008;**29**:1967-1972

2010;**119**(2):477-484

Nucci D, Abalsamo A, Acito M,

review and meta-analysis of observational studies. Nutrients.

2018;10(12):1886-1886

2001;**167**:175-182

Villarini M, Moretti M, Realdon S. Green tea consumption and risk of breast cancer and recurrence-A systematic

[167] Inoue M, Tajima K, Mizutani M, Iwata H, et al. Regular consumption of green tea and the risk of breast cancer recurrence: follow-up study from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan. Cancer Lett.

[168] Dai Q, Shu XO, Li H, Yang G, et al. Is green tea drinking associated with a later onset of breast cancer? Ann

[169] Iwasaki M, Inoue M, Sasazuki S, Sawada N, et al. Green tea drinking and subsequent risk of breast cancer in a

Epidemiol. 2010;**20**:74-81

[166] Gianfredi V,

*Micronutrient Antioxidants in the Chemoprevention of Breast Cancer and Effect on Breast… DOI: http://dx.doi.org/10.5772/intechopen.95886*

breast cancer in Asian Americans. Int J Cancer. 2003;**106**:574-579

*Antioxidants - Benefits, Sources, Mechanisms of Action*

risk of breast cancer. Cancer Res.

Rosner B, Tamimi RM, Tworoger SS, Hankinson SE. Plasma carotenoids and risk of breast cancer over 20 y of follow-up. Am J Clin Nutr.

[154] Sesso HD, Buring JE, Zhang SM, Norkus EP, Gaziano JM. Dietary and plasma lycopene and the risk of breast cancer. Cancer Epidemiol Biomarkers

[155] Bae JM, Kim EH. Breast density and risk of breast cancer in Asian Women: A Meta-analysis of observational studies. J Prev Med Public Health.

Blumberg JB. Lutein and zeaxanthin and their potential roles in disease prevention. J Am Coll Nutr. 2004;**23**(6

[157] Yan B, Lu MS, Wang L, Mo XF, Luo WP, Du YF, Zhang CX. Specific serum carotenoids are inversely associated with breast cancer risk among Chinese women: a case-control study. Br J Nutr. 2016;115(1):129-137.

[158] Toniolo P, Van Kappel AL, Akhmedkhanov A, et al. Serum carotenoids and breast cancer. Am J Epidemiol. 2001;**153**:1142-1147

[159] Rossi M, Bosetti C, Negri E, Lagiou P, La Vecchia C. Flavonoids, proanthocyanidins, and cancer risk: A network of case-control studies from Italy. Nutr Cancer. 2010;**62**(7):871-877

[160] Zhang M, Holman CD, Huang JP, Xie X. Green tea and the prevention of breast cancer: a case-control study in Southeast China. Carcinogenesis.

[161] Wu AH, Yu MC, Tseng CC,

Hankin J, Pike MC. Green tea and risk of

2007;**28**:1074-1078

2009;**69**(24):9323-9329

2015;**101**(6):1197-1205

Prev. 2005;**14**(5):1074-1081

2016;**49**(6):367-375

Suppl):567S–587S

[156] Ribaya-Mercado JD,

[153] Eliassen AH, Liao X,

recurrence related to HER2 status. Nutr

[146] Dong JY, Qin LQ. Soy isoflavones consumption and risk of breast cancer incidence or recurrence: a meta-analysis of prospective studies. Breast Cancer Res Treat. 2011;**125**(2):315-323

Cancer. 2012;**64**(2):198-205

[147] Nachvak SM, Moradi S, Anjom-Shoae J, Rahmani J,

2019;**119**(9):1483-1500

Nasiri M, Maleki V, Sadeghi O. Soy, Soy isoflavones, and protein intake in relation to mortality from all causes, cancers, and cardiovascular diseases: A Systematic Review and Dose-

Response Meta-Analysis of Prospective Cohort Studies. J Acad Nutr Diet.

[148] Levi F, Pasche C, Lucchini F, La Vecchia C. Dietary intake of selected micronutrients and breast-cancer risk. Int J Cancer. 2001;**15**;91(2):260-263

[149] Freudenheim JL, Marshall JR, Vena JE, Laughlin R, Brasure JR, Swanson MK, Nemoto T, Graham S. Premenopausal breast cancer risk and intake of vegetables, fruits, and related

[150] Zhang S, Tang G, Russell RM, Mayzel KA, Stampfer MJ, Willett WC, Hunter DJ. Measurement of retinoids and carotenoids in breast adipose tissue and a comparison of

concentrations in breast cancer cases and control subjects. Am J Clin Nutr.

[151] Eliassen AH, Hendrickson SJ, Brinton LA, Buring JE, Campos H, Dai Q, Dorgan JF, Franke AA et al. Circulating carotenoids and risk of breast cancer: pooled analysis of eight prospective studies. J Natl Cancer Inst.

nutrients. J Natl Cancer Inst.

1996;**88**(6):340-348

1997;**66**(3):626-632

2012;**104**(24):1905-1916

[152] Tamimi RM, Colditz GA,

Hankinson SE. Circulating carotenoids, mammographic density, and subsequent

**50**

[162] Shrubsole MJ, Lu W, Chen Z, Shu XO, et al. Drinking green tea modestly reduces breast cancer risk. J Nutr. 2009;**139**:310-316

[163] Yuan JM, Koh WP, Sun CL, Lee HP, Yu MC. Green tea intake, ACE gene polymorphism and breast cancer risk among Chinese women in Singapore. Carcinogenesis. 2005;**26**:1389-1394

[164] Inoue M, Robien K, Wang R, Van Den Berg DJ, et al. Green tea intake, MTHFR/TYMS genotype and breast cancer risk: the Singapore Chinese Health Study. Carcinogenesis. 2008;**29**:1967-1972

[165] Ogunleye AA, Xue F, Michels KB. Green tea consumption and breast cancer risk or recurrence: a metaanalysis. Breast Cancer Res Treat. 2010;**119**(2):477-484

[166] Gianfredi V,

Nucci D, Abalsamo A, Acito M, Villarini M, Moretti M, Realdon S. Green tea consumption and risk of breast cancer and recurrence-A systematic review and meta-analysis of observational studies. Nutrients. 2018;10(12):1886-1886

[167] Inoue M, Tajima K, Mizutani M, Iwata H, et al. Regular consumption of green tea and the risk of breast cancer recurrence: follow-up study from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan. Cancer Lett. 2001;**167**:175-182

[168] Dai Q, Shu XO, Li H, Yang G, et al. Is green tea drinking associated with a later onset of breast cancer? Ann Epidemiol. 2010;**20**:74-81

[169] Iwasaki M, Inoue M, Sasazuki S, Sawada N, et al. Green tea drinking and subsequent risk of breast cancer in a

population to based cohort of Japanese women. Breast Cancer Res. 2010;12:R88. doi: 10.1186/bcr2756

[170] Nagano J, Kono S, Preston DL, Mabuchi K. A prospective study of green tea consumption and cancer incidence, Hiroshima and Nagasaki (Japan) Cancer Causes Control. 2001;**12**:501-508

[171] Suzuki Y, Tsubono Y, Nakaya N, Koizumi Y, Tsuji I. Green tea and the risk of breast cancer: pooled analysis of two prospective studies in Japan. Br J Cancer. 2004;90:1361-1363

[172] Musial, C., Kuban-Jankowska, A., & Gorska-Ponikowska, M. (2020). Beneficial Properties of Green Tea Catechins. International Journal of Molecular Sciences, 2020;**21**(5):1744. https://doi.org/10.3390/ijms21051744

[173] Singh, BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochemical Pharmacology, 2001;**82(**12): 1807- 1821. https://doi.org/10.1016/j. bcp.2011.07.093

[174] Samavat H, Ursin G, Emory TH, Lee E, Wang R, Torkelson CJ, Dostal AM, Swenson K, Le CT, Yang CS, Yu MC, Yee D, Wu AH, Yuan JM, Kurzer MS. A randomized controlled trial of green tea extract supplementation and mammographic density in postmenopausal women at increased risk of breast cancer. Cancer Prev Res (Phila). 2017;**10**(12):710-718

[175] Zhang G, Wang Y, Zhang Y, Wan X, Li J, Liu K, Wang F, Liu K, Liu Q, Yang C, Yu P, Huang Y, Wang S, Jiang P, Qu Z, Luan J, Duan H, Zhang L, Hou A, Jin S, Hsieh TC, Wu E. Anticancer activities of tea epigallocatechin-3-gallate in breast cancer patients under radiotherapy. Curr Mol Med. 2012;**12**(2):163-176

**53**

(**Figure 1**).

**Chapter 3**

**Abstract**

Role of Antioxidants

of Male Infertility

infertility treatment outcomes with ART.

the initiation and propagation of ROS [4, 5].

phenomenon is termed as Oxidative stress [6–8].

**Keywords:** antioxidants, male infertility, semen quality, ART

**1. Introduction: The impact of oxidative stress on spermatozoa**

ROS include a broad category of species including: a) Oxygen free radicals, such as superoxide anion (O2), hydroxyl radical (OH) and hyperoxyl radical (HOO). b) Non radical species, such as hypochlorous acid (HOCl) and hydrogen peroxide (H2O2). c) Reactive nitrogen species and free nitrogen radicals such as nitroxylion, nitrous oxide, peroxynitrite, etc. [1–3]. These ROS are generated during normal aerobic metabolism and their level increases under stress which reflects a basic health danger. Mitochondrion is the primary cell organelle involved in ROS production. Besides, several endogenous cells and cellular components contribute towards

Overproduction of ROS or the deficiency of antioxidants provokes an imbalance between the per-oxidation and the anti-oxidation in the normal human body. This

Subsequently, it leads to alterationsin peroxidation of lipid membranes of sperm, disrupting the structure of membrane receptors, enzymes, transport proteins, and causes an increase in the level of DNA fragmentation of sperm [9]

ROS have a significant effect on the sperm plasma membrane and subsequent functional integrity of the sperm resulting in a loss of acrosome reaction [11],

Supplementation in the Treatment

Nutritional utilization of antioxidants, such as vitamins C, E, ß-Carotene and micronutrients, such as folate and zinc, have been shown to be critically essential for normal semen quality and reproductive function. However, it is still, a large knowledge gap exists concerning the role of antioxidants on semen parameters and the role in treatment of male subfertility. Therefore, the current review article designed to find out the positive effect of antioxidants on semen quality, alterations in physiological functions of spermatozoa and infertility treatment It is advisable that patients with oxidative DNA disruption should be asked to take a simple course of antioxidants prior to undertaking assisted reproduction treatment (ART). In conclusion, antioxidant may be employed as a potent antioxidant and may improve

*Houda Amor, Nyaz Shelko, Massooma Mohammed,* 

*Peter Michael Jankowski and Mohamad Eid Hammadeh*

## **Chapter 3**
