4. Adjuvant endocrine therapy

• experimental methods: ovarian suppression with gonadotropin-releasing hormone (GnRH)

Several polychemotherapy regimens are accepted as adjuvant chemotherapy regimen with strong evidence in patients with early stage breast cancer. The preferred regimens vary according to characteristics of disease, patients' comorbidities, patients' preferences, age, pre-

Early Breast Cancer Trialists' Collaborative Group (EBCTCG) reports a meta-analysis periodically to review the data on adjuvant treatment of breast cancer. The previous data supported the adjuvant chemotherapy particularly cyclophosphamide, methotrexate and fluorouracil

Trials with CMF-treated controls revealed that standard 4 AC and standard CMF were equivalent (P = 067), but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4 AC [e.g., CAF or cyclophosphamide & epirubicin & fluorouracil (CEF)] were superior to standard CMF (RR 0.78, P = 0.0004) [45]. However, NSABP B-36 randomized phase III trial compared six cycles of FEC-100 with four cycles of standard AC in pts. with T1- 3 N0 breast cancer [46]. Primary and secondary endpoint analyses at 8 years did not reveal any significant differences in DFS, OS, recurrence free interval (RFI), or distant RFI, although patients and tumor characteristics were equally distributed between the two groups (<50 years old: 40%, lumpectomy: 68%, and hormone positivity: 65%). Overall, Grade 3 and 4 expected toxicities were more frequent in the FEC arm. Thus, international guidelines excluded six

In trials adding four separate cycles of a taxane to a fixed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0.86, SE 0.04, two-

In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumor diameter or differentiation, ER status, or adjuvant tamoxifen. Hence, largely independently of age (up to at least 70 years) or the tumor characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regi-

Thus, based on these strong evidences, AC followed by a taxane (either triweekly docetaxel, paclitaxel or two weekly or weekly paclitaxel) is now usually preferred regimen in most cases

Nonanthracycline-based chemotherapy regimens should be preferred in certain patients with lower risk disease (node-negative), cardiac contraindication, advanced age, previous chest wall irradiation or patients who do not accept the risks of anthracycline-based therapy. In these patients, four cycles of docetaxel and cyclophosphamide (TC) are most preferred regimen.

(CMF), anthracyclines and taxane compared with no treatment in adjuvant setting.

cycles of FEC-100 from adjuvant breast cancer treatment recommendations.

mens (not requiring stem cells) reduced breast cancer mortality about one-third.

agonists (GnRHa) and ovarian tissue cryopreservation [44].

3.1. Chemotherapy regimen

134 Breast Cancer and Surgery

scribing doctor, institution, or country.

sided significance P = 0.0005) [45].

in whom adjuvant chemotherapy is indicated.

Estrogen receptor expression is the main indicator of potential responses to endocrine therapy (ET) which block estrogen-driven tumor growth through a variety of mechanisms. The use of hormonal therapy in breast cancer has improved the overall outcome for patients with earlystage hormone receptor-positive disease. The choice of hormone therapy is related to multiple factors, including menopausal state, patient preference, and potential side effects. Molecular profiling has allowed therapy to be tailored for an individual patient to some extent. However, further molecular studies are needed to individualize the choice and length of adjuvant hormone therapy.

Adjuvant ET currently consists of (i) ovarian suppression, (ii) selective estrogen receptor modulators (SERMs) and down-regulators, and (iii) AIs.

In patients with ER+ tumors, pharmacologic ovary suppression with gonadotropin-releasing hormone agonists in combination with standard adjuvant therapy is generally more effective than adjuvant chemotherapy alone.

• After or during 5 years of tamoxifen, extend the adjuvant ET with an AI up to 5 years

Adjuvant Systemic Treatment in Hormone Receptor Positive, HER2 Negative Breast Cancer

http://dx.doi.org/10.5772/intechopen.76578

137

The initial results from the Suppression of Ovarian Function Trial (SOFT) indicate that tamoxifen is a suitable therapy for premenopausal women with low risk clinical-pathologic features. For women at sufficient risk to receive chemotherapy who have premenopausal E2 levels within 8 months of completion, the addition of ovarian suppression to tamoxifen for 5 years resulted in some reduction of recurrence. The use of ovarian suppression combined with an AI

The joint analysis of SOFT and Tamoxifen and Exemestane Trial (TEXT) found the combination of ovarian suppression and exemestane significantly reduced recurrence, compared with ovarian suppression plus tamoxifen. Premenopausal women with ER+ve HER2-negative breast cancer with high-risk features can derive a meaningful improvement in 5-year invasive breast cancer-free interval with exemestane plus ovarian suppression, as an alternative to tamoxifen. Very young women under age 35 with ER+ve breast cancer have higher risks of recurrence,

Adjuvant endocrine therapy for 5 years is the standard adjuvant treatment for ER+ breast cancer while the benefits of extended adjuvant endocrine therapy (EAET) beyond 5 years are still controversial. In a recent meta-analysis, 5 years of adjuvant endocrine therapy only was compared with EAET [52]. Eleven controlled trials including 29,000 women were analyzed. There was no advantage of EAET in OS from all causes mortality (P = 0.67). On the other hand, compared with standard therapy, the pooled effects showed that EAET was associated with improvement in breast cancer-specific survival (OR = 0.87; P = 0.004), DFS (OR = 0.87; P = 0.002), disease recurrence (OR = 0.76; P = 0.001), and contralateral breast recurrence (OR = 0.74; P = 0.008). Improvement in DFS or disease recurrence was not shown in studies that compared 5 years of tamoxifen versus tamoxifen beyond 5 years. Subgroup analysis showed that EAET conferred more benefit for patients with positive lymph nodes. Rates of positive lymph nodes, the study size, and the median duration of follow-up were identified as variables that explained most of the demonstrated data heterogeneity. EAET should be considered as a preferred strategy for high-risk hormone-positive early breast cancer patients with

and the use of ovarian suppression with oral endocrine therapy should be considered.

positive lymph nodes; however, the benefit on OS could not be demonstrated.

Extended adjuvant endocrine therapy results in increased toxicity based on the type of extended endocrine agents. Risk of bone fractures is reported to be higher with AI, whereas the risk of endometrial cancer and venous thromboembolism are more frequently than with TAM. No difference was shown between AI (mono- or sequenced therapy) and TAM for

• After 5 years of tamoxifen, consider five additional years of tamoxifen

4.1. Combination of ovarian suppression either exemestane or tamoxifen in

exemestane for 5 years resulted in further reduction of recurrence [50, 51].

4.2. Extended adjuvant endocrine therapy beyond 5 years

(category 1)

premenopausal women

Tamoxifen is the best established SERM, has favorable effects on breast cancer control and bone metabolism, but also has adverse effects due to its estrogenic activity in other tissues. For these reasons, other SERMs have been developed.

Fulvestrant is an ER down-regulator with several potential advantages over SERMs, including a 100-fold increase in its affinity for ER compared with tamoxifen and no estrogen-like activity in the uterus.

The inhibition of the aromatase system with third-generation AIs is associated with improved survival in patients with advanced breast cancer compared with SERMs. In postmenopausal patients with ER+ breast cancer adjuvant treatment with AIs should be performed, either as sequential treatment after tamoxifen or as upfront therapy.

According to NCCN guidelines [49], subdivide the adjuvant endocrine therapy recommendations in HR+ breast cancer patients based on the menopausal status of women. Three main subgroups are (i) postmenopausal at initial diagnosis, (ii) premenopausal at initial diagnosis and remain premenopausal after 5 years of adjuvant ET, (iii) premenopausal at initial diagnosis, but become postmenopausal during adjuvant ET.

	- an AI as initial adjuvant therapy for 5 years (category 1),
	- initially tamoxifen for 2–3 years followed by an AI to complete 5 years of adjuvant ET (category 1),
	- initially tamoxifen for 2–3 years followed by 5 years of AI (category 2B),
	- tamoxifen for 4.5–6 years followed by 5 years of an AI (category 1) or consideration of tamoxifen for up to 10 years.
	- Five years up to 10 years of tamoxifen without AI should only be given to patients who have a contraindication to AI.
	- tamoxifen with or without ovarian suppression for 5 years (category 1)
	- an AI with ovarian suppression for 5 years (category 1)
	- tamoxifen continuing up to 10 years

Decision of menopausal status is the most important point because amenorrhea does not mean menopause, because ovaries may continue to product estrogens in amenorrheic women. Thus, before starting AI without ovarian suppression, serum LH, FSH and estradiol must be evaluated.

