2.4. EndoPredict

accurately identifies the major intrinsic biological subtypes of breast cancer commonly known as luminal A, luminal B, HER2 enriched, and basal-like [20] and predicts the risk of recurrence (ROR) at 10 years. Tumors that are named as luminal A in PAM50 intrinsic subtype indicate usually very good prognosis with only adjuvant endocrine therapy, whereas luminal B sub-

Four versions of ROR exist in the research setting: ROR based on subtype information (ROR-S), ROR-S with proliferation (ROR-P), ROR-S with tumor size (ROR-T), and ROR-P with tumor size (ROR-PT) [20]. The minimum ROR score of all Luminal B scores was assigned as the lowrisk threshold for each model and the maximum ROR score of all Luminal A scores as the high-risk threshold [20]. Large validation studies (ATAC and ABCSG8) for the PAM50 assay were performed using the standardized version with pre-specified cutoffs based on actual survival outcomes (<10, 10–20, and > 20% risk of distant relapse at 10 years) and not subtype

The Prosigna Breast Cancer Prognostic Gene Signature Assay is an in vitro diagnostic assay, which is performed on the NanoString nCounter® Dx Analysis System using FFPE breast tumor tissue previously diagnosed as invasive breast carcinoma. The Prosigna Score is a numerical value on a 0–100 scale that correlates with the probability of distant recurrence within 10 years. The gene expression profile of a patient's tumor is compared with each of the four PAM50 prototypical molecular profiles to determine the degree of similarity. The results in combination with a proliferation score and tumor size produce an individualized Prosigna Score. This qualitative assay utilizes gene expression data, weighted together with clinical variables to generate a risk category and numerical score, to assess a patient's risk of distant

In node-negative patients, the 10-year distant recurrence-free survival (DRFS) rates were > 95% for the low-risk group, 90.4% for the intermediate-risk group, and < 85% for the high-risk group [22, 23]. In node-positive patients, the 10-year DRFS rates were 94.2% for the low-risk

The Prosigna Breast Cancer Prognostic Gene Signature Assay is indicated in female breast cancer patients who have undergone surgery in conjunction with locoregional treatment

i. A prognostic indicator for distant recurrence-free survival at 10 years in postmenopausal women with HR+, lymph node-negative, stage I or II breast cancer to be treated with adjuvant endocrine therapy alone, when used in conjunction with other clinicopatholog-

ii. A prognostic indicator for distant recurrence-free survival at 10 years in postmenopausal women with HR+, lymph node-positive (1–3 positive nodes), stage II breast cancer to be treated with adjuvant endocrine therapy alone, when used in conjunction with other

The assay should not be used for patients with four or more positive nodes.

types have increased risk of recurrence without adjuvant chemotherapy.

distribution [21].

128 Breast Cancer and Surgery

recurrence of disease.

ical factors.

group and 75.8% for the high-risk group [22].

consistent with standard of care, either as:

clinicopathological factors.

The EndoPredict (EP) assay combines the expression of three proliferative and five ERsignaling/differentiation-associated genes and is normalized by three housekeeping genes [24]. EP may be measured in formalin-fixed, paraffin-embedded tissue sections by quantitative real-time polymerase chain reaction in decentralized laboratories and provides a score that ranges between 0 and 15 after scaling [25].

EPclin was derived from EP by incorporating nodal status and tumor size to create an integrated diagnostic algorithm for clinical decisions [24]. Both EP and EPclin were trained on a cohort of 964 patients with ER+, HER2-negative carcinomas treated with adjuvant endocrine therapy only. Thresholds for EP and EPclin to differentiate between patients at low or high risk corresponding to a 10% probability of distant recurrence at 10 years were set at 5 and 3.3, respectively. Patients with an EP score < 5 (EPclin score < 3.3) were classified as low risk for distance recurrence, whereas patients with an EP score ≥5 (EPclin score ≥3.3) were stratified as high risk. Both EP and EPclin were shown to be prognostic for early and late distant recurrence in the ABCSG-6 and ABCSG-8 trials involving patients with ER+/HER2-negative breast cancer treated with adjuvant endocrine therapy only [26]. EndoPredict provides prognostic information beyond all common clinicopathological parameters and clinical guidelines.

There are several prognostic multigene-based tests for managing breast cancer, but limited data comparing them in the same cohort. The prognostic performance of the EP test was compared with the research-based PAM50 non-standardized qRT-PCR assay in node-positive ER+ and HER2-negative breast cancer patients receiving adjuvant chemotherapy followed by endocrine therapy (ET) in the GEICAM/9906 trial [27]. EP and PAM50 ROR scores [based on subtype (ROR-S) and on subtype and proliferation (ROR-P)] were compared in 536 ER+/ HER2patients. Scores combined with clinical information were evaluated: ROR-T (ROR-S, tumor size), ROR-PT (ROR-P, tumor size), and EPclin (EP, tumor size, nodal status). Patients were assigned to risk categories according to prespecified cutoffs. ROR-S, ROR-P, and EP scores identified a low-risk group with a relative better outcome (10-year distant metastasisfree survival: ROR-S 87%; ROR-P 89%; EP 93%). No significant difference between tests was found. Predictors including clinical information showed superior prognostic performance compared to molecular scores alone (10-year MFS, low-risk group: ROR-T 88%; ROR-PT 92%; EPclin 100%). The EPclin-based risk stratification achieved a significantly improved prediction of MFS compared to ROR-T, but not ROR-PT. All signatures added prognostic information to common clinical parameters.

EPclin provided independent prognostic information beyond ROR-T and ROR-PT. ROR and EP can reliably predict risk of distant metastasis in node-positive ER+/HER2 negative breast cancer patients treated with chemotherapy and ET. Addition of clinical parameters into risk scores improves their prognostic ability.

Recently, in a secondary analysis of a randomized clinical trial, the prognostic value of six multigene signatures was compared in women with early ER+ breast cancer [28]. In this study, 774 postmenopausal women with ER+, HER2-negative disease, 591 had node-negative disease and patients received endocrine therapy for 5 years (the Anastrozole or Tamoxifen Alone or Combined randomized clinical trial comparing 5-year treatment with anastrozole vs. tamoxifen) in addition to the Clinical Treatment Score (nodal status, tumor size, grade, age, and endocrine treatment) for distant recurrence for 0–10 years and 5–10 years after diagnosis [28]. The signatures included the Oncotype Dx recurrence score, ROR, Breast Cancer Index (BCI), EPclin, Clinical Treatment Score, and 4-marker immunohistochemical score. The ROR (HR, 2.56), followed by the BCI (HR, 2.46) and EPclin (HR, 2.14) were shown to be the signatures which have the most prognostic information. Each provided significantly more information than the Clinical Treatment Score (HR, 1.99), the recurrence score (HR, 1.69), and the 4-marker immunohistochemical score (HR, 1.95). Substantially less information was provided by all six molecular tests for the 183 patients with 1–3 positive nodes, but the BCI and EPclin provided more additional prognostic information than the other signatures. For women with nodenegative disease, the ROR, BCI, and EPclin were shown to be significantly more prognostic for overall and late distant recurrence. For women with 1–3 positive nodes, limited independent information was available from any test.

of the US population. There have been concerns regarding the quality of the data about cause of death [31]. Additionally, the SEER database specifically includes patients between 35 and

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Adjuvant! Online tends to overestimate the number of patients at high risk. Cardoso et al. reported that Adjuvant! Online classified 23% of patients as high clinical risk when Oncotype

Olivotto et al. performed a population-based validation study and suggested that Adjuvant! Online would overestimate survival in patients under 35 years of age with lymphovascular invasion. It was also found that Adjuvant! Online tends to overestimate the survival rates of younger women with ER+ breast cancer [16] and that it overestimated the added value of

The validity of the predictive score is calculated by Adjuvant! Online was deemed weak in the clinician-based validation [33]. Predictions on loco-regional relapse and distant metastases may vary greatly, making it difficult to make clear recommendations for adjuvant treatment [34]. This is reflected in two studies that suggest that when patients are involved in a discussion to decide on adjuvant chemotherapy, they are less likely to choose chemotherapy if using

The database does not include information regarding the benefits of adjuvant trastuzumab, thereby reducing the utility of Adjuvant! Online in clinical decisions about HER2-positive disease treatment [31]. This deficiency of Adjuvant! Online with regard to HER2-positive disease has significant implications for the prediction of metastatic spread. In a recent in vitro study using murine models, the HER2 status of cells predicted the response to progesteroneinduced signaling, with HER2-deficient cells being more likely to migrate and HER2-enriched cells tending toward increased proliferation [36]. This recent evidence underlines the importance of HER2 in predicting prognosis and highlights the significance of this inherent short-

The ethnic variation in the data on which these online tools are based seriously affects the generalizability of these online tools. The SEER database is representative of the usual US population in terms of age, sex and ethnic distribution. However, the ethnic mix of the US

Predict is an another online prognostication and treatment benefit tool based on UK cancer registry data and included information on 5694 women treated in East Anglia from 1999 to 2003 [38]. It is designed to help clinicians and patients make informed decisions about treatment following breast cancer surgery. The model was validated in a second UK cancer registry dataset. It would able to provide not only the accurate prediction of survival but also subse-

Data of an individual patient including patient age, tumor size, tumor grade, number of positive nodes, ER status, HER2 status, KI67 status and mode of detection are submitted to online PREDICT tool. It originally did not include HER2 status and KI67 status, but in 2011,

69 years and provides limited information on the socio-economic status of people.

DX classified them as low genomic risk [15].

coming in online cancer registry-based prognostic tools.

population is different from that of England and Wales [37].

quent calculation of treatment benefit.

chemotherapy for older patients [32].

Adjuvant! Online [35].

2.6.2. Predict

#### 2.5. Breast cancer index

The breast cancer index assay previously has been developed and validated. It consists of two independently developed gene expression biomarkers: molecular grade index (MGI) and HOXB13/IL17BR (H/I) [20, 26]. MGI, a 5-gene predictor that recapitulates tumor grade/proliferation, is highly prognostic in ER+ breast cancer patients. H/I, which was developed independent of tumor grade/proliferation, is prognostic for early and late distant recurrences and is predictive of extended adjuvant AI benefit in early stage of ER+ breast cancer patients.

#### 2.6. Online prognostification and prediction tools

The online tools referred to earlier primarily use clinicopathological variables and cancer registry data as the basis of risk prediction. The clinical pathological variables used include age, tumor size and grade, mode of detection, number of lymph nodes involved, ER status, HER2 status, Ki67 status and type of chemotherapy [29].

#### 2.6.1. Adjuvant online

Adjuvant!Online is a free online tool and probably the most widely used tool that estimate risks and benefits of adjuvant endocrine therapy and chemotherapy after breast cancer surgery based on factors, such as the patient's stage, pathologic features, age and comorbidity level. Entering information on age and selected tumor characteristics (tumor size and grade, number of positive axillary nodes, and hormone receptors status) allows for prediction of the 10-year risk of relapse-free and overall survival.

Despite these strengths, Adjuvant! has several limitations. The relapse estimates include localregional recurrence as well as distant metastases; this is important as the proportions of both may vary greatly depending on stage and tumor phenotype. The baseline risk estimation for Adjuvant! Online was derived from the SEER (surveillance, epidemiology and end results) database [30]. The SEER database program is a collation of nine databases covering one-sixth of the US population. There have been concerns regarding the quality of the data about cause of death [31]. Additionally, the SEER database specifically includes patients between 35 and 69 years and provides limited information on the socio-economic status of people.

Adjuvant! Online tends to overestimate the number of patients at high risk. Cardoso et al. reported that Adjuvant! Online classified 23% of patients as high clinical risk when Oncotype DX classified them as low genomic risk [15].

Olivotto et al. performed a population-based validation study and suggested that Adjuvant! Online would overestimate survival in patients under 35 years of age with lymphovascular invasion. It was also found that Adjuvant! Online tends to overestimate the survival rates of younger women with ER+ breast cancer [16] and that it overestimated the added value of chemotherapy for older patients [32].

The validity of the predictive score is calculated by Adjuvant! Online was deemed weak in the clinician-based validation [33]. Predictions on loco-regional relapse and distant metastases may vary greatly, making it difficult to make clear recommendations for adjuvant treatment [34]. This is reflected in two studies that suggest that when patients are involved in a discussion to decide on adjuvant chemotherapy, they are less likely to choose chemotherapy if using Adjuvant! Online [35].

The database does not include information regarding the benefits of adjuvant trastuzumab, thereby reducing the utility of Adjuvant! Online in clinical decisions about HER2-positive disease treatment [31]. This deficiency of Adjuvant! Online with regard to HER2-positive disease has significant implications for the prediction of metastatic spread. In a recent in vitro study using murine models, the HER2 status of cells predicted the response to progesteroneinduced signaling, with HER2-deficient cells being more likely to migrate and HER2-enriched cells tending toward increased proliferation [36]. This recent evidence underlines the importance of HER2 in predicting prognosis and highlights the significance of this inherent shortcoming in online cancer registry-based prognostic tools.

The ethnic variation in the data on which these online tools are based seriously affects the generalizability of these online tools. The SEER database is representative of the usual US population in terms of age, sex and ethnic distribution. However, the ethnic mix of the US population is different from that of England and Wales [37].

## 2.6.2. Predict

and patients received endocrine therapy for 5 years (the Anastrozole or Tamoxifen Alone or Combined randomized clinical trial comparing 5-year treatment with anastrozole vs. tamoxifen) in addition to the Clinical Treatment Score (nodal status, tumor size, grade, age, and endocrine treatment) for distant recurrence for 0–10 years and 5–10 years after diagnosis [28]. The signatures included the Oncotype Dx recurrence score, ROR, Breast Cancer Index (BCI), EPclin, Clinical Treatment Score, and 4-marker immunohistochemical score. The ROR (HR, 2.56), followed by the BCI (HR, 2.46) and EPclin (HR, 2.14) were shown to be the signatures which have the most prognostic information. Each provided significantly more information than the Clinical Treatment Score (HR, 1.99), the recurrence score (HR, 1.69), and the 4-marker immunohistochemical score (HR, 1.95). Substantially less information was provided by all six molecular tests for the 183 patients with 1–3 positive nodes, but the BCI and EPclin provided more additional prognostic information than the other signatures. For women with nodenegative disease, the ROR, BCI, and EPclin were shown to be significantly more prognostic for overall and late distant recurrence. For women with 1–3 positive nodes, limited indepen-

The breast cancer index assay previously has been developed and validated. It consists of two independently developed gene expression biomarkers: molecular grade index (MGI) and HOXB13/IL17BR (H/I) [20, 26]. MGI, a 5-gene predictor that recapitulates tumor grade/proliferation, is highly prognostic in ER+ breast cancer patients. H/I, which was developed independent of tumor grade/proliferation, is prognostic for early and late distant recurrences and is

The online tools referred to earlier primarily use clinicopathological variables and cancer registry data as the basis of risk prediction. The clinical pathological variables used include age, tumor size and grade, mode of detection, number of lymph nodes involved, ER status,

Adjuvant!Online is a free online tool and probably the most widely used tool that estimate risks and benefits of adjuvant endocrine therapy and chemotherapy after breast cancer surgery based on factors, such as the patient's stage, pathologic features, age and comorbidity level. Entering information on age and selected tumor characteristics (tumor size and grade, number of positive axillary nodes, and hormone receptors status) allows for prediction of the 10-year

Despite these strengths, Adjuvant! has several limitations. The relapse estimates include localregional recurrence as well as distant metastases; this is important as the proportions of both may vary greatly depending on stage and tumor phenotype. The baseline risk estimation for Adjuvant! Online was derived from the SEER (surveillance, epidemiology and end results) database [30]. The SEER database program is a collation of nine databases covering one-sixth

predictive of extended adjuvant AI benefit in early stage of ER+ breast cancer patients.

dent information was available from any test.

2.6. Online prognostification and prediction tools

HER2 status, Ki67 status and type of chemotherapy [29].

2.5. Breast cancer index

130 Breast Cancer and Surgery

2.6.1. Adjuvant online

risk of relapse-free and overall survival.

Predict is an another online prognostication and treatment benefit tool based on UK cancer registry data and included information on 5694 women treated in East Anglia from 1999 to 2003 [38]. It is designed to help clinicians and patients make informed decisions about treatment following breast cancer surgery. The model was validated in a second UK cancer registry dataset. It would able to provide not only the accurate prediction of survival but also subsequent calculation of treatment benefit.

Data of an individual patient including patient age, tumor size, tumor grade, number of positive nodes, ER status, HER2 status, KI67 status and mode of detection are submitted to online PREDICT tool. It originally did not include HER2 status and KI67 status, but in 2011, HER2 status was included (PREDICT version 1.1) and later KI67 was added to model (PRE-DICT version 1.2) to improve the estimates of breast cancer-specific mortality, especially in HER2-positive patients [29, 39].

Newer technologies including next-generation sequencing, liquid biopsy, tumor-infiltrating

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Several pathological factors including histological subtype, ER or PR expression, tumor grade, lymphovascular invasion, tumor stage, and clinical factors such as patient age, preferences and comorbidities should be taken into consideration during adjuvant chemotherapy indication is being decided. The genomic tests and benefit–risk calculators which were developed to be used in determining appropriate candidates for adjuvant chemotherapy in early stage HR+

Patients with HR+ breast cancer less than 5 mm and treated with only endocrine therapy have usually very good prognosis. Thus, they typically are not treated with adjuvant chemotherapy. However, patients with stage III HR+ breast cancer still require adjuvant chemotherapy since they carry high risk of recurrence without chemotherapy. Many patients with HR+ HER2 negative breast cancer fall in between these two categories, and they are called as intermediate risk group based on clinicopathological variables, genomic tests or online risk calculators.

Clinicians should inform the patients who required adjuvant chemotherapy about the risks and benefits of chemotherapy. Risks include acute or long-term toxicities such as emesis,

Breast cancer is the most frequent malignancy in women of reproductive age. Treatments for breast cancer may eliminate or diminish fertility. Additionally, even in patients who do not require chemotherapy, long duration of adjuvant endocrine therapy often leads natural decline

The chemotherapy-related risk of premature ovarian insufficiency is influenced by age, body mass index, the type and duration of therapy. After six cycles of CMF, the risk of amenorrhea is 33 and 81% in patients <40 and ≥ 40 years of age, respectively. Newer chemotherapy regimens including adriamycin & cyclophosphamide (AC), adriamycin & cyclophosphamide & taxane (ACT), fluorouracil & adriamycin & cyclophosphamide (FAC) and fluorouracil & adriamycin & cyclophosphamide & taxane (FACT) result in lower rates of persisting amenorrhea. The risk of amenorrhea is 10–20 and 13–68% in patients <30 years and in patients >30 years, respectively [43]. Hence, the rate of infertility risk with particular chemotherapy regimen at particular age should be discussed with patients prior to initiation of gonadotoxic therapies. Furthermore, premenopausal women who are willing to be pregnant in the future should be referred to a

alopecia, myelosuppression, neuropathy, cardiotoxicity, infertility and leukemias.

fertility specialist to be informed about various techniques of fertility preservation.

chapter, fertility preservation methods can be summarized as • established methods: oocyte or embryo cryopreservation

Although methods of fertility preservation in breast cancer should be a subject of a separate

lymphocytes or PD-1 determination are at this investigational point.

breast cancer have been discussed in previous section.

in ovarian reserve during adjuvant treatment.

3. Adjuvant chemotherapy

While the overall fit of the model has been good in multiple independent case series, PREDICT has been shown to underestimate breast cancer specific mortality in women diagnosed under the age of 40, particularly those with ER+ disease. Another limitation of the model is the use of discrete categories for tumor size and node status which result in "step" changes in risk estimates on moving from one category to the next. For example, a woman with an 18 or 19 mm tumor will be predicted to have the same breast cancer specific mortality if all the other prognostic factors are the same whereas breast cancer-specific morality of women with a 19 or 20 mm tumor will differ. The PREDICT prognostic model was refitted using the original cohort of cases from East Anglia with updated survival time in order to take into account age at diagnosis and to smooth out the survival function for tumor size and node status. The fit of the model has been tested in three independent data sets that had also been used to validate the original version of PREDICT [40].

KI67 positivity for the PREDICT model was defined as greater than 10% of tumor cells staining positive. Survival estimates, with and without adjuvant therapy, are presented in visual and text formats. Treatment benefits for hormone therapy and chemotherapy are calculated by applying relative risk reductions from the Oxford overview to the breast cancer specific mortality. Predicted mortality reductions are available for both second-generation (anthracyclinecontaining, >4 cycles or equivalent) and third-generation (taxane-containing) chemotherapy regimens. The survival estimates, presented both with and without adjuvant hormone therapy, chemotherapy and trastuzumab, are provided for 5 and 10 years.

The Cambridge Breast Unit uses the absolute 10-year survival benefit from chemotherapy to guide decision-making for adjuvant chemotherapy as follows: <3% no chemotherapy; 3–5% chemotherapy discussed as a possible option; >5% chemotherapy recommended.

Online tools are valuable in guiding adjuvant treatment, especially in resource-constrained countries. However, in the era of personalized therapy, molecular profiling appears to be superior in predicting clinical outcome and guiding therapy.

The AJCC Prognostic Stage Group containing multigene panels has been globally used from January 1, 2018. It suggests that prognostic stage grouping should be used in countries where biomarker tests are routinely performed, indicating that multigene molecular profiling will become part of cancer stage evaluation and will need to be taken into consideration when making clinical decisions [41].

Oncotype DX and MammaPrint have the strongest evidence supporting their clinical utility and decision effectiveness in HR+ breast cancer [42]. The future of multigene panels is promising in personalizing treatment as more studies continue. However, many issues remain to be solved before multigene panels have a wider influence on breast cancer treatment. Importantly new issues, such as how to accurately predicate late recurrence in ER+ cancer and how to provide more access to multigene panels, should be solved in the future.

Newer technologies including next-generation sequencing, liquid biopsy, tumor-infiltrating lymphocytes or PD-1 determination are at this investigational point.
