Management of Hormone Receptor-Positive, HER2-Negative Early Breast Cancer

Abstract

The majority of breast cancers are diagnosed at an early stage and are hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative. Significant advances have been made in the management of early stage HR-positive, HER2-negative breast cancer, resulting in improved survival outcomes. In this review, we discuss important factors to consider in the management of this disease. In particular, we discuss the role of adjuvant endocrine therapy, specific endocrine therapy agents, the duration of adjuvant endocrine therapy, treatment-related side effects, and the role of genomic assays and other biomarkers when considering treatment recommendations for individuals with HR-positive, HER2-negative early breast cancer. Finally, we address emerging data to individualize therapeutic decision-making and provide future considerations.

1. Introduction

Breast cancer is the most common malignancy diagnosed in women worldwide with greater than 1.3 million cases and 450,000 deaths each year (1). According to the American Cancer Society, there will be an estimated 279,100 new cases of breast cancer and an estimated 42,690 deaths due to breast cancer in the United States in 2020 (2). The vast majority of patients with a new breast cancer diagnosis have early stage disease (3, 4). Approximately 70-80% of all breast cancers are HR positive, which includes expression of estrogen receptor (ER) and/or progesterone receptor (PR) on tumor cells. The majority of HR-positive breast cancers are HER2-negative. Therefore, early stage, HR-positive, HER2-negative breast cancer is a significant public health issue.

2. Breast Cancer Diagnosis and Staging

Whether patients present with symptomatic or screen-detected breast abnormalities, clinical staging including tumor size (T stage), lymph node involvement (N stage) and metastases (M stage) should be documented at presentation using a combination of both clinical and radiological examinations (5). Tissue biopsy of a suspicious area should be performed and standard pathological evaluation carried out as recommended by the College of American Pathologists (CAP) (6, 7), including an assessment of ER, PR and HER2 status if invasive cancer is detected. Breast cancers that have ≥1% of cells staining positive for ER are considered ER-positive and those with ≥1% of cells with PR staining are considered PR-positive (7, 8). The newly defined ER Low Positive tumors have low levels of ER positivity (1-10%) and tend to behave more like HR-negative tumors (9, 10). American Society of Clinical Oncology (ASCO) guidelines suggest that risks and benefits of endocrine therapy should be discussed in patients whose tumors have low levels of ER expression (<10%) (11). The American Joint Commission on Cancer (AJCC) 8^th Edition Breast Cancer Staging System incorporates both extent of disease (TNM staging) and tumor characteristics including ER, PR, HER2, grade and, in certain cases, genomic profiling. For breast cancers treated with upfront surgery, AJCC 8^th Edition pathological prognostic stage should be reported, and for those treated with upfront systemic therapy, AJCC 8^th Edition clinical prognostic stage should be reported (12). For patients with stage I-II HR-positive disease with no concerning signs or symptoms, routine staging for metastatic disease is not recommended. Current National Comprehensive Cancer Network (NCCN) guidelines recommend that imaging to evaluate for distant metastatic disease should be considered for patients presenting with locally advanced HR-positive disease or for those who present with concerning signs or symptoms (5).

3. Overview of Systemic Therapy Options

The treatment modalities generally employed for early stage HR-positive, HER2-negative breast cancer encompass a combination of definitive local therapy, which includes primary surgical management of the breast and axilla with or without adjuvant radiation, and adjuvant endocrine therapy with or without chemotherapy. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) analysis of adjuvant chemotherapy in early stage breast cancer demonstrated that the risk of disease recurrence and death is significantly reduced with the use of adjuvant chemotherapy, irrespective of HR status. In addition, adjuvant endocrine therapy is associated with decreased risk of recurrence and death in early stage ER-positive breast cancer (13, 14). Newer studies incorporating biomarkers have demonstrated that the benefit of chemotherapy is not uniform for all HR-positive breast cancers, and these are discussed in more detail below.

With few exceptions, all patients with early stage, HR-positive breast cancers should be considered candidates for adjuvant endocrine therapy. The decision to proceed with adjuvant chemotherapy, however, varies based on predicted risk of disease recurrence, the magnitude of expected benefit from chemotherapy and patient factors such as co-morbidities and preference (15, 16). Occasionally, in early stage HR-positive disease, neoadjuvant endocrine therapy or chemotherapy may be offered prior to surgery. The role of neoadjuvant therapy in HR-positive breast cancer is outside the scope of this review but is discussed in the literature (17, 18).

4. Factors to Consider when Discussing Adjuvant Systemic Therapy

Clinical decision-making is a complex process that incorporates patient and tumor characteristics, the expected benefit of systemic therapy, individualized prognostic information and patient preference. Several large groups have provided guidance for the use of adjuvant systemic therapy in early stage HR-positive breast cancer. Cancer Care Ontario (CCO) and ASCO guidelines recommend consideration of patient demographics such as age, menopausal status and co-morbidities when making adjuvant systemic therapy decisions. In addition, characteristics including tumor size, lymph node status, presence or absence of lymphovascular invasion, histological subtype and genomic testing prognostic information should be considered. Finally, patient preference is a critical consideration in the shared adjuvant systemic therapy decision-making process (19-21).

The decision to administer chemotherapy is based primarily on tumor factors such as lymph node involvement and aggressive histological features. In the setting of lymph node negative disease, high-risk features such as young age, larger tumor size, poor prognosis as identified by genomic assays and the predicted benefit from chemotherapy are considered when deciding about chemotherapy (19, 22). NCCN guidelines stratify recommendations for adjuvant chemotherapy according to the presence or absence of lymph node metastases. In lymph node negative disease and tumors >0.5cm, genomic assays should be considered to guide chemotherapy decisions. In patients with 1-3 positive lymph nodes, initial decision making should consider clinical characteristics, tumor stage, pathology and the availability and appropriateness of genomic assays. In patients with ≥4 positive lymph nodes, chemoendocrine therapy should be recommended (5). St. Gallen guidelines recommend shared clinical decision-making considering the magnitude of therapy benefit along with the role of genomic signatures (23).

Summarizing these different guidelines, in the absence of high-risk features, lymph node involvement or poor prognostic features identified from genomic assays, endocrine therapy alone is sufficient. When some or all of these high-risk features are present, the risk of breast cancer recurrence and metastases is high with endocrine therapy alone and the addition of chemotherapy is expected to reduce the risk of recurrence and should be considered (22). Genomic assays and online risk assessment calculators are useful resources to assist with clinical decision-making by providing information about risk of recurrence and about the expected benefit of chemotherapy and endocrine therapy (22, 24). These resources are discussed in more detail later in this review.

5. Choice of Adjuvant Endocrine Therapy in Pre-Menopausal Women

a. Tamoxifen

Several therapeutic options are available for women with early stage HR-positive breast cancer who are pre-menopausal at diagnosis (Figure 1). EBCTCG analyses demonstrated that 5 years of adjuvant tamoxifen reduces local, contralateral and distant breast cancer recurrence by 30-50% for the first 10 years after diagnosis. In addition, breast cancer mortality is reduced by about one-third for the first 15 years after diagnosis, irrespective of tumor size, grade lymph node status, the use of adjuvant chemotherapy or patient factors such as age (13, 25).

Figure 1: Suggested Adjuvant Endocrine Therapy Approach for Women who are Pre-Menopausal at Diagnosis.

AI: Aromatase Inhibitor; ET: Endocrine Therapy; OFS: Ovarian Function Suppression

*High risk disease defined as tumors with lymph node involvement or aggressive histological features. In lymph node negative disease, high risk defined as young patient age, large tumor size or poor prognosis identified by genomic assays

^ There are currently no available data regarding the use of extended OFS beyond 5 years in patients who are deemed candidates for extended endocrine therapy

Several studies have demonstrated that 5 years of adjuvant tamoxifen is superior to shorter duration of therapy and that the reduction in mortality after 5 years of tamoxifen remains clinically significantly 15 years later (13, 25). While 5 years of tamoxifen is a historical standard, newer data indicate even greater benefit with ovarian function suppression (OFS) and other data support up to 10 years of endocrine therapy as discussed in more detail below.

b. Ovarian Function Suppression with Tamoxifen or an Aromatase Inhibitor

OFS by surgical or pharmacological means should be considered in high-risk pre-menopausal patients. Surgical OFS via bilateral salpingo-oophorectomy is irreversible and may be a suitable option for women with increased risk of ovarian cancer, and in those who desire permanent OFS. Pharmacological methods are generally reversible and use gonadtropin-releasing hormone (GnRH) agonists such as goserelin and leuprolide to suppress luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and subsequently reducing estrogen production from the ovaries (5). While initial studies of OFS versus no adjuvant therapy and OFS versus adjuvant chemotherapy failed to demonstrate a reduction in recurrence or death overall (26-28), data have suggested that OFS benefits may be observed in younger, pre-menopausal women (27, 29).

With this in mind, in 2003, the International Breast Cancer Study Group (IBCSG) commenced two studies: Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) for pre-menopausal women with HR-positive early breast cancer (30). The SOFT trial was designed to determine the value of adding OFS to tamoxifen (tamoxifen-OFS) and to determine the role of exemestane plus OFS (exemestane-OFS). The TEXT trial was designed to determine the value of exemestane versus tamoxifen in women treated with OFS. The original statistical analyses planned for TEXT and SOFT were to compare disease free survival (DFS) between treatment groups within each trial separately followed by a planned secondary combined analysis of exemestane-OFS versus tamoxifen-OFS. However, at the time of the primary analyses, patient outcomes were better than expected, meaning that an additional 7 years of follow up for TEXT and 13 years of follow up for SOFT would have been required in order to report study results. Therefore, the analytic plan was amended and the new primary objective was to compare DFS for exemestane-OFS versus tamoxifen-OFS versus tamoxifen alone using combined data from SOFT and TEXT (30-34). The results demonstrated that the addition of OFS to tamoxifen improved both DFS and overall survival (OS) compared to tamoxifen alone. Exemestane-OFS resulted in further improvement in DFS compared to tamoxifen alone. Furthermore, when comparing exemestane-OFS to tamoxifen-OFS, exemestane-OFS resulted in improved DFS compared to tamoxifen-OFS. The largest magnitude of benefit with the use of OFS was observed in patients at high risk of recurrence (e.g. those with high-risk clinico-pathological features and age <40 years) and those treated with chemotherapy (31).

Current ASCO and NCCN guidelines recommend tamoxifen alone for the adjuvant treatment of pre-menopausal women with low-risk disease in whom chemotherapy is not warranted. For patients with high-risk disease, younger patients and those requiring chemotherapy, either aromatase inhibitor (AI)-OFS or tamoxifen-OFS are recommended, although ASCO guidelines favor exemestane-OFS (5, 31, 35). Longer follow-up from the SOFT and TEXT studies will help further evaluate the benefit of OFS in pre-menopausal women, and determine whether the DFS benefit observed in patients treated with exemestane-OFS translates to OS advantage. Of particular interest is the role of OFS in very young women (<35 years), as these very young patients represented only 12% of all patients in the combined SOFT and TEXT studies. Patient selection and patient preference should also be considered in treatment decisions for pre-menopausal women. Another area of interest is whether AI-OFS is a safe and feasible alternative to chemotherapy in certain high-risk women and studies are ongoing in this area.

6. Choice of Adjuvant Endocrine Therapy in Post-Menopausal Women

Endocrine therapy options for women who are post-menopausal at diagnosis are shown in Figure 2. In post-menopausal women, an AI administered instead of or in sequence with tamoxifen is superior to 5 years of tamoxifen alone. A meta-analysis of approximately 18,000 patients demonstrated that 5 years of adjuvant AI therapy was associated with a 2.9% absolute reduction in the risk of recurrence and a 1.1% absolute reduction in breast cancer mortality compared to 5 years of tamoxifen. In patients treated with 2-3 years of tamoxifen followed by 2-3 years of AI, there was a 3.1% and 0.7% reduction in breast cancer recurrence and mortality, respectively, compared to those treated with tamoxifen alone for 5 years (36). The Intergroup Exemestane Study (IES) reported that patients who completed 5 years of endocrine therapy by switching to an AI after an initial 2-3 years of tamoxifen had significantly reduced disease recurrence and breast cancer mortality compared to patients who received tamoxifen for 5 years (37, 38). An EBCTCG meta-analysis of >30,000 post-menopausal patients studied the sequential treatment of AIs and tamoxifen. When 5 years of an AI was compared to 5 years of tamoxifen or to 2–3 years of tamoxifen followed by an AI for a total of 5 years, AIs were associated with lower rates of breast cancer recurrence and a 15% improvement in 10-year mortality. Similarly, when 5 years of tamoxifen was compared to 2–3 years of tamoxifen followed by AI for a total of 5 years, the rates of recurrence for AIs were significantly lower during years 2–4 and the 10-year breast cancer mortality was lower with switching to AIs than with remaining on tamoxifen (39).

Figure 2: Suggested Adjuvant Endocrine Therapy Approach for Women who are Post-Menopausal at Diagnosis.

AI: Aromatase Inhibitor; ET: Endocrine Therapy;

*High risk disease defined as tumors with lymph node involvement or aggressive histological features. In lymph node negative disease, high risk defined as large tumor size or poor prognosis identified by genomic assays

^ Extended tamoxifen may be appropriate in post-menopausal patients if toxicities or contraindications to AI

Several adjuvant endocrine therapy options are available for post-menopausal women including AI for 5 years, tamoxifen for 5 years (if AI is contraindicated or not well tolerated), tamoxifen for 2-3 years followed by AI to complete 5 years, tamoxifen for 2-3 years followed by 5 years of AI, tamoxifen for 5 years followed by AI for 5 years. While patient factors and patient preferences should be considered, most guidelines recommend the use of an AI, either for 5 years, or for 2-3 years after prior tamoxifen use if possible (5, 40). Extended AI therapy may be considered for select women and is discussed below.

7. Extended Endocrine Therapy

Five years of adjuvant endocrine therapy has historically been the standard approach for patients with early stage HR-positive breast cancer and has been shown to decrease the risks of both locoregional and distant recurrence, contralateral breast cancer, death from breast cancer and death from any cause (13, 25, 39, 41). However, it is recognized that upon discontinuation of 5 years of endocrine therapy, the rates of recurrence and death from breast cancer increase in a linear fashion. An EBCTCG meta-analysis of almost 63,000 patients with ER-positive breast cancer treated with 5 years of adjuvant endocrine therapy in 88 randomized trials demonstrated that distant breast cancer recurrences occurred steadily and consistently for at least 15 years after cessation of endocrine therapy (years 5-20). While women with higher stage at diagnosis faced the highest risks of late recurrence, even women with stage I disease had a substantial risk of late recurrence and death over time. The risk of distant recurrence in years 5-20 ranged from 13% to 41% in pT1N0 and pT2N2 tumors respectively, while the 20-year risk of breast cancer mortality ranged from 15% in patients with N0 disease to 49% in patients with N2 disease (41). To reduce the risk of late recurrence and death, multiple studies have examined extended adjuvant endocrine therapy (Table 1).

Table 1:

Select Extended Endocrine Therapy Studies

	Number (% Node Positive)	Study design	Key Findings
ATLAS (42)	6846 (47%)	Tamoxifen for 5 vs. 10 years	HR 0.75 for DFS; HR 0.71 for BC mortality
aTTom (43)	6596 (31%)	Tamoxifen for 5 vs. 10 years	HR 0.75 for DFS; HR 0.77 for BC mortality; HR 0.86 for OS
MA.17 (44-46)	5187 (45%)	Tamoxifen for 5 years, followed by 5 years AI or placebo	HR 0.58 for DFS & contralateral breast cancer; HR for OS (LN+) 0.61
NSABP B33 (47)	1562 (48%)	Tamoxifen for 5 years, followed by 5 years AI or placebo	HR 0.68 for DFS; HR 0.44 for RFS
DATA (153)	1912 (67%)	Tamoxifen for 2-3 years, followed by 3 or 6 years of AI	None significant
MA.17R (48)	1918 (53%)	AI for 5 years followed by 5 years AI or placebo (68.5% received 5 years of tamoxifen prior to initial AI)	HR 0.66 for DFS; HR 0.42 for contralateral breast cancer
NSABP B42 (49, 50)	3966 (42%)	AI for 5 years (or Tamoxifen for ≤3 years followed by AI to complete 5 years), followed by 5 years of AI or placebo	HR 0.84 for DFS; HR 0.74 for contralateral breast cancer; HR 0.71 for distant recurrence
IDEAL (51)	1824 (74%)	5 years of endocrine treatment, followed by 2.5 or 5 years of AI or placebo	HR 0.39 for contralateral breast cancer
SOLE (52)	4884 (99%)	4-6 years of endocrine treatment, followed by continuous AI (5 years) or intermittent AI (for 5 years total)	None significant

AI: Aromatase inhibitor; BC: Breast cancer; DFS: Disease free survival; HR: Hazard ratio; LN: Lymph node; OS Overall survival; RFS: Relapse free survival; vs: Versus

a. Extended Tamoxifen Therapy

The role of extended tamoxifen therapy has been evaluated in several studies and the largest of those are discussed here in more detail. In the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, >12,000 patients who were treated with tamoxifen for 5 years were randomized to either stopping therapy or continuing tamoxifen for 5 additional years. Ten years of tamoxifen resulted in reductions in the risk of breast cancer recurrence, breast cancer mortality and overall mortality. The risk of recurrence in years 5-14 was reduced by 3.7% with extended tamoxifen, whereas breast cancer mortality was reduced by 2.8% (42). In the Adjuvant Tamoxifen-To Offer More (aTTom) study, almost 7,000 patients were randomized to stop tamoxifen after 5 years, or to continue to year 10. Ten years of tamoxifen was associated with a 2.6% reduction in breast cancer recurrence, which was most notable beyond year 7, and a 1.4% reduction in breast cancer mortality (43).

b. Sequential Use of Tamoxifen and Aromatase inhibitors

Multiple trials evaluated the benefit of extended endocrine therapy using the strategy of switching to an AI after initial therapy with tamoxifen. For example, in the MA.17 study, 5 years of letrozole after completion of 5 years of tamoxifen was associated with improved DFS and OS compared to placebo (44-46). Likewise, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-33 trial demonstrated that 5 years of exemestane following 5 years of tamoxifen improved relapse free survival (RFS) in patients with HR-positive, lymph node positive breast cancer (47). These studies coupled with others support the use of up to 10 years of endocrine therapy using sequential approaches such as 2-3 years of tamoxifen followed by an AI for 5 years or tamoxifen for 5 years followed by 5 years of an AI.

c. Extended Aromatase Inhibitor Therapy

Several studies evaluated the role of extended endocrine therapy using more than 5 years of an AI. The MA.17R study demonstrated that 5 years of letrozole, after an initial course of 5 years of an AI (+/− prior tamoxifen) improved 5-year DFS, driven largely by reduction in new contralateral breast cancers, without OS advantage (48). Ten year follow up from the NSABP B-42 trial where patients received 5 years of letrozole after initial treatment with either an AI for 5 years, or tamoxifen for ≤3 years followed by an AI to complete 5 years, reported an improvement in DFS and a reduction in the development of a new breast primary tumor, without OS advantage (49, 50).

Pivotal studies evaluating the use of extended AI therapy, including the IDEAL (51) and SOLE studies, vary in overall duration of endocrine therapy and are summarized in Table 1. An EBCTCG meta-analysis presented at the 2018 San Antonio Breast Cancer Symposium demonstrated that the absolute benefit of extended AI increases as lymph node burden increased (53). Overall, the individual study data suggest that more than 5 years of AI provides modest, if any, DFS benefit and is likely associated with a reduction in the development of new contralateral breast primary cancers.

d. Extended Adjuvant Endocrine Therapy Recommendations

Recommendations for extended endocrine therapy are summarized in Figure 1 and Figure 2. In patients who are pre- or peri-menopausal at diagnosis and who do not receive OFS as part of their treatment paradigm, current ASCO guidelines recommend treatment with 5 years of adjuvant tamoxifen. After 5 years of tamoxifen, women who remain pre-menopausal are candidates for extended endocrine therapy with an additional 5 years of tamoxifen. Women who become post-menopausal during the first 5 years of tamoxifen in whom extended therapy is planned may either continue tamoxifen for an additional 5 years, or receive 5 years of an AI (54). NCCN guidelines recommend that women who are pre-menopausal at diagnosis, and who do not undergo treatment with OFS should consider tamoxifen for up to 10 years. Women who are pre-menopausal at diagnosis and who are treated with 5 years of tamoxifen-OFS or AI-OFS may consider an additional 5 years of tamoxifen if they remain pre-menopausal. Women who were pre-menopausal at diagnosis who become post-menopausal, may consider extended endocrine therapy with an AI for a further 5 years following tamoxifen (5).

There are currently no available data regarding the use of extended OFS beyond 5 years in patients who are deemed candidates for extended endocrine therapy (55). In fact, one phase II study that sought to answer this question closed early due to poor accrual suggesting that young patients may not be motivated to pursue extended OFS (56). Given the possible long term health implications that may result from prolonged premature menopause, until further data are available, guidelines do not recommend that pre-menopausal women be offered chemical OFS beyond 5 years. Women who become menopausal, either naturally or surgically should carefully consider the risk of recurrence and additional benefit that extended us of endocrine therapy may offer.

ASCO guidelines recommend that patients who are post-menopausal at diagnosis and have lymph node positive disease are candidates for extended endocrine therapy, including an AI as part of the treatment paradigm, for up to a total of 10 years. Post-menopausal patients with lymph node negative disease may consider extended endocrine therapy based on the individual risk of recurrence and patient preference, although the expected additional benefit associated with extended endocrine therapy is likely smaller than in lymph node positive disease (54). NCCN guidelines add that the optimal duration of endocrine therapy is not yet known, and provide recommendations based on menopausal status regardless of lymph node status. Post-menopausal women have several options including 5 years of an AI following 2-3 years of tamoxifen, 5 years of an AI after 5 years of tamoxifen, 10 years of an AI or 10 years of tamoxifen (5).

8. Side Effects Associated with Adjuvant Endocrine Therapy

Although the majority of women will have no or mild symptoms, endocrine therapy can be associated with specific and often bothersome side effects (Table 2). Both pharmacological and non-pharmacological approaches can help ameliorate these symptoms. As studies have demonstrated an association between side effects and early treatment discontinuation (57-59), it is important to educate patients about possible toxicities and encourage them to contact their health care team to discuss possible interventions. Menopausal symptoms such as hot flashes and sweats are seen in 40-60% of patients treated with tamoxifen or AIs, and may be more significant with tamoxifen (60, 61). Vaginal dryness, vaginal discharge and sexual dysfunction are seen with both tamoxifen and AIs (62). Weight gain, mood disturbances and fatigue are also commonly observed with both tamoxifen and AIs (37, 63, 64). AI use is associated with an increased risk of osteopenia/osteoporosis, AI-associated musculoskeletal syndrome (AIMSS), a constellation of symptoms that includes arthralgias, myalgias and stiffness, and is also associated with a potential risk of cardiovascular disease (65-68). Tamoxifen increases the risk of thromboembolic disease and endometrial cancer, although the incidence of both toxicities remain low, especially in pre-menopausal women (25).

Table 2:

Estimated Frequency of Endocrine Therapy-Associated Side Effects

Side Effect	Tamoxifen	Aromatase Inhibitor	Ovarian Function Suppression*
Hot Flashes/Sweats (32, 34, 37, 63, 64, 154-156)	39-80%	35-60%	40-93%
Sexual Dysfunction (32, 34, 156)	15-45%	30-50%	26-48%
Mood Changes/ Depression (32, 34, 37, 63, 64, 156)	5-47%	6-20%	50-52%
Vaginal Dryness (32, 34, 64, 156)	42%	7-26%	47-52%
Vaginal Discharge (37, 63, 64, 156)	4-15%	3-17%	-
Arthralgias/Myalgias (32, 34, 37, 63, 154, 155)	12-69%	6-50%	75-89%
Osteoporosis (32, 34, 37, 64, 154, 157)	5.5-12%	5-35%	20-40%
Thromboembolic Disease (32, 34, 37, 63, 155)	2-5%	1-3%	1-2%
Endometrial Cancer (63)	0.8-1.2%	0.2%	-
Ischemic Cardiovascular or Cerebrovascular Disease (34, 37, 63, 64, 154, 155)	1-7%	0.2-8%	<1%

^*Ovarian function suppression usually given with either tamoxifen or aromatase inhibitor

The addition of OFS to tamoxifen or AI increases the toxicity profile and is associated with higher rates of hot flashes, sweats and sexual dysfunction. Loss of bone mineral density resulting in osteopenia or osteoporosis is associated with both OFS and AI use and bone health should be monitored while on therapy (31, 32, 69). Notably, early discontinuation of endocrine therapy or endocrine-OFS in the SOFT and TEXT studies was >20%, especially in patients <35 years compared to those ≥35 years (55, 70).

As expected, extended endocrine therapy is associated with an increased rate of toxicities compared to 5 years of treatment. In the ATLAS trial, extended tamoxifen use was associated with increased risk of endometrial cancer (0.4% mortality) and an increased risk of pulmonary embolism (0.2% mortality) (42). Extended AI therapy is associated with higher rates of osteoporosis, bone fractures and concerns for cardiovascular events (48, 71, 72). Therefore, patient selection remains a critical component in the adjuvant endocrine therapy decision-making process. Toxicity profiles should be taken into consideration when discussing extended endocrine therapy.

9. Online Calculators, Composite Scores and Multi-Parameter Gene Expression Assays

Several tools are available to clinicians as they consider treatment recommendations for patients with early stage HR-positive, HER2- negative breast cancer.

a. Online Calculators

Online risk calculators have been developed using large datasets such as the EBTCTG meta-analyses to estimate a patient's risk of breast cancer recurrence and death, and in turn, to estimate the potential benefit from endocrine therapy alone and from chemoendocrine therapy. For example, the National Health Service (NHS) Predict tool, based on a United Kingdom (UK) cancer registry database, calculates benefits of adjuvant therapy for patients with all types of breast cancer, including HER2-positive disease (24). CancerMath, another online tool derived from the Surveillance, Epidemiology and End-Result (SEER) registry, takes HR and HER2 status into account, and calculates survival outcomes associated with and without various systemic therapies (73, 74). Validation studies have shown comparable results between CancerMath and the previously available Adjuvant! Online (75). While these and other calculators can add to prognostic information and assist clinical decision making, multi-parameter gene expression assays have the potential to provide more individualized prognostic and predictive information (22).

b. Composite Scores

In addition to individual tissue-based biomarkers such as ER, PR or HER2, investigators have attempted to combine biomarkers into composite scores to assist decision-making. For example, the immunohistochemical (IHC) score 4 (IHC4), based on the standard laboratory evaluations of ER, PR, HER2 and Ki67, has been shown to be prognostic for outcome, but not predictive for the choice of endocrine therapy (76, 77). However, the use of IHC4 in routine clinical practice is limited by the fact that Ki67 analysis and scoring remains variable (78, 79). An International Ki67 Working Group has attempted to standardize Ki67 scoring with web-based image analysis tools in order to decrease variability and improve the accuracy and consistency of Ki67 scoring (80-82) meaning that scores such as IHC4 could potentially be useful in routine clinical practice. Clinical Treatment Score post 5-years (CTS5) is a prognostic biomarker that uses routine clinical and pathological information including patient age, tumor grade, size and nodal status to predict the risk of late distant recurrence after 5 years of endocrine therapy. CTS5 was originally developed and validated in post-menopausal women in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) study (83). The CTS5 biomarker has recently been validated in the Trial Assigning Individualized Options for Treatment (TAILORx) cohort and demonstrated that patients with low/intermediate RS treated with endocrine therapy alone and patients with intermediate/high RS treated with chemo-endocrine therapy had low rates of distant recurrence. In patients >50 years, CTS5 was found to be highly prognostic in predicting late distant recurrence in patients with intermediate or high RS, but was not prognostic in patients with low RS (84). Therefore, CTS5 may have a role in clinical practice to predict those post-menopausal patients who are at risk of late recurrence and in whom more aggressive, or longer duration of therapy may be warranted. While there have been some retrospective data demonstrating the utility of CTS5 in pre-menopausal women (85, 86), the TAILORx analysis found that CTS5 was much less prognostic for women aged ≤50 years compared to those >50 years (84). Further validation efforts in pre-menopausal patients and other treatment settings are underway.

c. Multi-Parameter Gene Expression Assays

Multi-parameter gene expression assays provide prognostic and, in some cases, predictive information that can be incorporated into adjuvant therapy decision-making (87). Commercially available assays include the 21-gene Oncotype DX, 70-gene MammaPrint, 50-gene PAM50 (used with other clinico-pathological variables), 12-gene EndoPredict, and Breast Cancer Index. Among available tools, Oncotype DX assay remains the best validated as both a predictive and prognostic test (5). In patients with HR-positive, HER2-negative, lymph node negative disease, the Oncotype DX recurrence score (RS) has been used as a prognostic tool to predict the likelihood of distant recurrence and as a predictive tool to predict the benefit from both chemotherapy and endocrine therapy (88-90). The role of Oncotype DX was evaluated in the prospective TAILORx study. In this trial, patients with HR-positive, lymph node negative breast cancer were assigned adjuvant treatment based on RS. Patients with RS <11 received endocrine therapy alone, those with RS >25 were recommended chemoendocrine therapy, while those with RS 11-25 were randomized to receive either chemoendocrine therapy or endocrine therapy alone. Overall, endocrine therapy was found to be non-inferior to chemoendocrine therapy for invasive DFS and OS in patients with RS 11-25, but exploratory analyses demonstrated that chemotherapy benefit varies when age and RS were combined, with some chemotherapy benefit seen in women ≤50 years with RS 16-25. Women with RS <11 had excellent outcomes, with rates of invasive DFS of 94% and 84% at 5 and 9 years respectively and OS of 98% and 94% at 5 and 9 years respectively (91). Patients with RS >25 who were treated with chemoendocrine therapy had 5-year invasive DFS of 87% and OS of 96%, outcomes which were better than expected with endocrine therapy alone (92). Clinical risk, based on tumor size and grade, was also found to be prognostic of distant recurrence when used in combination with RS. In pre-menopausal women in particular, integrating clinical risk with RS identified patients who derived the most benefit from chemoendocrine therapy (93).

Oncotype DX has also been shown to be prognostic in lymph node positive disease and the predictive benefit in this setting is being studied prospectively. A retrospective analysis of samples that were prospectively collected through the Southwest Oncology Group (SWOG) 8814 study demonstrated that patients with RS <18 did not derive additional benefit from chemoendocrine therapy compared to endocrine therapy alone, but that patients with RS >30 significantly benefited from the addition of chemotherapy to endocrine therapy (94). Additional studies have demonstrated that patients with lymph node positive disease and low RS have excellent outcomes when treated with endocrine therapy alone. In the prospective Plan B study that evaluated the role of an anthracycline-free chemotherapy regimen, patients with RS ≤11 who were treated with endocrine therapy alone had 5-year DFS rates of 94% (95). In a retrospective analysis of a prospectively designed registry, patients with RS <18 who received endocrine therapy alone had a 3% rate of distant recurrence and <1% of death from breast cancer at 5 years (96). The ongoing Rx for Positive Node Endocrine Responsive Breast Cancer (RxPONDER) study aims to prospectively evaluate the benefit of adjuvant chemotherapy in patients with 1-3 positive lymph nodes and a RS of ≤25 and aims to definitely inform our decision making about the use of Oncotype DX in lymph node positive disease (97).

The MammaPrint assay provides prognostic information in early stage breast cancer. In the Microarray in Node Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy (MINDACT) study, patients with breast cancer and 0-3 positive lymph nodes were assigned a genomic risk using MammaPrint and a clinical risk using Adjuvant! Online in order to inform decisions on withholding adjuvant chemotherapy. Patients with low clinical and low genomic risk did not receive chemotherapy, patients with high clinical and high genomic risk received chemotherapy and patients with discordant risk results were randomized to either chemotherapy or no chemotherapy. The majority of patients included in the study had lymph node negative, HR-positive, HER2-negative tumors. The 5-year distant metastases free survival (DMFS) in patients with discordant results (high clinical risk and low genomic risk) who were not randomized to chemotherapy was 94.7%, meeting the primary endpoint of the study by demonstrating that the DMFS exceeded 92% in this subgroup. Therefore, MammaPrint may be used to identify patients with 0-3 positive lymph nodes and high clinical risk in whom the risk of distant recurrence is likely to be low if chemotherapy is omitted. However, although the study was not statistically designed to test these differences, further analyses of these patients with high clinical and low genomic risk demonstrated that absolute rates of 5-year DMFS, DFS and OS were higher in those patients who were treated with chemotherapy (98). Recommendations for the use and interpretation of Oncotype DX and MammaPrint are summarized in Table 3.

Table 3(a):

Guidelines for the Use of Oncotype DX

Guidelines for the Use of Oncotype DX
Panel	Patient Population	Recurrence Score	Recommendations
ASCO	Age ≤50 with Lymph Node Negative Disease	RS <16	Recommend Endocrine Therapy
		RS 16-30	Offer Chemoendocrine Therapy
		RS >30	Recommend Chemoendocrine Therapy
	Age >50 with Lymph Node Negative Disease	RS <26	Recommend Endocrine Therapy
		RS 26-30	Offer Chemoendocrine Therapy
		RS >30	Recommend Chemoendocrine Therapy
NCCN	Age ≤50 with T1b-T2, Lymph Node Negative Disease	RS <16	Recommend Endocrine Therapy
		RS ≥16	Consider Chemoendocrine Therapy
	Age >50 with T1b-T2, Lymph Node Negative Disease	RS <26	Recommend Endocrine Therapy
		RS 26-30	Recommend Chemoendocrine Therapy based on individual clinical and pathological factors
		RS ≥31	Recommend Chemoendocrine Therapy
	Lymph Node Positive Disease (1-3 nodes)	Low RS (optimal RS cutoff <11 or <18 has not been identified)	Recommend Endocrine Therapy
		RS ≥18	Recommend Chemoendocrine Therapy

ASCO: American Society of Clinical Oncology; NCCN: National Comprehensive Cancer Network; RS: Recurrence score

Both ASCO and NCCN guidelines note that genomic assays other than Oncotype DX and MammaPrint may be used to obtain prognostic information that may guide treatment decisions. These include PAM50, EndoPredict, Breast Cancer Index, urokinase plasminogen activator and plasminogen activator inhibitor type 1 (5, 87). These commercially available genomic assays may help distinguish patients who require chemoendocrine therapy from those who can be adequately treated with endocrine therapy alone, but they have not been directly compared prospectively. Therefore, practice guidelines have recommended that only one assay be ordered per patient and tumor (5, 87, 99).

10. Choice of Chemotherapy

At this time, there is no standard recommended adjuvant chemotherapy regimen for women with HR-positive, HER2-negative breast cancer. EBCTCG investigators demonstrated that among 100,000 patients enrolled in 123 randomized trials, the risk of disease recurrence, breast cancer mortality and overall mortality was reduced with the use of anthracycline-taxane-based regimens compared to anthracycline-based regimens, irrespective of HR status. Anthracycline-based regimens were associated with reduced risk of recurrence, reduced breast cancer mortality and reduced overall mortality compared with CMF, although benefits by HR status could not be compared due to small patient subgroups. Overall, this meta-analysis suggested that 4 cycles of an anthracycline-based chemotherapy regimen was equivalent to 6 cycles of CMF chemotherapy, whereas the addition of a taxane to an anthracycline-based chemotherapy regimen reduced breast cancer mortality by 24% (14).

The ABC trials were a series of adjuvant trials that included 2,125 patients with early stage, HER2-negative, lymph node positive or high-risk, lymph node negative breast cancer and compared taxane-based regimens to anthracycline-taxane-based regimens. The primary endpoint of the study was to determine if a non-anthracycline-based regimen was non-inferior to an anthracycline-based regimen with respect to DFS. This study failed to demonstrate non-inferiority, meaning that an anthracycline-taxane-based regimen was associated with improved DFS compared to a taxane-based regimen. Exploratory subgroup analyses suggested that the magnitude of benefit for anthracycline-taxane-based regimens appeared to be larger in patients with HR-negative tumors, and in those with HR-positive, lymph node positive disease (100).

Based on the results of these two large experiences, in patients with HR-positive, HER2-negative, lymph node negative disease, with other favorable tumor features for whom chemotherapy is recommended, a taxane-(non-anthracycline) based regimen can be considered. In such cases, a regimen such as docetaxel plus cyclophosphamide (TC) has comparable outcomes and is preferable to an anthracycline-taxane-based regimen, given the shorter duration of treatment and the ability to avoid the risks of cardiac toxicity and secondary acute leukemia associated with anthracyclines (100). In patients with a significant lymph node burden, who do not have contraindications, we generally recommend an anthracycline-taxane-based regimen such as dose dense doxorubicin and cyclophosphamide followed by paclitaxel administered weekly or in a dose dense fashion (ddAC-T) (5, 14, 100-102). In patients with low volume lymph node burden (1-3 positive lymph nodes), either ddAC-T or TC may be considered based on patient preference, co-morbidities and the expected benefit from chemotherapy.

11. Other Considerations

When discussing adjuvant systemic therapy with patients with HR-positive, HER2-negative early stage breast cancer, clinicians should consider special populations and other interventions to support patients as they receive adjuvant systemic therapy. Some considerations include bone health, fertility preservation, and genetic testing and counseling. All patients should also be encouraged to maintain ideal body weight and be physically active (103).

a. Male Breast Cancer

Male breast cancer is uncommon, accounting for <1% of all breast cancers diagnosed per year. Like their female counterparts, the adjuvant treatment of HR-positive breast cancer in men incorporates locoregional therapies and endocrine therapy with or without chemotherapy. Until recently, men have been excluded from participation in prospective breast cancer trials and therefore the benefits of adjuvant therapy have been extrapolated from studies of women and from retrospective trials (104, 105). Similarly, data pertaining to the use of genomic assays to predict benefit of adjuvant chemoendocrine therapy and to predict prognosis in men are limited (106, 107). In general, tamoxifen is preferred over an AI as adjuvant therapy due to concerns about inadequate estradiol suppression with AI therapy. If tamoxifen is contraindicated, AIs can be used with concurrent use of GnRH agonists in order to suppress estradiol levels (106). Like women, extended tamoxifen may be considered in high risk male breast cancer cases (108).

b. Bone Modifying Therapies

As estrogen plays an important role in bone homeostasis, systemic therapies that potentially decrease levels of estrogen can also reduce bone mineral density (BMD). In breast cancer, the potential risk of BMD loss is affected both by patient age and by therapy received (109). Patients receiving AIs or GnRH agonists may have increased short and long term osteoporotic fracture risks. In these patients, BMD testing at least every 2 years is recommended, in addition to dietary supplementation of calcium and vitamin D, exercise and lifestyle modifications such as smoking cessation (110, 111).

In view of the potential toxicities associated with adjuvant endocrine therapy, OFS and chemotherapy, bone modifying agents such as bisphosphonates and RANK-ligand inhibitors such as denosumab have been investigated as potential strategies to mitigate BMD loss in patients with early stage breast cancer (109). In pre-menopausal women, chemotherapy-induced ovarian failure is associated with significant BMD loss at 6 and 12 months following chemotherapy (112). In these cases, if required, bisphosphonates are the treatment of choice to preserve or improve BMD (113, 114). In the Women’s Health Initiative Observational Study, women with a history of breast cancer diagnosed after age 55 had higher fracture rates than women without a history of breast cancer (115). Therefore, in post-menopausal women, and in pre-menopausal women undergoing OFS, the risk of osteoporosis is greater. In this cohort, either bisphosphonates or denosumab may be considered (111, 116, 117).

In addition to the effects on BMD, bisphosphonates have been shown to have anti-cancer therapeutic effects and are associated with improved breast cancer survival in post-menopausal women. An EBCTCG meta-analysis demonstrated that among post-menopausal women, the use of bisphosphonates reduced bone fractures, breast cancer recurrence, breast cancer recurrence in bone, distant metastases and breast cancer related deaths, irrespective of HR status, tumor grade, nodal involvement or chemotherapy use (118).

Current NCCN guidelines recommend that patients being treated with an AI or those experiencing treatment-induced ovarian failure should have BMD evaluated at baseline and periodically thereafter, and that bisphosphonates are the preferred intervention, if required, in this patient population (5). In post-menopausal patients who are candidates for adjuvant systemic therapy, and in pre-menopausal patients treated with OFS, ASCO guidelines recommend that adjuvant bisphosphonates should be considered (119) and St. Gallen guidelines recommend that bisphosphonates should be prescribed in view of a 4-8% reduction in breast cancer recurrence at 5 years (23). However, there are concerns that these recommendations may lead to overtreatment with small absolute benefits and no OS benefit if applied to all post-menopausal women with early stage breast cancer who are candidates for adjuvant systemic therapy, irrespective of risk, HR status, or duration of menopause (23, 120).

Data pertaining to the use of denosumab as adjuvant therapy in early stage breast cancer are conflicting. The Austrian Breast Cancer Study Group (ABCSG)-18 trial of post-menopausal patients with HR-positive early stage breast cancer reported an 18% improvement in DFS, namely second primary cancers and non-histologically confirmed distant metastases, with the use of denosumab (121). In contrast, the D-CARE Study which included pre-menopausal and post-menopausal patients with early stage breast cancer at moderate to high risk of recurrence and any HR or HER2 status, failed to show any improvement in either bone metastases-free survival or DFS in women treated with denosumab compared to placebo (122).

We have generally followed NCCN guidelines by evaluating BMD at baseline when starting either an AI or OFS, and repeating BMD evaluations periodically thereafter. We recommend the use of bisphosphonates or denosumab for women with osteopenia or osteoporosis with the intent of mitigating loss of BMD. For higher risk women, with normal bone health, we consider incorporation of bisphosphonates as part of the adjuvant breast cancer treatment paradigm in individual cases.

c. Fertility Preservation

Chemotherapy is gonadotoxic and pre-menopausal women who receive chemotherapy are at risk of amenorrhea, infertility and early menopause. The risk of early menopause is significantly increased when chemotherapy is administered to patients >35 years (123). Even patients whose menstrual cycles return after cessation of chemotherapy may experience early menopause or infertility. In addition, in patients with HR-positive disease who require at least 5 years, and in some cases up to 10 years, of endocrine therapy, fertility naturally declines during this period of time, irrespective of chemotherapy use. In the era of extended endocrine therapy and OFS, the long term impact on fertility remains unknown.

Fertility preservation should be discussed with all pre-menopausal patients irrespective of parity, prognosis or socioeconomic status (124). In women who have not completed childbearing, the risk of treatment-related infertility should be discussed prior to initiating adjuvant systemic therapy and properly selected patients who desire future fertility should be referred for fertility preservation. Decisions about fertility preservation should also take tumor characteristics, patient age, planned therapy and anticipated treatment delays into account (5). Fertility preservation generally entails ovarian stimulation plus oocyte harvesting, followed by either oocyte or embryo cryopreservation. In patients with HR-positive breast cancer, in view of concerns about ovarian stimulation increasing estrogen levels, AIs have been incorporated into ovarian stimulation protocols. While there are conflicting data about the use of chemical ovarian suppression with GnRH analogs as a means of fertility preservation, ASCO guidelines recognize that this method may be offered to patients when proven methods are not feasible as well as in the setting of young women with breast cancer (124).

The majority of women <35 years resume menses and have normal fertility after adjuvant treatment (5). In one retrospective study, women who were treated for early stage HR-positive breast cancer and subsequently became pregnant had comparable breast cancer outcomes to those who did not become pregnant, suggesting that pregnancy should not be discouraged in this patient population (125). Accrual to The IBCSG/National Clinical Trials Network (NCTN) Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer (POSITIVE) study has recently been completed. The study is evaluating the pregnancy outcomes and safety of interrupting endocrine therapy for young women with HR-positive breast cancer who desire pregnancy. In particular, this study will determine whether temporary interruption of endocrine therapy to facilitate pregnancy is associated with higher rates of breast cancer recurrence (126).

d. Genetic Counseling

Patients with significant personal or family histories should undergo genetic counseling. NCCN guidelines recommend germline breast and/or ovarian cancer genetic assessment in the following circumstances: (i) breast cancer diagnosed <50 years; (ii) triple negative breast cancer diagnosed <60 years; (iii) two breast cancer diagnoses in the same patient; (iv) breast cancer at any age with a family history (first, second or third degree relative) of breast cancer <50 years, ovarian cancer, male breast cancer, pancreatic cancer, or high grade/metastatic prostate cancer; and for any individuals (v) with a known family history of a pathogenic variant in a cancer susceptibility gene; (vi) found to have a pathogenic somatic mutation in a cancer susceptibility gene; (vii) diagnosed at any age with ovarian cancer, pancreatic cancer, metastatic prostate cancer, breast or high grade prostate cancer in patients of Ashkenazi Jewish ancestry (127). In addition, NCCN guidelines recommend that all men with breast cancer undergo genetic testing (5).

The U.S. Preventative Services Task Force (USPTF) (128) and the National Institute for Health and Clinical Excellence (NICE) (129) have issued clear guidelines outlining which individuals should have germline testing performed and which individuals should be referred to a specialist genetics clinic (130). However, more recent guidelines from the American Society of Breast Surgeons have recommended genetic testing for all patients with a personal history of breast cancer, and that individuals without breast cancer should be tested as per the NCCN guidelines (131). Similarly, recent data from the UK has demonstrated that unselected multi-gene testing of all patients with breast cancer is more cost-effective than screening based on family history or high-risk features and therefore genetic testing should be offered to all women with breast cancer (132).

A recent study compared the NCCN recommendations with those issued by the American Society of Breast Surgeons by analyzing breast cancer predisposition genes in patients with invasive and in situ breast cancer and found that NCCN criteria are not optimal for selecting patients for germline testing. Based on NCCN guidelines in this study, 48% of patients met criteria for germline testing and 9.6% carried pathogenic variants in breast cancer predisposition genes. However, almost 30% of patients were found to have pathogenic variants but did not meet NCCN criteria for testing. The sensitivity of NCCN testing criteria was reported as 71%, with specificity of 54%. When NCCN criteria were expanded to include all women diagnosed with breast cancer age ≤65 years, the sensitivity increased to 92% with a specificity of 22% (133).

Based on these recent publications, we recommend discussing genetic testing with all patients with newly diagnosed breast cancer. Patients who are found to have a genetic predisposition to breast cancer, and whose life expectancy is ≥10 years, should be counseled about the benefits of risk-reducing measures including therapeutic and prophylactic mastectomies, chemoprevention, screening for other malignancies and lifestyle modifications (134). We further recommend that patients with a genetic predisposition to ovarian cancer should consider risk-reducing surgery with bilateral salpingo-oophorectomy, instead of OFS as part of their adjuvant therapy.

12. Future Considerations

Despite the overall excellent prognosis that most women with early ER-positive, HER2-negative breast cancer enjoy, some women may still suffer a recurrence years or decades after their initial diagnosis and treatment. Other women may be at a substantial risk of recurrence due to tumor stage, features, or age. Multiple ongoing efforts are attempting to prospectively identify those women who are at highest risk of recurrence in order to tailor current therapies. New targeted therapies such as cyclin dependent kinase (CDK) 4/6 inhibitors and other cytotoxic agents such as mechanistic target of rapamycin (mTOR) inhibitors that have demonstrated benefit in the advanced setting are now being studied in the adjuvant setting. Other approaches such as The Breast Cancer Weight Loss (BWEL) and the Aspirin in Preventing Recurrence of Cancer in Patients with Breast Cancer (ABC) studies are ongoing.

a. Cyclin Dependent Kinase Inhibitors

The role of CDK 4/6 inhibitors is well established as first or second line therapy of metastatic HR-positive breast cancer. There are three CDK 4/6 inhibitors (palbociclib, ribociclib and abemaciclib) approved by the United States Food and Drug Administration (FDA) in combination with endocrine therapies for the treatment of HR-positive metastatic breast cancer (135) and both ribociclib and abemaciclib have demonstrated OS benefits (136, 137). Given the PFS and OS benefits seen in advanced disease, these agents are currently being evaluated in the neoadjuvant, adjuvant and residual disease post neoadjuvant settings in an attempt to reduce the rate of recurrence after definitive treatment for early stage HR-positive disease (138). The PENELOPE-B study is a phase III study of 13 cycles of palbociclib plus standard endocrine therapy for patients with residual disease after taxane-based neoadjuvant chemotherapy (139). The PALLAS study is a phase III study assessing the addition of 2 years of palbociclib to 5 years of standard endocrine therapy in stage II-III disease (140). The MonarchE study is a phase III study of abemaciclib plus standard endocrine therapy in patients with high risk, lymph node positive breast cancer (141) and the NATALEE study is a phase III study of ribociclib plus endocrine therapy in the adjuvant setting (142). Until the results of these studies are reported, the use of adjuvant CDK 4/6 inhibitors, outside of the clinical trial setting, is not recommended.

b. PI3K Inhibitors

Approximately 40% of all HR-positive, HER2-negative breast cancers have activating mutations in PIK3CA and these mutations are known to be implicated with resistance to endocrine therapy (143, 144). Based on the recent Clinical Studies of Alpelisib in Breast Cancer 1 (SOLAR-1) study (144), alpelisib has recently been FDA approved, in combination with endocrine therapy, for PIK3CA-mutated hormone receptor positive metastatic breast cancer. It is anticipated that PI3 kinase inhibitors will also be studied in earlier stage disease.

c. Novel Biomarkers

Efforts are focusing on the identification of biomarkers that may predict patients at risk of late disease recurrence. Preliminary data suggests that circulating tumor cells (CTCs) may identify patients likely to develop late recurrences. Sparano et al. performed CTC analysis of patients who had participated in the Eastern Cooperative Oncology Group (ECOG) E5103 study of adjuvant chemotherapy with or without bevacizumab in lymph node positive or high-risk lymph node negative breast cancer (145, 146). Recurrence rates were significantly higher in patients who had CTCs detectable 5 years after diagnosis, compared to those without detectable CTCs and positive CTCs were associated with a 13-fold higher risk of disease recurrence (146). Another study evaluated the presence of CTCs in patients on the SUCCESS A trial which compared two adjuvant chemotherapy regimens followed by 2 or 5 years of zoledronic acid. Patients who had CTCs detectable 2 years after chemotherapy had inferior DFS and OS, and these differences were most notable in HR-positive patients (147). In both studies, even as little as one positive CTC assay, either 2 or 5 years after diagnosis, was found to be a prognostic biomarker for late clinical recurrence (146, 147).

Circulating tumor DNA (ctDNA) is another noninvasive liquid biopsy that, used together with next-generation sequencing (NGS) methods, can directly detect early stage cancers. Investigators have demonstrated that ctDNA was detectable at diagnosis in 67% of patients with stage I breast cancer, 59% of patients with stage II and 46% of patients with stage III disease and the presence of ctDNA may be prognostic (148). ctDNA has also been proposed as a means of detecting early disease recurrence after primary treatment, of identifying patients who may benefit from more aggressive adjuvant therapy and identifying molecular aberrations in tumors that may benefit from targeted therapies (149). Similarly, disseminated tumor cells (DTCs) in bone marrow aspirates are thought to represent residual disease (150). In the Pooled Analysis of DTC Detection in Early Breast Cancer (PADDY) study, 27% of patients with early stage breast cancer had DTCs detectable at diagnosis. DTCs were associated with HR status, tumor grade, tumor size and lymph nodes. In turn, DTCs were also associated with inferior DFS, breast cancer specific survival (BCSS) and OS (151). DTCs have been proposed as a prognostic biomarker and studies are ongoing to evaluate their role in this regard (152).

Although current research is heavily focused on the role of CTCs, ctDNA, DTCs and other prognostic biomarkers, the clinical utility and optimal way to incorporate these biomarkers into treatment paradigms is not yet known and the use of liquid biopsies for detection or surveillance are not yet standard of care. The lead-time for many of these assays is short, and there are no prospective data informing us how to intervene in the presence of CTCs or ctDNA post definitive therapy, nor do we know the frequency at which these assays should be tested. Large multi-institutional, prospective studies are planned to study the role of CTCs, ctDNA and other emerging biomarkers in HR-positive early stage breast cancer.

13. Conclusions

As we advance our knowledge of the biology and behavior of HR-positive breast cancer, the complexity of treating this disease in the early stage increases. Treatment recommendations should take patient age, menopausal status, tumor characteristics, predictive and prognostic genomic assays and perceived magnitude of benefit of therapy into consideration. Ultimately, treatment recommendations are individualized and decision-making should be a shared process between the patient and physician, taking patient preference and other prognostic factors into consideration. The treatment paradigm for this disease is likely to change in the future with the addition of novel agents such as CDK4/6 inhibitors and PI3K inhibitors, but currently endocrine therapy, with or without OFS, with or without chemotherapy remains standard of care for early stage HR-positive breast cancer.

Table 3(b):

Guidelines for the Use of MammaPrint

Guidelines for the Use of MammaPrint
Panel	Clinical Risk*	Patient Population	Recommendations
ASCO	Low Clinical Risk	Lymph Node Negative Disease	MammaPrint not recommended as no benefit from chemotherapy
		Lymph Node Positive Disease	MammaPrint not recommended as insufficient data
	High Clinical Risk	Lymph Node Negative Disease	Use MammaPrint to identify patients who may omit chemotherapy
		1-3 Positive Nodes	Use MammaPrint to identify patients who may omit chemotherapy (chemotherapy benefit can’t be excluded, especially in those with ≥2 lymph nodes)
NCCN	Low or High Clinical Risk	0-3 Positive Nodes	Use MammaPrint to identify patients who may consider omission of chemotherapy (test is prognostic but not predictive)

^*Clinical risk defined by hormone receptor status, tumor grade, tumor size and nodal status

ASCO: American Society of Clinical Oncology; NCCN: National Comprehensive Cancer Network