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Systemic Therapy of Hormone-Sensitive HER2-Negative Breast Cancer: Adjuvant and Neoadjuvant
Introduction
Breast cancer is the most common malignancy diagnosed in women worldwide. In the United States alone, more than 284,000 new cases are expected in 2021. Breast cancer mortality has declined in recent years, in part due to early diagnosis via screening, and in part due to advances in systemic therapy for early stage disease. Today, most patients diagnosed with breast cancer have early-stage disease, for which cure is frequently possible.
Among the different subtypes of breast cancer, hormone receptor (ER/PR)-positive disease is the most common, accounting for approximately 75% of new diagnoses, the majority of which are also human epidermal growth factor-2 (HER2)-negative. Despite overall improvements in outcomes for early-stage breast cancer, late recurrence of ER/PR-positive, HER2-negative breast cancer remains an ongoing clinical challenge.
Treatment of early-stage ER/PR-positive, HER2-negative breast cancer typically includes both local therapy (surgery with or without radiation therapy) and adjuvant systemic therapy. The main types of systemic therapies used in the management of early-stage ER/PR-positive, HER2-negative breast cancer are endocrine therapy and, in some cases, chemotherapy. Emerging data also support the use of targeted therapies in specific scenarios. Systemic therapy for early-stage ER/PR-positive, HER2-negative breast cancer is generally administered postoperatively in the adjuvant setting, although neoadjuvant therapy initiated before surgery is utilized in some cases.
Adjuvant systemic therapy is given with curative intent. Meta-analyses performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) evaluating individual patient-level data from multiple clinical trials have consistently demonstrated that adjuvant systemic therapy reduces the risks of locoregional recurrence, distant recurrence, contralateral new primary breast cancer, and death. For ductal carcinoma in situ (DCIS), the intent of adjuvant therapy is limited to prevention of ipsilateral in-breast recurrence for those who undergo breast conservation and prevention of contralateral breast cancers.
In this chapter, we will review the current approach to systemic therapy for ER/PR-positive DCIS and ER/PR-positive, HER2-negative early-stage invasive breast cancer. We will discuss the strategies used to guide selection of therapies, timing of therapy, key trials that have led to the current standard of care and summarize our management approach, plus ongoing unanswered questions and future directions.
Overview of Types of Systemic Therapy for Er/Pr-Positive, Her2-Negative Early Breast Cancer
Endocrine Therapy
The observation that endocrine manipulation can be therapeutic for breast cancer predates the discovery of the ER and PR in breast tumors in the 1970s. It was subsequently established that the benefit from adjuvant endocrine therapy is limited to ER/PR-positive breast cancer, making endocrine therapy the first “targeted therapy.” ER status (positive or negative) is the single most important factor predictive of benefit from endocrine therapy. The strength of ER expression is predictive of the degree of benefit from adjuvant endocrine therapy, with stronger expression associated with greater benefit. Current guidelines use 1% expression on immunohistochemical (IHC) assay as the cut-off to define ER/PR-positivity. However, guidelines grant clinicians discretion with regard to administration of endocrine therapy for patients whose tumors have low positive ER expression (typically defined as 1%–10% expression on IHC assay), as the benefit of endocrine therapy is less certain for these patients than for patients whose tumors have stronger ER/PR expression.
The binding of estrogen to the ER results in a series of downstream steps that modulate transcription of genes responsible for cellular function, tumor growth, invasion, angiogenesis, and survival. Endocrine therapy either antagonizes the ER or causes estrogen deprivation. Types of endocrine therapy used in the treatment of early-stage ER/PR-positive breast cancer include selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), ovarian ablation (OA), and ovarian function suppression (OFS) ( Table 51.1 ). Although endocrine therapy may be initiated preoperatively in the neoadjuvant setting in certain instances, the majority of endocrine therapy is administered postoperatively in the adjuvant setting, with treatment continuing for 5 or more years.
Table 51.1
Current Endocrine Therapy Options for Early-Stage ER/PR-Positive Breast Cancer
| Selective Estrogen Receptor Modulators | Aromatase Inhibitors | Ovarian Ablation | Ovarian Function Suppression a |
|---|---|---|---|
| Tamoxifen 20 mg oral daily | Anastrozole 1 mg oral daily | Oophorectomy | Goserelin 3.6 mg subcutaneous every 28 days |
| Tamoxifen 5 mg oral daily b | Letrozole 2.5 mg oral daily | Ovarian irradiation | Triptorelin 3.75 mg intramuscular every 28 days |
| Exemestane 25 mg oral daily | Leuprolide 3.75 mg intramuscular every 28 days |
a Ovarian function suppression is typically administered by every-28-day injection of an LHRH agonist. Although formulations that require less frequent dosing are available, limited data support their use in breast cancer and every 28-day dosing is usually recommended.
b Consideration for patients with DCIS who have concerns about toxicity or who are not able to tolerate the 20 mg dose.
Selective Estrogen Receptor Modulators
Tamoxifen, a nonsteroidal oral SERM that competes for estrogen binding sites in target tissues including the breast, is the only SERM approved for the adjuvant treatment of breast cancer, with single-agent activity observed regardless of menopausal status. Notably, its effects on target genes and tissues are mixed, with antagonistic effects in breast tissue but agonistic effects on other tissues such as the uterus and bone.
Aromatase Inhibitors
Conversion of adrenal androgens to estrogen by peripheral tissues is the primary source of estrogen in postmenopausal women. AIs block aromatase, the enzyme that converts adrenal androgens to estrogen. Currently available AIs are the third-generation reversible nonsteroidal inhibitors, anastrozole and letrozole, and the irreversible steroidal inactivator, exemestane. Adjuvant therapy with steroidal and nonsteroidal AIs is equally effective. AI monotherapy is not effective in premenopausal women, as it does not block production of estrogen in the ovaries. Thus, while AIs can be administered as single agents to postmenopausal women, premenopausal women treated with an AI must either receive concurrent OFS or undergo OA prior to AI initiation.
Ovarian Ablation and Ovarian Function Suppression
The ovaries are the primary site of estrogen production in premenopausal women. Ovarian estrogen production can be blocked by OA or OFS. OA is permanent and may be accomplished by oophorectomy or by ovarian irradiation. OFS is typically reversible and accomplished with gonadotropin-releasing hormone (GnRH) agonists, also called luteinizing hormone–releasing hormone (LHRH) agonists. In randomized clinical trials evaluating OFS strategies, LHRH agonists were typically given every 28 days, although some data suggest noninferiority of every-3-month injections with regard to estrogen suppression and induction of amenorrhea in women with early-stage ER/PR-positive breast cancer.
Chemotherapy
Chemotherapy is recommended for high-risk early-stage invasive ER/PR-positive, HER2-negative breast cancer. When administered, there is no single optimal chemotherapy regimen for early-stage ER/PR-positive, HER2-negative breast cancer. Common chemotherapy regimens used for invasive early-stage ER-positive, HER-negative breast cancer in the United States include docetaxel/cyclophosphamide and, for higher risk disease, doxorubicin/cyclophosphamide followed by a taxane. Chemotherapy is usually administered in the adjuvant setting for ER/PR-positive, HER2-negative breast cancer, although it can be administered in the neoadjuvant setting if the treatment decision can be made without information obtained at surgery.
Targeted Therapies
While endocrine therapy with or without chemotherapy is the backbone of systemic therapy for early-stage ER/PR-positive, HER2-negative breast cancer, data indicate benefit from the addition of targeted therapies in certain clinical scenarios. For example, inclusion of adjuvant olaparib, a poly ADP ribose polymerase (PARP) inhibitor, in the systemic therapy regimen for high-risk ER/PR-positive, HER2-negative breast cancer associated with pathogenic germline mutations in BRCA1 or BRCA2 reduces recurrence. Additionally, data demonstrate that two years of adjuvant abemaciclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, given in conjunction with 5 or more years of endocrine therapy reduces early recurrence in patients with high-risk invasive ER/PR-positive, HER2-negative early-stage breast cancer.
Adjuvant Systemic Therapy for Er/Pr-Positive Ductal Carcinoma in Situ
The prognosis for patients with DCIS is excellent, with minimal risk of distant metastases or breast cancer mortality. However, patients with DCIS are at risk for new contralateral primary breast cancers, and those who have undergone breast-conserving therapy are at risk for invasive and in situ ipsilateral recurrences. Endocrine therapy can be administered for chemoprevention after local therapy for DCIS, with the aim of reducing the risk of an in-breast recurrence for those who have had breast-conserving surgery and reducing new contralateral primary breast cancers. However, endocrine therapy has no impact on the risk of distant metastases or mortality after DCIS. Randomized trials have evaluated both tamoxifen and AIs as adjuvant endocrine therapy for DCIS.
Tamoxifen
The NSABP B-24 study investigators randomized 1799 women with DCIS who had undergone breast-conserving surgery and radiation to either tamoxifen 20 mg daily or to placebo for 5 years. Compared with placebo, tamoxifen reduced the risk of invasive ipsilateral breast tumor recurrence (IBTR) by 32% (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.49–0.95, P = 0.025) and the rate of contralateral new breast cancers by 32% (HR 0.68, 95% CI 0.48–0.95, P = 0.023). Tamoxifen also reduced the risk of recurrent DCIS in the ipsilateral breast, although this was not statistically significant (HR 0.84, 95% CI 0.60–1.19, P = 0.33). Younger women, those who presented with a palpable abnormality, and those with positive surgical margins had higher risk of invasive and noninvasive IBTR, although the prognostic impact of positive margins was less strong among those who received tamoxifen. In addition, the presence of comedonecrosis was associated with higher risk of recurrent ipsilateral DCIS. The risk of distant metastases in the absence of a prior invasive recurrence was low in both arms, and tamoxifen receipt did not affect mortality. However, mortality was increased among women who developed a subsequent invasive ipsilateral recurrence (HR 1.75, 95% CI 1.45–2.96, P < 0.001).
Of note, ER/PR-positive status was not required for patients with DCIS who participated in the NSABP B-24 trial. Subsequent to publication of the primary findings from the NSABP B-24 trial, the investigators assessed ER and PR in a subset of the study participants (n = 732). ER and PR were positive in 76% and 66% of cases, respectively, and the benefits of tamoxifen were limited to the ER/PR-positive group. Moreover, as is the case for invasive breast cancer, the addition of PR to ER status did not add to prediction of benefit from adjuvant tamoxifen. Among the ER-positive group, tamoxifen was associated with a statistically significant reduction in the risk of any breast cancer event (HR 0.58, 95% CI 0.415–0.81, P = 0.0015), any invasive breast cancer (HR 0.53, 95% CI 0.34–0.82, P = 0.005), and any contralateral breast cancer (HR 0.5, 95% CI 0.28–0.88, P = 0.02). The risk of any future breast cancer event was 31% and 20% for the placebo and tamoxifen arms, respectively. For invasive breast cancer, these risks were 19% and 12%, respectively, while for future contralateral breast cancer these risks were 11% and 6%. Aside from tamoxifen, the only factor associated with breast cancer recurrence was age, with greater risk in participants under 50 years at study entry.
The UK/ANZ DCIS trial investigators randomized 1694 women with DCIS who had undergone breast-conserving surgery with negative margins to radiation, tamoxifen 20 mg daily for 5 years, or both in a 2 × 2 factorial design. The majority of the study participants were 50 to 64 years old, with only a small fraction of younger women. ER/PR-positive status was not required for eligibility. After a median follow-up of 12.7 years, tamoxifen reduced the 10-year risk of new breast events from 24.6% to 18.1% (HR 0.71, 95% CI 0.58–0.88, P = 0.002). However, the ipsilateral benefit of tamoxifen was limited to reducing the risk of future DCIS (HR 0.70, 95% CI 0.51–0.86, P = 0.03), as tamoxifen did not reduce the risk of future ipsilateral invasive breast cancer (HR 0.95, 95% CI 0.66–1.38, P = 0.79). It is not clear why the UK/ANZ and B-24 findings differ with regard to the effect of tamoxifen on future ipsilateral invasive breast cancer, although it may be partly explained by differences in age distribution between B-24 and UK/ANZ study participants. Overall, tamoxifen reduced the 10-year risk of future contralateral breast cancer events from 4.2% to 1.9% in the UK/ANZ study (HR 0.44, 95% CI 0.25–0.77, P = 0.005), a similar degree of risk reduction as in the B-24 study. Similar to the B-24 study, tamoxifen did not impact mortality in the UK/ANZ trial.
Despite established benefits of tamoxifen for chemoprevention after DCIS, uptake is relatively low, potentially due to concerns about side effects and the lack of survival benefit in randomized studies. Moreover, a significant proportion of patients do not complete 5 years of therapy. Based on preclinical data suggesting equivalent antiproliferative effects using a 5-mg dose of tamoxifen compared to the standard 20-mg dose, investigators more recently randomized 500 patients who had undergone surgery for DCIS, lobular carcinoma in situ, or atypical ductal hyperplasia to receipt of tamoxifen 5 mg daily for 3 years or to placebo. Approximately two-thirds of study participants had DCIS, and the majority of study participants had undergone breast-conserving surgery. After a median follow-up of 5.1 years, the cumulative rates of breast cancer events (invasive or DCIS) in the tamoxifen and placebo arms were 6.4% and 11%, respectively (HR 0.48, 95% CI 0.26–0.92, P = 0.02). The toxicity profile associated with tamoxifen was favorable without an observed increase in serious adverse events compared to placebo. Although 3 years of tamoxifen at the 5 mg daily dose has not been compared to 5 years of tamoxifen at the 20 mg daily dose, the shorter, lower-dose regimen is a reasonable consideration for patients with concerns about toxicity and/or those who are not able to tolerate the 20 mg dose for 5 years.
Aromatase Inhibitors
Based on the observed benefits of adjuvant AI therapy compared to tamoxifen for postmenopausal women with invasive breast cancer that will be discussed later in this chapter, several trials evaluated AI therapy for chemoprevention in postmenopausal women with ER/PR-positive DCIS. The phase III NSABP B-35 investigators randomized 3104 postmenopausal women to anastrozole 1 mg daily or to tamoxifen 20 mg daily for 5 years after completion of breast-conserving therapy. With a median follow-up of 9 years, anastrozole was associated with a 27% reduction in the risk of any future breast cancer event, with 93.1% of participants in the anastrozole arm and 89.1% of participants in the tamoxifen arm estimated to be free of breast cancer after 10 years. Notably, a significant time-by-treatment interaction was observed, with the benefit of anastrozole compared to tamoxifen emerging after 5 years of follow-up (interaction P = 0.04). Additionally, there was a significant age-by-treatment interaction with the benefit of anastrozole in reducing future breast events compared to tamoxifen observed in participants under age 60 years (interaction P = 0.04). While future ipsilateral events were not reduced with the use of anastrozole compared to tamoxifen, the reduction in risk of future contralateral invasive breast cancer was statistically significant (HR 0.52, 95% CI 0.31–0.88, P = 0.01). Overall survival (OS) was excellent, with no difference between arms.
In contrast to NSABP B-35, in the similarly designed IBIS-II DCIS trial (n = 2980), anastrozole 1 mg daily for 5 years was noninferior to tamoxifen 20 mg daily for 5 years with regard to recurrence events, but superiority of the AI was not demonstrated ( P = 0.49). The explanation for the difference in findings between the NSABP B-35 and IBIS-II DCIS trials is not certain, although the lack of superiority of anastrozole in the IBIS-II DCIS trial may be due to inadequate power in the setting of low event rates. Regardless, it is safe to conclude that either adjuvant tamoxifen or an AI is an appropriate option for chemoprevention for postmenopausal women with ER-positive DCIS, and the choice may be driven by side effect profile for many patients. Additionally, while most trials evaluating adjuvant endocrine therapy for chemoprevention after surgery for ER/PR-positive DCIS focused on patients who had undergone breast-conserving surgery, endocrine therapy can be reasonably considered after mastectomy for ER/PR-positive DCIS for the purposes of contralateral prevention.
Adjuvant Endocrine Therapy for Er/Pr-Positive, Her2-Negative Early-Stage Invasive Breast Cancer
Beginning in the 1980s, the EBCTCG meta-analyses established 5 years of tamoxifen as a standard adjuvant therapy for early-stage invasive breast cancer. Adjuvant endocrine therapy reduces the risk of locoregional recurrence, distant recurrence, contralateral new primary breast cancer, and death. The benefits of adjuvant endocrine therapy are substantial, with recurrence rates almost halved and mortality rates reduced by approximately one-third. Benefits are long-lasting, with a carry-over benefit continuing at least 5 years beyond the conclusion of therapy.
Despite these established and lasting benefits of 5 years of endocrine therapy, late recurrence of ER/PR-positive, HER2-negative invasive breast cancer is a critical clinical problem. More than half of recurrences occur more than 5 years after diagnosis. A recent EBCTCG meta-analysis using data from 62,923 women who were disease-free after completion of 5 years of endocrine therapy demonstrated that the risk of distant recurrence and death due to breast cancer increases steadily during years 5 to 20 ( Table 51.2 ). Approximately two-thirds of the patients included in this meta-analysis had received 5 years of tamoxifen alone as their initial endocrine therapy. The risk of late recurrence varied substantially according to tumor characteristics at diagnosis, with higher risks observed in patients with greater nodal burden and larger tumor size. For example, among individuals with four to nine involved axillary nodes, estimated 20-year risks of distant recurrence and death were approximately 50%. While risks were significantly lower in patients with node-negative disease, a significant proportion still experienced late recurrence. Even among patients with node-negative disease, the estimated 20-year risks of distant recurrence and death due to breast cancer were 22% and 15%, respectively. Although modern therapies have mitigated this risk to some extent, late recurrence still remains an important clinical problem.
Table 51.2
Estimated 10- and 20-Year Risks of Distant Recurrence and Death Due to Breast Cancer by Nodal Status Among Patients Who Were Disease-Free After 5 years of Endocrine Therapy
Data from Pan H, Gray R, Braybrooke J, et al. 20-Year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med . 2017;377(19):1836-1846.
| Negative Nodes (%) | One to Three Involved Nodes (%) | Four or More Involved Nodes (%) | ||
|---|---|---|---|---|
| Distant recurrence | 10-year risk | 11 | 19 | 36 |
| 20-year risk | 22 | 31 | 52 | |
| Death due to breast cancer | 10-year risk | 8 | 14 | 29 |
| 20-year risk | 15 | 28 | 49 | |
While 5 years of tamoxifen remains an option for some individuals, multiple clinical trials have evaluated alternative endocrine therapy strategies to improve upon the outcomes achieved with 5 years of tamoxifen. Broad strategies that have been evaluated include longer durations of therapy, sequential use of tamoxifen and AIs, AI monotherapy, and the use of OA or OFS with tamoxifen or an AI ( Fig. 51.1 ). With expanding data from these trials, adjuvant endocrine therapy decisions are increasingly complex and differ by menopausal status and recurrence risk.
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