Endocrine Therapy in Premenopausal Hormone Receptor–Positive Breast Cancer

Abstract

Systemic therapy for premenopausal women with hormone receptor–positive breast cancer has evolved in the last 5 years, but critical questions remain. Recent randomized trials have demonstrated a benefit for the addition of ovarian suppression to endocrine therapy in patients with breast cancers considered to be at high risk for recurrence, whereas those with lower-risk cancers seem to have a favorable outcome with tamoxifen alone. Two large randomized trials have demonstrated a benefit for extending adjuvant tamoxifen beyond 5 years. Currently the choice of systemic therapy is selected empirically but molecular profiling may, in the near future, provide a more conclusive means of selecting an endocrine therapeutic approach for premenopausal patients. Given that a significant subset of hormone receptor–positive cancers are intrinsically resistant to endocrine agents, as well as the finding that inhibiting cyclin-dependent kinases 4 and 6 and mammalian target of rapamycin appears to potentially reverse this resistance in patients with metastatic disease, evaluation of these agents in the early-stage setting is ongoing.

Younger women have a higher incidence of estrogen receptor– and progesterone receptor–negative breast cancer compared with older patients.¹ Nevertheless, breast cancers expressing either estrogen receptor and/or progesterone receptor (also known as hormone receptor positive) remain the most common subtype of breast cancer in premenopausal women.¹ The role of ovarian removal in treating breast cancer dates back to the late 1800s, with the pivotal finding that oophorectomy could induce breast cancer remissions in premenopausal women.² With modern pharmaceutical developments, ovarian function suppression can now be achieved medically via gonadotropin-releasing hormone (GnRH) analogs³ as well as through surgery or radiation therapy.

Six randomized trials (Table 1) have recently had an impact on our understanding of the role of ovarian suppression as well as the duration of endocrine therapy for premenopausal women with hormone receptor–positive breast cancers. Prior trials had evaluated the role of ovarian function suppression as an adjuvant therapy for premenopausal women with hormone receptor–positive breast cancer, culminating in a meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group.³ None conclusively demonstrated a benefit for ovarian function suppression when added to other adjuvant strategies such as chemotherapy or tamoxifen. As a result, 5 years of tamoxifen without ovarian function suppression became the standard adjuvant endocrine therapy for premenopausal women diagnosed with hormone receptor–positive breast cancer.

Table 1.

Overview of Completed and Ongoing Randomized Trials Evaluating Adjuvant Endocrine Treatment in Premenopausal Women With Hormone Receptor–Positive Breast Cancers

This is reflected in the 2011 guidelines endorsed by ASCO.⁴ However, the effect of adding ovarian function suppression to tamoxifen, or substituting an aromatase inhibitor for tamoxifen after ovarian function suppression, remained unclear. Given that aromatase inhibitors are more effective than tamoxifen in postmenopausal women,^5,6 a strong rationale existed for studying the outcomes of aromatase inhibitor plus ovarian function suppression compared with single-agent tamoxifen for premenopausal women with hormone receptor–positive breast cancer.

Four randomized trials^7-10 have been reported in the last 5 years that demonstrate a benefit for ovarian function suppression in addition to either tamoxifen or an aromatase inhibitor in at least certain subsets of premenopausal women with early-stage hormone receptor–positive breast cancer (Table 1). These trials led to the revised 2016 ASCO guidelines that now recommend the addition of ovarian function suppression to either tamoxifen or aromatase inhibitor for premenopausal women with high-risk hormone receptor–positive breast cancer.¹¹

However, key questions remain unanswered in the adjuvant setting: how to define high-risk hormone receptor–positive breast cancer, whether ovarian function suppression is necessary in patients who will also be recommended adjuvant endocrine therapy for more than 5 years (extended endocrine therapy), the optimal sequence of tamoxifen or aromatase inhibitor plus ovarian function suppression, and whether to change women at high risk who are already receiving tamoxifen to tamoxifen/aromatase inhibitor plus ovarian function suppression. It seems unlikely that any prospective trials will be devised to answer these questions. Furthermore, including ovarian function suppression as part of adjuvant endocrine therapy clearly results in added toxicity^7,9 and may increase the risk of early discontinuation.

In contrast to the early-stage setting, the role of ovarian suppression in addition to endocrine therapy with tamoxifen in premenopausal patients with hormone receptor–positive metastatic breast cancer has been established.^12,13 Recent trials have demonstrated that the addition of cyclin-dependent kinase (CDK)^14-16 and mammalian target of rapamycin (mTOR) inhibitors^17,18 to endocrine therapy in postmenopausal patients with metastatic hormone receptor–positive breast cancer results in improved outcomes. These findings have led to ongoing randomized trials evaluating these agents in the adjuvant setting, which may lead to further increases in the complexity of treatment decisions for premenopausal women receiving adjuvant endocrine therapy.

ADJUVANT THERAPY WITH OVARIAN FUNCTION SUPPRESSION FOR PREMENOPAUSAL HORMONE RECEPTOR–POSITIVE BREAST CANCER

In four recent randomized trials,^7-10 the inclusion of ovarian function suppression as part of the adjuvant endocrine therapy regimen was tested in premenopausal hormone receptor–positive breast cancer (Table 1). Premenopausal status in these trials was defined as continuing menses or estradiol levels in premenopausal range within 6 to 8 months of study entry. These four trials provide important insights into the impact of including ovarian function suppression in adjuvant endocrine therapy for premenopausal women. Regarding the methods used to induce ovarian function suppression, no difference in disease-free survival (DFS) or overall survival (OS) has been demonstrated with the use of GnRH analogs compared with surgical or radiation-induced ablation. Therefore, any of these three modalities were allowed in the majority of these trials.^7,9,10 Interestingly, however, in vitro studies have demonstrated a direct antitumor effect of GnRH analogs on human breast cancer cells, although the effects in vivo are unclear.^19,20

The Eastern Cooperative Oncology Group E-3193 trial¹⁰ compared tamoxifen alone to tamoxifen plus ovarian function suppression as adjuvant therapy in premenopausal patients with hormone receptor–positive node-negative breast cancer measuring ≤ 3 cm in size. Ovarian function suppression could be achieved by surgery, radiation, or with GnRH analogs. Human epidermal growth factor receptor 2 (HER2) status is unknown for the vast majority of participants in E-3193. Patients were not permitted to have received adjuvant chemotherapy. At a median follow-up of nearly 10 years, this underpowered trial found no significant difference in DFS between the two arms (Table 1). However, this trial was prospectively designed and powered for its quality-of-life end points. Ovarian function suppression results in more menopausal symptoms and sexual dysfunction when added to tamoxifen. This increased symptom burden contributed to inferior self-reported health-related quality of life in E-3193.

The Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12 trial⁸ randomly assigned premenopausal women with stage I to II hormone receptor–positive breast cancers to tamoxifen or anastrozole, both combined with ovarian function suppression achieved using goserelin. Adjuvant therapy was given for only 3 years, shorter than the duration used in the other three trials. HER2 status is not reported for ABCSG-12, and only a minority of participants received chemotherapy. At a median follow-up of nearly 8 years, there remained no difference in DFS between the endocrine therapy arms of this trial (Table 1). Thus, ABCSG-12 did not show a benefit for aromatase inhibitors compared with tamoxifen when added to ovarian function suppression. In fact, the authors reported an unfavorable OS outcome compared with tamoxifen. One possible explanation is that premenopausal women who experience relapse despite adjuvant aromatase inhibitor therapy have more rapidly progressive disease that is unlikely to respond to endocrine treatment in the metastatic setting.

The Suppression of Ovarian Function (SOFT) trial⁹ randomly assigned patients to tamoxifen alone, ovarian function suppression plus tamoxifen, or ovarian function suppression plus exemestane. The companion Tamoxifen and Exemestane (TEXT) trial²¹ randomly assigned patients to ovarian function suppression with either tamoxifen or exemestane. Given lower than expected event rates, the primary end point of SOFT was changed to a comparison of tamoxifen plus ovarian function suppression versus tamoxifen. The comparison of exemestane plus ovarian function suppression compared with tamoxifen alone became a secondary end point.

In addition, the ovarian function suppression arms of TEXT and SOFT were combined for a planned evaluation of tamoxifen plus ovarian function suppression versus exemestane plus ovarian function suppression.^21,22 In contrast to E-3193 and ABCSG-12, patients receiving chemotherapy were included, as long as they were deemed premenopausal within 8 months of receiving chemotherapy or premenopausal upon starting endocrine therapy. Approximately 50% and 60% of patients accrued to the SOFT and TEXT trials, respectively, received chemotherapy.²¹ Those participants who received chemotherapy are considered to have higher-risk cancers solely on this basis. HER2 status was reported for the SOFT/TEXT trials; overall, 12.1% were HER2 positive, but this percentage is enriched among those receiving chemotherapy.

After a median follow-up of just more than 5.5 years,⁷ DFS in SOFT was not significantly different in those receiving tamoxifen alone compared with tamoxifen plus ovarian function suppression (84.7% v 86.6%; hazard ratio [HR], 0.83; 95% CI, 0.66 to 1.04; P = .10; Table 1). However, the rate of freedom from breast cancer for exemestane plus ovarian function suppression was found to be superior to tamoxifen alone (HR, 0.65; 95% CI, 0.49 to 0.87; Table 1). For the combined analysis of SOFT/TEXT after a median follow-up of 68 months, DFS was 91.1% versus 87.3% for the exemestane plus ovarian function suppression compared with tamoxifen plus ovarian function suppression (HR, 0.72; 95% CI, 0.60 to 0.85; P < .001).²¹

However, the inclusion of ovarian function suppression in endocrine therapy affects quality of life as a result of menopausal symptoms, such as hot flashes, loss of libido, and vaginal dryness.^7,21 These symptoms may impact compliance; approximately 20% of patients in the SOFT trial stopped ovarian function suppression therapy by 4 years after randomization.²¹ However, in E-3193, the rate of discontinuation as a result of adverse events was 8.9% for the tamoxifen plus ovarian function suppression arm and not significantly different than the single-agent tamoxifen arm (8.6%).¹⁰ The long-term effects of ovarian function suppression, particularly in younger women, are unknown, and monitoring of bone health is imperative.

WHICH PATIENTS BENEFIT FROM THE INCLUSION OF OVARIAN FUNCTION SUPPRESSION AS PART OF THE ADJUVANT ENDOCRINE THERAPY REGIMEN?

Given the added toxicity and relatively modest benefit in distant DFS,^7,21 subset analyses are being used to determine which patients benefit most from the addition of ovarian function suppression to endocrine therapy. In the SOFT trial,^7,21 patients who received chemotherapy were noted to have improved DFS with ovarian function suppression with either tamoxifen or exemestane compared with tamoxifen alone. This difference was especially notable in the small number of patients (n = 233) younger than 35 years of age, where the rate of freedom from breast cancer differed markedly for tamoxifen alone (67.7%) versus tamoxifen plus ovarian function suppression (78.9%) versus exemestane plus ovarian function suppression (83.4%).

Moreover, in the planned subset analysis of SOFT/TEXT trials for patients receiving adjuvant chemotherapy, there was evidence of benefit for tamoxifen plus ovarian function suppression versus tamoxifen alone in terms of reduction of breast cancer recurrences at 5 years (82.5% v 78.0%; HR, 0.78; 95% CI, 0.60 to 1.02), with a further improvement among those receiving exemestane plus ovarian function suppression (90.9%; 95% CI, 88.9 to 92.6).²¹ However, the receipt of chemotherapy among patients was high (94%), especially among younger women.

Additionally, we do not know what proportion of these young women had HER2-positive cancer or whether they received HER2-targeted therapies in addition to adjuvant chemotherapy. In the SOFT/TEXT studies, there seems to be no advantage for the addition of ovarian function suppression in patients with breast cancer deemed to be sufficiently low risk that adjuvant chemotherapy is not justified.⁷ This is also supported by findings from the Eastern Cooperative Oncology Group trial,¹⁰ in which patients did not receive chemotherapy.

The definition of high-risk breast cancer is rather arbitrary. The use of chemotherapy, although often determined on the basis of tumor characteristics such as stage, receptors, and grade, can be triggered solely by a patient’s age. Furthermore, enrollment in the SOFT/TEXT trials predated the current era in which molecular assays are often used to aid chemotherapy decision making. Currently, a number of molecular assays are available in the adjuvant setting for determining the risk for recurrence of hormone receptor–positive breast cancer and influencing chemotherapy administration. Thus, the patients who received chemotherapy in these trials would probably not be approached the same way today. The key question is whether the inherent risk for recurrence of the breast cancer solely determines the benefit from type of adjuvant endocrine therapy or if the biology of certain tumors is more indicative of the benefit.

Initial results prospectively validating the 21-gene recurrence score from the TAILORx trial²³ demonstrated an impressively low rate of recurrence at 5 years for patients with hormone receptor–positive cancers with recurrence score ≤ 10 (Table 2). Of these women with low-risk cancers treated with endocrine therapy alone, 30% were premenopausal at study entry. Using the 70-gene signature, the MINDACT trial²⁴ likewise noted a favorable outcome for patients with clinico-pathologically plus genomically low-risk cancers treated with endocrine therapy or no therapy, depending on receptor status (Table 2).

Table 2.

Molecular Assays Examining Prognosis in Hormone Receptor–Positive Breast Cancer

Luminal A cancers, determined either using immunohistochemistry²⁵ or genomically,^26,27 have additionally been demonstrated to have a favorable outcome. Other molecular assays, such as Breast Cancer Index (BCI)^28,29 and EndoPredict,³⁰ can also differentiate lower-risk from higher-risk cancers. In breast cancers with low risks of recurrence per these gene assays, it is unclear that the use of ovarian function suppression would further improve outcomes for patients. It seems probable that many of the patients identified as low risk in the SOFT trial,⁷ as well as patients recruited to E-3193¹⁰ and ABCSG-12,⁸ would have low-risk cancers according to these assays.

We can perhaps extrapolate that use of these assays might allow rational decision making regarding the inclusion of ovarian function suppression for many premenopausal patients. Further analysis of SOFT and TEXT results using these assays is ongoing. This should shed further light on which cancers merit the additional toxicity of ovarian function suppression with or without substitution of an aromatase inhibitor as opposed to single-agent tamoxifen.

DURATION OF ADJUVANT ENDOCRINE THERAPY IN PREMENOPAUSAL WOMEN

Another area of significant and recent change regards the duration of endocrine therapy. The Early Breast Cancer Trialists’ Collaborative Group clearly demonstrated a continuing, sustained risk of recurrence beyond 5 years.³¹ However, results of the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial³² demonstrated that 10 years of tamoxifen was no better than 5 years in patients with node-negative hormone receptor–positive breast cancer. This led to global abandonment of extended endocrine therapy use (eg, > 5 years). Subsequently, several trials demonstrated an advantage for aromatase inhibitor therapy after 5 years of tamoxifen in postmenopausal women.^33-35

Notably, MA.17^33,36 demonstrated a significant improvement in outcome for patients who were premenopausal at diagnosis and were postmenopausal after 5 years of tamoxifen who then received letrozole, regardless of whether the aromatase inhibitor was started immediately after tamoxifen or after a period of no therapy. Subsequently, two large trials^37,38 demonstrated a benefit for extending tamoxifen from 5 to 10 years, although the benefit was not derived until > 10 years after diagnosis (Table 1).

Most recently, MA.17R³⁹ reported a significant improvement in DFS (defined as survival without recurrent or new breast cancer events) for patients who received 10 versus 5 years of an aromatase inhibitor preceded by any duration of tamoxifen. MA.17R did allow patients who had been off aromatase inhibitor therapy for as long as 2 years to enroll; however, the majority of patients (90%) enrolled within 6 months of last receiving an aromatase inhibitor.³⁹ Much of the benefit seen in MA.17R was as the result of a decrease in contralateral breast cancer in the treatment arm; the rate of distant recurrence was 4.4% for those taking letrozole compared with 5.5% for those receiving placebo.³⁹

On the basis of these studies, extended adjuvant endocrine therapy should be considered in premenopausal patients with hormone receptor–positive breast cancer. The decision of which agent to use can be made on the basis of the patient’s menopausal status after 5 years of tamoxifen. In women who have received 5 years of tamoxifen and are still premenopausal, a further 5 years of tamoxifen can be considered. In women who become postmenopausal, 5 further years of endocrine therapy with an aromatase inhibitor can be considered.

However, there are limited data for other scenarios. For women who have received 10 years of tamoxifen, there are no data to support then changing to aromatase inhibitor therapy. Also, for premenopausal women who have received 5 years of aromatase inhibitor therapy plus ovarian function suppression, there are no data to support a further 5 years of endocrine therapy. Furthermore, extended adjuvant endocrine therapy is associated with increased toxicities. This includes uterine cancer in postmenopausal women receiving tamoxifen: ATLAS notes a cumulative risk of endometrial cancer during years 5 to 14 of 3.1% (mortality, 0.4%) for women allocated to continue tamoxifen compared with 1.6% (mortality, 0.2%) for control subjects (absolute mortality increase of 0.2%). Conversely, aromatase inhibitors confer a risk of bone loss and resultant fractures, particularly with extended durations of therapy.^37-39 MA.17R noted a fracture rate of 14% for participants on extended aromatase inhibitor therapy, despite high rates of bisphosphonate use.³⁹ Therefore, a better understanding of which patients should receive extended endocrine therapy is needed.

In the MA.17 trial, patients with node-positive disease as well as those with cancers expressing both estrogen and progesterone receptors seemed to derive the greatest benefit from extended adjuvant therapy.^33,40 Several molecular assays, including PAM50 risk of recurrence,⁴¹ BCI,⁴² and EndoPredict,⁴³ have been shown to be predictive of the likelihood of recurrence in years 5 to 10 after diagnosis (Table 2). Recently, a combination of the recurrence score and the single-gene estrogen receptor expression has been demonstrated to be prognostic for later recurrences.⁴⁴ Each of these molecular assays is able to identify individual patients with cancers with a low risk of late recurrences, such that extended adjuvant endocrine therapy is unlikely to have a significant impact on this risk. The HOXB13:IL17BR (H/I) ratio of BCI is the only assay to date that has been demonstrated to be predictive of benefit of extended adjuvant endocrine therapy with letrozole from the MA.17 trial.⁴³ The BCI has not yet been evaluated as a predictor of extended endocrine therapy in premenopausal women.

In summary, extended adjuvant endocrine therapy should be discussed with patients at the completion of 5 years of tamoxifen. Decisions should be made on an individual basis for each patient, and use of a molecular assay could be considered to aid with decision making. A key question remains regarding how much additional benefit an individual premenopausal patient will receive following an initial 5 years of adjuvant therapy that includes ovarian function suppression and either tamoxifen or an aromatase inhibitor. Similarly, the addition of ovarian function suppression with its attendant increased toxicity may not be necessary in patients for whom extended adjuvant endocrine therapy is planned. Hopefully, further analysis and correlative studies from the randomized trials can shed more light on these critical questions.

THE ADDITION OF TARGETED AGENTS TO ENDOCRINE THERAPY

Within the past 5 years, the CDK inhibitor palbociclib and the mTOR inhibitor everolimus were approved in addition to endocrine therapy for postmenopausal patients with metastatic hormone receptor–positive disease. The addition of palbociclib to letrozole in the first-line setting has been demonstrated in two randomized trials^15,16 to double PFS compared with letrozole alone. The addition of palbociclib or everolimus to endocrine therapy has been demonstrated to significantly improve PFS in patients with hormone receptor–positive metastatic breast cancer previously treated with endocrine therapy, including nonsteroidal aromatase inhibitors.^14,17,18

There is a paucity of trials specifically focused on optimal endocrine therapy in premenopausal patients with hormone receptor–positive metastatic breast cancer. A pivotal randomized trial,¹² however, demonstrated improved PFS for premenopausal patients with hormone receptor–positive metastatic breast cancer, treated with ovarian function suppression plus tamoxifen compared with either modality alone. These findings were later confirmed in a meta-analysis.¹³ Thus, the standard approach for premenopausal patients is to render them postmenopausal; this allows the use of aromatase inhibitors and potential entry into clinical trials evaluating novel approaches in postmenopausal patients. The MONALEESA-7 trial is evaluating ovarian function suppression with either tamoxifen or an aromatase inhibitor, with or without the CDK inhibitor ribociclib, as first-line treatment in premenopausal patients with hormone receptor–positive metastatic breast cancer.

The addition of either everolimus or palbociclib to endocrine therapy is being evaluated in the early-stage setting in the SWOG 1207 and PALLAS trials, respectively (Table 1). Premenopausal women are eligible for these trials and can receive tamoxifen alone, or tamoxifen or an aromatase inhibitor with ovarian suppression. These trials are enrolling patients at higher risk on the basis of nodal status or molecular assays. However, predictive biomarkers for determining who will potentially benefit from mTOR or CDK inhibitors would be desirable.

SUMMARY

Adjuvant endocrine therapy for premenopausal patients has changed considerably and rapidly in the past 5 years. Clinical trials have shown the benefit for both extended durations of endocrine therapy as well as more complete estrogen suppression. With the advent of data from the SOFT/TEXT, ATLAS, and aTTom trials, there are a number of critical decisions to be made with regard to type and duration of adjuvant endocrine therapy for premenopausal patients with hormone receptor–positive breast cancer. On the basis of the SOFT/TEXT trials, the use of ovarian function suppression should probably be restricted to patients with higher-risk cancers, as outlined by the ASCO guidelines.¹¹

The definition of high risk, however, remains imprecise, and the need for chemotherapy and patient age are our best surrogates at this time. Overall, the subset analysis data support the use of an aromatase inhibitor with ovarian function suppression rather than tamoxifen in these high-risk cancers. The need to assess menopausal status biochemically for patients treated by ovarian function suppression remains controversial and is currently not recommended as standard practice. In general, the use of GnRH analogs as a means of achieving ovarian suppression is preferred to surgery or radiation, at least initially, and clearly is optimal in patients who want to ultimately become pregnant.

For patients with lower-risk cancers, including those for whom chemotherapy is not recommended and potentially those with low-risk cancers on the basis of molecular assays, tamoxifen alone seems to be optimal. All patients regardless of whether they have low- or high-risk disease should be considered for extended adjuvant endocrine therapy, the choice of which should be on the basis on the patient’s menopausal status upon completion of 5 years of tamoxifen. Molecular assays predicting late-recurrence risk may be considered as an aid to shared decision making for extended therapy. Entry into clinical trials evaluating the addition of targeted agents to endocrine therapy should be discussed, especially for patients with higher-risk cancers.

AUTHOR CONTRIBUTIONS

Conception and design: All authors

Collection and assembly of data: All authors

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Endocrine Therapy in Premenopausal Hormone Receptor–Positive Breast Cancer

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jop.ascopubs.org/site/misc/ifc.xhtml.

Amye J. Tevaarwerk

Research Funding: Takeda (Inst)

Kari B. Wisinski

Research Funding: Novartis (Inst), Daiichi Sankyo (Inst), Genentech (Inst), AstraZeneca (Inst), Eli Lilly (Inst)

Ruth M. O’Regan

Consulting or Advisory Role: Genentech, Eisai, Eli Lilly, Pfizer, Puma Biotechnology, bioTheranostics

Research Funding: Eisai (Inst), Pfizer (Inst), Novartis (Inst)

Travel, Accommodations, Expenses: Genentech, Eli Lilly, bioTheranostics