Extending Adjuvant Endocrine Therapy in Breast Cancer: Who, What, Why?

Oncology (Williston Park). 33(6):243-6.

Shaveta Vinayak, MD, MS

Nancy E. Davidson, MD

Adjuvant endocrine therapy provides substantial benefit by reducing breast cancer recurrences and improving associated mortality in early-stage endocrine-responsive breast cancers (estrogen receptor– and/or progesterone receptor–positive). Residual risk of relapse, even after completion of 5 years of adjuvant endocrine therapy, has fueled development of extended therapy (beyond 5 years) trials. However, several questions remain when recommending extended adjuvant endocrine therapy, such as those concerning patient selection, agent of choice, use of biomarkers or clinical variables to assess residual risk of relapse, and duration of treatment. In this article, we will provide a case-based expert opinion on: 1) the duration of extended adjuvant endocrine therapy in both premenopausal and postmenopausal women; 2) use of biomarkers in guiding this decision; and 3) toxicities to be considered when recommending extended adjuvant endocrine therapy. We also provide key factors to consider, including patient preference, when guiding our patients in this important treatment decision.

Case Scenario

Ms. BC is a 48-year-old woman who was diagnosed with breast cancer in 2012 when she was premenopausal (pT2N1 left breast invasive ductal carcinoma-grade 2, strongly positive estrogen receptor [ER; > 90%], strongly positive progesterone receptor [PR; > 90%], and human epidermal growth factor receptor 2 [HER2]/neu-negative). She underwent left lumpectomy with left sentinel lymph node biopsy, which revealed a 2.5-cm tumor and involvement of 1 of 5 sentinel lymph nodes, with a metastatic focus of 0.5 cm. She received adjuvant anthracycline/taxane-based chemotherapy followed by left breast radiation, and has now completed 5 years of tamoxifen for adjuvant endocrine therapy. She has not had a menstrual period in 3 years.

Several key questions arise in our shared decision-making process on the role of extended adjuvant endocrine therapy with Ms. BC. These include: 1) What is her residual risk of distant breast cancer relapse after 5 years of tamoxifen? 2) Can additional clinicopathologic factors or biomarkers inform this decision? 3) What is the potential additional benefit of extended endocrine therapy? 4) What is the optimal agent-tamoxifen or aromatase inhibitors (AIs)? 5) Does she have any comorbidities that will affect this decision? 6) What side effects are acceptable to Ms. BC? We will provide our expert opinion on Ms. BC’s case throughout this article.

Endocrine-responsive breast cancers (ER- and/or PR-positive) represent the majority of early breast cancers in the United States; therefore, effective treatments for this breast cancer subtype can significantly reduce breast cancer recurrences and improve associated mortality. Indeed, endocrine therapy was the first “precision” cancer therapy for hormone-responsive breast cancers, and it remains the cornerstone. For many years, 5 years of adjuvant endocrine therapy, regardless of the agent, was considered standard of care for early-stage breast cancer. However, the unrelenting risk of relapse for up to 20 years from diagnosis, which is observed despite completing 5 years of endocrine therapy, demands improvement in our standard of care.[1]

Key Clinical Questions to Be Addressed

1. What is the recommended duration of adjuvant endocrine therapy for premenopausal and postmenopausal women?

2. Can biomarkers help guide us in this decision?

3. What are the side effects of extended adjuvant endocrine therapy, and how can we help improve our patients’ quality of life while on these agents?

1. What is the recommended duration of adjuvant endocrine therapy for premenopausal and postmenopausal women?

Though it is generally accepted that all women with early-stage hormone-responsive invasive breast cancer should receive 5 years of adjuvant endocrine therapy, there is no single approach for the recommendation of extended adjuvant endocrine therapy (ie, more than 5 years). Key considerations include residual risk of relapse, expected benefit of extended therapy, menopausal status, medication toxicity, and patient perspective. Independent of menopausal status, two pivotal randomized trials (ATLAS and aTTom) provide high level of evidence supporting the use of tamoxifen for up to 10 years, which shows a large impact on reduction of distant recurrence and overall mortality (seen in the ATLAS trial).[2,3] The largest risk reduction in both recurrence (relative risk [RR], 0.75; P = .003) and breast cancer mortality (RR, 0.71; P = .002) was seen after year 10, which can be attributed to the carryover benefit of tamoxifen as seen in other studies.[3] Thus, strong evidence supports the use of 10 years of tamoxifen.

Though this patient was diagnosed before the use of ovarian function suppression (OFS) in premenopausal women, the role of OFS as a component of adjuvant endocrine therapy upfront was elucidated in the recent SOFT/TEXT trials, in which premenopausal women received tamoxifen alone or combination therapy with OFS and either tamoxifen or the steroidal AI exemestane for 5 years.[4] Together, these studies showed that OFS plus tamoxifen or OFS plus exemestane improves disease-free survival (DFS) compared with tamoxifen alone; however, overall survival (OS) benefit has not yet been seen. Not surprisingly, the high-risk subgroup with factors such as receipt of adjuvant chemotherapy, lymph node involvement (4 or more positive nodes), and young age (< 35 years) benefitted the most from OFS plus exemestane, with a 10% to 15% improvement in the 5-year breast cancer–free interval.[5] No data exist on the utility of the combined approach beyond 5 years, nor is there information to guide decisions on selection of a strategy of 10 years of tamoxifen vs 5 years of an AI with OFS at the time of diagnosis.

In our practice, a thorough discussion of benefits and toxicities is advised. In general, combination endocrine therapy with OFS is more poorly tolerated than tamoxifen alone. OFS is given as a monthly injection and can lead to abrupt menopause, with symptoms of hot flashes, vaginal atrophy, and sexual dysfunction. AIs may be associated with bothersome symptoms, such as arthralgias and myalgias, which may impact daily activities. Some high-risk women for whom combination endocrine therapy with OFS is recommended may choose not to proceed with this option because of concern about these symptoms. For those who select this option, we typically advise a trial of the OFS-based therapy before proceeding with any permanent procedures, such as bilateral salpingo-oophorectomy, in case they have poor tolerance of either the AI or the OFS injection. We do not generally extend OFS-based therapy beyond 5 years.

For postmenopausal women, several randomized trials, including the National Cancer Institute of Canada Clinical Trials Group MA.17 and MA.17R trials, the Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 6a, and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-33 trial,[6-9] have shown that up to 10 years of endocrine therapy (generally involving a switch from tamoxifen to AIs) improves outcomes. In most of these trials, the initial therapy was variable, and a switch to an AI was made later during the treatment. Extended therapy AI trials have predominantly shown a benefit in DFS (eg, MA17.R), but no OS benefit has been shown as of yet.[7] This may reflect the relatively short-term follow-up (median follow-up, 6.3 years), since the hormone-responsive breast cancer subtype tends to have delayed distant recurrences that impact mortality. It is noteworthy that much of the disease-free interval benefit in these trials was related to contralateral breast cancer risk,[7] and we take this into consideration when counseling patients regarding extended use. At present, we particularly consider extended AI therapy for healthy postmenopausal women with high-risk breast cancer at the time of diagnosis. These recommendations are congruent with the recently updated focused American Society of Clinical Oncology (ASCO) guidelines on adjuvant endocrine therapy in postmenopausal women.[10]

In sum, several questions about treatment selection remain unanswered in clinical practice when recommending adjuvant endocrine therapy. One is the role of subsequent treatment for premenopausal women who have completed 5 years of combination AIs with OFS upfront, based on the SOFT/TEXT trials. For postmenopausal women, we still await evidence of a survival advantage with the use of extended AI treatment, as the data mature. Finally, at this time there are few data on the use of any extended adjuvant endocrine therapy beyond 10 years, though it is possible that there may be a role for this in very high-risk patients.

Case follow-up

Given that Ms. BC had premenopausal breast cancer with a tumor size greater than 2 cm and axillary lymph node involvement, and received adjuvant chemotherapy, she fits the high-risk profile. Had she been diagnosed today, use of OFS plus AIs or OFS plus tamoxifen for 5 years might have been recommended, but this was not a standard option when she was diagnosed in 2012. Her last menstrual period was 3 years ago, but it is possible that she is still chemically premenopausal, and evaluation of hormone levels would be important. If she is chemically postmenopausal, her options for extended therapy include AIs or tamoxifen for 5 years. Ms. BC reports a significant history of early-onset osteoporosis in her family and wants to obtain a bone density test before making her decision. Moreover, her friend who is a breast cancer survivor has recommended the Breast Cancer Index test.

2. Can biomarkers help guide us in this decision?

Two important unmet needs in hormone- responsive breast cancer are better identification of patients who are at risk for late recurrences, and demonstration that additional therapy like extended adjuvant endocrine therapy will improve outcomes. There is no consensus on the level of risk that is acceptable for avoiding extended adjuvant endocrine therapy. Several efforts in identifying factors, including tissue-based clinicopathologic features, genomic assays, and circulating markers, that might help predict late relapses are ongoing.

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis, which analyzed 62,923 women with hormone-responsive breast cancer, provided significant insight into the risk of late recurrence after 5 years of adjuvant endocrine therapy, based on traditional clinicopathologic features.[1] For example, at 10 years, T1N0 patients had the lowest risk of recurrence at 4%, compared with T1N4–9 patients, who had a recurrence rate of 15%. The risk of recurrence continued to increase, regardless of tumor diameter and nodal status (TN), and reached a 20-year cumulative recurrence risk of 13% for T1N0, 20% for T1N1–3, 34% for T1N4–9,19% for T2N0, 26% for T2N1–3, and 41% for T2N4–9 patients.[1] Thus, initial tumor size and nodal status-but not PR status, grade, or Ki-67 index-remain critical determinants of recurrence, even decades out from diagnosis.[1] This important meta-analysis provides us with data to inform discussions with our patients who are considering extended endocrine therapy, though some have discounted these studies as an inadequate reflection of the results that we might expect in contemporary practice.

Genomic assays, such as the PAM50 risk of recurrence score, the Breast Cancer Index, Oncotype DX, and EndoPredict, have all shown analytical validity and clinical validity by biomarker standards, but their clinical utility in this setting has not been established.[11-15] In the absence of data on clinical utility, we do not recommend use of these assays to make an extended adjuvant endocrine therapy treatment decision. Our practice is congruent with guidelines from national organizations like the ASCO and the National Comprehensive Cancer Network. To our knowledge, there are no planned prospective clinical trials that incorporate these assays to address the issue of clinical utility. Recent interest has turned to studies involving detection of circulating tumor cells or circulating free DNA, which have shown some initial promise in being able to discern late recurrences.[16] Prospective evaluation of these markers in clinical trials will be critical.

Case follow-up

Based on her initial TN status, Ms. BC appears to have a 20-year estimated risk of recurrence of 26%, based on the EBCTCG meta-analysis.[1] We recommended against the use of any additional genomic testing at this juncture. With hormone level testing, she was confirmed to be postmenopausal. She is interested in extended endocrine therapy with continuation of tamoxifen or switching to an AI. The pros and cons of the two approaches were discussed with the patient. Because of a family history of osteoporosis, the patient requested a bone density test to guide her choice.

3. What are the side effects of extended adjuvant endocrine therapy, and how can we help improve our patients’ quality of life while on these agents?

It is estimated that only about half of patients complete their recommended course of adjuvant endocrine therapy, with younger women being at higher risk for treatment interruption and discontinuation.[17,18] Several factors contribute to non-adherence, but, in practice, poor patient tolerance of these agents is the biggest reason for discontinuation. Since non-adherence can alter prognosis significantly, the “optimal” endocrine therapy is the one that the patient takes. This requires constant reassessment and close attention to patient-reported symptoms.

In the studies of extended use of tamoxifen, risks of thromboembolic events (RR for pulmonary embolus, 1.87; P = .01) and endometrial cancer (RR, 1.74; P = .002) remain of concern.[3] With extended AI use, predominant concerns are related to known toxicities of bone loss, hyperlipidemia, and potential impact on cardiovascular health. Recent studies have shown that nonpharmacologic interventions, such as acupuncture and exercise, may be effective in the management of AI-associated arthralgias,[19,20] a symptom of considerable importance to many patients. Other interventions, such as eliciting patient-reported adverse events between clinic visits and integrating other specialists into our clinics for symptom management, may boost adherence to endocrine therapy. A potential strategy of intermittent vs continuous AI use to reduce time with symptoms can be explored in clinical trials, as long as the effectiveness of therapy is not compromised.

We are also mindful that certain toxicities, such as cognitive dysfunction or sexual symptoms, may be under-reported or poorly captured in clinical trials, and we need to provide an open environment in which patients feel comfortable sharing these concerns. Young women may also struggle with fertility, contraception, and timing of pregnancy during endocrine therapy, and their perspectives must be taken into consideration when making treatment recommendations and designing clinical trials. For example, the POSITIVE clinical trial (International Breast Cancer Study Group 48-14/Breast International Group 8-13; ClinicalTrials.gov identifier: NCT02308085) is currently recruiting premenopausal women who desire pregnancy and have been on endocrine therapy for 18 to 30 months to hold endocrine therapy for pregnancy, and resume after delivery. This is a critical question for many young patients.

Finally, it is important to remember that our imperfect knowledge about optimal endocrine therapy continues to advance. There are exciting novel agents, such as mammalian target of rapamycin (mTOR) inhibitors or cyclin-dependent kinase (CDK)4/6 inhibitors, being tested in combination with endocrine therapy in the adjuvant setting, which may change the future landscape of how we treat early-stage hormone-responsive breast cancer.

Case follow-up

Ms. BC returns 2 weeks after her last follow-up. Because her bone density test shows significant osteoporosis, she decided to stay on tamoxifen for an additional 5 years, rather than switch to an AI.

Key Recommendations

1. Upfront adjuvant endocrine therapy (up to 5 years after diagnosis). For premenopausal women, options include tamoxifen, an AI with OFS, or tamoxifen with OFS for 5 years; OFS plus an AI or tamoxifen for 5 years is recommended for high-risk women.

2. Extended adjuvant endocrine therapy (beyond 5 years after diagnosis). For high-risk women (young age at diagnosis, lymph node positivity) who have become postmenopausal, we recommend extended endocrine therapy (up to 10 years) with an AI or tamoxifen alone, guided by menopausal status and patient preference, after 5 years of initial endocrine therapy. Studies show that both DFS and OS improve with extended tamoxifen use (for up to 10 years), regardless of menopausal status. Extended AI use (for up to 10 years) is associated with DFS, but not OS, in postmenopausal women. No studies support the use of any adjuvant endocrine therapy beyond 10 years.

3. Use of prognostic factors such as tumor size and nodal status can help predict residual risk of recurrence after 5 years of endocrine therapy. However, we do not currently recommend use of genomic or circulating assays to inform the decision on the use of extended adjuvant endocrine therapy.

4. Extended endocrine therapy should only be considered in healthy women without other life-threatening conditions. If extended AI use is being considered, bone density assessment is recommended. The best choice of endocrine therapy is the one that is well tolerated and acceptable to the patient.

Financial Disclosure:Dr. Vinayak has served on advisory boards for OncoSec and Tesaro. Dr. Davidson has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Acknowledgments:This article is supported in part by the National Institutes of Health grant P30CA015704 (both authors) and the Breast Cancer Research Foundation (Dr. Davidson).

References:

1. 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;377:1836-46.

2. Gray RG, Rea D, Handley K, et al. aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol. 2013;31(suppl):abstr 5.

3. Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381:805-16.

4. Pagani O, Regan MM, Walley BA, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371:107-18.

5. Regan MM, Francis PA, Pagani O, et al. Absolute benefit of adjuvant endocrine therapies for premenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: TEXT and SOFT trials. J Clin Oncol. 2016;34:2221-31.

6. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349:1793-802.

7. Goss PE, Ingle JN, Pritchard KI, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med. 2016;375:209-19.

8. Jakesz R, Greil R, Gnant M, et al. Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J Natl Cancer Inst. 2007;99:1845-53.

9. Mamounas EP, Jeong JH, Wickerham DL, et al. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 trial. J Clin Oncol. 2008;26:1965-71.

10. Burstein HJ, Lacchetti C, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: ASCO clinical practice guideline focused update. J Clin Oncol. 2019;37:423-38.

11. Dowsett M, Sestak I, Lopez-Knowles E, et al. Comparison of PAM50 risk of recurrence score with Oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol. 2013;31:2783-90.

12. Dubsky P, Brase JC, Jakesz R, et al. The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients. Br J Cancer. 2013;109:2959-64.

13. Sestak I, Buus R, Cuzick J, et al. Comparison of the performance of 6 prognostic signatures for estrogen receptor-positive breast cancer: a secondary analysis of a randomized clinical trial. JAMA Oncol. 2018;4:545-53.

14. Sestak I, Cuzick J, Dowsett M, et al. Prediction of late distant recurrence after 5 years of endocrine treatment: a combined analysis of patients from the Austrian Breast and Colorectal Cancer Study Group 8 and arimidex, tamoxifen alone or in combination randomized trials using the PAM50 risk of recurrence score. J Clin Oncol. 2015;33:916-22.

15. Sgroi DC, Sestak I, Cuzick J, et al. Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncol. 2013;14:1067-76.

16. Sparano J, O’Neill A, Alpaugh K, et al. Association of circulating tumor cells with late recurrence of estrogen receptor-positive breast cancer: a secondary analysis of a randomized clinical trial. JAMA Oncol. 2018;4:1700-6.

17. Cluze C, Rey D, Huiart L, et al. Adjuvant endocrine therapy with tamoxifen in young women with breast cancer: determinants of interruptions vary over time. Ann Oncol. 2012;23:882-90.

18. Huiart L, Bouhnik AD, Rey D, et al. Early discontinuation of tamoxifen intake in younger women with breast cancer: is it time to rethink the way it is prescribed? Eur J Cancer. 2012;48:1939-46.

19. Hershman DL, Unger JM, Greenlee H, et al. Effect of acupuncture vs sham acupuncture or waitlist control on joint pain related to aromatase inhibitors among women with early-stage breast cancer: a randomized clinical trial. JAMA. 2018;320:167-76.

20. Irwin ML, Cartmel B, Gross CP, et al. Randomized exercise trial of aromatase inhibitor-induced arthralgia in breast cancer survivors. J Clin Oncol. 2015;33:1104-11.