Adjuvant Endocrine Therapy for Breast Cancer: Longer Therapy and the Need for Personalized Treatment-Should We Treat Beyond the Data?

December 15, 2013

In the future, we also need to improve our ability to personalize the duration of endocrine therapy, with a goal of optimizing patient selection for extended therapy. Hopefully, clinical-pathologic indices and predictive biomarkers similar to the Oncotype DX 12-gene recurrence score or the PAM50 risk of recurrence score for adjuvant chemotherapy will soon emerge to guide adjuvant endocrine therapy.

Women with hormone receptor (HR)-positive breast cancer carry an ongoing risk of disease recurrence despite our best current management. In fact, 50% of recurrences occur 6 to 15 years after a patient’s initial diagnosis.[1-3] This likely reflects a subset of breast cancers that are dependent on endocrine treatment to prevent recurrence and that do not acquire secondary resistance.[4] Now, multiple large clinical trials indicate that longer durations of adjuvant endocrine therapy are superior in both pre- and postmenopausal breast cancer.[5-7] These data are clearly set forth in the comprehensive overview by Jankowitz and Davidson.[8] However, important questions remain regarding the optimal duration and sequence of adjuvant endocrine therapy.

In premenopausal patients, treatment decisions are much clearer, given the recent Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) and Adjuvant Tamoxifen-To Offer More? (aTTom) clinical trial results.[5,6,9] Tamoxifen should be standard in premenopausal patients for 10 years. This recommendation must, of course, be individualized based on a patient’s risk of recurrence, medical comorbidities, side effects, risk of serious complications, and quality of life. Compliance will also be a major issue for women undergoing extended therapy. Discontinuation rates reach as high as 30% among women receiving 5 years of adjuvant endocrine therapy.[10,11] Further educational and support programs will be needed to foster and encourage long-term compliance, especially among young women who are at highest risk for early discontinuation.[10] Younger patients will also have to balance the risk of interrupting their tamoxifen treatment against a desire to pursue becoming pregnant. Further research is needed to define the safety of interrupting endocrine therapy for pregnancy. Additionally, one of the biggest questions will be whether or not to continue tamoxifen past 10 years. We are not likely to have clinical data to guide this decision: Should we continue for longer?

In postmenopausal patients, decision making is even more complex, since we are still awaiting the results of clinical trials that are investigating long-term use of aromatase inhibitors. At present, there are numerous options and clinical data to support the use of either tamoxifen, aromatase inhibitors, or sequencing strategies. Clinical trials have demonstrated that aromatase inhibitors are superior to tamoxifen in preventing early recurrence in postmenopausal breast cancer.[12] As a result, we favor starting therapy with an aromatase inhibitor after diagnosis. After 5 years of an aromatase inhibitor, patients should be re-evaluated for ongoing extended therapy. We are in theory in favor of longer durations of endocrine therapy; however, decisions must be individualized based on each patient’s benefit, risk, and desire to continue therapy. We recommend a clear discussion of the potential value of extended endocrine therapy strategies while we await further data from clinical trials investigating 10-year use of aromatase inhibitors in postmenopausal women. The first option to discuss is the possibility of continuing an aromatase inhibitor beyond 5 years, perhaps for 1 more year initially, with this decision reviewed annually based on the emerging data. The second option is to offer a switch strategy-following 5 years of an aromatase inhibitor with 5 years of tamoxifen-given that the recent ATLAS and aTTom data show increased benefit from 10 years of adjuvant therapy.[5,6]

The treatment algorithm proposed above goes beyond current recommendations based on available clinical trial data; however, we believe this extended endocrine strategy may be the optimal therapy for postmenopausal women until more definitive evidence becomes available. Nonetheless, the decision to extend therapy must carefully balance a patient’s age, medical comorbidities, aggressiveness of disease, side effects, and risk of serious complications. Bone health should be monitored closely in postmenopausal women taking aromatase inhibitors, and osteoporosis should be managed accordingly.[10,13] Further study is also needed to define any potential cardiovascular risk associated with extended treatment with aromatase inhibitors.[14] Overall, however, we believe that by extrapolating from recent clinical trial results, clinicians can safely conclude that longer-term adjuvant endocrine therapy is advantageous and will significantly help to reduce late recurrences once implemented widely among women diagnosed with HR-positive breast cancer.[5-7]

In the future, we also need to improve our ability to personalize the duration of endocrine therapy, with a goal of optimizing patient selection for extended therapy. Hopefully, clinical-pathologic indices and predictive biomarkers similar to the Oncotype DX 12-gene recurrence score or the PAM50 risk of recurrence score for adjuvant chemotherapy will soon emerge to guide adjuvant endocrine therapy.[4,15-17] Such biomarkers may also help us identify low-risk women who can be treated effectively with short-course therapy. In addition, we must further define the optimal duration of extended endocrine therapy required in high-risk patients to avoid ongoing late recurrences. These are the challenges that lie ahead in order to truly optimize our use of adjuvant endocrine therapy for HR-positive breast cancer.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687-717.

2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG); Davies C, Godwin J, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378:771-84.

3. Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol. 1996;14:2738-46.

4. Metzger-Filho O, Sun Z, Viale G, et al. Patterns of recurrence and outcome according to breast cancer subtypes in lymph node-negative disease: results from International Breast Cancer Study Group trials VIII and IX. J Clin Oncol. 2013;31:3083-90.

5. 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.

6. Gray R. aTTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,934 women with early breast cancer. J. Clin Oncol. 2013;31(suppl): abstr 5.

7. 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;349:1793-1802.

8. Jankowitz R, Davidson NE. Adjuvant endocrine therapy for breast cancer. How long is enough? Oncology (Williston Park). 2013;27:1210-6.

9. Petrelli F, Coinu A, Cabiddu M, et al. Five or more years of adjuvant endocrine therapy in breast cancer: a meta-analysis of published randomised trials. Breast Cancer Res Treat. 2013;140:233-40.

10. Hershman DL, Kushi LH, Shao T, et al. Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol. 2010;28:4120-8.

11. Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol. 2003;21:602-6.

12. Cuzick J, Sestak I, Baum M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010;11:1135-41.

13. Amir E, Seruga B, Niraula S, et al. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst. 2011;103:1299-1309.

14. Ewer MS, Gluck S. A woman’s heart: the impact of adjuvant endocrine therapy on cardiovascular health. Cancer. 2009;115:1813-26.

15. 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.

16. 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 Oct 24. [Epub ahead of print]

17. 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.