Treatment of Premenopausal Women: Finding the Right-Sized Endocrine Therapy

Abstract

Breast cancer is not pink ribbons and easy decision making. Worldwide, premenopausal women accounted for just over 30% of global breast cancer diagnoses in 2018 and nearly all global regions demonstrate increasing rates of breast cancer in this population. 1 Although biology may be at play for poorer outcomes, we also note that premenopausal women, particularly the very young (, 40 years of age), have been shown to have higher rates of endocrine therapy non-adherence (40% more likely) or early discontinuation (50% more likely) than those persons age 50-65 years, likely because of side effects and negative impact on overall quality of life. 2 Enter the modern age, where we look back to move forward: sifting through the data from the 8-year combined analysis of the SOFT/TEXT trials, 3 which accrued patients from 2003 to 2011, and the TailorX trial, 4 which accrued patients from 2006 to 2010, to inform practice in 2021. But during those time intervals, practice advanced in many ways, including the contemporary impact of both trials on the other. Although SOFT/TEXT may drive more use of ovarian function suppression (OFS), TailorX may limit the number of premenopausal women treated with che-motherapy and subsequently developing chemotherapy-induced OFS. Other practice advances include improved access to genetic testing, 5 standard adoption of the 21-gene recurrence score, 6 human epidermal growth factor receptor 2-directed therapy becoming an adjuvant standard of care, 7 as well as technical advances in radiation, pathology, and surgical sciences. Layering the complex missingness of OFS across available trials and small numbers of pre-menopausal volunteers participating in these clinical trials leave a complex landscape ripe for interpretation. In the companion to this article, Sella et al 8 offer a pragmatic approach to the question of OFS and length of adjuvant endocrine therapy in a premenopausal patient population. Adding the guiding principles of medical ethics 9 onto their suggested decision aid, we can take a deeper look at how to guide a woman (or man, given male breast cancer is most biologically similar to premen-opausal breast cancer) through these decisions. Be-neficence drives many of our interactions in the clinic. Oncologists look at the distant recurrence-free survival curves at 9 years for persons with a 21-gene recurrence scores # 10 of 96.8% 4 and feel comfortable offering adjuvant endocrine therapy alone in that population. Meanwhile, we observe the 86.8% 4 distant recurrence-free survival for those with scores. 25 and feel that, despite already receiving chemotherapy and endocrine therapy, there must be something more we can offer in the best interest of our patient. Nuance emerges in the space between. Both TailorX 4 for persons with scores between 16 and 25 and MINDACT 10,11 show a small benefit for persons age younger than 50 years. As these data emerged, the oncology community debated whether OFS would close this gap, given striking similarity in the cross-trial statistics and the possibility that chemotherapy was simply an excessively toxic form of functional ovarian suppression. But two facts remain: First, in the SOFT trial, the benefit of OFS was limited to those who received chemotherapy, suggesting that the roles of OFS and chemotherapy are not overlapping in this high-risk population. 12 Second, patients with breast cancer repeatedly demonstrate a preference for best outcomes despite small statistical differences or potential risk of toxicity. 13,14 Taken together, both the highest risk and the intermediate-risk premenopausal population should be offered OFS for 5 years and beyond, which in this population will often be in combination with chemotherapy based on profiling or nodal status. Although the 21-gene recurrence score does not predict risk of recurrence beyond 9 years or offer guidance as to duration or type of adjuvant endocrine therapy, it is clear that people with high-risk scores still have a substantial risk of recurrence with chemo-therapy and traditional adjuvant endocrine therapy alone. Although the authors do not include these genomically selected patients in their criteria, 8 this population remains at high risk and should also be appropriate candidates for prolonged OFS. As we weigh our patient's best interests and which endocrine therapy agent to recommend, tamoxifen or an aromatase inhibitor (AI), whether to include OFS, and the length of time for either, we turn back to the slow separation of the curves in trials looking at ad-juvant endocrine therapy. Notably, we see that the risk of recurrence for hormone receptor-positive (HR1) disease continues to climb, even 20 years after diagnosis. 15 It is for persons who are age younger than 50 years at diagnosis for whom this has striking implications. In the ATLAS trial, exploring 5 versus 10