Still Refining Adjuvant Endocrine Therapy in Premenopausal Women: Not Too Much, Not Too Little

Oophorectomy was the first treatment described for young women with advanced breast cancer. In 1995, the selective estrogen receptor (ER) modulator tamoxifen was recognized as effective adjuvant therapy for premenopausal ER-positive disease. One hundred twenty years after Beatson’s seminal observation, ovarian function suppression (OFS)—achieved reversibly with luteinizing hormone-releasing hormone agonists or permanently with bilateral oophorectomy—has become an established therapeutic option for the treatment of hormone receptor (HR) –positive early-stage breast cancer in premenopausal women, now further supported by two recent studies, the Suppression of Ovarian Function Trial (SOFT; ClinicalTrials.gov identifierNCT00066690) and the Trial of Exemestane and Tamoxifen (TEXT; ClinicalTrials.gov identifier NCT00066703). The complex history of breast cancer endocrine therapy was made more complex by several challenges. One was the accurate testing and interpretation of ER and progesterone-receptor status, which partly explain the now-defunct belief that endocrine therapy offered benefit for patients with HR-negative disease. Another was the prevailing view that adjuvant polychemotherapy should be recommended to young women with localized breast cancer, regardless of risk. This led to poor accrual into trials testing endocrine therapy without chemotherapy in premenopausal women. Indeed, the Premenopausal Endocrine Responsive Chemotherapy Trial (PERCHE; ClinicalTrials.gov identifier NCT00066807), a study designed to test the benefit of chemotherapy added to OFS/antiestrogen therapy, closed prematurely without results. SOFT compared 5 years of tamoxifen, OFS plus tamoxifen, andOFS plus the aromatase inhibitor (AI) exemestane inwomenwho did not receive chemotherapy or who continued to have premenopausal estradiol levels after chemotherapy. In TEXT, premenopausal women were randomly assigned to OFS with either tamoxifen or the same AI. In broad terms, these trials demonstrated that adjuvant OFS/AI significantly reduced recurrence compared with OFS/tamoxifen. Interestingly, adding OFS to tamoxifen only improved disease outcomes in women who received adjuvant chemotherapy and remained premenopausal, with further improvement if OFS was partnered with an AI. The improvements observed in SOFT and TEXT come with trade-offs, particularly in terms of toxicity and potential future adverse events. Treatment decisions are further complicated by the fact that the decision to give chemotherapy in SOFTand TEXT was driven by the treating physician and the patient, on the basis of provider assessment of recurrence risk. Consequently, the greater absolute improvements in outcome observed in the chemotherapy cohorts were potentially driven by higher individual patient risk, as determined by routine histopathologic and clinical parameters. In the article that accompanies this editorial, Regan et al evaluated the magnitude of absolute benefit of the therapeutic options in SOFT and TEXT (tamoxifen, OFS/tamoxifen, and OFS/exemestane) against a composite measure of recurrence risk, using an approach similar to their prior report on the selection of endocrine therapy in postmenopausal women. The authors evaluated absolute treatment effects as the impact on breast cancer-free interval using a continuous composite measure of recurrence risk on the basis of a Cox model including age, node status, tumor size, centrally confirmed HR-positive/human epidermal growth factor receptor 2–negative status, and centrally tested Ki-67. In the SOFT trial, they found an absolute 10% to 15% improvement in 5-year breast cancer-free interval with OFS/exemestane compared with OFS/tamoxifen or tamoxifen in those with intermediate-to-high composite risk disease who received chemotherapy. Similar improvements occurred in relatively lower-risk TEXT patients given chemotherapy who were treated with OFS/exemestane versus OFS/tamoxifen, whereas the nonchemotherapy cohorts with the lowest composite risks from both studies did well with all endocrine options. These data reinforce the importance of our ability to individualize therapy decisions, guided by biology and its impact on efficacy, toxicities, and patient preferences. Should OFS always be preferentially partnered with an AI and not tamoxifen? Should all patients who remain premenopausal after adjuvant chemotherapy receive OFS? The answer to these two questions is a definitive no; treatment choices should be tailored to risk and preference. A third andmore complex question is whether patients treated with OFS plus endocrine therapy could be spared chemotherapy. Although the PERCHE trial closed prematurely, recent data indicate that clinical and molecular risk parameters can be used to identify patients with HR-positive disease who can be spared chemotherapy.