Ovarian function suppression as a potential mechanism of chemotherapy

Abstract

Neoadjuvant chemotherapy (NAC) is occasionally considered for treatment of early-stage hormone receptor positive (HR+) breast cancer, primarily for downstaging of disease to allow for lesser aggressive surgical interventions. Classically, however, HR+ disease demonstrates a less robust response relative to HR negative (HR-) disease, although there is increasing evidence regarding benefit of chemotherapy in general for use in pre-menopausal versus postmenopausal women [1]. Pre-menopausal women with early-stage HR+ breast cancer demonstrate higher rates of achieving a pathologic complete response upon receipt of NAC, as compared to neoadjuvant endocrine therapy (NET) [2], a finding in contrast to observations made from trials evaluating responses to neoadjuvant therapy in post-menopausal patients. In CORALLEEN, post-menopausal patients with HR+ HER2-, luminal B disease received either NAC or endocrine therapy (ET) plus a CDK inhibitor. Changes in risk of recurrence from high to low risk as assessed by the Prosigna Breast Cancer Prognostic Gene Signature Assay (formerly known as PAM50 test was roughly equivalent between the groups [3]. Similarly, in SOLTI-1501 VENTANA, postmenopausal patients that received metronomic doses of vinorelbine plus letrozole did not display statistically superior anti-proliferative effects with regard to decreases in PAM50 score as compared to patients receiving letrozole only [4]. To parse the mechanism underlying the benefit of NAC in premenopausal women, it can be argued that there may be intrinsic gene profiles in this population that are differentially altered as a result of exposure to chemotherapy as compared to their post-menopausal counterparts. In this issue of EBioMedicine, Chic et al endorse this hypothesis by identifying a predominant effect of genes that are altered as a result of chemotherapy effect on ovarian suppression [5]. Utilizing gene expression data from CORALLEEN [3], VENTANA [4], PAMELA [6], NEOERIBULIN, and two retrospective cohorts from the