Abstract DEB1-1: Pro - RxPONDER: Was it all OFS?
Authors: Gnant M 
Published: March 2022

Abstract
SWOG’s great randomized RxPONDER trial has answered an important question (that adjuvant chemotherapy does not provide general benefit for patients with low and intermediate risk (RS 0-25) hormone-receptor positive breast cancer), but the observed strong interaction of chemotherapy benefit with menopausal status P=.004) triggers the debate about the true benefit and mechanism of action of adjuvant cytotoxic chemotherapy in premenopausal patients. While the observed relative risk reduction of 45% in premenopausal women of that risk group appears impressive at first sight, we must understand what cytotoxic therapy does in premenopausal patients: Depending on age and treatment regimen used, the vast majority of women will develop at least temporary amenorrhea as a consequence of adjuvant chemotherapy, and - strongly depending on age - a proportion will remain in treatment-induced menopause. Ovarian function suppression itself is hugely therapeutic in hormone-responsive breast cancer, and the respective data - albeit from old studies - show impressive risk reductions, at least comparable with what was shown by SWOG S1007. A series of “classical” trials (e.g., ZEBRA, ABCSG-05, IBCSG-VIII, GROCTA-02, ECOG/SWOG Intergroup 0101), have demonstrated excellent outcomes for ovarian suppression based endocrine treatment regimens, with similar or even better results than chemotherapy (back then). Contemporary trials with large cohorts of premenopausal patients and long-term follow-up (e.g., ABCSG-12, SOFT, TEXT, TAILORx, MINDACT) demonstrate excellent 5- and 10-year outcomes for patients who did not receive adjuvant chemotherapy. Taken together, these data support that most if not all of the chemotherapy benefit observed in the specific RxPONDER cohort is in fact the result of indirect endocrine effects of cytotoxic treatment. This was also the result of a survey among St. Gallen Panelists earlier this year (80% of whom attributed 50 per cent or more of chemotherapy activity to its endocrine “side effects”; Burstein HJ et al, Ann Oncol 2021; 32: 1216-35). Clearly, there may be individual patients with endocrine-resistant disease or at very young age who benefit from the addition of cytotoxic therapy, but additional research is needed to accurately define them. Eventually, we will need a well-conducted (global?) academic clinical trial investigating the addition of modern and optimized chemotherapy to optimal endocrine therapy in a well-defined cohort of patients for whom the issues remain unclear. Only by generating this urgently needed evidence we will be able to overcome the strong beliefs on both sides of the argument (that had also rendered recruitment into IBCSG’s brave PERCHE trial impossible two decades ago). Until then, adjuvant chemotherapy remains a graceless method to achieve an optimal endocrine effect for the vast majority of premenopausal patients with intermediate-risk hormone receptor positive breast cancer.
Citation Format: M Gnant. Pro - RxPONDER: Was it all OFS? [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr DEB1-1.