Joseph A. Sparano, MD, FACP, on Premenopausal HR-positive Early Breast Cancer: What to Do Outside the OFSET Trial?

As many of you know, we often face therapeutic equipoise in managing patients with early-stage breast cancer who have clinical high-risk genomic or low-risk disease. The NRG-BR009 trial or the OFSET Trial is designed to address that uncertainty. It will include pre-menopausal women with hormone receptor-positive HERTU-negative early breast cancer, who have one to three positive axillary lymph nodes in a recurrent score of zero to 25 or node-negative disease with a recurrent score of 16 to 20 and high clinical risk, or a recurrent score of 21 to 25. Patients will be random-ized to receive ovarian function suppression and an aromatase inhibitor for five years with tamoxi-fen used if there is intolerance to an AI or chemotherapy plus the same endocrine therapy back-bone. The trial is designed as a superiority trial to determine whether adding chemotherapy im-proves clinical outcomes, but we won't have a result from the trial in somewhere between seven to 10 years. So the question remains, how do we handle patients that we see in our clinic in the room, and what advice do we offer them and what evidence do we use to help drive a treatment recommen-dation? So I think it's important to keep the following principles in mind when a clinician ap-proaches a situation. First, understand that adjuvant chemotherapy in pre-menopausal women cer-tainly reduces recurrence risk of breast cancer, and there's a proportionally greater effect in pre-menopausal women compared with post-menopausal women. And this differential effect in pre-compared with post-menopausal women is believed to be due in part due to an endocrine therapy effect in chemotherapy bringing on menopause at an earlier age than natural menopause would've occurred. This is supported by the fact that there's a consistent association between chemotherapy induced amenorrhea and improved disease-free survival in estrogen receptor-positive breast can-cer. Secondly, the 21 gene recurrence score that we often use in this clinical situation provides both prognostic information for disease recurrence in the context of receiving adjuvant endocrine therapy and predictive information for chemotherapy benefit. We already know that high recurrence score is prognostic for higher recurrence risk in the context of endocrine therapy, but, and that high recurrence score is also predictive of chemotherapy bene-fit. We also know that a low to mid-range recurrence score is associated with a lower recurrence risk in part due to an endocrine therapy effect. In other words, patients who have clinical high risk genomic low risk breast cancer really need endocrine therapy to enjoy a good prognosis and low recurrence risk with regard to the benefit of adjuvant chemotherapy and estimating that benefit in patients that we see in our practice. The absolute benefit is driven by their recurrence risk based on clinical pathologic features including noble status, tumor size and tumor grade, and also the re-currence score and predictive factors for chemotherapy benefit, which is also provided by the re-currence score. We also know that some absolute benefit is driven by a higher underlying recur-rence risk that's influenced by clinical pathologic features and chemotherapy-induced amenorrhea. We've also recently learned that at low AMH anti-malarial hormone level in pre-menopausal wom-en under the age of 55 identifies 20% of patients who don't derive benefit from adjuvant chemo-therapy, but also possibly from ovarian function suppression. And the clinical utility of this observa-tion currently remains unknown. Finally, we have decision aids that can help provide better esti-mates of recurrence risk and also chemotherapy benefit then can be provided by either clinical pathologic features alone or recurrence score alone. One of these tools includes the RS-Clin tool, which does provide an estimate of absolute chemotherapy benefit, but does not distinguish what is driving that benefit. Is it due to the chemotherapy-induced amenorrhea or is there a separate cy-totoxic effect of chemotherapy eradicating micrometastatic disease? In addition, currently the RS-Clin is limited to negative breast cancer, and we now have long-standing twelve-year data in which the RS-Clin has been validated. So we have long-term outcomes. There's also a new RS-Clin N-positive for patients with one to three positive nodes that's been re-ported and may soon be available for clinical use. With that background, how do we make a clinical decision for patients who fall in this gray zone with a clinical high-risk, low-genomic risk disease? Well, factors that would favor use of endocrine therapy alone generally including ovarian function suppression and an AI include little or no RS-Clin benefit derived from chemotherapy as predicted by the RS-Clin tool, which would include lower-grade tumors and patients with zero to one positive nodes. Factors that would drive a chemotherapy recommendation include a high RS-Clin estimated chemotherapy benefit and a higher grade, and also patients with two to three positive nodes. And finally, patient preference also can help drive a therapeutic decision in the setting with therapeutic equipoise in the shared decision-making process, which can be facilitated by the RS clinical tool.