Chemotherapy Benefit May Stem From Ovarian Function Suppression in Premenopausal HR+/HER2- Breast Cancer

Nicholas P. McAndrew, MD, MSCE

Patients with hormone receptor (HR)–positive, HER2-negative breast cancer may receive clinical benefit from chemotherapy or from the ovarian function suppression associated with its administration. The answer may fall somewhere in the middle of both possibilities, and it could vary from patient to patient based on their clinical characteristics, according to Nicholas P. McAndrew, MD, MSCE, who participated in a debate on the topic at the 2022 International Congress on the Future of Breast Cancer West^®.

“There are situations in which the main benefit is going to be [from the] cytotoxic [effects of chemotherapy], and we know in some situations the main benefit has to be ovarian function suppression,” McAndrew said. “It is about choosing which patients we think fit into that category while we’re waiting for more prospective data.”

In an interview with OncLive^®, McAndrew, an assistant clinical professor of medicine at the University of California, Los Angeles (UCLA); and a hematologist-oncologist at the UCLA David Geffen School of Medicine of UCLA Medical Center, discussed considerations to take when examining the relationship between chemotherapy, ovarian function suppression, and treatment benefits experienced by patients with HR-positive, HER2-negative breast cancer.

OncLive^®: What was the focus of your side of the debate on the relationship between ovarian function suppression and the chemotherapy benefit observed in patients with premenopausal HR-positive early breast cancer?

McAndrew: In this debate, we are trying to learn whether the benefit we see for premenopausal [patients with] HR-positive, HER2-negative breast cancer from getting chemotherapy is a cytotoxic benefit due to the chemotherapy killing cancer cells directly via cytotoxic effects, or if [the benefit] is associated with ovarian function suppression in an estrogen-depleted state, which then indirectly kills cancer cells by restricting the amount of estrogen-related growth.

It is an intense debate, especially [following] the results of [phase 3] RxPONDER trial [NCT01272037]. My side of the debate was to take the position that the primary effect that we see in these studies is because of ovarian function suppression, rather than the cytotoxic effects of chemotherapy.

Why is the debate between the source of this benefit an important one to consider?

It is important to consider because in many of the studies that showed that there was chemotherapy benefit, the comparator arms [consisting] of endocrine therapy didn’t have a lot of patients who received effective [or any] ovarian function suppression.

For example, in RxPONDER, most patients who were premenopausal and assigned to endocrine therapy were receiving tamoxifen and weren’t specifically receiving ovarian function suppression. It’s important to consider because if we think that most of the benefit is from the ovarian function suppression effects of chemotherapy, we have other ways of suppressing a patient’s ovarian function without having to use chemotherapy.

What data did you use to help support your argument?

There are a variety of studies that were published. [These include] data from RxPONDER and the [phase 3] TAILORx trial [NCT00310180], which [examined] the usage of Oncotype recurrence score in [patients with] node-negative or early-stage HR-positive, HER2-negative [breast cancer]. I also used some of the contemporary data to examine these specific subgroups and some important exploratory analyses that have been done.

But there are several meta-analyses and other studies that predate the Oncotype recurrence score that we can draw important conclusions from, and they do help support the notion that there is at least a subpopulation that does benefit from the ovarian function [suppression] effects of chemotherapy. Maybe we can use these data to help our patients in the setting of more contemporary [clinical] trial designs.

How would you convince someone who would argue chemotherapy benefit is not due to ovarian function suppression?

Part of the challenge is that [premenopausal] patients who have HR-positive, HER2-negative, early-stage breast cancer are not [all the same]. It comes down to thinking about the specifics of the patient at hand. Do you have a patient who had a borderline elevated or intermediate Oncotype score? But [maybe] they have [other high-risk] clinical features such as high grade, high Ki-67, [or others], that are more suggestive that the tumor would respond well to cytotoxic chemotherapy. I don’t believe that in every situation we should [believe that the benefit stems fully from] ovarian function suppression or chemotherapy.

[If there is a patient with] some clinically higher-risk features, that [could] suggest that the tumor would respond to the cytotoxic effects of chemotherapy. But if you have a patient who is young, has 1 positive lymph node, and a grade 1 lobular tumor with a low Ki-67 index, these are the tumors that are not necessarily going to respond to the cytotoxic effects of chemotherapy. Furthermore, a very young patient would likely not be put into ovarian function suppression from chemotherapy. They would probably have a temporary period of ovarian function suppression, but they would be more likely to regain it afterward. Under those circumstances, chemotherapy may not result in the dual action of both cytotoxicity and ovarian function suppression. In those situations, it might be [beneficial] to at least have the conversation about using ovarian function suppression rather than chemotherapy.

If chemotherapy benefit does stem from ovarian function suppression, how would that affect clinical decisions for these patients?

It remains a challenge, even if it does turn out that the majority of the [benefit] is because of ovarian function suppression. There are still situations in which one can think that the effect may be ovarian function suppression. However, in this specific patient, maybe they’ve taken endocrine therapy in the past, for whatever reason, and they are going to not tolerate it well in the future. Doing chemotherapy [could potentially] be a more surefire way to get them into ovarian function suppression, especially if they’re on the borderline of menopause. In those situations, patients are more likely to have a chemotherapy-induced amenorrhea and subsequently are more likely to derive some benefit from that.

Even if it turns out that the main effect of chemotherapy is ovarian function suppression, there may be some situations in which [chemotherapy] may be a viable option or a more preferred option for that specific patient. Of course, if a patient seems motivated to avoid chemotherapy, or if a patient wants to try ovarian function suppression and it clinically makes sense if they have a low-grade tumor that is not very proliferative, we could take some comfort in knowing that they would likely derive just as much benefit, assuming they’re able to be compliant with the therapy.