Ovarian Function Suppression Drives Chemotherapy Benefits in Premenopausal HR+/HER2- Breast Cancer

Premenopausal patients with early hormone receptor (HR)–positive, HER2-negative breast cancer can benefit from chemotherapy, although it is still debatable whether that benefit stems from the chemotherapy itself or the ovarian function suppression that happens as a result of chemotherapy, according to Kevin Kalinsky, MD, MS.

At the 2022 International Congress on the Future of Breast Cancer East^®, Kalinsky participated in a debate on the topic, arguing that amenorrhea stemming from chemotherapy provides the clinical benefit seen in patients with HR-positive, HER2-negative breast cancer, adding that these patients could see the same benefit from ovarian function suppression and endocrine therapy alone.

“There has been research, including meta-analyses and some smaller studies, that have demonstrated that just [administering] ovarian function suppression was equivalent to [administering] chemotherapy,” Kalinsky explained.

In an interview with OncLive^®, Kalinsky, associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine; director of the Glenn Family Breast Center and Breast Medical Oncology; and the Louisa and Rand Glenn Family Chair in Breast Cancer Research at Winship Cancer Institute of Emory University, discussed his position on the role of ovarian function suppression on the benefits derived from chemotherapy in premenopausal patients with HR-positive, HER2-negative early breast cancer.

OncLive^®: What was the focus of your presentation on the relationship between ovarian function suppression and the benefits of chemotherapy in patients with HR-positive, HER2-negative breast cancer?

Kalinsky: I talked about whether ovarian function suppression and the benefits that we see from chemotherapy for patients with HR-positive and HER2-negative breast cancer, including [patients with] both node-negative and node-positive [disease], are due to the amenorrhea from the chemotherapy, or to some direct effect from the chemotherapy.

[In the debate], my role was to argue that [these benefits] are due strictly to the amenorrhea that is related to the chemotherapy.

Why is it important to consider the factors driving these chemotherapy benefits for these patients?

We have seen for patients who are node negative and high risk, [plus] those patients who are node positive with 1 to 3 nodes involved, that there are some patients who benefit from chemotherapy. [For instance], in the phase 3 RxPONDER trial [NCT01272037], patients with 1 to 3 nodes involved [and] had a recurrence score between 0 and 25 benefited from chemotherapy.

What we don’t truly know is whether patients would have the same benefit if they receive ovarian function suppression plus endocrine therapy, as opposed to chemotherapy followed by endocrine therapy. Is the benefit the same? That’s been the question that has come out of that study. Is it a direct effect or indirect effect in terms of the benefit of the chemotherapy?

What data did you use to support your position on the role of amenorrhea leading to the benefit from chemotherapy?

My argument was that the chemotherapy benefit that we’re seeing in patients is due to the ovarian function suppressive effects of chemotherapy.

We already had data from pooled analyses and smaller studies demonstrating that potentially just giving a GnRH agonist was the same as giving chemotherapy. Part of the issue in a study like RxPONDER is that only 16% of patients had optimal ovarian function suppression. That’s why it’s hard to know the answer from that particular study. However, that’s the background to help support my argument.

How would you respond to a colleague that believes chemotherapy benefit is not due to ovarian function suppression?

When looking at the RxPONDER data, regardless of whether a patient had chemotherapy or just endocrine therapy, as long the patients got to the point where they weren’t having regular periods, they did better. That [supports the argument] that the rate of not having regular periods is higher if a patient has chemotherapy, but I would argue if you were doing ovarian function suppression and endocrine therapy, that patients would achieve the same rates. We see that regardless of whether patients were getting chemotherapy, if they stopped having regular periods, they did better.

Following the idea that chemotherapy benefit is due to ovarian function suppression, how does that affect clinical decision making when it comes to deciding the appropriate treatment regimen and duration for patients?

From the results of the phase 3 TAILORx trial [NCT00310180] and RxPONDER, it can be a hard conversation to have with the patient, because the default [treatment] is to do chemotherapy. But maybe patients would have the same benefit if you did ovarian function suppression and endocrine therapy. On the other end, giving 5 years of ovarian function suppression is hard for some patients. If you start ovarian function suppression for a year and then stop, are patients still having the continued benefit?

There will be a National Cancer Institute–sponsored study within the next year being run by the NRG called the OV-OFFSET trial. This study will really address this question [of the role of ovarian function suppression on the benefits of chemotherapy], because about 4000 patients are being randomized to ovarian function suppression plus endocrine therapy, or chemotherapy, ovarian function suppression, and endocrine therapy. This is really asking whether patients really need that chemotherapy.

Is there any other ongoing or planned research that could help determine more definitively what is driving this chemotherapy benefit?

We are awaiting the results of other studies in patients that are utilizing genomic assays, such as the AUTOMA study. However, the OV-OFFSET study will be a study that is specifically addressing the role of chemotherapy in a genomically defined population, where patients are all getting optimal endocrine therapy.