Who Needs Chemotherapy? For Breast Cancer Patients, the RxPONDER Trial Refines the Answer

By Thomas Crocker
Tuesday, March 30, 2021

Initial results from the Southwest Oncology Group (SWOG) phase 3 RxPONDER trial demonstrate that postmenopausal women with a common form of breast cancer may be able to forego chemotherapy — and its potential adverse effects — in favor of standalone hormone therapy.

Careful, individualized use of chemotherapy to treat breast cancer is of paramount importance because of the treatment’s potential to cause a variety of physical and emotional side effects. Sponsored by the National Cancer Institute (NCI), RxPONDER is one of many studies in which researchers have sought to better understand which patients with breast cancer need chemotherapy and which ones can avoid it. Unlike other large, randomized trials, RxPONDER explored this issue in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer with involvement of one to three lymph nodes.

“Two-thirds of breast cancers are HR-positive and HER2-negative,” says RxPONDER Principal Investigator Kevin Kalinsky, MD, MS, Director of the Glenn Family Breast Center at the Winship Cancer Institute at Emory University and Associate Professor in the Department of Hematology and Medical Oncology at the Emory University School of Medicine. “We did look within SEER [an NCI cancer statistics database] to get a sense of approximately how many patients per year would fit this criterion of involvement of one to three lymph nodes, and of that group, it’s about 20%.”

A Pre- and Post-menopausal Divide

The RxPONDER trial included 5,015 patients — two-thirds of whom were postmenopausal — with stage 2 or 3 breast cancer that had spread to one to three lymph nodes and who scored 0–25 on a frequently-used, 21-tumor gene expression assay, the Oncotype DX Breast Recurrence Score (RS) test. Participants were randomized to receive hormone therapy or hormone therapy plus standard chemotherapy. Initial results encompassing 54% of anticipated invasive disease-free survival events and representing a median follow-up period of 5.1 years were presented at the 2020 San Antonio Breast Cancer Symposium.

The researchers found that for postmenopausal women, five-year invasive disease-free survival rates of those who received hormone therapy plus chemotherapy and those who received hormone therapy alone were essentially identical — 91.6% and 91.9%, respectively. Premenopausal women who received both treatments had a five-year invasive disease-free survival rate of 94.2% compared with a rate of 89% for those who only received hormone therapy, a marked difference. The addition of chemotherapy did not improve overall survival for postmenopausal women. In the premenopausal group, however, individuals who received chemotherapy plus endocrine therapy had an overall survival rate of 98.6% vs. 97.3% for endocrine therapy alone. The researchers will follow patients for 15 years.

“What was surprising, recognizing this is only about 50% of the anticipated events we’ll see, is that there were no subgroups that benefited from the addition of chemotherapy in the postmenopausal group,” Dr. Kalinsky says. “For the premenopausal group, we couldn’t identify a subpopulation that did not benefit from the addition of chemotherapy.”

Like RxPONDER, earlier studies used the Oncotype DX test to attempt to identify which breast cancer patients needed chemotherapy, and these studies pinpointed subgroups of patients that benefited from chemotherapy. SWOG 8814, for example, found that postmenopausal women with HR-positive, HER2-negative and lymph node-positive disease with a high RS (31–100) derived a significant breast cancer-specific survival benefit from the addition of chemotherapy to hormone therapy vs. hormone therapy alone. The TAILORx trial — an NCI-sponsored precursor to RxPONDER — concluded that postmenopausal women with HR-positive, HER2-negative and lymph node-negative disease with a RS of 0–25 did not benefit from chemotherapy and hormone therapy compared with hormone therapy alone.

‘Practice Changing’ Results

Sarah Sammons, MD, Assistant Professor of Medicine at Duke University Hospital and Duke Cancer Institute, was encouraged by its initial findings.

“I think that these ... results were immediately practice changing,” says Dr. Sammons, who was not involved with the study. “Clinicians should now discuss ordering the RS with postmenopausal women with HR-positive, HER2-negative breast cancer and one to three positive lymph nodes [who] are candidates for chemotherapy. In most circumstances, chemotherapy can be safely eliminated in those postmenopausal women with a RS between 0–25.”

Dr. Kalinsky agrees.

“These data support potentially not needing to treat patients who are postmenopausal with chemotherapy and sparing them the unnecessary side effects and costs … that can be associated with chemotherapy,” he says. “This also gives us reassurance right now about the use of the Oncotype DX test for patients who are premenopausal in terms of giving them chemotherapy.”

The RxPONDER team will report quality-of-life data in the future.