Results of the SWOG S1007 RxPONDER clinical trial suggest that many postmenopausal women with early-stage hormone receptor (HR)-positive, human epidermal growth receptor 2 (HER2)-negative breast cancer, and 1 to 3 positive axillary lymph nodes may be able to avoid adjuvant chemotherapy. By contrast, premenopausal women can derive benefit from adjuvant chemotherapy, based on findings of a prespecified interim analysis of the trial. These findings were presented at the 2020 San Antonio Breast Cancer Symposium.
The interim analysis showed that invasive disease–free survival (IDFS) was improved when chemotherapy was added to standard endocrine therapy in premenopausal women with HR-positive, HER2-negative, lymph node–positive breast cancer and a 21-gene recurrence score between 0 and 25. However, no improvement was seen in IDFS with the addition of chemotherapy to endocrine therapy in postmenopausal women with these same disease characteristics.
Among premenopausal patients, the 5-year IDFS rate was 94.2% in the chemotherapy plus endocrine therapy arm compared with 89% in the endocrine therapy alone arm. By contrast, in postmenopausal patients, the 5-year IDFS rate was 91.6% and 91.9%, respectively.
“Premenopausal patients with 1 to 3 positive nodes and a recurrence score of 25 or less should consider adjuvant chemotherapy. The invasive disease–free survival rate improved by 5% with chemotherapy in this group,” said Kevin Kalinsky, MD, MS, Director, Glenn Family Breast Center, Winship Cancer Institute of Emory University, Atlanta, GA.
The phase 3 RxPONDER study sought to determine if any subset of patients with HR-positive, HER2-negative breast cancer and 1 to 3 positive axillary lymph nodes would benefit from chemotherapy when added to endocrine therapy, and if any patients could safely avoid chemotherapy. This is the first large, randomized clinical trial to try to answer this question. (The TAILORx study looked at this question in node-negative patients with a recurrence score of <25 and showed no benefit for the addition of chemotherapy in postmenopausal women, whereas a benefit was found for women under age 50 years and a recurrence score of 16-25.)
RxPONDER enrolled 5015 patients with stage II or stage III breast cancer, 1 to 3 positive lymph nodes, and a recurrence score ≤25. Of these, 3350 were postmenopausal women and 1665 were premenopausal women. Patients were assigned to receive endocrine therapy versus endocrine therapy plus standard chemotherapy.
The primary end point was IDFS, defined as local, regional, or distant recurrence, any second invasive cancer, or death from any cause.
At a median follow-up of 5.1 years, no association was observed between chemotherapy benefit and recurrence score values between 0 and 25 for the entire population (P = .30). However, a prespecified analysis did show a significant association between chemotherapy benefit and menopausal status (P = .004), which led to further subset analyses based on menopausal status.
At 5 years, premenopausal women with recurrence scores of 0 to 25 had an absolute IDFS benefit of 5.2% with the addition of chemotherapy, whereas postmenopausal women did not.
The follow-up is still relatively short in this patient population with HR-positive breast cancer who are known to have late disease recurrences. Even with this short follow-up, a 1.3% absolute benefit in 5-year overall survival was observed in the premenopausal cohort, which was not significant: 98.6% versus 97.3%, respectively. In postmenopausal women, the 5-year overall survival rates were 96.2% and 96.1%, respectively.
Extrapolation of Results?
C. Kent Osborne, MD, Founding Director, Dan L Duncan Comprehensive Cancer Center, and Dudley and Tina Sharp Chair for Cancer Research, Baylor College of Medicine, Houston, TX, said that the study results were clear, but he was concerned about extrapolating the findings to all premenopausal women with these disease characteristics.
“The results of RxPONDER clearly show no benefit to adding chemotherapy to standard endocrine therapy in postmenopausal patients, despite their having positive nodes. This emphasizes that node positivity, while an important prognostic marker, is not a predictive marker of chemotherapy sensitivity. In premenopausal patients, a different result was obtained,” Dr Osborne said at a press conference where these findings were discussed.
Dr Osborne questioned whether the improvement in IDFS could be a result of ovarian suppression, which has been found to improve outcomes in younger women with early breast cancer. “Unfortunately, we may never know,” he said.
“I’m still skeptical that chemotherapy works differently in premenopausal women, and I would hate for oncologists to come away with the message that all premenopausal patients fitting these criteria should get chemotherapy,” Dr Osborne noted.