New results from the phase 3 RxPONDER trial add to mounting evidence that most postmenopausal women with early-stage breast cancer derive no added benefits from chemotherapy and can be effectively treated with endocrine therapy alone.
The study, published in The New England Journal of Medicine, conversely shows that premenopausal women do benefit from adjuvant chemotherapy, theorized by many to largely be the result of chemotherapy-induced ovarian function suppression.
The RxPONDER trial results are in line with those from the practice-changing TAILORx trial and underscore that “postmenopausal women with 1 to 3 positive nodes and [a recurrence score] of 0 to 25 can likely safely forgo adjuvant chemotherapy without compromising invasive disease-free survival,” first author Kevin Kalinsky, MD, of the Winship Cancer Institute at Emory University, Atlanta, told Medscape Medical News. “This will save tens of thousands of women the time, expense, and potentially harmful side effects that can be associated with chemotherapy infusions.”
However, the authors note, “premenopausal women with 1-3 positive lymph nodes had a significant benefit from chemotherapy.”
The study, conducted by the Southwest Oncology Group (SWOG) Cancer Research Network, involved 5018 women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer with one to three positive axillary lymph nodes — a breast cancer profile that represents approximately 20% of cases in the US.
All women had recurrence scores on the 100-point 21-gene breast cancer assay (Oncotype Dx) under 25, which is considered the lowest risk of recurrence. Patients were randomized to treatment with endocrine therapy only (n = 2507) or chemotherapy followed by endocrine therapy (n = 2511).
After a median follow-up of 5.3 years, women treated with adjunctive chemotherapy plus endocrine therapy exhibited no significant improvements in invasive disease-free survival compared to those who received endocrine therapy alone.
A prespecified analysis stratifying women by menopausal status underscored those results among postmenopausal women. In this cohort, researchers reported invasive disease-free survival was 91.9% in the endocrine-only group and 91.3% in the chemotherapy group (HR, 1.02; P = .89), indicating no benefit of the adjunctive chemotherapy.
However, among premenopausal women, the invasive disease-free survival rate was significantly higher with the addition of chemotherapy — 89.0% with endocrine-only therapy and 93.9% with both therapies (HR, 0.60; P = .002). Increases in distant relapse-free survival observed in the dual-therapy group similarly favored adding chemotherapy (HR, 0.58; P = .009).
Even when the authors further stratified the women into recurrence scores of 0 to 13 or 14 to 25, the results remained consistent. Postmenopausal women in each of the recurrence score groups continued to show no difference in invasive disease recurrence, new primary cancer, or death from chemotherapy (HR, 1.01 for each score group). Conversely, premenopausal women showed significant improvements in those outcomes when chemotherapy was added to endocrine therapy.
To what degree were the effects observed in premenopausal women the result of chemotherapy-induced ovarian suppression?
“I think it’s fair to say it’s the most interesting question right now in early-stage breast cancer for ER-positive tumors,” Harold Burstein, MD, of the Dana-Farber Cancer Institute and Harvard Medical School, said during a debate at the recent San Antonio Breast Cancer Symposium.
According to Sibylle Loibl, MD, PhD, when it comes to the use of chemotherapy, “age matters.”
“I strongly believe the biology of tumors is different in younger women with HR-positive/HER2-negative breast cancer,” Loibl, an associate professor at the University of Frankfurt, Germany, said during the debate. “It’s a different disease and the effects of chemotherapy are different.”
In young women, chemotherapy has “a direct cytotoxic effect, which cannot be neglected, and an endocrine effect on ovarian function suppression,” Loibl added. “I think both are needed in young premenopausal patients.”
According to the RxPONDER authors, “whether a chemotherapy benefit in premenopausal women is due to both direct cytocidal effects and treatment-induced menopause remains unclear,” but noted “it is possible that the contribution of these mechanisms may vary according to age.”
Further complicating matters, Loibl added, is that age appears to be poorly represented in genetic diagnostic tools.
“I think the gene expression profiles we are currently using as standard diagnostic tools do not capture the right biology for our premenopausal patients,” she said. “We have to keep in mind that these tests were designed and validated in postmenopausal patients and were only retrospectively used in premenopausal patients.”
The study was funded by the National Cancer Institute and others. Loibl has received honoraria from Prime and Chugai and numerous institutional research grants.
New Engl J Med. Published online December 2, 2021. Full text
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