Gene study finds adjuvant chemo beneficial in premenopausal women

Postmenopausal women with breast cancer, one to three positive lymph nodes, and recurrence scores of 0-25 can safely skip adjuvant chemotherapy without lowering their invasive disease-free survival or distant relapse-free survival, according to results from the RxPONDER (A Clinical Trial RX for Positive Node, Endocrine Responsive Breast Cancer) study, published in The New England Journal of Medicine.

But importantly, researchers also found that premenopausal women with breast cancer and the same characteristics would benefit from adjuvant chemotherapy, and gain a significant improvement in these survival rates.

“The development of multigene prognostic assays has led to increased precision in estimating the absolute risk of recurrence among women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary lymph-node–negative breast cancer. The clinical usefulness of a recurrence score based on the 21-gene breast cancer assay (Oncotype DX, Genomic Health [now Exact Sciences]) was established in a series of prospective–retrospective studies and then validated in the prospective Trial Assigning Individualized Options for Treatment (TAILORx),” wrote researchers, led by Kevin Kalinsky, MD, MS, director of the Glenn Family Breast Center at Winship Cancer Institute of Emory University, Atlanta.

These researchers explained the impetus for their prospective study, which was conducted at 632 sites in nine countries and funded, in part, by the National Cancer Institute.

“The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary lymph-node–negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear,” they wrote.

Recurrence scores range from 0 to 100, with a higher score denoting worse prognosis.

To assess the effect of chemotherapy on invasive disease-free survival (DFS) and whether this was affected by this recurrence score, Kalinsky et al conducted a study that randomized 5,018 women with hormone-receptor-positive, HER2-negative, axillary lymph-node-negative breast cancer to treatment with endocrine therapy alone or to chemoendocrine therapy (chemotherapy plus endocrine therapy).

Nearly one-third of women with newly diagnosed hormone-receptor-positive, HER2-negative breast cancer have lymph-node positive disease. This characteristic is associated with increased risks of recurrence.

Kalinsky et al defined premenopausal status as less than six months since a last menstrual period and postmenopausal as previous bilateral oophorectomy (but no hysterectomy) or over 12 months since a last period.

At the third interim analysis, researchers found that the benefits of chemotherapy on increased invasive disease-free survival were different according to menopausal status (P=0.008 for benefit in premenopausal versus postmenopausal).

In postmenopausal women, invasive disease-free five-year survival was 91.9% in those treated with endocrine therapy alone, compared with 91.3% in those treated with chemoendocrine therapy, with no chemotherapy benefit (HR for invasive disease recurrence, new primary cancer, or death: 1.02; 95% CI: 0.82-1.26; P=0.89).

In premenopausal women, invasive disease-free five-year survival was 89.0% in women treated with endocrine-only therapy, compared with 93.9% in those who received chemoendocrine therapy (HR: 0.60; 95% CI: 0.43-0.83; P=0.002). Similar increases in distant relapse-free survival were seen (HR: 0.58; 95% CI: 0.39-0.87; P=0.009).

Relative chemotherapy benefit did not increase with increasing recurrence scores.

“Whether a chemotherapy benefit in premenopausal women is due to both direct cytocidal effects and treatment-induced menopause remains unclear. It is possible that the contribution of these mechanisms may vary according to age within the premenopausal group,” noted Kalinsky and fellow researchers.

“In the 67% of participants who were postmenopausal, no chemotherapy benefit was seen. In contrast, adjuvant chemotherapy resulted in a relative increase of 40% in invasive disease–free survival and a relative increase of 42% in distant relapse–free survival among premenopausal women. In premenopausal participants, a chemotherapy benefit was seen across all subgroups, regardless of the recurrence-score value,” they concluded.

  1. Postmenopausal women with breast cancer and low recurrence scores who skip adjuvant chemotherapy won’t lower disease-free survival or distant relapse-free survival.

  2. Premenopausal women with the same characteristics, however, can gain significant survival benefits with adjuvant chemotherapy.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

This study was supported by grants from the National Cancer Institute and by the Susan G. Komen for the Cure Research Program, the Hope Foundation for Cancer Research, the Breast Cancer Research Foundation, and Genomic Health.

Kalinsky reported receiving grants or cotnracts from Acetylon, Amgen, Calithera, Cytomx, Eli Lilly and Company, Genentech, Immunomedics, Novartis, Pfizer, Seattle Genetics, and Zentalis; serving as a consultant for 4D Pharma, AstraZeneca, cyclocel, Daiichi Sankyo Company, Eisai, Eli Lilly and Company, Merck, Novartis, oncosec, Pfizer, and Seattle Genetics; employment with Array BioPharma and Grail; serving on the steering committee for Ambryx and Immunomedics; and travel fees from AstraZeneca and Eli Lilly and Company.

Cat ID: 115

Topic ID: 78,115,496,497,730,115,935,39,691,192,925