Some women with early breast cancer may skip adjuvant chemotherapy
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Menopausal status may determine which women with lymph node-positive early breast cancer and low recurrence scores require adjuvant chemotherapy, according to findings presented at the virtual San Antonio Breast Cancer Symposium.
Interim analysis results of the randomized phase 3 RxPONDER trial — which included women with one to three positive axillary lymph nodes and recurrence scores of 25 or less — showed postmenopausal women derived no benefit from the addition of chemotherapy to adjuvant endocrine therapy.
However, premenopausal women who received chemotherapy prior to adjuvant endocrine therapy achieved longer invasive DFS, and early data suggest a potential OS benefit.
“Our goal in cancer care is to improve upon achieving precision medicine so we base decisions on the biology of a patient’s tumor,” Kevin Kalinsky, MD, MS, director of Glenn Family Breast Center at Winship Cancer Institute of Emory University, told Healio. “When patients meet with a medical oncologist, the question that is always at top of mind is: Do I need chemotherapy? These data really help inform that decision.”
The randomized phase 3 TAILORx trial established the clinical utility of recurrence scores to predict chemotherapy benefit for patients with hormone receptor-positive, HER2-negative early breast cancer with no axillary lymph node involvement.
Kalinsky and SWOG Cancer Research Network colleagues conducted the SWOG S1007 RxPONDER trial to assess whether recurrence score also may predict chemotherapy benefit for patients with lymph node-positive breast cancer, who are at higher risk for recurrence.
The analysis included 5,083 women aged 18 years or older with stage II or stage III hormone receptor-positive, HER2-negative breast cancer with one to three positive lymph nodes and no contraindications to anthracycline- and/or taxane-based chemotherapy.
All women had recurrence scores of 25 or less as determined by the Oncotype Dx test (Exact Sciences). The test, which provides individualized risk assessments for patients with early-stage invasive breast cancer based on evaluation of 16 cancer-related genes and five reference genes, yields scores on a scale of 0 to 100.
Approximately two-thirds (66.8%) of the women were postmenopausal and one-third (33.2%) were premenopausal.
Researchers randomly assigned women 1:1 to endocrine therapy with or without chemotherapy, stratifying by recurrence score (0-13 vs. 14-25), menopausal status, and axillary nodal dissection vs. sentinel node biopsy.
The effect of chemotherapy on invasive DFS — as well as whether that effect varied based on recurrence score — served as the primary objective. OS served as a secondary objective.
Median follow-up was 5.1 years, at which time 447 invasive DFS events had been observed (53.7% of expected).
Results showed no association between recurrence score values between 0 and 25 and chemotherapy benefit for the overall cohort.
An analysis of postmenopausal women adjusted for continuous recurrence score showed no invasive DFS benefit with the addition of chemotherapy to endocrine therapy overall (HR = 0.97; 95% CI, 0.78-1.22) or in any subgroup. Five-year invasive DFS rates were comparable between those who received chemotherapy and those who did not (91.6% vs. 91.9%).
Among premenopausal women, results showed a statistically significant benefit of chemotherapy receipt on invasive DFS (HR = 0.54; 95% CI, 0.38-0.76), with 5-year DFS rates of 94.2% for those assigned to chemotherapy and 89% for those who were not.
Researchers also observed early indications of an OS benefit among premenopausal women who received chemotherapy (HR = 0.47; 95% CI, 0.24-0.94). This trend was similar among women with recurrence scores of 0 to 13 and those with scores of 14 to 25.
Investigators acknowledged the number of events was limited at the time of analysis. Updated results will be reported after longer follow-up, but Kalinsky said he believes the results can be used now to guide clinical decision-making.
“To see these findings so clearly at the time of interim analysis is really notable,” Kalinsky said. “We will follow these patients for a total of 15 years but, based on what we know about the timing of the benefit of chemotherapy, even though the confidence intervals may become a bit narrower, the differential effect between the postmenopausal and premenopausal groups likely will remain.”
In the premenopausal group, 16% of women assigned endocrine therapy alone and 3% of those assigned chemotherapy with endocrine therapy underwent ovarian suppression.
It remains unclear to what extent chemotherapy-induced menopause contributed to the chemotherapy benefit among premenopausal women, Kalinsky said.
“The study was not powered to look at this question,” he said. “We will explore the impact of ovarian function suppression. We did capture prospectively at various time points whether patients had regular periods. This can be hypothesis-generating, but whether we can say the effect was due specifically to the ovarian function effect or because it is also due to direct impact on the tumor will be hard to tease out.”
Perspective
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The results of the RxPONDER trial show the addition of chemotherapy to endocrine therapy provided no benefit for postmenopausal women with ER-positive, HER2-negative disease with one to three positive lymph nodes and Oncotype DX recurrence scores of 25 or less.
The fact these women could be spared chemotherapy is a great advance, as they automatically would have received adjuvant chemotherapy in the past.
Further, these results are consistent with those of the TAILORx trial, which included postmenopausal women with node-negative disease and recurrence scores of 25 or less. Hence, biology is biology of tumors with recurrence scores of 25 or less, irrespective of nodal status.
Results of RxPONDER also show premenopausal women with recurrence scores of 25 or less will benefit from chemotherapy.
Knowing precisely who does or does not benefit from adjuvant chemotherapy is powerful information for women and cannot be overemphasized.
There are several caveats in the RxPONDER trial, as in all randomized trials.
First, this was an interim analysis with half the number of events projected for the final analysis. In ER-positive, HER2-negative or luminal breast cancers, more than 50% of recurrences occur after 5 years. Further follow-up — out to 15 years — is planned in this trial.
Also, the definition of menopause does appear in this abstract. Was menopausal status determined by self-report or using the definition of 12 months without a menstrual period, or did they draw levels of estradiol and a follicle-stimulating hormone? I am confident that the publication in a journal will specify how menopausal status was determined.
The RxPONDER trial is practice-changing. The trial de-escalates treatment, sparing postmenopausal women with one to three positive nodes and Oncotype Dx recurrence scores of 25 or less from adjuvant chemotherapy. This is a victory for most women who can achieve long-term breast cancer survival without the long-term effects of adjuvant chemotherapy.
Icahn School of Medicine at Mount Sinai
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C. Kent Osborne, MD
The results clearly show no benefit of adding chemotherapy to standard endocrine therapy for postmenopausal patients, even if they have positive nodes. This emphasizes that node positivity — while an important prognostic marker — is not a predictive marker of chemotherapy sensitivity.
A different result was obtained for premenopausal patients. The endocrine therapy in this group was nearly always tamoxifen. The standard approach today for this group would be ovarian suppression plus either an aromatase inhibitor or tamoxifen, both of which have been shown to be superior to tamoxifen alone in this subgroup.
Because adjuvant chemotherapy causes ovarian suppression in many premenopausal patients, these patients then, in fact, received ovarian suppression plus tamoxifen, while tamoxifen alone was the endocrine therapy for the no-chemotherapy group.
Is the difference in outcome in this subset due to the endocrine effects of chemotherapy? Unfortunately, we may never know the answer to this question.
Baylor College of Medicine
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Kalinsky K, et al. Abstract GS3-00. Presented at: San Antonio Breast Cancer Symposium (virtual meeting); Dec. 8-11, 2020.
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