Torsten Nielsen, MD, PhD
Premenopausal women with high-risk breast cancer of the luminal A subtype derive no benefit from adjuvant chemotherapy, according to an analysis of the phase III Danish Breast Cancer Cooperative Group (DBCG) 77B trial.
Ten-year disease-free survival (DFS) was not different between women with luminal type A disease who were randomized to chemotherapy or no chemotherapy in DBCG 77B, said Torsten Nielsen, MD, PhD, who reported the data at the 2015 San Antonio Breast Cancer Symposium.
“This is clearly part of a body of evidence that’s building up … that we can probably back off on the aggressiveness of our treatments and still achieve the same results,” said Nielsen, professor of pathology at the University of British Columbia, Vancouver, Canada. “Once upon a time, people got radical mastectomies … that backed off to modified radicals and breast-conserving surgery. Now maybe we can back off chemotherapy. It has been accepted in some groups, and maybe we can extend that group of women where we can consider that.”
DBCG 77B examined the relative efficacy of levamisole, single-agent oral cyclophosphamide, and the combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) against no adjuvant systemic therapy in premenopausal women with node-positive invasive breast cancer >5 cm who were treated with local therapy (mastectomy, axillary node dissection, and radiotherapy). None of the women received endocrine therapy. The main results showed that chemotherapy significantly improved DFS and overall survival compared with controls, and the benefits persisted for at least 25 years.
Distinguishing between intrinsic cancer subtypes has proven to be prognostic in many settings, and appears promising for predicting the benefit of chemotherapy, “but the level of evidence behind these predictive questions is often from in vitro studies, animal studies, and cohort studies,” said Nielsen.
Luminal breast cancer subtype A, a subtype that comprises 30% to 70% of invasive breast cancers, is defined by a high expression of the estrogen receptor and progesterone receptor, and low expression of the cell-growth marker Ki67 and the HER2 oncoprotein on a six-marker immunohistochemical panel. Evidence suggests that the luminal A subtype of breast cancer has a much better prognosis than the other subtypes, with a low risk of local or regional recurrence.
To answer the question of whether women with molecularly low-risk luminal A breast cancer could forgo chemotherapy without adversely affecting their outcome, Nielsen and colleagues assessed intrinsic breast cancer subtypes by immunohistochemistry (IHC) performed on tissue microarrays from 709 of the 1146 patients enrolled in DBCG 77B. IHC was informative for subtype in 633 of the tissue samples. Luminal subtype A was identified in 165 of the 633 samples while 468 were nonluminal A, which included luminal B, HER2E, and triple-negative subtypes.
The study set reflected the overall DBCG 77B study population, with similar proportions having node-positive, grade 2-3 disease, and a similar response to chemotherapy.
Patients with nonluminal A breast cancer had a 50% improvement in 10-year DFS with randomization to chemotherapy compared with control. In contrast, the hazard ratio for 10-year DFS was 1.07 in luminal A patients treated with chemotherapy compared with no chemotherapy. An interaction test between luminal A status and chemotherapy for 10-year invasive DFS was significant at P
<.05, indicating that intrinsic subtype was predictive of outcome.
The direct relevance of the study to today’s breast cancer population is not known, Nielsen said, as the DCBG 77B population did not receive current standards of care such as endocrine therapy, anti-HER2 treatment, anthracyclines, or taxanes. But given that women with luminal A subtype did not benefit from chemotherapy, it would be expected that women with similar tumor characteristics who receive endocrine therapy would also receive no benefit from chemotherapy, he indicated.
“It does seem that there’s some evidence to suggest that it [withholding chemotherapy] may be safe for women with the lowest molecular group,” he said.
The SWOG S1007 phase III clinical trial is assessing whether women with node-positive, HR-positive, and HER2-negative breast cancer who have a low recurrence score via Oncotype Dx benefit from adding adjuvant chemotherapy to hormonal therapy, commented Virginia Kaklamani, MD, leader of the Breast Cancer Program at the Cancer Therapy & Research Center at the University of Texas Health Science Center, San Antonio.