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Subtype of Triple Negative Breast Cancer Responds Better to Chemotherapy

Researchers at Yale Cancer Center have identified a new subtype of triple negative breast cancer that shows significantly improved response to chemotherapy. Patients with the newly defined subtype — BRCA-deficient triple negative breast cancer — had significantly higher survival rates with chemotherapy.

The study was published on Dec. 13 in PLOS Medicine.

Triple negative breast cancer (TNBC) disproportionately affects young women of all races and women of African ancestry, contributing to health disparities. In an era when personalized cancer therapy has improved survival rates, patients with TNBC remain at considerably higher risk of relapse and death than patients with other types of breast cancer. This fact is due to the aggressive nature of TNBC and the lack of newer targeted therapies for the disease.

The researchers in the Yale-led study performed whole exome sequencing — a technique for sequencing all the expressed genes in a genome — on TNBC tumors. They used the technique to identify mutations in specific genes, or pathways, that might indicate response or resistance to the standard of care, which is anthracycline/taxane (ACT) chemotherapy.

The research team found that TNBC tumors carrying mutations in the AR and FOXA1 pathways had a significantly higher response rate — 94.1% compared to 16.6% in tumors without the mutations.

Their analysis also revealed that the combinations of mutations lowered levels of BRCA1 and BRCA2, two genes linked to increased risk of breast cancer. The presence of these mutations in TNBC was associated with significantly better survival outcomes.

“Analysis revealed that mutations in the BRCA genes yielded many more immune responsive mutations. This may explain the greater chemosensitivity of these tumors and better outcomes for patients,” said Christos Hatzis, assistant professor of medicine (medical oncology) and director of bioinformatics and breast medical oncology at Yale Cancer Center, and senior author of the paper.

“The strong connection of ACT chemosensitivity and immune activity in the newly defined BRCA-deficient subtype of TNBC could help to develop future treatment strategies for our patients,” said Dr. Lajos Pusztai, professor of medicine (medical oncology), and leader of the disease-aligned research team for the Breast Center at Smilow Cancer Hospital.

Additional Yale authors of the study include Tingting Jiang, Weiwei Shi, Vikram Wali, Charles Li, and Richard Lifton.

The study was funded with grant support from the Breast Cancer Research Foundation.

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