New Breast Cancer Mutations Linked to Endocrine Therapy Resistance in HR-Positive Forms of Disease

In PLOS Genetics, an Italian-led team describes molecular changes associated with relapse on endocrine therapy in hormone receptor-positive, HER2-negative forms of breast cancer. From a set of more than 200 surgically resected tumor samples, the researchers used targeted sequencing to profile 134 breast cancer-related genes in samples representing 74 HR-positive, HER2-negative breast cancer cases that relapsed during or after endocrine therapy treatment. They uncovered previously unappreciated MAP3K mutations and amplifications involving the estrogen receptor-coding gene ESR1 that were overrepresented in metastatic tumors, particularly in relapsing patients on adjuvant aromatase inhibitor or luteinizing hormone-releasing hormone agonist treatment in combination with tamoxifen. Moreover, they report, the presence of MAP3K mutations in the metastatic tumors appeared to coincide with shorter relapse-free survival and overall survival times. "Along with expected acquired molecular alterations … we found that an increase of the number of copies of the ESR1 gene (amplification) and mutations in MAP3K are significantly enriched in relapsing tumors," the authors write, "thus expanding the spectrum of known endocrine therapy resistance mechanisms."