Possible reason for breast cancer treatment resistance.

Abstract

Investigators think they know one reason why metastatic breast cancers that initially respond to hormone therapy such as tamoxifen eventually become resistant to treatment. It could be attributed to a mutation in the receptor of the cancer cell to which tamoxifen binds, according to a recent study.1 Nearly all patients with metastatic breast cancer who initially respond to endocrine treatment eventually develop resistance, says Ido Wolf, MD, head of the medical oncology department at the Tel Aviv Sourasky Medical Center in Israel. He and his colleagues identified a new mutation in the estrogen receptor, which is the target for endocrine treatments. The mutation, which they found in 38% of the patients with metastatic breast cancer, makes the receptor more active and resistant to treatment. The researchers used breast cancer samples from 13 patients, collected from both the breast and the liver, to which the tumor had spread. Although all the patients had initially received endocrine therapy, they later experienced failure with multiple lines of treatment. A genomic analysis of the tumors found that the estrogen receptor was mutated in 5 of the samples. The mutation, called D538G, was only found in the metastatic liver tumor samples. The mutation altered the receptor in such a way that it could no longer bind to tamoxifen, causing the drug to be ineffective. Further analysis showed that the change in the receptor's structure actually led it to function independently and to cause uncontrolled multiplication of cancer cells, which made the tumors less responsive to treatments.