HER2 Mutations May Become New Treatment Targets

Caroline Helwick

March 2013, Highlights - Breast Cancer

Some patients who test HER2 negative by conventional tests may still benefit from anti-HER2 agents. This is the conclusion of a study that examined HER2 mutations in detail which was presented by Ron Bose, MD, PhD, Assistant Professor, Oncology Division, Department of Medicine, Washington University School of Medicine in St Louis, MO.

In a genetic analysis of 1500 women, 25 had HER2 mutations in the absence of gene amplification, which is the hallmark of HER2-positive breast cancer, Dr Bose reported.

These genes seemed to be impor­tant, he added. Many of the variants were “activating events” that drove tumor growth in laboratory models.

“The activating mutations are turning on HER2’s functioning and will probably result in abnormal, unregulated HER2 signaling, which is likely driving the cancer cell,” Dr Bose explained.

The mutations appeared in 2 regions of the HER2 gene. The first cluster of mutations was in the extracellular domain, at amino acid (aa) 309-310 (exon 8). The second cluster of mutations was at aa 755-781, which is in the kinase domain (exons 19-20) along with aa 835-896 (exons 21-22).

The investigators further evaluated 13 of the variants, examining enzyme activity, tissue cultures, and tumor growth in mice. They found that many variants were susceptible to currently approved drugs, including trastuzumab (Herceptin) and lapatinib (Tykerb; a tyrosine kinase inhibitor [TKI]). But all of the variants were susceptible to the investigational TKI neratinib, which has prompted a clinical trial of neratinib in stage IV patients who have HER2 mutations.

The press briefing moderator C. Kent Osborne, MD, Professor of Medicine and Cellular and Structural Biology, and Director of the Smith Breast Center at Baylor College of Medicine in Houston, TX, said the study “has limited usefulness right now,” but it is important, because it offers elucidation about heretofore unappreciated genetic mutations that may have a role in breast cancer and that can be targeted. It is possible that these mutations exist in other subtypes of breast cancer as well, Dr Osborne noted.