Dr Nathanson on Next Steps for Identifying Novel Resistance Mechanisms in Breast Cancer

“Now that we’ve elucidated reversions, which are clearly underestimated in many patients, we’re able to look at other mechanisms of resistance. The next step that we’re planning to do is to look in the nonresistant, nonreverted samples to see whether we can identify other mechanisms."

Katherine L. Nathanson, MD, director, Penn Medicine Center for Genomic Medicine; deputy director, Abramson Cancer Center; principal investigator, Pearl Basser Professor of BRCA-related Research, Perelman School of Medicine, University of Pennsylvania, discusses the next steps for identifying novel mechanisms of resistance beyond reversion mutations in breast cancer.

A study conducted in collaboration with Foundation Medicine analyzed a dataset of 717 cancer samples with reversion mutations, including many cases with multiple reversion events, to systematically identify reversion mutations in breast cancer. This analysis identified 3 new genes with reversion mutations that had not been previously reported, expanding the scope of genetic alterations linked to resistance mechanisms in cancer. The study also characterized the mutation spectrum, revealing that specific mutations—such as missense mutations—do not result in reversion.

Building on these findings, future research will focus on identifying additional mechanisms of resistance beyond BRCA1/2 reversion mutations, Nathanson states. She and her colleagues plan to analyze nonreverted samples to uncover other genetic alterations that contribute to treatment resistance. For example, point mutations in homologous recombination–related genes, such as PARP1, represent a potential area for further exploration, she notes. By systematically characterizing both reverted and nonreverted samples, researchers aim to refine the understanding of how cancers evade targeted therapies like PARP inhibitors, Nathanson details. Given that reversion mutations are estimated to account for 10% to 40% of PARP inhibitor resistance, but that their incidence may be underestimated, this work could provide more accurate estimates and uncover additional resistance mechanisms, she explains. This expanded analysis may reveal novel resistance pathways that are currently underrecognized, thereby informing the development of combination treatments or next-generation inhibitors designed to overcome or prevent resistance, Nathanson concludes.