Katherine L. Nathanson, MD, discusses the next steps for identifying novel mechanisms of resistance beyond reversion mutations 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 

 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 

, 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.

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Katherine L. Nathanson, MD, discusses the next steps for identifying novel mechanisms of resistance beyond reversion mutations in breast cancer.
 

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“We’ve identified 3 new genes in which reversions had not been previously reported. This is particularly important in terms of therapy, as these are not mechanisms of resistance in patients with those underlying mutations. This is the first time that we have a large and broad overview of the landscape of reversions [in breast cancer].”

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 identification of reversion mutations in 

 that arise in response to therapy among patients with breast cancer.

A study conducted in collaboration with Foundation Medicine used a dataset of 717 cancer samples with reversion mutations, many with multiple reversion events, to comprehensively identify reversion mutations in breast cancer, Nathanson begins. Reversion mutations, defined as secondary mutations that reverse the effects of the primary mutations, commonly occur in 

 genes and are associated with treatment resistance, according to Nathanson.

In this analysis, Nathanson and colleagues identified 3 new genes in which reversion mutations were previously unreported, expanding the understanding of genetic alterations linked to resistance mechanisms in cancer. The study also delved into the spectrum of mutations, establishing that certain mutations—such as missense mutations—do not lead to reversion, Nathanson states. Large genomic rearrangements and bi-allelic deletions were similarly not associated with reversion events. Interestingly, splice site mutations were found to have a relatively low incidence of reversion mutations, she notes. These insights have important therapeutic implications, as they reveal that reversion mutations do not contribute to resistance in patients with specific underlying mutations, offering guidance for clinical decision-making, Nathanson explains.

 emerged as the most frequently reverted gene, with the most common mechanism involving the loss of large exon 11, Nathanson reports. This novel finding indicates that despite the loss of this exon, the structure of the protein remains functional, she says. Structural modeling conducted by the research team provided supporting evidence for the structural integrity of 

 even without this large internal exon, Nathanson notes.

Although certain functional domains within genes were less likely to undergo large deletions, no specific regions emerged as distinct hotspots for reversion mutations, contrary to findings from prior studies, Nathanson continues. This broad overview of the reversion mutation landscape provides an invaluable resource for understanding the role of reversion mutations in cancer resistance, she explains. The findings open the door to better-informed strategies for targeting these mutations in therapeutic interventions, ultimately enhancing the precision and efficacy of cancer treatments, Nathanson concludes.

Katherine L. Nathanson, MD, discusses the identification of reversion mutations in BRCA1/2 in response to therapy among patients with breast cancer.

Katherine L. Nathanson, MD

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