Katherine L. Nathanson, MD, serves as director of the Penn Medicine Center for Genomic Medicine and deputy director of Abramson Cancer Center. She is also principal investigator and Pearl Basser Professor of BRCA-related Research at Perelman School of Medicine, of the University of Pennsylvania.

Dr Nathanson on the Role of Reversion Mutations in PARP Inhibitor Resistance

"This is the first time that we have a large and broad overview of the landscape of reversions. In our 717 samples, many of them [had] multiple reversions, and it gives us a much broader picture about the landscape of reversion mutations."

Katherine L. Nathanson, MD, Pearl Basser Professor for BRCA-Related Research at the Abramson Cancer Center of the University of Pennsylvania, highlights findings from a comprehensive analysis evaluating reversion mutations (REVs) across multiple DNA damage repair (DDR) genes and their implications for PARP inhibitor resistance in breast cancer.

CDK12, PALB2, BARD1, BRIP1, RAD51C, and RAD51D.

 These findings brought into question whether tumors with pathogenic variants in these genes will respond effectively to PARP inhibition. Notably, missense mutations, large genomic rearrangements, and bi-allelic deletions did not undergo reversion; splice site mutations had a lower frequency of reversion events.

 was the most frequently reverted gene, with exon 11 loss as the predominant mechanism. Structural modeling indicated that despite this deletion, the BRCA2 protein retains functional integrity, conferring homologous recombination repair (HRR) activity and driving therapeutic resistance. Approximately 15% of 

 reversion mutations resulted in complete exon 11 deletion, eliminating all BRCA repeats and maintaining a functional structure. In contrast, 

 REVs often involved alternative resistance mechanisms, such as Δ11 splice site alterations and translational re-initiation.

Lower reversion rates were seen in functional domains and were rarely associated with alterations exceeding 10 amino acids, and no hot spot regions for REVs were identified, except for a higher frequency of 

These insights offer a broader understanding of reversion mutations and their role in PARP inhibitor resistance, emphasizing the importance of mutation type and gene location in predicting therapeutic response. These findings may inform future treatment strategies, particularly for patients with 

After analyzing REVs, investigators could now examine other mechanisms of resistance in patients with breast cancer receiving PARP inhibition, Nathanson explains. Previously, it had been estimated that anywhere from 10% to 40% of PARP inhibitor resistance stemmed from REVs, and these data suggest that rate is higher, she continues. Combining these findings with data for other non-reverted mechanisms of resistance could paint a fuller picture, she concludes.

Videos

Katherine L. Nathanson, MD, discusses the impact of reversion mutations on resistance to PARP inhibitors across various DNA damage repair genes.

Dr Nathanson on the Role of Reversion Mutations in PARP Inhibitor Resistance in Breast Cancer

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.

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

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

Dr Nathanson on BRCA1/2 Reversion Mutations in Response to Therapy in Breast Cancer

“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

Articles

Dr Nathanson on the Role of Reversion Mutations in PARP Inhibitor Resistance in Breast Cancer

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

Dr Nathanson on BRCA1/2 Reversion Mutations in Response to Therapy in Breast Cancer