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

"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.

The study identified REVs in BRCA1 and BRCA2, as well as 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.

Among the DDR genes analyzed, BRCA2 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 BRCA2 reversion mutations resulted in complete exon 11 deletion, eliminating all BRCA repeats and maintaining a functional structure. In contrast, BRCA1 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 BRCA2 exon 11 deletions.

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 BRCA and DDR gene alterations, Nathanson concludes.

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.