Reversion Mutations with Clinical Use of PARP Inhibitors: Many Genes, Many Versions

Q: What does this research mean for the field?

Reversion mutations conferring PARP inhibitor resistance occur across multiple genes including RAD51C, RAD51D, PALB2, BRCA1, and BRCA2, can present as multiple distinct mutations in a single patient, and are detectable via circulating cell-free DNA. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.NEUTRAL.

Susan M. Domchek

doi:10.1158/2159-8290.cd-17-0734

August 31, 2017Cancer Discovery

Reversion Mutations with Clinical Use of PARP Inhibitors: Many Genes, Many Versions

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Key Points

To evaluate the spectrum and diversity of secondary reversion mutations that confer clinical resistance to PARP inhibitor therapy.
Reviewed clinical findings regarding secondary reversion mutations across homologous recombination repair genes, including BRCA1, BRCA2, RAD51C, RAD51D, and PALB2.
Assessed molecular detection strategies for identifying resistance mutations through the profiling of circulating cell-free DNA.
Secondary reversion mutations restore functional protein expression and drive PARP inhibitor resistance across tumors with RAD51C, RAD51D, PALB2, BRCA1, and BRCA2 mutations.
Multiple distinct reversion mutations frequently co-occur within a single patient, demonstrating high polyclonal heterogeneity under therapeutic pressure.
Analysis of circulating cell-free DNA reliably identifies these heterogeneous reversion mutations non-invasively.

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Implication

Clinical analysis demonstrates diverse reversion mutations driving PARP inhibitor resistance across multiple tumor types, highlighting circulating cell-free DNA as a key monitoring tool.

Abstract

Summary: Reversion mutations associated with PARP inhibitor resistance have been identified in tumors with RAD51C, RAD51D, and PALB2 as well as BRCA1 and BRCA2 mutations. Multiple different reversion mutations can occur in a single patient, and they can be detected by analysis of circulating cell-free DNA. Cancer Discov; 7(9); 937–9.

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Susan M. Domchek (2017) studied this question.

synapsesocial.com/papers/6aa95c346ef768addceeaa46 https://doi.org/10.1158/2159-8290.cd-17-0734

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Reversion Mutations with Clinical Use of PARP Inhibitors: Many Genes, Many Versions

Key Points

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Implication

Abstract

Discussion

Cite This Study

Reversion Mutations with Clinical Use of PARP Inhibitors: Many Genes, Many Versions

Key Points

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Implication

Abstract

Discussion

Cite This Study

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