ESMO Virtual Congress 2020: Pan-Cancer Analysis of Homologous Recombination Associated Alterations and Genome-Wide Loss of Heterozygosity

(UroToday.com) While alterations in the homologous recombination repair (HRR) genes BRCA1 and BRCA2 are associated with response to PARP inhibitors and certain chemotherapies, the relevance of alterations in other HRR genes for treatment response is less well understood. In this presentation, Dr. Westphalen presented analysis of alterations in homologous recombination repair denes across a pan-cancer cohort of 160,674 tumors. The pan-cancer cohort is described below:



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The authors divided up the cancers studied into “BRCA-associated cancers” (ovarian, breast, prostate, pancreatic) or non-BRCA-associated cancers. HRR alterations were found across all tumor types, and HRR alterations are more commonly biallelic in BRCA-associated cancers.

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Genomic loss of heterozygosity (gLOH), ascertained here by a score reflecting the number of genomic regions identified as having loss of heterozygosity, has been associated with HRR deficiency and may correlate with response to PARP inhibitors. Biallelic alterations in BRCA1, BRCA2, RAD51D, PALB2, and RAD51C were associated with gLOH < 16, the cutoff used for gLOH positivity in this study. Alterations in other HRR genes were not strongly associated with high gLOH.

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Biallelic alterations in the 5 genes associated with high-levels of gLOH, were present at higher rates in BRCA-associated cancers, but also in multiple other cancer types.
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In summary, these results suggest that bi-allelic alterations in certain HRR genes (BRCA1, BRCA2, PALB2, RAD51C and RAD51D) are associated with genomic readouts of deficiency in HRR, specifically gLOH. Ascertaining the zygosity in alterations in these genes may be important as predictive biomarkers for therapies that have activity in the context of HRR deficiency.

Presented by: Christoph Benedikt Westphalen, MD, Comprehensive Cancer Center Munich and the Department of Medicine III, Ludwig Maximilian University of Munich, Munich, Germany

Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the 2020 European Society for Medical Oncology Virtual Congress (#ESMO20), September 19th-September 21st, 2020.

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