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Actionable co-alterations in breast tumors with pathogenic mutations in the homologous recombination DNA damage repair pathway.

Abstract：

PURPOSE:Homologous recombination (HR)-deficient breast tumors may have genomic alterations that predict response to treatment with PARP inhibitors and other targeted therapies. METHODS:Comprehensive molecular profiles of 4647 breast tumors performed at Caris Life Sciences using 592-gene NGS were reviewed to identify somatic pathogenic mutations in HR genes ARID1A, ATM, ATRX, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, FANCA/C/D2/E/F/G/L, KMT2D, MRE11, NBN, PALB2, RAD50/51/51B, and WRN, as well as 41 markers that may be associated with treatment response to targeted anticancer therapies. RESULTS:17.9% of breast tumors had HR mutations (HR-MT, 831/4647) [ER/PR+ , HER2- 18.3%, n = 2183; TNBC 18.2%, n = 1568; ER/PR+ , HER2+ 15.6%, n = 237; ER/PR-, HER2+ 12.9%, n = 217; unknown n = 442]. Mean TMB was higher for HR-MT tumors across subtypes (9.2 mut/Mb vs 7.6 h-wild type (HR-WT), p ≤ 0.0001) and independent of microsatellite status. MSI-H/dMMR was more frequent among HR-MT tumors (2.1% HR-MT vs 0.2% HR-WT, p ≤ 0.0001), as was tumor PD-L1 overexpression (13.2% HR-MT vs 11.0% HR-WT, p = 0.08). Additional co-alterations were similar between HR-MT and HR-WT, with the exception of PIK3CA (30.3% HR-WT vs 26.4% HR-MT, p = 0.024) and AKT1 (3.7% HR-WT vs 2.1% HR-MT, p = 0.021). AR overexpression and PIK3CA mutations were more common among ER/PR+ tumors. ERBB2 mutations were seen in both HER2+ and HER2- tumors. CONCLUSIONS:HR-MT was common across breast cancer subtypes and co-occurred more frequently with markers of response to immunotherapy (MSI-H/dMMR, TMB) compared to HR-WT tumors. Mutations were identified in both HR-MT and HR-WT tumors that suggest other targets for treatment. Clinical trials combining HRD-targeted agents and immunotherapy are underway and could be enriched through comprehensive molecular profiling.

journal_name

Breast Cancer Res Treat

journal_title

Breast cancer research and treatment

authors

Heeke AL,Xiu J,Elliott A,Korn WM,Lynce F,Pohlmann PR,Isaacs C,Swain SM,Vidal G,Schwartzberg LS,Tan AR

doi

10.1007/s10549-020-05849-2

subject

Has Abstract

pub_date

2020-11-01 00:00:00

pages

265-275

issue

eissn

0167-6806

issn

1573-7217

pii

10.1007/s10549-020-05849-2

journal_volume

184

pub_type

杂志文章

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Actionable co-alterations in breast tumors with pathogenic mutations in the homologous recombination DNA damage repair pathway.