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.
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AH developed study design, analyzed dataset, composed manuscript, and read and approved the final manuscript. JX contributed to study design, provided and analyzed dataset, performed statistical analyses, and read and approved the final manuscript. AE provided and analyzed dataset, provided methodology for testing, performed statistical analyses, and read and approved the final manuscript. MK provided and analyzed dataset and read and approved the final manuscript. FL, PP, CI, SS, GV, and LS interpreted the data and read and approved the final manuscript. AT contributed to study design, interpreted the data, and read and approved the final manuscript.
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A.H.: Consultant (Caris Life Sciences). J.X.: Employment (Caris Life Sciences). A.E.: Employment (Caris Life Sciences). M.K.: Consultant (Merck), employment and ownership interest (Caris Life Sciences). F.L.: Fees (Pfizer, ASCO), contracted research (Bristol-Myers Squibb, Calithera, Chugai, Immunomedics, Inivata, Pfizer, Regeneron, Roche/Genentech, Tesaro). P.P.: Consultant (Caris Life Sciences, Heron, Immunonet BioSciences, OncoPlex Diagnostics, Personalized Cancer Therapy, Pfizer, Xcenda), speaker’s bureau (Roche/Genentech), contracted research (Advanced Cancer Therapeutics, Caris Centers of Excellence, Cascadian Therapeutics, Fabre-Kramer, Klus Pharma, Pfizer, Pieris Pharmaceuticals, Roche/Genentech), stock/other ownership (Immunonet BioSciences), patents (No.US 8,501,417; No.US 9,745,377; No.US 9,023,362; No.US 8,486,413). C.I.: Consultant (AstraZeneza, Novartis, Pfizer, PUMA, Roche/Genentech), speaker’s bureau (Roche/Genentech). S.S.: Grants (Pfizer, Roche/Genentech), fees (AstraZeneca, Athenex, Daiichi-Sankyo, Eli Lilly & Company, Genomic Health, Inivata, Pieris Pharmaceuticals, Roche/Genentech, Tocagen), reimbursements (AstraZeneca, Athenex, Bristol-Myers Squibb, Caris Life Sciences, Daiichi-Sankyo, Eli Lilly & Company, Inivata, NanoString Technologies, Novartis, Pieris Pharmaceuticals, Roche/Genentech). G.V.: Fees (AstraZeneca, Eli Lilly, Immunomedics, Novartis, Puma, Pfizer, Roche/Genentech), contracted research (AstraZeneca, Bristol-Myers Squibb, Celcuity, Eli Lilly, GTx Inc, Halozyme, Immunomedics, Merck, Puma, Pfizer, Roche/Genentech, Tesaro), ownership/stocks (Oncodisc). L.S.: Consultant (Amgen, AstraZeneca, Bristol-Myers Squibb, Genomic Health, Merck, Myriad, Napo, Pfizer, Roche/Genentech), contracted research (Amgen, Pfizer). A.T.: Reimbursement (Caris Life Sciences).
Research involving human participants and/or animals
This research study was conducted retrospectively from data obtained for clinical purposes. We consulted extensively with the IRB at the Levine Cancer Institute, Atrium Health, who determined that our study did not need ethical approval.
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Heeke, A.L., Xiu, J., Elliott, A. et al. Actionable co-alterations in breast tumors with pathogenic mutations in the homologous recombination DNA damage repair pathway. Breast Cancer Res Treat 184, 265–275 (2020). https://doi.org/10.1007/s10549-020-05849-2
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DOI: https://doi.org/10.1007/s10549-020-05849-2