TY - JOUR
T1 - Actionable co-alterations in breast tumors with pathogenic mutations in the homologous recombination DNA damage repair pathway
AU - Heeke, Arielle L.
AU - Xiu, Joanne
AU - Elliott, Andrew
AU - Korn, W. Michael
AU - Lynce, Filipa
AU - Pohlmann, Paula R.
AU - Isaacs, Claudine
AU - Swain, Sandra M.
AU - Vidal, Gregory
AU - Schwartzberg, Lee S.
AU - Tan, Antoinette R.
N1 - Publisher Copyright:
© 2020, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Co-alterations
KW - Homologous recombination deficiency
KW - Molecular profiling
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U2 - 10.1007/s10549-020-05849-2
DO - 10.1007/s10549-020-05849-2
M3 - Article
C2 - 32776290
AN - SCOPUS:85089291499
SN - 0167-6806
VL - 184
SP - 265
EP - 275
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 2
ER -