Metastatic Prostate Cancers with BRCA2 versus ATM Mutations Exhibit Divergent Molecular Features and Clinical Outcomes

Justin Hwang; Xiaolei Shi; Andrew Elliott; Taylor E. Arnoff; Julie McGrath; Joanne Xiu; Phillip Walker; Hannah E. Bergom; Abderrahman Day; Shihab Ahmed; Sydney Tape; Allison Makovec; Atef Ali; Rami M. Shaker; Eamon Toye; Rachel Passow; John R. Lozada; Jinhua Wang; Emil Lou; Kent W. Mouw; Benedito A. Carneiro; Elisabeth I. Heath; Rana R. McKay; W. Michael Korn; Chadi Nabhan; Charles J. Ryan; Emmanuel S. Antonarakis

doi:10.1158/1078-0432.CCR-22-3394

Metastatic Prostate Cancers with BRCA2 versus ATM Mutations Exhibit Divergent Molecular Features and Clinical Outcomes

Justin Hwang, Xiaolei Shi, Andrew Elliott, Taylor E. Arnoff, Julie McGrath, Joanne Xiu, Phillip Walker, Hannah E. Bergom, Abderrahman Day, Shihab Ahmed, Sydney Tape, Allison Makovec, Atef Ali, Rami M. Shaker, Eamon Toye, Rachel Passow, John R. Lozada, Jinhua Wang, Emil Lou, Kent W. MouwBenedito A. Carneiro, Elisabeth I. Heath, Rana R. McKay, W. Michael Korn, Chadi Nabhan, Charles J. Ryan, Emmanuel S. Antonarakis

Research output: Contribution to journal › Article › peer-review

Abstract

Purpose: In patients with metastatic prostate cancer (mPC), ATM and BRCA2 mutations dictate differences in PARPi inhibitor response and other therapies. We interrogated the molecular features of ATM- and BRCA2-mutated mPC to explain the divergent clinical outcomes and inform future treatment decisions. Experimental Design: We examined a novel set of 1,187 mPCs after excluding microsatellite-instable (MSI) tumors. We stratified these based on ATM (n ¼ 88) or BRCA2 (n ¼ 98) mutations. As control groups, mPCs with mutations in 12 other homologous recombination repair (HRR) genes were considered non-BRCA2/ ATM HRR-deficient (HRDother, n ¼ 193), whereas lack of any HRR mutations were considered HRR-proficient (HRP; n ¼ 808). Gene expression analyses were performed using Limma. Real-world overall survival was determined from insurance claims data. Results: In noncastrate mPCs, only BRCA2-mutated mPCs exhibited worse clinical outcomes to AR-targeted therapies. In castrate mPCs, both ATM and BRCA2 mutations exhibited worse clinical outcomes to AR-targeted therapies. ATM-mutated mPCs had reduced TP53 mutations and harbored coamplification of 11q13 genes, including CCND1 and genes in the FGF family. BRCA2-mutated tumors showed elevated genomic loss-of-heterozygosity scores and were often tumor mutational burden high. BRCA2-mutated mPCs had upregulation of cell-cycle genes and were enriched in cell-cycle signaling programs. This was distinct from ATM-mutated tumors. Conclusions: Tumoral ATM and BRCA2 mutations are associated with differential clinical outcomes when patients are stratified by treatments, including hormonal or taxane therapies. ATM- and BRCA2-mutated tumors exhibited differences in co-occurring molecular features. These unique molecular features may inform therapeutic decisions and development of novel therapies.

Original language	English (US)
Pages (from-to)	2702-2713
Number of pages	12
Journal	Clinical Cancer Research
Volume	29
Issue number	14
DOIs	https://doi.org/10.1158/1078-0432.CCR-22-3394
State	Published - Jul 2023

Bibliographical note

Funding Information:
A. Elliott reports other support from Caris Life Sciences outside the submitted work. J. Xiu reports other support from Caris Life Sciences during the conduct of the study. E. Lou reports research grants from the American Cancer Society (RSG-22-022-01-CDP) from 2022 to 2026 and the Minnesota Ovarian Cancer Alliance in 2019, 2021, and 2022; honorarium and travel expenses for a research talk at GlaxoSmithK-line in 2016; honoraria and travel expenses for laboratory-based research talks from 2018 to 2021, and equipment for laboratory-based research from 2018 to the present, and Novocure, Ltd.; honorarium for panel discussion organized by Antidote Education for a CME module on diagnostics and treatment of HER2+ gastric and colorectal cancers, funded by Daiichi-Sankyo, 2021 (honorarium donated to laboratory); compensation for scientific review of proposed printed content, Elsevier Publishing and Johns Hopkins Press; consultant, Nomocan Pharmaceuticals (no financial compensation); scientific advisory board member, Minnetronix, LLC, from 2018 to 2019 (no financial compensation); and consultant and speaker honorarium, Boston Scientific US, 2019. In addition, E. Lou is an institutional principal investigator for clinical trials sponsored by Celgene, Novocure, Intima Biosciences, and the National Cancer Institute, and holds a University of Minnesota membership in the Caris Life Sciences POA (no financial compensation). K.W. Mouw reports personal fees from Riva Therapeutics, other support from Pfizer, and personal fees from UroGen Pharmaceuticals and EMD Serono outside the submitted work. E.I. Heath reports other support from Caris Life Science during the conduct of the study. R.R. McKay reports advisory/consulting with AstraZeneca, Aveo, Bayer, BMS, Calithera, Caris, Dendreon, Exelixis, Lilly, JNJ, Myovant, Merck, Novartis, Pfizer, Sanofi, SeaGen, Sorrento Therapeutics, Tempus, and Telix; as well as research funding with AstraZeneca, Bayer, Exelixis, and Tempus. W.M. Korn reports other support from Caria Life Sciences and Invitae Corporation outside the submitted work. C. Nabhan reports other support from Caris Life Sciences outside the submitted work. E.S. Antonarakis reports grants and personal fees from Janssen, Sanofi, Bayer, Bristol Myers Squibb, Curium, Merck, AstraZeneca, and Clovis; personal fees from Astellas, Amgen, Blue Earth, Exact Sciences, Invitae, Pfizer, Eli

Funding Information:
We acknowledge Dr. A. Elliott from Caris Life Sciences for facilitating our study and the Division of Hematology, Oncology, and Transplantation, University of Minnesota to provide the research funds.

Funding Information:
Lilly, and Foundation Medicine; and grants from Novartis, Celgene, and Constellation outside the submitted work; and reports a patent for an ARV7 biomarker technology issued and licensed to Qiagen. No disclosures were reported by the other authors.

Publisher Copyright:
©2023 American Association for Cancer Research.

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Hwang, J., Shi, X., Elliott, A., Arnoff, T. E., McGrath, J., Xiu, J., Walker, P., Bergom, H. E., Day, A., Ahmed, S., Tape, S., Makovec, A., Ali, A., Shaker, R. M., Toye, E., Passow, R., Lozada, J. R., Wang, J., Lou, E., ... Antonarakis, E. S. (2023). Metastatic Prostate Cancers with BRCA2 versus ATM Mutations Exhibit Divergent Molecular Features and Clinical Outcomes. Clinical Cancer Research, 29(14), 2702-2713. https://doi.org/10.1158/1078-0432.CCR-22-3394

Hwang, J, Shi, X, Elliott, A, Arnoff, TE, McGrath, J, Xiu, J, Walker, P, Bergom, HE , Day, A, Ahmed, S, Tape, S, Makovec, A, Ali, A, Shaker, RM, Toye, E, Passow, R, Lozada, JR, Wang, J , Lou, E, Mouw, KW, Carneiro, BA, Heath, EI, McKay, RR, Korn, WM, Nabhan, C, Ryan, CJ & Antonarakis, ES 2023, 'Metastatic Prostate Cancers with BRCA2 versus ATM Mutations Exhibit Divergent Molecular Features and Clinical Outcomes', Clinical Cancer Research, vol. 29, no. 14, pp. 2702-2713. https://doi.org/10.1158/1078-0432.CCR-22-3394

@article{835284b05dc544e5916148d5d3d0da4e,

title = "Metastatic Prostate Cancers with BRCA2 versus ATM Mutations Exhibit Divergent Molecular Features and Clinical Outcomes",

abstract = "Purpose: In patients with metastatic prostate cancer (mPC), ATM and BRCA2 mutations dictate differences in PARPi inhibitor response and other therapies. We interrogated the molecular features of ATM- and BRCA2-mutated mPC to explain the divergent clinical outcomes and inform future treatment decisions. Experimental Design: We examined a novel set of 1,187 mPCs after excluding microsatellite-instable (MSI) tumors. We stratified these based on ATM (n ¼ 88) or BRCA2 (n ¼ 98) mutations. As control groups, mPCs with mutations in 12 other homologous recombination repair (HRR) genes were considered non-BRCA2/ ATM HRR-deficient (HRDother, n ¼ 193), whereas lack of any HRR mutations were considered HRR-proficient (HRP; n ¼ 808). Gene expression analyses were performed using Limma. Real-world overall survival was determined from insurance claims data. Results: In noncastrate mPCs, only BRCA2-mutated mPCs exhibited worse clinical outcomes to AR-targeted therapies. In castrate mPCs, both ATM and BRCA2 mutations exhibited worse clinical outcomes to AR-targeted therapies. ATM-mutated mPCs had reduced TP53 mutations and harbored coamplification of 11q13 genes, including CCND1 and genes in the FGF family. BRCA2-mutated tumors showed elevated genomic loss-of-heterozygosity scores and were often tumor mutational burden high. BRCA2-mutated mPCs had upregulation of cell-cycle genes and were enriched in cell-cycle signaling programs. This was distinct from ATM-mutated tumors. Conclusions: Tumoral ATM and BRCA2 mutations are associated with differential clinical outcomes when patients are stratified by treatments, including hormonal or taxane therapies. ATM- and BRCA2-mutated tumors exhibited differences in co-occurring molecular features. These unique molecular features may inform therapeutic decisions and development of novel therapies.",

author = "Justin Hwang and Xiaolei Shi and Andrew Elliott and Arnoff, {Taylor E.} and Julie McGrath and Joanne Xiu and Phillip Walker and Bergom, {Hannah E.} and Abderrahman Day and Shihab Ahmed and Sydney Tape and Allison Makovec and Atef Ali and Shaker, {Rami M.} and Eamon Toye and Rachel Passow and Lozada, {John R.} and Jinhua Wang and Emil Lou and Mouw, {Kent W.} and Carneiro, {Benedito A.} and Heath, {Elisabeth I.} and McKay, {Rana R.} and Korn, {W. Michael} and Chadi Nabhan and Ryan, {Charles J.} and Antonarakis, {Emmanuel S.}",

note = "Funding Information: A. Elliott reports other support from Caris Life Sciences outside the submitted work. J. Xiu reports other support from Caris Life Sciences during the conduct of the study. E. Lou reports research grants from the American Cancer Society (RSG-22-022-01-CDP) from 2022 to 2026 and the Minnesota Ovarian Cancer Alliance in 2019, 2021, and 2022; honorarium and travel expenses for a research talk at GlaxoSmithK-line in 2016; honoraria and travel expenses for laboratory-based research talks from 2018 to 2021, and equipment for laboratory-based research from 2018 to the present, and Novocure, Ltd.; honorarium for panel discussion organized by Antidote Education for a CME module on diagnostics and treatment of HER2+ gastric and colorectal cancers, funded by Daiichi-Sankyo, 2021 (honorarium donated to laboratory); compensation for scientific review of proposed printed content, Elsevier Publishing and Johns Hopkins Press; consultant, Nomocan Pharmaceuticals (no financial compensation); scientific advisory board member, Minnetronix, LLC, from 2018 to 2019 (no financial compensation); and consultant and speaker honorarium, Boston Scientific US, 2019. In addition, E. Lou is an institutional principal investigator for clinical trials sponsored by Celgene, Novocure, Intima Biosciences, and the National Cancer Institute, and holds a University of Minnesota membership in the Caris Life Sciences POA (no financial compensation). K.W. Mouw reports personal fees from Riva Therapeutics, other support from Pfizer, and personal fees from UroGen Pharmaceuticals and EMD Serono outside the submitted work. E.I. Heath reports other support from Caris Life Science during the conduct of the study. R.R. McKay reports advisory/consulting with AstraZeneca, Aveo, Bayer, BMS, Calithera, Caris, Dendreon, Exelixis, Lilly, JNJ, Myovant, Merck, Novartis, Pfizer, Sanofi, SeaGen, Sorrento Therapeutics, Tempus, and Telix; as well as research funding with AstraZeneca, Bayer, Exelixis, and Tempus. W.M. Korn reports other support from Caria Life Sciences and Invitae Corporation outside the submitted work. C. Nabhan reports other support from Caris Life Sciences outside the submitted work. E.S. Antonarakis reports grants and personal fees from Janssen, Sanofi, Bayer, Bristol Myers Squibb, Curium, Merck, AstraZeneca, and Clovis; personal fees from Astellas, Amgen, Blue Earth, Exact Sciences, Invitae, Pfizer, Eli Funding Information: We acknowledge Dr. A. Elliott from Caris Life Sciences for facilitating our study and the Division of Hematology, Oncology, and Transplantation, University of Minnesota to provide the research funds. Funding Information: Lilly, and Foundation Medicine; and grants from Novartis, Celgene, and Constellation outside the submitted work; and reports a patent for an ARV7 biomarker technology issued and licensed to Qiagen. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright}2023 American Association for Cancer Research.",

year = "2023",

month = jul,

doi = "10.1158/1078-0432.CCR-22-3394",

language = "English (US)",

volume = "29",

pages = "2702--2713",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "14",

}

TY - JOUR

T1 - Metastatic Prostate Cancers with BRCA2 versus ATM Mutations Exhibit Divergent Molecular Features and Clinical Outcomes

AU - Hwang, Justin

AU - Shi, Xiaolei

AU - Elliott, Andrew

AU - Arnoff, Taylor E.

AU - McGrath, Julie

AU - Xiu, Joanne

AU - Walker, Phillip

AU - Bergom, Hannah E.

AU - Day, Abderrahman

AU - Ahmed, Shihab

AU - Tape, Sydney

AU - Makovec, Allison

AU - Ali, Atef

AU - Shaker, Rami M.

AU - Toye, Eamon

AU - Passow, Rachel

AU - Lozada, John R.

AU - Wang, Jinhua

AU - Lou, Emil

AU - Mouw, Kent W.

AU - Carneiro, Benedito A.

AU - Heath, Elisabeth I.

AU - McKay, Rana R.

AU - Korn, W. Michael

AU - Nabhan, Chadi

AU - Ryan, Charles J.

AU - Antonarakis, Emmanuel S.

N1 - Funding Information: A. Elliott reports other support from Caris Life Sciences outside the submitted work. J. Xiu reports other support from Caris Life Sciences during the conduct of the study. E. Lou reports research grants from the American Cancer Society (RSG-22-022-01-CDP) from 2022 to 2026 and the Minnesota Ovarian Cancer Alliance in 2019, 2021, and 2022; honorarium and travel expenses for a research talk at GlaxoSmithK-line in 2016; honoraria and travel expenses for laboratory-based research talks from 2018 to 2021, and equipment for laboratory-based research from 2018 to the present, and Novocure, Ltd.; honorarium for panel discussion organized by Antidote Education for a CME module on diagnostics and treatment of HER2+ gastric and colorectal cancers, funded by Daiichi-Sankyo, 2021 (honorarium donated to laboratory); compensation for scientific review of proposed printed content, Elsevier Publishing and Johns Hopkins Press; consultant, Nomocan Pharmaceuticals (no financial compensation); scientific advisory board member, Minnetronix, LLC, from 2018 to 2019 (no financial compensation); and consultant and speaker honorarium, Boston Scientific US, 2019. In addition, E. Lou is an institutional principal investigator for clinical trials sponsored by Celgene, Novocure, Intima Biosciences, and the National Cancer Institute, and holds a University of Minnesota membership in the Caris Life Sciences POA (no financial compensation). K.W. Mouw reports personal fees from Riva Therapeutics, other support from Pfizer, and personal fees from UroGen Pharmaceuticals and EMD Serono outside the submitted work. E.I. Heath reports other support from Caris Life Science during the conduct of the study. R.R. McKay reports advisory/consulting with AstraZeneca, Aveo, Bayer, BMS, Calithera, Caris, Dendreon, Exelixis, Lilly, JNJ, Myovant, Merck, Novartis, Pfizer, Sanofi, SeaGen, Sorrento Therapeutics, Tempus, and Telix; as well as research funding with AstraZeneca, Bayer, Exelixis, and Tempus. W.M. Korn reports other support from Caria Life Sciences and Invitae Corporation outside the submitted work. C. Nabhan reports other support from Caris Life Sciences outside the submitted work. E.S. Antonarakis reports grants and personal fees from Janssen, Sanofi, Bayer, Bristol Myers Squibb, Curium, Merck, AstraZeneca, and Clovis; personal fees from Astellas, Amgen, Blue Earth, Exact Sciences, Invitae, Pfizer, Eli Funding Information: We acknowledge Dr. A. Elliott from Caris Life Sciences for facilitating our study and the Division of Hematology, Oncology, and Transplantation, University of Minnesota to provide the research funds. Funding Information: Lilly, and Foundation Medicine; and grants from Novartis, Celgene, and Constellation outside the submitted work; and reports a patent for an ARV7 biomarker technology issued and licensed to Qiagen. No disclosures were reported by the other authors. Publisher Copyright: ©2023 American Association for Cancer Research.

PY - 2023/7

Y1 - 2023/7

N2 - Purpose: In patients with metastatic prostate cancer (mPC), ATM and BRCA2 mutations dictate differences in PARPi inhibitor response and other therapies. We interrogated the molecular features of ATM- and BRCA2-mutated mPC to explain the divergent clinical outcomes and inform future treatment decisions. Experimental Design: We examined a novel set of 1,187 mPCs after excluding microsatellite-instable (MSI) tumors. We stratified these based on ATM (n ¼ 88) or BRCA2 (n ¼ 98) mutations. As control groups, mPCs with mutations in 12 other homologous recombination repair (HRR) genes were considered non-BRCA2/ ATM HRR-deficient (HRDother, n ¼ 193), whereas lack of any HRR mutations were considered HRR-proficient (HRP; n ¼ 808). Gene expression analyses were performed using Limma. Real-world overall survival was determined from insurance claims data. Results: In noncastrate mPCs, only BRCA2-mutated mPCs exhibited worse clinical outcomes to AR-targeted therapies. In castrate mPCs, both ATM and BRCA2 mutations exhibited worse clinical outcomes to AR-targeted therapies. ATM-mutated mPCs had reduced TP53 mutations and harbored coamplification of 11q13 genes, including CCND1 and genes in the FGF family. BRCA2-mutated tumors showed elevated genomic loss-of-heterozygosity scores and were often tumor mutational burden high. BRCA2-mutated mPCs had upregulation of cell-cycle genes and were enriched in cell-cycle signaling programs. This was distinct from ATM-mutated tumors. Conclusions: Tumoral ATM and BRCA2 mutations are associated with differential clinical outcomes when patients are stratified by treatments, including hormonal or taxane therapies. ATM- and BRCA2-mutated tumors exhibited differences in co-occurring molecular features. These unique molecular features may inform therapeutic decisions and development of novel therapies.

AB - Purpose: In patients with metastatic prostate cancer (mPC), ATM and BRCA2 mutations dictate differences in PARPi inhibitor response and other therapies. We interrogated the molecular features of ATM- and BRCA2-mutated mPC to explain the divergent clinical outcomes and inform future treatment decisions. Experimental Design: We examined a novel set of 1,187 mPCs after excluding microsatellite-instable (MSI) tumors. We stratified these based on ATM (n ¼ 88) or BRCA2 (n ¼ 98) mutations. As control groups, mPCs with mutations in 12 other homologous recombination repair (HRR) genes were considered non-BRCA2/ ATM HRR-deficient (HRDother, n ¼ 193), whereas lack of any HRR mutations were considered HRR-proficient (HRP; n ¼ 808). Gene expression analyses were performed using Limma. Real-world overall survival was determined from insurance claims data. Results: In noncastrate mPCs, only BRCA2-mutated mPCs exhibited worse clinical outcomes to AR-targeted therapies. In castrate mPCs, both ATM and BRCA2 mutations exhibited worse clinical outcomes to AR-targeted therapies. ATM-mutated mPCs had reduced TP53 mutations and harbored coamplification of 11q13 genes, including CCND1 and genes in the FGF family. BRCA2-mutated tumors showed elevated genomic loss-of-heterozygosity scores and were often tumor mutational burden high. BRCA2-mutated mPCs had upregulation of cell-cycle genes and were enriched in cell-cycle signaling programs. This was distinct from ATM-mutated tumors. Conclusions: Tumoral ATM and BRCA2 mutations are associated with differential clinical outcomes when patients are stratified by treatments, including hormonal or taxane therapies. ATM- and BRCA2-mutated tumors exhibited differences in co-occurring molecular features. These unique molecular features may inform therapeutic decisions and development of novel therapies.

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U2 - 10.1158/1078-0432.CCR-22-3394

DO - 10.1158/1078-0432.CCR-22-3394

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SN - 1078-0432

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SP - 2702

EP - 2713

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 14

ER -

Metastatic Prostate Cancers with BRCA2 versus ATM Mutations Exhibit Divergent Molecular Features and Clinical Outcomes

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