TY - JOUR
T1 - Genomic, transcriptomic, and proteomic profiling of metastatic breast cancer
AU - Akcakanat, Argun
AU - Zheng, Xiaofeng
AU - Cruz Pico, Christian X.
AU - Kim, Tae Beom
AU - Chen, Ken
AU - Korkut, Anil
AU - Sahin, Aysegul
AU - Holla, Vijaykumar
AU - Tarco, Emily
AU - Singh, Gopal
AU - Damodaran, Senthil
AU - Mills, Gordon B
AU - Gonzalez-Angulo, Ana Maria
AU - Meric-Bernstam, Funda
N1 - Funding Information:
G.B. Mills reports personal fees from Amphista, Chrysallis Biotechnology, PDX Pharmaceuticals, Symphogen, Turbine, and Zentalis; personal fees and other from AstraZeneca, GSK, ImmunoMET, Ionis, Lilly, Signalchem Lifesciences, and Tarveda; other from Catena, Myriad Genetics, Nanostring, and Genentech; and grants from Adelson Medical Research Foundation, Breast Cancer Research Foundation, Komen Research Foundation, Ovarian Cancer Research Foundation, and Prospect Creek Foundation outside the submitted work. F. Meric-Bernstam reports grants and personal fees from AstraZeneca during the conduct of the study. F. Meric-Bernstam also reports personal fees from Arduro BioTech, Alkermes, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche, Genentech, IBM Watson, Jackson Laboratory, Kolon Life Sciences, OrgiMed, PACT Pharma, Parexel International, Pfizer, Samsung Bioepis, Seattle Genetics, Tyra Biosciences, Xencor, Zymeworks, Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis, Chugai Biopharmaceuticals, Mayo Clinic, and Rutgers Cancer Institute of New Jersey; grants from Aileron Therapeutics, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis, Inc, CytomX Therapeutics, Daiichi Sankyo, DebioPharm, eFFECTOR Therapeutics, Genentech, Guardant Health, Klus Pharma, Millennium Pharmaceuticals Inc., Novartis, Puma Biotechnology, and Taiho Pharmaceutical; and nonfinancial support from Beth Israel Deaconess Medical Center outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
This study was partially funded by a grant from AstraZeneca, and the Nellie B. Connally Breast Cancer Endowment OCRA Collaborative Research Development Award, ICI Fund Award, CPRIT RP170640, NIH/NCI U24CA210950, NIH/NCAT UL1TR003167 (to F. Meric-Bernstam and A. Korkut), and NIH/NCI P30CA016672/ Cancer Center Support (core) grant (to A. Korkut and F. Meric-Bernstam). The
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - Purpose: Metastatic breast cancer (MBC) is not curable and there is a growing interest in personalized therapy options. Here we report molecular profiling of MBC focusing on molecular evolution in actionable alterations. Experimental Design: Sixty-two patients with MBC were included. An analysis of DNA, RNA, and functional proteomics was done, and matched primary and metastatic tumors were compared when feasible. Results: Targeted exome sequencing of 41 tumors identified common alterations in TP53 (21; 51%) and PIK3CA (20; 49%), as well as alterations in several emerging biomarkers such as NF1 mutations/deletions (6; 15%), PTEN mutations (4; 10%), and ARID1A mutations/deletions (6; 15%). Among 27 hormone receptor-positive patients, we identified MDM2 amplifications (3; 11%), FGFR1 amplifications (5; 19%), ATM mutations (2; 7%), and ESR1 mutations (4; 15%). In 10 patients with matched primary and metastatic tumors that underwent targeted exome sequencing, discordances in actionable alterations were common, including NF1 loss in 3 patients, loss of PIK3CA mutation in 1 patient, and acquired ESR1 mutations in 3 patients. RNA sequencing in matched samples confirmed loss of NF1 expression with genomic NF1 loss. Among 33 patients with matched primary and metastatic samples that underwent RNA profiling, 14 actionable genes were differentially expressed, including antibody-drug conjugate targets LIV-1 and B7-H3. Conclusions: Molecular profiling in MBC reveals multiple common as well as less frequent but potentially actionable alterations. Genomic and transcriptional profiling demonstrates intertumoral heterogeneity and potential evolution of actionable targets with tumor progression. Further work is needed to optimize testing and integrated analysis for treatment selection.
AB - Purpose: Metastatic breast cancer (MBC) is not curable and there is a growing interest in personalized therapy options. Here we report molecular profiling of MBC focusing on molecular evolution in actionable alterations. Experimental Design: Sixty-two patients with MBC were included. An analysis of DNA, RNA, and functional proteomics was done, and matched primary and metastatic tumors were compared when feasible. Results: Targeted exome sequencing of 41 tumors identified common alterations in TP53 (21; 51%) and PIK3CA (20; 49%), as well as alterations in several emerging biomarkers such as NF1 mutations/deletions (6; 15%), PTEN mutations (4; 10%), and ARID1A mutations/deletions (6; 15%). Among 27 hormone receptor-positive patients, we identified MDM2 amplifications (3; 11%), FGFR1 amplifications (5; 19%), ATM mutations (2; 7%), and ESR1 mutations (4; 15%). In 10 patients with matched primary and metastatic tumors that underwent targeted exome sequencing, discordances in actionable alterations were common, including NF1 loss in 3 patients, loss of PIK3CA mutation in 1 patient, and acquired ESR1 mutations in 3 patients. RNA sequencing in matched samples confirmed loss of NF1 expression with genomic NF1 loss. Among 33 patients with matched primary and metastatic samples that underwent RNA profiling, 14 actionable genes were differentially expressed, including antibody-drug conjugate targets LIV-1 and B7-H3. Conclusions: Molecular profiling in MBC reveals multiple common as well as less frequent but potentially actionable alterations. Genomic and transcriptional profiling demonstrates intertumoral heterogeneity and potential evolution of actionable targets with tumor progression. Further work is needed to optimize testing and integrated analysis for treatment selection.
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U2 - 10.1158/1078-0432.CCR-20-4048
DO - 10.1158/1078-0432.CCR-20-4048
M3 - Article
C2 - 33782032
AN - SCOPUS:85106998035
SN - 1078-0432
VL - 27
SP - 3243
EP - 3252
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 11
ER -