학술논문
Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer.
Document Type
Academic Journal
Author
Arai H; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.; Yang Y; Department of Population and Public Health Sciences, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Baca Y; Clinical & Translational Research, Medical Affairs, Caris Life Sciences, Phoenix, AZ, USA.; Millstein J; Department of Population and Public Health Sciences, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Denda T; Department of Gastroenterology, Chiba Cancer Center, Chiba, Japan.; Ou FS; Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN, USA.; Innocenti F; UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Takeda H; Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.; Kubota Y; Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.; Doi A; Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.; Horie Y; Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.; Umemoto K; Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.; Izawa N; Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.; Wang J; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Battaglin F; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Jayachandran P; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Algaze S; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Soni S; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Zhang W; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Goldberg RM; West Virginia University Cancer Institute, Morgantown, WV, USA.; Hall MJ; Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.; Scott AJ; Department of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA.; Hwang JJ; Department of Solid Tumor Oncology, GI Medical Oncology, Levine Cancer Institute, Charlotte, NC, USA.; Lou E; Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA.; Weinberg BA; Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.; Marshall J; Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.; Goel S; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.; Xiu J; Clinical & Translational Research, Medical Affairs, Caris Life Sciences, Phoenix, AZ, USA.; Michael Korn W; Clinical & Translational Research, Medical Affairs, Caris Life Sciences, Phoenix, AZ, USA.; Venook AP; University of California, San Francisco, San Francisco, CA, USA.; Sunakawa Y; Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.; Lenz HJ; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: lenz@usc.edu.
Source
Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 9005373 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0852 (Electronic) Linking ISSN: 09598049 NLM ISO Abbreviation: Eur J Cancer Subsets: MEDLINE
Subject
Language
English
Abstract
Background: CDC37 is a key determinant of client kinase recruitment to the HSP90 chaperoning system. We hypothesized that kinase-specific dependency on CDC37 alters the efficacy of targeted therapies for metastatic colorectal cancer (mCRC).
Material and Methods: Two independent mCRC cohorts were analyzed to compare the survival outcomes between CDC37-high and CDC37-low patients (stratified by the median cutoff values): the CALGB/SWOG 80405 trial (226 and 207 patients receiving first-line bevacizumab- and cetuximab-containing chemotherapies, respectively) and Japanese retrospective (50 refractory patients receiving regorafenib) cohorts. A dataset of specimens submitted to a commercial CLIA-certified laboratory was utilized to characterize molecular profiles of CDC37-high (top quartile, N = 5055) and CDC37-low (bottom quartile, N = 5055) CRCs.
Results: In the bevacizumab-treated group, CDC37-high patients showed significantly better progression-free survival (PFS) (median 13.3 vs 9.6 months, hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44-0.79, p < 0.01) than CDC37-low patients. In the cetuximab-treated group, CDC37-high and CDC37-low patients had similar outcomes. In the regorafenib-treated group, CDC37-high patients showed significantly better overall survival (median 11.3 vs 6.0 months, HR 0.24, 95% CI 0.11-0.54, p < 0.01) and PFS (median 3.5 vs 1.9 months, HR 0.51, 95% CI 0.28-0.94, p = 0.03). Comprehensive molecular profiling revealed that CDC37-high CRCs were associated with higher VEGFA, FLT1, and KDR expressions and activated hypoxia signature.
Conclusions: CDC37-high mCRC patients derived more benefit from anti-VEGF therapies, including bevacizumab and regorafenib, but not from cetuximab. Molecular profiles suggested that such tumors were dependent on angiogenesis-relating pathways.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: H-JL reports receiving honoraria from consultant/advisory board membership for Merck Serono, Bayer, and Genentech. EL reports research grants from the American Cancer Society (RSG-22–022-01-CDP) 2022–2026, and the Minnesota Ovarian Cancer Alliance in 2019, 2021, and 2022; The Randy Shaver Cancer Research and Community Fund; honoraria and travel expenses for lab-based research talks 2018–21, and equipment for laboratory-based research 2018-present, 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 lab); 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, 2018–2019 (no financial compensation); consultant and speaker honorarium, Boston Scientific US, 2019. Institutional Principal Investigator for clinical trials sponsored by Celgene, Novocure, Intima Biosciences, and the National Cancer Institute, and University of Minnesota membership in the Caris Life Sciences Precision Oncology Alliance (no financial compensation). YB, JX, and WMK are employees of Caris Life Sciences. All remaining authors have declared no conflicts of interest.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Material and Methods: Two independent mCRC cohorts were analyzed to compare the survival outcomes between CDC37-high and CDC37-low patients (stratified by the median cutoff values): the CALGB/SWOG 80405 trial (226 and 207 patients receiving first-line bevacizumab- and cetuximab-containing chemotherapies, respectively) and Japanese retrospective (50 refractory patients receiving regorafenib) cohorts. A dataset of specimens submitted to a commercial CLIA-certified laboratory was utilized to characterize molecular profiles of CDC37-high (top quartile, N = 5055) and CDC37-low (bottom quartile, N = 5055) CRCs.
Results: In the bevacizumab-treated group, CDC37-high patients showed significantly better progression-free survival (PFS) (median 13.3 vs 9.6 months, hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44-0.79, p < 0.01) than CDC37-low patients. In the cetuximab-treated group, CDC37-high and CDC37-low patients had similar outcomes. In the regorafenib-treated group, CDC37-high patients showed significantly better overall survival (median 11.3 vs 6.0 months, HR 0.24, 95% CI 0.11-0.54, p < 0.01) and PFS (median 3.5 vs 1.9 months, HR 0.51, 95% CI 0.28-0.94, p = 0.03). Comprehensive molecular profiling revealed that CDC37-high CRCs were associated with higher VEGFA, FLT1, and KDR expressions and activated hypoxia signature.
Conclusions: CDC37-high mCRC patients derived more benefit from anti-VEGF therapies, including bevacizumab and regorafenib, but not from cetuximab. Molecular profiles suggested that such tumors were dependent on angiogenesis-relating pathways.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: H-JL reports receiving honoraria from consultant/advisory board membership for Merck Serono, Bayer, and Genentech. EL reports research grants from the American Cancer Society (RSG-22–022-01-CDP) 2022–2026, and the Minnesota Ovarian Cancer Alliance in 2019, 2021, and 2022; The Randy Shaver Cancer Research and Community Fund; honoraria and travel expenses for lab-based research talks 2018–21, and equipment for laboratory-based research 2018-present, 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 lab); 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, 2018–2019 (no financial compensation); consultant and speaker honorarium, Boston Scientific US, 2019. Institutional Principal Investigator for clinical trials sponsored by Celgene, Novocure, Intima Biosciences, and the National Cancer Institute, and University of Minnesota membership in the Caris Life Sciences Precision Oncology Alliance (no financial compensation). YB, JX, and WMK are employees of Caris Life Sciences. All remaining authors have declared no conflicts of interest.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)