Giovanni Randon1, Rona Yaeger2, Jaclyn F Hechtman3, Paolo Manca1, Giovanni Fucà1, Henry Walch4,5, Jeeyun Lee6, Elena Élez7, Jenny Seligmann8, Benedetta Mussolin9, Filippo Pagani1, Marco Maria Germani10,11, Margherita Ambrosini1, Daniele Rossini10,11, Margherita Ratti12, Francesc Salvà7, Susan D Richman8, Henry Wood8, Gouri Nanjangud13, Annunziata Gloghini14, Massimo Milione14, Alberto Bardelli9,15, Filippo de Braud1,6, Federica Morano1, Chiara Cremolini10,11, Filippo Pietrantonio1,16. 1. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy. 2. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 3. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 4. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 5. Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 6. Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 7. Vall D'Hebron University Hospital (HUVH) and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain. 8. St James's Institute of Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, UK. 9. Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy. 10. Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. 11. Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. 12. Oncology Unit, Oncology Department, ASST of Cremona, 26100 Cremona, Italy. 13. Molecular Cytogenetics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 14. Department of the Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy. 15. Department of Oncology, University of Torino, Candiolo, Torino, Italy. 16. Oncology and Hemato-oncology Department, University of Milan, Milano, Italy.
Abstract
BACKGROUND: EGFR amplification occurs in about 1% of metastatic colorectal cancers (mCRCs) but is not routinely tested as a prognostic or predictive biomarker for patients treated with anti-EGFR monoclonal antibodies. Herein, we aimed to characterize the clinical and molecular landscape of EGFR-amplified mCRC. METHODS: In this multinational cohort study, we compared clinical data of 62 patients with EGFR-amplified vs 1459 EGFR nonamplified mCRC, as well as comprehensive genomic data of 35 EGFR-amplified vs 439 EGFR nonamplified RAS/BRAF wild-type and microsatellite stable (MSS) tumor samples. All statistical tests were 2-sided. RESULTS: EGFR amplification was statistically significantly associated with left primary tumor sidedness and RAS/BRAF wild-type status. All EGFR-amplified tumors were MSS and HER2 nonamplified. Overall, EGFR-amplified samples had higher median fraction of genome altered compared with EGFR-nonamplified, RAS/BRAF wild-type MSS cohort. Patients with EGFR-amplified tumors reported longer overall survival (OS) (median OS = 71.3 months, 95% confidence interval [CI] = 50.7 to not available [NA]) vs EGFR-nonamplified ones (24.0 months; 95% CI = 22.8 to 25.6; hazard ratio [HR] = 0.30, 95% CI = 0.20 to 0.44; P < .001; adjusted HR = 0.46, 95% CI = 0.30 to 0.69; P < .001). In the subgroup of patients with RAS/BRAF wild-type mCRC exposed to anti-EGFR-based therapy, EGFR amplification was again associated with better OS (median OS = 54.0 months, 95% CI = 35.2 to NA, vs 29.1 months, 95% CI = 27.0 to 31.9, respectively; HR = 0.46, 95% CI = 0.28 to 0.76; P = .002). CONCLUSION: Patients with EGFR-amplified mCRC represent a biologically defined subgroup and merit dedicated clinical trials with novel and more potent EGFR-targeting strategies beyond single-agent monoclonal antibodies.
BACKGROUND: EGFR amplification occurs in about 1% of metastatic colorectal cancers (mCRCs) but is not routinely tested as a prognostic or predictive biomarker for patients treated with anti-EGFR monoclonal antibodies. Herein, we aimed to characterize the clinical and molecular landscape of EGFR-amplified mCRC. METHODS: In this multinational cohort study, we compared clinical data of 62 patients with EGFR-amplified vs 1459 EGFR nonamplified mCRC, as well as comprehensive genomic data of 35 EGFR-amplified vs 439 EGFR nonamplified RAS/BRAF wild-type and microsatellite stable (MSS) tumor samples. All statistical tests were 2-sided. RESULTS: EGFR amplification was statistically significantly associated with left primary tumor sidedness and RAS/BRAF wild-type status. All EGFR-amplified tumors were MSS and HER2 nonamplified. Overall, EGFR-amplified samples had higher median fraction of genome altered compared with EGFR-nonamplified, RAS/BRAF wild-type MSS cohort. Patients with EGFR-amplified tumors reported longer overall survival (OS) (median OS = 71.3 months, 95% confidence interval [CI] = 50.7 to not available [NA]) vs EGFR-nonamplified ones (24.0 months; 95% CI = 22.8 to 25.6; hazard ratio [HR] = 0.30, 95% CI = 0.20 to 0.44; P < .001; adjusted HR = 0.46, 95% CI = 0.30 to 0.69; P < .001). In the subgroup of patients with RAS/BRAF wild-type mCRC exposed to anti-EGFR-based therapy, EGFR amplification was again associated with better OS (median OS = 54.0 months, 95% CI = 35.2 to NA, vs 29.1 months, 95% CI = 27.0 to 31.9, respectively; HR = 0.46, 95% CI = 0.28 to 0.76; P = .002). CONCLUSION: Patients with EGFR-amplified mCRC represent a biologically defined subgroup and merit dedicated clinical trials with novel and more potent EGFR-targeting strategies beyond single-agent monoclonal antibodies.
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