{"doi":"10.1200/jco-25-01003","title":"Impact of Human Epidermal Growth Factor Receptor 2 in Patients With Metastatic Colorectal Cancer Treated With Chemotherapy Plus Bevacizumab or Anti-EGFRs: Exploratory Analysis of Eight Randomized Trials","abstract":"\n PURPOSE\n \n Human epidermal growth factor receptor 2 (HER2) amplification/overexpression (HER2-pos) is detected in 5% of\n RAS/BRAF\n wild-type metastatic colorectal cancers (mCRCs). Its prognostic/predictive role in terms of benefit from anti-EGFR/bevacizumab (bev) is debated. Similarly, the role of activating\n HER2\n mutations (mut) is unclear.\n \n \n \n METHODS\n \n We collected individual data of 1,604 patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS)\n RAS/BRAF\n wild-type untreated mCRC with HER2 amplification/expression status available enrolled in eight randomized clinical trials (RCT; TRIBE2, TRIPLETE, VALENTINO, ATEZOTRIBE, PANDA, PANAMA, PARADIGM, and CALGB/SWOG80405). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were assessed with respect to HER2 amplification/expression and\n HER2\n mutational status and according to biologics (anti-EGFR/bev).\n \n \n \n RESULTS\n \n Patients with HER2-pos were 81 (5%). HER2-pos patients experienced shorter PFS (median PFS [mPFS]: 9.8\n v\n 12.2 months, hazard ratio [HR], 1.31,\n P\n = .02) and OS (median OS [mOS]: 28.0\n v\n 34.9 months, HR, 1.37,\n P\n = .01), also after adjustment for covariates (\n P\n adj\n PFS = .02,\n P\n adj\n OS = .048). ORR was similar between HER2-pos and HER2-negative (HER2-neg) tumors (75%\n v\n 72%, odds ratio [OR], 1.21,\n P\n = .47). We found no interaction between HER2 amplification/expression status and biologics' effect in terms of PFS (\n P\n int\n = .76), OS (\n P\n int\n = .76), and ORR (\n P\n int\n = .64). In left-sided HER2-pos tumors, outcomes were similar with chemotherapy plus bev/anti-EGFRs in terms of PFS (9.8\n v\n 9.3 months, HR, 0.73,\n P\n = .29), OS (29.8\n v\n 28.0 months, HR, 1.29,\n P\n = .40), and ORR (59%\n v\n 79%, OR, 0.39,\n P\n = .10).\n HER2\n -mutant tumors (2% of patients with HER2-neg tumors) showed shorter OS than\n HER2\n wild-type ones (mOS: 23.7\n v\n 34.4 months, HR, 1.56,\n P\n = .04) with no differential effect of biologics (\n P\n int\n ORR = .81;\n P\n int\n PFS = .95;\n P\n int\n OS = .92).\n \n \n \n CONCLUSION\n \n To our knowledge, this is the largest analysis of HER2 status in patients with untreated mCRC enrolled in RCT. Waiting for targeted approaches, HER2-pos and mut do not predict benefit from bev/anti-EGFRs and should be regarded as negative prognostic factors in pMMR/MSS\n RAS/BRAF\n wild-type mCRC.\n \n ","journal":"Journal of Clinical Oncology","year":2025,"id":613842,"datarank":0.38474240361923057,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.0,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1538787,"name":"Beatrice Borelli","orcid":"0000-0002-9739-408X","position":1,"is_corresponding":false},{"id":1581559,"name":"Tadayoshi Hashimoto","orcid":"0000-0003-3759-1214","position":2,"is_corresponding":false},{"id":1083777,"name":"Yoshiaki Nakamura","orcid":"0000-0002-5241-6855","position":3,"is_corresponding":false},{"id":1083785,"name":"Simone Oldani","orcid":"0009-0004-8589-3502","position":4,"is_corresponding":false},{"id":350297,"name":"Francesca Battaglin","orcid":"0000-0002-9869-0163","position":5,"is_corresponding":false},{"id":1083781,"name":"Francesca Bergamo","orcid":"0000-0002-8795-4653","position":6,"is_corresponding":false},{"id":1538772,"name":"Lisa Salvatore","orcid":"0000-0003-3864-0719","position":7,"is_corresponding":false},{"id":1581560,"name":"Arndt Stahler","orcid":"0000-0003-1041-0137","position":8,"is_corresponding":false},{"id":1538771,"name":"Carlotta Antoniotti","orcid":"0000-0001-6881-3188","position":9,"is_corresponding":false},{"id":788862,"name":"Kohei Shitara","orcid":"0000-0001-5196-3630","position":10,"is_corresponding":false},{"id":36111,"name":"Alan P. Venook","orcid":"0000-0001-9749-6548","position":11,"is_corresponding":false},{"id":265915,"name":"Eiji Oki","orcid":"0000-0002-9763-9366","position":12,"is_corresponding":false},{"id":1581561,"name":"Kei Muro","orcid":"0000-0002-5572-743X","position":13,"is_corresponding":false},{"id":1107537,"name":"Clara Ugolini","orcid":"0000-0002-3489-8280","position":14,"is_corresponding":false},{"id":1581563,"name":"Junpei Soeda","orcid":"0000-0003-3753-0999","position":15,"is_corresponding":false},{"id":477415,"name":"Sara Lonardi","orcid":"0000-0002-7593-8138","position":16,"is_corresponding":false},{"id":692545,"name":"Filippo Pietrantonio","orcid":"0000-0002-8530-8420","position":17,"is_corresponding":false},{"id":350298,"name":"Heinz‐Josef Lenz","orcid":"0000-0003-2178-9568","position":18,"is_corresponding":false},{"id":1581565,"name":"Dominik Paul Modest","orcid":"0000-0002-6853-0599","position":19,"is_corresponding":false},{"id":310797,"name":"Takayuki Yoshino","orcid":"0000-0002-0489-4756","position":20,"is_corresponding":false},{"id":692544,"name":"Chiara Cremolini","orcid":"0000-0002-0520-4841","position":21,"is_corresponding":false},{"id":692537,"name":"Marco Maria Germani","orcid":"0000-0002-1036-5869","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Impact of Human Epidermal Growth Factor Receptor 2 in Patients With Metastatic Colorectal Cancer Treated With Chemotherapy Plus Bevacizumab or Anti-EGFRs: Exploratory Analysis of Eight Randomized Trials","abstract":"\n PURPOSE\n \n Human epidermal growth factor receptor 2 (HER2) amplification/overexpression (HER2-pos) is detected in 5% of\n RAS/BRAF\n wild-type metastatic colorectal cancers (mCRCs). Its prognostic/predictive role in terms of benefit from anti-EGFR/bevacizumab (bev) is debated. Similarly, the role of activating\n HER2\n mutations (mut) is unclear.\n \n \n \n METHODS\n \n We collected individual data of 1,604 patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS)\n RAS/BRAF\n wild-type untreated mCRC with HER2 amplification/expression status available enrolled in eight randomized clinical trials (RCT; TRIBE2, TRIPLETE, VALENTINO, ATEZOTRIBE, PANDA, PANAMA, PARADIGM, and CALGB/SWOG80405). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were assessed with respect to HER2 amplification/expression and\n HER2\n mutational status and according to biologics (anti-EGFR/bev).\n \n \n \n RESULTS\n \n Patients with HER2-pos were 81 (5%). HER2-pos patients experienced shorter PFS (median PFS [mPFS]: 9.8\n v\n 12.2 months, hazard ratio [HR], 1.31,\n P\n = .02) and OS (median OS [mOS]: 28.0\n v\n 34.9 months, HR, 1.37,\n P\n = .01), also after adjustment for covariates (\n P\n adj\n PFS = .02,\n P\n adj\n OS = .048). ORR was similar between HER2-pos and HER2-negative (HER2-neg) tumors (75%\n v\n 72%, odds ratio [OR], 1.21,\n P\n = .47). We found no interaction between HER2 amplification/expression status and biologics' effect in terms of PFS (\n P\n int\n = .76), OS (\n P\n int\n = .76), and ORR (\n P\n int\n = .64). In left-sided HER2-pos tumors, outcomes were similar with chemotherapy plus bev/anti-EGFRs in terms of PFS (9.8\n v\n 9.3 months, HR, 0.73,\n P\n = .29), OS (29.8\n v\n 28.0 months, HR, 1.29,\n P\n = .40), and ORR (59%\n v\n 79%, OR, 0.39,\n P\n = .10).\n HER2\n -mutant tumors (2% of patients with HER2-neg tumors) showed shorter OS than\n HER2\n wild-type ones (mOS: 23.7\n v\n 34.4 months, HR, 1.56,\n P\n = .04) with no differential effect of biologics (\n P\n int\n ORR = .81;\n P\n int\n PFS = .95;\n P\n int\n OS = .92).\n \n \n \n CONCLUSION\n \n To our knowledge, this is the largest analysis of HER2 status in patients with untreated mCRC enrolled in RCT. Waiting for targeted approaches, HER2-pos and mut do not predict benefit from bev/anti-EGFRs and should be regarded as negative prognostic factors in pMMR/MSS\n RAS/BRAF\n wild-type mCRC.\n \n ","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40906970","pmcid":"PMC12509457","openalex_id":null,"authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"U10 CA180888","title":null},{"funder_name":"NCI NIH HHS","grant_id":"U10 CA180882","title":null},{"funder_name":"NCI NIH HHS","grant_id":"U10 CA180821","title":null}],"total_grants":3,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"hybrid","license":"cc-by-nc-nd","oa_locations":[{"url":"https://doi.org/10.1200/jco-25-01003","host_type":"publisher"},{"url":"https://ascopubs.org/doi/pdfdirect/10.1200/JCO-25-01003","host_type":"publisher"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12509457/","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12509457","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12509457?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":[],"mesh_terms":["Humans","Colorectal Neoplasms","Antineoplastic Combined Chemotherapy Protocols","Gene Amplification","Mutation","Adult","Aged","Middle Aged","Female","Male","Randomized Controlled Trials as Topic","ErbB Receptors","Bevacizumab","Progression-Free Survival","Erb-b2 Receptor Tyrosine Kinases"],"keywords":[],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T09:23:45.095446Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}