Mutation Profiling and Microsatellite Instability in Stage II and III Colon Cancer: An Assessment of Their Prognostic and Oxaliplatin Predictive Value
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| Title: | Mutation Profiling and Microsatellite Instability in Stage II and III Colon Cancer: An Assessment of Their Prognostic and Oxaliplatin Predictive Value |
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| Authors: | Gavin, Patrick G, Colangelo, Linda H, Fumagalli, Debora, Tanaka, Noriko, Remillard, Matthew Y, Yothers, Greg, Kim, Chungyeul, Taniyama, Yusuke, Kim, Seung Il, Choi, Hyun Joo, Blackmon, Nicole L, Lipchik, Corey, Petrelli, Nicholas J, O'Connell, Michael J, Wolmark, Norman, Paik, Soonmyung, Pogue-Geile, Kay L |
| Source: | Clinical Cancer Research. 18:6531-6541 |
| Publisher Information: | American Association for Cancer Research (AACR), 2012. |
| Publication Year: | 2012 |
| Subject Terms: | Proto-Oncogene Proteins B-raf, Colonic Neoplasms -- drug therapy -- genetics -- mortality -- pathology, Organoplatinum Compounds, Antineoplastic Agents, Prognosis, DNA Mismatch Repair, Sciences biomédicales, 3. Good health, Cancérologie, Oxaliplatin, Treatment Outcome, Mutation Rate, Colonic Neoplasms, Mutation, Antineoplastic Agents -- therapeutic use, Organoplatinum Compounds -- therapeutic use, Humans, Proto-Oncogene Proteins B-raf -- genetics, Microsatellite Instability, Neoplasm Staging |
| Description: | Purpose: The purpose of this study was to examine the prognostic and oxaliplatin predictive value of mismatch repair (MMR) status and common hot spot mutations, which we previously identified in stage II and III colon cancer. Experimental Design: Mutations in BRAF, KRAS, NRAS, MET, and PIK3CA were profiled in 2,299 stage II and III colon tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials C-07 (n = 1,836) and C-08 (n = 463) with Type Plex chemistry and mass spectrometry. C-07 tested the worth of adding oxaliplatin to 5-fluorouracil plus leucovorin, and C-08 tested the worth of adding bevacizumab to FOLFOX. Cox proportional hazard models were used to assess prognostic or oxaliplatin predictive value of mutations for tumor recurrence, overall survival (OS), and survival after recurrence (SAR). Results: BRAF mutations were associated with MMR-deficient tumors (P < 0.0001), poor OS [HR, 1.46; 95% confidence interval (CI), 1.20–1.79; P ≤ 0.0002], and poor SAR (HR, 2.31; 95% CI, 1.83–2.95; P < 0.0001). Mutations in KRAS, NRAS, MET, and PIK3CA were not associated with recurrence, OS, or SAR. MMR-deficient tumors were associated with an improved prognosis based on recurrence (HR, 0.48; 95% CI, 0.33–0.70; P < 0.0001). Mutations and MMR status were not predictive for oxaliplatin benefit. Conclusions: This study shows that BRAF mutations profiled from stage II and III colon cancer tumors were associated with poor SAR and validates and explains, at least in part, previous observations associating it with poor OS. Profiling of all of these mutations is warranted for future clinical trials testing new targeted therapies that block relevant signaling pathways. Such clinical trials are under development at NSABP. Clin Cancer Res; 18(23); 6531–41. ©2012 AACR. |
| Document Type: | Article |
| File Description: | 1 full-text file(s): application/pdf |
| Language: | English |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-12-0605 |
| Access URL: | https://europepmc.org/articles/pmc4273673?pdf=render https://pubmed.ncbi.nlm.nih.gov/23045248 http://www.ncbi.nlm.nih.gov/pubmed/23045248/ https://pubmed.ncbi.nlm.nih.gov/23045248/ https://tohoku.pure.elsevier.com/en/publications/mutation-profiling-and-microsatellite-instability-in-stage-ii-and https://europepmc.org/article/MED/23045248 http://clincancerres.aacrjournals.org/content/clincanres/18/23/6531.full.pdf http://clincancerres.aacrjournals.org/lookup/doi/10.1158/1078-0432.CCR-12-0605 |
| Accession Number: | edsair.doi.dedup.....6df1a222c37409173d5ec19bb8ec0eed |
| Database: | OpenAIRE |
Nájsť tento článok vo Web of Science | Abstract: | Purpose: The purpose of this study was to examine the prognostic and oxaliplatin predictive value of mismatch repair (MMR) status and common hot spot mutations, which we previously identified in stage II and III colon cancer. Experimental Design: Mutations in BRAF, KRAS, NRAS, MET, and PIK3CA were profiled in 2,299 stage II and III colon tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials C-07 (n = 1,836) and C-08 (n = 463) with Type Plex chemistry and mass spectrometry. C-07 tested the worth of adding oxaliplatin to 5-fluorouracil plus leucovorin, and C-08 tested the worth of adding bevacizumab to FOLFOX. Cox proportional hazard models were used to assess prognostic or oxaliplatin predictive value of mutations for tumor recurrence, overall survival (OS), and survival after recurrence (SAR). Results: BRAF mutations were associated with MMR-deficient tumors (P < 0.0001), poor OS [HR, 1.46; 95% confidence interval (CI), 1.20–1.79; P ≤ 0.0002], and poor SAR (HR, 2.31; 95% CI, 1.83–2.95; P < 0.0001). Mutations in KRAS, NRAS, MET, and PIK3CA were not associated with recurrence, OS, or SAR. MMR-deficient tumors were associated with an improved prognosis based on recurrence (HR, 0.48; 95% CI, 0.33–0.70; P < 0.0001). Mutations and MMR status were not predictive for oxaliplatin benefit. Conclusions: This study shows that BRAF mutations profiled from stage II and III colon cancer tumors were associated with poor SAR and validates and explains, at least in part, previous observations associating it with poor OS. Profiling of all of these mutations is warranted for future clinical trials testing new targeted therapies that block relevant signaling pathways. Such clinical trials are under development at NSABP. Clin Cancer Res; 18(23); 6531–41. ©2012 AACR. |
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| ISSN: | 15573265 10780432 |
| DOI: | 10.1158/1078-0432.ccr-12-0605 |