Van Morris1, Michael J Overman2, Zhi-Qin Jiang2, Christopher Garrett2, Shweta Agarwal2, Cathy Eng2, Bryan Kee2, David Fogelman2, Arvind Dasari2, Robert Wolff2, Dipen Maru3, Scott Kopetz4. 1. Department of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX. 2. Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. 3. Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. 4. Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Electronic address: skopetz@mdanderson.org.
Abstract
BACKGROUND: BRAF mutations occur in 5% to 10% of metastatic colorectal cancers and are biomarkers associated with a poor prognosis. However, the outcomes with standard chemotherapy over sequential lines of therapy in a large cohort of patients with BRAF-mutant tumors have not been described. PATIENTS AND METHODS: We searched the M.D. Anderson Cancer Center databases for patients with colorectal cancer and identified BRAF mutations between December 2003 and May 2012. Patients were analyzed for clinical characteristics, PFS, overall survival, and chemotherapeutic agents used. Survival was estimated according to the Kaplan-Meier method. RESULTS: Among the 1567 patients tested for BRAF mutations at our institution, 127 (8.1%) had tumors with BRAF mutations. The 71 patients who presented with metastatic disease received a median of 2 lines of chemotherapy. For the first 3 lines of chemotherapy, median PFS was 6.3 months (n = 69 patients; 95% confidence interval [CI], 4.9-7.7 months), 2.5 months (n = 58 patients; 95% CI, 1.8-3.0 months), and 2.6 months (n = 31 patients; 95% CI, 1.0-4.2 months), respectively. Median PFS was not affected by the backbone chemotherapeutic agent in the first-line setting, whether oxaliplatin-based or irinotecan-based (6.4 months vs. 5.4 months, respectively; P = .99). CONCLUSION: PFS is expectedly poor for patients with BRAF-mutated metastatic colorectal cancer. Despite the ascertainment bias present (with testing preferentially performed in patients suitable for clinical trials in refractory disease), these data provide historic controls suitable for future study design and support the idea that novel therapeutic options are essential in this population.
BACKGROUND:BRAF mutations occur in 5% to 10% of metastatic colorectal cancers and are biomarkers associated with a poor prognosis. However, the outcomes with standard chemotherapy over sequential lines of therapy in a large cohort of patients with BRAF-mutant tumors have not been described. PATIENTS AND METHODS: We searched the M.D. Anderson Cancer Center databases for patients with colorectal cancer and identified BRAF mutations between December 2003 and May 2012. Patients were analyzed for clinical characteristics, PFS, overall survival, and chemotherapeutic agents used. Survival was estimated according to the Kaplan-Meier method. RESULTS: Among the 1567 patients tested for BRAF mutations at our institution, 127 (8.1%) had tumors with BRAF mutations. The 71 patients who presented with metastatic disease received a median of 2 lines of chemotherapy. For the first 3 lines of chemotherapy, median PFS was 6.3 months (n = 69 patients; 95% confidence interval [CI], 4.9-7.7 months), 2.5 months (n = 58 patients; 95% CI, 1.8-3.0 months), and 2.6 months (n = 31 patients; 95% CI, 1.0-4.2 months), respectively. Median PFS was not affected by the backbone chemotherapeutic agent in the first-line setting, whether oxaliplatin-based or irinotecan-based (6.4 months vs. 5.4 months, respectively; P = .99). CONCLUSION: PFS is expectedly poor for patients with BRAF-mutated metastatic colorectal cancer. Despite the ascertainment bias present (with testing preferentially performed in patients suitable for clinical trials in refractory disease), these data provide historic controls suitable for future study design and support the idea that novel therapeutic options are essential in this population.
Authors: T André; C Louvet; F Maindrault-Goebel; C Couteau; M Mabro; J P Lotz; V Gilles-Amar; M Krulik; E Carola; V Izrael; A de Gramont Journal: Eur J Cancer Date: 1999-09 Impact factor: 9.162
Authors: Paul T C Wan; Mathew J Garnett; S Mark Roe; Sharlene Lee; Dan Niculescu-Duvaz; Valerie M Good; C Michael Jones; Christopher J Marshall; Caroline J Springer; David Barford; Richard Marais Journal: Cell Date: 2004-03-19 Impact factor: 41.582
Authors: C Pritchard; L Carragher; V Aldridge; S Giblett; H Jin; C Foster; C Andreadi; T Kamata Journal: Biochem Soc Trans Date: 2007-11 Impact factor: 5.407
Authors: Michael A Choti; James V Sitzmann; Marcelo F Tiburi; Wuthi Sumetchotimetha; Ram Rangsin; Richard D Schulick; Keith D Lillemoe; Charles J Yeo; John L Cameron Journal: Ann Surg Date: 2002-06 Impact factor: 12.969
Authors: Y Fong; A M Cohen; J G Fortner; W E Enker; A D Turnbull; D G Coit; A M Marrero; M Prasad; L H Blumgart; M F Brennan Journal: J Clin Oncol Date: 1997-03 Impact factor: 44.544
Authors: Wade S Samowitz; Carol Sweeney; Jennifer Herrick; Hans Albertsen; Theodore R Levin; Maureen A Murtaugh; Roger K Wolff; Martha L Slattery Journal: Cancer Res Date: 2005-07-15 Impact factor: 12.701
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Authors: Fairooz Kabbinavar; Herbert I Hurwitz; Louis Fehrenbacher; Neal J Meropol; William F Novotny; Grazyna Lieberman; Susan Griffing; Emily Bergsland Journal: J Clin Oncol Date: 2003-01-01 Impact factor: 44.544
Authors: Helen Davies; Graham R Bignell; Charles Cox; Philip Stephens; Sarah Edkins; Sheila Clegg; Jon Teague; Hayley Woffendin; Mathew J Garnett; William Bottomley; Neil Davis; Ed Dicks; Rebecca Ewing; Yvonne Floyd; Kristian Gray; Sarah Hall; Rachel Hawes; Jaime Hughes; Vivian Kosmidou; Andrew Menzies; Catherine Mould; Adrian Parker; Claire Stevens; Stephen Watt; Steven Hooper; Rebecca Wilson; Hiran Jayatilake; Barry A Gusterson; Colin Cooper; Janet Shipley; Darren Hargrave; Katherine Pritchard-Jones; Norman Maitland; Georgia Chenevix-Trench; Gregory J Riggins; Darell D Bigner; Giuseppe Palmieri; Antonio Cossu; Adrienne Flanagan; Andrew Nicholson; Judy W C Ho; Suet Y Leung; Siu T Yuen; Barbara L Weber; Hilliard F Seigler; Timothy L Darrow; Hugh Paterson; Richard Marais; Christopher J Marshall; Richard Wooster; Michael R Stratton; P Andrew Futreal Journal: Nature Date: 2002-06-09 Impact factor: 49.962
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