Diana L Hanna1, Fotios Loupakis2, Dongyun Yang3, Chiara Cremolini2, Marta Schirripa2, Meng Li4, Satoshi Matsusaka5, Martin D Berger5, Yuji Miyamoto5, Wu Zhang5, Yan Ning5, Carlotta Antoniotti2, Lisa Salvatore2, Miriana Moran6, Gary Zeger6, Stephanie H Astrow6, Alfredo Falcone2, Heinz-Josef Lenz7. 1. Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA; Hoag Family Cancer Institute, Newport Beach, CA. 2. Unito of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy. 3. Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA. 4. Health Sciences Bioinformatics Core, University of Southern California Keck School of Medicine, Los Angeles, CA. 5. Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA. 6. Response Genetics, Inc, Los Angeles, CA. 7. Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA. Electronic address: lenz@med.usc.edu.
Abstract
BACKGROUND: No biomarkers exist to predict benefit from antiangiogenic therapy in metastatic colorectal cancer patients. ACVRL1 (activin receptor like-protein 1) encodes for ALK1, a member of the transforming growth factor-β receptor family, which directs pathologic angiogenesis. We examined the intratumoral expression of ACVRL1 and other angiogenesis pathway-related genes to identify molecular markers in the TRIBE study. MATERIALS AND METHODS: Of 503 randomized patients, 228 had sufficient tissue for analysis. Formalin-fixed paraffin-embedded specimens were examined for expression of VEGF-A, VEGF-B, VEGF-C, VEGFR1, VEGFR2, ACVRL1, EphB4, and EGFL7 using reverse transcription polymerase chain reaction. A maximal χ2 approach was used to determine the messenger RNA levels associated with progression-free survival (PFS), overall survival (OS), response rate, early tumor shrinkage, and depth of response. Recursive partitioning trees were constructed to identify composite prognostic biomarker profiles. External validation was conducted in silico using the Oncomine database. RESULTS:High ACVRL1 expression was associated with superior OS in both treatment arms (FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan]-bevacizumab, 32.7 vs. 13.5 months, hazard ratio [HR], 0.38, P = .023; FOLFIRI [5-fluorouracil, leucovorin, irinotecan]-bevacizumab, 35.1 vs. 22.0 months, HR, 0.36, P = .006) and prolonged PFS (11.7 vs. 5.9 months, multivariate HR, 0.17; P = .001) for patients receiving FOLFOXIRI-bevacizumab on univariate and multivariate analyses. In recursive partitioning analysis, ACVRL1 was the strongest discriminator of the response rate, PFS, and OS in patients receiving FOLFOXIRI-bevacizumab and of OS in patients receiving FOLFIRI-bevacizumab. In silico validation revealed significant associations between ACVRL1 expression, disease recurrence, and 1-year survival (P < .05) among all colorectal cancer stages. CONCLUSION:ACVRL1 expression could serve as a prognostic biomarker in metastatic colorectal cancer patients receivingchemotherapy and bevacizumab and warrants further evaluation in prospective studies.
RCT Entities:
BACKGROUND: No biomarkers exist to predict benefit from antiangiogenic therapy in metastatic colorectal cancerpatients. ACVRL1 (activin receptor like-protein 1) encodes for ALK1, a member of the transforming growth factor-β receptor family, which directs pathologic angiogenesis. We examined the intratumoral expression of ACVRL1 and other angiogenesis pathway-related genes to identify molecular markers in the TRIBE study. MATERIALS AND METHODS: Of 503 randomized patients, 228 had sufficient tissue for analysis. Formalin-fixed paraffin-embedded specimens were examined for expression of VEGF-A, VEGF-B, VEGF-C, VEGFR1, VEGFR2, ACVRL1, EphB4, and EGFL7 using reverse transcription polymerase chain reaction. A maximal χ2 approach was used to determine the messenger RNA levels associated with progression-free survival (PFS), overall survival (OS), response rate, early tumor shrinkage, and depth of response. Recursive partitioning trees were constructed to identify composite prognostic biomarker profiles. External validation was conducted in silico using the Oncomine database. RESULTS: High ACVRL1 expression was associated with superior OS in both treatment arms (FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan]-bevacizumab, 32.7 vs. 13.5 months, hazard ratio [HR], 0.38, P = .023; FOLFIRI [5-fluorouracil, leucovorin, irinotecan]-bevacizumab, 35.1 vs. 22.0 months, HR, 0.36, P = .006) and prolonged PFS (11.7 vs. 5.9 months, multivariate HR, 0.17; P = .001) for patients receiving FOLFOXIRI-bevacizumab on univariate and multivariate analyses. In recursive partitioning analysis, ACVRL1 was the strongest discriminator of the response rate, PFS, and OS in patients receiving FOLFOXIRI-bevacizumab and of OS in patients receiving FOLFIRI-bevacizumab. In silico validation revealed significant associations between ACVRL1 expression, disease recurrence, and 1-year survival (P < .05) among all colorectal cancer stages. CONCLUSION:ACVRL1 expression could serve as a prognostic biomarker in metastatic colorectal cancerpatients receiving chemotherapy and bevacizumab and warrants further evaluation in prospective studies.
Authors: Herbert Hurwitz; Louis Fehrenbacher; William Novotny; Thomas Cartwright; John Hainsworth; William Heim; Jordan Berlin; Ari Baron; Susan Griffing; Eric Holmgren; Napoleone Ferrara; Gwen Fyfe; Beth Rogers; Robert Ross; Fairooz Kabbinavar Journal: N Engl J Med Date: 2004-06-03 Impact factor: 91.245
Authors: Nicole K Noren; Mark Lu; Andrew L Freeman; Mitchell Koolpe; Elena B Pasquale Journal: Proc Natl Acad Sci U S A Date: 2004-04-05 Impact factor: 11.205
Authors: Leisa Johnson; Mahrukh Huseni; Tanya Smyczek; Anthony Lima; Stacey Yeung; Jason H Cheng; Rafael Molina; David Kan; Ann De Mazière; Judith Klumperman; Ian Kasman; Yin Zhang; Mark S Dennis; Jeffrey Eastham-Anderson; Adrian M Jubb; Olivia Hwang; Rupal Desai; Maike Schmidt; Michelle A Nannini; Kai H Barck; Richard A D Carano; William F Forrest; Qinghua Song; Daniel S Chen; Louie Naumovski; Mallika Singh; Weilan Ye; Priti S Hegde Journal: J Clin Invest Date: 2013-08-15 Impact factor: 14.808