title: Primary tumor location as a prognostic factor in metastatic colorectal cancer.
abstract: BACKGROUND
  We sought to clarify the prognostic impact of primary tumor location in metastatic colorectal cancer (mCRC).
  
  
  METHODS
  We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy ± bevacizumab in three independent cohorts: a prospective pharmacogenetic study (PROVETTA) and two randomized phase III trials, AVF2107g and NO16966. Cancers proximal or distal of the splenic flexure were classified as right-sided or left-sided, respectively. The primary end point was overall survival (OS). Data were analyzed with Cox proportional hazards and logistic regression models. All statistical tests were two-sided.
  
  
  RESULTS
  Among evaluable patients in the PROVETTA (n = 200), AVF2107g (n = 559), and NO16966 (n = 1268) studies, 72.0%, 63.1%, and 73.7% had left-sided tumors, respectively. In PROVETTA, patients with left-sided tumors had superior OS (left-sided vs right-sided: hazard ratio [HR] = .44, 95% confidence interval [CI] = .28 to .70, P < .001) and progression-free survival (HR = .52, 95% CI = .36 to .75, P < .001) outcomes. Multivariable analyses confirmed right-sided location as a negative prognostic variable, independent of mucinous histology and BRAF mutational status. Data from the AVF2107g (HR for OS = .55, 95% CI = .43 to .70) and NO16966 trials (HR for OS = .71, 95% CI = .62 to .82 both P < .001) also showed favorable outcomes in patients with left-sided tumors. In both randomized studies, the efficacy of bevacizumab was independent of tumor location.
  
  
  CONCLUSIONS
  These data demonstrate that primary tumor location is an important prognostic factor in previously untreated mCRC. Given the consistency across an exploratory set and two confirmatory phase III studies, side of tumor origin should be considered for stratification in randomized trials.
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM).
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM).
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM).
authors.forename: Linda
authors.initials: L
authors.lastname: Yau
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM).
authors.forename: Shibao
authors.initials: S
authors.lastname: Feng
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM).
authors.forename: Chiara
authors.initials: C
authors.lastname: Cremolini
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM).
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM).
authors.forename: Martin K H
authors.initials: MK
authors.lastname: Maus
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM).
authors.forename: Carlotta
authors.initials: C
authors.lastname: Antoniotti
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM).
authors.forename: Christiane
authors.initials: C
authors.lastname: Langer
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM).
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Scherer
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM).
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM).
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM).
authors.forename: Leonard
authors.initials: L
authors.lastname: Saltz
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM).
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA (FL, DY, WZ, HJL); U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy (FL, CC, CA, AF); Genentech, Inc., South San Francisco, CA (LY, SF, CL, SJS, TM); Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany (MKHM); Response Genetics, Inc., Los Angeles, CA (MKHM); Department of Medical Oncology and Transplantation, Duke University, Durham, NC (HIH); Memorial Sloan-Kettering Cancer Center, New York, NY (LS) Current Affiliations: Onyx Pharmaceuticals, Inc. South San Francisco, CA (SF); Biocenter, Physiological Chemistry 1, University of Wuerzburg, Wuerzburg, Germany (SJS); Biomarker, Translational and Predictive Medicine Consulting, San Francisco, CA (TM). lenz@med.usc.edu.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab