title: Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses of the CRYSTAL and FIRE-3 Trials.
abstract: OBJECTIVE
  Metastatic colorectal cancer (mCRC) is heterogeneous, and primary tumors arising from different regions of the colon are clinically and molecularly distinct.
  
  
  OBJECTIVE
  To examine the prognostic and predictive value of primary tumor location in patients with RAS wild-type (wt) mCRC treated with first-line fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab in the Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial and FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab as First-Line Treatment For Patients With Metastatic Colorectal Cancer (FIRE-3) trial.
  
  
  METHODS
  In this retrospective analysis patients with RAS wt metastatic colorectal cancer from the CRYSTAL and FIRE-3 trials were classified as having left-sided or right-sided mCRC, defined, respectively, as patients whose tumors originated in the splenic flexure, descending colon, sigmoid colon, or rectum vs appendix, cecum, ascending colon, hepatic flexure, or transverse colon.
  
  
  METHODS
  Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were assessed according to tumor location and treatment arm.
  
  
  RESULTS
  In the RAS wt populations of the CRYSTAL and FIRE-3 trials, patients with left-sided tumors (n = 142 and n = 157, respectively) had markedly superior PFS, OS, and ORR compared with patients with right-sided tumors (n = 33 and n = 38, respectively). Among CRYSTAL and FIRE-3 study patients with RAS wt left-sided tumors, FOLFIRI plus cetuximab significantly improved OS relative to the respective comparators (FOLFIRI and FOLFIRI plus bevacizumab); in contrast, in RAS wt patients with poor-prognosis right-sided tumors, limited efficacy benefits were observed upon the addition of cetuximab to FOLFIRI in CRYSTAL, and comparable outcomes were observed between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab arms of FIRE-3. A significant interaction was observed between primary tumor location and treatment for OS (CRYSTAL: hazard ratio [HR], 1.95; 95% CI, 1.09-3.48 and FIRE-3: HR, 0.40; 95% CI, 0.23-0.70) within the RAS wt populations of both studies in multivariable models that also included sex, prior adjuvant therapy, and BRAF mutational status.
  
  
  CONCLUSIONS
  In the RAS wt populations of CRYSTAL and FIRE-3, patients with left-sided tumors had a markedly better prognosis than those with right-sided tumors. First-line FOLFIRI plus cetuximab clearly benefitted patients with left-sided tumors (vs FOLFIRI or FOLFIRI plus bevacizumab, respectively), whereas patients with right-sided tumors derived limited benefit from standard treatments.
  
  
  BACKGROUND
  clinicaltrials.gov Identifiers: CRYSTAL, NCT00154102, and FIRE-3, NCT00433927.
authors.affiliation: Molecular Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.affiliation: Department of Hematology and Oncology, University of Munich (Ludwig-Maximilians-Universität), Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stintzing
authors.affiliation: Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale, Seconda Università di Napoli, Naples, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Digestive Oncology, University Hospitals Leuven and KULeuven, Leuven, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Beier
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Esser
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.affiliation: Department of Hematology and Oncology, University of Munich (Ludwig-Maximilians-Universität), Munich, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Heinemann