title: A let-7 microRNA-binding site polymorphism in KRAS predicts improved outcome in patients with metastatic colorectal cancer treated with salvage cetuximab/panitumumab monotherapy.
abstract: OBJECTIVE
  An inherited mutation in KRAS (LCS6-variant or rs61764370) results in altered control of the KRAS oncogene. We studied this biomarker's correlation to anti-EGFR monoclonal antibody (mAb) therapy response in patients with metastatic colorectal cancer.
  
  
  METHODS
  LCS6-variant and KRAS/BRAF mutational status was determined in 512 patients with metastatic colorectal cancer treated with salvage anti-EGFR mAb therapy, and findings correlated with outcome. Reporters were tested in colon cancer cell lines to evaluate the differential response of the LCS6-variant allele to therapy exposure.
  
  
  RESULTS
  In this study, 21.2% (109 of 512) of patients with metastatic colorectal cancer had the LCS6-variant (TG/GG), which was found twice as frequently in the BRAF-mutated versus the wild-type (WT) group (P=0.03). LCS6-variant patients had significantly longer progression-free survival (PFS) with anti-EGFR mAb monotherapy treatment in the whole cohort (16.85 vs. 7.85 weeks; P=0.019) and in the double WT (KRAS and BRAF) patient population (18 vs. 10.4 weeks; P=0.039). Combination therapy (mAbs plus chemotherapy) led to improved PFS and overall survival (OS) for nonvariant patients, and brought their outcome to levels comparable with LCS6-variant patients receiving anti-EGFR mAb monotherapy. Combination therapy did not lead to improved PFS or OS for LCS6-variant patients. Cell line studies confirmed a unique response of the LCS6-variant allele to both anti-EGFR mAb monotherapy and chemotherapy.
  
  
  CONCLUSIONS
  LCS6-variant patients with metastatic colorectal cancer have an excellent response to anti-EGFR mAb monotherapy, without any benefit from the addition of chemotherapy. These findings further confirm the importance of this mutation as a biomarker of anti-EGFR mAb response in patients with metastatic colorectal cancer, and warrant further prospective confirmation.
authors.affiliation: Laboratory of Tumor Cell Biology School of Medicine, University of Crete, Heraklion, Greece.|Laboratory of Molecular Digestive Oncology, Department of Oncology , Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Zenia
authors.initials: Z
authors.lastname: Saridaki
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, USA.
authors.forename: Joanne B
authors.initials: JB
authors.lastname: Weidhaas
authors.affiliation: Department of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.affiliation: UMR-S775 INSERM laboratory, Descartes University Medical School, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.affiliation: Laboratory of Molecular Digestive Oncology, Department of Oncology , Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Jacobs
authors.affiliation: Laboratory of Molecular Digestive Oncology, Department of Oncology , Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: De Schutter
authors.affiliation: Oncology Unit, Ziekenhuis Oost-Limburg, Genk, Belgium.
authors.forename: Wendy
authors.initials: W
authors.lastname: De Roock
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Salzman
authors.affiliation: Department of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA.
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.affiliation: Faculté de Médecine, Université Paris Descartes, Paris, France.
authors.forename: Camilla
authors.initials: C
authors.lastname: Pilati
authors.affiliation: Service d'Hépato Gastroentérologie et de Cancérologie Digestive, CHU Robert Debré, Reims, Champagne Ardenne, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bouché
authors.affiliation: Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Hubert
authors.initials: H
authors.lastname: Piessevaux
authors.affiliation: Laboratory of Molecular Digestive Oncology, Department of Oncology , Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D001665:Binding Sites; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D000077544:Panitumumab; D011110:Polymorphism, Genetic; D057285:Precision Medicine; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D000077544:Panitumumab; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab