title: FOLFIRI and Cetuximab Every Second Week for First-Line Treatment of KRAS Wild-Type Metastatic Colorectal Cancer According to Phosphatase and Tensin Homolog Expression: A Phase II Study.
abstract: BACKGROUND
  Retrospective studies have suggested that phosphatase and tensin homolog (PTEN) expression might predict the efficacy of cetuximab in patients with KRAS wild-type metastatic colorectal cancer (mCRC). The present study was designed to prospectively evaluate the efficacy of first-line irinotecan, fluorouracil, and folinate (FOLFIRI) plus cetuximab every second week according to PTEN expression.
  
  
  METHODS
  Originally, patients with KRAS wild-type mCRC were randomly assigned to receive either FOLFIRI or cetuximab plus FOLFIRI (FOLFIRI-C). After a protocol amendment, the FOLFIRI arm was discontinued, and additional patients received FOLFIRI-C. Cox proportional hazard models were used to investigate the effect of PTEN and MET expression and BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α mutations on progression-free survival (PFS) and overall survival (OS).
  
  
  RESULTS
  A total of 35 and 54 patients received FOLFIRI and FOLFIRI-C, respectively. For the patients assigned to FOLFIRI and FOLFIRI-C, the median OS was 17.7 and 23.3 months and the median PFS was 8.2 and 6.6 months, respectively. For patients receiving FOLFIRI-C, the loss of PTEN expression did not affect PFS or OS. Significant interactions for PFS were detected between the MET expression levels (P = .047) and BRAF mutation (P = .018) and treatment. On univariate analysis, BRAF mutation was significantly associated with shorter OS for patients receiving either FOLFIRI-C (P = .016) or FOLFIRI (P = .035). Multivariate analysis confirmed the independent prognostic value of BRAF mutation on OS and that of MET expression levels on PFS (P = .025) and OS (P = .028) but only in the patients receiving FOLFIRI alone. Adverse events with FOLFIRI-C were consistent with those expected from FOLFIRI plus weekly cetuximab.
  
  
  CONCLUSIONS
  Although prospective analysis of PTEN did not allow a validation of the prognostic value of this biomarker, an every second week cetuximab schedule, in addition to first-line FOLFIRI, was effective and well tolerated. The possible predictive value of MET expression levels warrants additional investigation.
authors: Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy; Department of Medical Biotechnology and Translational Medicine, University of Milano, Milano, Italy. Electronic address: nic_personeni@hotmail.com.
authors: Nicola
authors: N
authors: Personeni
authors: Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Lorenza
authors: L
authors: Rimassa
authors: Medical Oncology Unit, A.O. Busto Arsizio, P.O. Saronno, Saronno, Italy.
authors: Claudio
authors: C
authors: Verusio
authors: Oncology Department, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Treviglio, Italy.
authors: Sandro
authors: S
authors: Barni
authors: Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Luca
authors: L
authors: Rubino
authors: Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Silvia
authors: S
authors: Bozzarelli
authors: Department of Oncology, Ospedale San Raffaele, Milan, Italy.
authors: Eugenio
authors: E
authors: Villa
authors: Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Carlo
authors: C
authors: Carnaghi
authors: Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Maria Chiara
authors: MC
authors: Tronconi
authors: Department of Oncology, Laboratory of Clinical Research, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors: Chiara
authors: C
authors: Gerardi
authors: Department of Oncology, Laboratory of Clinical Research, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors: Francesca
authors: F
authors: Galli
authors: Department of Oncology, Laboratory of Clinical Research, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors: Irene
authors: I
authors: Floriani
authors: Department of Pathology, Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Annarita
authors: A
authors: Destro
authors: Department of Pathology, Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Carlotta
authors: C
authors: Raschioni
authors: Ospedale Papa Giovanni XXIII, Bergamo, Italy.
authors: Roberto
authors: R
authors: Labianca
authors: Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Armando
authors: A
authors: Santoro
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068818:Cetuximab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: Anti-EGFR antibody; BRAF; MET; PIK3CA; Phosphatase and tensin homolog