Prognostic and predictive role of EGFR pathway alterations in biliary cancer patients treated with chemotherapy and anti-EGFR

PLoS One. 2018 Jan 19;13(1):e0191593. doi: 10.1371/journal.pone.0191593. eCollection 2018.

Abstract

The association of anti-EGFR to gemcitabine and oxaliplatin (GEMOX) chemotherapy did not improve survival in biliary tract carcinoma (BTC) patients. Multiple mechanisms might be involved in the resistance to anti-EGFR. Here, we explored the mutation profile of EGFR extracellular domain (ECD), of tyrosine kinase domain (TKD), and its amplification status. EGFR mutational status of exons 12, 18-21 was analyzed in 57 tumors by Sanger sequencing. EGFR amplification was evaluated in 37 tumors by Fluorescent In Situ Hybridization (FISH). Kaplan-Meier curves were calculated using the log-rank test. Six patients had mutations in exon 12 of EGFR ECD and 7 in EGFR TKD. Neither EGFR ECD nor TKD mutations affected progression free survival (PFS) or overall survival (OS) in the entire population. In the panitumumab plus GEMOX (P-GEMOX) arm, ECD mutated patients had a worse OS, while EGFR TKD mutated patients had a trend towards shorter PFS and OS. Overall, the presence of mutations in EGFR or in its transducers did not affect PFS or OS, while the extrahepatic cholangiocarcinoma (ECC) mutated patients had a worse prognosis compared to WT. Nineteen out of 37 tumors were EGFR amplified, but the amplification did not correlate with survival. ECC EGFR amplified patients had improved OS, whereas the amplification significantly correlated with poor PFS (p = 0.03) in gallbladder carcinoma patients. The high molecular heterogeneity is a predominant feature of BTC: the alterations found in this work seem to have a prognostic impact rather than a predictive role towards anti-EGFR therapy.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Bile Duct Neoplasms / drug therapy
  • Bile Duct Neoplasms / genetics
  • Bile Duct Neoplasms / metabolism
  • Biliary Tract Neoplasms / drug therapy*
  • Biliary Tract Neoplasms / genetics*
  • Biliary Tract Neoplasms / metabolism
  • Cholangiocarcinoma / drug therapy
  • Cholangiocarcinoma / genetics
  • Cholangiocarcinoma / metabolism
  • DNA Mutational Analysis
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism
  • Gallbladder Neoplasms / drug therapy
  • Gallbladder Neoplasms / genetics
  • Gallbladder Neoplasms / metabolism
  • Gemcitabine
  • Gene Amplification
  • Genes, erbB-1*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Kaplan-Meier Estimate
  • Mutation*
  • Organoplatinum Compounds / administration & dosage
  • Organoplatinum Compounds / therapeutic use
  • Oxaliplatin
  • Panitumumab
  • Prognosis

Substances

  • Antibodies, Monoclonal
  • Organoplatinum Compounds
  • Oxaliplatin
  • Deoxycytidine
  • Panitumumab
  • EGFR protein, human
  • ErbB Receptors
  • Gemcitabine

Grants and funding

This work was supported by a 5 per Mille 2010 Ministero della Salute, Fondazione Piemontese per la Ricerca sul Cancro (FPRC)—Onlus grant and a Associazione Italiana Ricerca sul Cancro–AIRC 5X1000 2010-Ministry of Health, FPO grant to MA. FL received a grant from Università di Torino anno 2014 (Fondo per la ricerca locale (Linea B), LEOF_RIC_LOC_14_01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.