Gain of ALK gene copy number may predict lack of benefit from anti-EGFR treatment in patients with advanced colorectal cancer and RAS-RAF-PI3KCA wild-type status

PLoS One. 2014 Apr 1;9(4):e92147. doi: 10.1371/journal.pone.0092147. eCollection 2014.

Abstract

Introduction: Although cetuximab and panitumumab show an increased efficacy for patients with KRAS-NRAS-BRAF and PI3KCA wild-type metastatic colorectal cancer, primary resistance occurs in a relevant subset of molecularly enriched populations.

Patients and methods: We evaluated the outcome of 68 patients with advanced colorectal cancer and RAS, BRAF and PI3KCA status according to ALK gene status (disomic vs. gain of ALK gene copy number--defined as mean of 3 to 5 fusion signals in ≥ 10% of cells). All consecutive patients received cetuximab and irinotecan or panitumumab alone for chemorefractory disease.

Results: No ALK translocations or amplifications were detected. ALK gene copy number gain was found in 25 (37%) tumors. Response rate was significantly higher in patients with disomic ALK as compared to those with gain of gene copy number (70% vs. 32%; p = 0.0048). Similarly, progression-free survival was significantly different when comparing the two groups (6.7 vs. 5.3 months; p = 0.045). A trend was observed also for overall survival (18.5 vs. 15.6 months; p = 0.885).

Conclusion: Gain of ALK gene copy number might represent a negative prognostic factor in mCRC and may have a role in resistance to anti-EGFR therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anaplastic Lymphoma Kinase
  • Colorectal Neoplasms / drug therapy*
  • Demography
  • Disease-Free Survival
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Female
  • GTP Phosphohydrolases / genetics*
  • Gene Dosage*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Nuclear Proteins / genetics*
  • Proto-Oncogene Proteins B-raf / genetics*
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Transcription Factors / genetics*
  • Treatment Outcome

Substances

  • Membrane Proteins
  • Nuclear Proteins
  • PI3KCA protein, human
  • Transcription Factors
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • ErbB Receptors
  • Receptor Protein-Tyrosine Kinases
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • GTP Phosphohydrolases
  • NRAS protein, human

Grants and funding

This work was supported in part by funds obtained through Italian law Law 12 november 2011 n. 183 that allows taxpayers to allocate 0.5 percent share of their income tax contribution to a research institution of their choice. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.