Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials.

Abstract

BACKGROUND:

REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma.

PATIENTS AND METHODS:

Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect.

RESULTS:

RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival.

CONCLUSIONS:

The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.

• Authors: A F C Okines, D Gonzalez de Castro, D Cunningham, I Chau, R E Langley, L C Thompson, S P Stenning, C Saffery, Y Barbachano, F Coxon, G Middleton, D Ferry, T Crosby, S Madhusudan, J Wadsley, J Waters, M Hall, D Swinson, A Robinson, D Smith, J S Reis-Filho, T S Waddell, L Puckey, S Hulkki Wilson, Z Eltahir, M Band, A Wotherspoon
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 49 Issue 9 Pg. 2116-25 (Jun 2013) ISSN: 1879-0852 [Electronic] England
• PMID: 23481512 (Publication Type: Clinical Trial, Phase II, Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Genetic Markers
• KRAS protein, human
• Proto-Oncogene Proteins
• Phosphatidylinositol 3-Kinases
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• Proto-Oncogene Proteins B-raf
• PTEN Phosphohydrolase
• PTEN protein, human
• Proto-Oncogene Proteins p21(ras)
• ras Proteins

Topics

• Adenocarcinoma (drug therapy, genetics, mortality)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Class I Phosphatidylinositol 3-Kinases
• Esophageal Neoplasms (drug therapy, genetics, mortality)
• Genetic Markers (genetics)
• Humans
• Mutation (genetics)
• PTEN Phosphohydrolase (genetics)
• Phosphatidylinositol 3-Kinases (genetics)
• Prognosis
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins B-raf (genetics)
• Proto-Oncogene Proteins p21(ras)
• Stomach Neoplasms (drug therapy, genetics, mortality)
• Survival Analysis
• ras Proteins (genetics)