Tailoring heated intraperitoneal mitomycin C for peritoneal metastases originating from colorectal carcinoma: a translational approach to improve survival

Br J Cancer. 2015 Mar 3;112(5):851-6. doi: 10.1038/bjc.2015.18. Epub 2015 Feb 10.

Abstract

Background: Patients with peritoneal metastases (PMs) originating from colorectal carcinoma (CRC) are curatively treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC). We aim to improve patient selection for HIPEC by predicting MMC sensitivity.

Methods: The MMC sensitivity was determined for 12 CRC cell lines and correlated to mRNA expression of 37 genes related to the Fanconi anaemia (FA)-BRCA pathway, ATM-ATR pathway and enzymatic activation of MMC. Functionality of the FA-BRCA pathway in cell lines was assessed using a chromosomal breakage assay and western blot for key protein FANCD2. Bloom syndrome protein (BLM) was further analysed by staining for the corresponding protein with immunohistochemistry (IHC) on both CRC cell lines (n=12) and patient material (n=20).

Results: High sensitivity correlated with a low BLM (P=0.01) and BRCA2 (P=0.02) at mRNA expression level. However, FA-BRCA pathway functionality demonstrated no correlation to MMC sensitivity. In cell lines, weak intensity staining of BLM by IHC correlated to high sensitivity (P=0.04) to MMC. Low BLM protein expression was significantly associated with an improved survival in patients after CRS and HIPEC (P=0.04).

Conclusions: Low BLM levels are associated with high MMC sensitivity and an improved survival after HIPEC.

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology*
  • Antibiotics, Antineoplastic / therapeutic use
  • Biomarkers, Tumor / metabolism*
  • Caco-2 Cells
  • Cell Line, Tumor
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / therapy*
  • Fanconi Anemia Complementation Group D2 Protein / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Hyperthermia, Induced / methods*
  • Mitomycin / pharmacology*
  • Mitomycin / therapeutic use
  • Peritoneal Neoplasms / mortality
  • Peritoneal Neoplasms / secondary*
  • Peritoneal Neoplasms / therapy*
  • RecQ Helicases / metabolism
  • Signal Transduction / drug effects
  • Survival Analysis
  • Translational Medical Research

Substances

  • Antibiotics, Antineoplastic
  • Biomarkers, Tumor
  • FANCD2 protein, human
  • Fanconi Anemia Complementation Group D2 Protein
  • Mitomycin
  • Bloom syndrome protein
  • RecQ Helicases