Predictive genetic markers in neoadjuvant chemoradiotherapy for locally advanced esophageal cancer: a long way to go. Review of the literature.

The role of genetic molecular markers in neoadjuvant treatment for locally advanced esophageal cancer has been reviewed, focusing strictly on concurrent chemoradiation protocols followed by surgery. Eleven studies evaluated the role of mRNA expression profile; the end point was overall survival (OS) in two studies and different definitions of histological response in nine. Genes reported as significant were involved in cell cycle control (30), apoptosis (7), structural molecules (9), cell metabolism (6) and DNA repair (1). Seven studies reported about 15 microRNA (miRNA) molecules associated with OS (2) or histological response (13), however, defined with different classifications. Their target genes were prevalently involved in cell cycle control (4), apoptosis (1), cell adhesion (1), migration (1) and angiogenesis (1). Gene polymorphisms (single-nucleotide polymorphisms (SNPs)) have been evaluated in 8 studies reporting 10 variants associated with survival or pathological response. OS was the end point in six of these studies. SNPs reported as significant were involved in DNA repair system (4), detoxification (2), folate metabolism (6), drug efflux (2) and others (2). In a study, a panel including histology, pathological response and five SNPs discriminated two subsets of patients with 5-year survival rates of 79.3% and 26.3% (hazard ratio 6.25, P<0.0001). In another study, combination of stage, grade and 4 miRNAs improved prediction of pathological response (P=10-30). At present, given the great inconsistency of the data and the variability of the end points, definite conclusions are extremely difficult, if not impossible. More consistent data can derive only from analyses obtained from patients included in prospective randomized trials while panels combining genetic and clinical factors may improve prediction.

Genetic prediction of long-term survival after neoadjuvant chemoradiation in locally advanced esophageal cancer.

Candidate genes involved in DNA repair, 5-fluorouracil metabolism and drug detoxification were genotyped in 124 patients receiving neoadjuvant chemoradiation treatment for locally advanced esophageal cancer and their predictive role for long-term relapse-free survival (RFS) and cancer-specific survival (CSS) were evaluated. A panel including MTHFR 677TT, MDR1 2677GT, GSTP1 114CC, XPC 499CC and XPC 939AC+CC, defined as high-risk genotypes, discriminated subgroups with significantly different outcomes. When the panel was combined with histology, patients split into two subsets with 5-year RFS and CSS rates of 65% vs 27% (hazard ratio (HR) 3.0, P<0.0001) and 69% vs 31% (HR 2.9, P<0.0001), respectively. Combining the 5-single-nucleotide polymorphism (5-SNP) panel with pathological response defined two major informative risk classes with 5-year PFS and CSS rates of 79.4% vs 17.7% (HR 6.71, P<0.0001) and 79.3% vs 26.3% (HR 6.25, P<0.0001), respectively. This classification achieved a sensitivity of 79%, a specificity of 85.4% and an accuracy of 81.8%.