DNA Repair Biomarkers Predict Response to Neoadjuvant Chemoradiation in Esophageal Cancer

Abstract

Purpose/Objective(s)There were approximately 16,470 new cases of esophageal cancer and 14,530 deaths in 2009. The addition of neoadjuvant chemoradiotherapy prior to surgical resection has improved outcomes in some series. Pathologic compete response (pCR) following neoadjuvant therapy is associated with better outcome in these patients, but only 23-40% achieve pCR. Since chemoradiotherapy is effective by inducing DNA damage, we attempted to use immunohistochemical analysis of the DNA repair capacity of tumors prior to therapy as a biomarker of response and outcome.Materials/MethodsWe identified 85 patients diagnosed with esophageal cancer between October 1994 and September 2002 who underwent neoadjuvant chemoradiotherapy prior to surgery at the Massachusetts General Hospital and used their archived, formalin-fixed, paraffin-embedded biopsies to create a tissue microarray (TMA). The TMA was stained using antibodies against proteins in various DNA repair pathways including XPF, FANCD2, PAR, MLH1, PARP1 and MK2. Stained tissue was evaluated using machine-based image analysis and scoring that represented both the intensity and quantity of positive tumor nuclei. Biomarker scores and clinical data were assessed for correlations with outcome.ResultsHigher scores for MLH1 (p = 0.018) and lower scores for FANCD2 (p = 0.037) were associated with pathologic response to neoadjuvant chemoradiation on multivariable analysis. MLH1, PARP1, XPF and PAR staining were associated with recurrence free survival and PARP1 and FANCD2 were associated with overall survival on multivariable analysis.ConclusionsImmunohistochemical analysis of DNA repair proteins may be useful as predictive markers for response to neoadjuvant chemoradiotherapy in patients with esophageal cancer. Purpose/Objective(s)There were approximately 16,470 new cases of esophageal cancer and 14,530 deaths in 2009. The addition of neoadjuvant chemoradiotherapy prior to surgical resection has improved outcomes in some series. Pathologic compete response (pCR) following neoadjuvant therapy is associated with better outcome in these patients, but only 23-40% achieve pCR. Since chemoradiotherapy is effective by inducing DNA damage, we attempted to use immunohistochemical analysis of the DNA repair capacity of tumors prior to therapy as a biomarker of response and outcome. There were approximately 16,470 new cases of esophageal cancer and 14,530 deaths in 2009. The addition of neoadjuvant chemoradiotherapy prior to surgical resection has improved outcomes in some series. Pathologic compete response (pCR) following neoadjuvant therapy is associated with better outcome in these patients, but only 23-40% achieve pCR. Since chemoradiotherapy is effective by inducing DNA damage, we attempted to use immunohistochemical analysis of the DNA repair capacity of tumors prior to therapy as a biomarker of response and outcome. Materials/MethodsWe identified 85 patients diagnosed with esophageal cancer between October 1994 and September 2002 who underwent neoadjuvant chemoradiotherapy prior to surgery at the Massachusetts General Hospital and used their archived, formalin-fixed, paraffin-embedded biopsies to create a tissue microarray (TMA). The TMA was stained using antibodies against proteins in various DNA repair pathways including XPF, FANCD2, PAR, MLH1, PARP1 and MK2. Stained tissue was evaluated using machine-based image analysis and scoring that represented both the intensity and quantity of positive tumor nuclei. Biomarker scores and clinical data were assessed for correlations with outcome. We identified 85 patients diagnosed with esophageal cancer between October 1994 and September 2002 who underwent neoadjuvant chemoradiotherapy prior to surgery at the Massachusetts General Hospital and used their archived, formalin-fixed, paraffin-embedded biopsies to create a tissue microarray (TMA). The TMA was stained using antibodies against proteins in various DNA repair pathways including XPF, FANCD2, PAR, MLH1, PARP1 and MK2. Stained tissue was evaluated using machine-based image analysis and scoring that represented both the intensity and quantity of positive tumor nuclei. Biomarker scores and clinical data were assessed for correlations with outcome. ResultsHigher scores for MLH1 (p = 0.018) and lower scores for FANCD2 (p = 0.037) were associated with pathologic response to neoadjuvant chemoradiation on multivariable analysis. MLH1, PARP1, XPF and PAR staining were associated with recurrence free survival and PARP1 and FANCD2 were associated with overall survival on multivariable analysis. Higher scores for MLH1 (p = 0.018) and lower scores for FANCD2 (p = 0.037) were associated with pathologic response to neoadjuvant chemoradiation on multivariable analysis. MLH1, PARP1, XPF and PAR staining were associated with recurrence free survival and PARP1 and FANCD2 were associated with overall survival on multivariable analysis. ConclusionsImmunohistochemical analysis of DNA repair proteins may be useful as predictive markers for response to neoadjuvant chemoradiotherapy in patients with esophageal cancer. Immunohistochemical analysis of DNA repair proteins may be useful as predictive markers for response to neoadjuvant chemoradiotherapy in patients with esophageal cancer.