EP1.01-71 Thymidylate Synthase and Folate Receptor Alpha Expression as Potential Biomarkers for Efficacy of Pemetrexed in NSCLC

Abstract

Predictive biomarkers for chemotherapy in advanced non-squamous NSCLC are lacking. Thymidylate synthase (TS) and folate receptor alpha (FRA) are target enzymes for pemetrexed. Here we investigated TS and FRA expression and their role as a prognostic and predictive biomarker for efficacy of pemetrexed-based chemotherapy. We performed immunohistochemistry on pre-treatment tumour specimens for TS and FRA expression and correlated it with patient’s demographic and clinical characteristics, treatment responses and survivals in a retrospective training cohort of patients with advanced non-squamous NSCLC treated with pemetrexed-based chemotherapy. Similar analysis for validation was performed in a prospective cohort of patients participating in a randomized control trial “to compare efficacy and safety of pemetrexed-carboplatin versus paclitaxel-carboplatin as induction regimen in advanced non-squamous NSCLC”. Chi-square test was used to co-relate TS and FRA expression with clinico-pathological characteristics. Kaplan-Meier methods, Log-rank test and Cox proportional-hazards model were used for survival analysis. In the retrospective training cohort median age was 57 (26-70) years with male predominance (ratio=2:1). TS and FRA expression were evaluable in 55 and 47 patients respectively. In this cohort TS and FRA expression didn’t co-relate with best overall response rates (ORR), however, low TS expression and positive FRA expression were associated with improved progression free survival (PFS), albeit non-significant. In the prospective validation cohort median age was 52 (28-65) years with 70% males. In this cohort TS and FRA expression were analysed in 113 and 97 patients respectively. High TS expression was significantly associated with better ORR in patients treated with paclitaxel-carboplatin (p=0.04) but there was no co-relation of TS expression with response rates in pemetrexed-carboplatin group. Younger patients (age<40 years) had more TS ‘low or negative’ status (p=0.04). High TS expression was associated with ALK positivity (p=0.02), bone metastases (p=0.01) and brain metastases (p=0.002). Positive FRA expression was associated with EGFR positivity (p=0.004) and liver metastases (p=0.020). Positive FRA expression was associated with improved PFS in patients treated with pemetrexed-carboplatin (median: 9.23 versus 4.27 months, p=0.01), paclitaxel-carboplatin (median: 10.87 versus 6.47 months, p=0.08) as well as improved OS (median: OS not reached versus 10.13 months, p=0.01), especially in patients treated with pemetrexed-carboplatin (median: 18.73 versus 10.46 months, p=0.08). In conclusion, the results from this study suggest that TS or FRA expression doesn’t predict efficacy of Pemetrexed, however, high TS expression may predict better ORR in patients receiving paclitaxel-carboplatin. FRA expression may serve as a prognostic factor in patients receiving chemotherapy irrespective of the regimen.