Pretreatment Red Blood Cell Total Folate Concentration Is Associated With Response to Pemetrexed in Stage IV Nonsquamous Non–Small-cell Lung Cancer

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d14628696e202">Objectives</h5> <p id="P1">Pemetrexed inhibits folate-dependent enzymes involved in pyrimidine and purine synthesis. Prior studies of genetic variation in these enzymes as predictors of pemetrexed efficacy have yielded inconsistent results. We investigated whether red blood cell (RBC) total folate, a phenotypic rather than genotypic marker of cellular folate status, was associated with response to pemetrexed-based chemotherapy in advanced non-squamous non-small-cell lung cancer (NSCLC). </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d14628696e207">Materials and methods</h5> <p id="P2">We conducted a prospective cohort study of patients with stage IV non-squamous NSCLC receiving first-line chemotherapy containing pemetrexed. Pretreatment RBC total folate was quantified using liquid chromatography/mass spectrometry. We then compared objective response rate (ORR) between patients with RBC total folate concentrations above and below an optimal cut-off value determined from the receiver operating characteristic (ROC) curve. A logistic regression model was used to adjust for age, sex, and use of bevacizumab. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d14628696e212">Results</h5> <p id="P3">The ORR was 62% (32 of 52 patients). ROC analysis was used to establish that a RBC total folate cutoff value of 364.6 nM optimally discriminated between pemetrexed responders and non-responders. Patients with RBC total folate below 364.5 nM had an ORR of 27%, compared to 71% in patients with RBC total folate above this value (p=0.01). This difference persisted after adjusting for age, sex, and use of bevacizumab (OR 0.07, 95% CI 0.01 - 0.57, p=0.01). </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d14628696e217">Conclusions</h5> <p id="P4">Low pretreatment RBC total folate is associated with inferior response to pemetrexed-based chemotherapy in stage IV non-squamous NSCLC. Larger, multicenter studies are needed to validate RBC total folate as a predictive marker of pemetrexed response. </p> </div>