A phase II trial of pemetrexed in advanced breast cancer: Clinical response and association with molecular target expression

Purpose: This phase II trial of pernetrexed explored potential correlations between treatment outcome (antitumor activity) and molecular target expression. Experimental Design: Chemonaive patients with advanced breast cancer received up to three cycles of pernetrexed 500 mg/m(2) (10-minute i.v. infusion) on day 1 of a 21-day cycle, with folic acid and vitamin B-12 supplementation. Tumors were surgically removed after the last cycle of pernetrexed as clinically indicated. Biopsies were taken at baseline, 24 hours after infusion in cycle 1, and after cycle 3. Results: Sixty-one women (median age, 46 years; range, 32-72 years) were treated and were evaluable for response. Objective response rate was 31%. Simple logistic regression suggested a potential relationship between mRNA expression of thymidylate synthase (TS) and pemetrexed response (P = 0.103). Based on threshold analysis, patients with "low" baseline TS (<= 71) were more likely to respond to pernetrexed than patients with "high" baselineTS (>71). Expression of baseline dihydrofolate reductase and glycinamide ribonucleotide formyl transferase tended to be higher in responders but this association was not significant (P > 0.311). TS expression increased significantly between baseline and biopsy 2 (P = 0.004) and dropped to near baseline levels at biopsy 3. Conversely, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase decreased after pernetrexed chemotherapy. Conclusions: Our results suggest a potential association between "low" pretreatment TS expression levels and response to pernetrexed chemotherapy. Future trials examining expression levels of other genes important to the folate pathway and/or breast cancer may identify a more robust multigene profile that can better predict response to this novel antifolate.