Randomized, phase II study of two doses of pemetrexed as first-line chemotherapy for locally advanced or metastatic breast cancer (MBC): Clinical results and exploratory pharmacogenomic analysis

Abstract

3077 Background: Pemetrexed, a folate antimetabolite, has shown varied response in MBC, depending on the dose, vitamin supplementation, and patient pre-treatment status. We conducted a randomized, double-blind, phase II study, in patients with locally advanced or MBC to evaluate 2 doses of pemetrexed. Primary objective was to assess the response rates on the 2 arms. Methods: Women with histologic/cytologic diagnosis of breast cancer, evidence of locally recurrent disease or distant metastasis, not amenable to local therapy were eligible. Patients received pemetrexed (600 mg/m2 Arm A; or 900 mg/m2 Arm B), on D1 of a 21-day cycle. All patients received folic acid and vitamin B12 supplementation. Forty-three patients were planned on each arm. Results: Ninety-two patients (median age 57 years, range 33–81) enrolled: 47 on arm A and 45 on arm B. Arms A and B had response rates of 17.0% (95% CI, 7.7%-30.8%), and 15.6% (95% CI, 6.5%-29.5%), median progression free survival times of 4.2 and 4.1 months, and median times to tumor progression (TtTP) of 4.2 and 4.6 months, respectively. On both arms, a median of 6 cycles was delivered. Toxicity was mild (grade 3/4 toxicity on both arms; neutropenia <20%, leucopenia <9%). Primary tumor samples from 49 patients were assessed for 10 folate or pyrimidine metabolism related gene expressions by reverse transcriptase-polymerase chain reaction methodology. Two markers, folypolyglutamate synthase (FPGS) and thymidine phosphorylase (TP), showed significant results. Best response rates and median TtTP for high vs low FPGS expression subgroups were 37.5% vs 10.0% and 8.6 vs 3.0 months. The corresponding results for TP were 27.6% vs 6.3% and 5.4 vs 1.9 months. Conclusions: Efficacy and safety of the two pemetrexed doses were similar; thus, the lower dose (600 mg/m2) is suitable in patients with MBC. Exploratory biomarker analysis suggests efficacy correlation for FPGS and TP. Further evaluation of these markers appears warranted. [Table: see text]