A randomized, double-blind, phase II study of two doses of pemetrexed as first-line chemotherapy for advanced breast cancer.
OBJECTIVE
Pemetrexed has shown varied response rates in advanced breast cancer. This randomized, double-blind, phase II study was conducted to assess the efficacy and safety of two doses of pemetrexed in a homogeneous population. A secondary objective was to identify molecular biomarkers correlating with response and toxicity.


METHODS
Patients with newly diagnosed metastatic breast cancer or locally recurrent breast cancer received 600 mg/m(2) (P600 arm) or 900 mg/m(2) (P900 arm) of pemetrexed on day 1 of a 21-day cycle. All patients received folic acid and vitamin B(12) supplementation.


RESULTS
The P600 (47 patients) and P900 (45 patients) arms had response rates of 17.0% (95% confidence interval, 7.7-30.8%) and 15.6% (95% confidence interval, 6.5-29.5%) with approximately 50% stable disease per arm, median progression-free survival of 4.2 and 4.1 months, and median times to tumor progression of 4.2 and 4.6 months, respectively. Both arms exhibited minimal toxicity (grade 3/4 neutropenia <20%, leukopenia <9%, and other toxicities <5%). Tumor samples from 49 patients were assessed for the expression levels of 12 pemetrexed-related genes. Folylpolyglutamate synthetase and thymidine phosphorylase correlated with efficacy. Best response rates and median time to tumor progression for high versus low thymidine phosphorylase expression were 27.6% versus 6.3% (P = 0.023) and 5.4 versus 1.9 months (P = 0.076), and for folylpolyglutamate synthetase were 37.5% versus 10.0% (P = 0.115) and 8.6 versus 3.0 months (P = 0.019), respectively. gamma-Glutamyl hydrolase expression correlated with grade 3/4 toxicities: 78.6% for high versus 27.3% for low gamma-glutamyl hydrolase (P = 0.024).


CONCLUSIONS
The two pemetrexed doses yielded similar efficacy and safety profiles. Exploratory biomarker analysis identified efficacy and toxicity correlations and warrants further evaluation.
Llombart-Cussac
Antonio
A
Hospital Universitario Arnau Vilanova, Lleida, Spain. allombart@arnau.scs.es
Martin
Miguel
M
Harbeck
Nadia
N
Anghel
Rodica M
RM
Eniu
Alexandra E
AE
Verrill
Mark W
MW
Neven
Patrick
P
De Grève
Jacques
J
Melemed
Allen S
AS
Clark
Romnee
R
Simms
Lorinda
L
Kaiser
Christopher J
CJ
Ma
Doreen
D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy*; D019587:Dietary Supplements; D004311:Double-Blind Method; D005260:Female; D005492:Folic Acid; D015870:Gene Expression / Q000187:drug effects; D005971:Glutamates / Q000008:administration & dosage* / Q000009:adverse effects; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D006801:Humans; D008875:Middle Aged; D000068437:Pemetrexed; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014805:Vitamin B 12
D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D005971:Glutamates; D012333:RNA, Messenger; D000068437:Pemetrexed; D006147:Guanine; D005492:Folic Acid; D014805:Vitamin B 12