Llombart-Cussac Antonio, Martin Miguel, Harbeck Nadia, Anghel Rodica M, Eniu Alexandra E, Verrill Mark W, Neven Patrick, De Grève Jacques, Melemed Allen S, Clark Romnee, Simms Lorinda, Kaiser Christopher J, Ma Doreen
Hospital Universitario Arnau Vilanova, Lleida, Spain.
Clin Cancer Res. 2007 Jun 15;13(12):3652-9. doi: 10.1158/1078-0432.CCR-06-2377.
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.
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.
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).
The two pemetrexed doses yielded similar efficacy and safety profiles. Exploratory biomarker analysis identified efficacy and toxicity correlations and warrants further evaluation.
培美曲塞在晚期乳腺癌中显示出不同的缓解率。本随机、双盲、II期研究旨在评估两种剂量培美曲塞在同质人群中的疗效和安全性。次要目的是确定与缓解和毒性相关的分子生物标志物。
新诊断的转移性乳腺癌或局部复发性乳腺癌患者在21天周期的第1天接受600mg/m²（P600组）或900mg/m²（P900组）的培美曲塞治疗。所有患者均接受叶酸和维生素B12补充。
P600组（47例患者）和P900组（45例患者）的缓解率分别为17.0%（95%置信区间，7.7 - 30.8%）和15.6%（95%置信区间，6.5 - 29.5%），每组约50%为疾病稳定，无进展生存期的中位数分别为4.2个月和4.1个月，肿瘤进展时间的中位数分别为4.2个月和4.6个月。两组均表现出最小毒性（3/4级中性粒细胞减少<20%，白细胞减少<9%，其他毒性<5%）。对49例患者的肿瘤样本评估了12个与培美曲塞相关基因的表达水平。叶酰聚谷氨酸合成酶和胸苷磷酸化酶与疗效相关。胸苷磷酸化酶高表达与低表达的最佳缓解率和肿瘤进展时间中位数分别为27.6%对6.3%（P = 0.023）和5.4对1.9个月（P = 0.076），叶酰聚谷氨酸合成酶分别为37.5%对10.0%（P = 0.115）和8.6对3.个月（P = 0.019）。γ-谷氨酰水解酶表达与3/4级毒性相关：高γ-谷氨酰水解酶表达为78.6%，低表达为27.3%（P = 0.024）。
两种培美曲塞剂量产生相似的疗效和安全性。探索性生物标志物分析确定了疗效和毒性的相关性，值得进一步评估。
