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.
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.
复制标题
两种剂量培美曲塞作为局部晚期或转移性乳腺癌 (MBC) 一线化疗的随机 II 期研究：临床结果和探索性药物基因组分析。
作者：
A. Llombart;M. Martín;N. Harbeck;R. Anghel;A. Eniu;A. Melemed;R. Clark;L. Simms;C. Kaiser;D. Ma
3077背景：培美曲塞是一种叶酸类抗代谢药，在MBC中显示出不同的反应，取决于剂量、维生素补充和患者治疗前状态。我们在局部晚期或MBC患者中进行了一项随机、双盲、II期研究，以评价2种剂量的培美曲塞。主要目的是评估2组的缓解率。
方法
组织学/细胞学诊断为乳腺癌、有局部复发或远处转移证据、不适合局部治疗的女性入选。患者在21天周期的第1天接受培美曲塞治疗（A组600 mg/m2;或B组900 mg/m2）。所有患者均补充叶酸和维生素B12。每组计划43例患者。
结果
入组了92例患者（中位年龄57岁，范围33-81岁）：A组47例，B组45例。A组和B组的缓解率分别为17.0%（95% CI，7.7%-30.8%）和15.6%（95% CI，6.5%-29.5%），中位无进展生存期分别为4.2和4.1个月，中位肿瘤进展时间（TtTP）分别为4.2和4.6个月。在两组中，中位数为6个周期。毒性轻微（两组均为3/4级毒性;中性粒细胞减少症<20%，白细胞减少症<9%）。采用逆转录-聚合酶链反应方法检测49例原发性肿瘤组织中10个叶酸或嘧啶代谢相关基因的表达。两个标记，叶聚谷氨酸合成酶（FPGS）和胸苷磷酸化酶（TP），显示了显着的结果。高与低FPGS表达亚组的最佳缓解率和中位TtTP分别为37.5%与10.0%和8.6与3.0个月。TP的相应结果分别为27.6% vs 6.3%和5.4 vs 1.9个月。
结论
两种培美曲塞剂量的疗效和安全性相似;因此，较低剂量（600 mg/m2）适用于MBC患者。探索性生物标志物分析表明FPGS和TP的疗效相关性。对这些标记物的进一步评价似乎是必要的。[表：见正文]。
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].