Metzger R, Leichman C G, Danenberg K D, Danenberg P V, Lenz H J, Hayashi K, Groshen S, Salonga D, Cohen H, Laine L, Crookes P, Silberman H, Baranda J, Konda B, Leichman L
University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.
J Clin Oncol. 1998 Jan;16(1):309-16. doi: 10.1200/JCO.1998.16.1.309.
We have previously shown that relative thymidylate synthase (TS) mRNA levels in primary gastric adenocarcinomas treated with fluorouracil (5-FU) and cisplatin are inversely associated with response and survival. This is a presumed function of TS as a target for 5-FU activity. We now test the hypotheses that the relative mRNA level of the excision repair cross-complementing (ERCC1) gene is inversely associated with response and survival as an independent function of cisplatin efficacy.
Patients had intact, untreated, primary gastric adenocarcinoma cancer and were evaluated for eligibility on a preoperative cisplatin infusion-5-FU protocol. cDNA, derived from primary gastric tumors before chemotherapy, was used to determine ERCC1 mRNA levels, expressed as the ratio of polymerase chain reaction (PCR) product of the ERCC1 gene and the beta-actin gene.
The median ERCC1 mRNA level from 38 primary gastric cancers (33 assessable for response) was 5.8 x 10(-3) (range, 1.8 x 10(-3) to 19.5 x 10(-3)). Of 17 responding patients, 13 (76%) were less than or equal to 5.8 x 10(-3) and four were greater than 5.8 x 10(-3) (P = .003). The median survival for patients with ERCC1 mRNA levels less than or equal to 5.8 x 10(-3) has not been reached, whereas for those greater than 5.8 x 10(-3) it was 5.4 months (P = .034). The median TS mRNA level, 3.7 x 10(-3) (range, 0.9 to 18.9) also segregated responsive versus resistant tumors (P = .024). With both ERCC1 and TS mRNA levels below their medians, 11 of 13 patients (85%) responded; with both ERCC1 and TS mRNA levels above their medians, two of 10 patients (20%) responded (P = .003).
Considered separately, either ERCC1 or TS mRNA levels in a primary gastric adenocarcinoma has a statistically significant relationship to response. ERCC1 mRNA levels have a statistically significant association with survival; in this cohort TS mRNA levels did not reach statistically significant association with survival as in our previous publication. Whether these molecular parameters are independent of each other as predictors of outcome remains to be determined.
我们之前已经表明，接受氟尿嘧啶（5-FU）和顺铂治疗的原发性胃腺癌中，相对胸苷酸合成酶（TS）mRNA水平与反应和生存率呈负相关。这被认为是TS作为5-FU活性靶点的一种功能。我们现在检验以下假设：切除修复交叉互补（ERCC1）基因的相对mRNA水平作为顺铂疗效的独立功能，与反应和生存率呈负相关。
患者患有完整的、未经治疗的原发性胃癌，并根据术前顺铂输注-5-FU方案评估其 eligibility。化疗前从原发性胃肿瘤中提取的cDNA用于测定ERCC1 mRNA水平，以ERCC1基因与β-肌动蛋白基因的聚合酶链反应（PCR）产物的比值表示。
38例原发性胃癌（33例可评估反应）的ERCC1 mRNA水平中位数为5.8×10⁻³（范围为1.8×10⁻³至19.5×10⁻³）。在17例有反应的患者中，13例（76%）小于或等于5.8×10⁻³，4例大于5.8×10⁻³（P = 0.003）。ERCC1 mRNA水平小于或等于5.8×10⁻³的患者的中位生存期尚未达到，而大于5.8×10⁻³的患者为5.4个月（P = 0.034）。TS mRNA水平中位数为3.7×10⁻³（范围为0.9至18.9），也区分了反应性肿瘤和耐药性肿瘤（P = 0.024）。当ERCC1和TS mRNA水平均低于中位数时，13例患者中有11例（85%）有反应；当ERCC1和TS mRNA水平均高于中位数时，10例患者中有2例（20%）有反应（P = 0.003）。
单独考虑，原发性胃腺癌中的ERCC1或TS mRNA水平与反应均有统计学上的显著关系。ERCC mRNA水平与生存率有统计学上的显著关联；在这个队列中，TS mRNA水平与生存率没有达到如我们之前发表的那样有统计学上的显著关联。这些分子参数作为结果的预测指标是否相互独立仍有待确定。
