Weberpals Johanne, Garbuio Kyla, O'Brien Anna, Clark-Knowles Katherine, Doucette Steve, Antoniouk Olga, Goss Glenwood, Dimitroulakos Jim
Division of Gynaecologic Oncology, The Ottawa Hospital, Ottawa, Ontario, Canada.
Int J Cancer. 2009 Feb 15;124(4):806-15. doi: 10.1002/ijc.23987.
This study compares Breast Cancer 1 (BRCA1) and excision repair cross complementation group 1 (ERCC1) expression as predictive markers and evaluates the in vitro enhancement of platinum sensitivity using targeted agents in sporadic ovarian cancer (OC). A retrospective study was performed of advanced stage OC patients receiving platinum-based chemotherapy. BRCA1 and ERCC1 mRNA expression was determined from frozen tissue of 51 patients. Median overall survival (OS) was longer for patients with lower BRCA1 vs. higher BRCA1 (46 vs.33 months, p = 0.03). High BRCA1 was predictive of poorer OS specifically in patients with residual disease (RD) <2 cm (p = 0.03). There was a non-significant association for patients with lower ERCC1 and RD <2 cm in favor of improved OS and time to progression. Patients who expressed higher levels of both BRCA1 and ERCC1 mRNA had a shorter OS compared to patients with lower levels of either or both transcript (33 vs.46 months, p = 0.04). When Cox proportional modeling was used by representing BRCA1 and ERCC1 mRNA expression as a continuous variable, both emerge as potential predictors of survival. OC cell lines were exposed to chemotherapy in combination with DNA repair pathway inhibitors and cell viability was assessed. In vitro histone deacetylase (HDAC) inhibition increased the sensitivity of A2780s/cp cells to cisplatin and carboplatin but not to taxol, coincident with a significant decrease in BRCA1 and ERCC1 expression, suggesting that this compound directly targets DNA repair. In summary, this study shows that low BRCA1 and ERCC1 expression correlate with improved survival in advanced OC and HDAC inhibition induces synergistic cytotoxicity with platinum in vitro.
本研究比较了乳腺癌1（BRCA1）和切除修复交叉互补组1（ERCC1）的表达作为预测标志物，并评估了在散发性卵巢癌（OC）中使用靶向药物体外增强铂敏感性的情况。对接受铂类化疗的晚期OC患者进行了一项回顾性研究。从51例患者的冷冻组织中测定BRCA1和ERCC1 mRNA表达。BRCA1水平较低的患者与较高的患者相比，中位总生存期（OS）更长（46个月对33个月，p = 0.03）。高BRCA1尤其在残留病灶（RD）<2 cm的患者中预测OS较差（p = 0.03）。ERCC1水平较低且RD<2 cm的患者与改善的OS和疾病进展时间之间存在非显著关联。与两种转录本水平较低的患者相比，同时表达较高水平BRCA1和ERCC1 mRNA的患者OS较短（33个月对46个月，p = 0.04）。当将BRCA1和ERCC1 mRNA表达作为连续变量使用Cox比例模型时，两者均成为生存的潜在预测指标。将OC细胞系暴露于化疗联合DNA修复途径抑制剂，并评估细胞活力。体外组蛋白去乙酰化酶（HDAC）抑制增加了A2780s/cp细胞对顺铂和卡铂的敏感性，但对紫杉醇不敏感，同时BRCA1和ERCC1表达显著降低，表明该化合物直接靶向DNA修复。总之，本研究表明低BRCA1和ERCC1表达与晚期OC患者生存率提高相关，且HDAC抑制在体外可诱导与铂的协同细胞毒性。
