Department of Oncology, National University Hospital of Copenhagen, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark.
Cancer Chemother Pharmacol. 2012 Nov;70(5):743-54. doi: 10.1007/s00280-012-1965-0. Epub 2012 Sep 8.
Malignant pleural mesothelioma (MPM) has a dismal prognosis. Treatment results may be improved by biomarker-directed therapy. We investigated the baseline expression and impact on outcome of predictive biomarkers ERCC1, BRCA1, and class III β-tubulin in a cohort of MPM patients treated with cisplatin-vinorelbine. We further explored the possibility of combining markers into a treatment-response profile to increase the predictive power.
Formalin-fixed paraffin-embedded tumor specimens from 54 MPM patients included in a phase II trial were evaluated for ERCC1, BRCA1, and class III β-tubulin by immunohistochemistry (IHC). Immunostaining was quantified by an H-score and dichotomized according to upper quartile values. The ERCC1- and class III β-tubulin-status classified patients as treatment resistant (ERCC1 positive + class III β-tubulin positive) or treatment responsive (ERCC1 negative + class III β-tubulin negative). The remaining marker combinations were considered inconclusive.
Fifty patients had tumor tissue available for IHC. Eleven had a responsive profile, and nine had a resistant profile. Thirty patients had an inconclusive profile. Median progression-free survival (PFS) was 6.7 months in the treatment-resistant group, 15.3 months in the treatment-responsive group, and 8.1 months in the inconclusive group (log-rank p = 0.03). Multivariate analysis revealed that treatment-resistant patients had a decreased PFS and overall survival (OS) compared with the treatment-responsive patients (HR 6.45, CI 95 % [2.02-20.64] p = 0.002 and HR 4.64, CI 95 % [1.56-13.79], p = 0.006, respectively). BRCA1 status was associated with neither PFS nor OS.
Combined negative ERCC1 and class III β-tubulin immunostaining is associated with significantly prolonged PFS and OS in MPM patients receiving cisplatin-vinorelbine therapy.
恶性胸膜间皮瘤（MPM）预后不良。通过生物标志物指导的治疗，可能会改善治疗结果。我们研究了在接受顺铂-长春瑞滨治疗的 MPM 患者队列中，预测生物标志物 ERCC1、BRCA1 和 III 类 β-微管蛋白的基线表达及其对结果的影响。我们进一步探索了将标志物组合成治疗反应谱以提高预测能力的可能性。
对 54 名参与 II 期临床试验的 MPM 患者的福尔马林固定石蜡包埋肿瘤标本进行 ERCC1、BRCA1 和 III 类 β-微管蛋白的免疫组织化学（IHC）检测。免疫染色通过 H 评分进行量化，并根据上四分位数值进行二分类。根据 ERCC1 状态和 III 类 β-微管蛋白状态将患者分为治疗抵抗（ERCC1 阳性+III 类 β-微管蛋白阳性）或治疗敏感（ERCC1 阴性+III 类 β-微管蛋白阴性）。其余的标志物组合被认为是不确定的。
50 名患者有肿瘤组织进行 IHC。11 名患者具有反应性特征，9 名患者具有抵抗性特征。30 名患者的特征不确定。治疗抵抗组的中位无进展生存期（PFS）为 6.7 个月，治疗敏感组为 15.3 个月，不确定组为 8.1 个月（对数秩检验 p=0.03）。多变量分析显示，与治疗敏感组相比，治疗抵抗组的 PFS 和总生存期（OS）降低（HR 6.45，95%CI [2.02-20.64]，p=0.002 和 HR 4.64，95%CI [1.56-13.79]，p=0.006）。BRCA1 状态与 PFS 或 OS 均无关。
在接受顺铂-长春瑞滨治疗的 MPM 患者中，联合阴性 ERCC1 和 III 类 β-微管蛋白免疫染色与 PFS 和 OS 显著延长相关。
