Concordant gene expression signatures predict clinical outcomes of cancer patients undergoing systemic therapy.
Concordant gene expression signatures predict clinical outcomes of cancer patients undergoing systemic therapy.
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DOI：
10.1158/0008-5472.can-09-0798
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发表时间：
2009-11-01
期刊：
影响因子：
11.2
通讯作者：
Lee JK
中科院分区：
文献类型：
--
作者：
Williams PD;Cheon S;Havaleshko DM;Jeong H;Cheng F;Theodorescu D;Lee JK
预测癌症患者治疗反应的多基因表达模型（GEM）的传统开发是基于对接受特定方案治疗的患者的分析，这限制了对不同或新型药物组合的推广。我们通过基于体外药物敏感性和 NCI-60 癌细胞系组的微阵列分析开发 GEM，克服了这一限制。在七个独立队列中，以盲法方式评估这些 GEM 作为肿瘤反应和/或患者生存的预测因子，这些患者接受多药化疗治疗乳腺癌 (N=275)、膀胱癌 (N=59) 和卵巢癌 (N=143)，其中 233 名患者来自前瞻性临床试验。在所有研究中，GEM 有效地对肿瘤反应和患者生存进行了分层，独立于已确定的临床和病理肿瘤变量。在接受新辅助 MVAC（甲氨蝶呤、长春花碱、阿霉素、顺铂）治疗的膀胱癌患者中，GEM 评分良好的患者的 3 年总生存率为 81%，而评分较差的患者的 3 年总生存率为 33% (p=0.002)。使用 FAC（氟尿嘧啶、阿霉素、环磷酰胺）治疗的乳腺癌患者和使用含铂方案治疗的卵巢癌患者的 GEM 也对患者生存进行了分层（5 年总生存率分别为 100% vs. 74% (p=0.05) 和 3 年总生存率 68% vs. 43% (p=0.008)。重要的是，使用我们的体外 GEM 进行的临床预测优于我们展示了一种简单而有效的 GEM 衍生方法，可以识别最有可能从选定的多药治疗中受益的患者，使用这种基于体外的 GEM 可以为个性化癌症治疗提供一种稳健且通用的方法。
Conventional development of multi-gene expression models (GEMs) predicting therapeutic response of cancer patients are based on analysis of patients treated with specific regimens, which limits generalization to different or novel drug combinations. We overcome this limitation by developing GEMs based on in vitro drug sensitivities and microarray analyses of the NCI-60 cancer cell line panel. These GEMs were evaluated in blind fashion as predictors of tumor response and/or patient survival in seven independent cohorts of patients with breast (N=275), bladder (N=59), and ovarian (N=143) cancer treated with multi-agent chemotherapy, of which 233 patients were from prospectively-enrolled clinical trials. In all studies, GEMs effectively stratified tumor response and patient survival independent of established clinical and pathologic tumor variables. In bladder cancer patients treated with neoadjuvant MVAC (Methotrexate, Vinblastine, Doxorubicin, Cisplatin), the 3-year overall survival for those with favorable GEM scores was 81% vs. 33% for those with less favorable scores (p=0.002). GEMs for breast cancer patients treated with FAC (Fluorouracil, Doxorubicin, Cyclophosphamide) and ovarian cancer patients treated with platinum-containing regimens also stratified patient survival (5-year overall survival 100% vs. 74% (p=0.05) and 3-year overall survival 68% vs. 43% (p=0.008), respectively. Importantly, clinical prediction using our in vitro GEM was superior to that of conventionally-derived GEMs. We demonstrate a facile yet effective approach to GEM derivation that identifies patients most likely to benefit from selected multi-agent therapy. Use of such in vitro-based GEMs may provide a robust and generalizable approach to personalized cancer therapy.