Lerner Seth P, McConkey David J, Tangen Catherine M, Meeks Joshua J, Flaig Thomas W, Hua Xing, Daneshmand Siamak, Alva Ajjai Shivaram, Lucia M Scott, Theodorescu Dan, Goldkorn Amir, Milowsky Matthew I, Choi Woonyoung, Bangs Rick, Gustafson Daniel L, Plets Melissa, Thompson Ian M
Baylor College of Medicine, Houston, Texas.
Johns Hopkins School of Medicine, Baltimore, Maryland.
Clin Cancer Res. 2024 Jan 17;30(2):444-449. doi: 10.1158/1078-0432.CCR-23-0602.
The Coexpression Extrapolation (COXEN) gene expression model with chemotherapy-specific scores [for methotrexate, vinblastine, adriamycin, cisplatin (ddMVAC) and gemcitabine/cisplatin (GC)] was developed to identify responders to neoadjuvant chemotherapy (NAC). We investigated RNA-based molecular subtypes as additional predictive biomarkers for NAC response, progression-free survival (PFS), and overall survival (OS) in patients treated in S1314.
A total of 237 patients were randomized between four cycles of ddMVAC (51%) and GC (49%). On the basis of Affymetrix transcriptomic data, we determined subtypes using three classifiers: TCGA (k = 5), Consensus (k = 6), and MD Anderson (MDA; k = 3) and assessed subtype association with path response to NAC and determined associations with COXEN. We also tested whether each classifier contributed additional predictive power when added to a model based on predefined stratification (strat) factors (PS 0 vs. 1; T2 vs. T3, T4a).
A total of 155 patients had gene expression results, received at least three of four cycles of NAC, and had pT-N response based on radical cystectomy. TCGA three-group classifier basal-squamous (BS)/neuronal, luminal (Lum), Lum infiltrated, and GC COXEN score yielded the largest AUCs for pT0 (0.59, P = 0.28; 0.60, P = 0.18, respectively). For downstaging (<pT2), the three-category Consensus classifier [BS/neuroendocrine (NE)-like, Lum, stroma-rich] increased the AUC from 0.57 (strat factors alone) to 0.61 (P = 0.10). The MDA classifier AUC was 0.63 (P = 0.18) and the GC COXEN score AUC was 0.62 (P = 0.23), but neither significantly improved the AUC. There was no statistically significant association of stratification factors and subtypes with PFS or OS.
The Consensus classifier, based in part on the TCGA and MDA classifiers, modestly improved prediction for pathologic downstaging but subtypes were not associated with PFS or OS.
开发具有化疗特异性评分（针对甲氨蝶呤、长春碱、阿霉素、顺铂（ddMVAC）和吉西他滨/顺铂（GC））的共表达外推法（COXEN）基因表达模型，以识别新辅助化疗（NAC）的反应者。我们研究了基于RNA的分子亚型，作为S1314研究中患者NAC反应、无进展生存期（PFS）和总生存期（OS）的额外预测生物标志物。
总共237例患者被随机分配接受四个周期的ddMVAC（51%）或GC（49%）治疗。基于Affymetrix转录组数据，我们使用三种分类器确定亚型：TCGA（k = 5）、共识分类器（k = 6）和MD安德森癌症中心（MDA；k = 3），并评估亚型与NAC病理反应的相关性以及与COXEN的相关性。我们还测试了在基于预定义分层（strat）因素（PS 0 vs. 1；T2 vs. T3、T4a）的模型中加入每个分类器时是否能提供额外的预测能力。
总共155例患者有基因表达结果，接受了至少四个周期NAC中的三个周期治疗，并根据根治性膀胱切除术有pT - N反应。TCGA三组分类器的基底 - 鳞状（BS）/神经元型、管腔型（Lum）、Lum浸润型以及GC的COXEN评分在预测pT0时获得了最大的曲线下面积（AUC）（分别为0.59，P = 0.28；0.60，P = 0.18）。对于降期（<pT2），三类共识分类器[BS/神经内分泌（NE）样、Lum、富含基质型]将AUC从0.57（仅分层因素）提高到0.61（P = 0.10）。MDA分类器的AUC为0.63（P = 0.18），GC的COXEN评分AUC为0.62（P = 0.23），但两者均未显著提高AUC。分层因素和亚型与PFS或OS之间无统计学显著相关性。
部分基于TCGA和MDA分类器的共识分类器适度改善了对病理降期的预测，但亚型与PFS或OS无关。
