O'Donnell Peter H, Alanee Shaheen, Stratton Kelly L, Garcia-Grossman Ilana R, Cao Hongyuan, Ostrovnaya Irina, Plimack Elizabeth R, Manschreck Christopher, Ganshert Cory, Smith Norm D, Steinberg Gary D, Vijai Joseph, Offit Kenneth, Stadler Walter M, Bajorin Dean F
The University of Chicago, Chicago, IL.
Memorial Sloan Kettering Cancer Center, New York, NY.
Clin Genitourin Cancer. 2016 Dec;14(6):511-517. doi: 10.1016/j.clgc.2016.03.006. Epub 2016 Mar 10.
Level 1 evidence has demonstrated increased overall survival with cisplatin-based neoadjuvant chemotherapy for patients with muscle-invasive urothelial cancer. Usage remains low, however, in part because neoadjuvant chemotherapy will not be effective for every patient. To identify the patients most likely to benefit, we evaluated germline pharmacogenomic markers for association with neoadjuvant chemotherapy sensitivity in 2 large cohorts of patients with urothelial cancer.
Patients receiving neoadjuvant cisplatin-based chemotherapy for muscle-invasive urothelial cancer were eligible. Nine germline single nucleotide polymorphisms (SNPs) potentially conferring platinum sensitivity were tested for an association with a complete pathologic response to neoadjuvant chemotherapy (pT0) or elimination of muscle-invasive cancer (<pT2).
The data from 205 patients were analyzed-59 patients were included in the discovery set and 146 in an independent replication cohort-from 3 institutions. The stage pT0 (26%) and < pT2 (50%) rates were consistent across the discovery and replication populations. Using a multivariate recessive genetic model, rs244898 in RARS (odds ratio, 6.8; 95% confidence interval, 1.8-28.9; P = .006) and rs7937567 in GALNTL4 (odds ratio, 4.8; 95% confidence interval, 1.1-22.6; P = .04) were associated with pT0 in the discovery set. Despite these large effects, neither were associated with achievement of pT0 in the replication set. A third SNP, rs10964552, was associated with stage < pT2 in the discovery set but also failed to replicate.
Germline SNPs previously associated with platinum sensitivity were not associated with the neoadjuvant chemotherapy response in a large replication cohort of patients with urothelial cancer. These results emphasize the need for replication when evaluating pharmacogenomic markers and demonstrate that multi-institutional efforts are feasible and will be necessary to achieve advances in urothelial cancer pharmacogenomics.
一级证据表明，对于肌层浸润性尿路上皮癌患者，基于顺铂的新辅助化疗可提高总生存率。然而，其使用率仍然较低，部分原因是新辅助化疗并非对每个患者都有效。为了确定最可能受益的患者，我们在2个大型尿路上皮癌患者队列中评估了种系药物基因组标记与新辅助化疗敏感性的相关性。
接受基于顺铂的新辅助化疗的肌层浸润性尿路上皮癌患者符合条件。对9个可能赋予铂敏感性的种系单核苷酸多态性（SNP）进行检测，以确定其与新辅助化疗完全病理缓解（pT0）或消除肌层浸润性癌（<pT2）的相关性。
分析了来自3家机构的205例患者的数据，其中59例纳入发现集，146例纳入独立验证队列。发现集和验证队列中的pT0期（26%）和<pT2期（50%）发生率一致。使用多变量隐性遗传模型，发现集中RARS基因的rs244898（比值比，6.8；95%置信区间，1.8 - 28.9；P = .006）和GALNTL4基因的rs7937567（比值比，4.8；95%置信区间，1.1 - 22.6；P = .04）与pT0相关。尽管有这些显著影响，但在验证集中两者均与达到pT0无关。第三个SNP，rs10964552，在发现集中与<pT2期相关，但也未能得到验证。
在一个大型尿路上皮癌患者验证队列中，先前与铂敏感性相关的种系SNP与新辅助化疗反应无关。这些结果强调了评估药物基因组标记时进行验证的必要性，并表明多机构合作是可行的，对于实现尿路上皮癌药物基因组学的进展将是必要的。
