Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Decipher Biosciences Inc., Vancouver, British Columbia.
J Urol. 2020 Aug;204(2):239-246. doi: 10.1097/JU.0000000000000798. Epub 2020 Feb 14.
Urothelial carcinoma of the luminal molecular subtype is associated with lower rates of pathological up staging from clinical stage T1-T2 to nonorgan confined (pT3 or greater and/or pN+) disease at radical cystectomy. However, approximately a third of luminal urothelial carcinoma cases were up staged to nonorgan confined disease, and these may be under treated if neoadjuvant chemotherapy is withheld. In this study we trained a genomic classifier to predict luminal nonorgan confined disease in patients diagnosed with clinically organ confined (cT1/T2) disease.
Specimens from transurethral resected high grade cT1-T2N0M0 urothelial carcinoma of the bladder that belonged to the luminal subtype (Seiler 2017) were randomly split into training (75) and testing (25) sets for the development of a single sample luminal up staging classifier using lasso/ridge-penalized logistic regression. All patients underwent radical cystectomy without neoadjuvant chemotherapy and the primary end point was up staging to nonorgan confined disease. A radical cystectomy cohort and a platinum treated neoadjuvant chemotherapy cohort were used to evaluate the luminal up staging classifier.
Up staging to nonorgan confined disease occurred in 34% of luminal cases. The luminal up staging classifier predicted up staging in 32 of 34 cases, with 6 false-positives (AUC 0.96). The sensitivity for detection of luminal pN+ disease was 95% (20 of 21). Patients with predicted nonorgan confined luminal tumors had worse survival than those with organ confined luminal tumors (p=0.001). On multivariable analysis the luminal up staging classifier was a significant predictor of overall survival after adjusting for clinical variables available at transurethral resection. The luminal up staging classifier also predicted overall survival for aggressive luminal TCGA (The Cancer Genome Atlas) cases (n=83, p=0.043). In the neoadjuvant chemotherapy cohort the luminal up staging classifier predicted 9 up staging cases, all of which had excellent prognosis.
A luminal up staging classifier was developed that distinguishes a subset of cT1-T2N0M0 luminal urothelial carcinoma cases at high risk for up staging to nonorgan confined disease at radical cystectomy and of death. Validation of this model in an independent, large patient cohort is necessary to determine how molecular stratification of luminal tumors could be used to guide treatment of these patients.
腔面分子亚型的尿路上皮癌与从临床 T1-T2 期到非局限性（pT3 或更高和/或 pN+）疾病的病理分期升高率较低相关。然而，大约三分之一的腔面尿路上皮癌病例被分期为非局限性疾病，如果不使用新辅助化疗，这些病例可能治疗不足。在这项研究中，我们训练了一个基因组分类器，以预测临床局限性（cT1/T2）疾病患者的腔面非局限性疾病。
从经尿道切除的高级别 cT1-T2N0M0 膀胱尿路上皮癌的腔面亚型（Seiler 2017）标本中随机分为训练（75）和测试（25）集，用于开发使用lasso/岭惩罚逻辑回归的单一样本腔面分期升高分类器。所有患者均接受根治性膀胱切除术且无新辅助化疗，主要终点是分期升高至非局限性疾病。使用根治性膀胱切除术队列和铂类治疗新辅助化疗队列评估腔面分期升高分类器。
腔面病例中有 34%分期升高至非局限性疾病。腔面分期升高分类器预测了 34 例中的 32 例，假阳性 6 例（AUC 0.96）。预测的腔面 pN+疾病的敏感性为 95%（21 例中的 20 例）。预测为非局限性腔面肿瘤的患者的生存状况比局限性腔面肿瘤的患者差（p=0.001）。多变量分析显示，在调整经尿道切除时可用的临床变量后，腔面分期升高分类器是总生存的显著预测因子。腔面分期升高分类器还预测了侵袭性 TCGA（癌症基因组图谱）病例的总生存（n=83，p=0.043）。在新辅助化疗队列中，腔面分期升高分类器预测了 9 例分期升高的病例，所有这些病例的预后均良好。
开发了一种腔面分期升高分类器，可区分在根治性膀胱切除术中高风险分期升高至非局限性疾病和死亡的 cT1-T2N0M0 腔面尿路上皮癌病例亚组。在独立的大型患者队列中验证该模型对于确定如何对腔面肿瘤进行分子分层以指导这些患者的治疗是必要的。
