Circulating tumor cells detection has independent prognostic impact in high-risk non-muscle invasive bladder cancer

Abstract

High-risk non-muscle invasive bladder cancer (NMIBC) progresses to metastatic disease in 10-15% of cases, suggesting that micrometastases may be present at first diagnosis. The prediction of risks of progression relies upon EORTC scoring systems, based on clinical and pathological parameters, which do not accurately identify which patients will progress. Aim of the study was to investigate whether the presence of CTC may improve prognostication in a large population of patients with Stage I bladder cancer who were all candidate to conservative surgery. A prospective single center trial was designed to correlate the presence of CTC to local recurrence and progression of disease in high-risk T1G3 bladder cancer. One hundred two patients were found eligible, all candidate to transurethral resection of the tumor followed by endovesical adjuvant immunotherapy with BCG. Median follow-up was 24.3 months (minimum-maximum: 4-36). The FDA-approved CellSearch System was used to enumerate CTC. Kaplan-Meier methods, log-rank test and multivariable Cox proportional hazard analysis was applied to establish the association of circulating tumor cells with time to first recurrence (TFR) and progression-free survival. CTC were detected in 20% of patients and predicted both decreased TFR (log-rank p < 0.001; multivariable adjusted hazard ratio [HR] 2.92 [95% confidence interval: 1.38-6.18], p 5 0.005), and time to progression (log-rank p < 0.001; HR 7.17 [1.89-27.21], p 5 0.004). The present findings provide evidence that CTC analyses can identify patients with Stage I bladder cancer who have already a systemic disease at diagnosis and might, therefore, potentially benefit from systemic treatment.High-risk, non-muscle invasive bladder cancer (NMIBC) is defined as any transitional cell carcinoma (TCC) of the bladder that is high-grade, whether it is primary or recurrent. This high-risk group includes patients with high-grade papillary Stage Ta or T1 tumors and any patient with carcinoma in situ (CIS). 1 Following transurethral resection bladder (TURB) of the initial tumor with no additional therapy, there is a recurrence rate of 50-70% and a progression rate of 25-50%, leading to cancer death after bladder-sparing treatment within 5 years in about 16-23% of cases. 2 To date, the European Organization for Research and Treatment of Cancer (EORTC) risk tables is the best-established predictive tools to help decision making for patients with NMIBC. These tables group patients by risk (low, intermediate and high) with the sums of factors (number of tumors, tumor size, prior recurrence rate, T category, presence of CIS and grade) to enable easy prediction of the recurrence and progression of NMIBC. 3 CUETO tables were developed with a similar structure to the EORTC tables but were adapted for patients treated with Bacillus Calmette Guerin (BCG). 4 Nevertheless, recent studies underline that both EORTC and CUETO risk tables have a low positive predictive value (PPV), thus not able to identify patients with higher risk to progress. 5 Circ...

Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy

“…Promising studies demonstrating signifi cant correlations between CTC counts and metastatic relapse have been observed in other tumor entities, such as colorectal cancer ( 8 ), bladder cancer ( 45,46 ), liver cancer ( 47 ), and esophageal cancer ( 48 ). Taken together, larger cohorts need to be analyzed using more sensitive CTC assays to further explore the clinical relevance of CTCs in nonmetastatic cancer patients.…”

Circulating tumor cells in early bladder cancer: insight into micrometastatic disease

“…We thus come back to wonder about the accuracy of considering these forms as early cancers. More recently in a larger and homogeneous population of high-risk non-muscle-invasive bladder cancer patients, we demonstrated that the presence of at least one CTC is a strong predictor of progression, defined as an increase in T stage to T2 or greater or lymph node (N+) disease or distant metastasis (M1), according to international guidelines [14]. Our thought are that these tumors are understaged at the time of diagnosis; in this context, we propose that the American Joint Committee on Cancer category cM0(i+), recently included for breast cancer, might be appropriate for bladder cancer staging as well.…”

A Phase II Clinical Trial of TRC105 (Anti-Endoglin Antibody) in Adults With Advanced/Metastatic Urothelial Carcinoma

“…55,56 It has been reported that CTCs have been detected in localized, high-risk nonmuscle-invasive, and metastatic bladder cancer, and that CTCs have potential prognostic value. [56][57][58][59] In the current study, we applied an integrated magnetic pre-enrichment and multiparameter flow cytometric analysis, a novel method that we recently developed.…”