IBCN 2017: Biomarkers II

Lisbon, Portugal (UroToday.com) This session was centered on biomarkers for patients with muscle-invasive bladder cancer and treatment selection. Ulrika Segersten from Uppsala University, Uppsala, Sweden presented their work entitled ‘Choline Phosphate Cytidylyltransferase α (CCTα) as a Novel Predictor of Response to Cisplatin Neoadjuvant Chemotherapy in Urothelial Cancer of the Bladder’. A total of 238 patients with T1-T4 bladder cancer enrolled into two prior randomized trials comparing neoadjuvant chemotherapy before cystectomy and surgery only were used as discovery and validation data sets. Protein expression was determined with immunohistochemistry and was assessed with H-scoring. In the discovery data set, which included 61 patients, negative CCTα staining was associated with better 5-year overall survival (OS) (p=0.001) when neoadjuvant cisplatin treatment (NAC) was applied. On the contrary CCTα positive patients had no survival improvement with neoadjuvant treatment. In the validation data set that included 177 patients, negative CCTα stained group had better survival ratios after NAC treatment while positive CCTα group had no additional survival benefit. In a pooled database of both patient data sets multivariate analyses showed CCTα status as an independent factor for 5-year OS (p=0.016; HR=1.81, 95% CI: 1.12-2.96). The CCTα negative patients had an absolute risk reduction of 21% (95% CI 6.85-34.9) and the number needed to treat (NNT) was 5. The authors concluded patients with decreased expression of CCTα protein have an increased sensitivity to cisplatin therapy, aiding in predicting survival benefit. As we move towards precision-based medicine in selecting patients most appropriate for NAC incorporation of these data including genotypes and subtypes will be critical. Moreover, cost analyses and value-based studies are needed in order to allow dissemination of these biomarkers.

Polat Turker from Uppsala University, Uppsala, Sweden presented their validation data of Bcl-2 as a predictive marker of neoadjuvant cisplatin chemotherapy response in a patient cohort from randomized cystectomy trials. Tumor samples from 247 patients with T2-T4 bladder cancer enrolled in two randomized trials comparing cystectomy with or without neoadjuvant chemotherapy were used. Bcl-2 expression was positive in 38% of the patients. Bcl-2 negative patients that received neoadjuvant chemotherapy had significant increase in survival (p=0.009) while Bcl-2 positive patients showed no difference (p=0.4). These results remained significant in multivariate analyses. When the prognostic value of Bcl-2 was assessed in the no chemotherapy group, 5-year overall survival times for Bcl-2 positive patients were significantly better compared to Bcl-2 negative patients (42 months vs 33 months respectively, p=0.04). In conclusion, Bcl-2 immunoreactivity is a potential marker for predicting patients responding to neoadjuvant chemotherapy.

Per-Uno Malmström from Uppsala University, Uppsala, Sweden further summarized predictive biomarkers in urinary bladder cancer – validation studies. Using a biobank with tumor specimens from five large Nordic prospective randomized clinical trials. Among patients treated with neoadjuvant chemotherapy emmprin, CCT-alpha and BCL-2 predicted time to overall and cancer-specific survival. Combining two of later, emmprin and CCT-alpha increased the C-index from 0.648 to 0.684. A multicenter prospective trial is planned with emmprin targeted neoadjuvant chemotherapy. These findings need to be taken in context of study design and retrospective nature. While data are derived from prior randomized population, data was limited in total number of cycles completed as well as regimens used in combination. Perhaps extrapolating to other populations with more granular chemotherapy data will elucidate these findings.

Siamak Daneshmand from the University of Southern California, Los Angeles, CA presented ‘Association Between Epithelial Tumor Markers’ trends during the course of treatment and Oncological Outcomes in Urothelial Bladder Cancer’. Serum levels of Carbohydrate Antigen 125 (CA-125), Carbohydrate Antigen 19-9 (CA 19-9) and Carcinoembryonic Antigen (CEA) were prospectively measured in 480 patients with invasive disease. Elevated pre-cystectomy level of any tumor markers (31% of patients) was independently associated with worse RFS (HR=2.81; p<0.001) and OS (HR=3.97; p<0.001). 125 (37%) patients underwent NAC, of whom 59 had a complete tumor marker profile before and after therapy and 30 (51%) had one or more elevated pre-NAC tumor markers. Following completion of chemotherapy, 10/30 (33%) patients normalized their tumor markers, while 20/30 (67%) had one or more persistently elevated markers. There was no difference in clinical or pathological stage between groups (p=0.54 and p=0.09, respectively). Further analysis showed a significantly lower rate and longer median time to recurrence/progression in the responder group (50% in responders vs. 90% in non-responders at a median time of 22 vs. 4.8 months respectively; p=0.015). There was also significant difference in mortality rates and median overall survival between the study groups (30% in responders vs. 70% in non-responders at a median time of 27.3 vs. 11.6 months respectively; p=0.037). Use of these relatively inexpensive tumor markers readily available at most institutions may help in identifying chemotherapy-resistant tumors. Moreover, patients with marker relapse following cystectomy are at significant increased risk of recurrence and mortality and may aid in selecting patients for adjuvant therapy. Given the lack of relatively inexpensive and readily available markers at most institutions, these data provide a cost-effective means at identifying and following these patients post-treatment.

Speaker(s): Ulrika Segersten, Uppsala University; Polat Turker, Uppsala University; Per-Uno Malmström, Uppsala University; Siamak Daneshmand, University of Southern California

Written by: Stephen B. Williams, M.D., Associate Professor, Division of Urology, The University of Texas Medical Branch, Galveston, TX. and Ashish M. Kamat, M.D. Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX., at the International Bladder Cancer Network - October 21, 2017- Lisbon, Portugal

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