ASCO GU 2018: Use of Molecular Markers in Bladder Preservation Therapy

San Francisco, CA (UroToday.com) As part of the Current and Future Directions of Muscle-Invasive Bladder Cancer (MIBC) session at GU ASCO, Dr. Peter Hoskin from the UK provided an update regarding the use of molecular markers in bladder preservation therapy. Dr. Hoskin started by noting that based on a propensity score analysis of highly selected patients with MIBC from the Princess Margaret Cancer Centre, there was no difference in survival between patients undergoing radical cystectomy or bladder-sparing trimodal therapy over a median follow-up of > 4 years [1]. 

A recent systematic review and meta-analysis of 19 studies and 12,380 subjects assessing radical cystectomy compared to combined modality treatment for MIBC showed no difference in OS at 5 years (HR 0.96, 95%CI 0.72-1.29) or 10 years (1.02, 95%CI 0.73-1.42) [2], thus solidifying bladder sparing, multi-modal therapy as a legitimate treatment option for MIBC.

Dr. Hoskin feels there are several challenges moving forward:
  • Can we identify patients who may not do well with non-surgical treatment?
  • Do poor responders to radiotherapy respond better to surgery?
  • Do poor responders require specific modification of radiotherapy: chemoradiation or bladder carbogen nicotinamide (BCON)
Certainly, there are several molecular marker candidates for potentially identifying patients who may not do well with non-surgical treatment, including: proliferation (Ki-67), hypoxia (Glut1, CAIX, miR201), DNA repair (ERBB2, ERCC1, XRCC1, MRE11), immune response (PD-L1) and gene profiling (basal/luminal subtypes). In a study of 94 patients, high Ki-67 expression was associated with better 5-year cancer specific survival (CSS) compared to low expression CSS of 46% (p=0.019) among patients treated with a chemoradiation bladder sparing protocol [3]. Furthermore, there are several studies assessing hypoxia markers for response to chemo-radiotherapy, notably a 24-gene hypoxia signature that has strong and independent prognostic and predictive value for MIBC, as well as predicting benefit of adding carbogen and nicotinamide to radiotherapy [4]. MRE11 expression has also been shown to have predictive value for CSS following radiotherapy, specifically high MRE11 showing significantly improved CSS compared to low MRE11 expression (HR 0.43, 95%CI 0.21-0.87) [5]. Furthermore, PD-L1 expression (compared to negative expression), as well as molecular subtyping for basal subtype (compared to p53-like and luminal subtypes) has also demonstrated poor CSS outcomes.

MRE11 expression has also been used to predict patients that may do better with radical cystectomy when compared to radiotherapy. Specifically, patients with low MRE11 expression do better undergoing cystectomy compared to those undergoing radiotherapy, whereas patients with high MRE11 expression fair better with radiotherapy. Unfortunately, several small studies have not demonstrated a benefit for hypoxic tumors responding to radical cystectomy.

Whether poor responders require specific modification of radiotherapy has been assessed in a recent study looking at a benefit of hypoxia modification of radiotherapy for high risk bladder cancer patients [4]. Among BCON high hypoxia patients, those receiving radiotherapy + BCON had significantly improved local relapse-free survival compared to radiotherapy alone, although these outcomes did not remain consistent in low-hypoxia patients. Similarly, there has been no benefit for adding BCON to radiotherapy for patients with basal vs luminal subtyped tumors.

Dr. Hoskin concluded with several take-home points:
  • At this point we can in fact identify patients who may not do well with non-surgical treatment
  • Poor responders to radiotherapy may benefit more from surgery when stratifying by MRE11 expression, although this not seen when assessing hypoxia
  • Poor responders do in fact require specific modifications of radiotherapy, notably with the addition of BCON in the setting of hypoxia
Presented by: Peter Hoskin, Mount Vernon Cancer Centre, Northwood, UK

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre  @zklaassen_md at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA

References:
1. Kulkarni GS, Hermanns T, Wei Y, et al. Propensity score analysis of radical cystectomy versus bladder-sparing trimodal therapy in the setting of a multidisciplinary bladder cancer clinic. J Clin Oncol 2017;35(20):2299-2305.

2. Vashistha V, Wang H, Mazzone A, et al. Radical cystectomy compared to combined modality treatment for muscle-invasive bladder cancer: A systematic review and meta-analysis. Int J Radiat Oncol Biol Phys. 2017;97(5):1002-1020.

3. Tanabe K, Yoshida S, Koga F, et al. High Ki-67 expression predicts favorable survival in muscle-invasive bladder cancer patients treated with chemoradiation-based bladder-sparing protocol. Clin Genitourin Cancer 2015;13:e243-e251.

4. Yang L, Taylor J, Eustace A, et al. A gene signature for selecting benefit from hypoxia modification of radiotherapy for high-risk bladder cancer patients. Clin Cancer Res. 2017;23(16):4761-4768.

5. Choudhury A, Nelson LD, Teo MT, et al. MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer. Cancer Res. 2010;70(18):7017-7026.
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