ASCO 2017: Subclonal mutational heterogeneity and survival in cisplatin-resistant muscle-invasive bladder cancer

Chicago, IL ( Based on Level 1 evidence demonstrating cancer-specific survival benefit, neoadjuvant cisplatin-based chemotherapy (NAC) remains the standard of care for patients with muscle-invasive bladder urothelial cancer (MIBC). However, the 5-7% survival benefit along with the associated theoretical risk of treatment delay (in patients who don’t respond to NAC) and adverse events had led to significant underutilization. Better understanding of patient response to NAC will help guide potential adjunct therapy or alternative therapy.

In this multi-institutional study, the authors identified 30 patients with MIBC who were treated with NAC. Matched pre- and post-NAC tumor samples were obtained, followed by whole exome sequencing of these “trios” (pre- and post-NAC tumor with matched germline samples). They then analyzed these matched cohorts for the following: to identify subclones, their associated mutations, and the corresponding enrichment in post-treatment tumors. Intratumoral heterogeneity was assessed by the proportion of mutations that were subclonal; the number of inferred subclones; and associated with overall survival using a Cox Proportional Hazards model.

An increased proportion of subclonal mutations in post-treatment tumors was associated with worse overall survival (HRR 1.86 [95% CI 1.12-3.06], p = 0.02). In contrast, pre-treatment proportion of subclonal mutations was not statistically significant. However, pre- and post-treatment heterogeneity were not statistically related – suggesting that both may play a role in clinical outcomes.

As such, they then calculated a composite score of pre- and post-treatment subclones. The total number of inferred tumor subclones was strongly associated with overall survival (HRR 1.60 [95% CI 1.05-2.43], p = 0.03), which can be interpreted as a 60% increase in death rate per additional inferred subclone.

There was no single gene that was enriched in post-chemotherapy samples, but certain pathways were altered. Specifically, there was new post-treatment amplifications in cell-cycle genes (E2F3, c-JUN), biallelic events in cell-cycle regulators (FBXW7), and amplification of immune checkpoint genes (PDL1/2). Interestingly, in treatment-resistant patients with post-treatment amplication of the PDL1/2 pathway, the pre-treatment samples had some amplification – suggesting that cisplatin-based therapy and failure may have been based on pre-treatment changes.

Based on this the authors conclude intratumoral heterogeneity, particularly in post-chemotherapy samples, is associated with worse overall survival and potentially worse response to NAC. Based on the enrichment of the immune checkpoint PD-1 pathway, they also suggest that attempting immune checkpoint blockade during NAC or, in high risk patients, following NAC may be warranted.

1. The authors define the presence of residual disease in the bladder as evidence of NAC failure. However, the principle behind NAC administration is not specifically for primary tumor burden reduction. While patients who are pT0 (complete response) or 2. In this highly comorbid elderly patient population, overall-survival is perhaps not the best survival outcome. Cancer-specific survival would have been a better survival metric.

Discussion Points:
While interesting, this remains a small, selected cohort. As discussed above, perhaps the selection of the cohort and the lack of cancer-specific survival outcomes limits its utility in decision making. However, it does add value to the importance of subclones and their impact on treatment response.

Presented By: David Liu, MD, MPH, MS, Dana-Farber Cancer Institute, Boston, MA

Co-Author(s): Philip Abbosh, Daniel Keliher, Brendan Reardon, Kent William Mouw, Amaro Taylor-Weiner, Stephanie Anne Mullane, Garam Han, MinYuen Teo, Jaegil Kim, Hikmat Al-Ahmadie, Gopa Iyer, Essel Dulaimi, David Chen, Jean H. Hoffman-Censits, Scott L. Carter, Joaquim Bellmunt, Elizabeth R. Plimack, Jonathan E. Rosenberg, Eliezer Mendel Van Allen

Institution(s): Fox Chase Cancer Center, Abington, PA; Dana-Farber Cancer Institute, Brookline, MA; Broad Institute, Cambridge, MA; Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin, Ireland; Broad Institute of MIT and Harvard, Cambridge, MA; Memorial Sloan-Kettering Cancer Center, New York, NY; Fox Chase Cancer Center, Philadelphia, PA; The Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA; Memorial Sloan Kettering Cancer Center, New York, NY

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA

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