AUA 2018: Debate: Molecular Profiling Influences My Treatment Selection

San Francisco, CA (UroToday.com) Peter Black, MD, from the University of British Columbia provided his rationale for molecular profiling with regards to treatment selection for patients with muscle-invasive bladder cancer. Dr. Black started by highlighting the current landscape of neoadjuvant chemotherapy for MIBC:

  • The Evidence: multiple prospective randomized trials and meta-analyses demonstrate survival advantages from neoadjuvant chemotherapy for all eligible patients with MIBC.
  • The Gap: only 40% of patients with major response appear to benefit from neoadjuvant chemotherapy. Furthermore, neoadjuvant chemotherapy is not widely used in most parts of the world.
  • The Solution: if we can identify who is likely to respond to neoadjuvant chemotherapy and avoid neoadjuvant chemotherapy in likely non-responders, we will be able to optimize delivery and increase uptake. 
There are several molecular predictors of response to neoadjuvant chemotherapy, including molecular subtypes, the COXEN model, and genomic alterations. Black’s group recently published their experience with whole transcriptome profiling on pre-neoadjuvant chemotherapy TUR specimens from 343 patients with MIBC to identify molecular profiles of patients to predict response to neoadjuvant chemotherapy [1]. They found that luminal tumors had the best OS with and without neoadjuvant chemotherapy, while Claudin-low tumors were associated with poor OS irrespective of the treatment regimen. Basal tumors showed the most improvement in OS with neoadjuvant chemotherapy compared with surgery alone.

The COXEN model or “Co-eXpression ExtrapolatioN” model is comprised of a series of steps. Step 1 is coregulation, following by step 2 – correlation with drug sensitivity. Finally, step 3 constructions a Gene Expression Model (GEM) for each test compound. There are 1000 genes per drug that have expression levels associated with drug sensitivity leading to the smallest number of genes that when combined offer the best correlation of expression with drug sensitivity. Finally, Dr. Black highlights that ERCC2 mutations predict survival, namely as a biomarker for chemotherapy response in patients with MIBC, as do mutations in DNA repair genes. 

Black concluded noting that we do not need to be overly dogmatic since patients with MIBC do not have alternatives. Some may argue that it is reasonable to perform radical cystectomy followed by adjuvant chemotherapy, if necessary. However, Black says that we tend to favor neoadjuvant chemotherapy because we have better evidence although everything we know about adjuvant chemotherapy suggests similar efficacy. Neoadjuvant chemotherapy is “good for the masses” but undoubtedly harms a subset of individual patients by delaying non-responders with undue toxicity.

References:
1. Seiler R, Ashab HAD, Erho N, et al. Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy. Eur Urol 2017;72(4):544-554

Presented by: Peter C. Black,  MD, Vancouver Prostate Centre, Vancouver, BC, Canada

Written by:  Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre at the 2018 AUA Annual Meeting - May 18 - 21, 2018 – San Francisco, CA USA

Read the Opposing Presentation: Molecular Subtypes: Not Ready for Prime Time
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