BCAN TT 2022: Clonal Architecture and Tumor Microenvironment of Cisplatin Resistant Localized Muscle-Invasive Bladder Cancer

(UroToday.com) Dr. Filipe LF Carvalho, MD, PhD, is a urologic oncologist at the Brigham and Women’s Hospital in Boston, MA. He is the recipient of the 2021 BCAN Young Investigator Award for his research focused on characterizing intratumoral heterogeneity and tumor microenvironment in muscle invasive bladder cancer (MIBC) patients receiving cisplatin-based neoadjuvant chemotherapy.

The standard of care management for all patients with cT2+ bladder cancer is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. While patients who achieve a complete pathologic response to neoadjuvant therapy have excellent post-cystectomy survival outcomes, the 5-year survival for patients with residual muscle-invasive disease (ypT2+ or N+) is only 43%.

Identifying inherent cisplatin resistant tumors has significant clinical utility. Prior studies have shown that greater degrees of intratumoral heterogeneity in cisplatin resistant tumors is associated with worse survival. The objective of this study was to define cellular transcriptional programs within bladder cancer cells and infiltrating immune cells that contribute to cisplatin resistance.

The investigators took post-treatment tissue samples from the Dana Farber tissue bank from patients with MIBC who underwent neoadjuvant cisplatin-based chemotherapy. Patients were selected for either inherent cisplatin sensitivity (N=6 complete responders) or resistance (N=15 patients who progressed on NAC, ypT3+). Tissue was dissociated to single cells and subjected to single cell RNAseq. This was a homogeneous cohort as patients had pure urothelial histology and received at least 3 cycles of NAC.

ssRNAseq of complete responders or non-responders was used to cluster cells based on common gene expression profiles. Notably, in cisplatin non-responders, there appeared to be two distinct clusters of cancer cells in addition to multiple immune cell populations and cancer-associated fibroblasts. The investigators also identified copy number alterations that were exclusively found in non-responders.

The investigators identified distinct tumor clones with different transcriptional programs and chromosomal copy number variations which require further characterization and contextualization with regards to interaction with the tumor microenvironment and possible therapeutic targeting after poor response to cisplatin-based therapy. Future studies could also characterize these findings in paired pre- and post-treatment specimens to look at induced phenotypic changes within the tumor as well as in primary and nodal metastatic specimens.

Presented by: Dr. Filipe LF Carvalho, MD, PhD, a urologic oncologist at the Brigham and Women’s Hospital in Bostom, MA

Written by: Patrick Hensley, MD, Urologic Oncologist at the University of Kentucky (@pjhensley11) with Ashish Kamat, MD, Urologic Oncologist at MD Anderson Cancer Center (@UroDocAsh) during the 2022 Bladder Cancer Advocacy Network Think Tank (#BCANTT22) Wednesday Aug 3 – Friday Aug 5, 2022 

References:

  1. Zargar H, Espiritu PN, Fairey AS, Mertens LS, Dinney CP, Mir MC, Krabbe LM, Cookson MS, Jacobsen NE, Gandhi NM, Griffin J, Montgomery JS, Vasdev N, Yu EY, Youssef D, Xylinas E, Campain NJ, Kassouf W, Dall'Era MA, Seah JA, Ercole CE, Horenblas S, Sridhar SS, McGrath JS, Aning J, Shariat SF, Wright JL, Thorpe AC, Morgan TM, Holzbeierlein JM, Bivalacqua TJ, North S, Barocas DA, Lotan Y, Garcia JA, Stephenson AJ, Shah JB, van Rhijn BW, Daneshmand S, Spiess PE, Black PC. Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol. 2015 Feb;67(2):241-9. doi: 10.1016/j.eururo.2014.09.007. Epub 2014 Sep 23. PMID: 25257030; PMCID: PMC4840190.
  2. Liu D, Abbosh P, Keliher D, Reardon B, Miao D, Mouw K, Weiner-Taylor A, Wankowicz S, Han G, Teo MY, Cipolla C, Kim J, Iyer G, Al-Ahmadie H, Dulaimi E, Chen DYT, Alpaugh RK, Hoffman-Censits J, Garraway LA, Getz G, Carter SL, Bellmunt J, Plimack ER, Rosenberg JE, Van Allen EM. Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer. Nat Commun. 2017 Dec 19;8(1):2193. doi: 10.1038/s41467-017-02320-7. PMID: 29259186; PMCID: PMC5736752.
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