ESMO Virtual Congress 2020: Molecular Profiling of Post-pembrolizumab Muscle-Invasive Bladder Cancer Reveals Unique Features That May Inspire New Sequential Therapies in Pathological Non-responders

(UroToday.com) Molecular characterization of bladder cancer by gene expression profiling has generated disease subtypes that are associated with response to neoadjuvant therapy in muscle-invasive bladder cancer. Post-treatment residual disease appears to undergo changes in molecular profile, characterized recently by a publication1 into four expression profile clusters: CC1 (basal), CC2 (Luminal), CC3 (Immune) and CC4 (Scar-like). These profiles (postNAC) were generated from residual disease in patients treated with platinum chemotherapy. In this poster presentation, the authors endeavored to create a molecular characterization system for residual bladder cancer after pembrolizumab therapy.

To accomplish this, the authors assembled molecular data from three cohorts: (1) patients from the PURE-01 study (residual invasive bladder cancer after pembrolizumab), (2) a post neoadjuvant chemotherapy cohort, and (3) a cohort of patient who received no systemic treatment and underwent radical cystectomy. They applied the postNAC signature as well as TCGA, Decipher, and Consensus gene expression profiles to samples from all collected cohorts. Within the postNAC cohort, consistency was observed between all classifiers and the postNAC basal/luminal signatures, but the CC4 scar-like signature was classified more by the Consensus stroma-rich signature.

The authors also observed notable switching in molecular subtype in the PURE-01 patients between TURBT samples prior to pembrolizumab and matched post-pembrolizumab radical cystectomy samples. Most samples post-pembrolizumab resembled the stroma-rich consensus subtype.

The authors investigated whether the scar phenotype was due to treatment, or due to wound-healing from pembrolizumab. Samples with scar as well as samples from the PURE-01 cohort and the untreated cystectomy cohort were subjected to clustering. Clustering revealed a three-cluster solution which was characterized by basal (CC1), luminal (CC2), and scar-like (CC3) gene expression profiles, with scar samples clustering in the CC3 profile. Though some pembrolizumab treated samples had similar gene expression profiles to scar tissue, in general these post-treatment samples had a higher expression level of luminal signatures as well, suggesting that pembrolizumab induces a different gene expression profile than TURBT scarring.

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When utilizing the three de novo (CC1 – basal, CC2 – luminal, CC3 – scar like) signatures to examine patient outcome, there was no difference in outcome for patients who received no systemic therapy prior to cystectomy. However, in the neoadjuvant chemo and PURE-01 neoadjuvant pembrolizumab cohorts, the expression of the scar-like CC3 signature was associated with improved recurrence free survival.

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The authors concluded that their work identified a TURBT-induced scar-like phenotype due to wound healing, and that the development of this signature was associated with better recurrence free survival. They also noted that PURE-01 pembrolizumab treated samples tended to have higher luminal signatures, suggesting that this phenotype is associated with resistance to immunotherapy.


References: 
1.  Seiler R., Gibb E. A., Wang N. Q.., et al., Divergent Biological Response to Neoadjuvant Chemotherapy in Muscle-invasive Bladder Cancer. CCR. 2019; 25(16):5082-5093

Presented by: Andrea Necchi, MD, PhD, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori


Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the 2020 European Society for Medical Oncology Virtual Congress (#ESMO20), September 19th-September 21st, 2020.
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