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Comprehensive assessment of immuno-oncology biomarkers in adenocarcinoma, urothelial carcinoma, and squamous-cell carcinoma of the bladder

  • Andrea Necchi,
  • Russell Madison,
  • Daniele Raggi,
  • Joseph M. Jacob,
  • Gennady Bratslavsky,
  • Oleg Shapiro,
  • Julia A. Elvin,
  • Jo-Anne Vergilio,
  • Jonathan K. Killian,
  • Nhu Ngo,
  • Shakti Ramkissoon,
  • Eric Severson,
  • Amanda C. Hemmerich,
  • Richard Huang,
  • Siraj M. Ali,
  • Jon H. Chung,
  • Prasanth Reddy,
  • Vincent A. Miller,
  • Alexa B. Schrock,
  • Laurie M. Gay,
  • Brian M. Alexander,
  • Petros Grivas,
  • Jeffrey S. Ross

Background

In patients with rare histologies of bladder cancer, including adenocarcinoma of the bladder (ACB) and squamous-cell carcinoma (SCC), there are limited standard therapy options, defining an unmet medical need.

Objective

In this comparative comprehensive genomic profiling (CGP) study, genomic alterations (GAs), and immuno-oncology (IO) biomarkers have been analyzed.

Design, setting, and participants

Within the Foundation Medicine database, 143 cases with centrally reviewed pure ACB, 2142 with pure urothelial carcinoma (UC), and 83 with pure SCC were subjected to CGP. All patients developed advanced disease following a primary diagnosis of bladder cancer.

Intervention

CGP using a hybrid capture–based assay and immunohistochemistry (IHC).

Outcome measurements and statistical analysis

Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA, and microsatellite instability (MSI) was determined on 114 loci. Programmed cell-death ligand-1 (PD-L1) expression was determined by IHC (Ventana SP-142 assay), with >1% tumor cells (TCs) or tumor-infiltrating lymphocytes (TILs) scoring positive.

Results and limitations

Pure ACB patients were younger and more often female than pure UC and pure SCC patients. UC and SCC had a significantly higher median TMB than ACB (p < 0.001). Rare CD274 (PD-L1) amplification cases were more frequently seen in SCC than in UC (5% vs 1%), and were not seen in ACB. MSI high status was very uncommon in all tumor types (0–1%). The frequencies of PD-L1 expression in both TCs and TILs was higher in UC and SCC (both 30%) than in ACB (18%). The results are limited by their retrospective nature and lack of clinical data annotation.

Conclusions

Deep sequencing revealed significant differences in IO biomarkers among the three major subtypes of bladder carcinomas. UC and SCC revealed higher frequencies of PD-L1 expression and higher TMB than ACB, and SCC has the highest frequency of CD274 amplification. The presence of pure SCC features should not disqualify patients for inclusion in IO trials.

Commented by Dr. Xylinas

Urothelial carcinoma (UC) is the most frequent histology of bladder cancer.

UC has a propensity for divergent differentiation called variant histologies. In addition to these variant histologies mixed with UC, there are tumors characterized by a pure non-UC histology that are rare phenotypes (accounting for <5% of all bladder tumors), usually displaying an aggressive clinical course and poor response to conventional chemotherapy. For these patients, there are limited standard therapy options, defining an unmet medical need.

Necchi and colleagues analyzed the molecular features of pure rare histologies of bladder cancer. They focused using the Foundation Medicine database on pure adenocarcinoma of the bladder (ACB) (n=143) and pure squamous-cell carcinoma (SCC) (n=83).

They found that Pure ACB patients were younger and more often female than pure UC and pure SCC patients. UC and SCC had a significantly higher median tumor mutational burden than ACB (p < 0.001). Rare CD274 (PD-L1) amplification cases were more frequently seen in SCC than in UC (5% vs 1%), and were not seen in ACB. MSI high status was very uncommon in all tumor types (0-1%). The frequencies of PD-L1 expression in both TCs and TILs was higher in UC and SCC (both 30%) compared to ACB (18%).

These results underline significant differences in IO biomarkers among the three major subtypes of bladder carcinomas. UC and SCC revealed higher frequencies of PD-L1 expression and higher TMB than ACB, and SCC has the highest frequency of CD274 amplification. Therefore, the presence of pure SCC features should not disqualify patients for inclusion in IO trials or treatment.

Patients with pure ACB histology appear potentially less responsive to immunotherapy. For these patients, after failure of the few standard chemotherapy options that are used in routine practice, there may be intriguing possibilities for targeted therapy, for example, against ERBB2, EGFR, and MET in selected patients.