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Gene Profiling of Bladder Tumors Shows Promise for Identifying Candidates for Trimodality Therapy

Key findings

  • In a retrospective study of 136 patients with muscle-invasive bladder cancer who received trimodality therapy (TMT), tumors with higher expression of genes associated with immune activity had significantly improved disease-specific survival
  • Among 223 patients treated with neoadjuvant chemotherapy and radical cystectomy (NAC/RC), no differences in outcomes based on immune signatures were noted
  • High expression of a stromal gene signature was associated with worse outcomes after NAC/RC, whereas there was no significant difference in outcomes in the TMT cohort
  • If prospective trials confirm these findings, it should be possible to use gene profiling to select candidates for TMT

Trimodality therapy (TMT) as a means of bladder preservation for patients with muscle-invasive bladder cancer (MIBC) is underutilized, partly because of difficulty in identifying appropriate candidates. There is an urgent need for reliable predictive biomarkers to guide treatment selection.

Response to radiation has been associated with immune activation in bladder cancer, and fibroblasts in the tumor microenvironment have been shown to influence response to immunotherapy in urothelial cancer. Intrigued by this research, Jason A. Efstathiou, MD, DPhil, director of the Genitourinary Service in the Department of Radiation Oncology at Massachusetts General Hospital and clinical co-director of the Bertucci Center for Genitourinary Cancers at the Mass General Cancer Center, and David T. Miyamoto, MD, PhD, attending radiation oncologist with the Department of Radiation Oncology at the Mass General Cancer Center and physician-scientist in the Center for Cancer Research, and colleagues investigated the prognostic value of immune and stromal infiltration in MIBC patients. They found that immune-activated tumors seemed to derive benefit from TMT, whereas there was no significant difference in outcomes based on stromal gene signature. Their report appears in European Urology.

Tumor Samples

Using specimens from pretreatment transurethral resection of bladder tumors, the researchers generated transcriptome-wide gene expression profiles for two cohorts:

  1. The TMT cohort: 136 MIBC patients treated with TMT (median follow-up five years)
  2. The NAC/RC cohort: 223 MIBC patients treated with neoadjuvant chemotherapy and radical cystectomy (median follow-up 3.5 years)

Gene Expression Subtypes

The researchers classified the TMT cohort into four gene expression subtypes:

  1. Basal (n=54)
  2. Luminal (n=40)
  3. Luminal-infiltrated (n=26)
  4. Claudin-low (n=16)

Molecular subtype did not significantly affect the rate of complete response, disease-specific survival (DSS) or overall survival (OS) after TMT. In contrast, in the NAC/RC cohort, DSS and OS were worse among patients with claudin-low tumors.

Immune Infiltration

The researchers stratified patients according to quartiles of a T-cell–inflamed gene expression signature that correlates with killer T-cell infiltration in bladder tumors. Compared with patients in the lowest quartile, patients whose tumors exhibited higher levels of immune infiltration had significantly improved DSS, although not OS. This association remained significant in a multivariable model that included clinical prognostic factors such as age, gender and clinical stage.

In the NAC/RC cohort, there was no significant association between immune score and survival.

For interferon (IFN) signaling, which drives immune activation in tumor cells, the results were similar to the T-cell–inflamed signature. Patients in the TMT cohort with higher IFN-gamma signature scores had significantly improved DSS, but not improved OS. A higher IFN-gamma score remained significantly associated with improved DSS in a multivariable model including clinical factors.

In the NAC/RC cohort, there was no association between IFN-gamma score and survival.

Stromal Infiltration

The researchers defined a stromal infiltration signature based on nine genes typically expressed in fibroblasts or myofibroblasts. In both the TMT and NAC/RC cohorts, stromal signature scores were highest in the luminal-infiltrated subgroup and lowest in the luminal subgroup.

Both cohorts were then divided into quartiles of stromal infiltration signature. In the TMT cohort, there was no association between stromal infiltration and DSS or OS. However, in the NAC/RC cohort, patients in the top three quartiles had significantly worse DSS and OS than those in the lowest quartile. Radiation delivered as part of TMT could counter the treatment-resistant phenotype associated with stromal infiltration.

There were substantial differences in clinical characteristics within and between the TMT and NAC/RC cohorts.

Before gene profiling can be used to select candidates for TMT, these findings need to be validated in prospective trials.

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Rapidly emerging molecular biomarkers will allow oncologists to choose more confidently between radical cystectomy and trimodality therapy for patients with muscle-invasive bladder cancer, as well as identify which patients undergoing trimodality therapy are likely to benefit from adding immunotherapy.