Standard Pathology Tests Outperform Molecular Subtyping in Bladder Cancer

Evolving diagnostic approaches include compiling databanks on gene expression and mutations present in a cancer type to find patterns of gene expression that are then used to subtype tumors that "pathologically look similar" but are molecularly different.

Studies indicate that molecular subtypes in muscle invasive bladder cancer predict the clinical outcome. The idea is that molecular subtypes are better equipped to indicate which cancer is more or less aggressive and to help steer treatment options like whether chemotherapy before surgery to remove a diseased bladder is better.

A team of scientists led by those at the Medical College of Georgia (Augusta, GA, USA) subtyped institutional cohort of 52 patients, including 39 with muscle invasive bladder cancer, an Oncomine (Thermo Fisher Scientific, Waltham, MA, USA) data set of 151 with muscle invasive bladder cancer and TCGA (The Cancer Genome Atlas) data set of 402 with muscle invasive bladder cancer. Subtyping was done using simplified panels (MCG-1 and MCG-Ext) which included only transcripts common in published studies and were analyzed for predicting metastasis, and cancer specific, overall and recurrence-free survival.

The team reported that MCG-1 was only 31% -36% accurate at predicting important indicators like likelihood of metastasis; disease specific survival, meaning surviving bladder cancer; or overall survival, meaning survival from all causes of death from the time of cancer diagnosis or beginning of treatment until the study's end. They looked again at the 402 patients whose specimens were in the dataset and found that 21 patients' tumors were actually low-grade. Patients with low-grade tumors have higher survivability and a better prognosis than patients with high-grade muscle invasive disease.

When they removed the low-grade cases from the TCGA dataset, MCG-1 accurately predicted essentially nothing, not even overall survival. Then they included some patients with low-grade tumors into their own dataset, which they had looked at originally, and MCG-1 was now able to predict metastasis and disease specific survival. All the existing subtypes are categorized as bad or better based on the cancer prognosis. The presence of the low-grade tumors in the classification of subtypes skewed the data to make it look like subtypes were predicting overall survival when really it was the grade of the cancer itself that was predictive.

Vinata B. Lokeshwar, PhD, a professor and corresponding author of the study, said, “Genetic profiling of a patient's tumor definitely has value in enabling you to discover the drivers of growth and metastasis that help direct that individual's treatment, even as it helps to identify new treatment targets. But using this information to subtype tumors does not appear to add diagnostic or prognostic value for patients.”

The authors concluded that molecular subtypes reflect bladder tumor heterogeneity and are associated with tumor grade. In multiple cohorts and subtyping classifications the clinical parameters outperformed subtypes for predicting the outcome. The study was published on January 1, 2020 in the Journal of Urology.

Related Links:
Medical College of Georgia
Oncomine