乌鸦传媒

Clinical outcomes in urothelial carcinoma have improved significantly with the use of immune checkpoint blockade (ICB) therapy. In spite of this, predicting which patients will benefit remains a challenge. Currently, only a of patients have long-lasting clinical benefit from ICB. Previous have identified molecular markers associated with clinical benefit from ICB therapy in urothelial carcinoma. These markers, however, which include PD-(L)1 expression, immunophenotype, and minimal residual disease status, require specific assays.

In a recent study in the , researchers reported that DNA sequencing made it possible to identify four distinct genomic-based classifiers that correlated with patient outcomes after ICB. These classifiers were based on tumor mutational burden (TMB), tumor cell purity, and ARID1A mutation.

The subtype associated with the longest progression-free survival (PFS) following ICB was ARID1A mutation (hazard ratio [HR] 0.43, 95% CI 0.25–0.73, P=0.002). ARID1A mutation was also associated with improved overall survival (HR 0.52, 95% CI 0.29-0.92, P=0.025). Conversely, tumor cell purity was a negative predictor of ICB benefit, and low TMB demonstrated the worst clinical outcome, with a median PFS of less than 6 months.

"Our study proposes a novel molecular subtyping of bladder cancer on the basis of genetic features easily quantified using DNA," wrote Jonathan E. Rosenberg, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York City, and colleagues. "This approach can be adapted to targeted sequencing panels and clinical WES [whole-exome sequencing]. The stability of DNA enhances the feasibility of our approach in clinical environments."

Tumors with low TMB were classified as subtype 1; tumors with high TMB and high tumor cell purity as subtype 2; ARID1A-mutant tumors with high TMB and low tumor cell purity were classified as subtype 3; and ARID1A wild-type tumors as subtype 4.

After validating the findings in an independent patient cohort from the and in patients who did not receive ICB therapy from bladder cancer cohort, the researchers found that subtype 2 was more common in the TCGA cohort and was associated with increased survival. This suggests that "high TMB and high purity tumors are associated with a propensity to progress more slowly or metastasize less frequently," the team explained.

In the following interview, Rosenberg, who is chief of the Genitourinary Oncology Service at MSKCC, along with first author Michal Sarfaty, MD, also of MSKCC and Sheba Medical Center and Tel Aviv University in Israel, discussed the findings in greater detail.

Did any of your findings come as a surprise?

Our findings were aligned with previous research identifying ARID1A mutation, intratumoral heterogeneity, tumor cell purity, and tumor mutational burden as predictors of ICB response. Interestingly, we found that patients with ICB-treated bladder cancer with a high ratio of non-synonymous to synonymous mutations in the immunopeptidome [immune dN/dS] had superior PFS after ICB therapy.

This suggests that strategies to identify neoantigens may prove fruitful for future research.

What is your take-home message for physicians?

Our study defines molecular subgroups of bladder cancer that influence benefit from ICB, including ARID1A mutation, tumor mutational burden, and tumor cell purity. These can be identified from next-generation sequencing and may prove useful to stratify patients for therapy.

Are you saying the findings could potentially point to a more accessible, accurate way to select patients for ICB?

PDL1 staining has not proven clinically useful in advanced urothelial cancer. Our study provides insights on the molecular characteristics that correlate with benefit from ICB, which may potentially set the groundwork for a more refined clinical decision-making algorithm in selecting patients for ICB.

The use of readily obtainable sequencing data to derive these clinically relevant factors may set the stage for novel predictive approaches to identify patients most likely to benefit from single-agent immune checkpoint blockade.

What are the "cons" of using DNA sequencing to determine ICB response?

The most significant barrier is that molecular subtyping correlates with response but does not completely distinguish between responders and non-responders. This means that a patient with an unfavorable subtype may still potentially respond to ICB.

In the current landscape of metastatic urothelial cancer treatment, where the prognosis is dismal for many, we offer all patients the opportunity to benefit from exposure to ICB, even those in biomarker-low populations. With combinations of immunotherapy and other therapies such as FGFR3 inhibitors, and antibody drug conjugates, for example, the need for selection may be less, although some patients may fare well with ICB alone and may be overtreated with combination therapy.

In your study cohort of 88 patients with advanced bladder cancer, what percentage had the molecular subtypes that correlated with ICB benefit?

Half of the patients or 51% were identified as molecular subsets 3 and 4 [18 and 27 patients, respectively], which correlated with a longer duration of response to ICB. If these are further validated in other studies, it may allow future selection in trials to show that it is associated with clinical benefit.

What is the significance of your findings among patients who were not treated with ICB?

We evaluated whether our molecular classification could also provide prognostic information for patients with bladder cancer who were not treated with ICB. Our classification was able to segregate patient groups with differing survival in the TCGA bladder cancer cohort, which included primarily localized disease. Notably, in the TCGA cohort, the most common subtype was subtype 2, which was associated with better survival, as opposed to the ICB-treated cohort, which represents advanced disease.

What's next for your research?

Similar work needs to be done to understand which patients do not derive benefit from ICB combinations with other agents.

Read the study here.