A classification based on tumor-stroma ratio and tumor budding for patients with muscle-invasive bladder cancer

ABSTRACT

Background

Tumor-stroma ratio (TSR) and tumor budding (TB) play important roles in muscle-invasive bladder cancer (MIBC). We developed a rating system (TSR-TB type) based on the morphological evaluation of TSR and TB for predicting patient outcome and using individualized care.

Methods

TSR and TB were assessed in publicly accessible MIBC tumor slides from the TCGA database. MIBC patients were classified as low stromal or high stromal type based on TSR, and high stromal type was further classified as compartmentalized or mixed stromal type based on TB.

Results

TSR-TB type was an independent adverse prognostic factor for OS (P < 0.001). Low stromal type had a greater prognosis (P < 0.001) and were enriched for FGFR3 mutations (P = 0.001). The mixed stromal type was distinguished by increased M2 macrophage penetration (P < 0.001), anti-tumor immune activity, DNA repair pathway mutations, and poor survival. GSEA showed that certain cancer-related pathways, such as mitotic spindle, PI3K-AKT-MTOR signalingwere hyperactivated in high stromal type (all FDR<0.05). Furthermore, mixed stromal type demonstrated enhanced activation of epithelial mesenchymal transformation (EMT), inflammatory response (all FDR<0.05).

Conclusion

TSR and TB-based MIBC classification coincides with patient survival and molecular alterations. The identified subtypes may have important implications for individualized MIBC therapy.

KEYWORDS:

• Muscle-invasive bladder cancer
• tumor-stroma ratio
• tumor budding
• prognosis
• TCGA

Article highlights

• TSR-TB type was an independent adverse prognostic factor for OS in MIBC.

• Low stromal type had a greater prognosis than the other subtypes and were enriched for FGFR3 mutations.

• The mixed stromal type was distinguished by increased M2 macrophage penetration, anti-tumor immune activity, DNA repair pathway mutations, and poor survival.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A review on this paper has served on the advisory board for Bristol Myers Squibb, Genentech, EMD Serono, Merck, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Immunomedics/Gilead, Scholar Rock, G1 Therapeutics, Eli Lilly/Loxo Oncology, Infinity Pharmaceuticals. They have received research support to their institution from Sanofi, Astrazeneca, Immunomedics/Gilead, QED, Predicine and Bristol Myers Squibb. They have served on the steering committee of studies for Bristol Myers Squibb, Bavarian Nordic, Seattle Genetics, QED, G1 Therapeutics (all unpaid), and Astrazeneca, EMD Serono, Debiopharm (paid). They have served on the data safety monitoring committee for Mereo, have received travel expenses from Bristol Myers Squibb and Astrazeneca. They have received writing/Editor fees from Uptodate, and the Editor of Elsevier Practice Update Bladder Cancer Center of Excellence. They have also received speaking fees from the Physicians Education Resource (PER), Onclive, Research to Practice, Medscape, Cancer Network and Masters Lecture Series (MLS). Reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Author contributions

XS and XS, designed the research; DY and JW collected the data. JL, CL and KH analyzed the data and wrote the draft. AA revised the language of the paper. All authors read and approved the final manuscript.

Data availability statement

The results shown here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. Data can be obtained from the corresponding author as requested.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China [grant nos. 11872146].