Molecular heterogeneity in urothelial carcinoma and determinants of clinical benefit to PD-L1 blockade

Checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have revolutionized cancer therapy across many indications including urothelial carcinoma (UC). Because many patients do not benefit, a better understanding of the molecular mechanisms underlying response and resistance is needed to improve outcomes. We profiled tumors from 2,803 UC patients from four late-stage randomized clinical trials evaluating the PD-L1 inhibitor atezolizumab by RNA sequencing (RNA-seq), a targeted DNA panel, immunohistochemistry, and digital pathology. Machine learning identifies four transcriptional subtypes, representing luminal desert, stromal, immune, and basal tumors. Overall survival benefit from atezolizumab over standard-of-care is observed in immune and basal tumors, through different response mechanisms. A self-supervised digital pathology approach can classify molecular subtypes from H&E slides with high accuracy, which could accelerate tumor molecular profiling. This study represents a large integration of UC molecular and clinical data in randomized trials, paving the way for clinical studies tailoring treatment to specific molecular subtypes in UC and other indications.

Habib Hamidi,¹ Yasin Senbabaoglu,¹ Niha Beig,¹ Juliette Roels,¹ Cyrus Manuel,¹ Xiangnan Guan,¹ Hartmut Koeppen,¹ Zoe June Assaf,¹ Barzin Y Nabet,¹ Adrian Waddell,¹ Kobe Yuen,¹ Sophia Maund,¹ Ethan Sokol,² Jennifer M Giltnane,¹ Amber Schedlbauer,¹ Eloisa Fuentes,¹ James D Cowan,¹ Edward E Kadel 3rd,¹ Viraj Degaonkar,¹ Alexander Andreev-Drakhlin 1, Patrick Williams 1, Corey Carter 1, Suyasha Gupta 1, Elizabeth Steinberg 1, Yohann Loriot 3, Joaquim Bellmunt 4, Petros Grivas 5, Jonathan Rosenberg,⁶ Michiel S van der Heijden,⁷ Matthew D Galsky,⁸ Thomas Powles,⁹ Sanjeev Mariathasan,¹ Romain Banchereau,¹⁰

Genentech, South San Francisco CA, USA.
Foundation Medicine, Cambridge MA, USA.
Institut de Cancérologie Gustave Roussy, Université Paris-Saclay, Villejuif, France.
Dana Farber Cancer Institute, Boston MA, USA.
Fred Hutchinson Cancer Center, Seattle WA, USA.
Memorial Sloan Kettering Cancer Center, New York NY, USA.
Netherlands Cancer Institute, Amsterdam, the Netherlands.
Mount Sinai, New York NY, USA.
BART Cancer Institute, London, UK.
Genentech, South San Francisco CA, USA. Electronic address: .

Source: Hamidi H., Senbabaoglu Y., Beig N. et al. Molecular heterogeneity in urothelial carcinoma and determinants of clinical benefit to PD-L1 blockade. Cancer Cell. 2024 Dec 9;42(12):2098-2112.e4. doi: 10.1016/j.ccell.2024.10.016.

Read an Expert Commentary by Bishoy Faltas, MD

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