Bladder preservation therapy in combination with atezolizumab and radiation therapy trial, which was a multicenter, open-label, single-arm phase 2 study, showed a promisingly high interim clinical complete response (cCR) rate of 84. 4% (38/45). In the present study, we aimed to identify potential tissue biomarkers for achieving cCR using bladder preservation therapy in combination with atezolizumab and radiation therapy.
We used tumor tissue samples of the bladder and blood samples collected from patients at baseline to analyze the tumor immune microenvironment at baseline using an integrated approach of immunophenotyping, genomic, and tumor-infiltrating lymphocyte (TIL) profiling.
Immune phenotype analysis revealed that cCR rates of patients with the desert phenotype were as similarly high as patients with excluded/inflamed phenotypes (73.3% [11/15] vs 93.3% [14/15], P = .33) despite lower programmed death-ligand 1 expression levels in the desert phenotype. Genomic and TIL profiling then revealed that increased CD8+ and CD204+ TIL infiltration, high CD8:forkhead box protein P3 ratios in the stroma of the excluded/inflamed phenotypes, and gene alterations, such as CDK12, GNAS, NOTCH2, and AR1D1A, were associated with a high cCR rate (93.3%). Furthermore, the characteristics of these dual TILs, CD8-forkhead box protein P3 ratios, and gene alterations (especially FGFR3) bifurcated the desert phenotype into 2 subgroups with different cCR rates (100% [11/11] and 0% [0/4]).
These potential subgroups, defined by combined molecular subclass and immune phenotype, could lead to the identification of good responders to atezolizumab plus radiation therapy for invasive bladder cancer. However, given the small cohort size and limited number of tumor samples, these findings should be viewed as hypothesis-generating and require further validation in larger studies.
International journal of radiation oncology, biology, physics. 2025 Jan 02 [Epub ahead of print]
Yoshiyuki Nagumo, Kyosuke Hattori, Tomokazu Kimura, Yuta Sekino, Taku Naiki, Yasuyuki Kobayashi, Takashi Matsumoto, Takahiro Osawa, Yuki Kita, Masae Takemura, Bryan J Mathis, Susumu Suzuki, Toyonori Tsuzuki, Hitoshi Ishikawa, Hiroyuki Nishiyama
Department of Urology, University of Tsukuba, Ibaraki, Japan., Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Surgical Pathology, Aichi Medical University Hospital, Aichi, Japan., Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Department of Radiation Oncology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan., Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan., Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan., Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Department of Urology, Hokkaido University Hospital, Sapporo, Japan., Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan., Department of Clinical Research Support Center, Tsukuba Clinical Research and Development Organization (T-CReDO), University of Tsukuba, Ibaraki, Japan., Department of Cardiovascular Surgery, University of Tsukuba Institute of Medicine, Ibaraki, Japan., Research Creation Support Centre, Aichi Medical University, Nagakute, Aichi, Japan., Department of Surgical Pathology, Aichi Medical University Hospital, Aichi, Japan., National Institutes for Quantum Science and Technology Hospital, Chiba, Japan., Department of Urology, University of Tsukuba, Ibaraki, Japan. Electronic address: .