Hyperprogression after anti-programmed cell death ligand-1 therapy in a patient with recurrent metastatic urothelial bladder carcinoma following first-line cisplatin-based chemotherapy: a case report

Abstract

Background

Immune checkpoint blockade targeting programmed cell death ligand-1 (PD-L1)/programmed death-1 (PD-1) signaling was approved recently for locally advanced and metastatic urothelial bladder carcinoma (UBC). Some patients experience a very rapid tumor progression, rather than clinical benefit, from anti-PD-L1/PD-1 therapy.

Case presentation

A 58-year-old male diagnosed with non-muscle-invasive bladder cancer 3 years ago received transurethral resection of bladder tumor (TURBT) and intravesical chemotherapy. TURBT was repeated a year later for recurrent and progressive UBC. Following further disease progression, he received a radical cystectomy (RC), pathologically staged as T2bN2M0, and adjuvant cisplatin-containing combination chemotherapy. When his disease progressed to metastatic UBC, he was started on anti-PD-L1 monotherapy and experienced ultrarapid disease progression within 2 months; imaging scans ruled out pseudoprogression. We observed a fourfold increase in tumor growth rate, defined as the ratio of post- to pretreatment rates. Next-generation sequencing of formalin-fixed paraffin-embedded RC tissues showed MDM2 amplification without MDM4 amplification, EGFR aberrations, or DNMT3A alterations. Immunohistochemistry showed grade 2+ PD-L1 labeling intensity of the RC tissues, with 15%–25% and 5%–10% PD-LI immunopositive tumor cells and tumor-infiltrating immune cells, respectively.

Conclusion

Even in cases with PD-L1-positive tumors, MDM2 gene amplification may result in failure of anti-PD-L1 immunotherapy and rapid tumor growth. Therefore, genomic profiling may identify patients at risk for hyperprogression before immunotherapy.

Keywords:

• urothelial bladder carcinoma
• programmed cell death ligand-1
• immune checkpoint blockade
• hyperprogression
• MDM2

Acknowledgments

This study was funded by the Natural Science Foundation of China (grant number 81472389) and Shanghai Health and Family Planning Commission Key Project (grant number 20124008). The abstract of this paper was presented at the Global Congress on Bladder Cancer 2018 as a poster presentation with interim findings. The poster’s abstract was published in Abstract book (ISBN 9789462210165) and as an e-poster online: https://abstracts.mirrorsmed.org/abstracts/hyperprogression-after-immunotherapy-patient-recurrent-and-metastatic-urothelial-bladder.

Author contributions

YY and XY designed and guided the present study. SM, JZ, and YG collected the study data. SM, YW, ZZ, and WZ analyzed and interpreted the data. LW, JZ, and YG made figures and tables. SM was a major contributor in writing the manuscript. JG, YY, and XY revised the manuscript. All authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

Supplementary material

Table S1 Gene detection list