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Molecular Features of Invasive Bladder Cancer Resemble Those of Breast Cancer

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Key Points

  • Basal muscle-invasive bladder cancers shared biomarkers with basal breast cancers and were characterized by p63 activation, squamous differentiation, and more aggressive disease at presentation.
  • Luminal muscle-invasive bladder cancers contained features of active PPARγ and estrogen receptor transcription and were enriched with activating FGFR3 mutations and potential FGFR inhibitor sensitivity.
  • The p53-like muscle-invasive bladder cancers closely resembled luminal A breast cancers and were resistant to neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy.

Using whole-genome mRNA-expression profiling, researchers have identified three molecular subtypes of muscle-invasive bladder cancers that shared molecular features with basal and luminal breast cancers. The findings have important implications for prognostication, the future clinical development of targeted drugs, and disease management with conventional chemotherapy. The study by Choi et al is published in Cancer Cell.

The researchers first analyzed 73 flash-frozen bladder cancer tumor samples and then validated the initial findings in a more conventional set of 57 formalin-fixed, paraffin-embedded samples. The findings were confirmed in publicly available gene-expression profiling data sets.

Study Findings

The scientists discovered basal muscle-invasive bladder cancers shared biomarkers with basal breast cancers and were characterized by p63 activation, squamous differentiation, and more aggressive disease at presentation. Luminal muscle-invasive bladder cancers contained features of active PPARγ and estrogen receptor transcription and were enriched with activating FGFR3 mutations and potential FGFR inhibitor sensitivity. The p53-like muscle-invasive bladder cancers, which closely resemble luminal A breast cancers, were consistently resistant to neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy, and all chemoresistant tumors adopted a p53-like phenotype after therapy.

“Together, the data indicate that ‘p53-ness’ plays a central role in chemoresistance in bladder cancer and suggest that it should be possible to prospectively identify the patients who most likely will not benefit from neoadjuvant chemotherapy,” wrote the researchers.

Next Steps

“Several of our findings have immediate potential impact on how we address muscle-invasive bladder cancer with chemotherapy,” David McConkey, PhD, Professor of Urology at The University of Texas MD Anderson Cancer Center and a senior author of the study, said in a statement. “There are no targeted therapies for this high-grade cancer now, so a future implication of these findings [will be in] developing new, better approaches for treating our patients.”

A multi-institutional prospective phase II clinical trial for muscle-invasive bladder cancer is launching soon led by SWOG (formerly the Southwest Oncology Group) and will allow an even more rigorous assessment of the subtypes’ clinical value to guide therapy, said Dr. McConkey.

According to the National Cancer Institute (NCI), about 70,000 new cases of bladder cancer are diagnosed annually and approximately 15,000 people die each year.

Dr. McConkey is the corresponding author for the Cancer Cell article.

This study was funded by the Dexter F. and Dorothy H. Baker Foundation, the MD Anderson Bladder Specialized Program in Research Excellence grant from the NCI, and the MD Anderson’s Cancer Center Support Grant from the NCI. The study authors disclosed that the MD Anderson Cancer Center has submitted a patent that covers some of the findings reported in this study.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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