Genomic Landscape of Vinflunine Response in Metastatic Urothelial Cancer

Background and Aims: Metastatic urothelial carcinoma (mUC) remains an incurable disease with limited treatment options after platinum-based chemotherapy and immune checkpoint blockade (ICB). Vinflunine has shown a modest increase in overall survival and remains a therapeutic option for chemo- and immunotherapy refractory tumours. However, biomarkers that could identify responding patients to vinflunine and possible alternative therapies after failure to treatment are still missing. In this study, we aimed to identify potential genomic biomarkers of vinflunine response in mUC patient samples and potential management alternatives. Methods: Formalin-fixed paraffin-embedded samples of mUC patients (n = 23) from three university hospitals in Spain were used for genomic targeted-sequencing and transcriptome (using the Immune Profile panel by NanoString) analyses. Patients who received vinflunine after platinum-based chemotherapy failure were classified in non-responders (NR: progressive disease ≤ 3 months; n= 11) or responders (R: response ≥ 6 months; n = 12). Results: Genomic characterization revealed that the most common alteration, TP53 mutations, had comparable frequency in R (6/12; 50%) and NR (4/11; 36%). Non-synonymous mutations in KTM2C (4/12; 33.3%), PIK3CA (3/12; 25%) and ARID2 (3/12; 25%) were predominantly associated with response. No significant difference was observed in tumour mutational burden (TMB) between R and NR patients. The NR tumours showed increased expression of diverse immune-related genes and pathways, including various interferon gamma-related genes. We also identified increased MAGEA4 expression as a potential biomarker of non-responding tumours to vinflunine treatment. Conclusions: Our data may help to identify potential genomic biomarkers of response to vinflunine. Moreover, tumours refractory to vinflunine showed immune signatures potentially associated with response to ICB. Extensive validation studies, including longitudinal series, are needed to corroborate these findings.

Biomarkers for therapy selection in metastatic urothelial cancer

The treatment of metastatic urothelial cancer (mUC) has been transformed by recent progress in clinical trials and drug development. There are now three therapeutic classes with proven benefits in mUC: chemotherapy, immunotherapy, and targeted therapy. The optimal sequence and combination of these classes remain to be defined. Biomarker development is essential to guide treatment selection at each therapeutic juncture. Two biomarkers, programmed death-ligand 1 expression and fibroblast growth factor receptor alterations, have been incorporated into the mUC treatment paradigm thus far. This review discusses predictive biomarkers in development and their potential to influence mUC treatment selection moving forward.

Qualitative Analysis of Pain in Patients With Locally Advanced or Metastatic Urothelial Carcinoma

Background: Pain is not well described in patients with locally advanced or metastatic urothelial cancer (la/mUC). Objective: To characterize pain and assess the content validity of the Brief Pain Inventory Short Form (BPI-SF) worst pain item in patients with la/mUC receiving first-line treatment in the US. Methods: Qualitative interviews were conducted in patients aged≥45 years with confirmed la/mUC, self-reported la/mUC-attributed pain before enrollment, and no major surgery≤3 months prior to being interviewed. Interview participants were asked open-ended questions about their la/mUC symptoms and pain. “Think aloud” cognitive debriefing was conducted for the BPI-SF worst pain item. Results: Ten participants with laUC and six (38%) with mUC were interviewed. First-line treatments included cisplatin (n = 14; 88%) or carboplatin (n = 2; 13%). The average past-week worst pain score (0–10 scale) was 6.2 (range, 3–10); seven (44%) participants reported severe pain (score≥7). Pain was most frequently reported in the back (n = 14; 88%) and/or pelvic/lower abdominal area (n = 10; 63%). Pain impacted all participants’ physical and daily activities; 81%reported it impacted their overall quality of life. All participants interpreted and completed the BPI-SF worst pain item without difficulty; 15 (94%) reported it was relevant to their la/mUC experience. Participants understood the 24-hour recall period; most supported daily (n = 13; 81%) or weekly (n = 14; 88%) assessment, preferring electronic administration using their phone (n = 14; 88%). Conclusions: Pain attributed to la/mUC impacted physical and daily activities in all participants undergoing first-line treatment for la/mUC. Content validity was demonstrated for the BPI-SF worst pain item in this population.

Trop-2 Therapy in Metastatic Triple-Negative Breast Cancer in Italy: Clinical Opportunity and Regulatory Pitfalls

Trop-2 is an ideal candidate for targeted therapeutics because it is a transmembrane protein with an extracellular domain overexpressed in a wide variety of tumors, and is upregulated in normal cells. Consequently, several Trop-2-targeted drugs have recently been developed for clinical use, such as anti-Trop-2 antibodies. Sacituzumab govitecan, a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate, was recently approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of metastatic triple-negative breast cancer and metastatic urothelial cancer. In Italy, this treatment cannot be used in clinical practice because it has not yet been approved by the Agenzia Italiana del Farmaco (AIFA, Rome, Italy). In Italy, this is not a new problem, in fact, when a new compound is approved by the U.S. and Europe, there is often a delay in its approval for use. The adoption of universal guidelines and the standardization of Trop-2 evaluation is urgently needed.

Role of checkpoint inhibitors immunotherapy in non-muscle invasive bladder cancer: current methods and future perspectives

Immuno-therapy involvement in bladder urothelial malignancies is growing very fast. The use of Immuno-therapy with check-point inhibitor has greatly developed since it was first approved as a second-line treatment for cases who had formerly failed platinum-based chemotherapy. There are recognized applications for first-line metastatic illness in platinum-ineligible or cisplatin-ineligible PD-L1 diagnosed cases, as well as a label for BCG-refractory high-risky non-muscle invasive bladder cancer (NMIBC). It is now being studied in neo-adjuvant and adjuvant muscle invasive bladder cancer (MIBC) clinical trials. This review discusses the clinical trials that led to these FDA agreements, as well as prospective and ongoing trials. Current clinical guidelines support Bacillus Calmette-Guérin (BCG) as the primary treating option for intermediate to high-risk NMIBC. Despite the intra-vesical BCG-instillation, intra-vesical relapse occurs in a considerable number of individuals with intermediate to high risk NMIBC. Furthermore, treating BCG-nonresponsive NMIBC is still difficult. For these individuals with BCG-nonresponsive NMIBC, there are no viable therapy alternatives other than radical cystectomy, which has been shown to have excellent oncological results. In this regard, for the care of BCG-nonresponsive NMIBC, safe and reliable noninvasive or lesser-invasive therapeutic alternatives with adequate oncological results are needed. Regarding the latest introduction of immuno-therapeutic medications, the treatment of progressive or metastatic urothelial cancer has substantially advanced. These developments have sparked a surge in interest in immuno-therapeutic medications for NMIBC, particularly BCG-nonresponsive NMIBC. The goal of this literature review is to provide and debate the most up-to-date information on the function of Immuno-therapy in BCG-nonresponsive NMIBC and the presently accessible treatment options. Furthermore, this page highlights the current research in this topic. We wanted to convey the current state of Immuno-therapy in NMIBC and discuss future directions.

Transcriptional signatures associate with the clinical outcomes of immune checkpoint inhibitor treatment in advanced bladder cancer

Background Urothelial bladder cancer (UBC) is one of the most lethal cancers worldwide, the 5-year survival rate remain poor with platinum-based chemotherapy regimens as the standard of cancer treatment protocol. Recent FDA approval of a programmed death ligand-1 (PD-L1) inhibitor, atezolizumab, in advanced UBC patients is changing the therapeutic landscape. Although the response to anti-PD-L1 is correlated to PD-L1 expression and tumor mutation burden, the molecule determinants of responsiveness or non-responsiveness to immune checkpoint inhibitor (ICI) is largely unknown. Result A published immunotherapy cohort with whole exome sequencing, RNAseq and clinic outcome data for 29 metastatic urothelial cancer patients was used, paralleled with The Cancer Genome Altas Bladder Cancer cohort for validation. Genomic mutational profiling, mutational signature, a panel genes in antigen presentation and interferon signaling in bladder cancer were delineated with little correlation with durable clinic benefit (DCB) or non-DCB of PD-L1 inhibitor treatment. Whereas, characterized immune-responsive or resistant associated genes showed differentially expressed between DCB group and non-DCB group. Further more, transcriptional signature and transcriptional regulators between DCB and non-DCB were identified from transcripome data. Conclusion Our exploratory analyses provided multidimension view of complexity of determinants of immune-responsiveness and suggest the influences of transcriptional reprogram in immune checkpoint blockage therapy.