PURPOSE OF REVIEW: In this review, we aimed to summarize the available evidence on pretreatment molecular biomarkers that may help to predict oncologic and pathologic outcomes in patients treated with neoadjuvant systemic therapy (NAST) for urothelial carcinoma of the bladder (UCB). RECENT FINDINGS: Several readily available and easily measurable blood-based biomarkers (e.g., neutrophil to lymphocyte or platelet-lymphocyte ratios) seems to help improve the selection of UCB patients who are most likely to benefit from NAST. Recent evidence suggests liquid biopsy including circulating tumor DNA (ctDNA) to be a promising tool to guide the administration of NAST in UCB patients. Pretreatment molecular and genetic characterization of transurethral resection of the bladder tumor samples may also help understand the tumor biology as luminal and basal tumor subtypes seems to be more responsive to NAST, while claudin-low and luminal-infiltrated tumor subtypes are less. In the context of neoadjuvant immunotherapy, programmed death-ligand 1 (PD-L1) status and ctDNA remain the only biomarker with possible value as the clinical utility of tumor mutational burden remains controversial/poor. SUMMARY: Biomarker approach is a necessary step to usher the age of precision/personalized medicine for muscle-invasive UCB with the overarching good to prevent both over- and under-therapy. The present review may offer a robust framework to compare and assess current and future molecular biomarkers for the selection of NAST in muscle-invasive UCB.

Cancer Prognostics and Health Outcomes Unit University of Montreal Health Centre Montreal Canada

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Urology La Croix Du Sud Hospital Quint Fonsegrives France

Department of Urology University of Texas Southwestern Dallas Texas USA

Department of Urology Weill Cornell Medical College New York New York USA

Hourani Center for Applied Scientific Research Al Ahliyya Amman University Amman Jordan

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

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Witjes JA, Bruins HM, Cathomas R, et al. European Association of Urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2020 guidelines. Eur Urol 2021; 79:82–104.

Witjes JA, Babjuk M, Bellmunt J, et al. EAU-ESMO consensus statements on the management of advanced and variant bladder cancer—an international collaborative multistakeholder effort: under the Auspices of the EAU-ESMO Guidelines Committees. Eur Urol 2020; 77:223–250.

Zargar H, Espiritu PN, Fairey AS, et al. Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol 2015; 67:241–249.

Moschini M, Soria F, Klatte T, et al. Validation of preoperative risk grouping of the selection of patients most likely to benefit from neoadjuvant chemotherapy before radical cystectomy. Clin Genitourin Cancer 2017; 15:e267–e273.

Aziz A, May M, Burger M, et al. Prediction of 90-day mortality after radical cystectomy for bladder cancer in a prospective European multicenter cohort. Eur Urol 2014; 66:156–163.

Lotan Y, Woldu SL, Sanli O, et al. Modeling cost-effectiveness of a biomarker-based approach to neoadjuvant chemotherapy for muscle-invasive bladder cancer. BJU Int 2019; 122:434–440.

Laukhtina E, Pradere B, Mori K, et al. Prognostic blood-based biomarkers in patients treated with neoadjuvant chemotherapy for urothelial carcinoma of the bladder: a systematic review. Urol Oncol Semin Orig Investig 2021; 39:471–479.

Laukhtina E, Pradere B, Mori K, et al. Catalog of prognostic tissue-based biomarkers in patients treated with neoadjuvant systemic therapy for urothelial carcinoma of the bladder: a systematic review. Urol Oncol Semin Orig Investig 2021; 39:180–190.

Bensalah K, Montorsi F, Shariat SF. Challenges of cancer biomarker profiling. Eur Urol 2007; 52:1601–1609.

Seah J-A, Leibowitz-Amit R, Atenafu EG, et al. Neutrophil-lymphocyte ratio and pathological response to neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer. Clin Genitourin Cancer 2015; 13:e229–e233.

Buisan O, Orsola A, Areal J, et al. Low pretreatment neutrophil-to-lymphocyte ratio predicts for good outcomes in patients receiving neoadjuvant chemotherapy before radical cystectomy for muscle invasive bladder cancer. Clin Genitourin Cancer 2017; 15:145.e2–151.e2.

Leibowitz-Amit R, Israel A, Gal M, et al. Association between the absolute baseline lymphocyte count and response to neoadjuvant platinum-based chemotherapy in muscle-invasive bladder cancer. Clin Oncol 2016; 28:790–796.

Ojerholm E, Smith A, Hwang WT, et al. Neutrophil-to-lymphocyte ratio as a bladder cancer biomarker: assessing prognostic and predictive value in SWOG 8710. Cancer 2017; 123:794–801.

Kaiser J, Li H, North SA, et al. The prognostic role of the change in neutrophil-to-lymphocyte ratio during neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer: a retrospective, multi-institutional study. Bl Cancer 2018; 4:185–194.

Kuwada M, Miyake M, Gotoh D, et al. Pretreatment platelet-to-lymphocyte ratio as biomarker for neoadjuvant chemotherapy prior to radical cystectomy in muscle-invasive bladder cancer. J Nara Med Assoc 2017; 68:29–41.

Shariat SF, Lotan Y, Vickers A, et al. Statistical consideration for clinical biomarker research in bladder cancer. Urol Oncol Semin Orig Investig 2010; 28:389–400.

Soygür T, Bedük Y, Baltaci S, et al. The prognostic value of peripheral blood lymphocyte subsets in patients with bladder carcinoma treated using neoadjuvant M-VEC chemotherapy. BJU Int 1999; 84:1069–1072.

Ornstein MC, Diaz-Montero CM, Rayman P, et al. Myeloid-derived suppressors cells (MDSC) correlate with clinicopathologic factors and pathologic complete response (pCR) in patients with urothelial carcinoma (UC) undergoing cystectomy. Urol Oncol 2018; 36:405–412.

Douglas J, Sharp A, Chau C, et al. Serum total hCGβ level is an independent prognostic factor in transitional cell carcinoma of the urothelial tract. Br J Cancer 2014; 110:1759–1766.

Bazargani ST, Clifford TG, Djaladat H, et al. Association between precystectomy epithelial tumor marker response to neoadjuvant chemotherapy and oncological outcomes in urothelial bladder cancer. Urol Oncol 2019; 37:1–11.

Shariat SF, Kattan MW, Traxel E, et al. Association of pre and postoperative plasma levels of transforming growth factor beta(1) and interleukin 6 and its soluble receptor with prostate cancer progression. Clin Cancer Res 2004; 10:1992–1999.

Shariat SF, Kattan MW, Song W, et al. Early postoperative peripheral blood reverse transcription PCR assay for prostate-specific antigen is associated with prostate cancer progression in patients undergoing radical prostatectomy. Cancer Res 2003; 63:5874–5878.

Rink M, Chun FK, Dahlem R, et al. Prognostic role and HER2 expression of circulating tumor cells in peripheral blood of patients prior to radical cystectomy: a prospective study. Eur Urol 2012; 61:810–817.

Pantel K, Speicher MR. The biology of circulating tumor cells. Oncogene 2016; 35:1216–1224.

Soave A, Riethdorf S, Dahlem R, et al. A nonrandomized, prospective, clinical study on the impact of circulating tumor cells on outcomes of urothelial carcinoma of the bladder patients treated with radical cystectomy with or without adjuvant chemotherapy. Int J Cancer 2017; 140:381–389.

Alva A, Friedlander T, Clark M, et al. Circulating tumor cells as potential biomarkers in bladder cancer. J Urol 2015; 194:790–798.

Laukhtina E, Hassler MR, Pradere B, et al. Circulating tumour DNA is a strong predictor of outcomes in patients treated with systemic therapy for urothelial carcinoma. Eur Urol Focus 2022; doi:10.1016/j.euf.2022.04.017. DOI

Christensen E, Birkenkamp-Demtröder K, Sethi H, et al. Early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing of plasma cell-free DNA in patients with urothelial bladder carcinoma. J Clin Oncol 2019; 37:1547–1557.

Togneri FS, Ward DG, Foster JM, et al. Genomic complexity of urothelial bladder cancer revealed in urinary cfDNA. Eur J Hum Genet 2016; 24:1167–1174.

Patel KM, van der Vos KE, Smith CG, et al. Association of plasma and urinary mutant DNA with clinical outcomes in muscle invasive bladder cancer. Sci Rep 2017; 7:5554.

Shariat SF, Ashfaq R, Karakiewicz PI, et al. Survivin expression is associated with bladder cancer presence, stage, progression, and mortality. Cancer 2007; 109:1106–1113.

Margulis V, Shariat SF, Ashfaq R, et al. Ki-67 is an independent predictor of bladder cancer outcome in patients treated with radical cystectomy for organ-confined disease. Clin Cancer Res 2006; 12:7369–7373.

Byrne RR, Shariat SF, Brown R, et al. E-cadherin immunostaining of bladder transitional cell carcinoma, carcinoma in situ and lymph node metastases with long-term followup. J Urol 2001; 165:1473–1479.

Shariat SF, Zlotta AR, Ashfaq R, et al. Cooperative effect of cell-cycle regulators expression on bladder cancer development and biologic aggressiveness. Mod Pathol 2007; 20:445–459.

Shariat SF, Chade DC, Karakiewicz PI, et al. Combination of multiple molecular markers can improve prognostication in patients with locally advanced and lymph node positive bladder cancer. J Urol 2010; 183:68–75.

Seiler R, Ashab HAD, Erho N, et al. Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy. Eur Urol 2017; 72:544–554.

Seiler R, Gibb EA, Wang NQ, et al. Divergent biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer. Clin Cancer Res 2019; 25:5082–5093.

Efstathiou JA, Mouw KW, Gibb EA, et al. Impact of immune and stromal infiltration on outcomes following bladder-sparing trimodality therapy for muscle-invasive bladder cancer. Eur Urol 2019; 76:59–68.

Lotan Y, Jong JJ De, Liu VYT, et al. Patients with muscle-invasive bladder cancer with nonluminal subtype derive greatest benefit from platinum based neoadjuvant chemotherapy. J Urol 2022; 207:541–550.

Necchi A, Raggi D, Gallina A, et al. Impact of molecular subtyping and immune infiltration on pathological response and outcome following neoadjuvant pembrolizumab in muscle-invasive bladder cancer. Eur Urol 2020; 77:701–710.

Yang Z, Zhang R, Ge Y, et al. Somatic FGFR3 mutations distinguish a subgroup of muscle-invasive bladder cancers with response to neoadjuvant chemotherapy. EBioMedicine 2018; 35:198–203.

Kiss B, Wyatt AW, Douglas J, et al. Her2 alterations in muscle-invasive bladder cancer: Patient selection beyond protein expression for targeted therapy. Sci Rep 2017; 7:42713.

Choueiri TK, Jacobus S, Bellmunt J, et al. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol 2014; 32:1889–1894.

Plimack ER, Dunbrack RL, Brennan TA, et al. Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. Eur Urol 2015; 68:959–967.

Van Allen EM, Mouw KW, Kim P, et al. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov 2014; 4:1140–1153.

Font A, Taron M, Gago JL, et al. BRCA1 mRNA expression and outcome to neoadjuvant cisplatin-based chemotherapy in bladder cancer. Ann Oncol 2011; 22:139–144.

Kato Y, Zembutsu H, Takata R, et al. Predicting response of bladder cancers to gemcitabine and carboplatin neoadjuvant chemotherapy through genome-wide gene expression profiling. Exp Ther Med 2011; 2:47–56.

Vinall RL, Tepper CG, Ripoll AAZ, et al. Decreased expression of let-7c is associated with nonresponse of muscle-invasive bladder cancer patients to neoadjuvant chemotherapy. Genes Cancer 2016; 7:86–97.

Xylinas E, Robinson BD, Kluth LA, et al. Association of T-cell co-regulatory protein expression with clinical outcomes following radical cystectomy for urothelial carcinoma of the bladder. Eur J Surg Oncol 2014; 40:121–127.

Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): an open-label, single-arm, phase II study. J Clin Oncol 2018; 36:3353–3360.

Powles T, Kockx M, Rodriguez-Vida A, et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med 2019; 25:1706–1714.

Rose TL, Harrison MR, Deal AM, et al. Phase II study of gemcitabine and split-dose cisplatin plus pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive bladder cancer. J Clin Oncol 2021; 39:3140–3148.

Necchi A, Raggi D, Gallina A, et al. Updated results of PURE-01 with preliminary activity of neoadjuvant pembrolizumab in patients with muscle-invasive bladder carcinoma with variant histologies. Eur Urol 2020; 77:439–446.

Bandini M, Ross JS, Raggi D, et al. Predicting the pathologic complete response after neoadjuvant pembrolizumab in muscle-invasive bladder cancer. J Natl Cancer Inst 2020; 113:48–53.

Passoni NM, Shariat SF, Bagrodia A, et al. Concordance in biomarker status between bladder tumors at time of transurethral resection and subsequent radical cystectomy: results of a 5-year prospective study. Bl Cancer 2016; 2:91–99.

Groenendijk FH, de Jong J, Fransen van de Putte EE, et al. ERBB2 mutations characterize a subgroup of muscle-invasive bladder cancers with excellent response to neoadjuvant chemotherapy. Eur Urol 2016; 69:384–388.

Miron B, Hoffman-Censits JH, Anari F, et al. Defects in DNA repair genes confer improved long-term survival after cisplatin-based neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol Oncol 2020; 3:544–547.

Hassler MR, Bray F, Catto JWF, et al. Molecular characterization of upper tract urothelial carcinoma in the era of next-generation sequencing: a systematic review of the current literature. Eur Urol 2020; 78:209–220.

Adjuvant Immune Checkpoint Inhibitors for Muscle-Invasive Urothelial Carcinoma: An Updated Systematic Review, Meta-analysis, and Network Meta-analysis