Dataset Information

Neoadjuvant Cisplatin, Gemcitabine, and Docetaxel in Sarcomatoid Bladder Cancer: Clinical Activity and Whole Transcriptome Analysis.

ABSTRACT:

Background

Sarcomatoid urothelial cancer of the bladder (SBC) is a rare, but aggressive histological subtype for which novel treatments are needed.

Objective

We evaluated the clinical activity and safety of neoadjuvant cisplatin plus gemcitabine plus docetaxel (CGD) in muscle-invasive patients with SBC and assessed SBC tumor biology by whole transcriptome RNA sequencing.

Methods

A single-institution, retrospective analysis of muscle-invasive SBC patients treated with neoadjuvant CGD with molecular analysis. Patients received cisplatin 35 mg/m2 + gemcitabine 800 mg/m2 + docetaxel 35 mg/m2 intravenously on days 1 and 8 + pegfilgrastim 6 mg subcutaneously on day 9 every 3 weeks for 4 cycles followed by cystectomy. The primary endpoint was pathologic complete response (ypCR) rate.

Results

Sixteen patients with SBC received neoadjuvant CGD with a ypCR rate of 38% and a < ypT2 rate of 50%. Grade 3 and 4 toxicity occurred in 80% and 40% of patients, but was manageable with 81% of patients completing > 3 CGD cycles. Whole transcriptome RNA sequencing demonstrates co-clustering of SBC with conventional urothelial tumors. SBC tumors are characterized by basal-squamous and stroma rich gene signatures with frequent increased expression of immune checkpoint (CD274 (PD-L1)), chemokine (CXCL9), and T-cell (CD8A) genes.

Conclusions

SBC is a chemosensitive subtype, with ypCR rate similar to urothelial bladder cancer following CGD neoadjuvant therapy. Whole transcriptome tissue analyses demonstrate increased expression of immune checkpoint and T-cell genes with therapeutic implications.

SUBMITTER: Johnson Iii BA

PROVIDER: S-EPMC11308648 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Publications

Neoadjuvant Cisplatin, Gemcitabine, and Docetaxel in Sarcomatoid Bladder Cancer: Clinical Activity and Whole Transcriptome Analysis.

Johnson Iii Burles A BA Teply Benjamin A BA Kagemann Catherine C McGuire Bridget B Lombardo Kara K Jing Yuezhou Y Langbo William W Epstein Jonathan I JI Netto George J GJ Baras Alex S AS Matoso Andres A McConkey David J DJ Gupta Amol A Ahuja Nita N Ross Ashley E AE Pierorazio Phillip M PM Comperat Eva E Hoffman-Censits Jean J Singla Nirmish N Patel Sunil H SH Kates Max M Choi Woonyoung W Bivalacqua Trinity J TJ Hahn Noah M NM

Bladder cancer (Amsterdam, Netherlands) 20240618 2

<h4>Background</h4>Sarcomatoid urothelial cancer of the bladder (SBC) is a rare, but aggressive histological subtype for which novel treatments are needed.<h4>Objective</h4>We evaluated the clinical activity and safety of neoadjuvant cisplatin plus gemcitabine plus docetaxel (CGD) in muscle-invasive patients with SBC and assessed SBC tumor biology by whole transcriptome RNA sequencing.<h4>Methods</h4>A single-institution, retrospective analysis of muscle-invasive SBC patients treated with neoadj ...[more]

PMID: 39131872

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Project description:Purpose Neoadjuvant chemotherapy followed by radical cystectomy (RC) is a standard of care for the management of muscle-invasive bladder cancer (MIBC). Dose-dense cisplatin-based regimens have yielded favorable outcomes compared with standard-dose chemotherapy, yet the optimal neoadjuvant regimen remains undefined. We assessed the efficacy and tolerability of six cycles of neoadjuvant dose-dense gemcitabine and cisplatin (ddGC) in patients with MIBC. Patients and Methods In this prospective, multicenter phase II study, patients received ddGC (gemcitabine 2,500 mg/m2 on day 1 and cisplatin 35 mg/m2 on days 1 and 2) every 2 weeks for 6 cycles followed by RC. The primary end point was pathologic downstaging to non-muscle-invasive disease (< pT2N0). Patients who did not undergo RC were deemed nonresponders. Pretreatment tumors underwent next-generation sequencing to identify predictors of chemosensitivity. Results Forty-nine patients were enrolled from three institutions. The primary end point was met, with 57% of 46 evaluable patients downstaged to < pT2N0. Pathologic response correlated with improved recurrence-free survival and overall survival. Nineteen patients (39%) required toxicity-related dose modifications. Sixty-seven percent of patients completed all six planned cycles. No patient failed to undergo RC as a result of chemotherapy-associated toxicities. The most frequent treatment-related toxicity was anemia (12%; grade 3). The presence of a presumed deleterious DNA damage response (DDR) gene alteration was associated with chemosensitivity (positive predictive value for < pT2N0 [89%]). No patient with a deleterious DDR gene alteration has experienced recurrence at a median follow-up of 2 years. Conclusion Six cycles of ddGC is an active, well-tolerated neoadjuvant regimen for the treatment of patients with MIBC. The presence of a putative deleterious DDR gene alteration in pretreatment tumor tissue strongly predicted for chemosensitivity, durable response, and superior long-term survival.

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Dataset Information

Neoadjuvant Cisplatin, Gemcitabine, and Docetaxel in Sarcomatoid Bladder Cancer: Clinical Activity and Whole Transcriptome Analysis.

Background

Objective

Methods

Results

Conclusions

Publications

Neoadjuvant Cisplatin, Gemcitabine, and Docetaxel in Sarcomatoid Bladder Cancer: Clinical Activity and Whole Transcriptome Analysis.

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