Highlights
- •In small cell carcinoma of the bladder, neoadjuvant chemotherapy improves survival.
- •Pathologic response is associated with superior long-term survival.
- •Metastatic disease is associated with poor clinical outcomes.
- •Small cell carcinoma of the bladder harbors high tumor mutation burden.
- •ERCC2 mutations are associated with complete response to neoadjuvant chemotherapy.
Abstract
Introduction
Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with
poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic
(M1) SCCB and correlated pathologic response with genomic alterations of patients
treated with neoadjuvant chemotherapy (NAC).
Patients and Methods
Clinical history and pathology samples from SCCB patients diagnosed at our institution
were reviewed.
Results
One hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52
[26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only:
23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy
alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1
years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and
1.2 years, respectively. NAC patients had pathologic response (<pT2pN0) and pathologic
complete response (pT0pN0) rates of 48% and 38%, respectively, with median follow-up
of 7.2 years, and median DFS and OS of 5.6 and 14.5 years, respectively. NAC responders
(<ypT2N0) had superior median DFS (14.5 vs. 0.6 years, hazard ratio [HR] 0.24, P< .001) and OS (14.5 vs. 2.5 years, HR 0.31, P = .002). DFS rates for responders and nonresponders were 76% and 27% at 5 years,
and 71% and 23% at 10 years, respectively. Local and central nervous system recurrences
were infrequent. Median progression-free survival (PFS) and OS for M1 disease were
6.9 and 10.3 months, respectively. Genomic profiling was performed on 47 NAC patients.
Loss of ERCC2 function was significantly enriched among those with pathologic complete
response to NAC (mutations present in 50% of pathologic complete responders vs. 15%
nonresponders, P = .045).
Conclusion
M0 SCCB is chemo-sensitive and patients have excellent long-term survival following
response to NAC. Patients with M1 disease have poor survival despite systemic therapy.
Loss-of-function mutations of ERCC2 were associated with pathologic complete response
to NAC.
Keywords
Abbreviations:
CNS (Central nervous system), DFS (Disease-free survival), FGA (Fraction of genome altered), HR (Hazard ratio), M0 (Non-metastatic), M1 (Metastatic), MSK-IMPACT (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets), NAC (Neoadjuvant chemotherapy), NOS (Not otherwise specified), OS (Overall survival), PFS (Progression-free survival), RC (Radical cystectomy), SCCB (Small cell carcinoma of the bladder), TMB (Tumor mutation burden)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinical Genitourinary CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- A population-based study of incidence and patient survival of small cell carcinoma in the United States, 1992-2010.BMC Cancer. 2015; 15: 185
- Should patients with extrapulmonary small-cell carcinoma receive prophylactic cranial irradiation?.J Thorac Oncol. 2013; 8: 1215-1221
- Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.Nat Med. 2017; 23: 703-713
- COSMIC: somatic cancer genetics at high-resolution.Nucleic Acids Res. 2017; 45: D777-D783
- Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.Nat Biotechnol. 2016; 34: 155-163
- OncoKB: a precision oncology knowledge base.OncoKB: A Precision Oncology Knowledge Base. JCO Precis Oncol. Jul;2017:PO.17.00011. doi:10.1200/PO.17.00011. Epub 2017 May 16. PMID: 28890946; PMCID: PMC5586540. 2017;
- Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma.Cancer Discov. 2014; 4: 1140-1153
- ERCC2 helicase domain mutations confer nucleotide excision repair deficiency and drive cisplatin sensitivity in muscle-invasive bladder cancer.Clin Cancer Res. 2019; 25: 977-988
- A method and server for predicting damaging missense mutations.Nat Methods. 2010; 7: 248-249
- Treatment outcomes for small cell carcinoma of the bladder: results from a UK patient retrospective cohort study.Int J Radiat Oncol Biol Phys. 2021; 110: 1143-1150
- Survival of contemporary patients with non-metastatic small-cell carcinoma of urinary bladder, according to alternative treatment modalities.Clin Genitourin Cancer. 2020; 18: e450-e456
- Prognostic variables in patients with non-metastatic small-cell neuroendocrine carcinoma of the bladder: a population-based study.Clin Genitourin Cancer. 2019; 17: e724-e732
- Small-cell carcinoma of the bladder: 20-year single-institution retrospective review.Clin Genitourin Cancer. 2017; 15: e337-e343
- Treatment patterns and survival outcomes for patients with small cell carcinoma of the bladder.Eur Urol Focus. 2018; 4: 900-906
- Neuroendocrine carcinoma of the urinary bladder: a large, retrospective study from the French Genito-urinary tumor group.Clin Genitourin Cancer. 2020; 18 (e293): 295-303
- Neoadjuvant chemotherapy in small cell urothelial cancer improves pathologic downstaging and long-term outcomes: results from a retrospective study at the MD Anderson Cancer Center.Eur Urol. 2013; 64: 307-313
- Outcome of recurrent and metastatic small cell carcinoma of the bladder.BMC Urol. 2009; 9: 4
- Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study.J Clin Oncol. 2000; 18: 3068-3077
- Small-cell carcinomas of the bladder and lung are characterized by a convergent but distinct pathogenesis.Clin Cancer Res. 2018; 24: 1965-1973
- Urothelial cancers with small cell variant histology have confirmed high tumor mutational burden, frequent tp53 and rb mutations, and a unique gene expression profile.Eur Urol Oncol. 2021; 4: 297-300
- Helicase domain mutations confer nucleotide excision repair deficiency and drive cisplatin sensitivity in muscle-invasive bladder cancer.Clin Cancer Res. 2019; 25: 977-988
- DNA damage response and repair gene alterations are associated with improved survival in patients with platinum-treated advanced urothelial carcinoma.Clin Cancer Res. 2017; 23: 3610-3618
- Clinical validation of chemotherapy response biomarker ERCC2 in muscle-invasive urothelial bladder carcinoma.JAMA Oncol. 2016; 2: 1094-1096
- Pembrolizumab as second-line therapy for advanced urothelial carcinoma.N Engl J Med. 2017; 376: 1015-1026
- Enfortumab vedotin in previously treated advanced urothelial carcinoma.N Engl J Med. 2021; 384: 1125-1135
- Immune exclusion is frequent in small-cell carcinoma of the bladder.Dis Markers. 2019; 20192532518
- PD-L1 expression in urothelial carcinoma with predominant or pure variant histology: concordance among 3 commonly used and commercially available antibodies.Am J Surg Pathol. 2019; 43: 920-927
- A phase II trial of durvalumab and tremelimumab in metastatic, non-urothelial carcinoma of the urinary tract.Cancer Med. 2021; 10: 1074-1083
- Results of a multicenter, phase 2 study of nivolumab and ipilimumab for patients with advanced rare genitourinary malignancies.Cancer. 2021; 127: 840-849
- Expression of Nectin-4 in Bladder Urothelial Carcinoma, in Morphologic Variants, and Nonurothelial Histotypes.Appl Immunohistochem Mol Morphol. 2021; 29 (Sep 1. PMID: 33901032; PMCID: PMC84290501): 619-625https://doi.org/10.1097/PAI.0000000000000938
Article info
Publication history
Published online: May 10, 2022
Accepted:
May 8,
2022
Received in revised form:
May 5,
2022
Received:
January 17,
2022
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.