Comprehensive genomic profiling of relapsed and refractory small cell neuroendocrine carcinoma of the urinary bladder.

350 Background: Small cell neuroendocrine carcinoma of the bladder (SCCB) is rare but aggressive form of genitourinary cancer that can arise de novo or in conjunction with urothelial carcinoma (UCB). Methods: DNA was extracted from 40 microns of FFPE specimen from 29 cases of relapsed, refractory and metastatic SCCB and 1,113 UCB. Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay to a mean coverage depth of > 503X. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations (GA), including base substitutions, insertions and deletions (short variants; SV), fusions, and copy number changes including amplifications (amp) and homozygous deletions. Results: 29 SCCB cases were confirmed on routine histology and featured positive IHC staining for chromogranin, synaptophysin or both. Patients had a mean age of 68.1 years (range 49-90 years) and 25 (86%) were male. At the time of CGP, 3 (10%) SCCB were Stage III and 26 (90%) were stage IV. The primary SCCB was used for sequencing in 14 (48%) of cases and a metastasis sample in 15 (52%). The 29 SCCB featured 2.86 GA/case.The genomics of SCCB differed significantly from UCB (Table). The most frequent clinically relevant GA in SCCB were RICTOR amp (21%) and PIK3CA (10%), BRCA1, HGF, FBXW7 and CCND2 SV (7% each). The relatively high TMB in SCCB (7% TMB > 20 mut/Mb and 28% TMB > 10 mut/Mb) is similar to that seen in UCB. No SCCB cases were MSI-high. ERBB2 and FGFR1 GA frequencies (both 3%) in SCCB were lower than in similarly studied UCB. Conclusions: SCCB differs in genomic landscape from UCB in having higher frequencies of TP53 and RB1 GA and lower frequencies of FGFR3 and ERBB2 GA. However, like UCB, SCCB shares the presence of multiple GA associated with potential responses to targeted therapies and high TMB associated with response to immune checkpoint inhibitor therapy. [Table: see text]

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710P Comprehensive genomic profiling (CGP) of small cell neuroendocrine carcinoma of the bladder (NEBC)

Annals of Oncology ◽

10.1016/j.annonc.2021.08.106 ◽

2021 ◽

Vol 32 ◽

pp. S718

Author(s):

A. Necchi ◽

P. Grivas ◽

G. Bratslavsky ◽

P.E. Spiess ◽

S. Millis ◽

...

Keyword(s):

Neuroendocrine Carcinoma ◽

Small Cell ◽

Genomic Profiling ◽

Small Cell Neuroendocrine Carcinoma ◽

Comprehensive Genomic Profiling ◽

Carcinoma Of The Bladder

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Comprehensive genomic profiling of neuroendocrine carcinoma of the prostate.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.187 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 187-187

Author(s):

Sumanta K. Pal ◽

Matthew I. Milowsky ◽

Julia Andrea Elvin ◽

Siraj Mahamed Ali ◽

Jean H. Hoffman-Censits ◽

...

Keyword(s):

Neuroendocrine Carcinoma ◽

Stage Iv ◽

Mtor Inhibitors ◽

Mtor Pathway ◽

Tumor Type ◽

Genomic Profiling ◽

Genomic Alterations ◽

Carcinoma Of The Prostate ◽

Comprehensive Genomic Profiling ◽

Metastatic Sites

187 Background: Neuroendocrine carcinoma of the prostate (NCAP) is an aggressive high grade malignancy that often presents as metastatic disease. Current treatments of this tumor have only modest benefit leading investigators to query whether comprehensive genomic profiling (CGP) would have potential to discover novel targets of therapy. Methods: DNA was extracted from 40 microns of FFPE sections from 37 consecutive cases of relapsed/metastatic NCAP. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 583X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Genomic alterations (GA) included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: The median age of the men in this study was 65.1 years (range 43 to 83 years). All (100%) cases were positive for neuroendocrine markers on immunohistochemical staining and were Stage IV at the time of CGP. Samples used for sequencing were obtained from the primary tumor in 9 (24%) of NCAP and from metastatic sites in 28 (76%) of NCAP (12 liver, 6 LN, 2 each from bladder, pelvis and soft tissue, and 1 each from rectum, bone, urethra and ureter. There were 213 total GA (5.8 GA/sample) and 47 CRGA (1.3 CRGA/sample). The most frequent GA were non-CRGA mutations in TP53 (68%) and RB1 (51%). TMPRSS:ERG fusions were identified in 32% of cases whereas AR was altered in 8% (1 mutation and 2 amplifications). The most frequent CRGA involved PTEN (32%), BRCA2 (14%), FGFR1 (5%), PIK3CA (5%) and AKT2 (3%). No alterations in BRAF were identified. Clinical responses to MTOR inhibitors in patients with MTOR pathway alterations will be presented. Conclusions: NCAP has distinctive genomic alterations from classic acinar CAP including reduced frequencies of alterations in TMPRSS:ERG and AR and frequent RB1 mutations. Multiple alterations in the MTOR pathway identified in this infrequent tumor type suggest that these patients may be candidates for MTOR inhibitors and other targeted therapies.

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Comprehensive genomic profiling of urethral cancer to reveal distinctive features compared to bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.429 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 429-429

Author(s):

Tanya B. Dorff ◽

Julia Andrea Elvin ◽

Jo-Anne Vergilio ◽

James Suh ◽

Shakti Ramkissoon ◽

...

Keyword(s):

Cell Carcinoma ◽

Genomic Alteration ◽

Genomic Profiling ◽

Rare Form ◽

Distinctive Features ◽

Ffpe Specimen ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden ◽

Copy Number Changes ◽

Homozygous Deletions

429 Background: Relapsed and refractory urethral cancer (UrethC) is a rare form of genito-urinary malignancy that includes urothelial carcinoma (UC), squamous cell carcinoma (SCC), adenocarcinoma (AC) and clear cell carcinoma (CCC) subtypes. No standard treatment exists. Methods: DNA was extracted from 40 microns of FFPE specimen from 46 cases of mUrethC. Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay to a mean coverage depth of >500X. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations (GA), including base substitutions, insertions and deletions (short variants; SV), fusions, and copy number changes including amplifications (amp) and homozygous deletions. Results: The clinical features, GA, TMB findings in the mUrethC patients and the subtypes of UrethC are shown in the Table. In comparison with 1,183 similarly profiled UC of the bladder (UCB), all 46 mUrethC and the 21 urothelial mUrethC as a separate group widely differed in GA frequencies. With the exception of similar TP53 GA frequencies, there were significantly lower GA in ERBB2, FGFR1-3 and PIK3CAin the mUrethC cases (p<0.0001 for all comparisons) In addition, mUrethC featured as significantly lower frequency of TMB > 20 mut/Mb (4%; p=0.0001). Conclusions: CGP of mUrethC reveals distinctive genomic alteration frequencies among the 4 disease subtypes with higher numbers of GA in the AC than in the UC, SCC and CCC. The TMB appears to be lower in mUrethC than classically seen in UCB where checkpoint inhibition is now approved. Further study of this rare form of genitourinary cancer appears warranted. [Table: see text]

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Complete Response of a Colonic High-Grade Neuroendocrine Carcinoma to Platinum-Based Therapy: Insights from Comprehensive Genomic Profiling

10.21203/rs.3.rs-1063168/v1 ◽

2021 ◽

Author(s):

Richard Wood ◽

Daniel Rayson ◽

Thomas Arnason ◽

Ryan C DeCoste ◽

Daniel Gaston ◽

...

Keyword(s):

Neuroendocrine Carcinoma ◽

Stage Iv ◽

Large Cell ◽

Complete Response ◽

Response To Therapy ◽

Hereditary Cancer Syndrome ◽

Genomic Profiling ◽

Cancer Syndrome ◽

Optimal Care ◽

Comprehensive Genomic Profiling

Abstract Background Comprehensive genomic profiling (CGP) is an essential tool in precision medicine, providing diagnostic, prognostic, and predictive (therapeutic) information that enables personalized optimal care for cancer patients. We present the case of a 54-year-old woman with stage IV large-cell neuroendocrine carcinoma (LCNEC) of the colon with liver and nodal metastases with complete response to therapy and demonstrate the value of CGP in identifying potential targets for treatment in these tumors. Results CGP performed on the tumor showed pathogenic mutations in multiple oncogenes and tumor suppressor genes including BRCA1, BAP1, and BRAF, high tumor mutation burden (TMB), and high microsatellite instability (MSI-H). Treatment with platinum-based therapy resulted in a complete radiographic response of the metastases, with no evidence of recurrence after 6.5 years. Assessment by Medical Genetics did not identify any evidence of hereditary cancer syndrome. The dramatic response to therapy is likely due to loss of BRCA1 and/or BAP1 function, as deleterious mutations in both genes predict response to platinum-based therapy through exploitation of deficient homologous recombination repair (HRR). The information provided by CGP also suggested potential tumor sensitivity to poly(ADP-Ribose) polymerase inhibitors (PARPi), immunotherapy (IT) and BRAF/MEK inhibitor therapy, should the tumor recur. Conclusion This case highlights the value of CGP in guiding diagnosis and management of rare and aggressive tumors.

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Prognostic Variables in Patients With Non-metastatic Small-cell Neuroendocrine Carcinoma of the Bladder: A Population-Based Study

Clinical Genitourinary Cancer ◽

10.1016/j.clgc.2019.03.010 ◽

2019 ◽

Vol 17 (4) ◽

pp. e724-e732 ◽

Cited By ~ 2

Author(s):

Carlo Cattrini ◽

Luigi Cerbone ◽

Alessandra Rubagotti ◽

Linda Zinoli ◽

Maria Maddalena Latocca ◽

...

Keyword(s):

Neuroendocrine Carcinoma ◽

Population Based ◽

Small Cell ◽

Prognostic Variables ◽

Small Cell Neuroendocrine Carcinoma ◽

Population Based Study ◽

Carcinoma Of The Bladder

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SMALL CELL NEUROENDOCRINE CARCINOMA OF THE BLADDER: REPORT OF FOUR CASES AND A REVIEW OF THE LITERATURE

International Journal of Surgery and Medicine ◽

10.5455/ijsm.small-cell-neuroendocrine-carcinoma-management ◽

2017 ◽

pp. 1

Author(s):

Imane Bourhafour ◽

Sanaa Elmajjaoui ◽

Hanane Elkacemi ◽

Tayeb Kebdani ◽

Noureddine Benjaafar

Keyword(s):

Neuroendocrine Carcinoma ◽

Small Cell ◽

Review Of The Literature ◽

Small Cell Neuroendocrine Carcinoma ◽

Carcinoma Of The Bladder

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Complete response of a colonic high-grade neuroendocrine carcinoma to platinum-based therapy: Insights from comprehensive genomic profiling

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqab191.305 ◽

2021 ◽

Vol 156 (Supplement_1) ◽

pp. S143-S143

Author(s):

R Wood ◽

T Arnason ◽

R DeCoste ◽

D Gaston ◽

M D Carter ◽

...

Keyword(s):

Neuroendocrine Carcinoma ◽

Systemic Therapy ◽

Stage Iv ◽

Large Cell ◽

Complete Response ◽

Response To Therapy ◽

Genomic Profiling ◽

High Grade ◽

Cancer Management ◽

Comprehensive Genomic Profiling

Abstract Introduction/Objective Comprehensive genomic profiling (CGP) is an essential tool in precision medicine, providing diagnostic, prognostic, and predictive (therapeutic) information to enable personalized and optimized care for cancer patients. We present the case of a patient with a metastatic high-grade tumor of the colon who showed an impressive response to systemic therapy and discuss the role of CGP in cancer management. Methods/Case Report A 54-year-old woman with was diagnosed with stage IV large-cell neuroendocrine carcinoma (LCNEC) of the colon with large volume liver and nodal metastases with imminent hepatic failure. CGP was performed on the resected tumor (TSO500 panel, 523 cancer-related genes, Illumina), showing pathogenic mutations in multiple oncogenes and tumor suppressor genes, including BRCA1, BAP1, and BRAF. Additionally, global parameters revealed a very high tumor mutation burden (TMB, 351 / Mb), and high-degree microsatellite instability (MSI-H). Treatment of the patient’s metastases with platinum-based systemic therapy resulted in a complete radiographic response, with no evidence of disease recurrence after 6.5 years. This type of complete response to therapy is rarely reported in colonic LCNEC. Assessment by Medical Genetics did not identify a germline mutation suggestive of hereditary breast/ovarian cancer or Lynch syndrome. Results (if a Case Study enter NA) NA Conclusion The patient’s extraordinary response to therapy is likely due to loss of BRCA1 and/or BAP1 function, as deleterious mutations in both genes predict sensitivity to platinum-based therapy through exploitation of deficient homologous recombination repair (HRR). The high TMB and MSI-H status suggest the immune system may have contributed to tumor clearance through neoantigen activation of T-cells. The information provided by CGP also suggested potential tumor sensitivity to poly(ADP-Ribose) polymerase inhibitors (PARPi), immunotherapy (IT), and BRAF/MEK inhibitor therapy, should the tumor recur. This case highlights the value of CGP in guiding management of rare and aggressive tumors.

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