Penile and uterine cervical squamous cell carcinomas: A comparative genomic profiling study.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 514-514 ◽  
Author(s):  
Joseph Jacob ◽  
Rubin Pinkhasov ◽  
Oleg Shapiro ◽  
Nick Liu ◽  
Laurie M. Gay ◽  
...  
Keyword(s):  
Squamous Cell ◽  
Treatment Options ◽  
Cervical Squamous Cell Carcinoma ◽  
Mtor Pathway ◽  
Comparative Genomic ◽  
High Status ◽  
Genomic Profiling ◽  
Hpv Status ◽  
Comprehensive Genomic Profiling ◽  
Tumor Types

514 Background: Metastatic penile (mPSCC) and uterine cervical squamous cell carcinoma (mCSCC) are aggressive forms of malignancy with limited treatment options. We used comprehensive genomic profiling (CGP) to compare the genomic alterations (GA) and their potential impact on targeted and immunotherapy options of mPSCC and mCSCC. Methods: 78 metastatic mPSCC and 604 mCSCC underwent CGP using a hybrid-capture-based next-generation sequencing assay with a mean coverage depth of > 500X. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The median age of mPSCC men was higher than mCSCC women. The HPV+/CDKN2A- status was more frequent in the mCSCC than mPSCC. The GA/tumor were similar for both tumor types (table). TP53 mutations were more common in mPSCC likely linked to loss of original HPV+ status. TERT, NOTCH1 and FAT1 GA were more frequent in mPSCC whereas PIK3CA GA were more common in mCSCC. MTOR pathway targets (GA in STK11, FBXW7 and PTEN) were more common in mCSCC. MSI-High status was extremely rare in all cases, but the relatively high frequencies of TMB ≥ 10/20 mut/Mb in both mPSCC and mCSCC were noteworthy. Examples of patients with mCSCC and mPSCC responding to targeted and immunotherapies will be presented. Conclusions: Although mCSCC and mPSCC share a variety of genomic features, the 2 tumor types can nonetheless be sharply differentiated on CGP. The TP53, CDKN2A and HPV status of the tumor types differ significantly with viral identification much higher in the mCSCC group. There are opportunities for targeted therapies in both groups predominantly identified in the MTOR pathway. Numerous cases with significantly elevated TMB in both mPSCC and mCSCC suggest that immunotherapies might be of benefit in a subset of patients. [Table: see text]

Comparative genomic profiling (CGP) of refractory/metastatic penile (mPSCC) and non-penile cutaneous squamous cell carcinoma (mCSCC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 552-552 ◽  
Author(s):  
Joseph M Jacob ◽  
Oleg Shapiro ◽  
Elizabeth Kate Ferry ◽  
Laurie M. Gay ◽  
Julia Andrea Elvin ◽  
...  
Keyword(s):  
Uv Light ◽  
Treatment Options ◽  
Comparative Genomic ◽  
High Status ◽  
Genomic Profiling ◽  
Exposed Skin ◽  
Ffpe Samples ◽  
Tumor Mutational Burden ◽  
Tumor Types ◽  
Generation Sequencing

552 Background: mPSCC is an aggressive malignancy with limited treatment options. Using CGP, we compared the therapy impacting genomic alterations (GA) between mPSCC and cutaneous mCSCC. Methods: DNA was extracted from 40 microns of FFPE samples from 78 cases of mPSCC and 338mCSCC.Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assayto a mean coverage depth of > 500X. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: mPSCC patients were younger than mCSCC (Table). Both tumors types feature high CDKN2A, TERT and FAT1 GA frequencies. NOTCH1 and PTCH1 GA are also more common in mCSCC than mPSCC. CD274 ( PD-L1) amplification was rare in both tumor types. Targeted therapy opportunities in mPSCC included alterations in kinase pathways ( EGFR GA in 6%; FGFR3 and ERBB2 GA in 4%); MTOR pathway ( NF1 GA in 7% and PTENGA in4%) and DNA repair pathway ( BRCA2and ATMGA in 7%). TMB was significantly higher in the UV light exposed mSCC than mPSCC with both tumor types having potential for responsiveness to immunotherapies. MSI-High status was extremely rare for both mPSCC and mCSCC. HPV viral DNA was identified in 29% on mPSCC but only in 5% of mCSCC. TP53 GA were significantly more frequent in HPV- than HPV+ mPSCC and mCSCC respectively (P < 0.0001 for both). Clinical outcomes of selected patients will be presented. Conclusions: mPSCC is a unique subtype of SCC with distinctive genomic features that contrast with those identified in mCSCC of non-penile UV light exposed skin. Given the potential opportunities for targeted therapies and immunotherapies that can be uncovered, continued study of CGP for the guidance of treatment for patients with mPSCC appears warranted.[Table: see text]

Clinically advanced pelvic squamous cell carcinomas (pSCC) in men and women: A comprehensive genomic profiling (CGP) study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3130-3130
Author(s):  
Philippe E. Spiess ◽  
Petros Grivas ◽  
Douglas A. Mata ◽  
Gennady Bratslavsky ◽  
Joseph M Jacob ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Parp Inhibitor ◽  
Treatment Options ◽  
Clinical Manifestations ◽  
Mtor Pathway ◽  
Hpv Status ◽  
Damage Response ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Tumor Types

3130 Background: Given that the clinical manifestations, disease course, and treatment options for pSCC differ between tumor types, we performed CGP to examine possible genomic differences. Methods: 1,741 clinically advanced pSCCs including 230 penile (penSCC), 17 male urethral (murthSCC), 125 male anal (manSCC), 7 female urethral (furthSCC), 263 vulvar (vulSCC), 822 cervical (crvSCC), and 277 female anal SCCs (fanSCC) underwent hybrid capture-based CGP to evaluate all classes of genomic alterations (GAs). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: HPV-16/18 detection was lowest in murthSCC and vulSCC and highest in manSCC, fanSCC, and crvSCC. TP53 GAs were inversely associated with HPV status. PIK3CA GA frequency varied (22-43%). DNA-damage response (DDR) GAs (e.g., BRCA1/2, ATM, others) were low ( < 1-3%) throughout. Cell-cycle GAs were most frequent in external cases (penSCC, furthSCC, vulSCC). MTOR pathway GAs ( PTEN, FBXW7) were the most frequently identified “actionable” GAs. FGFR3 GA were present in >5% of murthSCC, crvSCC, and fanSCC; other receptor-tyrosine kinase (RTK) targeted options were 1% in BRAF/ ERBB2. NOTCH1 GAs were present in > 15% of penSCC and vulvSCC. TMB ≥10 mut/Mb was >15% in manSCC, fanSCC, and crvSCC. PD-L1 low expression was > 25% in all pSCC except crvSCC and high expression was > 18% in all pSCC except urthSCC and manSCC. Conclusions: Despite similar histology, pSCC differ widely in GAs and HPV status. PIK3CA is the most frequent “targetable” GA followed by MTOR pathway and cell cycle; RTK targets are extremely rare. PARP inhibitor options appear low given the infrequent finding of DDR GAs. Anti-PD(L)1 could be considered in a number of cases based on TMB>10 mut/Mb and PD-L1 expression.[Table: see text]

Metastatic penile (mPSCC), uterine cervical (mCSCC), and skin (mSSCC) squamous cell carcinomas: A comparative genomic profiling (CGP) study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4585-4585 ◽  
Author(s):  
Joseph Jacob ◽  
Gennady Bratslavsky ◽  
Oleg Shapiro ◽  
Nick Liu ◽  
Julia Andrea Elvin ◽  
...  
Keyword(s):  
Uv Light ◽  
Light Exposure ◽  
Mtor Pathway ◽  
Genomic Alteration ◽  
Comparative Genomic ◽  
High Status ◽  
Mutational Burden ◽  
Hpv Status ◽  
Tumor Mutational Burden ◽  
Tumor Types

4585 Background: We compared the genomic alteration (GA) profiles of mCSCC, mPSCC and mSSCC to study impact on the targeted and immunotherapy options for the men and women suffering from these refractory cancers. Methods: 78 mPSCC, 604 mCSCC and 338 mSSCC underwent CGP using a hybrid-capture based assay. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and and microsatellite instability (MSI) was determined on 114 loci. Results: The HPV+/CDKN2A- status was significantly more frequent in the mCSCC than mPSCC or mSSCC (P < 0.0001). The GA/tumor frequencies were similar for mCSCC and mPSCC, but significantly higher in mSSCC (P < 0.0001). TP53 mutations were more common in mSSCC (UV light exposure) and mPSCC (likely due to loss of an original HPV+ status). TERT, NOTCH1 and FAT1 GA were more frequent in mPSCC and mSSCC whereas PIK3CA GA were more common in mCSCC. MTOR pathway targets (GA in STK11, FBXW7 and PTEN) were more common in mCSCC than mPSCC or mSSCC. MSI high status was extremely rare in all cases. TMB ≥ 10/20 mut/Mb frequencies were noteworthy in mPSCC and mCSCC but extraordinarily high in mSSCC. Examples of patients with mCSCC, mPSCC and mSSCC responding to targeted and immunotherapies will be presented. Conclusions: Although mCSCC, mPSCC and mSSCC share a variety of clinicopathologic features, the 3 tumor types can be sharply differentiated on CGP. The TP53, CDKN2A and HPV status of the tumor types differ significantly with HPV+ higher in the mCSCC group. There are opportunities for targeted therapies in all groups predominantly identified in the MTOR pathway. The relatively high numbers of cases with significantly elevated TMB in all 3 tumor types suggest that immunotherapies would be beneficial in a large subset of patients. [Table: see text]

Adenocarcinoma (ACB), urothelial carcinoma (UCB) and squamous cell carcinoma (SCCB) of the bladder: A Comprehensive Genomic Profiling (CGP) Study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4533-4533 ◽  
Author(s):  
Joseph Jacob ◽  
Gennady Bratslavsky ◽  
Oleg Shapiro ◽  
Nick Liu ◽  
Elizabeth Kate Ferry ◽  
...  
Keyword(s):  
High Status ◽  
Genomic Profiling ◽  
Dna Repair Genes ◽  
Genomic Profile ◽  
Hybrid Capture ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Tumor Types ◽  
Repair Genes

4533 Background: We performed a CGP to compare the genomic alterations (GA) in ABC, UBC and SCCB. Methods: 143 cases of ACB, 2,142 cases of UCB and 83 cases of SCCB were subjected to CGP using a hybrid-capture based assay. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC. Results: ABC patients were younger and more often female than UBC and SCCB (P < 0.0001). UBC and SCCB had a higher GA/tumor than ABC (P = 0.01). Un-targetable GA were similar in all 3 groups involving TP53 and KRAS. APC GA were more frequent in ABC whereas TERT, CDKN2A/B and DNA-repair genes ( ARID1A and KDM6A) more frequently altered in UBC and SCCB. Targetable MTOR pathway GA ( PIK3CA, TSC1, PTEN) were more frequent in UBC and SCCB as were targetable kinase alterations ( FGFR3 and ERBB2). The UBC and SCCB had a significantly higher TMB than ABC (P < 0.0001) including mean TMB and TMB > 20 mut/Mb (P < 0.0001). CD274 (PD-L1) was amplified more frequently in SCCB than ACB or UBC (P < 0.0001). MSI high status was very uncommon in all tumor types. Conclusions: Deep sequencing reveals that ABC features a widely different genomic profile from UBC and SCCB. UBC has the highest frequencies of targetable kinase GA and high TMB. SCCB has the highest frequencies of IO efficacy predicting biomarkers including mean TMB and PD-L1 amp. Nonetheless, ABC does feature potential kinase targets such as FGFR3 and ERBB2. [Table: see text]

Comprehensive genomic profiling (CGP) of cervical squamous cell carcinoma (cSCC) to identifiy targeted therapy options.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. 5602-5602 ◽  
Author(s):  
Julia Andrea Elvin ◽  
Mark Bailey ◽  
Benedito A. Carneiro ◽  
Siraj Mahamed Ali ◽  
Jo-Anne Vergilio ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Targeted Therapy ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Cervical Squamous Cell Carcinoma ◽  
Genomic Profiling ◽  
Therapy Options ◽  
Comprehensive Genomic Profiling

Anal melanoma: A comparative comprehensive genomic profiling study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9566-9566
Author(s):  
Jeffrey S. Ross ◽  
Russell Madison ◽  
Julia Andrea Elvin ◽  
Jo-Anne Vergilio ◽  
Jonathan Keith Killian ◽  
...  
Keyword(s):  
Uv Light ◽  
Light Exposure ◽  
Mtor Pathway ◽  
Braf V600e ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Ffpe Tissues ◽  
Tumor Types

9566 Background: We performed a comprehensive genomic profiling (CGP) study of AM and CM to learn of potential genomic alterations (GA) linked to targeted and immune checkpoint inhibitor (ICPI) therapies. Methods: 90 AM and 1804 CM FFPE tissues from late stage underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC. Results: AM and CM had a similar age, but AM females and CM males were significantly more common (P < 0.0001). GA/tumor was significantly higher in CM (UV light exposure) as were the median TMB and frequency of TMB ≥ 10 and 20 mutations/Mb (P < 0.0001 for all comparisons). PD-L1 expression was higher in AM than CM (P = 0.0023). AM and CM were all MS-stable. The contrast in S FB1 mutations in AM and TERT GA in CM were significant (P < 0.0001). Of potentially targetable GA, AM featured significantly more KIT GA than CM (P < 0.0001), whereas CM featured significantly more BRAF GA (P < 0.0001). Only 11% of AM BRAF GA were V600E whereas 74% of CM BRAF GA were V600E (P < 0.0001). MTOR pathway GA were common in both tumor types. Additional potentially targetable alterations in PDGFRA and ERBB2 kinases were seen in AM but not in CM. Conclusions: CM is distinct from AM featuring higher GA/tumor, higher TMB and frequent BRAF V600E GA that predict benefit from ICPI and anti-BRAF therapies. Although both AM and CM feature MTOR pathway targets, AM does have higher PD-L1 expression than CM and is characterized by an array of potentially targetable kinase genes including KIT, PDGFRA, ERBB2 and to a lesser extent than CM, BRAF.[Table: see text]

Anal melanoma: A comparative comprehensive genomic profiling study.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 551-551
Author(s):  
Jeffrey S. Ross ◽  
Laurie M. Gay ◽  
Julia Andrea Elvin ◽  
Jo-Anne Vergilio ◽  
Jonathan Keith Killian ◽  
...  
Keyword(s):  
Immune Checkpoint Inhibitor ◽  
Uv Light ◽  
Light Exposure ◽  
Mtor Pathway ◽  
Genomic Profiling ◽  
Anal Melanoma ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Ffpe Tissues ◽  
Tumor Types

551 Background: Anal melanomas (AM) share histologic features with cutaneous melanomas (CM), are highly aggressive and behave in a distinct clinicopathologic pattern. We performed comprehensive genomic profiling (CGP) of AM to learn of potential matched targeted and immunotherapies that may improve clinical outcomes for the disease. Methods: FFPE tissues from late stage AM (81 cases) and CM (1804 cases) underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: AM and CM had a similar age, but AM females and CM males were significantly more common (P < 0.0001) (Table). Given the UV light exposure in the CM, the GA/tumor was significantly higher than AM as were the median TMB and frequency of TMB ≥ 10 and 20 mutations/Mb (P < 0.0001 for all comparisons). All AM and CM were MS-stable. The contrast in S FB1 mutations in AM and TERT GA in CM were significant (P < 0.0001). AM featured significantly more KIT GA than CM (P < 0.0001), whereas CM featured significantly more BRAF GA (P < 0.0001). Only 11% of AM BRAF GA were V600E whereas 74% of CM BRAF GA were V600E (P < 0.0001). MTOR pathway targets including NF1 and PTEN were commonly altered in both tumor types. Potentially targetable PDGFRA and ERBB2 GA were found in AM but not in CM. Conclusions: UV light exposure drives high GA/tumor and TMB in CM, both associated with immune checkpoint inhibitor (ICPI) responsiveness, whereas AM lacks the high TMB and therefore is far less likely to benefit from ICPI treatments. CM is classically associated with opportunities for anti-BRAF therapies and AM with an array of kinase targets including KIT, BRAF, PDGFRA and ERBB2. Finally, MTOR pathway targets are common to both tumor types. [Table: see text]

scholarly journals Clinically Advanced Pheochromocytomas and Paragangliomas: A Comprehensive Genomic Profiling Study

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3312
Author(s):  
Gennady Bratslavsky ◽  
Ethan S. Sokol ◽  
Michael Daneshvar ◽  
Andrea Necchi ◽  
Oleg Shapiro ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Therapeutic Targets ◽  
High Status ◽  
Genomic Profiling ◽  
Expression Levels ◽  
Systemic Treatments ◽  
Predisposition Genes ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Tumor Types

Patients with clinically advanced paragangliomas (CA-Para) and pheochromocytomas (CA-Pheo) have limited surgical or systemic treatments. We used comprehensive genomic profiling (CGP) to compare genomic alterations (GA) in CA-Para and CA-Pheo to identify potential therapeutic targets. Eighty-three CA-Para and 45 CA-Pheo underwent hybrid-capture-based CGP using a targeted panel of 324 genes. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined. The GA/tumor frequencies were low for both tumor types (1.9 GA/tumor for CA-Para, 2.3 GA/tumor for CA-Pheo). The most frequent potentially targetable GA in CA-Para were in FGFR1 (7%, primarily amplifications), NF1, PTEN, NF2, and CDK4 (all 2%) and for CA-Pheo in RET (9%, primarily fusions), NF1 (11%) and FGFR1 (7%). Germline mutations in known cancer predisposition genes were predicted in 13 (30%) of CA-Pheo and 38 (45%) of CA-Para cases, predominantly involving SDHA/B genes. Both CA-Para and CA-Para had low median TMB, low PD-L1 expression levels and none had MSI high status. While similar GA frequency is seen in both CA-Para and CA-Para, germline GA were seen more frequently in CA-Para. Low PD-L1 expression levels and no MSI high status argue against strong potential for novel immune checkpoint inhibitors. However, several important potential therapeutic targets in both CA-Para and CA-Para are identified using CGP.

Sign in / Sign up

Export Citation Format

Share Document