Analysis of DNA damage response (DDR) genes and tumor mutational burden (TMB) across 17,486 carcinomas of the tubular GI tract: Implications for therapy.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 43-43
Author(s):  
Aparna Raj Parikh ◽  
Yuting He ◽  
Theodore S. Hong ◽  
Ryan Bruce Corcoran ◽  
Jeffrey W. Clark ◽  
...  
Keyword(s):  
Small Bowel ◽  
Checkpoint Inhibitors ◽  
Tumor Biology ◽  
Parp Inhibition ◽  
Gi Tract ◽  
Damage Response ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Brca1 Brca2 ◽  
Tumor Types

43 Background: The DDR pathway is important in tumor biology, allowing cancer cells a mechanism to resist damage by chemotherapy and radiotherapy. BRCA1/2 are the most well described genes in the pathway, but several others ( ATM, ATR, PALB2, etc.) are involved with DDR and are mutated in many cancers. Tumors with a DDR defect are susceptible to PARP inhibition (PARPi) in some cases, but also potentially to immune checkpoint inhibitors (ICPIs), given immunomodulatory effects of PARPi and the hypermutated phenotype commonly associated with these genomic alterations (GA). We looked at the prevalence of select DDR defects in tubular GI cancers and the correlation between DDR and TMB. Methods: We prospectively analyzed samples from 17,486 unique patients with advanced colorectal (CRC), esophageal, gastric, or small bowel carcinomas using hybrid-capture based comprehensive genomic profiling. TMB (mutations/Mb) was calculated from 1.11 Mb of sequenced DNA. We looked at GA in 8 genes- ARID1A, ATM, ATR, BRCA1, BRCA2, CDK12, PALB2, RAD51 across these tumors types. Results: DDR GA were found in 16% of cases: gastric 464/1,750 (27%), small bowel 141/666 (21%), esophageal 441/2,501 (18%), and CRC 1,824/12,569 (15%). ARID1A (9.0%) and ATM (5%) were the most commonly altered DDR genes in this series, followed by BRCA2 (2.3%), BRCA1 (1.1%), ATR (0.8%), CDK12 (0.7%), PALB2 (0.6%), and RAD51 (0.1%), with 24% (675/2,870) of DDR-altered cases having GA in more than one DDR gene. Among DDR-altered cases, 21% had high TMB (≥20 mut/Mb) compared to just 1.4% high TMB in DDR-wild-type cases (p < 0.001). Microsatellite instability (MSI) status was available for a subset of cases and 19% (419/2,154) of those with a DDR GA were MSI high. CDK12 and ATR altered cases had the highest proportion of high TMB: CDK12 (55%, median TMB 31.5 mut/Mb) and ATR (55%, median TMB 35.1 mut/Mb), followed by cases with GA in BRCA2 (40%), BRCA1 (28%), ARID1A (27%), ATM (22%), and RAD51 (20%). Conclusions: DDR defects are relatively common across tubular GI tumor types and are associated with a hypermutated phenotype in over 20% of cases. This may be important to identify likely responders to both PARPi and ICPIs.

Tumor mutational burden (TMB) and co-existing actionable mutations in biliary tract cancers (BTC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4086-4086 ◽  
Author(s):  
Apurva Jain ◽  
Rachna T. Shroff ◽  
Mingxin Zuo ◽  
Jacqueline Weatherly ◽  
Funda Meric-Bernstam ◽  
...  
Keyword(s):  
Dna Repair ◽  
Biliary Tract ◽  
Checkpoint Inhibitors ◽  
Repair Pathway ◽  
Biliary Tract Cancers ◽  
Mutational Burden ◽  
Study Results ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Brca1 Brca2

4086 Background: Mutations in DNA repair pathway were identified in 13% of Biliary Tract Cancers (BTC) [ Cancer2016;122:3838–3847]. High TMB tumors including melanoma, lung cancer and those with microsatellite instability (MSI-H) are associated with susceptibility to immune blockade using checkpoint inhibitors. TMB data in BTC is limited and its association with actionable somatic mutation (mut) profiles in BTC is unknown. Methods: Comprehensive genomic profiling (CGP) of 309 FFPE tissue blocks of BTC pts with a hybrid capture of all coding exons of 236 cancer-related genes and 47 introns of 19 genes rearranged in cancer was done using FoundationOne. Base substitutions, indels, gene fusion/rearrangements, TMB, and MSI status were assessed. TMB was calculated by counting mutations across a 1.25Mb region and classified into high (TMBH; ≥20 mut/Mb), intermediate (TMBI; 6 - 19mut/Mb) and low (TMBL; < 6mut/Mb). MSI high (MSIH) and Stable (MSS) status was assigned by a computational algorithm examining 114 intronic homopolymer loci. Patients with TMB ≥6 mut/Mb (N = 60) were included in the clinical correlative portion of this study. Results: Sixty patients with TMB ≥6 mut were identified out of 309 pts of which 9 (15%) were TMBH and 51 (85%) were TMBI. These included 3 (5%) MSIH and 18 (30 %) MSS. The median age was 59 years (range: 29-86), 35 (58%) were females, majority were intrahepatic cholangiocarcinoma (n = 31; 52%) and 28 (47%) presented with advanced disease at diagnosis. Twenty three (38%) pts had received radiation therapy, 28 (47%) surgery and 3 (5%) received immunotherapy. Most frequent co-existing mut seen was TP53 (N = 35; 58%). APC mut was seen in 7 (12%) pts. DNA repair pathway muts ( MSH6, BRCA1, BRCA2, ATM, MLH1, or MSH2 genes) were identified in 78% of TMBH versus 16% in TMBI cases (p < 0.0001). Frequency of PIK3CA mut differed significantly between TMBH and TMBI (44% vs 10%, p < 0.0001). Pts with TMBI had a significantly better median OS (110 weeks) as compared to TMBH (43 weeks) (p = 0.003). Conclusions: DNA repair pathway and PIK3CA mut maybe associated with TMBH in BTC. A better understanding of TMB and associated actionable mutations in BTC may be of value for the management of BTC patients with targeted agents and immunotherapy.

scholarly journals Multitumor Case Series of Germline BRCA1, BRCA2 and CHEK2-Mutated Patients Responding Favorably on Immune Checkpoint Inhibitors

2021 ◽  
Vol 28 (5) ◽  
pp. 3227-3239
Author(s):  
Lisa Kinget ◽  
Oliver Bechter ◽  
Kevin Punie ◽  
Philip R. Debruyne ◽  
Hilde Brems ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Case Series ◽  
Predictive Biomarkers ◽  
Solid Malignancies ◽  
Tumor Mutational Burden ◽  
Brca1 Brca2 ◽  
Tumor Types ◽  
Selection Of

In recent years, immune checkpoint inhibitors (ICPI) have become widely used for multiple solid malignancies. Reliable predictive biomarkers for selection of patients who would benefit most are lacking. Several tumor types with somatic or germline alterations in genes involved in the DNA damage response (DDR) pathway harbor a higher tumor mutational burden, possibly associated with an increased tumoral neoantigen load. These neoantigens are thought to lead to stronger immune activation and enhanced response to ICPIs. We present a series of seven patients with different malignancies with germline disease-associated variants in DDR genes (BRCA1, BRCA2, CHEK2) responding favorably to ICPIs.

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]

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.

Genomic landscape of non-small cell lung cancer (NSCLC) with methylthioadenosine phosphorylase (MTAP) deletion.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9116-9116
Author(s):  
Stephen L. Graziano ◽  
Dean C. Pavlick ◽  
Ethan Sokol ◽  
Shakti H. Ramkissoon ◽  
Eric Allan Severson ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Synthetic Lethality ◽  
Checkpoint Inhibitors ◽  
Large Cell ◽  
Combination Strategies ◽  
Genomic Landscape ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Cell Expression ◽  
The Impact

9116 Background: NSCLC remains a major cause of cancer-associated mortality despite major advancements in treatments. In addition to immune checkpoint inhibitors (ICPI), new strategies for clinically advanced NSCLC now include the development of new synthetic lethality targets focused on protein arginine methyl transferases such as PRMT5 that exploit the impact of tumor cell genomic loss of MTAP. Methods: 29,379 advanced/metastatic NSCLC cases underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA). 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 tumor cell expression was determined by DAKO 22C3 immunohistochemistry (IHC); low positive was a tumor proportion score (TPS) 1-49% and high positive was a TPS ≥50%. Results: 3,928 NSCLC exhibited MTAP homozygous loss. Cases had the following subtypes: adenocarcinoma (59%), squamous cell ca (22%), NSCLC NOS (16%), and large cell neuroendocrine, sarcomatoid, adenosquamous ca (all 1%). GA/tumor were similar when CDKN2A/B losses associated with 9p21 co-deletion with MTAP loss are excluded. Significant differences in currently targetable GA included KRAS G12C higher in MTAP-intact NSCLC (P =.0003) and EGFR short variant mutations higher in MTAP-deleted NSCLC (P <.0001). MTAP-intact NSCLC had higher frequencies of GAs in TP53 (P <.0001) and RB1 and a lower frequency of SMARCA4 (P <.0001). GAs frequencies in ERBB2, MET, ALK, ROS1 and NTRK1 were similar. Biomarkers for potential ICPI efficacy were higher in MTAP-intact including TMB ≥10mut/Mb (P =.0002) and low and high PD-L1 IHC staining (P =.01). Biomarkers potentially predictive of ICPI resistance ( STK11 and KEAP1) were similar in both groups. Conclusions: MTAP loss occurs in 13% of NSCLC, supporting the development of novel targeted therapies designed to exploit PRMT5 hyper-dependence in these tumors. MTAP loss in NSCLC is accompanied by differences in targeted and ICPI options for these patients which may impact future combination strategies. Further study of anti-PRMT5 drugs that are enabled by MTAP loss in NSCLC appears warranted.[Table: see text]

Stromal characterization of small bowel adenocarcinomas.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 288-288
Author(s):  
Katrina Pedersen ◽  
Thomas C. Smyrk ◽  
Robert R. McWilliams
Keyword(s):  
Small Bowel ◽  
T Lymphocytes ◽  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Membrane Integrity ◽  
Tumor Infiltrating Lymphocytes ◽  
Tumor Stroma ◽  
Cd8 Cells ◽  
Tumor Types ◽  
E Cadherin

288 Background: Programmed-death 1 (PD-1) receptor and its corresponding ligand, PD-L1, have been found to be clinically relevant in maintaining immune tolerance to malignant cells in an increasing number of tumor types. We have previously shown that nearly half of 48 randomly selected, resected small bowel adenocarcinomas at any stage exhibit positive PD-L1 expression. Furthermore, a larger quantity of tumor infiltrating lymphocytes (TILs) within the tumor stroma or microsatellite instability (MSI-H) have been associated with improved likelihood of response to PD-1 and PD-L1 inhibitors. We have descriptively characterized the stromal components of small bowel adenocarcinomas to determine if similar tumor/stromal features to drug-responsive tumors can be seen. Methods: 30 tumors were immunohistochemically stained for CD8 (T-lymphocytes), CD68 (macrophages), and e-cadherin. They were morphologically screened for MSI-H status with light microscopy. PD-L1 staining was previously performed and reported. Results: Of the 30 tumors, there was no correlation between the density of macrophages and T-lymphocytes, nor was there a correlation with the burden of immune cells with e-cadherin expression. 14/30 (47%) tumors had 3+/4+ expression of CD8+ lymphocytes. 7/14 (50%) of these tumors were morphologically MSI-H. No tumors with low CD8+ cells (1+/2+) were MSI-H. PD-L1 expression colocalized exclusively with macrophages and not with lymphocytes. Conclusions: There appears to be no association between the proportions of immune cells and basement membrane integrity. MSI-H tumors are more likely to have a greater quantity of CD8+ lymphocytes in the stroma; however, PD-L1 stromal expression appears to colocalize with macrophages. Further pathologic characterization is needed in patients treated with PD-1 and other immune checkpoint inhibitors to determine the clinical significance of these observations.

Comprehensive genomic profiling to identify tumor mutational burden (TMB) as an independent predictor of response to immunotherapy in diverse cancers.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14508-e14508 ◽  
Author(s):  
Aaron Goodman ◽  
Shumei Kato ◽  
Lyudmila Bazhenova ◽  
Sandip Pravin Patel ◽  
Garrett Michael Frampton ◽  
...  
Keyword(s):  
Strong Dependence ◽  
Multivariable Analysis ◽  
Favorable Outcome ◽  
Genomic Profiling ◽  
Outcome Parameters ◽  
Patients With Cancer ◽  
Comprehensive Genomic Profiling ◽  
Response Biomarker ◽  
Tumor Mutational Burden ◽  
Tumor Types

e14508 Background: Immunotherapy induces durable responses in a subset of patients with cancer. High TMB may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. Methods: We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free and overall survival (PFS, OS). Results: Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥ 20 mutations/mb) vs. low to intermediate TMB was 22/38 (58%) vs. 23/113 (20%) (P = 0.0001); median PFS, 12.8 vs. 3.3 months (P = <0.0001); median OS, not reached vs. 16.3 months (P = 0.0036) (Table). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders vs. non-responders treated with anti-PD-1/PD-L1 monotherapy was 18.0 vs. 5.0 mutations/mb (P < 0.0001). Comparable data was observed when patients with melanoma (N = 52) and NSCLC (N = 36) were excluded (N = 63 patients; 19 tumor types). Interestingly, anti-CTLA4/anti-PD-1 combinations vs. anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%) (P = 0.004) and PFS (P = 0.024). Conclusions: Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB. [Table: see text]

Ductal (PDC), acinar (PAC) and neuroendocrine (PNC) carcinomas of the prostate: A comparative comprehensive genomic profiling (CGP) study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5064-5064
Author(s):  
Gennady Bratslavsky ◽  
Joseph Jacob ◽  
Oleg Shapiro ◽  
Nick Liu ◽  
Elizabeth Kate Ferry ◽  
...  
Keyword(s):  
Mtor Inhibitors ◽  
Parp Inhibitors ◽  
Low Frequencies ◽  
Mek Inhibitors ◽  
Genomic Signatures ◽  
Disease Biology ◽  
Pathologic Features ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Tumor Types

5064 Background: PDC, PAC and PNC are histologic subtypes of prostate cancer (PC). We queried whether these subsets would share similar genomic alterations (GA) reflecting their disease biology and clinical features. Methods: CGP was performed using a hybrid capture-based assay on 61 PDC, 4,132 PAC and 217 PNC. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The age, GA per tumor and TP53 GA of PDC, PAC and PNC were similar (Table). RB1 GA were predominant in PNC. TMPRSS2:ERG fusions were most frequent in PNC, intermediate in PAC and lowest in PDC. AR GA were more often identified in PAC than PDC or PNC whereas PTEN GA were most frequent in PDC than PAC or PNC. Targetable GA were identified in all 3 groups when focused on BRCA2 (PARP inhibitors) and PIK3CA (MTOR inhibitors). ATM GA (PARP inhibitors) were more common in PAC than PDC or PNC. BRAF GA (BRAF/MEK inhibitors) were more frequent in PDC and PAC than PNC. CDK12 GA potentially associated with immunotherapy (IO) benefit were similar in PDC and PAC and low in PNC. Low frequencies of MSI-High and low median TMB levels were similar in all 3 groups. Conclusions: The pathologic features of PDC, PAC and PNC have been classically maintained as representative of 3 different tumor types with potentially contrasting histogenesis. In the current CGP based study, all 3 tumor types did not display significant differences in genomic signatures other than the high RB1 GA. CGP may reveal biomarkers that could direct patients to targeted (PARP, MTOR and BRAF/MEK inhibitors) or immunotherapies ( CDK12 GA, MSI-High or high TMB status) especially in PDC and PAC. [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]

Refractory testicular pure seminoma (PS) and non-seminomatous(NS) germ cell tumors (GCT): A comprehensive genomic profiling (CGP) study.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 565-565 ◽  
Author(s):  
Joseph M Jacob ◽  
Elizabeth Kate Ferry ◽  
Oleg Shapiro ◽  
Sherri Z. Millis ◽  
Jon Chung ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Germ Cell Tumors ◽  
Small Subset ◽  
High Status ◽  
Systemic Treatments ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Ffpe Tissues ◽  
Pure Seminoma ◽  
Tumor Types

565 Background: Although PSand NS testicular GCT have a favorable prognosis, on occasion these tumors can be refractory to conventional systemic treatments. Methods: FFPE tissues from 22 PS and 86 NSunderwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mutations (mut) per megabase (Mb) and microsatellite instability (MSI) was determined on 114 loci. Results: PS patients were older than NS (P=0.007). The primary tumor was sequenced in 41% of PS and 18% of NS with a metastasis sample in 59% of PS and 82% of NS.Four (18%) of PS had syncytial trophoblast cells identified. The mean GA frequency at 4.1 mut/case for NS was higher than that seen in PS and this difference reached near significance (P=0.08). The KRAS, TP53, CCND2 and FGF6/23 GA frequencies were similar in both tumor types (Table). GA in KIT, PIK3CA/ MTOR, PTEN and BRCA2 were more frequent in PS than NS whereas BRAF and ERBB2 GA were more frequent in NS (Table). MSI-High status was absent in in PS (0%) and identified in 2% of NS. Higher levels of TMB were not encountered in PS (0% TMB ≥10 mut/Mb), but higher TMB levels were more frequent in NS (5% ≥ 10 mut/B and 1% ≥ 20 mut/Mb). Conclusions: The GA found in refractory PS and NS differ significantly. PS features a lower GA frequency with slightly higher potential for targeted therapies in kinase (KIT) and MTOR pathways but, has very low TMB predicting limited opportunities for immunotherapy for these patients. For NS targeted therapy biomarkers appear even more uncommon than seen in PS with only extremely rare kinase inhibitor opportunities. However, based on rare high TMB and MSI-High status, immunotherapies may be of benefit in a small subset of NS patients. Further study of genomic findings in relapsed and clinically aggressive PS and NS appears warranted. [Table: see text]

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