scholarly journals Primary Adult Retroperitoneal Sarcoma: A Comprehensive Genomic Profiling Study

2021 ◽  
Vol 2 (4) ◽  
pp. 216-228
Author(s):  
Andrea Necchi ◽  
Giuseppe Basile ◽  
Filippo Pederzoli ◽  
Marco Bandini ◽  
Petros Grivas ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Follicular Dendritic Cell ◽  
Genomic Profiling ◽  
Histological Subtypes ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Synovial Sarcomas ◽  
Retroperitoneal Sarcomas ◽  
Primary Retroperitoneal ◽  
Generation Sequencing

Background: Adult primary retroperitoneal sarcomas (RPSs) are a group of heterogeneous tumors with different histological subtypes. Comprehensive genomic profiling (CGP) analyses have recently provided significant insights into the biology of sarcomas by identifying genomic alterations (GAs) which could benefit from targeted therapies. Methods: RPS were evaluated by CGP using next-generation sequencing of up to 406 cancer-related genes. Tumor mutational burden (TMB) was determined on 0.83 to 1.14 mut/Mb of sequenced DNA. Finally, PD-L1 expression was determined. Results: Overall, 296 cases of primary RPS were analyzed. Liposarcoma (LPS) subtype had more GA/tumor than leiomyosarcoma (LMS) subtypes, with follicular dendritic cell sarcomas harboring the highest and synovial sarcomas the lowest. TP53 and Rb1 alterations were the highest in LMS, and CDK4/6 and MDM2 in LPS. However, both the TMB and targetable GA rates were low across subtypes. PD-L1 immunostaining was low positive in 21% and high positive in 5% of patients, respectively. Conclusions: CGP analysis revealed that potentially actionable genomic targets were rare in our cohort of RPS. Moreover, RPSs seem less likely to respond to immune checkpoint inhibitors based on putative biomarkers status. Nevertheless, genomic stratification according to histological subtypes led to description of GAs that can inform future clinical trials design.

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]

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.

Targeted therapy for HER2 driven colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3583-3583 ◽  
Author(s):  
Jeffrey S. Ross ◽  
Siraj Mahamed Ali ◽  
Julia Andrea Elvin ◽  
Alexa Betzig Schrock ◽  
James Suh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Genomic Profiling ◽  
Hybrid Capture ◽  
Mutational Burden ◽  
Precision Therapy ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Upper Gastrointestinal ◽  
Colonic Adenocarcinomas

3583 Background: ERBB2 ( HER2) genomic alterations (GA) are evolving therapy taregets in metastatc coorectal cancer (mCRC). Methods: Hybrid capture based comprehensive genomic profiling (CGP) was performed on 8874 (9.6%) mCRC including both colonic adenocarcinomas (7587 cases; 85%) and rectal adenocarcinomas (1287 cases, 15%) Tumor mutational burden (TMB) was calculated from a minimum of 1.2 Mb of sequenced DNA. Results: ERBB2 amplifications or a short variant (SV) alterations or both were found in 433 (4.9%) of the total mCRC. 195 (45%) of the ERBB2 positive mCRC were female and 238 (55%) were male. Median age was 54 years (range 22 to 88 years). The most frequently co-altered genes were SV GA in TP53 (82%), APC (70%), KRAS (26%), SMAD4 (15%) and PIK3CA (13%). Clinically relevant GA significantly under-represented in ERBB2-altered CRC included significantly reduced GA in KRAS at 26% (p = 0.001) and BRAF at 4% (p = 0.003) as well as other kinases at 1% including EGFR, KIT, MET and RET. The frequency of TMB at > 10 mut/Mb (p < 0.0001), but at > 20 mut/Mb mCRC cases demonstrated virtually the same results regardless to ERBB2 status at a frequency of x%. The overall ERBB2 GA frequency at 5.3% in rectal mCRC is slightly higher than that seen in colonic mCRC at 4.9%, (p = 0.36). The frequency of TMB > 10 mut/Mb in ERBB2 WT mCRC is greater in the colonic mCRC than the rectal mCRC (p < 0.0001 for both comparisons). When > 20 mut/Mb is used as the cut-off, the greater frequency of TMB in colonic mCRC versus rectal mCRC remains significant (p < 0.0001). When the ERBB2altered mCRC cases are evaluated, the greater frequency of TMB > 10 mu/Mb in colonic mCRC versus rectal mCRC remains significant (p = 0.009), but the greater frequency in colonic verses rectal mCRC at the > 20 mut/Mb is not significant (p = 0.37). Conclusions: Although lower than observed in breast and upper gastrointestinal carcinomas where anti-HER2 therapies are approved indications, the frequency of ERBB2 GA in CRC at 4.9% is significant. Importantly, nearly half of CRC ERBB2 alterations are SVs, not detectable by routine IHC and FISH testing. However, the success of anti-HER2 therapies shown here and progress in on-going clinical trials indicates that targeting ERBB2 has potential to become an approved advance in precision therapy for mCRC patients.

Genomic alterations (GA) and tumor mutational burden (TMB) in large cell neuroendocrine carcinoma of lung (L-LCNEC) as compared to small cell lung carcinoma (SCLC) as assessed via comprehensive genomic profiling (CGP).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8517-8517 ◽  
Author(s):  
Young Kwang Chae ◽  
Keerthi Tamragouri ◽  
Jon Chung ◽  
Alexa Betzig Schrock ◽  
Bhaskar Kolla ◽  
...  
Keyword(s):  
Small Cell Lung Carcinoma ◽  
Clinical Care ◽  
Large Cell ◽  
Smoking History ◽  
Genomic Profiling ◽  
Wild Type ◽  
Cell Lung Carcinoma ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden

8517 Background: SCLC and L-LCNEC are aggressive neoplasms that are both associated with smoking history and are thought to overlap in clinical, histogenetic, and genomic features. We reviewed the genomic profiles of >1187 patients to assess the genomic similarities of these diseases. Methods: Comprehensive genomic profiling (CGP) of tumors from 300 L-LCNEC and 887 SCLC patients in the course of clinical care was performed to suggest pathways to benefit from therapy. Results: Commonly altered genes in both diseases included TP53, RB1, MYC/MYCL1, MLL2, LRP1B and PTEN; alterations in other genes occurred at somewhat differing frequencies (table). For both diseases, RB1 mutation significantly co-occurred with TP53 mutations (p<0.001), but occurred in a mutually exclusive fashion to STK11 and CDKN2A (p<0.001). RB1 was mutually exclusive with KRAS for L-LCNEC but not for SCLC. The interquartile range for SCLC and L-LCNEC TMB is 7.9 and 12.6 with the 75% quartile being 14.4 and 17.1 respectively. Cases of both diseases will be presented with radiographic response to genomically matched targeted therapy and immunotherapy, particularly in cases of high TMB. Conclusions: Given the similar overall genomic profiles and clinical behavior of a subset of these diseases, they could be conceived of as a single disease to be further classified by genomically defined classes such as SCLC-type ( TP53/ RB1mutated) and NSCLC-like (wild type for one or both). By analogy to NSLC and melanoma, benefit from immunotherapy appears most likely for only the upper quartile of cases in TMB. [Table: see text]

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]

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

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]

Difference of genomic signatures and opportunities for targeted and immunotherapies in castrate resistant TMPRSS2:ERG fusion positive and TMPRSS2:ERG wild type refractory acinar (CRPC) and neuroendocrine prostate cancer (CRNEPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 348-348 ◽  
Author(s):  
Gennady Bratslavsky ◽  
Hugh A.G. Fisher ◽  
Timothy Byler ◽  
Joseph M Jacob ◽  
Jon Chung ◽  
...  
Keyword(s):  
High Status ◽  
Genomic Profiling ◽  
Wild Type ◽  
Genomic Signatures ◽  
Mutational Burden ◽  
Neuroendocrine Prostate Cancer ◽  
Stage Disease ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Castrate Resistant

348 Background: We performed comprehensive genomic profiling (CGP) to learn whether sub-categorization of TMPRSS2 fusion status would impact therapy opportunities in patients with refractory CRPC and CRNEPC. Methods: DNA was extracted from 40 µm of FFPE sections of 2,424CRPC and 143 CRNEPC. CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes. 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 ages for all 4 groups was similar (Table). TMPRSS2+( TMP+) CRPC features significantly greater TP53 and PTEN GA and TMPRSS2-( TMP-) CRPC featured higher MYC and ATM GA. Differences in BRCA2 and RB1 GA were not significant in the CRPC group. RB1 GA were more frequent in CRNEPC than CRPC. TP53 GA were higher in TMP+ CRNEPC than in TMP+ CRPC whereas GA in PTEN and MYC were similar in comparative groups. GA in AR and ATM were more frequent in CRPC than CRNEPC. The median TMB was higher in CRNEPC than CRPC and higher in TMP- than TMP+ tumors. TMP- CRPC and TMP- CRNEPC had higher TMB levelsthan TMP+ tumors in both groups. MSI-High status was more frequent in the TMP- CRPC and TMP- CRNEPC groups. Conclusions: For CRPC but not CRNEPC, the frequency of TMP+CRPC cases appears lower in advanced vsearly stage disease (TCGA data). CGP reveals significant differences in both targetable GA and markers of immunotherapy response between TMP+ and TMP- CRPC and CRNEC. Thus, when CRPC and CRNEPC areevaluated as to their TMPRSS2:ERG fusion status, significant genomic differences emerge which may impact therapy selection.[Table: see text]

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