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]

scholarly journals Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer

2021 ◽  
Vol 22 (8) ◽  
Author(s):  
Federica Pecci ◽  
Luca Cantini ◽  
Alessandro Bittoni ◽  
Edoardo Lenci ◽  
Alessio Lupi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Cancer Progression ◽  
Checkpoint Inhibitors ◽  
Tnm Classification ◽  
Standard Of Care ◽  
First Line Therapy ◽  
Combination Strategies ◽  
The Impact

Opinion statementAdvanced colorectal cancer (CRC) is a heterogeneous disease, characterized by several subtypes with distinctive genetic and epigenetic patterns. During the last years, immune checkpoint inhibitors (ICIs) have revamped the standard of care of several tumors such as non-small cell lung cancer and melanoma, highlighting the role of immune cells in tumor microenvironment (TME) and their impact on cancer progression and treatment efficacy. An “immunoscore,” based on the percentage of two lymphocyte populations both at tumor core and invasive margin, has been shown to improve prediction of treatment outcome when added to UICC-TNM classification. To date, pembrolizumab, an anti-programmed death protein 1 (PD1) inhibitor, has gained approval as first-line therapy for mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) advanced CRC. On the other hand, no reports of efficacy have been presented in mismatch-repair-proficient (pMMR) and microsatellite instability-low (MSI-L) or microsatellite stable (MSS) CRC. This group includes roughly 95% of all advanced CRC, and standard chemotherapy, in addition to anti-EGFR or anti-angiogenesis drugs, still represents first treatment choice. Hopefully, deeper understanding of CRC immune landscape and of the impact of specific genetic and epigenetic alterations on tumor immunogenicity might lead to the development of new drug combination strategies to overcome ICIs resistance in pMMR CRC, thus paving the way for immunotherapy even in this subgroup.

scholarly journals Unique Genomic Landscape of High-Grade Neuroendocrine Cervical Carcinoma: Implications for Rethinking Current Treatment Paradigms

2020 ◽  
pp. 972-987
Author(s):  
Ramez N. Eskander ◽  
Julia Elvin ◽  
Laurie Gay ◽  
Jeffrey S. Ross ◽  
Vincent A. Miller ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Current Treatment ◽  
High Grade ◽  
Novel Treatment ◽  
Sample Average ◽  
Genomic Landscape ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Sample Range ◽  
Novel Treatment Strategies

PURPOSE High-grade neuroendocrine cervical cancer (HGNECC) is an uncommon malignancy with limited therapeutic options; treatment is patterned after the histologically similar small-cell lung cancer (SCLC). To better understand HGNECC biology, we report its genomic landscape. PATIENTS AND METHODS Ninety-seven patients with HGNECC underwent comprehensive genomic profiling (182-315 genes). These results were subsequently compared with a cohort of 1,800 SCLCs. RESULTS The median age of patients with HGNECC was 40.5 years; 83 patients (85.6%) harbored high-risk human papillomavirus (HPV). Overall, 294 genomic alterations (GAs) were identified (median, 2 GAs/sample; average, 3.0 GAs/sample, range, 0-25 GAs/sample) in 109 distinct genes. The most frequently altered genes were PIK3CA (19.6% of cohort), MYC (15.5%), TP53 (15.5%), and PTEN (14.4%). RB1 GAs occurred in 4% versus 32% of HPV-positive versus HPV-negative tumors ( P < .0001). GAs in HGNECC involved the following pathways: PI3K/AKT/mTOR (41.2%); RAS/MEK (11.3%); homologous recombination (9.3%); and ERBB (7.2%). Two tumors (2.1%) had high tumor mutational burden (TMB; both with MSH2 alterations); 16 (16.5%) had intermediate TMB. Seventy-one patients (73%) had ≥ 1 alteration that was theoretically druggable. Comparing HGNECC with SCLC, significant differences in TMB, microsatellite instability, HPV-positive status, and in PIK3CA, MYC, PTEN, TP53, ARID1A, and RB1 alteration rates were found. CONCLUSION This large cohort of patients with HGNECC demonstrated a genomic landscape distinct from SCLC, calling into question the biologic and therapeutic relevance of the histologic similarities between the entities. Furthermore, 73% of HGNECC tumors had potentially actionable alterations, suggesting novel treatment strategies for this aggressive malignancy.

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.

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]

KRAS amplification and mutation as independent events in gastroesophageal adenocarcinomas (GEA).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15565-e15565
Author(s):  
Joseph Chao ◽  
Russell Madison ◽  
Jeffrey S. Ross ◽  
Vincent A. Miller ◽  
Siraj Mahamed Ali ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Older Patient ◽  
Kras Mutations ◽  
Independent Events ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Tissue Specimens ◽  
Kras Codon

e15565 Background: KRAS mutations are common oncogenic events across cancers, but effective RAS-directed therapies are lacking. However, recent studies support use of PD-1 blockade in most subsets of lung cancer with KRAS short variant mutations (KRASSV) (PMID: 28039262), and preclinical data supports combined MEK and SHP2 inhibition in KRAS amplified ( KRASa) GEA (PMID: 30093730). We sought to explore the landscape of KRAS altered GEA and compare genomic profiles of KRAS-altered and KRAS wild-type (WT) cases for biomarkers of response to targeted therapies and immune checkpoint inhibitors. Methods: 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture-based comprehensive genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Descriptive statistics were used to compare among subgroups. Results: KRASSV and KRASa were identified in 11% and 5.8% of gastric adenocarcinoma (GA), respectively, and in 7.2% and 17% of esophageal adenocarcinoma (EA), respectively. KRASa and KRASSV were nearly mutually exclusive, co-occurring in only 4.4% of KRAS altered cases. ERBB2 alterations were less common in KRASSV and KRASa GEA (both 9%) as compared with KRAS WT GEA (19%) (p = 1.9E-16). EGFRa was less common in KRASSV vs KRASa GEA (1.9% vs 9.3%, p = 2.6E-8), whereas PIK3CASV was more common in KRASSV vs KRASa (16% vs 5.0%, p = 1.5E-11). Median TMB for all groups was similar; however, KRASSV GEA had a higher mean TMB (9.7 mut/Mb) as compared to KRASa (5.1 mut/Mb, p = 5.0E-12) and KRAS WT cases (5.8 mut/Mb, p = 2.2E-07). KRAS codon 12/13 accounted for > 80% of predicted pathogenic mutations. MSI-high was also more prevalent in KRASSV (11.3%) vs KRASa (0.9%, p = 4.8E-15) and KRAS WT GEA (2.4%, p = 1.8E-25). MSI-high KRASSV GEA was associated with older patient age (median 72 years) and with high TMB (median 40.9 mut/mb). Conclusions: GA was enriched for KRAS mutation whereas EA was enriched for KRAS amplification. KRAS WT vs KRASSV vs KRASa each presented distinct genomic profiles. KRASa in the absence of KRAS mutation exists in 11% of GEA and warrants further exploration to inform combination treatment strategies.

Primary adult retroperitoneal sarcoma (RS): Comprehensive genomic profiling (CGP) study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11541-11541
Author(s):  
Andrea Necchi ◽  
Petros Grivas ◽  
Gennady Bratslavsky ◽  
Jonathan Keith Killian ◽  
Douglas I. Lin ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Mtor Pathway ◽  
Small Subset ◽  
Peripheral Nerve Sheath Tumors ◽  
Dna And Rna ◽  
Cell Staining ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Ffpe Tissues ◽  
Synovial Sarcomas

11541 Background: We performed CGP on 315 cases of RS to discover targetable genomic alterations (GA) and their potential impact on potential targeted and immunotherapy (IO) selection. Methods: FFPE tissues from 315 clinically advanced RS tissues underwent hybrid-capture based CGP (DNA and RNA). Tumor mutational burden (TMB) was determined on up to 1.2 Mbp of sequenced DNA, and tumor cell PD-L1 expression was determined by IHC (Dako 22C3) (low = 1-49%; High = >50% tumor cell staining). Results: 155 liposarcomas (LPS), 74 leiomyosarcomas (LMS), 46 pleomorphic sarcomas (PLS), 7 solitary fibrous tumors (SFT), 6 malignant peripheral nerve sheath tumors (MPNST), 5 synovial sarcomas (SS) and 5 dendritic follicular cell sarcomas (DFCS) were studied; 17 cases were excluded. Median age was 59. There were 5.1 GA/tumor, none were MSI-high, median TMB was low at 2.4; PD-L1 IHC staining was low-positive in 21% and high-positive in 5%. MPNST patients were younger (median 28 years vs. 59 years). LPS was more frequent in men and LMS in women. LPS had more GA/tumor than LMS, with DFCS having the highest and SS the lowest. TP53 and RB1 GA were the highest in LMS and CDK4/6 and MDM2 GA the highest in LPS. Molecular targets in mTOR pathway were most frequently altered. Targetable gene fusions in ALK, ROS1 and NTRK1-3 were rare. Non-targetable fusions in HMGA2 (LPS and some PLS), STAT6 (SFT) and SS18 (SS) were also identified. Conclusions: RS in our cohort are predominantly composed of LPS, LMS and PLS and we identified a small proportion with “actionable” genomic targets on CGP, albeit in association with uncertain mTOR pathway inhibitor benefit and uncommon targetable kinase fusions. Our analysis suggests that a small subset of RS may respond to immunotherapy based on putative biomarker expression. [Table: see text]

Differential genomic landscape of clinically advanced/metastatic chordomas (mChor) based on primary tumor site.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11521-11521
Author(s):  
Jonathan Keith Killian ◽  
Xiaohong Rose Yang ◽  
Natalie Danziger ◽  
Julia Andrea Elvin ◽  
Jo-Anne Vergilio ◽  
...  
Keyword(s):  
Primary Tumor ◽  
Drug Benefit ◽  
Genomic Alteration ◽  
Tumor Site ◽  
Primary Tumor Site ◽  
Genomic Landscape ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Ffpe Tissues ◽  
Immune Oncology

11521 Background: We queried whether comprehensive genomic profiling (CGP) could differentiate genomic alteration (GA) differences in mChor based on tumor site of origin Methods: 111 mChor FFPE tissues were sequenced using a hybrid-capture based CGP method 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: 27 clivus (Cliv), 12 cervical (Cerv), 10 thoracic (Thor) and 44 lumbosacral (Sacr) mChor were compared (Table). A separate set of 18 mChor were submitted as metastasis biopsies with no primary tumor site available (Unk). mChor was generally more common in men with Sacr tumors. Cliv patients were significantly younger (p = 0.00002). GA/tumor was highest in Sacr at 2.9 and lowest Thor at 1.5. All (100%) mChor were MSI stable and the TMB was low ( < 5 mut/Mb) for all cases. CDKN2A and CDKN2B mutation frequencies were highest in Sacr (52% and 46%, p = 0.009 and 0.0109). Potentially actionable GA in PTEN were highest in Thor and Sacr. PTCH1 GA were seen in Cliv and Cerv and PBRM1 GA potentially associated with immune-oncology (IO) drug response were present in all groups. Additional noteworthy targets were seen in all groups but were found in less than 11% of cases throughout the study (Table). Conclusions: Genomic profiles of our mChor cohort differ based on the site of tumor origin in the axial spine. Sacr appear to have the highest frequency of GA and the greatest number of potentially targetable GA. Although MSI and TMB biomarker results do not predict responsiveness, a significant PBRM1 GA frequency in all groups raises the possibility of IO drug benefit for some patients. [Table: see text]

KRAS amplification and mutation are independent events in gastroesophageal adenocarcinomas (GEA).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 70-70
Author(s):  
Russell Madison ◽  
Joseph Chao ◽  
Jeffrey S. Ross ◽  
Vincent A. Miller ◽  
Siraj Mahamed Ali ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Older Patient ◽  
Kras Mutations ◽  
Independent Events ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Tissue Specimens ◽  
Kras Codon

70 Background: KRAS mutations are common oncogenic events across cancers, but effective RAS-directed therapies are lacking. However, recent studies support use of PD-1 blockade in most subsets of lung cancer with KRAS short variant mutations (KRASSV) (PMID: 28039262), and preclinical data supports combined MEK and SHP2 inhibition in KRAS amplified ( KRASa) GEA (PMID: 30093730). We sought to explore the landscape of KRAS altered GEA and compare genomic profiles of KRAS-altered and KRAS wild-type (WT) cases for biomarkers of response to targeted therapies and immune checkpoint inhibitors. Methods: 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture-based comprehensive genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Descriptive statistics were used to compare among subgroups. Results: KRASSV and KRASa were identified in 11% and 5.8% of gastric adenocarcinoma (GA), respectively, and in 7.2% and 17% of esophageal adenocarcinoma (EA), respectively. KRASa and KRASSV were nearly mutually exclusive, co-occurring in only 4.4% of KRAS altered cases. ERBB2 alterations were less common in KRASSV and KRASa GEA (both 9%) as compared with KRAS WT GEA (19%) (p = 1.9E-16). EGFRa was less common in KRASSV versus KRASa GEA (1.9% vs. 9.3%, p = 2.6E-8), whereas PIK3CASV was more common in KRASSV versus KRASa (16% vs 5.0%, p = 1.5E-11). Median TMB for all groups was similar; however, KRASSV GEA had a higher mean TMB (9.7 mut/Mb) as compared to KRASa (5.1 mut/Mb, p = 5.0E-12) and KRAS WT cases (5.8 mut/Mb, p = 2.2E-07). KRAS codon 12/13 accounted for > 80% of predicted pathogenic mutations. MSI-high was also more prevalent in KRASSV (11.4%) versus KRASa (0.9%, p = 4.8E-15) and KRAS WT GEA (3.0%, p = 1.8E-25). MSI-high KRASSV GEA was associated with older patient age (median 72 years) and with high TMB (median 40.9 mut/mb). Conclusions: GA was enriched for KRAS mutation whereas EA was enriched for KRAS amplification. KRAS WT versus KRASSV versus KRASa each presented distinct genomic profiles. KRASa in the absence of KRAS mutation exists in 11% of GEA and warrants further exploration to inform combination treatment strategies.

In search of novel synthetic lethality anti-cancer drug targets in intrahepatic cholangiocarcinoma: MTAP genomic loss.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 337-337
Author(s):  
Jeffrey S. Ross ◽  
Alexa Betzig Schrock ◽  
Russell Madison ◽  
Natalie Danziger ◽  
Dean Pavlick ◽  
...  
Keyword(s):  
Intrahepatic Cholangiocarcinoma ◽  
Drug Targets ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Suppressor Gene ◽  
Cancer Drug ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden

337 Background: The association of BRCA tumor suppressor gene (TSG) inactivation and PARP inhibitor efficacy through a mechanism of synthetic lethality (SL) is now well-established. Recently, the PRMT5 arginine methyltransferase dependence in cells with MTAP (S-methyl-5'-thioadenosine phosphorylase) genomic alterations (GA) has been proposed as a new SL based anti-tumor strategy and under consideration for development for intrahepatic cholangiocarcinoma (IC). Methods: 2,170 cases of clinically advanced IC were submitted for comprehensive genomic profiling (CGP) to detect genomic alterations (GA), tumor mutational burden (TMB) and microsatellite instability (MSI) using a hybrid capture based assay (F1CDx). PD-L1 expression in tumor cells (Dako 22C3) was measured by IHC and scored using the tumor proportion score (TPS) method. Results: 328 (15%) ICs featured MTAP inactivation (MTAP-IC). 48% of MTAP-IC cases were female and 52% were male with a median age of 66 years (range 26-93 years). MTAP-IC featured 6.3 GA per sample. The median TMB was 2.5 mut/Mb with only 2% of cases with TMB ≥10 mut/Mb. No (0%) MTAP-IC cases were MSI-high. Of 112 MTAP-IC IHC stained for PD-L1, 4% were PD-L1 high (> 50%), 14% were PD-L1 low (1-49%) and 82% were PD-L1 negative. 99% of MTAP inactivation was by copy number (CN) loss and 1% was due to non-CN mutation. In MTAP-IC, 99% featured CDKN2A loss and 95% featured CDKN2B loss (9p21 co-deletion). TP53 was mutated in 31% and KRAS in 24% (3% G12C). Other currently non-targetable GA included ARID1A (19%), BAP1 (16%) and SMAD4 (13%). Among potentially targetable GA, the MTAP-IC featured 12% FGFR2 GA (8% rearrangements), 10% BRAF (8% V600E), 7% IDH1, 7% PIK3CA, 4% BRCA2, 4% ERBB2 (2% amplification) and 3% MET. Conclusions: Comprehensive genomic profiling elucidated that MTAP GA are frequent in IC and features relatively high GA/tumor, including 9p21 co-deletion, but relatively low TMB and PD-L1 expression. Isolated MTAP deletion without CDKN2A/B co-deletion was extremely rare. In addition to the potential targeting of PRMT5 in MTAP-IC tumors, co-altered genes known to be targets in IC such as FGFR2, IDH1 and BRAF are still prevalent in MTAP-IC, indicating potential for combining targeted therapies in some MTAP-IC patients.

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.

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