FGFR2-altered gastroesophageal adenocarcinomas (GEA) are a rare clinicopathologic entity with a distinct genomic landscape.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 72-72
Author(s):  
Samuel Jacob Klempner ◽  
Russell Madison ◽  
Jeffrey S. Ross ◽  
Vincent A. Miller ◽  
Siraj Mahamed Ali ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Tp53 Mutation ◽  
Fusion Partner ◽  
Wild Type ◽  
Genomic Landscape ◽  
Female Predominance ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Pre Treatment ◽  
Tissue Specimens

72 Background: Therapies directed at receptor tyrosine kinases (RTKs) in GEA have met with limited success. The small molecule FGFR2 inhibitor AZD4547 failed in a phase II biomarker-selected trial, though activity has been seen with FGFR2-directed strategies, including monoclonal antibodies. Despite observed activity, very little is known about the genomic landscape of FGFR2-altered GEA. Using a large genomic database, we sought to examine the classes of FGFR2 alterations and frequency of co-occurring alterations in GEA. Methods: 6,667 tissue specimens from unique patients with advanced GEA were assayed using hybrid capture-based comprehensive genomic profiling (CGP). 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: We identified a total of 269 (4.0%) FGFR2-altered cases consisting of FGFR2 amplified (amp; 209, 78% of FGFR2-altered), FGFR2 mutated (mut; 40, 15%) and FGFR2 rearranged (re, 37, 14%). There was a female predominance in FGFR2-altered cases (M:F = 1.6:1) vs FGFR wild-type (WT) (2.8:1). Cases with FGFR2amp and FGFR2re were exclusively MS-stable. The most common fusion partner was TACC2 (22%). FGFR2amp GEA had higher rates of TP53 mutation versus either FGFR2re of FGFR2mut cases (p = 4.4E-6). Co-occurring alterations in the other GEA RTK targets including ERBB2 (10%) , EGFR (8%) and MET (3%) were observed in all types of FGFR2-altered GEA. Co-occurring downstream alterations in MYC (17%), KRAS (10%) and PIK3CA (5.6%) were observed frequently in each class of FGFR2-altered GEA. The median TMB for FGFR2-altered GEA was 3.6 mut/mb, which was not significantly different from a median of 4.3 mut/mb seen in FGFR2 WT samples (p = 0.53). Conclusions: FGFR2-altered GEA is a heterogenous subgroup with approximately 20% of FGFR2-altered samples harboring concurrent RTK alterations. Putative co-occurring modifiers of FGFR2 directed therapy including oncogenic MYC, KRAS, PIK3CA alterations were also frequent, suggesting that pre-treatment CGP and combination approaches may be needed to optimize patient selection.

Analysis of EGFR mutant urothelial carcinoma (UC) reveals distinct mutational landscape.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4545-4545
Author(s):  
Russell Madison ◽  
Sumati Gupta ◽  
Jeffrey S. Ross ◽  
Sumanta K. Pal ◽  
Alexa Betzig Schrock ◽  
...  
Keyword(s):  
Age Distribution ◽  
Genitourinary Cancer ◽  
Mutational Burden ◽  
Genomic Landscape ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Exon 19 Deletion ◽  
Exon 20 ◽  
Tissue Specimens ◽  
Egfr Mutant

4545 Background: Genomic alterations (GA) of EGFR, are well recognized as druggable oncogenic drivers in NSCLC, but the druggable GA EGFR L858R and exon 19 deletion (ex19del), are rarely observed in genitourinary cancer. We reviewed the genomic landscape of advanced upper tract and bladder UC (UTUC and BUC) to assess the frequencies of druggable EGFR GA. Methods: Tissue specimens from patients with UTUC (407) and BUC (2,402) were assayed using hybrid capture-based comprehensive genomic profiling (CGP). 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. Results: EGFR alterations ( EGFR alt) were present in 17 UTUC and 93 BUC (4.2% and 3.9%). Age distribution between the two subgroups was similar, but UTUC was more prevalent in female patients (47% v 29%). BUC had a higher median TMB (5.2mut/mb v 7.8 mut/mb; p = 0.046) and the prevalence of MSI-H cases was not significantly different. TERT (55% v 71%) and TP53 (59% v 74%) were the most frequently mutated genes in EGFR alt UTUC and BUC. Within EGFRalt, amplifications were the most common alterations in both UTUC and BUC (13/17, 76%; 57/93, 61%). Amplifications were mutually exclusive from cases with EGFR short variants (SV) in BUC (0/34, 0%), and co-occurred with EGFR SV in four UTUC cases (4/8 50%). The majority of EGFR SV were EGFR exon 20 insertions ( EGFRexon20), which made up a larger proportion of EGFR alt in UTUC than BUC (7/17, 41% v 13/93, 14%; p = 0.01). Compared to other EGFR alt , EGFRexon20 trended towards mutual exclusivity of GA in commonly altered UC genes: TP53 (UTUC EGFRexon20 v EGFR alt other: 0% v 100%, p = 5.1E-5; BUC EGFRexon20 v EGFR alt other: 0% v 86%, p = 2.2E-7) , PIK3CA (14% v 10%; 0% v 19%) , RAF1 (0% v 10%; 0% v 16%) , or FGFR3 (0% v 10%; 0% v 6.3%) alterations. Only 2.2% (2/93) of BUC EGFRalt were L858R mutations and none were ex19del (0/93), while neither mutation was detected in UTUC. Conclusions: EGFRexon20 defines a subset of UC cases, and is the most common non-amplification GA seen in EGFR in UC, with some enrichment in UTUC. Consideration should be given to developing a trial for EGFR exon20 UC patients given the recent investigational work on inhibitors with activity against EGFRexon20, such as poziotinib and TAK-788.

Analysis of EGFR mutant upper tract and bladder urothelial carcinoma (UC) reveals distinct mutational landscape.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 416-416
Author(s):  
Russell Madison ◽  
Sumati Gupta ◽  
Jeffrey S. Ross ◽  
Alexa Betzig Schrock ◽  
Luke Juckett ◽  
...  
Keyword(s):  
Age Distribution ◽  
Upper Tract ◽  
Genomic Landscape ◽  
Bladder Urothelial Carcinoma ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Exon 19 Deletion ◽  
Exon 20 ◽  
Tissue Specimens ◽  
Egfr Mutant

416 Background: Genomic alterations (GA) of EGFR, are well recognized as druggable oncogenic drivers in NSCLC, but the druggable GA EGFR L858R and exon 19 deletion (ex19del), are rarely observed in genitourinary cancer. We reviewed the genomic landscape of advanced upper tract and bladder UC (UTUC and BUC) to assess the frequencies of druggable EGFR GA. Methods: Tissue specimens from patients with UTUC (407) and BUC (2,402) were assayed using hybrid capture-based comprehensive genomic profiling (CGP). 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. Results: EGFR alterations ( EGFRalt) were present in 17 UTUC and 93 BUC (4.2% and 3.9%). Age distribution between the two subgroups was similar, but UTUC was more prevalent in female patients (47% v 29%). BUC had a higher median TMB (5.2mut/mb v 7.8 mut/mb; p = 0.046) and the prevalence of MSI-H cases was not significantly different. TERT (55% v 66%) and TP53 (58% v 74%) were the most frequently mutated genes in EGFRalt UTUC and BUC. Within EGFRalt, amplifications were the most common alterations in both UTUC and BUC (13/17, 76%; 57/93, 63%). Amplifications were mutually exclusive from cases with EGFR short variants (SV) in BUC (0/34, 0%), and co-occurred with EGFR SV in four UTUC cases (4/8 50%). The majority of EGFR SV were EGFR exon 20 insertions ( EGFRexon20), which made up a larger proportion of EGFRalt in UTUC than BUC (7/17, 38% v 13/93, 14%; p = 0.01). Compared to other EGFRalt, EGFRexon20 trended towards mutual exclusivity of GA in commonly altered UC genes: TP53 (0% v 100%, p = 5.1E-5; 0% v 86%, p = 2.2E-7) , PIK3CA (14% v 10%; 0% v 19%) , RAF1 (0% v 10%; 0% v 16%) , or FGFR3 (0% v 10%; 0% v 6.3%) alterations. Only 2.2% (2/93) of BUC EGFRalt were L858R mutations and none were ex19del (0/93), while neither mutation was detected in UTUC. Conclusions: EGFRexon20 defines a subset of UC cases, and is the most common non-amplification GA seen in EGFR in UC, with some enrichment in UTUC. Consideration should be given to developing a trial for EGFR exon20 UC patients given the recent investigational work on inhibitors with activity against EGFRexon20, such as poziotinib and TAK-788.

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.

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]

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]

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]

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.

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.

Comprehensive genomic profiling in FIGHT-202 reveals the landscape of actionable alterations in advanced cholangiocarcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4080-4080 ◽  
Author(s):  
Ian M. Silverman ◽  
Karthikeyan Murugesan ◽  
Christine F. Lihou ◽  
Luis Féliz ◽  
Garrett M. Frampton ◽  
...  
Keyword(s):  
Point Mutations ◽  
Fusion Partner ◽  
Genomic Profiling ◽  
Cancer Genes ◽  
Exact Test ◽  
Multiple Tumor ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Genomic Studies ◽  
Tumor Types

4080 Background: Genomic studies of cholangiocarcinoma (CCA) have identified actionable alterations in multiple genes including IDH1, IDH2, FGFR2 and BRAF, but no targeted therapies have been approved for this indication. Pemigatinib (formerly INCB054828) is a selective FGFR1-3 inhibitor currently being evaluated in multiple tumor types, including advanced CCA harboring FGFR2 rearrangements. Comprehensive genomic profiling (CGP) was used to identify and enroll advanced CCA patients with FGFR2 rearrangements into FIGHT-202 (NCT02924376). Here we provide an overview of the genomic landscape of advanced CCA and identify actionable alterations. Methods: CGP was performed on tumor samples from 1104 patients with advanced CCA using FoundationOne, a broad-based genomic panel which identifies mutations, rearrangements, and amplifications in 315 cancer genes. Results: The most frequently altered genes in advanced CCA were TP53 (38.1%), CDKN2A/B (28.8%), KRAS (21.9%), ARID1A (15.7%), SMAD4 (11.3%), BAP1 (10.6%), IDH1 (10.5%), PBRM1 (10.0%), FGFR2 (9.4%), ERBB2 (7.6%), PIK3CA (7.0%), MDM2/ FRS2 (5.8%), and BRAF (4.7%). FGFR2: BAP1 was the most significantly co-occurring alteration pair (odds ratio = 8.5; q-value = 1.08 x 10-13, Fisher’s exact test). 42.9% of patients had at least one alteration for which a targeted agent has been either approved or is under investigation. 91 (8.2%) patients had FGFR2 rearrangements, involving 44 unique partner genes, 37 (84.1%) of which were observed only once. The most prevalent FGFR2 rearrangement partner, BICC1, occurred in only 28 (30.7%) FGFR2 rearrangement positive patients. FGFR2 activating point mutations were found in 13 (1.2%) patients. Of 1,091 evaluable patients for microsatellite instability (MSI) or tumor mutational burden (TMB), only 10 (0.9%) were MSI-H and 13 (1.2%) had high TMB (≥ 20 mutations/megabase). None of the MSI-H or TMB-High patients had FGFR2, IDH1 or IDH2 activating alterations. Conclusions: The high frequency (42.9%) of patients with actionable alterations and myriad FGFR2 rearrangement partners strongly support the use of fusion partner-agnostic CGP in advanced CCA.

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