FGFR2: A pan-genomic target.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3099-3099
Author(s):  
Russell Madison ◽  
Ethan Sokol ◽  
Alexa Betzig Schrock ◽  
Adrienne Johnson ◽  
Dean Pavlick ◽  
...  
Keyword(s):  
Copy Number ◽  
High Status ◽  
Breast Carcinomas ◽  
Gi Tract ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Small Cohort ◽  
Copy Number Changes ◽  
Investigational Agents ◽  
Tumor Types

3099 Background: FGFR2 genomic alterations (GA) have been described in a variety of solid tumors and emerged as biomarkers for investigational agents undergoing clinical trials. Methods: 201,766 primarily relapsed/refractory malignancies were evaluated with a hybrid-capture based sequencing assay Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA and reported as mut/Mb. Microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3 antibody). Results: FGFR2 GA were detected in 2,993 (1.5%) cases featuring short variant (SV) mut (42%), copy number changes (27%), rearrangements/fusions (28%) and multiple GA (3%). The most frequent SV GA were S252W, N549K, C382R, P253R, Y375C, K659E and R664W. A small cohort (2%) of tumors featured the V564I and V564L GA that are associated with resistance to TKI drugs. The FGFR2-altered cases were 69% female/31% male with median age of 61 yrs. Most frequent GA in FGFR2 altered cancers: TP53 (47%), PIK3CA (22%), PTEN (20%), ARID1A (18%), CDKN2A/2B (18/14%) and MYC (12%). FGFR2 SVs most common in endometrial, breast carcinomas (ca) and CUP. FGFR2 amplification most common in breast, gastroesophageal and lung ca. FGFR rearrangement/fusions most common in cholangioca (37%), CUP (15%), pancreatobiliary (12%) and breast ca (6%). The FGFR2- BICC1 was the most frequent fusion followed by fusions with TACC2, AHCYL1, CCDC6, VCL, and KIAA1217. MSI-High status present in 6.8% of evaluable FGFR2 altered cases (63% in endometrial ca). Median TMB was 3.5 mut/Mb with 21.8% featuring ≥ 10 mut/Mb and 12.0% featuring ≥ 20 mut/Mb. Only 63% of MSI-High FGFR2 mut tumors had TMB ≥ 20 mut/Mb. 12.7% FGFR2 mut+ had > 1% PD-L1 staining with 3.4% > 50% staining. 29% of PD-L1 IHC+ cases in NSCLC. FGFR mut ca’s responding to anti-FGFR2 therapies will be presented. Conclusions: FGFR2 GA are most frequent in cholangioca, breast, GI tract, lung ca and CUP, with enrichment of FGFR2 fusions in biliary tract ca. Cases with FGFR2 GA typically do not feature other kinase driver GA and are associated with mut in the MTOR/PIK3CA/AKT pathways. Finally, in contrast with RTK driver GA in EGFR (5.7%) and ERBB2 (7.9%), at 12.0%, across all tumor types, FGFR2 mut cancers may have higher frequency of TMB ≥ 20 mut/Mb suggesting potential immunotherapy responsiveness.

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]

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

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

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

Abstract 3404: Landscape and genomic correlates of ctDNA-based tumor mutational burden across six solid tumor types

2019 ◽  
Author(s):  
Katie Quinn ◽  
Elena Helman ◽  
Tracy Nance ◽  
Jennifer Yen ◽  
John Latham ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Tumor Types

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]

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]

Comprehensive genomic profiling (CGP) of histologic subtypes of urethral carcinomas (UrthCa).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 426-426
Author(s):  
Joseph Jacob ◽  
Oleg Shapiro ◽  
Andrea Necchi ◽  
Petros Grivas ◽  
Ethan Sokol ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Metastatic Disease ◽  
Clear Cell ◽  
High Status ◽  
Genomic Profiling ◽  
Hybrid Capture ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Histologic Subtypes

426 Background: UrthCa is an uncommon GU malignancy that can progress to advanced metastatic disease. Methods: 126 metastatic UrthCa underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 49 (39%) urothelial (UrthUC), 31 (24%) squamous (UrthSCC), 34 (27%) adenocarcinomas (UrthAC) and 12 (9%) clear cell (UrthCC) were evaluated. UrthUC and UrthSCC were more common in men; UrthAC and UrthCC more common in women. Ages were similar in all groups. GA in PIK3CA were the most frequent potentially targetable GA; mTOR pathway GA in PTEN also identified. GA in other potentially targetable genes were also identified including ERBB2 (6% in UrthUC, 3% in UrthSCC and 12% in UrthAC), FGFR1-3 (3% in UrthSCC), BRAF (3% in UrthAC), PTCH1 (8% in UrthCC) and MET (8% in UrthCC). Possibly reflecting their higher GA/tumor status, potential for immunotherapy benefit associated with higher TMB and PD-L1 staining levels were seen in UrthUC and UrthSCC compared to UrthAC and UrthCC. MSI high status was absent throughout. Conclusions: CGP reveals GA that may be predictive of both targeted and immunotherapy benefit in patients with advanced UrthCa and that could potentially be used in future adjuvant, neoadjuvant and metastatic disease trials.[Table: see text]

Metastatic renal cell carcinoma (mRCC) in young patients: A comprehensive genomic profiling (CGP) study.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 727-727
Author(s):  
Gennady Bratslavsky ◽  
Andrea Necchi ◽  
Petros Grivas ◽  
Oleg Shapiro ◽  
Joseph Jacob ◽  
...  
Keyword(s):  
Statistical Evaluation ◽  
Clear Cell ◽  
Collecting Duct ◽  
Young Patients ◽  
High Status ◽  
Genomic Profiling ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Male Preponderance

727 Background: We studied the genomic alterations (GA) in patients with mRCC under 40 years of age (<40) and patients 40 years of age or older (>40). Methods: 2,128 mRCC underwent hybrid-capture based CGP. Clear cell (ccRCC), papillary (pRCC), sarcomatoid (sRCC), NOS (nosRCC), chromophobe (chrRCC), medullary (medRCC) and collecting duct (cdRCC) were separately evaluated. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: Male preponderance in all subsets increased in the >40 patients. The GA/tumor increased significantly in the >40 cohorts except for in medRCC. The relatively low TMB was higher in all >40 and MSI high status was infrequent in all groups. PD-L1 expression was generally low, the 44% high positive PD-L1 in sRCC was noteworthy. Significant differences in GA in <40 vs >40 RCC included increased PBRM1 and SETD2 GA in >40 vs <40 ccRCC; increased C DKN2A/B and TERT and decreased FH GA in >40 vs <40 pRCC; increased TP53, PTEN and TERT GA with decreased NF2 GA in >40 vs <40 sRCC; increased TP53, VHL and TERT in >40 vs <40 nosRCC. Changes in GA in <40 vs >40 chrRCC, medRCC and cdRCC were noted but insufficient cases prevented statistical evaluation. Conclusions: When evaluated by age, CGP of mRCC demonstrates significant differences in the genomic landscapes with >40 cases featuring increasing male preponderance and higher GA/tumor, TMB and increases in TP53, CDKN2A/B and TERT GA. These findings may play important roles in the planning of future clinical trials designed to personalize the treatment of mRCC.[Table: see text]

NF2 mutation-driven renal cell carcinomas (RCC): A comprehensive genomic profiling (CGP) study.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 726-726
Author(s):  
Evgeny Yakirevich ◽  
Carmen Perrino ◽  
Andrea Necchi ◽  
Petros Grivas ◽  
Gennady Bratslavsky ◽  
...  
Keyword(s):  
Clear Cell ◽  
Collecting Duct ◽  
High Status ◽  
Genomic Alterations ◽  
Mutational Burden ◽  
Gender And Age ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Male Preponderance ◽  
Ffpe Tissues

726 Background: NF2 genomic alterations (GA) have been associated with aggressive behavior in RCC. Methods: FFPE tissues from 1,386 clear cell (ccRCC), 307 papillary (pRCC), 72 chromophobe (chRCC), 145 sarcomatoid (sRCC), 54 collecting duct (cdRCC),37 medullary (medRCC) and 134 unclassified (nosRCC) underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and MSI was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 140 (7%) RCC featured NF2 GA which were predominantly short variant (SV) mutations. Gender and age were similar with male preponderance in all histologic subtypes. NF2 GA frequency was highest in cdRCC (20%) and sRCC (19%) and lowest in ccRCC (3%). The medRCC at 5% NF2 GA and chRCC at 0% NF2 GA were not further evaluated. VHL and PBRM1 GA were significantly more frequent in NF2 altered ccRCC than all other RCC (P < 0.001). Other mTOR pathway GA were uncommon. Potentially targetable kinase GA in NF2-mutated RCC included BRAF (2% of ccRCC), EGFR (3% of pRCC), ERBB3 (4% of sRCC) and PIK3CA (9% of cdRCC). No NF2 mutated RCC featured MSI -high status and both TMB and PD-L1 expression levels were extremely low in all subsets with exception of high PD-L1 staining in sRCC tumors. Conclusions: cdRCC, sRCC, pRCC and nosRCC are enriched in NF2 GA. Low PBRM1 GA, TMB and MSI- high predict resistance to immunotherapy in NF2 mutated RCC although the high PD-L1 expression in sRCC is noteworthy.[Table: see text]

Comprehensive genomic profiling (CGP) in post-systemic treatment (Post) metastatic sites (MET) and pretreatment (Pre) primary tumors (PT) of metastatic prostate cancer (mPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 175-175
Author(s):  
Andrea Necchi ◽  
Petros Grivas ◽  
Gennady Bratslavsky ◽  
Oleg Shapiro ◽  
Joseph Jacob ◽  
...  
Keyword(s):  
Systemic Treatment ◽  
High Status ◽  
Liquid Biopsies ◽  
Primary Tumors ◽  
Virtual Absence ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Metastatic Sites ◽  
Systemic Therapies

175 Background: CGP was performed on Pre PT and Post MET including bone (BO), liver (LIV), lung (LU), brain (BN), lymph node (LN) and soft tissue (ST) mPC. Methods: 1,294 mPC underwent hybrid-capture based CGP. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: GA in AR were lowest in the Pre PT (2%) and highest in Post LU (24%) and LIV (50%). GA/tumor was significantly higher in BN (8.0) compared to PT (3.8). BR MET also featured higher PTEN GA than PT. BRCA2 GA varied from 0% in BR to 7-9% in PT, BO, LU, LN and ST to a high of 15% in LI MET. ATM GA were significantly higher in LU MET and RAD21 GA highest in LN MET. Potential predictors of IO drug response included high CDK12 GA in LU MET, MSI high status at 29% in BR MET associated with higher TMB levels, but virtual absence of high PD-L1 expression. ERBB2 GA appeared to be increased in the MET group compared with PT but BRAF GA were not. RB1 GA were significantly increased in LIV MET cases. Conclusions: CGP of mPC PT and MET demonstrates significant differences likely linked to exposure to systemic therapies. These findings suggest that, in the future, liquid biopsies may have advantages over individual MET site biopsies in their ability to capture the entire range of therapeutic opportunities for patients with advanced mPC.[Table: see text]

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