Clinically advanced renal cell carcinoma (RCC) and renal sarcoma (RSC) in young patients: A comprehensive genomic profiling (CGP) study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5066-5066
Author(s):  
Gennady Bratslavsky ◽  
Andrea Necchi ◽  
Petros Grivas ◽  
Oleg Shapiro ◽  
Joseph M Jacob ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Young Patients ◽  
Positive Staining ◽  
High Status ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Male Preponderance ◽  
Ffpe Tissues ◽  
Over 40 Years ◽  
Metastatic Rcc

5066 Background: We queried whether the landscape of genomic alterations (GA) would differ in patients with metastatic RCC under 40 years of age (under40) and patients 40 years of age or older (over40). Methods: FFPE tissues from 2,128 clinically advanced RCC and 25 RSC underwent hybrid-capture based CGP to evaluate all classes of GA. Samples were classified at time of sequencing as the following RCC subtypes: clear cell (ccRCC), papillary (papRCC), chromophobe (chrRCC), medullary (medRCC), collecting duct (cdRC), sarcomatoid (sarcRCC) and NOS (nosRCC). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). Results: The male preponderance increased in the over40 patients. The GA/tumor increased in the over40 cohorts except for medRCC. Similarly, TMB was consistently higher in over40 groups. MSI high status was virtually absent. PD-L1 expression, available only in small subsets, was generally absent although 44% high positive staining in sarcRCC was noteworthy. Differences in GA in under40 vs over40 RCC were seen and included increased PBRM1 and SETD2 GA in over40 vs under40 ccRCC; increased C DKN2A/B and TERT and decreased FH GA in over40 vs under40 papRCC; increased TP53 and decreased VHL, BAP1, SETD2 and PTEN in over40 vs under40 chrRCC; increased TP53, PTEN and TERT GA with decreased NF2 GA in over40 vs under 40 sarcRCC; and increased TP53, VHL and TERT in over40 vs under40 nosRCC. Changes in GA in under40 vs over40 medRCC, cdRCC and RSC were noted but insufficient cases prevented further evaluation. Conclusions: When separately evaluated by under/over 40 years of age, CGP of clinically advanced RCC demonstrates differences in genomic landscapes with over40 cases featuring increasing male preponderance, higher GA/tumor, higher TMB and increases in a variety of GA. These findings may play important roles in the planning of future clinical trials designed to personalize the treatment of metastatic RCC. [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]

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]

Genomic landscape of CDK12 mutated metastatic castrate-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 165-165
Author(s):  
Petros Grivas ◽  
Gennady Bratslavsky ◽  
Joseph M Jacob ◽  
Andrea Necchi ◽  
Philippe E. Spiess ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Checkpoint Inhibitors ◽  
Unmet Need ◽  
Mtor Inhibitors ◽  
Positive Staining ◽  
High Status ◽  
Loss Of Function ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Castrate Resistant

165 Background: Identifying prostate cancer patients likely to benefit from immune checkpoint inhibitors (ICPI) remains an unmet need. Specific loss-of-function genomic alterations (GA) in CDK12 are associated with focal tandem duplications linked to fusion-induced production of neoantigens and are a promising candidate biomarker for ICPI. Using comprehensive genomic profiling (CGP) we compared the GA landscape of CDK12 altered (CDK12mut+) and unaltered (CDK12mut-) tumors. Methods: 4,918 mCRPC tumors were sequenced using a hybrid capture-based FDA-approved CGP assay. Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining -49% and high staining ≥50% expression. Results: Overall, 315 (6.4%) of the mCRPC cases were CDK12mut+ (Table). CDKmut+ cases had significantly fewer GA in TMPRSS2: ERG (P < .0001), TP53 (P < .0001), PTEN (P < .0001), ATM (P = .001), PIK3CA (P = .003), RB1 (P = .02), BRCA2 (P < .0001) and APC (P = .002). CDK12mut+ cases featured higher frequencies only in CCND1 (P < .0001), BRAF (P = .007) and ERBB2 (P < .001) as well as in cell cycle regulatory genes including MDM2/4 (P < .0001), CDK4 (P < .0001) and CDK6 (P = .002). CDK12mut+ cases featured more frequent MSI-H status (P = .007), significantly higher median TMB (P < .001) and more frequent low positive (1-49% staining) PD-L1 expression (P = .02). High (≥50%) PD-L1 expression was rarely identified in either cohort. Conclusions: CDK12mut+ mCRPC demonstrates a unique genomic profile with significant differences compared with CDK12mut- mCRPC. Lower frequencies of GA associated with homologous recombination defect and mTOR pathway may impact the use of platinum agents, as well as PARPi and PIK3CA/Akt/mTOR inhibitors. Opportunities for targeted therapies for BRAF and ERBB2 driven mCRPC may be enriched in the CDK12mut+ tumors and raise the possibility of combination therapy strategies although the numbers of patients are small and validation is needed. The slightly higher MSI High status, median TMB and PD-L1 staining may be associated with additional benefit from ICPI and warrants further prospective investigation. [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]

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]

Extra-mammary Paget’s disease (EMPD) of the skin: A comprehensive genomic profiling (CGP) study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9591-9591
Author(s):  
Julie Tse ◽  
Julia Andrea Elvin ◽  
Jo-Anne Vergilio ◽  
Jonathan Keith Killian ◽  
Nhu Ngo ◽  
...  
Keyword(s):  
Metastatic Disease ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Common Disease ◽  
High Status ◽  
Activating Mutations ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Mammary Paget’S Disease ◽  
Erbb2 Amplification

9591 Background: EMPD is an intraepidermal adenocarcinoma which frequently progresses into invasive/metastatic disease. Methods: 29 EMPD underwent 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 mut/Mb. Microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3 antibody). Results: All patients had locally recurrent and/or metastatic disease. The 20 (69%) male and 9 (31%) female patients had a median age of 70 years (range 45 to 101 years). The primary EMPD site, known in 90% of cases and involved the scrotum (6 cases), groin (6 cases), vulva (5 cases), anus (3 cases), perineum (2 cases), abdomen (2 cases), penis (1 case) and buttock (1 case). was used for sequencing in 15 (52%) cases and a metastatic site 14 (48%) cases. The GA/tumor frequency was 5.0. The most frequent currently untargetable GA involved TP53 (48%), CDKN2A (38%), CDKN2B (31%), KMT2C (28%), and MYC (14%). The most frequent potentially targetable GA were identified in ERBB2 (35%), ERBB3 (17%) and PTEN (14%) and rarely in PDGFRA, CDK4/6, NF1/2, and ROS1 (fusion) all at 3%. The ERBB2 GA included short variant (SV) activating mutations (21%), amplifications (10%) and multiple ERBB2 GA in 3%. This finding is in contrast with mammary Paget’s disease which classically features > 90% of cases with ERBB2 amplification. No EMPD cases were either MSI-High or stained positively for PD-L1 expression. The median and mean TMB were 5.2 mut/Mb and 6.3 mut/Mb, respectively; 4 (14%) had TMB ≥ 10 mut/Mb and 1 (3%) had TMB ≥ 20 mut/Mb. Conclusions: EMPD is a rare source of relapsed/metastatic adenocarcinoma which features GA that are distinct from the more common disease originating on the nipple of the breast including a lower ERBB2 GA frequency and lower relative frequency of ERBB2 amplification versus SV mutations. A variety of MTOR pathway, cell cycle and kinase targets are also identified when EMPD undergoes CGP. However, the low TMB and absence of both MSI-High status and PD-L1 expression in EMPD cohort indicates a likely lack of benefit for immunotherapies for patients suffering from this rare form of malignancy.

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]

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]

Sign in / Sign up

Export Citation Format

Share Document