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]

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]

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]

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]

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

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5087-5087
Author(s):  
Petros Grivas ◽  
Joseph M Jacob ◽  
Oleg Shapiro ◽  
Andrea Necchi ◽  
Ethan Sokol ◽  
...  
Keyword(s):  
Metastatic Disease ◽  
Clear Cell ◽  
High Status ◽  
Genomic Profiling ◽  
Control Cohort ◽  
Hybrid Capture ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Histologic Subtypes

5087 Background: UrthCa is an uncommon GU malignancy that can progress to advanced metastatic disease. Methods: 127 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 (19%) adenocarcinomas (UrthAC) and 13 (9%) clear cell (UrthCC) were evaluated along with a control cohort of 2,130 bladderUC cases. UrthUC and UrthSCC were more common in men; UrthAC and UrthCC more common in women. Age was similar in all 4 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). Higher TMB was seen in UrthUC and UrthCC compared to UrthAC and UrthSCC, possibly reflecting their higher GA/tumor status and suggesting potential for immunotherapy benefit. MSI high status was absent throughout. The bladderUC cases had similar genomic pattern as UrthUC with significantly lower frequency of HPV16/18 positive cases. 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]

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]

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]

The emerging target KRAS G12C in genitourinary malignancies.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 434-434
Author(s):  
Petros Grivas ◽  
Andrea Necchi ◽  
Gennady Bratslavsky ◽  
Oleg Shapiro ◽  
Joseph Jacob ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clear Cell ◽  
Ffpe Tissue ◽  
Genomic Alteration ◽  
Genomic Profiling ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Urothelial Bladder ◽  
Bladder Carcinomas

434 Background: KRAS has recently emerged as a druggable driver with novel agents targeting G12C genomic alteration (GA). Methods: FFPE tissue from 1453 renal clear cell carcinomas (RCCC), 3879 urothelial bladder carcinomas (UBC) and 8322 prostate acinar adenocarcinomas (PAAC) underwent comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on 0.8 to 1.2 Mbp of sequenced DNA and MSI was determined on 114 loci. PD-L1 expression (Dako 22C3) was measured by IHC. Results: KRAS GA were identified in 7 RCCC (<1%), 202 UBC (5.2%), and 158 PAAC (1.9%). KRAS G12C mutations were observed in 0 RCCC, 24 (2%) of UBC, and 1 (<1%) PAAC. Age/gender distributions were similar. VHL, SETD2, and PBRM1 mutations were the most frequent concurrent GA in the 7 RCCC with KRAS G12C GA. In KRAS G12C mutated UBC, co-mutations in TERT were significantly reduced and in KDM6A were significantly increased (both p<0.05) in cases with KRAS G12C GA versus KRAS G12C negative tumors. Conclusions: KRAS G12C mutations are extremely rare in the major genitourinary malignancies. However, given the emerging interest in identifying KRAS G12C for potential basket-type clinical trials using novel anti-KRAS G12C targeted therapies, further study of these alterations in genitourinary malignancies, especially bladder and prostatic carcinomas, appears warranted.[Table: see text]

Anal melanoma: A comparative comprehensive genomic profiling study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9566-9566
Author(s):  
Jeffrey S. Ross ◽  
Russell Madison ◽  
Julia Andrea Elvin ◽  
Jo-Anne Vergilio ◽  
Jonathan Keith Killian ◽  
...  
Keyword(s):  
Uv Light ◽  
Light Exposure ◽  
Mtor Pathway ◽  
Braf V600e ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Ffpe Tissues ◽  
Tumor Types

9566 Background: We performed a comprehensive genomic profiling (CGP) study of AM and CM to learn of potential genomic alterations (GA) linked to targeted and immune checkpoint inhibitor (ICPI) therapies. Methods: 90 AM and 1804 CM FFPE tissues from late stage 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. Results: AM and CM had a similar age, but AM females and CM males were significantly more common (P < 0.0001). GA/tumor was significantly higher in CM (UV light exposure) as were the median TMB and frequency of TMB ≥ 10 and 20 mutations/Mb (P < 0.0001 for all comparisons). PD-L1 expression was higher in AM than CM (P = 0.0023). AM and CM were all MS-stable. The contrast in S FB1 mutations in AM and TERT GA in CM were significant (P < 0.0001). Of potentially targetable GA, AM featured significantly more KIT GA than CM (P < 0.0001), whereas CM featured significantly more BRAF GA (P < 0.0001). Only 11% of AM BRAF GA were V600E whereas 74% of CM BRAF GA were V600E (P < 0.0001). MTOR pathway GA were common in both tumor types. Additional potentially targetable alterations in PDGFRA and ERBB2 kinases were seen in AM but not in CM. Conclusions: CM is distinct from AM featuring higher GA/tumor, higher TMB and frequent BRAF V600E GA that predict benefit from ICPI and anti-BRAF therapies. Although both AM and CM feature MTOR pathway targets, AM does have higher PD-L1 expression than CM and is characterized by an array of potentially targetable kinase genes including KIT, PDGFRA, ERBB2 and to a lesser extent than CM, BRAF.[Table: see text]

Genomic findings in adenocarcinoma of the urinary bladder.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 132-132
Author(s):  
Oleg Shapiro ◽  
Leszek Kotula ◽  
Timothy Byler ◽  
Joseph Jacob ◽  
Brian Michael Alexander ◽  
...  
Keyword(s):  
Ductal Carcinoma ◽  
Mtor Inhibitors ◽  
Parp Inhibitors ◽  
High Status ◽  
Genomic Alterations ◽  
Mek Inhibitors ◽  
Pathologic Features ◽  
Ffpe Samples ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden

132 Background: Prostatic ductal carcinoma (PDC) is an uncommon centrally located prostate with a characteristic tubulopapillary histology. PDC shares some biomarker features with the more common prostatic acinar carcinoma (PAC) including PSA expression. Methods: In this comparative comprehensive genomic profiling (CGP) study, FFPE samples from 61 clinically advanced PDC and 4,132 PAC were profiled for all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The age, frequency of genomic alterations (GA) per tumor and TP53 GA of PDA and PAC were similar (Table). TMPRSS2:ERG fusions and AR GA were more often identified in PAC than PDC whereas PTEN GA were more common in PDC than PAC. Targetable GA were identified at similar frequencies in both groups focused on BRCA2 (PARP inhibitors), BRAF (BRAF/MEK inhibitors) and PIK3CA (MTOR inhibitors). ATM GA (PARP inhibitors) were more common in PAC than PDC. CDK12 GA potentially associated with immunotherapy (IO) benefit were similar in PDA and PAC as were the frequencies of MSI-High status, median TMB and high TMB levels. Conclusions: The pathologic features of PDC and PAC have been classically maintained as representative of 2 different tumor types with potentially contrasting histogenesis. In the current CGP-based study, PDA and PAC did not display significant differences in genomic signatures. CGP may reveal biomarkers that could direct patients to targeted (PARP, MTOR and BRAF/MEK inhibitors) or immunotherapies ( CDK12 GA, MSI-High or high TMB status) in both PDA and PAC. [Table: see text]

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