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]

Ductal and acinar carcinomas of the prostate: A comparative comprehensive genomic profiling study.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 271-271
Author(s):  
Nick Liu ◽  
Leszek Kotula ◽  
Timothy Byler ◽  
Joseph Jacob ◽  
Brian Michael Alexander ◽  
...  
Keyword(s):  
Ductal Carcinoma ◽  
Mtor Inhibitors ◽  
Parp Inhibitors ◽  
High Status ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Mek Inhibitors ◽  
Pathologic Features ◽  
Ffpe Samples ◽  
Comprehensive Genomic Profiling

271 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]

Ductal (PDC), acinar (PAC) and neuroendocrine (PNC) carcinomas of the prostate: A comparative comprehensive genomic profiling (CGP) study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5064-5064
Author(s):  
Gennady Bratslavsky ◽  
Joseph Jacob ◽  
Oleg Shapiro ◽  
Nick Liu ◽  
Elizabeth Kate Ferry ◽  
...  
Keyword(s):  
Mtor Inhibitors ◽  
Parp Inhibitors ◽  
Low Frequencies ◽  
Mek Inhibitors ◽  
Genomic Signatures ◽  
Disease Biology ◽  
Pathologic Features ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Tumor Types

5064 Background: PDC, PAC and PNC are histologic subtypes of prostate cancer (PC). We queried whether these subsets would share similar genomic alterations (GA) reflecting their disease biology and clinical features. Methods: CGP was performed using a hybrid capture-based assay on 61 PDC, 4,132 PAC and 217 PNC. 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, GA per tumor and TP53 GA of PDC, PAC and PNC were similar (Table). RB1 GA were predominant in PNC. TMPRSS2:ERG fusions were most frequent in PNC, intermediate in PAC and lowest in PDC. AR GA were more often identified in PAC than PDC or PNC whereas PTEN GA were most frequent in PDC than PAC or PNC. Targetable GA were identified in all 3 groups when focused on BRCA2 (PARP inhibitors) and PIK3CA (MTOR inhibitors). ATM GA (PARP inhibitors) were more common in PAC than PDC or PNC. BRAF GA (BRAF/MEK inhibitors) were more frequent in PDC and PAC than PNC. CDK12 GA potentially associated with immunotherapy (IO) benefit were similar in PDC and PAC and low in PNC. Low frequencies of MSI-High and low median TMB levels were similar in all 3 groups. Conclusions: The pathologic features of PDC, PAC and PNC have been classically maintained as representative of 3 different tumor types with potentially contrasting histogenesis. In the current CGP based study, all 3 tumor types did not display significant differences in genomic signatures other than the high RB1 GA. 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) especially in PDC and PAC. [Table: see text]

Genomic features of metastatic testicular sex cord stromal tumors.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 532-532 ◽  
Author(s):  
Andrea Necchi ◽  
Gennady Bratslavsky ◽  
Rubin Pinkhasov ◽  
Oleg Shapiro ◽  
Laurie M. Gay ◽  
...  
Keyword(s):  
Mtor Inhibitors ◽  
Parp Inhibitors ◽  
Comparative Genomic ◽  
High Status ◽  
Genomic Alterations ◽  
Stromal Tumors ◽  
Therapy Targets ◽  
Genomic Study ◽  
Comprehensive Genomic Profiling ◽  
Sex Cord Stromal Tumors

532 Background: Metastatic testicular sex cord stromal tumors of the testis (MSCST) comprise an extremely uncommon form of genitourinary malignancy. In a comparative genomic study, we performed comprehensive genomic profiling (CGP) to characterize the genomic alterations (GA) in MSCST and to enable the search for potential therapy targets. Methods: The MSCST were classified as metastatic Leydig Cell Tumors (LCT), Sertoli Cell Tumors (SCT) and Undifferentiated (USCST). In this study, 10 cases of LCT, 6 cases of SCT and 3 cases of USCST underwent hybrid-capture based CGP to evaluate all classes of genomic alterations. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: All patients had clinically advanced recurrent and/or metastatic disease. The primary testis tumor was used for sequencing in 6 MSCST (32%) and a metastatic site in 9 (68%) of the MSCST. In 10 (91%) of 11 MSCST positively stained by IHC for inhibin expression. The overall frequencies of GA were similar in all LCT, SCT and UTST ranging from 3.0 to 3.5 GA/tumor. The most frequent untargetable GA found in all MSCST cases included CTNNB1 and CDKN2A/B, both ranging from 20-33% of cases. Targetable GA were uncommon in all MSCST sub-groups but several tumors featured potential for cell cycle inhibitors ( CDK4 in LCT), MTOR inhibitors ( RICTOR, NF2 and PTEN in all 3 tumor types), hedgehog inhibitors ( PTCH1 in LCT) and PARP inhibitors ( BAP1 in SCT). No MSI-High status was identified in any MSCST. The TMB was also low in all MSCST groups. Conclusions: Although the 3 subgroups of testicular MSCST feature defining histopathologic features, these tumors have similar genomic signatures on CGP. The low levels of GA per tumor, infrequent tumor aneuploidy, absence of MSI-High status and low TMB all indicate that testicular MSCST are genetically stable. However, rare cases of testicular MSCST reveal GA linked to potential targeted therapy benefits on CGP linked to dysregulation of multiple biologic pathways. In contrast, the lack of MSI-High status and overall low TMB in testicular MSCST indicates a likely lack of benefit for immunotherapies for these rare forms of malignancy.

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]

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]

Comprehensive genomic sequencing of appendiceal cancer tumors to identify different genomic alterations by subtype, novel treatment opportunities, and improved outcomes.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 599-599
Author(s):  
Celina Ang ◽  
Aatur D. Singhi ◽  
Alexa Betzig Schrock ◽  
Jeffrey S. Ross ◽  
Philip J. Stephens ◽  
...  
Keyword(s):  
Case Reports ◽  
Clinical Care ◽  
Current Treatment ◽  
Appendiceal Cancer ◽  
Genomic Alterations ◽  
Mek Inhibitors ◽  
Improved Outcomes ◽  
Individualized Approach ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden

599 Background: Appendiceal cancers are rare and consist of mucinous (M), adenocarcinoma (A), goblet cell carcinoma (GCC), pseudomyxoma peritonei (PMP), and several even rarer histologies. Current treatment involves surgical resection or debulking; no standard exists for adjuvant chemotherapy or metastatic disease treatment. Systemic treatment is often based on chemotherapy regimens used in colorectal cancer. Methods: Tissue from 518 appendiceal cancer patients was assayed by hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA: base substitutions, indels, amplifications, copy number alterations, fusions/rearrangements) and targeted therapy opportunities; 315 genes frequently altered in cancer were assayed. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb sequenced DNA and reported as mutations/Mb. Results: Profiling across all appendiceal cancer histological subtypes identified different patterns in GAs across subtypes (table), most notably in GNAS, KRAS, and TP53. No PMP exhibited microsatellite instability (MSI-H) or high TMB ( > 20 mutations/Mb); MSI-H cases included 3 M, 4 A, 1 GCC; 3-7% 12% A and 6% m had high TMB. Case reports of patients with tumors harboring GNAS alterations showed response to MEK inhibitors. Conclusions: Genomic profiles of tumors from patients with appendiceal cancers reveal differing profiles from colorectal cancers (CRC) and considerable heterogeneity between subtypes, suggesting an individualized approach to treatment. Therapeutic options include clinical trials targeting pathways involving KRAS, BRAF, GNAS, PIK3CA, FBXW7, SMAD4, APC, and ATM. Recent case reports indicate that GNAS is a clinical target for MEK inhibitors. Overall, given the poor prognosis of advanced stage appendiceal carcinoma patients, CGP may identify novel, unanticipated therapeutic targets in a significant subset of patients, including immunotherapy for high TMB patients. [Table: see text]

Profiling of 3,634 cholangiocarcinomas (CCA) to identify genomic alterations (GA), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4087-4087 ◽  
Author(s):  
Milind M. Javle ◽  
Karthikeyan Murugesan ◽  
Rachna T. Shroff ◽  
Mitesh J. Borad ◽  
Reham Abdel-Wahab ◽  
...  
Keyword(s):  
Lymph Node ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Parp Inhibitors ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Hybrid Capture ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden

4087 Background: The management of CCA has evolved as targeted and immune checkpoint inhibitor (ICPI) therapies have emerged. We used comprehensive genomic profiling (CGP) to characterize the genomic alterations (GA) that have potential to personalize therapy for CCA. Methods: 3634 CCA underwent hybrid capture based CGP on 0.8-1.1 Mb of the coding genome to identify GAs in exons and select introns in up to 404 genes, TMB, microsatellite status (MSI) and % monoallelic genome (gLOH). PD-L1 expression was determined by IHC (Dako 22C3). Results: 52% of CCA were female with a median age of 62 years (range 16 - > 89). The most common biopsy sites were liver (74%), lymph node (4%), bile duct (3.3%), and lung (2%). MSI-high was rare (1%), 118 and 47 cases had TMB > 10 and > 20 mut/mb respectively. Of the latter, 51% (24/47) were MSI-H. PD-L1 amplification (AMP) was present in 0.27%. Of 490 CCA tested, 43 (9%) were positive for PD-L1 expression. 11% of cases had gLOH > 16%, only 2 cases had both TMB > 20 and gLOH > 16%. GA were most common in TP53 (31%), CDKN2A (29%), KRAS (20%) and ARID1A (17%). Potentially targetable GAs included FGFR2 (11%, 85% fusions), BRAF (5%, 50% V600E), ERBB2 (5%, 72% AMP), MET (2%, 90% AMP), EGFR (0.52%) and rarer ( < 0.5%) FGFR3, RET, FGFR1, ALK, and ROS1 fusions. The FGFR2 fusions had 128 unique 3’ partner genes including BICC1 (26%), CCDC6 (3.2%), AHCYL1 (2.6%) and KIAA1217 (2.6%). FGFR2 fusions occurred in a mutually exclusive fashion from high gLOH (p < 0.002), but not high TMB. GA in IDH1 (15%) were mutually exclusive of FGFR2 fusions (p < 1e-13), but co-occurred with PBRM1 GA (23%, p < 1e-21), ARID1A (26% p < 1e-10). IDH1 GA had gLOH similar to the overall CCA population but were enriched for low TMB (p < 1e-3). Conclusions: Nearly 20% of CCA cases harbor targetable kinase GA, half of which were FGFR2 fusions. Independently, an additional 10% (gLOH) and 1% (high TMB, MSI and/or PD-L1 AMP) may benefit from PARP inhibitors and ICPI respectively. Independently, co-mutation of IDH1 and PBRM1/ARID1A defines a class of CCA that warrants further investigation for sensitivity to PARP inhibitors and may serve as a paradigm for other tumors (ie. gliomas) with a similar co-occurrence landscape.

Comprehensive genomic profiling of neuroendocrine carcinoma of the prostate.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 187-187
Author(s):  
Sumanta K. Pal ◽  
Matthew I. Milowsky ◽  
Julia Andrea Elvin ◽  
Siraj Mahamed Ali ◽  
Jean H. Hoffman-Censits ◽  
...  
Keyword(s):  
Neuroendocrine Carcinoma ◽  
Stage Iv ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Tumor Type ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Carcinoma Of The Prostate ◽  
Comprehensive Genomic Profiling ◽  
Metastatic Sites

187 Background: Neuroendocrine carcinoma of the prostate (NCAP) is an aggressive high grade malignancy that often presents as metastatic disease. Current treatments of this tumor have only modest benefit leading investigators to query whether comprehensive genomic profiling (CGP) would have potential to discover novel targets of therapy. Methods: DNA was extracted from 40 microns of FFPE sections from 37 consecutive cases of relapsed/metastatic NCAP. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 583X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Genomic alterations (GA) included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: The median age of the men in this study was 65.1 years (range 43 to 83 years). All (100%) cases were positive for neuroendocrine markers on immunohistochemical staining and were Stage IV at the time of CGP. Samples used for sequencing were obtained from the primary tumor in 9 (24%) of NCAP and from metastatic sites in 28 (76%) of NCAP (12 liver, 6 LN, 2 each from bladder, pelvis and soft tissue, and 1 each from rectum, bone, urethra and ureter. There were 213 total GA (5.8 GA/sample) and 47 CRGA (1.3 CRGA/sample). The most frequent GA were non-CRGA mutations in TP53 (68%) and RB1 (51%). TMPRSS:ERG fusions were identified in 32% of cases whereas AR was altered in 8% (1 mutation and 2 amplifications). The most frequent CRGA involved PTEN (32%), BRCA2 (14%), FGFR1 (5%), PIK3CA (5%) and AKT2 (3%). No alterations in BRAF were identified. Clinical responses to MTOR inhibitors in patients with MTOR pathway alterations will be presented. Conclusions: NCAP has distinctive genomic alterations from classic acinar CAP including reduced frequencies of alterations in TMPRSS:ERG and AR and frequent RB1 mutations. Multiple alterations in the MTOR pathway identified in this infrequent tumor type suggest that these patients may be candidates for MTOR inhibitors and other targeted therapies.

Impact of age on genomic alterations associated with pancreatic ductal adenocarcinoma (PDAC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 282-282
Author(s):  
Ben George ◽  
Mark Bailey ◽  
Alexa Betzig Schrock ◽  
Lauren Thorpe ◽  
Laurie M. Gay ◽  
...  
Keyword(s):  
Large Scale ◽  
Kinase Domain ◽  
Ductal Adenocarcinoma ◽  
Genomic Alterations ◽  
Kras Mutations ◽  
Entire Study ◽  
Formalin Fixed Paraffin Embedded ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Metastatic Sites

282 Background: Large scale, retrospective, sequencing projects have identified well-defined subtypes of PDAC, but therapeutic paradigms remain unchanged. We hypothesized that genomic alterations associated with PDAC in young adults (YA, age < 50) are distinctly different from that of older adults (OA, age > 50) to identify an enrichment of targetable alterations. Methods: DNA was extracted from formalin fixed paraffin embedded (FFPE) PDAC clinical specimens and comprehensive genomic profiling (CGP) was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of > 600 for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. Results: CGP was performed on 1533 FFPE PDAC specimens, 566 (36.9%) were from the primary tumor, 967 (63.1%) from metastatic sites. Median age at diagnosis was 63 years (yrs), 180 (11.7%) were YA. KRAS mutations were identified in 78.7 of YA and 87.7% of OA. The differentially altered genes between the two groups were KRAS (p = 0.004), TP53 (p = 0.04), BRCA2 (p = 0.02), AKT2 (p = 0.03), MAP2K4 (P = 0.003) and DNMT3A (p = 0.0002). The median tumor mutational burden (TMB) for the entire study set was 2.7 (YA – 2.5, OA –2.7). BRAF kinase domain deletion was observed in 1 patient (OA). ALK fusions were present in 2 patients (1 YA & 1 OA) and these patients had durable responses to specific ALK inhibitors. Conclusions: The majority of the genomic alterations identified were not significantly different on the basis of age. However, identification of subpopulations, such as ALK kinase fusions and BRAF kinase domain deletions that can translate into sustained clinical benefit from matched targeted therapy is promising. This underscores the importance of CGP in PDAC to investigate other targetable genomic alterations.

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]

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