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

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]

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Genomic findings in adenocarcinoma of the urinary bladder.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.132 ◽

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

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.5064 ◽

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]

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Genomic features of metastatic testicular sex cord stromal tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.532 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 532-532 ◽

Cited By ~ 1

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.

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Comprehensive genomic profiling of neuroendocrine carcinoma of the prostate.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.187 ◽

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.

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Malignant pheochromocytoma: A comprehensive genomic profiling study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.508 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 508-508

Author(s):

Gennady Bratslavsky ◽

Andrea Necchi ◽

Oleg Shapiro ◽

Joseph Jacob ◽

Laurie M. Gay ◽

...

Keyword(s):

Primary Tumor ◽

High Status ◽

Genomic Profiling ◽

Genomic Alterations ◽

Rare Form ◽

Metastatic Site ◽

Therapy Targets ◽

Metastatic Setting ◽

Predisposition Genes ◽

Comprehensive Genomic Profiling

508 Background: Malignant pheochromocytomas (MP) are a rare form of endocrine malignancy which can occur in familial and sporadic clinical settings. We performed comprehensive genomic profiling (CGP) to characterize the genomic alterations (GA) in MP and to enable the search for potential therapy targets. Methods: From a series of 181,782 consecutive clinical cases, 43 cases of clinically advanced MP underwent CGP using a hybrid-capture based commercial assay to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mutations/Mb and microsatellite instability (MSI) was determined on 114 loci. IHC for PD-L1 expression was performed on a subset of patients (DAKO 22C3 antibody). Results: All patients had clinically advanced recurrent and/or metastatic disease. There were 33 (77%) of MP known to have originated in the adrenal gland and 10 (23%) of the MP were sequenced from metastatic site. The primary tumor was used for sequencing in 13 (30%) of the MP cases and a non-primary tumor metastatic site (liver, lung, bone, soft tissue, lymph node, kidney, peritoneal cavity, and chest wall) in 30 (70%) of the MP cases. There were 2.3 GA/tumor. The most frequent un-targetable GA were ATRX (26%), TP53 (21%), SDHB (11%), CTNNB1 (7%), VHL (7%), and CDKN2A/2B, PIK3R2, NOTCH2 and MEN1 (all 5%). The most frequent potentially targetable GA included RET (9%), NF1 (9%) and FGFR1 (5%). PBRM1 GA were found in 2% of MAP. Germline mutations in known cancer predisposition genes were predicted in 7 (16%) of cases involving SDHB (4 cases) and BRCA1, MEN1, and MSH2 (1 case each). The mean TMB was 2.95 mutations/Mb, the median TMB was 2.4 mutations/Mb. 0 (0%) of 33 MP evaluated for MSI had a MSI-High status. Conclusions: MP represent a rare form of endocrine cancer that feature a variety of genomic alterations. Although the GA/tumor is relatively low for MP, CGP can reveal important potential targets for therapy in the metastatic setting including RET, NF1 and FGFR1. MAP do not reveal strong potential for immunotherapy with low TMB, absence of MSI-High status and low (2%) PBRM1 mutation frequencies. Based on this data, further study of CGP as a method of developing precision therapies for MP appears warranted.

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

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4087 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4087-4087 ◽

Cited By ~ 8

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.

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