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]

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]

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]

Anal melanoma: A comparative comprehensive genomic profiling study.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 551-551
Author(s):  
Jeffrey S. Ross ◽  
Laurie M. Gay ◽  
Julia Andrea Elvin ◽  
Jo-Anne Vergilio ◽  
Jonathan Keith Killian ◽  
...  
Keyword(s):  
Immune Checkpoint Inhibitor ◽  
Uv Light ◽  
Light Exposure ◽  
Mtor Pathway ◽  
Genomic Profiling ◽  
Anal Melanoma ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Ffpe Tissues ◽  
Tumor Types

551 Background: Anal melanomas (AM) share histologic features with cutaneous melanomas (CM), are highly aggressive and behave in a distinct clinicopathologic pattern. We performed comprehensive genomic profiling (CGP) of AM to learn of potential matched targeted and immunotherapies that may improve clinical outcomes for the disease. Methods: FFPE tissues from late stage AM (81 cases) and CM (1804 cases) 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. Results: AM and CM had a similar age, but AM females and CM males were significantly more common (P < 0.0001) (Table). Given the UV light exposure in the CM, the GA/tumor was significantly higher than AM as were the median TMB and frequency of TMB ≥ 10 and 20 mutations/Mb (P < 0.0001 for all comparisons). All AM and CM were MS-stable. The contrast in S FB1 mutations in AM and TERT GA in CM were significant (P < 0.0001). 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 targets including NF1 and PTEN were commonly altered in both tumor types. Potentially targetable PDGFRA and ERBB2 GA were found in AM but not in CM. Conclusions: UV light exposure drives high GA/tumor and TMB in CM, both associated with immune checkpoint inhibitor (ICPI) responsiveness, whereas AM lacks the high TMB and therefore is far less likely to benefit from ICPI treatments. CM is classically associated with opportunities for anti-BRAF therapies and AM with an array of kinase targets including KIT, BRAF, PDGFRA and ERBB2. Finally, MTOR pathway targets are common to both tumor types. [Table: see text]

Genomic landscape of non-small cell lung cancer (NSCLC) with methylthioadenosine phosphorylase (MTAP) deletion.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9116-9116
Author(s):  
Stephen L. Graziano ◽  
Dean C. Pavlick ◽  
Ethan Sokol ◽  
Shakti H. Ramkissoon ◽  
Eric Allan Severson ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Synthetic Lethality ◽  
Checkpoint Inhibitors ◽  
Large Cell ◽  
Combination Strategies ◽  
Genomic Landscape ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Cell Expression ◽  
The Impact

9116 Background: NSCLC remains a major cause of cancer-associated mortality despite major advancements in treatments. In addition to immune checkpoint inhibitors (ICPI), new strategies for clinically advanced NSCLC now include the development of new synthetic lethality targets focused on protein arginine methyl transferases such as PRMT5 that exploit the impact of tumor cell genomic loss of MTAP. Methods: 29,379 advanced/metastatic NSCLC cases underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 tumor cell expression was determined by DAKO 22C3 immunohistochemistry (IHC); low positive was a tumor proportion score (TPS) 1-49% and high positive was a TPS ≥50%. Results: 3,928 NSCLC exhibited MTAP homozygous loss. Cases had the following subtypes: adenocarcinoma (59%), squamous cell ca (22%), NSCLC NOS (16%), and large cell neuroendocrine, sarcomatoid, adenosquamous ca (all 1%). GA/tumor were similar when CDKN2A/B losses associated with 9p21 co-deletion with MTAP loss are excluded. Significant differences in currently targetable GA included KRAS G12C higher in MTAP-intact NSCLC (P =.0003) and EGFR short variant mutations higher in MTAP-deleted NSCLC (P <.0001). MTAP-intact NSCLC had higher frequencies of GAs in TP53 (P <.0001) and RB1 and a lower frequency of SMARCA4 (P <.0001). GAs frequencies in ERBB2, MET, ALK, ROS1 and NTRK1 were similar. Biomarkers for potential ICPI efficacy were higher in MTAP-intact including TMB ≥10mut/Mb (P =.0002) and low and high PD-L1 IHC staining (P =.01). Biomarkers potentially predictive of ICPI resistance ( STK11 and KEAP1) were similar in both groups. Conclusions: MTAP loss occurs in 13% of NSCLC, supporting the development of novel targeted therapies designed to exploit PRMT5 hyper-dependence in these tumors. MTAP loss in NSCLC is accompanied by differences in targeted and ICPI options for these patients which may impact future combination strategies. Further study of anti-PRMT5 drugs that are enabled by MTAP loss in NSCLC appears warranted.[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]

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]

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

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

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

Comprehensive genomic profiling (CGP) of upper-tract (UTUC) and bladder (BUC) urothelial carcinoma reveals opportunities for therapeutic and biomarker development.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4581-4581 ◽  
Author(s):  
Andrea Necchi ◽  
Sumanta K. Pal ◽  
Jeffrey S. Ross ◽  
Russell Madison ◽  
Neeraj Agarwal ◽  
...  
Keyword(s):  
Renal Pelvis ◽  
Therapy Initiation ◽  
Genome Wide ◽  
Genomic Landscape ◽  
Tier 1 ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Therapeutic Development ◽  
Ffpe Tissues ◽  
Tier 3

4581 Background: To understand the genomic landscape and inform the therapeutic development of UC, 2463 cases were analyzed by CGP for genomic alterations (GAs) and for genome wide signatures. Methods: 479 UTUC and 1984 BUC FFPE tissues (77%/70% primary [PT] and 23%/30% metastatic tumors [MT] from unmatched patients [pts]) underwent hybrid-capture based CGP to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Targetable GA and signatures were assessed according to the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Results: 48% of UC pts overall harbored ≥1 tier 1-2 GA suggesting benefit from approved or investigational targeted therapies (TT). Additionally, 17% had a tier 3 GA that provides a strong rationale for clinical trial consideration. Non- FGFR3 kinase fusions were observed in 1% of pts (0.6% UTUC v 1.1% BUC), including BRAF/RAF1 fusions in 0.5%. BRAF mut/fusions were observed in 2% (49/2463) of cases and were mutually exclusive with FGFR3 GA (p = 0.002). In comparing UC from anatomic sites, there were no differences of TMB-H (≥20 mut/mb)/MSI-H for PT and MT but UTUC was enriched for MSI-H (3.4%) relative to BUC (0.77%, p < 0.001, all TMB-H). Excluding MSI-H pts, UTUC has lower median TMB (4.35 mut/mb) than BUC (6.96 mut/mb). FGFR3 GA (26% v 19%, p < 0.05) and specifically short variants (SV) (20% v 13%) were enriched in UTUC vs BUC. HRAS SV were also enriched in UTUC vs BC (7.3% v 3.0%), attributed to an enrichment in renal pelvis UC (10.1%) v ureteral UC (1.8%, p < 0.05). RB1 GA were more frequent in BUC vs UTUC (21% v 7.8% p < 0.001). Conclusions: Against a background of 50% actionability in UC with opportunities for immunotherapy, TT, or combinations thereof, the UTUC cohort is enriched for FGFR3 and HRAS SV relative to BUC, with the observation of HRAS mutations predominantly in UC of the renal pelvis, that warrants further investigation into the distinct modes of oncogenesis for UC as stratified by anatomic origin. These results argue strongly for the routine incorporation of CGP prior to systemic therapy initiation in metastatic UC.

Clinically advanced pelvic squamous cell carcinomas (pSCC) in men and women: A comprehensive genomic profiling (CGP) study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3130-3130
Author(s):  
Philippe E. Spiess ◽  
Petros Grivas ◽  
Douglas A. Mata ◽  
Gennady Bratslavsky ◽  
Joseph M Jacob ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Parp Inhibitor ◽  
Treatment Options ◽  
Clinical Manifestations ◽  
Mtor Pathway ◽  
Hpv Status ◽  
Damage Response ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Tumor Types

3130 Background: Given that the clinical manifestations, disease course, and treatment options for pSCC differ between tumor types, we performed CGP to examine possible genomic differences. Methods: 1,741 clinically advanced pSCCs including 230 penile (penSCC), 17 male urethral (murthSCC), 125 male anal (manSCC), 7 female urethral (furthSCC), 263 vulvar (vulSCC), 822 cervical (crvSCC), and 277 female anal SCCs (fanSCC) underwent hybrid capture-based CGP to evaluate all classes of genomic alterations (GAs). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: HPV-16/18 detection was lowest in murthSCC and vulSCC and highest in manSCC, fanSCC, and crvSCC. TP53 GAs were inversely associated with HPV status. PIK3CA GA frequency varied (22-43%). DNA-damage response (DDR) GAs (e.g., BRCA1/2, ATM, others) were low ( < 1-3%) throughout. Cell-cycle GAs were most frequent in external cases (penSCC, furthSCC, vulSCC). MTOR pathway GAs ( PTEN, FBXW7) were the most frequently identified “actionable” GAs. FGFR3 GA were present in >5% of murthSCC, crvSCC, and fanSCC; other receptor-tyrosine kinase (RTK) targeted options were 1% in BRAF/ ERBB2. NOTCH1 GAs were present in > 15% of penSCC and vulvSCC. TMB ≥10 mut/Mb was >15% in manSCC, fanSCC, and crvSCC. PD-L1 low expression was > 25% in all pSCC except crvSCC and high expression was > 18% in all pSCC except urthSCC and manSCC. Conclusions: Despite similar histology, pSCC differ widely in GAs and HPV status. PIK3CA is the most frequent “targetable” GA followed by MTOR pathway and cell cycle; RTK targets are extremely rare. PARP inhibitor options appear low given the infrequent finding of DDR GAs. Anti-PD(L)1 could be considered in a number of cases based on TMB>10 mut/Mb and PD-L1 expression.[Table: see text]

scholarly journals Primary Adult Retroperitoneal Sarcoma: A Comprehensive Genomic Profiling Study

2021 ◽  
Vol 2 (4) ◽  
pp. 216-228
Author(s):  
Andrea Necchi ◽  
Giuseppe Basile ◽  
Filippo Pederzoli ◽  
Marco Bandini ◽  
Petros Grivas ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Follicular Dendritic Cell ◽  
Genomic Profiling ◽  
Histological Subtypes ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Synovial Sarcomas ◽  
Retroperitoneal Sarcomas ◽  
Primary Retroperitoneal ◽  
Generation Sequencing

Background: Adult primary retroperitoneal sarcomas (RPSs) are a group of heterogeneous tumors with different histological subtypes. Comprehensive genomic profiling (CGP) analyses have recently provided significant insights into the biology of sarcomas by identifying genomic alterations (GAs) which could benefit from targeted therapies. Methods: RPS were evaluated by CGP using next-generation sequencing of up to 406 cancer-related genes. Tumor mutational burden (TMB) was determined on 0.83 to 1.14 mut/Mb of sequenced DNA. Finally, PD-L1 expression was determined. Results: Overall, 296 cases of primary RPS were analyzed. Liposarcoma (LPS) subtype had more GA/tumor than leiomyosarcoma (LMS) subtypes, with follicular dendritic cell sarcomas harboring the highest and synovial sarcomas the lowest. TP53 and Rb1 alterations were the highest in LMS, and CDK4/6 and MDM2 in LPS. However, both the TMB and targetable GA rates were low across subtypes. PD-L1 immunostaining was low positive in 21% and high positive in 5% of patients, respectively. Conclusions: CGP analysis revealed that potentially actionable genomic targets were rare in our cohort of RPS. Moreover, RPSs seem less likely to respond to immune checkpoint inhibitors based on putative biomarkers status. Nevertheless, genomic stratification according to histological subtypes led to description of GAs that can inform future clinical trials design.

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