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  • Lin, Douglas I.  (12)
  • Necchi, Andrea  (12)
  • English  (12)
  • Medicine  (12)
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  • Medicine  (12)
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  • 1
    Online Resource
    Online Resource
    CDH1 -mutated clinically advanced urothelial bladder cancer (UBC): A genomic landscape and real-world clinical outcome study (RWCOS).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 6_suppl ( 2023-02-20), p. 564-564
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 6_suppl ( 2023-02-20), p. 564-564
    Abstract: 564 Background: CDH1 mutated UBCs are characterized by plasmacytoid histology and are associated with an aggressive clinical course at the time of diagnosis. Methods: Cohort 1: 6,676 clinically advanced UBC patients (pts) underwent comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA), microsatellite instability (MSI), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH, high ≥16%). Predominant genetic ancestry was determined using a SNP-based approach and classified as one of the 5 categories: African (AFR), European (EUR), Central and South American (AMR), South Asian (SAS), or East Asian (EAS). Cohort 2: 586 UBC pts underwent a RWCOS using the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine urothelial clinico-genomic database (FH-FMI CGDB). The de-identified data originated from approximately 280 US cancer clinics (~800 sites of care) Jan 2011-Apr 2022. Differences in real-world progression-free survival (rwPFS) and overall survival (rwOS) were evaluated by Cox proportional hazard models. Results: Cohort 1: 217 (3.3%) of UBC had a CDH1 short variant (SV) mutation with 65.2% featuring plasmacytoid histology. When compared with CDH1 wild-type (WT) UBC, the CDH1-mutated UBC had similar age, gender, and genetic ancestry. The CDH1-mutated UBC featured a higher frequency of MSI (2.7% vs 0.8%; p=.002), mean TMB (14.8 vs 9.9 mut/Mb p 〈 .0001), RB1 GA (52.5% vs 20.3%; p 〈 .0001), PTEN GA (9.2% vs 4.3%; p=.006) and PIK3CA GA (29.5% vs 21.8%; p=.02), but less gLOH high (6.8% vs 15.9%; p=.009), CDKN2A loss (12.4% vs 38.3%; p 〈 .0001), MTAP loss (10.1% vs 25.1%; p 〈 .0001) and FGFR3 GA (9.7% vs 18.1%; p=.002). TP53 GA were similar (62.3% vs 60.3%). Cohort 2: 22 (3.7%) featured CDH1 mutations. Compared with the CDH1 WT pts, the age, gender, ethnicity and ECOG status were similar. Evaluation of the RWCOS showed that CDH1 mutation was associated with less favorable outcomes for 270 UBC pts treated with immune checkpoint inhibitors (ICPI) including rwPFS (2.8 vs 3.5 months; p=.096) and rwOS (3.3 vs 9.5 months; p=.03). Similar comparisons for 316 UBC pts treated with chemotherapy showed no significant adverse impact of CDH1 mutation status on either rwPFS (7.9 vs 6.2 months) and rwOS (13.4 vs 13.4 months). Conclusions: In addition to its classic association with plasmacytoid histology, CDH1-mutated UBC features a unique CGP pattern including higher MSI and TMB status and activating GA in the MTOR pathway while harboring a lower FGFR3 GA frequency. RWCOS further supports that CDH1 mutation predicts resistance to ICPI-based treatments but does not impact responsiveness to chemotherapy. These results further support that CGP has the potential to customize the treatment and improve outcomes for UBC patients based on the determination of their genomic signatures.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.6_suppl.564
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 2
    Online Resource
    Online Resource
    CDH1 -mutated clinically advanced urothelial bladder cancer (UBC): A genomic landscape and real-world clinical outcome study (RWCOS).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 4587-4587
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 4587-4587
    Abstract: 4587 Background: CDH1 mutated bladder cancers are characterized by plasmacytoid histology and are associated with an aggressive clinical course. Methods: Cohort 1: 6,676 clinically advanced UBC patients underwent hybrid capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA) as well as microsatellite instability (MSI), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH, high ≥16%). Tumor cell PD-L1 expression was determined by immunohistochemistry (Dako 22C3). GAs were compared between CDH1 mutated and wild-type (WT) patients using Chi-square. Cohort 2: 586 UBC patients underwent a RWCOS using the de-identified Flatiron Health-Foundation Medicine urothelial clinicogenomic database. The de-identified data originated from approximately 280 US cancer clinics (~800 sites of care) between January 2011 and April 2022. Differences in real-world progression-free survival (rwPFS) and overall survival (rwOS) were evaluated by Cox proportional hazard models. Results: Cohort 1: 217 UBC patients featured a CDH1 short variant mutation with 65.2% featuring plasmacytoid histology (PLC). The PLC cohort was slightly younger, with a higher proportion of male patients, and MSI-High status. Cell-Cycle regulatory GAs were significantly higher in the non-PLC cohort, specifically CDKN2A (25.5% vs 9.7%, p=0.01) and CDKN2B (23.6% vs 5.8%, p 〈 0.01). CDH1-mutated UBCs featured a higher MSI high frequency (2.7% vs 0.8%; p=.002), mean TMB (14.8 vs 9.9mut/Mb p 〈 .0001), RB1 GA (52.5% vs 20.3%; p 〈 .0001), PTEN GA (9.2% vs 4.3%; p=.006) and PIK3CA GA (29.5% vs 21.8%; p=.02), but lower gLOH (6.8% vs 15.9%; p=.009), CDKN2A loss (12.4% vs 38.3%; p 〈 .0001), MTAP loss (10.1% vs 25.1%; p 〈 .0001), and FGFR3 GA (9.7% vs 18.1%; p=.002). TP53 GAs and PD-L1 expression levels were similar between groups. From cohort 2: 22 (3.7%) patients featured CDH1 mutations. When compared with the CDH1 WT patients, the age, gender, ethnicity and ECOG status were similar. CDH1 mutation was associated with less favorable outcomes for 270 UBC patients treated with immune checkpoint inhibitors (ICPI) including rwPFS (2.8 vs 3.5 months; p=.096) and rwOS (3.3 vs 9.5 months; p=.03). Similar comparisons for 316 UBC patients treated with chemotherapy showed no significant adverse impact of CDH1 mutation status on either rwPFS (7.9 vs 6.2 months; p=.11) and rwOS (13.4 vs 13.4 months; p=0.83). Conclusions: In addition to its classic association with PLC histology, CDH1-mutated UBC features an unique genomic landscape including higher MSI and TMB, activating GAs in the MTOR pathway, but lower frequency of FGFR3 GAs. RWCOS further supports that CDH1 mutation predicts resistance to ICPI-based treatment, but does not systemic chemotherapy. These findings support CGP to guide therapeutic approaches based on the personalized genomic signature of UBC.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.4587
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Penile squamous cell carcinoma (PSCC) with elevated tumor mutational burden (TMB): A genomic landscape study.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 6_suppl ( 2023-02-20), p. 4-4
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 6_suppl ( 2023-02-20), p. 4-4
    Abstract: 4 Background: TMB has emerged as a major biomarker of efficacy in immune checkpoint inhibitor (ICPI) therapies in the neoadjuvant, adjuvant and metastatic disease setting in a wide variety of malignancies, but not in PSCC. Methods: 397 clinically advanced (local major recurrence and/or metastatic disease) PSCC underwent hybrid capture-based comprehensive genomic profiling (CGP) 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. Trinucleotide mutation signatures were evaluated (Alexandrov, et al. 2013). Genome-wide loss of heterozygosity (gLOH) was determined using validated pipelines and excluding whole-arm and whole-chromosome events. TMB was categorized into three cohorts: 〈 10 mutations/Megabase [muts/Mb] (low), 10-19 muts/Mb (high), and 〉 20 muts/Mb (very high). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3) and defined as tumor proportion score (TPS) 〉 1. The presence of HPV16/18 was determined by next generation sequencing (NGS). Statistical comparisons were corrected for multiple comparisons using the Bonferonni method. Results: There were 339 (85.4%) TMB low, 40 (10.1%) TMB 10-19 and 18 (4.5%) TMB very high PSCC cases in this study. The mean age of PSCC with very high TMB at 70.1 yrs was older than for TMB low at 63.4 yrs (p=.08). There were no significant differences in genomic ancestry among the 3 groups. The TMB 10-19 and TMB very high tended to feature an APOBEC genomic mutational signature more than the TMB low PSCC cases (74 and 76% vs 44%). MSI high status was absent in the TMB low PSCC, but was present in 7.5% of the TMB 10-19 and 11.8% of the TMB very high cases. gLOH levels above 16% were similar in all 3 groups and ranged from 6.2 to 9.4%. GA associated with differences in TMB status in the PSCC cases included higher PIK3CA GA in TMB 10-19 (40.0%) vs TMB low (18.3%; p=.035) and TMB very high (66.7%) vs TMB low (p=.0002). CDKN2A GA were higher in TMB low (45.7%) than in the combined TMB 10-19 + very high (25.9%; p=.049). GA in KMT2D were higher in the combined TMB 10-19 + very high (29.3%) than the TMB low PSCC (7.7%; p=0002). FGFR3 GA were similar in all 3 groups. PD-L1 expression was not significantly different among the 3 groups with TMB low (78.3%), TMB 10-19 (64.2%) and TMB very high (54.5%). HPV identification was more frequent as TMB increased: 28.3% for the TMB low, 50.0% for the TMB high and 58.8% for the TMB very high groups. Conclusions: The evaluation of PSCC by CGP based on TMB levels revels significant differences in biomarkers for the near 15% of cases that have TMB 〉 10 muts/Mb. Further study of TMB as a biomarker in ICPI-based clinical trials for advanced PSCC appear warranted.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.6_suppl.4
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    Comprehensive genomic profiling (CGP) of chromophobe renal cell carcinoma (chrRCC) compared with clear cell RCC (ccRCC): Impact of FLCN genomic alteration (GA) status.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 6_suppl ( 2022-02-20), p. 292-292
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 6_suppl ( 2022-02-20), p. 292-292
    Abstract: 292 Background: FLCN is a tumor suppressor gene associated with cutaneous hair follicle development. FLCN germline mutations are linked to inherited chrRCC in the Birt-Hogg-Dube (BHD) syndrome. We queried whether clinically sporadic chrRCC featured FLCN mutations by comparing the genomic profiles of chrRCC with ccRCC. Methods: 108 chrRCC and 2110 ccRCC underwent hybrid-capture based comprehensive genomic profiling (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: Patients (pts) with chrRCC were more frequently female and younger than pts with ccRCC p 〈 .0001). None of the submitted clinical records in the chrRCC cases listed signs of BHD syndrome. FLCN GA were identified in only 2.3% of the ccRCC cases with 37% of the GA predicted to be germline. chrRCC did not reveal somatic or germline FLCN GA. GA/tumor were slightly higher in ccRCC vs chrRCC (3.6 vs 2.4; NS). GA more frequent in chrRCC included TP53, RB1 and PTEN. GA more frequent in the ccRCC included VHL, BAP1, PBRM1, SETD2, CDKN2A/B, ARID1A, NF2, PIK3CA and TERT. Putative biomarkers of immune checkpoint inhibitor (ICPI) response were infrequent in both groups with only a slightly higher, but still low, mean TMB in ccRCC vs chrRCC cases. IHC revealed moderate PD-L1 expression at low and minimal PD-L1 expression at high staining level, which was slightly increased in the chrRCC group. Conclusions: FLCN mutations that are associated with the familial incidence of chrRCC were not associated with sporadic chrRCC. Sporadic chrRCC has substantially different genomic profile from ccRCC and may harbor a few ‘targetable’ GA. The prediction of response to ICPI in RCC remains challenging with chrRCC featuring slightly higher PD-L1 expression and ccRCC featuring higher PBRM1 GA and higher TMB.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.6_suppl.292
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 5
    Online Resource
    Online Resource
    Genomic classification of clinically advanced major genito-urinary cancers (GUca) based on methylthioadenosine phosphorylase ( MTAP ) genomic loss.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 6_suppl ( 2022-02-20), p. 164-164
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 6_suppl ( 2022-02-20), p. 164-164
    Abstract: 164 Background: Novel treatments for clinically advanced GUca including castrate resistant prostate ca (PC), bladder urothelial ca (BUC) and clear cell renal ca (ccRCC) are widely needed. Recently, the targeting of cancer cells with arginine accumulation caused by MTAP loss has emerged as a new synthetic lethality-based anti-cancer program. Methods: 8,436 mCRPC, 2,683 BUC and 841 ccRCC underwent hybrid-capture based comprehensive genomic profiling (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 up to 114 loci. PD-L1 tumor cell expression was determined by IHC (Dako 22C3). Results: 1.3% of PC, 24.2% of BUC and 5.5% of ccRCC featured MTAP loss. There were no significant age or gender differences associated with MTAP loss. CDKN2A/B loss ranged from 94% in ccRCC to 〉 99% in PC and BUC. The GA/tumor frequencies were similar when CDKN2A/B GA are excluded. In PC, GA in TP53, PTEN and BRCA1 were more frequent, while GA in AR, CDK12, RB1 and BRCA2 were less frequent in cases with MTAP loss. In BUC, GA in TSC1 and FGFR3 were more frequent and GA in RB1and TP53 were less frequent in cases with MTAP loss. In ccRCC, GA in NF2 were more frequent in cases with MTAP loss, while GA in VHL and PBRM1 were less frequent in cases with MTAP loss. “Targetable” kinase GA were rare in all groups, except for FGFR3 GA in MTAP loss BUC. Immunotherapy (IO) putative biomarkers varied among tumors, with MSI-high status less frequent and TMB ≥ 10 mut/Mb more frequent in BUC MTAP-intact than BUC with MTAP loss. PD-L1 expression was similar except for high PD-L1 expression more frequent in MTAP-intact BUC. Conclusions: When compared with PC and ccRCC, the clinical development of novel drugs, such as PRMT5 and MTA2 inhibitors in GUca will likely be focused on BUC given the 24% frequency of MTAP loss in that tumor type. CGP of PC, BUC and ccRCC reveal significant differences in GA in MTAP-intact and tumors with MTAP loss, which may impact future combinatorial clinical trial designs.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.6_suppl.164
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 6
    Online Resource
    Online Resource
    Expanding the use of targeted therapy for urothelial bladder cancer (UBC): Non- FGFR3 receptor tyrosine kinase (RTK) gene rearrangements (ReAr) and fusions (fus).
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 6_suppl ( 2022-02-20), p. 550-550
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 6_suppl ( 2022-02-20), p. 550-550
    Abstract: 550 Background: After the regulatory approval of erdafitinib targeting FGFR genomic alterations (GA), molecular profiling and targeted therapy indications may further expand in UBC. We queried a large database of advanced UBC to study the landscape of RTK ReAr and Fus to categorize additional targets beyond FGFR1-3 that have potential to further personalize treatment of this disease. Methods: We analyzed data from 8,233 UBC cases, which underwent hybrid capture-based comprehensive genomic profiling (CGP). 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 in tumor cells was assessed by IHC (Dako 22C3). Results: A total of 1,210 (14.7%) UBC featured known and likely large-scale (LS) internal ReAr with 414 (5%) ReAr in RTK genes. The ReAr/fus were distributed among ABL1 (3), ALK (3), BRAF (29), CDK12 (44), CDK8 (1), EGFR (10 ), ERBB2 (3), FGFR1 (2), FGFR2 (16 ), FGFR3 (231), FLT3 (1), MAO2K4 (4), NTRK1 (7 ), NTRK2 (5), NTRK3 (7), RAF1 (31 ), RET (8) and ROS1 (9). LS ReAr were divided into LS ReAr-associated gene deletions (1%), truncations (1%), rearrangements (61%) and fusions (37%). FGFR3 fus accounted for 81% of RTK fus with BRAF and RAF1 both at 2%. The greatest frequencies of kinase ReAr were in CDK12 (29%), FGFR3 (16%), RAF1 (13%) and BRAF (12%). Additional noteworthy ‘targetable’ RTK ReAR and fus included NTRK1-3 (19 cases), ROS1 (9 cases), RET (8 cases) and ALK (1 case). 407 (98.4%) of the RTK ReAr/fus-positive UBC had only 1 RTK ReAr/fus GA and 7 (1.6%) had 2 ReAr ReAr/fus, 6 (85.7%) of which involved FGFR3. Compared with LS ReAR negative UBC, the LS ReAR UBC cases revealed similar gender and age characteristics, MSI status, similar frequencies of TMB ≥ 10 mut/Mb and PD-L1 expression in tumor cells ≥1% and ≥50%. Conclusions: At a 5% frequency, potentially ‘targetable’ RTK gene rearrangements and fusions are a rare but important opportunity to further personalize treatment selection of UBC, including RTK inhibitors, PARP inhibitors ( CDK12) and immunotherapy. This potential for clinical trials supports broader CGP, compared to targeted FGFR sequencing, in order to uncover additional opportunities for precision therapies that have the potential to improve patient outcomes.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.6_suppl.550
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 7
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    Online Resource
    Genomic landscape of MSH6 -mutated clinically advanced castrate-resistant prostate cancer (mCRPC).
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 5062-5062
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 5062-5062
    Abstract: 5062 Background: Loss-of-function genomic alterations (GAs) in MSH6 have been associated with a unique subtype of hypermutated mCRPC that is often microsatellite stable (MSS) and may occur in either a sporadic or familial Lynch Syndrome-like clinical setting. Methods: 5,617 mCRPC cases were sequenced to evaluate all classes of GA using a hybrid capture-based FDA-approved comprehensive genomic profiling (CGP) assay. Tumor mutational burden (TMB) was determined on 0.8 Mb of sequenced DNA and microsatellite instability high (MSI-High) was determined on 95 loci. MSI-low status was not assessed. Results: 78 (1.4%) mCRPC were MSH6 mut (Table). MSH6 mut mCRPC included 73.1% short variant mutations, 23.1% biallelic deletions, 2.6% genomic rearrangements, and 1.3% multiple GAs/sample. Co-mutation of MSH2 was found in 28% of MSH6 mut cases vs. 2% in MSH6 wt cases (P 〈 .0001) and was most frequently caused by biallelic co-deletion of both genes (73% of co-mutated cases). MSI-High status was present in 46% of MSH6 mut mCRPC, which was significantly greater than the 2% seen in MSH6 wt cases (P 〈 .0001). An MMR single nucleotide mutational signature was observed in 65% of MSH6 mut cases, compared to 3% MSH6 wt cases (P 〈 .0001). Among MSH6 mut cases with neither MSI-High nor MMR mutational signature, 87% did not have biallelic loss of MSH6 or any other MMR gene, confirming that monoallelic pathogenic mutations are insufficient to cause the MMR-D phenotype. For subjects whose variants could be classified, 45% (19/42) of pathogenic MSH6 alleles were germline; of these, 58% (11/19) had neither MSI-High nor an MMR single nucleotide signature. MSH6 mut cases had fewer TMPRSS2: ERG fusions (P =.01), but harbored significantly higher frequencies of GAs in AR (P =.0002), ATM (P =.04), PIK3CA (P =.0003), APC (P =.005), ERBB2 (P =.001), and CDK6 (p =.046), likely at least partially attributable to the higher TMB in MSH6 mut cases (P 〈 .0001). Conclusions: MSH6 mut mCRPC is a unique disease that often features a hypermutated genomic signature, although only 46% of cases exhibited MSI-high status. This complex phenotype highlights the potential utility of multiple rather than single biomarkers to understand tumor biology and determine patients who may benefit from immunotherapy.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.5062
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 8
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    Impact of PD-L1 expression on conventional urothelial bladder carcinoma (UBC) genomic alteration (GA) profile.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 6_suppl ( 2022-02-20), p. 563-563
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 6_suppl ( 2022-02-20), p. 563-563
    Abstract: 563 Background: Immunohistochemistry (IHC) to determine PD-L1 expression level has been proposed a companion assay related to the approval of immune checkpoint inhibitors in UBC. We hypothesized that the GA profiles would differ between UBC featuring high vs negative PD-L1 expression. Methods: 102 cases of advanced UBC with known PD-L1 expression underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of 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. Tumor cell (TC) PD-L1 expression was determined by IHC (Dako 22C3). Only PD-L1 high (H) (≥50% TC expression) and negative (N) (0% TC expression) cases were included with PD-L1 Low (1-49% TC expression) cases excluded from this study. Results: Overall, only 2 (8.3%) of the 24 PD-L1H UBC featured CD274 ( PD-L1) amplification (mean 19 copies) and none of 78 PD-L1N had CD274 amp (P =.05). The gender, age was similar in the groups. When compared with the PD-L1H UBC cases, FGFR3 GA were significantly more frequent in the UBC PD-L1N cases (p =.02). Currently “untargetable” GA that were more frequent in the PD-L1H UBC, but did not reach statistical significance, included TP53, TERT and RB1. MTAP loss, a potential target for PRMT5 and MTA2 inhibitors, were 3X more frequent in the PD-L1N UBC. ERBB2 amplification and ERBB3 and PIK3CA short variant (SV) GA were more frequent in the PD-L1N UBC with differences not reaching significance. Other ICPI-associated potential biomarkers, including MSI status, TMB level and GA in PBRM1, STK11 and MDM2 were not significantly different in the groups. For UBC cases where a mutational signature could be determined, 10/12 (83%) of PD-L1H and 21/29 (72%) of PD-L1N UBC featured APOBEC signature; 2 PD-L1N featured MMR signature and 6 PD-L1N UBC featured no dominant signature. Conclusions: PD-L1H and PD-L1N subtypes of UBC differ in their genomic profiles:PD-L1N UBC features greater frequencies of potentially “targetable” GA, including FGFR3, ERBB2, ERBB3 and PIK3CA. PD-L1 IHC may thus not only play a role in the selection of ICPI for advanced UBC but also in designing trials that may combine ICPI with targeted therapies. Limitations include small sample size, possible selection bias and lack of clinical annotation.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.6_suppl.563
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 9
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    Penile squamous cell carcinoma (PSCC) with elevated tumor mutational burden (TMB): A genomic landscape study.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 5044-5044
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 5044-5044
    Abstract: 5044 Background: TMB has emerged as a novel biomarker of immune checkpoint inhibitor (ICPI) response in a wide variety of malignancies, but not yet in PSCC. Methods: 397 clinically advanced PSCC underwent hybrid capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). TMB was determined on up to 1.1 Mb of sequenced DNA and categorized into three groups: 〈 10 mutations/Megabase [muts/Mb] (low), 10-19 muts/Mb (high), and 〉 20 muts/Mb (very high). MSI was determined on 114 loci. Genome-wide loss of heterozygosity (gLOH) was determined using validated pipelines and PD-L1 expression by IHC (TPS and Dako 22C3). Statistical comparisons utilized the Bonferonni correction method. Results: There were 339 (85.4%) TMB low, 40 (10.1%) TMB 10-19 and 18 (4.5%) TMB very high PSCC cases. The mean age of PSCC with very high TMB at 70.1 yrs was older than TMB low at 63.4 yrs (p=.08). The GA per tumor frequencies ranged from 5.4 to 5.5 in the 3 groups. There were no significant differences in genomic ancestry among the 3 groups. The TMB 10-19 and TMB very high tended to feature an APOBEC genomic mutational signature more than the TMB low PSCC cases (74 and 76% vs 44%). MSI high status was absent in the TMB low PSCC, but was present in 7.5% in the TMB 10-19 and 11.8% in the TMB very high cases. gLOH levels above 16% were similar in all 3 groups and ranged from 6.2 to 9.4%. GA associated with differences in TMB status in the PSCC cases included higher PIK3CA GA in TMB 10-19 (40.0%) vs TMB low (18.3%; p=.035) and TMB very high (66.7%) vs low (p=.0002). CDKN2A GA were higher in TMB low (45.7%) than the combined TMB 10-19 + very high (25.9%; p=.049). GA in KMT2D were higher in the combined TMB 10-19 + very high (29.3%) than TMB low (7.7%; p=0002). FGFR3 GA were similar in all 3 groups. In total, 6.5% of all GA were predicted to be of germline nature. The highest proportions of germline GA were seen for HRR genes ATM and CHEK2 (both 40%) and BRCA2 (37.5%) and PMS2 (40%) linked to Lynch syndrome. PD-L1 expression was not significantly different among the 3 groups with TMB low (78.3%), TMB 10-19 (64.2%) and TMB very high (54.5%). HPV identification was more frequent as TMB increased: 28.3% for TMB low, 50.0% for TMB high and 58.8% for TMB very high groups. Conclusions: The evaluation of PSCC by CGP based on TMB levels reveals significant differences in biomarkers for the near 15% of cases that have TMB ≥10 muts/Mb. TMB and MSI status can also serve as biomarkers of response to SOC anti-PD1 based on the current FDA indications. These data may be useful to provide rationale for inclusion of PSCC in basket or umbrella trials testing novel monotherapies or combination therapies. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.5044
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 10
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    Landscape of genomic alterations (GA) in urothelial bladder carcinoma (UBC) in patients of East Asian and South Asian ancestry.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 6_suppl ( 2023-02-20), p. 567-567
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 6_suppl ( 2023-02-20), p. 567-567
    Abstract: 567 Background: UBC is the 10 th most common cancer worldwide, with more than 550,00 new cases annually (WHO, International Agency for Research on Cancer, 2020). Rates vary by regions of the world, explained in part by the fact that different genetic ancestries demonstrate varying germline genetics, environmental exposures, and social risk factors. Methods: 8,728 UBC samples underwent hybrid capture-based comprehensive genomic profiling (CGP) to determine all classes of genomic alterations (GA), microsatellite instability (MSI) status, tumor mutational burden (TMB), and genomic trinucleotide signature. Predominant genetic ancestry was determined using a SNP-based approach using an algorithm trained on the 1000 Genomes data (Connelly et al. AACR 2018). Ancestry was classified as one of the five following categories: African (AFR), European (EUR), Central and South American (AMR), South Asian (SAS), or East Asian (EAS). Results: Of the cohort, 7,447 (85.3%) were EUR, 541 (6.2%) were AFR, 461 (5.3%) were of AMR, 74 (0.85%) were SAS, and 205 (2.3%) were EAS. Age, gender, genomic signature distributions, and MSI status (range 0.9%-1.5%) were similar in all cohorts. The frequency of TMB 〉 10 mutations/Megabase was similar in all cohorts (range 30.7%-39.1%) as was the median TMB (6.3 mutations/Megabase for all). At 67.6%, TP53 was the most frequent GA in SAS cohort. When compared with the non-SAS cohort, TERT GA were lower in the SAS cohort (58.1% vs 72.6%; p=0.06) as were GA in FGFR3 (9.5% vs 18.5%, p=0.25). In the EAS cohort, at 59.0%, GA in TP53 were the most common. TERT mutations were significantly lower in EAS compared to the non-EAS cohort (54.1% vs 72.9%; p 〈 0.001). When compared with the non-EAS cohort, PIK3CA alterations were significantly less common in the EAS cohort (12.7% vs 22.1%, p =0.005). GA in FGFR3 were similar in the EAS and non-EAS cohorts (16.6% vs 18.4%). There were no significant differences in genomic landscapes identified between the EAS and SAS cohorts when directly compared to one another. Conclusions: The results from this comprehensive genomic analysis of UBC in East Asian and South Asian patients provides important insight into the unique differences in the genomic landscapes that exist on a population level. These findings should motivate future investigators to include more diverse patient populations in clinical trials of targeted agents and immunotherapy strategies.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.6_suppl.567
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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