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  • 1
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    Angiogenic and T-effector subgroups identified by gene expression profiling (GEP) and propensity for PBRM1 and BAP1 alterations in clear cell renal cell carcinoma (ccRCC).
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 6_suppl ( 2021-02-20), p. 343-343
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 6_suppl ( 2021-02-20), p. 343-343
    Abstract: 343 Background: With the emergence of multiple active treatment options in RCC, predictive biomarkers for optimal treatment selection are lacking. Gene expression data from IMmotion151 and Javelin Renal 101 clinical trials generated anti-angiogenic and immune signatures that warrant further validation. We aimed to describe the genomic and gene expression profiles in a multi-institutional database of patients with ccRCC, and its association with other biomarkers of interest. Methods: Whole transcriptome sequencing was performed for ccRCC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) from February 2019 to September 2020. Tumor GEP and hierarchical clustering based on the validated 66-gene signature (D’Costa et al, 2020) were used to identify patient subgroups. Samples from both primary tumors and metastatic sites were included. Results: A total of 316 patients with ccRCC, median age 62 (range 32-90), 71.8% men, were included. Tissue samples were obtained from primary tumor (46.5%), lung (12.3%), bone (9.5%), liver (4.7%) and other metastatic sites (27%). Gene expression analysis identified angiogenic, mixed and T-effector subgroups in 24.1%, 51.3% and 24.7%, respectively. Patients with angiogenic subgroup tumors compared to those with T-effector subgroup tumors were more likely to be older (63 versus 60 years, p=0.035), female (40.8% versus 16.7%, p=0.0009) and more frequently found in pancreatic/small bowel metastases (75% versus 12.5%, p=0.0103). Biomarkers of potential response to immunotherapy such as PD-L1 (p=0.0021), TMB (not significant), and dMMR/MSI-H status (not significant) were more frequent in the T-effector subgroup. PBRM1 mutations were more common in the angiogenic subgroup (62.0% vs 37.5%, p=0.0034) while BAP1 mutations were more common in the T-effector subgroup (18.6% versus 3.0%, p= 0.0035). Immune cell population abundance (e.g. NK cells, monocytes) and immune checkpoint gene expression (TIM-3, PD-L1, PD-L2, CTLA4) were also increased in the T-effector subgroup. Conclusions: Our hierarchical clustering results based on the 66-gene expression signature were concordant with results from prior studies. Patient subgroups identified by evaluation of angiogenic and T-effector signature scores exhibit significantly different mutations and immune profiles. These findings require prospective validation in future biomarker-selected clinical trials.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.6_suppl.343
    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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  • 2
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    Comprehensive genomic profiling of 724 gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 15_suppl ( 2018-05-20), p. 4098-4098
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 4098-4098
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.15_suppl.4098
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Human papillomavirus (HPV) induced malignancies and markers of immunogenicity.
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 15_suppl ( 2017-05-20), p. e23083-e23083
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. e23083-e23083
    Abstract: e23083 Background: Approximately 5% of all cancers result from HPV, commonly leading to head and neck (HN) and anogenital (AG) cancers. Immune therapy is used in many cancers including HN. Positive PDL1 and high tumor mutation load (TML) have been proposed as potential markers of immunogenicity among many tumors, but little is known specifically among HPV driven cancers. Methods: A retrospective analysis of patients with HPV related cancers was performed based on tissue availability. TP53 wild type status was used as a surrogate for HPV positivity. Among oropharynx cases with TP53 wt, p16 testing was performed for confirmation. Next generation Sequencing (NGS Sanger) was used for tumor mutation load (TML) calculation. High TML cut off was defined as ≥17 mutations/megabase based on prior publications. PDL1 status was reported based on IHC ≥5%. A 2-tail Fisher’s exact test was utilized for statistical analysis. Results: A total of 737 patients with HN and AG (cervical, anal, vulvar, penile) squamous cell carcinoma were identified. Of these, 251 had complete 592 gene panel NGS data. HPV + TP53 Wt disease was detected in oropharynx (70%), cervical (88%), and anal (82%) cancer. HPV+ HNSCC had a trend to a higher PDL1 compared to HPV neg (50% vs 31%, p = 0.16) but there were no significant differences among PDL1 between HPV+ and neg patients across the entire combined disease cohorts (41% vs 36%, p = 0.56). TML-high patients showed a trend to increased PDL1 positivity (60% vs 38%, p = 0.09). However, high TML was less common in HPV+ HNSCC vs HPV neg (2.2 vs. % 9.7% p = 0.19). Unlike some other malignancies, high TML was uncommon across HPV+ tumors in general (8%). Conclusions: Despite fewer TML high cases among HPV + patients, there was no difference among PDL1 expression. It is possible that a lower threshold may need to be used when determining TML high vs. low in viral-driven cancers. It is also possible that in view of viral immunogenicity, certain genomic alterations contribute more to higher PDL1 expression rather than the sum of total genomic alterations. We are currently pursuing both lines of investigation. These findings are hypothesis generating for future trial design rather than treatment decision-making, and need to be confirmed in large prospective cohorts.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.35.15_suppl.e23083
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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  • 4
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    Profiling of targetable aberrations in advanced sarcoma.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e22559-e22559
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e22559-e22559
    Abstract: e22559 Background: Soft tissue and bone sarcoma (STS/BS) are heterogeneous and difficult to treat malignancies. Recent advances in molecular testing improved our understanding of the disease biology. Methods: Retrospective data on non-GIST sarcoma cases were analyzed using next genomic sequencing (NGS) (MiSeq on 47 genes, NextSeq on 592 genes), immunohistochemistry (IHC), fusion transcript detection and copy number alterations (CNA) by Caris Life Sciences between July 2010 and November 2018 at Karmanos Cancer Institute. Targetable aberrations (TA) were identified by searching available literature on therapeutics tested in clinical trials. Results: Demographic data on 64 patients were analyzed; median age 56 (21-87y) and a 1:1 gender ratio. Most frequent histologies include Leimyosarcoma (LMS) 15.3% (n = 10) and Undifferentiated Pleomorphic Sarcoma (UPS) 12.5% (n = 8). Genetic aberrations occurred in 78% of cases, with a cumulative 302 aberrations and a mean 4.7 TA (1-11)/case. Frequent aberrations by methodologies include a) IHC: TOP2A 64.3% (n = 36), MGMT 53.9% (n = 28), TUBB3 49% (n = 24); b) NGS: TP53 37.8% (n = 17); c) CNA: CDK4 and MDM2 at 9.3% (n = 4) respectively; d) fusion transcript: NOTCH2 fusion (n = 1), p 〈 0.05. All cases were MSI stable. TA constituted 37.1% (n = 112) of the identified aberrations in the cohort and existed in 89.1% (n = 57) cases with a mean of 3.08 TA/case, p 〈 0.05. Frequent TA other than TOP2A, TP53, MGMT by histologies included a) LMS: RRM1 28.6% (n = 4), PI3KCA and ER/PR at 14.3% (n = 1) each respectively; b) UPS: TUBB3 50% (n = 4), PD-1 25% (n = 2); c) Sarcoma NOS: CDK4 28.6% (n = 2), TS 28.6% (n = 2), C-MET and EGFR at 14.3% (n = 1) each respectively; d) Well Differentiated/Dedifferentiated Liposarcoma: CDK4, MDM2 and PD-1 at 20% (n = 1) each respectively. Conclusions: Incorporating genomic profiling has helped personalize treatment to include clinical trial enrollment. Further drug development and prospective studies are required in this population.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.e22559
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Consensus molecular subtyping of colorectal cancer to demonstrate cetuximab benefit in right-sided CMS2 tumors, and pembrolizumab benefit in MSS CMS1 tumors.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 3535-3535
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 3535-3535
    Abstract: 3535 Background: Consensus Molecular Subtypes (CMS) of colorectal cancer (CRC) were first developed in 2015 using microarray-based assays but are not widely used clinically. We developed a Caris CMS classifier on whole transcriptome sequencing data (WTS) with high concordance with the previously established CMS pipeline (Guinney et al 2015), and applied to a large clinic-genomic database of CRC to investigate the utility of CMS classification in identifying patients that may respond well to therapies commonly used in CRC. Methods: Next-generation sequencing (NGS) of DNA (592-gene or whole exome) and WTS was tested on CRC patient samples (n = 12,788) at a CLIA-certified lab (Caris Life Sciences, Phoenix, AZ). Caris CMS classifier was trained against the original CMS datasets using a classic SVM model and cross-validated for optimization of the SVM parameters. Possible overtraining was evaluated by predicting CMS from an independent blinded dataset (TCGA, N = 512) with an accuracy of 88.3%. Real-world overall survival was obtained from insurance claims and calculated from tissue collection to last contact (OS); time on treatment (TOT) was from first to last of treatment time. Kaplan-Meier estimates were calculated for molecularly defined cohorts. Significance was determined as p of 〈 0.05. Results: Among all patients, CMS1 was seen in 16%, CMS2 in 32%, CMS3 in 17% and CMS4 in 35%. MSI-H/MMRd (31%) and BRAF mut (33%) were most prevalent in CMS1 with KRAS mt the highest in CMS3 (66%). CMS2 was associated with the longest mOS (33m; 95% CI: 31m-35m), followed by CMS4 (29m; 28-31m), CMS3 (27m; 25-29m) and CMS1 (22m; 20-23m). In the microsatellite stable (MSS) tumors treated with pembrolizumab, CMS1 (N = 22, mTOT: 4.2m; 2.8-9.1m) had longer TOT than CMS2 (N = 45, mTOT: 2.1m; 1.4-3.1m), CMS3 (N = 21, 2.1m; 1.4m-3.0m) and CMS4 (N = 40; 2.1m; 1.4m-2.8m); CMS1 vs. CMS2-4 in MSS (HR: 0.58; CI: 0.34-0.97, p = 0.035). When investigating cetuximab, CMS2 had the longest mTOT (N = 189, mTOT: 6.3m; 5.4m-7.7m) among the four groups. Interestingly, although among all Ras WT tumors left-sided CRC showed longer mTOT on cetuximab (n = 457, mTOT: 5.4m; 4.7m-6.3m) than right-sided (n = 151, mTOT: 3.8m; 3.3m-4.5m), CMS2 showed similar mTOT from the left (n = 128) and the right (n = 16, mOT: 6.3m vs. 5.6m, HR = 0.896, 95% CI: 0.501-1.604, p = 0.722). Notably, CMS2 comprises 49% of left- and 15% of right-sided tumors, potentially underlying the TOT difference seen between left and right. Conclusions: A WTS based CMS classifier allows for investigation in a large real-world clinic-genomic database. We found that MSS CMS1 CRC’s may derive benefit from immunotherapy. Additionally, CMS2 subgroup of right-sided tumors may derive benefit from cetuximab. Routine CMS subgrouping of CRC provides important treatment associations that should be further investigated.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.3535
    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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  • 6
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    Biomarkers of Targeted Therapy and Immuno-Oncology in Cancers Metastatic to the Breast
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Applied Immunohistochemistry & Molecular Morphology Vol. 28, No. 9 ( 2020-10), p. 661-668
    Details
    In: Applied Immunohistochemistry & Molecular Morphology, Ovid Technologies (Wolters Kluwer Health), Vol. 28, No. 9 ( 2020-10), p. 661-668
    Abstract: The breast is a rare site for metastases, and their molecular characteristics have not been studied yet. Intrinsic molecular genetics, cancer characteristics, and breast tissue immune responses in diverse metastases to the breast have not been previously studied. We identified 64 patients with cancers metastatic to the breast: 51 carcinomas and 13 melanomas. Programmed death ligand 1 (PD-L1), steroid receptors, and HER2/neu expressions were evaluated using immunohistochemistry. Gene sequencing, copy number alterations, microsatellite instability, and tumor mutational burden were performed using next-generation sequencing platforms. The 3 most common primary sites for metastatic carcinomas were lung (37%), ovary (29%), and fallopian tubes/peritoneum (14%). TP53 mutations were commonly (50%) observed among the carcinoma cases, while other mutations were characteristic for the primary cancers ( VHL in renal, BRCA1 in the fallopian tube, and BRAF in melanomas). High tumor mutational burden was detected in 5/14 carcinomas and 3/7 melanomas. Tumor cell PD-L1 expression was detected in 6 carcinomas, but not in any of the melanomas, whereas immune cells’ expression of PD-L1 was seen in 17 carcinomas and 6 melanomas. Estrogen receptor status was positive in 13/49 carcinomas including 12 adenocarcinomas originating from the ovary and fallopian tube or peritoneum and 1 duodenal neuroendocrine carcinoma. No carcinoma was HER2/neu positive. Intrinsic genetic characteristics of the metastases to the breast followed the pattern commonly seen in primary tumors. Biomarkers of potential benefit to immune checkpoint inhibition therapy were limited to PD-L1-positive non–small cell lung cancer. No common characteristics of the heterogeneous group of tumor metastases to this organ were identified.
    Type of Medium: Online Resource
    ISSN: 1541-2016
    URL: Article
    DOI: 10.1097/PAI.0000000000000808
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2052398-1
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  • 7
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    Impact of Patient Age on Molecular Alterations of Left-Sided Colorectal Tumors
    Oxford University Press (OUP) ; 2019
    In:  The Oncologist Vol. 24, No. 3 ( 2019-03-01), p. 319-326
    Details
    In: The Oncologist, Oxford University Press (OUP), Vol. 24, No. 3 ( 2019-03-01), p. 319-326
    Abstract: The incidence of colorectal cancer (CRC) in younger patients is rising, mostly due to tumors in the descending colon and rectum. Therefore, we aimed to explore the molecular differences of left-sided CRC between younger (≤45 years) and older patients (≥65). Subjects, Materials, and Methods In total, 1,126 CRC tumor samples from the splenic flexure to (and including) the rectum were examined by next-generation sequencing (NGS), immunohistochemistry, and in situ hybridization. Microsatellite instability (MSI) and tumor mutational burden (TMB) were assessed by NGS. Results Younger patients (n = 350), when compared with older patients (n = 776), showed higher mutation rates in genes associated with cancer-predisposing syndromes (e.g., Lynch syndrome), such as MSH6 (4.8% vs. 1.2%, p = .005), MSH2 (2.7% vs. 0.0%, p = .004), POLE (1.6% vs. 0.0%, p = .008), NF1 (5.9% vs. 0.5%, p  & lt; .001), SMAD4 (14.3% vs. 8.3%, p = .024), and BRCA2 (3.7% vs. 0.5%, p = .002). Genes involved in histone modification were also significantly more mutated: KDM5C (1.9% vs. 0%, p = .036), KMT2A (1.1% vs. 0%, p = .033), KMT2C (1.6% vs. 0%, p = .031), KMT2D (3.8% vs. 0.7%, p = .005), and SETD2 (3.2% vs. 0.9%, p = .039). Finally, TMB-high (9.7% vs. 2.8%, p  & lt; .001) and MSI-high (MSI-H; 8.1% vs. 1.9%, p = .009) were more frequent in younger patients. Conclusion Our findings highlight the importance of genetic counseling and screening in younger CRC patients. MSI-H and TMB-high tumors could benefit from immune-checkpoint inhibitors, now approved for the treatment of MSI-H/deficient mismatch repair metastatic CRC patients. Finally, histone modifiers could serve as a new promising therapeutic target. With confirmatory studies, these results may influence our approach to younger adults with CRC.
    Type of Medium: Online Resource
    ISSN: 1083-7159 , 1549-490X
    URL: Article
    DOI: 10.1634/theoncologist.2018-0117
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2023829-0
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  • 8
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    Molecular profiling of signet-ring-cell carcinoma (SRCC) from the stomach and colon reveals potential new therapeutic targets
    Springer Science and Business Media LLC ; 2022
    In:  Oncogene Vol. 41, No. 26 ( 2022-06-24), p. 3455-3460
    Details
    In: Oncogene, Springer Science and Business Media LLC, Vol. 41, No. 26 ( 2022-06-24), p. 3455-3460
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    URL: Article
    DOI: 10.1038/s41388-022-02350-6
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2008404-3
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  • 9
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    Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets
    AME Publishing Company ; 2019
    In:  Journal of Gastrointestinal Oncology Vol. 10, No. 4 ( 2019-8), p. 652-662
    Details
    In: Journal of Gastrointestinal Oncology, AME Publishing Company, Vol. 10, No. 4 ( 2019-8), p. 652-662
    Type of Medium: Online Resource
    ISSN: 2078-6891 , 2219-679X
    URL: Journal
    URL: Article
    DOI: 10.21037/jgo
    DOI: 10.21037/jgo.2018.08.18
    Language: Unknown
    Publisher: AME Publishing Company
    Publication Date: 2019
    detail.hit.zdb_id: 2594644-4
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  • 10
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    Patterns and genomic correlates of PD-L1 expression in patients with biliary tract cancers
    AME Publishing Company ; 2019
    In:  Journal of Gastrointestinal Oncology Vol. 10, No. 6 ( 2019-12), p. 1099-1109
    Details
    In: Journal of Gastrointestinal Oncology, AME Publishing Company, Vol. 10, No. 6 ( 2019-12), p. 1099-1109
    Type of Medium: Online Resource
    ISSN: 2078-6891 , 2219-679X
    URL: Journal
    URL: Article
    DOI: 10.21037/jgo
    DOI: 10.21037/jgo.2019.08.08
    Language: Unknown
    Publisher: AME Publishing Company
    Publication Date: 2019
    detail.hit.zdb_id: 2594644-4
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