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  • American Association for Cancer Research (AACR)  (77)
  • 1
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    Randomized Phase II Study Evaluating Akt Blockade with Ipatasertib, in Combination with Abiraterone, in Patients with Metastatic Prostate Cancer with and without PTEN Loss
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 3 ( 2019-02-01), p. 928-936
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 3 ( 2019-02-01), p. 928-936
    Abstract: PI3K–Akt–mTOR and androgen receptor (AR) signaling are commonly aberrantly activated in metastatic castration-resistant prostate cancer (mCRPC), with PTEN loss associating with poor prognosis. We therefore conducted a phase Ib/II study of the combination of ipatasertib, an Akt inhibitor, with the CYP17 inhibitor abiraterone in patients with mCRPC. Patients and Methods: Patients were randomized 1:1:1 to ipatasertib 400 mg, ipatasertib 200 mg, or placebo, with abiraterone 1,000 mg orally. Coprimary efficacy endpoints were radiographic progression-free survival (rPFS) in the intent-to-treat population and in patients with PTEN-loss tumors. Results: rPFS was prolonged in the ipatasertib cohort versus placebo, with similar trends in overall survival and time-to-PSA progression. A larger rPFS prolongation for the combination was demonstrated in PTEN-loss tumors versus those without. The combination was well tolerated, with no treatment-related deaths. Conclusions: In mCRPC, combined blockade with abiraterone and ipatasertib showed superior antitumor activity to abiraterone alone, especially in patients with PTEN-loss tumors. See related commentary by Zhang et al., p. 901
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-0981
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 2
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    Association of the Colorectal CpG Island Methylator Phenotype with Molecular Features, Risk Factors, and Family History
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 24, No. 3 ( 2015-03-01), p. 512-519
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 24, No. 3 ( 2015-03-01), p. 512-519
    Abstract: Background: The CpG island methylator phenotype (CIMP) represents a subset of colorectal cancers characterized by widespread aberrant DNA hypermethylation at select CpG islands. The risk factors and environmental exposures contributing to etiologic heterogeneity between CIMP and non-CIMP tumors are not known. Methods: We measured the CIMP status of 3,119 primary population-based colorectal cancer tumors from the multinational Colon Cancer Family Registry. Etiologic heterogeneity was assessed by a case–case study comparing risk factor frequency of colorectal cancer cases with CIMP and non-CIMP tumors using logistic regression to estimate the case–case odds ratio (ccOR). Results: We found associations between tumor CIMP status and MSI-H (ccOR = 7.6), BRAF V600E mutation (ccOR = 59.8), proximal tumor site (ccOR = 9; all P & lt; 0.0001), female sex [ccOR = 1.8; 95% confidence interval (CI), 1.5–2.1], older age (ccOR = 4.0 comparing over 70 years vs. under 50; 95% CI, 3.0–5.5), and family history of CRC (ccOR = 0.6; 95% CI, 0.5–0.7). While use of NSAIDs varied by tumor CIMP status for both males and females (P = 0.0001 and P = 0.02, respectively), use of multivitamin or calcium supplements did not. Only for female colorectal cancer was CIMP status associated with increased pack-years of smoking (Ptrend & lt; 0.001) and body mass index (BMI; Ptrend = 0.03). Conclusions: The frequency of several colorectal cancer risk factors varied by CIMP status, and the associations of smoking and obesity with tumor subtype were evident only for females. Impact: Differences in the associations of a unique DNA methylation–based subgroup of colorectal cancer with important lifestyle and environmental exposures increase understanding of the molecular pathologic epidemiology of this heavily methylated subset of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(3); 512–9. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-14-1161
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 3
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    Characterization of the Cellular and Antitumor Effects of MPI-0479605, a Small-Molecule Inhibitor of the Mitotic Kinase Mps1
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 12 ( 2011-12-01), p. 2267-2275
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 12 ( 2011-12-01), p. 2267-2275
    Abstract: Mps1 is a dual specificity protein kinase that is essential for the bipolar attachment of chromosomes to the mitotic spindle and for maintaining the spindle assembly checkpoint until all chromosomes are properly attached. Mps1 is expressed at high levels during mitosis and is abundantly expressed in cancer cells. Disruption of Mps1 function induces aneuploidy and cell death. We report the identification of MPI-0479605, a potent and selective ATP competitive inhibitor of Mps1. Cells treated with MPI-0479605 undergo aberrant mitosis, resulting in aneuploidy and formation of micronuclei. In cells with wild-type p53, this promotes the induction of a postmitotic checkpoint characterized by the ATM- and RAD3-related-dependent activation of the p53–p21 pathway. In both wild-type and p53 mutant cells lines, there is a growth arrest and inhibition of DNA synthesis. Subsequently, cells undergo mitotic catastrophe and/or an apoptotic response. In xenograft models, MPI-0479605 inhibits tumor growth, suggesting that drugs targeting Mps1 may have utility as novel cancer therapeutics. Mol Cancer Ther; 10(12); 2267–75. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-11-0453
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 4
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    Abstract 2058: Systematic evaluation of drug combinations in vitro and in vivo .
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2058-2058
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2058-2058
    Abstract: In recent years great advances have been made in developing targeted cancer therapeutics that produce dramatic responses in a subset of rationally selected patients. The initial breakthrough of the targeted design concept was established by the treatment of chronic myelogenous leukemia with Abl inhibitors and has been expanded to other cancer indications. As a consequence of this early success in CML, the identification and targeting of genetic lesions that confer cancer dependence has become an established strategy for drug discovery efforts. However, this approach has met with mixed degrees of success as confounding factors, such as tumor heterogeneity, have often resulted in partial responses and/or the emergence of resistance when targeted therapies were employed as single agents. To improve the therapeutic benefit in cancer, rationally-devised novel combinations of two or more agents are being explored clinically. To discover combinations that may be more effective therapies, an unbiased, systematic approach was used to identify drug combinations in vitro, using a panel of genetically diverse, and well characterized cell lines from the cancer cell line encyclopedia (CCLE: Barretina et al. Nature 2012). For three cancer indications, all pairwise combinations of 18 selected drugs (both novel inhibitors and standards of care) were tested as dose matrices in a proliferation assay. Synergistic interactions were scored using isobologram/Loewe's excess inhibition and synergistic concentration ranges for each agent were identified. However, the clinical translation of positive combinations from in vitro matrix-based screens into clinically-relevant doses and schedules are challenging, due to host biology, tumor-stroma interactions, and the pharmacokinetic and pharmacodynamics of drug delivery. To explore this higher complexity, we evaluated the in vitro to in vivo translation of drug synergies in immune-compromised mouse tumor xenograft models. To recapitulate the pharmacological combination effects in vivo, mouse pharmacokinetic data and simulation was used to determine single agent doses that would result in the desired compound plasma concentration range and duration of action. Pharmakokinetics, pharmacodynamics, antitumor activity and tolerability of the combinations were then tested in tumor-bearing mice. Observed combination effects in vivo could in some cases be explained by either the expected biological pathway interactions or partially by physiological effects relating to drug-drug interactions. Citation Format: Marion Wiesmann, Mark Stump, Giordano Caponigro, David Duhl, Brant Firestone, Tom Gesner, Bjoern Gruenenfelder, Daniel Alexander Guthy, Jocelyn Holash, Fred King, Joseph Lehar, Christophe Leroy, Manway Liu, Lilli Petruzelli, Dale Porter, Paul McSheehy, Daniel Menezes, Anupama Reddy, Johannes Roesel, Christian Schnell, Timothy R. Smith, Markus Wartmann. Systematic evaluation of drug combinations in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2058. doi:10.1158/1538-7445.AM2013-2058
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-2058
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 5
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    Clinicopathologic Risk Factor Distributions for MLH1 Promoter Region Methylation in CIMP-Positive Tumors
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 25, No. 1 ( 2016-01-01), p. 68-75
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 25, No. 1 ( 2016-01-01), p. 68-75
    Abstract: Background: The CpG island methylator phenotype (CIMP) is a major molecular pathway in colorectal cancer. Approximately 25% to 60% of CIMP tumors are microsatellite unstable (MSI-H) due to DNA hypermethylation of the MLH1 gene promoter. Our aim was to determine if the distributions of clinicopathologic factors in CIMP-positive tumors with MLH1 DNA methylation differed from those in CIMP-positive tumors without DNA methylation of MLH1. Methods: We assessed the associations between age, sex, tumor-site, MSI status BRAF and KRAS mutations, and family colorectal cancer history with MLH1 methylation status in a large population-based sample of CIMP-positive colorectal cancers defined by a 5-marker panel using unconditional logistic regression to assess the odds of MLH1 methylation by study variables. Results: Subjects with CIMP-positive tumors without MLH1 methylation were significantly younger, more likely to be male, and more likely to have distal colon or rectal primaries and the MSI-L phenotype. CIMP-positive MLH1-unmethylated tumors were significantly less likely than CIMP-positive MLH1-methylated tumors to harbor a BRAF V600E mutation and significantly more likely to harbor a KRAS mutation. MLH1 methylation was associated with significantly better overall survival (HR, 0.50; 95% confidence interval, 0.31–0.82). Conclusions: These data suggest that MLH1 methylation in CIMP-positive tumors is not a completely random event and implies that there are environmental or genetic determinants that modify the probability that MLH1 will become methylated during CIMP pathogenesis. Impact: MLH1 DNA methylation status should be taken into account in etiologic studies. Cancer Epidemiol Biomarkers Prev; 25(1); 68–75. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-15-0935
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 6
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    Abstract 3006: Molecular characterization of baseline and serial multiple myeloma patients from the MMRF CoMMpass study
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3006-3006
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3006-3006
    Abstract: Multiple myeloma (MM) is a hematological malignancy of plasma cells accounting for ~2% of new cancer cases each year in the United States. Our understanding of MM pathogenesis has improved dramatically with the development of whole genome analysis technologies, however, to date no study has comprehensively analyzed a large cohort of MM patients. The Multiple Myeloma Research Foundation CoMMpass Study (NCT01454297) is a fully accrued observational clinical trial with 1143 newly diagnosed MM patients from sites in the United States, Canada, Spain, and Italy. Clinical parameters are collected at baseline and every three months through the eight-year observation period. Tumor samples are collected and characterized using whole genome, exome, and RNA sequencing at diagnosis and each progression event. This unique prospective study design differentiates CoMMpass from other large cancer genomics studies performed to date. This represents the first analysis of the CoMMpass interim analysis 12 dataset including 982 of whom are molecularly characterized at baseline. Median follow-up of the cohort exceeds 2 years, and while the median OS has still not been reached, median PFS of the cohort is 36 months. We identified a median of 153 non-immunoglobulin mutations, 29 structural events, and 133 copy number (CN) events per tumor at baseline. In order to identify a set of significantly mutated genes, we applied a consensus-based approach identifying 60 genes mutated in at least 1% of the baseline cohort. Consensus clustering of the CN and gene expression profiles identified 14 and 12 distinct MM subtypes, respectively. Integration of WGS and RNA sequencing data identified 1163 cross-validated fusion transcripts. An integrated analysis of all data sources identified a series of potential gain-of-function and loss-of-function genes, from which a pathway analysis highlighted alterations in the NF-kB, Ras, DNA repair, and cell-cycle pathways. This dataset includes serial data for 121 patients (171 specimens), 21 of whom had multiple progression events. Mutational analyses revealed that ~ 24% of mutations identified at progression were not identified at the previous timepoint. Although rarely mutated at baseline, RRBP1 was frequently mutated at relapse and may represent a novel driver of disease progression or treatment resistance in MM. In progression samples we observed a greater proportion of patients with NRAS mutations, attributable to four patients who acquire NRAS mutations and five patients with baseline KRAS mutations that shift to NRAS mutations at relapse. All patients who exhibit a KRAS to NRAS shift were bortezomib treated, suggesting this shift may represent a mechanism of resistance. This comprehensive study has identified distinct genetic subgroups with variable clinical outcome and demonstrates the value of prospective collections to identify mechanisms of progression and resistance. Citation Format: Sheri Skerget, Austin Christofferson, Sara Nasser, Jessica Aldrich, Daniel Penaherrera, Christophe Legendre, Martin Boateng, Lori Cuyugan, Jonathan Adkins, Erica Tassone, The MMRF CoMMpass Network, Jen Yesil, Daniel Auclair, Winnie Liang, Jonathan J. Keats. Molecular characterization of baseline and serial multiple myeloma patients from the MMRF CoMMpass study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3006.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-3006
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 7
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    ONCR-177, an Oncolytic HSV-1 Designed to Potently Activate Systemic Antitumor Immunity
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Immunology Research Vol. 9, No. 3 ( 2021-03-01), p. 291-308
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 9, No. 3 ( 2021-03-01), p. 291-308
    Abstract: ONCR-177 is an engineered recombinant oncolytic herpes simplex virus (HSV) with complementary safety mechanisms, including tissue-specific miRNA attenuation and mutant UL37 to inhibit replication, neuropathic activity, and latency in normal cells. ONCR-177 is armed with five transgenes for IL12, FLT3LG (extracellular domain), CCL4, and antagonists to immune checkpoints PD-1 and CTLA-4. In vitro assays demonstrated that targeted miRNAs could efficiently suppress ONCR-177 replication and transgene expression, as could the HSV-1 standard-of-care therapy acyclovir. Although ONCR-177 was oncolytic across a panel of human cancer cell lines, including in the presence of type I IFN, replication was suppressed in human pluripotent stem cell–derived neurons, cardiomyocytes, and hepatocytes. Dendritic cells activated with ONCR-177 tumor lysates efficiently stimulated tumor antigen–specific CD8+ T-cell responses. In vivo, biodistribution analyses suggested that viral copy number and transgene expression peaked approximately 24 to 72 hours after injection and remained primarily within the injected tumor. Intratumoral administration of ONCR-177 mouse surrogate virus, mONCR-171, was efficacious across a panel of syngeneic bilateral mouse tumor models, resulting in partial or complete tumor regressions that translated into significant survival benefits and to the elicitation of a protective memory response. Antitumor effects correlated with local and distant intratumoral infiltration of several immune effector cell types, consistent with the proposed functions of the transgenes. The addition of systemic anti–PD-1 augmented the efficacy of mONCR-171, particularly for abscopal tumors. Based in part upon these preclinical results, ONCR-177 is being evaluated in patients with metastatic cancer (ONCR-177-101, NCT04348916).
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-20-0609
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 8
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    Abstract 6577: CARMEN: A pan-HLA and pan-cancer proteogenomic database on antigen presentation to support cancer immunotherapy
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6577-6577
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6577-6577
    Abstract: Cancer immunotherapy has greatly improved the quality of life of cancer patients and it hinges on the discovery of novel cancer antigens that could be targeted to improve disease outcomes. The creation of databases such as IEDB, SysteMHC, TANTIGEN, caAtlas, HLA Ligand Atlas, Cancer Antigenic Peptide Database, SPENCER and IEAtlas support the immunopeptidomics community in understanding the landscape of antigen presentation. We have developed a pan-cancer, pan-HLA, and pan-tissue database containing immunopeptidomics data mapped to transcriptomic, genomic, immunological and biochemical data. The database was generated from 80 different publicly available immunopeptidomics mass spectrometry datasets collected between 2015-2022 (76 cancer and 4 normal datasets), covering 15 different types of cancers and 152 different HLA-I alleles. The peptides contained in our database were obtained by a combination of closed, open and de novo searches using an in-house developed computational pipeline. Following rigorous false discovery rate estimation at 1% and a second-round search to eliminate any false signals that may not have been detected in the previous round of FDR estimation, we obtained a list of 11.2 million peptide-HLA combinations comprising both coding and non-coding regions of the genome as well as bacterial peptides. These peptides have been mapped to chromosomal coordinates to facilitate adoption by the genomics community of this useful resource on antigen presentation. Pathway/biochemical analysis of each peptide was performed using the rWikiPathways package. Finally, mutations associated with each peptide were annotated using COSMIC and dbSNP resources. Our database includes a FAIR knowledge graph which contextualizes and enriches the data to enable clinicians to take effective therapeutic decisions on the appropriate form of treatment for cancer immunotherapy with the case study of clear cell renal cell carcinoma (ccRCC). We will continue to expand our database with new data over the next two years and expand the scope of its applications to facilitate uptake by the larger scientific community. Citation Format: Ashwin Adrian Kallor, Michał Waleron, Georges Bedran, Patrícia Eugénio, Catia Pesquita, Daniel Faria, Fabio Massimo Zanzotto, Christophe Battail, Ajitha Rajan, Javier Alfaro. CARMEN: A pan-HLA and pan-cancer proteogenomic database on antigen presentation to support cancer immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6577.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-6577
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 9
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    Genomic Profiling of Metastatic Castration-Resistant Prostate Cancer Samples Resistant to Androgen Receptor Pathway Inhibitors
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research ( 2023-07-19), p. OF1-OF14
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), ( 2023-07-19), p. OF1-OF14
    Abstract: The androgen receptor axis inhibitors (ARPI; e.g., enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown. Experimental Design: In the prospective trial MATCH-R (NCT02517892), 59 patients with mCRPC underwent whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) of samples collected before starting ARPI. Also, 18 patients with mCRPC underwent biopsy at time of resistance. The objectives were to identify genomic alterations associated with resistance to ARPIs as well as to describe clonal evolution. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher exact tests. Results: WES analysis indicated that no single-gene genomic alterations were strongly associated with primary resistance. RNA-seq analysis showed that androgen receptor (AR) gene alterations and expression levels were similar between responders and nonresponders. RNA-based pathway analysis found that patients with primary resistance had a higher Hedgehog pathway score, a lower AR pathway score and a lower NOTCH pathway score than patients with a response. Subclonal evolution and acquisition of new alterations in AR-related genes or neuroendocrine differentiation are associated with acquired resistance. ARPIs do not induce significant changes in the tumor transcriptome of most patients; however, programs associated with cell proliferation are enriched in resistant samples. Conclusions: Low AR activity, activation of stemness programs, and Hedgehog pathway were associated with primary ARPIs’ resistance, whereas most acquired resistance was associated with subclonal evolution, AR-related events, and neuroendocrine differentiation.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-3736
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 10
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    Abstract 448: High prevalence of pathogenic germline variants in patients with oncogene-driven non-small cell lung cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 448-448
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 448-448
    Abstract: BACKGROUND: Preliminary data has highlighted inherited predisposition to lung cancer related to certain genes. The frequency of pathogenic germline variants (PGV) PGV in patients (pts) with lung cancer according to the presence of an oncogenic driver is unknown. We studied the PGV of genes predisposing to cancer in pts with non-small cell lung cancer (NSCLC), and the somatic molecular profile of lung tumors. METHODS: Retrospective study of whole exome sequencing (WES) from tissue biopsies performed in pts with advanced NSCLC enrolled, after signature of the inform consent, in the MOSCATO/MATCH-R trials between 2012 and 2018. Variants were considered as PGVs in the cancer predisposing genes (PMID: 29625052) if they satisfied the following criteria: (i) they had a “PASS” flag in HaplotypeCaller, (ii) were annotated as “Pathogenic” or “Likely Pathogenic” in ClinVar (PMID: 29165669) or InterVar (PMID: 28132688), or (iii) were truncating variants. Somatic driver mutations and Loss of Heterozygocity (LOH) of PGV harboring genes were further evaluated. The overlap to loss of heterozygocity regions was reported only when the variant allele frequency of the PGV was significantly higher than in the normal tissue. Cancer history, clinical and molecular data were retrospectively collected. The somatic mutations (m) in EGFR/BRAF/MET/HER2/KRAS and fusions in ALK/ROS1/RET were also considered for analysis. RESULTS: Among 134 pts, 48% were women, median age was 61 (range 24-83), 45% were nonsmokers, 74% had adenocarcinoma. The most common somatic oncogenic driver alterations were: EGFRm in 44 pts (33%), KRASm in 19 pts (14%), BRAFm in 12 pts (9%) and ALK in 12 pts (9%).PGV were found in 22 out of 152 (15%) cancer-predisposing genes; 4 pts had additional somatic mutations (2) or LOHs (2) in the same genes. 77% of PGVs were in genes which are part of DNA repair pathways including 3.6% nucleotide excision repair (ERCC1/2/3, XPA), 6.5% homologous recombination/Fanconi Anemia: (FANC/A/C/M/D2, BRCA1, RECQL), 2.1% base excision repair (MUTYH, NTHL1), while the others were represented by genes related to cell signaling and metabolism (NF1, MET, ELANE, PRDM9, TRIM37).In the 22 PGV-carriers, 68% had a somatic oncogene-driven alteration (15/22) : EGFRm (n=7; 5 ex19del, 2 ex21(L858R)), KRASm (n=3; 2 G12D, 1 G12V), METm (n=2), HER2m (n=1), ROS1 (n=1) and RET (n=1). PGV were observed in 16% of EGFRm (7/44), 67% of METm (2/3), 15% in KRASm (3/19), 33% of HER2m (1/3), 25% of ROS1 (1/4), 50% of RET (1/2); but no PGV was identified in pts with BRAFVm (12) or ALK (12). CONCLUSION: In our cohort, 15% of pts with NSCLC were PGV-carriers; 68% of PGV-carriers had oncogene-driven tumors, particularly with somatic EGFR mutations. PGV and oncogene-driven lung carcinogenesis need further evaluation. Citation Format: Laura Mezquita, Andrei Iurchenko, Jose Carlos Benitez, Maria Baz, Sergey Nikolaev, David Planchard, Felix Blanc-Durand, Mihaela Aldea, Patricia Martín-Romano, Yohann Loriot, Claudio Nicotra, Maud Ngocamus, Jean-Yves Scoazec, Stefan Michiels, Sophie Postel-Vinay, Julien Viot, Luc Friboulet, Antoine Italiano, Fabrice Andre, Christophe Massard, Jean-Charles Soria, Etienne Rouleau, Daniel Gautheret, Benjamin Besse. High prevalence of pathogenic germline variants in patients with oncogene-driven non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 448.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-448
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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