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  • American Association for Cancer Research (AACR)  (3)
  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P4-01-03-P4-01-03
    Abstract: Aim: The prognostic value of circulating tumor cells (CTCs) in the adjuvant setting has recently been demonstrated in the SUCCESS A Study (Rack et al. JNCI 2014). As breast carcinomas depend on partly different pathways for progression, the relevance of CTCs could differ between molecular intrinsic subtypes of breast cancer. Aim of this study was therefore to analyze the prognostic impact of CTCs in molecular subtypes of a large patient cohort. Methods: Within the adjuvant SUCCESS A Study, patients were treated either with 5-Flourouracil, Epirubicin and Cyclophosphamid (FEC) followed by Docetaxel (D) or with FEC followed by D and Gemcitabine (DG). There was no restriction with regard to molecular subtype, however a high recurrence risk was required for study entry. In addition patients were assessed prospectively for the presence of CTCs before chemotherapy. Molecular subtypes were defined as: triple negative (TN), hormone receptor positive and grading 1/2 (LUM A like), hormone receptor positive and grading 3 (LUM B like), HER2 positive (HER2 like). We studied whether the addition of CTC status (0 CTC vs & gt; 0 CTCs) to well-known predictors such as age, BMI, tumor size, lymph node status improved the prediction of overall survival (OS) and disease free survival (DFS) across all patients and especially within molecular subtypes using likelihood ratio tests, which compared multivariable Cox regression models with and without CTC and the interaction between CTC and molecular subtype. Results: Information about molecular subtype and CTCs was available in a total of 1994 patients. At least one CTC was seen in 422 (21.2%) of patients. 383 (19.2%) were TN, 798 were LUM A like (40.0%), 328 (16.4%) were LUM B like (16.4%) and 485 (24.3%) were HER2 like. The effect of CTC on overall survival had a HR of 2.50 (95%: 1.75 to 3.58) for the entire cohort. However as the effect was different across subtypes (p=0.04, likelihood ratio test), subtype specific HR were calculated. The effects on OS were most prominent in LUM B like patients (HR=3.96; 95%CI: 1.93 to 8.14) and LUM A like patients (HR=3.57; 95%CI: 1.81 to 7.03), less strong in HER2 like (HR=2.35; 95%CI: 1.04 to 5.32) and not present in TN patients (HR=1.18; 95%CI: 0.62 to 2.24). CTC status had a clear effect on DFS as well (HR=1.93, 95%CI: 1.48 to 2.52). It could not be shown that this effect was different across subtypes (p=0.07, likelihood ratio test). However, the effect size was similarly distributed like the ones for OS. Conclusion: With regard to OS the prognostic effect of CTCs in this study cohort seems most prominent in patients with hormone receptor positive disease. It is still significant in HER2 positive, but not in TN breast cancer patients. Results with regard to DFS trended into the same direction, differences within subgroups could however not be shown, possibly due to power reasons. Citation Format: Wolfgang Janni, Andreas Schneeweiss, Lothar Häberle, Peter A Fasching, Lukas Schwentner, Mahdi Rezai, Jörn Hilfrich, Hans Tesch, Georg Heinrich, Helmut Forstbauer, Thomas Friedl, Fabienne Schochter, Susanne Albrecht, Bernadette Jäger, Julia Jückstöck, Tanja Fehm, Volkmar Müller, Klaus Friese, Werner Lichtenegger, Matthias B Beckmann, Brigitte Rack. Prognostic relevance of circulating tumor cells across different molecular subgroups in the adjuvant SUCCESS-A study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-01-03.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 810-810
    Abstract: Homologous recombination deficiency (HRD) leads to DNA double strand breaks and can be exploited by the use of PARP inhibitors to induce synthetic lethality of cancer cells. Over the last years, the clinical utility of this therapeutic concept was successfully demonstrated in ovarian, breast, prostate and pancreatic cancer. Currently, the role of HRD is investigated in trials testing immune checkpoint blockers alone or in combination with PARP inhibitors. But the relationship between HRD and immune cell contexture in cancer is incompletely understood. Here, we analyzed the association of HRD with tumor mutational burden (TMB), immune cell composition and gene expression in 10,000 tumors of 32 solid cancer types from the TCGA project. For each of the tumors, the HRD sum score (HRDsum) was calculated from allele-specific copy numbers (derived from genotyping data) and the TMB was calculated from the missense mutation calls (derived from WES data). HRDsum and tumor mutational burden (TMB) correlated positively pan-cancer (R=0.42) and within most cancer types. By contrast, HRD was absent in ultra-hypermutated (TMB & gt;= 100 mut/Mb) tumors. Ultra-hypermutation was typically associated with microsatellite instability (MSI) or POLE/POLD1 mutation. Significant positive correlation of the HRDsum and immune cell infiltration was observed pan-cancer, but only within a few cancer types. Significant positive correlation of HRDsum and the T-cell inflamed gene expression profile was observed only in 7 of 32 cancer types: in breast cancer, ovarian cancer, low grade glioma, testicular germ cell tumors and three kinds of kidney cancer. A functional genomics analysis was carried out by correlating genome-wide gene expression data (derived from RNA-Seq) with HRDsum. The resulting lists of significantly correlating genes were analyzed for enrichment of 50 hallmark gene sets (catalog H, MSigDB). We detected simultaneous enrichment of two proliferation-related categories, E2F_TARGETS and G2M_checkpoint, for 13 of the 32 cancer types (ACC, BLCA, BRCA, KIRC, KIRP, LGG, LIHC, LUAD, LUSC, MESO, PRAD, SARC, THYM). The study shows that HRD is associated with immunological activation of the tumor microenvironment only in a minority of cancer types. Our data support further studies of immune activating therapies in combination with immune checkpoint blockade in the not intrinsically activated cancer types and advocate to combine different genomic and transcriptomic biomarkers (including HRD and TMB) for comprehensive molecular diagnostics and therapy guidance. Citation Format: Jan Budczies, Klaus Kluck, Susanne Beck, Iordanis Ouralidis, Michael Allgäuer, Michael Menzel, Eugen Rempel, Daniel Kazdal, Lukas Perkhofer, Alexander Kleger, Peter Schirmacher, Thomas Seufferlein, Albrecht Stenzinger. HRD is inversely correlated with MSI and identifies immunologically cold tumors in most cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 810.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 13, No. 7 ( 2023-07-07), p. 1556-1571
    Abstract: Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non–small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. Significance: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2607892-2
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