GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    Moving Beyond Chemotherapy for Pancreaticobiliary Tumors: Targeted and Immunotherapy Strategies
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  American Society of Clinical Oncology Educational Book , No. 40 ( 2020-05), p. e333-e343
    Details
    In: American Society of Clinical Oncology Educational Book, American Society of Clinical Oncology (ASCO), , No. 40 ( 2020-05), p. e333-e343
    Abstract: Pancreaticobiliary cancers are a group of malignancies affecting the pancreas and biliary tract and are often associated with poor prognosis. Existing treatment strategies for these malignancies are limited. However, with the development of more advanced genomic analysis techniques, several mutations have been identified that may be targeted for the development of novel treatments. Key targets of interest include DNA damage repair (DDR) pathways for both pancreatic ductal adenocarcinoma (PDAC) and biliary tract cancer (BTC) as well as isocitrate dehydrogenase 1 (IDH1) and fibroblast growth factor receptor (FGFR) in BTC and mismatch repair (MMR) genes and germline mutations in PDAC. Additionally, a better understanding of the immune microenvironment of pancreatic and biliary cancers has revealed cell types and signaling pathways that may be leveraged for treatment. This includes PD-L1 and CTLA-4 immune checkpoints, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and dendritic cells (DCs). Together, targeted agents and immunotherapy strategies have the potential to significantly improve the existing treatment landscape for pancreaticobiliary cancers.
    Type of Medium: Online Resource
    ISSN: 1548-8748 , 1548-8756
    URL: Article
    DOI: 10.1200/EDBK_280901
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2431126-1
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    A phase Ib study of guadecitabine and durvalumab in patients with advanced hepatocellular carcinoma, pancreatic adenocarcinoma, and biliary cancers.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 4_suppl ( 2022-02-01), p. 574-574
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 4_suppl ( 2022-02-01), p. 574-574
    Abstract: 574 Background: Pancreatic (PC) and biliary cancers (BC) are cold tumors with limited activity of single agent immune checkpoint inhibitors. DNA methyltransferase inhibitors (DNMTi) have immunomodulatory effects manifested by upregulation of interferon pathways and expression of endogenous retroviral signatures. We performed a phase Ib study of the DNMTi guadecitabine (G) and durvalumab (D) in patients (pts) with hepatocellular carcinoma, PC and BC. We report initial results from the PC and BC cohorts. Methods: This is a phase Ib study to establish the maximum tolerated dose (MTD) of the combination (dose escalation; 3+3 design) and evaluate the objective response rate (ORR) in expansion cohorts of PC and BC. G was given at escalating doses of 30 mg/m2 and 45 mg/m2 subQ for 5 days q 28 days. D was given at 1500 mg IV on day 8 of each cycle. Expansion was started at the MTD. Eligibility criteria included ECOG 0-1, ANC ≥ 1,500, platelets 〉 100,000, albumin ≥ 2.5 g/dL, total bilirubin ≤ 2.5 x upper limit of normal, failure of ≥ 1 prior line of therapy for advanced disease. Prior anti PD-1/PDL-1 was not allowed. Tumor biopsies were performed during screening and on cycle 3 day 1. Results: A total of 11 pts were treated in dose escalation; 3 at dose level 1, and 8 (6 evaluable for DLT) at dose level 2. Given lack of dose-limiting toxicities, MTD was the highest planned dose of G at 45 mg/m2. 24 pts with PC and 23 pts with BC were treated in dose escalation and expansion. For the PC cohort: median age was 66 (43, 93), 29% female, 67% ECOG 1, and median number of prior therapies 2 (1,3). For the BC cohort: median age was 61 (41, 85), 52% female, 78% ECOG 1, and median number of prior therapies 1 (1,3). All grade treatment related AEs in ≥10% of pts were neutropenia (55%), leukopenia (50%), anemia (33%), fatigue (33%), thrombocytopenia (17%), nausea (15%), and anorexia (10%). Grade 3/4 AEs in ≥10% of pts were neutropenia (40%), leukopenia (35%), and anemia (13%). There was 1(5%) PR in PC cohort lasting 〉 24 mo and ongoing and 1(5%) in BC cohort lasting 12 mo; both were in MSS pts. SD was noted in 7/24 (29%) PC and 5/23 (22%) BC pts, 8 of which lasted ≥4 mo. Median PFS for PC and BC was 2.1 mo [1.9, 3.8] and 1.9 mo [1.4, 2] respectively. Median OS for PC and BC was 4.4 mo [3.4, NR] and 8.6 mo [6.4, NR] . Six and 12 mo OS rates are 38% [21, 66] and 27% [13, 56] for PC; 69% [52, 91] and 35% [19, 63] for BC. 4% of PC pts and 42% of BC pts received another therapy after progression. Conclusions: The combination of G and D has a manageable safety profile in pts with advanced PC and BC; grade 3/4 AEs were limited to myelosuppression. The combination had limited clinical activity based on ORR and PFS in this unselected, pretreated population; however, a subset of pts appeared to derive prolonged clinical benefit, and OS rates were comparable to standard second line chemotherapy, despite a minority of pts receiving subsequent treatment. Biomarker analyses are ongoing. Clinical trial information: NCT03257761.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.4_suppl.574
    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
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    The evolving landscape of oncolytic virotherapy (OV) clinical trials (CT): Meta-analysis.
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 15_suppl ( 2017-05-20), p. e14636-e14636
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. e14636-e14636
    Abstract: e14636 Background: The number of new OV CT have been increasing along with the evolution of cancer immunotherapy. The OVs induce direct oncolysis and enhances the host innate and adaptive immunity. There are ongoing efforts to improve the anticancer efficacy of OVs with combinational strategies. However, there has been no direct comparison of OV CTs to evaluate their different dose levels, administration routes, frequencies, and the types of OVs and combinations. Methods: A random-effect meta-analysis was performed to evaluate pooled best ORR of all the existing OV phase II and III trials from publications and presented abstracts from ASCO, AACR, and ASGCT from 1/1/2016 to 12/4/2016. MeSH term “oncolytic” was used in PubMed. The inclusion criteria were: phase II or III, solid tumor, reported ORR. We evaluated the best ORR among different viruses, DNA vs. RNA, intratumoral (IT) vs. intravenous (IV) / intra-arterial (IA), and single vs. combination. Results: From 79 publications and 176 presented abstracts identified, 6 published studies and 12 presented abstracts were selected and pooled (n=875). The best ORRs were: DNA OV 23% (15 ~ 34%) vs. RNA OV 31% (13 ~ 58%), IT 36% (23 ~ 51%) vs. IV/IA 16% (10 ~ 25%), and single agent 22% (16 ~ 31%) vs. combinations 35% (17 ~ 58%). The combination OV CTs were either with chemotherapy (n= 144), chemoradiation (n= 23), or immunotherapy (n= 69). Each OV’s ORR is summarized in the table below. Direct comparison of the secondary endpoints: clinical outcome and adverse events will be presented with the poster. In general, the OV CTs had good overall safety profile and most adverse events were less than grade 3. Conclusions: The antitumor effect of OVs against solid tumors is evident and consistent in many trials. The largest data currently available is with herpes virus and coxsackie virus appears to have the best ORR possibly due to the combination with immunotherapy. The above results confirm the promising clinical activity of novel oncolytic viral vectors both alone and in combination. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.35.15_suppl.e14636
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Characterization of TIM3 and its ligands in colorectal cancer.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 3547-3547
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 3547-3547
    Abstract: 3547 Background: TIM-3 is an inhibitory checkpoint glycoprotein found on innate and adaptive immune cells and is highly expressed on tumor infiltrating lymphocytes. TIM-3 and its ligands, Galectin 9 (Gal9), HMGB1 and CEACAM1 play a critical role in immune regulation and preclinical data suggest a role in the pathogenesis of colorectal cancer (CRC). We aimed to characterize the molecular features and prognostic value of TIM3 and its ligands in CRC. Methods: Tumor molecular profiling was performed from 15,026 FFPE samples by NextGen Sequencing on DNA (592 genes or WES) and RNA (WTS) and immunohistochemistry (IHC) at Caris Life Sciences (Phoenix, AZ). Top quartile transcripts per million (TPMs) for TIM-3, Gal9, HMGB1 and CEACAM1 were considered high (Q4) while bottom quartile low (Q1) expression (exp). X 2 /Fisher-exact tests were used for comparison and significance was determined as P-value adjusted for multiple comparison and this was found for the results reported here ( Q 〈 0.05). Cell infiltration in the tumor microenvironment (TME) was estimated by quanTIseq. Real-world overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined pts. Results: Gal 9/TIM3-high tumors had higher prevalence (prev) of high tumor mutational burden (TMB ≥ 10 Mut/Mb) (12% vs. 8%; 14% vs. 6%), deficiency in mismatch repair (dMMR) (9% vs. 5%; 10% vs. 4%), PD-L1 exp (5% vs. 3%; 7% vs. 2%), and was highest in transverse (Fold Change; FC: 1.05, 1.12) and right sided tumors (1.04, 1.10) compared to left sided tumors, and CMS4. In contrast, HMGB1 and CEACAM1-high tumors had lower prev of dMMR (5% vs. 8%, 3% vs. 12%), PD-L1 exp (3% vs. 5%, 3% vs. 6%) and TMB-H (8% vs. 11%, 6% vs. 16%), and was highest in CMS2. In MSS tumors, Gal9/TIM3-high tumors were associated (assoc) with lower frequency of TP53, amplifications (amp) of FLT1/3, CDX2, FOXO1, and CDK8 while CEACAM1 and HMGB1-high were assoc with higher mutation (mut) rates of TP53, APC, NRAS, amp of FLT1/3, CDX2, CDX8, and lower mut in GNAS, FBXW7 and RNF43. High Gal9 and TIM3 exp was assoc with higher infiltration of B cells, M1 and M2 macrophages, NK cells, CD4+ and C8+ T cells, and Tregs, while high HMGB1 and CEACAM1 exp was negatively assoc with Tregs, M1 macrophages, monocytes and CD8+ T cells. High exp of Gal9, TIM3, HMGB1, and CEACAM1 was assoc with worse OS in the entire cohort (HR 0.90, 95%CI, 0.84-0.97, P = 0.005, HR 0.81, 95% CI, 0.75-0.87, P 〈 0.00001; HR 0.88, 95% CI, 0.82-0.95, P 〈 0.001; HR 0.80; 95%CI, 0.74-0.86, P 〈 0.00003, respectively). Conclusions: Strong assoc were identified between Gal9/TIM3, HMGB1 and CEACAM1 gene exp and IO biomarkers, distinct molecular features, CMS, TME cell infiltration, and patient outcomes in CRC. Significantly different mut frequencies may signify unique subsets of CRC. These findings provide rationale for further evaluation of TIM3 and its ligands in CRC as prognostic biomarkers and potential therapeutic targets modifying the TME.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.3547
    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
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Molecular correlates of DSCR1 expression in colorectal cancer (CRC).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 4_suppl ( 2023-02-01), p. 185-185
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 4_suppl ( 2023-02-01), p. 185-185
    Abstract: 185 Background: Down syndrome (DS), a genetic disorder caused by trisomy of chr 21, is associated with a considerably lower risk for solid tumors and other angiogenesis related diseases. DSCR1 belongs to a family of evolutionary conserved protein-coding genes located on chr 21 and is highly upregulated in DS patients. Its product, calcipressin-1, has been shown to reduce cancer risk by suppressing angiogenesis. We previously reported that a germline polymorphism in DSCR1 was associated with time to recurrence in resected CRC and anti-VEGF treatment outcomes in metastatic CRC. Here, we analyzed the molecular landscape of CRC according to DSCR1 expression levels. Methods: 20,237 samples from CRC tested at Caris Life Sciences (Phoenix, AZ) with WTS (Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) were analyzed. Top quartile transcripts per million (TPM) for DSCR1 expression were considered high (Q4) while bottom quartile low (Q1). Cell infiltration (CI) in the tumor microenvironment (TME) was estimated by RNA deconvolution analysis using QuantiSEQ. Interferon-gamma and T-cell inflamed signatures were also calculated from RNA data. X 2 and Fisher-Exact tests were used and statistical significance was determined as P-value adjusted for multiple comparisons ( q 〈 0.05). Results: DSCR1 expression was higher in primary tumors than metastases (10.5 vs 8.1 median TPM, q 〈 0.05). No significant difference was observed in right- versus left-sided tumors, however rectal tumors showed the highest DSCR1 expression ( P 〈 0.05). Overall, high DSCR1 TPM were associated with TMB-high (11.3% vs 9.3%), dMMR/MSI-H (7.9% vs 5.9%), and PD-L1 (4.7% vs 3.1%) ( q 〈 0.01); the association with TMB-H was not significant in pMMR/MSS. DSCR1 high was associated with lower mutation rates of APC, KRAS, TP53 and amplification of FLT1/ FLT3, while higher mutation rates of KMT2C/D, BRAF, PTEN, RNF43, and RSPO3 fusions ( q 〈 0.0001). Gene set enrichment analysis showed that high DSCR1 expressing tumors were enriched in alterations of several pathways including hypoxia, apoptosis, DNA repair, KRAS signaling, inflammatory response, and oxidative stress-related pathways (all P 〈 0.05, FDR 〈 0.25). B cells, macrophages, neutrophils, NK cells, Tregs, cancer associated fibroblasts and endothelial cells were more abundant in the TME of tumors with high DSCR1 while myeloid dendritic cells were lower, regardless of MMR status (all q 〈 0.001). DSCR1 expression was associated with a higher T-cell inflamed signature and IFN score ( q 〈 0.05). Conclusions: This is the first and most extensive profiling study to investigate DSCR1 expression in CRC. Our data show a strong association between tumor DSCR1 gene expression and distinct molecular features and TME cell infiltration. These findings suggest that DSCR1 holds potential as a novel therapeutic target for CRC and may be an important player in TME modulation.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.4_suppl.185
    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
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    The genomic, transcriptomic, and immunological landscape of TROP2 in solid tumors.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 3118-3118
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 3118-3118
    Abstract: 3118 Background: TROP2 expression is associated with decreased overall survival in colorectal and pancreatic cancers. The antibody drug conjugate sacituzumab delivers a SN38 toxic payload to TROP2-expressing cells and is approved for the treatment of breast cancer and urothelial carcinoma. We aimed to explore the genomic and immunological landscape of TACSTD2 (TROP2-encoding gene) in different solid tumors. Methods: Tumors from breast cancer (BC, N=11,246), colorectal carcinoma (CRC, N= 15,425), liver cancer (LC, N=433), pancreatic cancer (PC, N=5,488) and urothelial carcinoma (UC, N=5,488) were assessed at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing of DNA (592-gene or whole exome) and RNA (whole transcriptome). PD-L1 (SP142; Positive (+): ≥2+, ≥5%) expression was assessed by IHC. When investigating the genomic landscape, mutation prevalence was calculated for pathogenic SNVs/indels. TACSTD2-High (H) and -Low (L) expression was defined as top and bottom quartile of TACSTD2 transcripts per million, respectively. A transcriptomic signature predictive of response to immunotherapy was applied (T cell-inflamed score [Bao, 2020]). tests were applied as appropriate, with P-values adjusted for multiple comparisons ( p 〈 .05). Real-world overall survival data was obtained from insurance claims and Kaplan-Meier estimates were calculated for molecularly defined subpopulations of patients. Results: Compared to TACSTD2-L, TACSTD2-H tumors had a higher prevalence of TP53 mutations in BC ( TACSTD2-H 59% vs -L 48%), CRC (77% vs 71%), LC (43% vs 23%) and PC (83% vs 69%), whereas UC TACSTD2-H had a lower prevalence (54% vs 67%, p 〈 .05 for all). TACSTD2-H tumors had a higher rate of KRAS mutations in CRC (55% vs 38%, p 〈 .05) and PC (96% vs 78%, p 〈 .05). In CRC, the percentage of KRAS mutations that were G12C was higher in TACSTD2-H (7.3% vs 6.4%, p 〈 .05). TACSTD2-H tumors had a higher rate of ARID1A mutations in CRC (6.7% vs 10%, p 〈 .05) and UC (29 vs 20%, p 〈 .05). A higher prevalence of PD-L1+ tumors was observed in CRC TACSTD2-H (6.4 vs 3.9%, p 〈 .05) and the opposite pattern was observed in UC (16% vs 37%, p 〈 .05). TACSTD2-H tumors were more frequently T cell-inflamed across investigated cancers (BC: TACSTD2-H 36% vs -L 19%, CRC: 29% vs 14%, LC: 54% vs 10%, PC: 42% vs 20%, UC: 32% vs 28%, all p 〈 .05). TACSTD2-H was associated with worse overall survival in PC (HR 1.31 [1.19-1.44], p 〈 .001), BC (HR 1.13 [1.03-1.23], p 〈 .007) and CRC (HR 1.33 [1.24-1.42], p 〈 .001), while this association was not observed in UC (HR .98 [.86-1.12], p = .75) or LC (HR 1.14[.82-1.57] , p = .44). Conclusions: The association of TACSTD2 expression with KRAS, TP53 and ARID1A mutations and T cell-inflamed tumors (ICI responsive) should be considered as possible combination therapies with TROP2 targeting antibody drug conjugates are investigated.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.3118
    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
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    Molecular and clinical correlates of DSCR1 expression in pancreatic cancer (PDAC).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 4151-4151
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 4151-4151
    Abstract: 4151 Background: Individuals with Down syndrome (DS) have a lower risk for solid tumors and angiogenesis related diseases. DSCR1 is highly upregulated in DS patients and its product, calcipressin-1, was shown to suppress angiogenesis and reduce cancer risk. High DSCR1 expression has been reported to decrease PDAC growth and metastasis in animal models. Here, we analyzed the molecular features and clinical outcomes associated with DSCR1 gene expression in PDAC. Methods: 8352 tumor samples tested at Caris Life Sciences (Phoenix, AZ) with WTS (Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) were analyzed. Top quartile transcripts per million for DSCR1 expression were considered high (Q4) while bottom quartile low (Q1). Cell infiltration in the tumor microenvironment (TME) was estimated using QuantiSEQ. Interferon-gamma (IFG) and T-cell inflamed (TIS) signatures were calculated from RNA data. Statistical significance was determined as P-value adjusted for multiple comparisons ( q 〈 .05). Real world survival was obtained from insurance claims data ( N = 4223) and Kaplan-Meier estimates were calculated. Results: DSCR1 expression was higher in primary tumors than metastases ( q 〈 .05). No significant differences were observed between high vs low DSCR1 PDAC in immune-related biomarkers (TMB, dMMR/MSI-H and PD-L1 protein), gene mutations and copy number alterations except for KRAS mutations which were more frequent in DSCR1 Q4 (93 vs 86%, Q4 vs Q1, q 〈 .0001). Gene set enrichment analysis showed that DSCR1 high tumors were enriched in alterations of several pathways including NOTCH signaling, DNA repair, IFG response, myogenesis and adipogenesis ( P 〈 .05, false discovery rate 〈 .25). B cells, M1 and M2 macrophages, neutrophils, NK cells, and Tregs were more abundant in the TME of tumors with high DSCR1 while dendritic cells, CD4+ T cells and monocytes were lower ( q 〈 .05). DSCR1 Q4 was associated with higher TIS score (50% inflamed vs 3.6%, q 〈 .05) and positively associated with immune-related gene expression including CTLA4, IDO1, CD80, PD-L1, LAG3, CD86, TIM3, IFG, PD-1, and PD-L2 (fold change: 2-4, q 〈 .0001). Overall, DSCR1 expression above median was associated with longer median OS (17 vs 11 months, HR 0.89 [0.83-0.95], P 〈 .0001). When stratified by quartiles, DSCR1 Q4 was associated with longer time on treatment [ToT] with gemcitabine/nab-paclitaxel (HR 0.75 [0.63-0.89] , P = .001), and marginal benefit on ToT (HR 0.81 [0.65-1.0]) but longer survival in FOLFIRINOX treated patients (HR 0.73 [0.58-0.92] , P = .008). Conclusions: This is the first and most extensive profiling study to investigate DSCR1 expression in PDAC. Our data show a strong association between tumor DSCR1 gene expression, several pathway alterations, immune-related gene expression, TME cell infiltration and patient survival. These findings suggest DSCR1 as a candidate prognostic biomarker and as a potential treatment target in PDAC.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.4151
    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
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    Comprehensive profiling of clock genes expression in colorectal cancer (CRC).
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 3129-3129
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 3129-3129
    Abstract: 3129 Background: Disruption of the circadian clock has been linked to cancer risk, development and progression. Core clock proteins are emerging as novel therapeutic targets in cancer. We previously showed that polymorphisms in clock genes were associated with anti-VEGF treatment outcome in metastatic CRC. Here we further evaluated the molecular landscape of clock pathway alterations in CRC. Methods: 7591 CRC tested at Caris Life Sciences (Phoenix, AZ) with WTS (Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) were analyzed. Clock gene Score (CS) was determined using expression of core clock genes Z scores (positives of CLOCK, ARNTL, RORA/B/C and negatives of repressors CRY1/2, PER1/2/3, REVERBA/B) stratified by quartiles. xCell was used to quantify cell infiltration in the tumor microenvironment (TME). Consensus molecular subtypes (CMS) were assessed by RNAseq. Significance was determined as P-values adjusted for multiple testing ( q) of 〈 .05. Real world survival was obtained from insurance claims data and Kaplan-Meier estimates were calculated for comparison. Results: CS was higher in primary tumors than metastases and in right- than left-sided CRC ( P 〈 .001). Liver metastases were associated with lower CS (23% Q1 vs 19% Q4, P 〈 .001). CS was positively associated with CMS1 and 3 (21 vs 11% and 23 vs 9%, respectively, Q4 vs Q1) and negatively correlated with CMS2 and 4 (22 vs 32% and 34 vs 48%) (all P 〈 .001). These associations were confirmed in mismatch repair proficient (pMMR) tumors. Overall, TMB-H and dMMR/MSI-H were positively associated with CS (11 vs 6% and 8 vs 4%, Q4 vs Q1, q 〈 .0001) and PD-L1 showed a similar trend ( P 〈 .01, q =.06); the association with TMB-H was not significant in pMMR. High CS was associated with alterations of genes in WNT signaling, RAS, PI3K, TGF-β, and NOTCH pathways, while negatively associated with TP53 mutations, HER2 expression and CDX2 copy numbers, confirmed in pMMR (all q 〈 .05). CS negatively correlated with the angiogenesis pathway signature (Q1 vs Q4 Z score: 6.6 vs -4.6, P 〈 .001). B cells, M1 and M2 macrophages, neutrophils, NK, Tregs, CD4+ and CD8+ T cells, and myeloid dendritic cells were more abundant in the TME of tumors with high CS while cancer associated fibroblasts were lower, regardless of MMR status (all q 〈 .001). Individually, ARNTL tumor expression below median was associated with better OS (overall: HR 0.88, 95% CI [0.82-0.94]; pMMR: HR 0.88 [0.81-0.94] ) and longer time on treatment of bevacizumab (overall: HR 0.91 [0.83-0.99]; pMMR: HR 0.91 [0.83-0.99] ). Conclusions: This is the most extensive profiling study to investigate the expression of clock genes in CRC. Our data show that clock genes expression is strongly associated with distinct molecular features, immune cell infiltration, angiogenesis pathway enrichment and patient outcomes. These findings support the clock pathway as a therapeutic target in CRC, with a major role in CRC biology and TME modulation.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.3129
    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
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    Single center real-world treatment and outcomes in patients with hepatocellular carcinoma receiving immunotherapy.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. e16134-e16134
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e16134-e16134
    Abstract: e16134 Background: Immune checkpoint inhibitor (ICI) based therapy has emerged as a therapeutic option in hepatocellular carcinoma (HCC), both in combination (IC-C) and as single agent (IC-SA). Approvals were based on clinical trials with strict eligibility criteria limiting generalizability to the entire spectrum of clinical practice. Survival outcomes have not been evaluated in a real-world population and there is no established post ICI treatment standard. Methods: Patients (pts) with advanced HCC treated with ICI across lines of therapy were included in this retrospective study. Data regarding demographics, comorbidities, HCC etiology, liver function (Child Pugh Score [CPS] and ALBI Grade [G] ), tumor burden, AFP, treatments, reason for discontinuation (dc) and outcomes were collected. Descriptive statistics and survival analysis were performed using Stata with cox regression analysis. Results: The cohort consisted of 138 pts: median age 63 years (24,95); 83% male; 38% Hispanic/Latino, 27% Asian, 17% Non-Hispanic White, 4% Black and 14% other/unknown. Etiology of cirrhosis: 16% Hepatitis B, 38% Hepatitis C, 12% alcohol liver disease, 9% NAFLD and 24 % mixed/other; Baseline CPS were 74% CPA, 23% CPB, and 2% CPC; ALBI Scores were G1 in 35%, G2 in 53%, and G3 in 12% pts; 62% had extrahepatic disease and/or portal invasion; AFP was ≥ 400ng/mL in 30% of pts. 88% of pts had prior local therapy. For the entire cohort, first line systemic therapy consisted of 52% ICI (18% IC-C and 34% IC-SA) and 48% TKI. mOS was 12 months (mo) (0,74) for first line ICI group and 19.5 mo (3,78) in those with first line TKI. In CPA pts, first line therapy was 51% ICI (24% IC-C and 27% IC-SA) and 39% TKI. 79% of CPA patients received ≥ 2 lines of therapy with second line consisting of 65% ICI and 20% TKI. First line therapy for pts with CPB cirrhosis was 58% ICI (2% IC-C and 55% IC-SA) and 42% TKI. 55% of CPB patients received ≥ 2 lines of therapy and second line therapy for CPB pts included 71% ICI and 18% TKI. mOS was 18 mo in CPA pts and 10 mo in CPB pts. Cirrhosis related complications resulted in treatment discontinuation in 2% of CPA pts vs. 14% of CPB pts. On multivariable analysis, Asian ethnicity (HR 0.41 p = 0.006), CPS (HR 1.64 p = 0.027), and number of treatment lines (HR 0.74 p = 0.005) were associated with OS. Conclusions: This single institution real-world cohort highlights the reality of sequential therapy in pts with advanced HCC. Survival outcomes in our CPA cohort are comparable to data from recent phase 3 trials. The survival in our CPB cohort in a tertiary care setting compares favorably with available data from clinical trials and suggests the feasibility of sequential and effective anti-cancer therapy in this population. Liver function, Asian ethnicity, and number of treatment lines are independent predictors of OS in this cohort of HCC patients receiving ICI. Prospective studies related to optimal treatment sequence and to CPB pts are needed.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.e16134
    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
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    Predictive value of MAOB gene expression for targeted therapy in patients (pts) with metastatic colorectal cancer (mCRC) enrolled in CALGB (Alliance)/SWOG 80405.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 3580-3580
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 3580-3580
    Abstract: 3580 Background: Monoamine oxidases (MAOs), including MAOA and MAOB, are mitochondrial enzymes responsible for catalyzing monoamine oxidation. Increased expression of MAOs were found in several cancer types and high MAOB was associated with worse disease stage and poorer survival in CRC. Positive and negative correlations of MAOB expression with mesenchymal type and epithelial type gene expressions, respectively, have been reported. Hence, we investigated whether MAOB expression is predictive for targeted therapies in mCRC. Methods: 430 mCRC pts treated with either bevacizumab (BEV, n = 224) or cetuximab (CET, n = 206) in combination with first-line chemotherapy within the CALGB/SWOG 80405 trial were included in the analysis. MAOB RNA was isolated from FFPE tumor samples and sequenced on the HiSeq 2500 (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared between groups of pts categorized by tertiles of MAOB expression into high (H), medium (M) and low (L). Hazard ratios (HR) and 95% confidence intervals (CI) were computed from multivariable Cox proportional hazards model, adjusting for age, sex, location, number of metastases, KRAS, MSI status, and treatment with FOLFOX or FOLFIRI. Sensitivity analyses were conducted after stratifying by sex. Logrank P-values describe differences without adjustment for patient characteristics. Results: In CET-treated pts, MAOB-L showed significantly longer OS (median 39.2 vs 30.9 vs 15.9 months, logrank P = 4.7E-05, L vs H (as reference) adjusted HR 0.42, 95% CI [0.27, 0.65]) and PFS (median 13.2 vs 11.8 vs 7.6 months, logrank P = 0.006, L vs H adjusted HR 0.59 [0.40, 0.88] ) compared to MAOB-M and MAOB-H, respectively. Similar results were observed when evaluating MAOB expression as a continuous variable. In BEV-treated pts, no significant differences were observed when comparing MAOB expression tertiles; however, pts with lower MAOB expression had significantly better OS, but not PFS, when evaluating MAOB as a continuous variable (Cox LRT P = 0.015, covariate adjusted). In CET-treated pts, the effect of MAOB expression was observed in male but not female pts (OS: median 40.3 vs 30.9 vs 16.1 months by MAOB-L, M, H, respectively, logrank P = 6.8E-05, L vs H adjusted HR 0.33 [0.19, 0.59]; PFS: median 13.8 vs 12.6 vs 7.9 months, logrank P = 0.001, L vs H adjusted HR 0.46 [0.28, 0.79] ). A significant interaction was observed between MAOB expression and treatment for OS ( P = 0.010) in males and females combined, but only in males ( P = 0.018) when stratified by sex. Conclusions: Our results suggest that pts with MAOB-L tumors may have greater benefit from CET-based treatment and that targeting MAOB may be a promising strategy to improve patient outcomes. Further validation studies are warranted to develop a novel personalized approach based on MAOB expression in mCRC pts. Clinical trial information: NCT00265850.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.3580
    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
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...