| 1. |
- Bremer, Troy, et al.
(författare)
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A Biological Signature for Breast Ductal Carcinoma In Situ to Predict Radiotherapy Benefit and Assess Recurrence Risk
- 2018
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 24:23, s. 5895-5901
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Ductal carcinoma in situ (DCIS) patients and their physicians currently face challenging treatment decisions with limited information about the individual's subsequent breast cancer risk or treatment benefit. The DCISionRT biological signature developed in this study provides recurrence risk and predicts radiotherapy (RT) benefit for DCIS patients following breast-conserving surgery (BCS).EXPERIMENTAL DESIGN: A biological signature that calculates an individualized Decision Score (DS) was developed and cross-validated in 526 DCIS patients treated with BCS ± RT. The relationship was assessed between DS and 10-year risk of invasive breast cancer (IBC) or any ipsilateral breast event (IBE), including IBC or DCIS. RT benefit was evaluated by risk group and as a function of DS.RESULTS: The DS was significantly associated with IBC and IBE risk, HR (per 5 units) of 4.2 and 3.1, respectively. For patients treated without RT, DS identified a Low Group with 10-year IBC risk of 4% (7% IBE) and an Elevated Risk Group with IBC risk of 15% (23% IBE). In analysis of DS and RT by group, the Elevated Risk Group received significant RT benefit, HR of 0.3 for IBC and IBE. In a clinicopathologically low-risk subset, DS reclassified 42% of patients into the Elevated Risk Group. In an interaction analysis of DS and RT, patients with elevated DS had significant RT benefit over baseline.CONCLUSIONS: The DS was prognostic for risk and predicted RT benefit for DCIS patients. DS identified a clinically meaningful low-risk group and a group with elevated 10-year risks that received substantial RT benefit over baseline.
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| 2. |
- Grövdal, Michael, et al.
(författare)
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Negative effect of DNA hypermethylation on the outcome of intensive chemotherapy in older patients with high-risk myelodysplastic syndromes and acute myeloid leukemia following myelodysplastic syndrome
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:23, s. 7107-7112
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Promoter hypermethylation of, for example, tumor-suppressor genes, is considered to be an important step in cancerogenesis and a negative risk factor for survival in patients with myelodysplastic syndromes (MDS); however, its role for response to therapy has not been determined. This study was designed to assess the effect of methylation status on the outcome of conventional induction chemotherapy. EXPERIMENTAL DESIGN: Sixty patients with high-risk MDS or acute myeloid leukemia following MDS were treated with standard doses of daunorubicin and 1-beta-d-arabinofuranosylcytosine. Standard prognostic variables and methylation status of the P15(ink4b) (P15), E-cadherin (CDH), and hypermethylated in cancer 1 (HIC) genes were analyzed before treatment. RESULTS: Forty percent of the patients achieved complete remission (CR). CR rate was lower in patients with high WBC counts (P = 0.03) and high CD34 expression on bone marrow cells (P = 0.02). Whereas P15 status alone was not significantly associated with CR rate (P = 0.25), no patient with hypermethylation of all three genes achieved CR (P = 0.03). Moreover, patients with CDH methylation showed a significantly lower CR rate (P = 0.008), and CDH methylation retained its prognostic value also in the multivariate analysis. Hypermethylation was associated with increased CD34 expression, but not with other known predictive factors for response, such as cytogenetic profile. CONCLUSIONS: We show for the first time a significant effect of methylation status on the outcome of conventional chemotherapy in high-risk MDS and acute myelogenous leukemia following MDS. Provided confirmed in an independent study, our results should be used as a basis for therapeutic decision-making in this patient group.
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| 3. |
- Humphries, Matthew P., et al.
(författare)
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A case-matched gender comparison transcriptomic screen identifies eIF4E and eIF5 as potential prognostic markers in male breast cancer
- 2017
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 23:10, s. 2575-2583
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar. Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico. Biomarkers were immunohistochemically assessed in 697 MBCs (n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor. Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed (P = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival. Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required.
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| 4. |
- Indira Chandran, Vineesh, et al.
(författare)
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Ultrasensitive Immunoprofiling of Plasma Extracellular Vesicles Identifies Syndecan-1 as a Potential Tool for Minimally Invasive Diagnosis of Glioma
- 2019
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 25:10, s. 3115-3127
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Liquid biopsy has great potential to improve the management of brain tumor patients at high risk of surgery-associated complications. Here, the aim was to explore plasma extracellular vesicle (plEV) immunoprofiling as a tool for noninvasive diagnosis of glioma.Experimental Design: PlEV isolation and analysis were optimized using advanced mass spectrometry, nanoparticle tracking analysis, and electron microscopy. We then established a new procedure that combines size exclusion chromatography isolation and proximity extension assay-based ultrasensitive immunoprofiling of plEV proteins that was applied on a well-defined glioma study cohort (n = 82).Results: Among potential candidates, we for the first time identify syndecan-1 (SDC1) as a plEV constituent that can discriminate between high-grade glioblastoma multiforme (GBM, WHO grade IV) and low-grade glioma [LGG, WHO grade II; area under the ROC curve (AUC): 0.81; sensitivity: 71%; specificity: 91%]. These findings were independently validated by ELISA. Tumor SDC1 mRNA expression similarly discriminated between GBM and LGG in an independent glioma patient population from The Cancer Genome Atlas cohort (AUC: 0.91; sensitivity: 79%; specificity: 91%). In experimental studies with GBM cells, we show that SDC1 is efficiently sorted to secreted EVs. Importantly, we found strong support of plEVSDC1 originating from GBM tumors, as plEVSDC1 correlated with SDC1 protein expression in matched patient tumors, and plEVSDC1 was decreased postoperatively depending on the extent of surgery.Conclusions: Our studies support the concept of circulating plEVs as a tool for noninvasive diagnosis and monitoring of gliomas and should move this field closer to the goal of improving the management of cancer patients.
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| 5. |
- Karlsson, Anna K, et al.
(författare)
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Genomic and transcriptional alterations in lung adenocarcinoma in relation to smoking history.
- 2014
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 20:18, s. 4912-4924
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Cigarette smoking is the major pathogenic factor for lung cancer. The precise mechanisms of tobacco-related carcinogenesis, and its effect on the genomic and transcriptional landscape in lung cancer are not fully understood. Experimental Design 1398 (277 never-smokers, 1121 smokers) genomic and 1449 (370 never-smokers, 1079 smokers) transcriptional profiles were assembled from public lung adenocarcinoma cohorts, including matched next-generation DNA-sequencing data (n=423). Unsupervised and supervised methods were used to identify smoking-related copy number alterations (CNAs), predictors of smoking status, and molecular subgroups. Results Genomic meta-analyses showed that never-smokers and smokers harbored a similar frequency of total CNAs, although, specific regions (5q, 8q, 16p, 19p, and 22q) displayed a 20-30% frequency difference between the two groups. Importantly, supervised classification analyses based on CNAs or gene expression could not accurately predict smoking status (balanced accuracies ~60-80%). However, unsupervised multicohort transcriptional profiling stratified adenocarcinomas into distinct molecular subgroups with specific patterns of CNAs, oncogenic mutations, and mutation transversion frequencies that were independent of the smoking status. One subgroup included ~55-90% of never-smokers and ~20-40% of smokers (both current and former) with molecular and clinical features of a less aggressive and smoking-unrelated disease. Given the considerable intra-group heterogeneity in smoking-defined subgroups, especially among former-smokers, our results emphasize the clinical importance of accurate molecular characterization of lung adenocarcinoma. Conclusions The landscape of smoking-related CNAs and transcriptional alterations in adenocarcinomas is complex, heterogeneous, and with moderate differences. Our results support a molecularly distinct less aggressive adenocarcinoma entity, arising in never-smokers and a subset of smokers.
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| 6. |
- Mangsbo, Sara M, et al.
(författare)
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The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T cell dependent tumor immunity.
- 2015
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 21:5, s. 1115-1126
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013. Experimental Design: We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 has been investigated in human and murine in vitro models. The in vivo effect has been investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse. Results: Activation of dendritic cells (DCs) by ADC-1013 results in up-regulation of the co-stimulatory molecules CD80 and CD86, and secretion of IL-12. ADC-1013 also activates dendritic cells from human CD40 transgenic mice, and peptide-pulsed and ADC-1013-stimulated dendritic cells induce antigen-specific T cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant anti-tumor effects and long-term tumor-specific immunity. Further, ADC-1013 demonstrates significant anti-tumor effects in a human bladder cancer transplanted into immunodeficient NSG mice. Conclusions: Our data demonstrate that ADC-1013 induces long-lasting anti-tumor responses and immunological memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer.
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| 7. |
- Wahlin, Björn Engelbrekt, et al.
(författare)
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T Cells in Tumors and Blood Predict Outcome in Follicular Lymphoma Treated with Rituximab
- 2011
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Ingår i: Clinical Cancer Research. - : American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 17:12, s. 4136-4144
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: T cells influence outcome in follicular lymphoma, but their contributions seem to be modified by therapy. Their impact in patients receiving rituximab without chemotherapy is unknown. EXPERIMENTAL DESIGN: Using flow cytometry, we evaluated the T cells in tumors and/or blood in a total of 250 follicular lymphoma patients included in two Nordic Lymphoma Group randomized trials that compared single rituximab with IFN-α2a-rituximab combinations. RESULTS: In univariate analysis, higher levels of CD3(+), CD4(+), and CD8(+) T cells in both tumors and blood correlated with superior treatment responses, and in multivariate analysis, tumor-CD3(+) (P = 0.011) and blood-CD4(+) (P = 0.029) cells were independent. CD4(+) cells were favorable regardless of treatment arm, but CD8(+) cells were favorable only in patients treated with single rituximab, because IFN-α2a improved responses especially in patients with low CD8(+) cell levels. Higher levels of blood-CD3(+) (P = 0.003) and blood-CD4(+) (P = 0.046) cells predicted longer overall survival, and higher levels of blood-CD8(+) cells longer times to next treatment (P = 0.046). CONCLUSIONS: We conclude that therapeutic effects of rituximab are augmented by tumor-associated T cells for rapid responses and by systemic T cells for sustained responses. CD4(+) and CD8(+) cells are both favorable in patients treated with rituximab. IFN-α2a abrogates the negative impact of few CD8(+) cells.
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| 8. |
- Xochelli, Aliki, et al.
(författare)
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Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors : Shared and Distinct Immunogenetic Features and Clinical Outcomes
- 2017
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 23:17, s. 5292-5301
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication. Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes. Results: We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (P < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). Conclusions: Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management.
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| 9. |
- Mehic, Merima, Sr., et al.
(författare)
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The role of deubiquitinating enzyme USP17, hyaluronan synthase 2, and hyaluronan in non-small-cell lung cancer oncogenic transformation
- 2018
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 24:1, s. 96-96
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Lung cancer is the result of a multistep accumulation of genetic and/or epigenetic alterations; therefore, a better understanding of the molecular mechanism by which these alterations affect lung cancer pathogenesis would provide new diagnostic procedures and prognostic factors for early detection of recurrence. The remarkable qualitative and quantitative modifications of extracellular matrix components as the deubiquitinating enzyme (USP17), hyaluronan (HA), and hyaluronan synthases 2 (HAS 2) may favor invasion, cellular motility, and proliferation in several cancers including lung.Results: The silencing of USP17 led to decreased hyaluronan production, whereas the suppression of USP4 increased hyaluronan synthesis. Importantly, high levels of USP17 and HAS2 were detected in a panel of cancer cell lines compared to normal cells, and immunohistochemical stainings revealed higher expression of USP17 and HAS2 in tissues of lung cancer patients compared to normal tissue. Numerous epithelial cells expressed USP17 and HAS2 in dysplasia compared to squamous cell carcinoma (SqCC) (p=0.001). USP17 and HAS2 were prominently expressed in adenocarcinoma (ADC) (p≤0.005). HA immunostaining indexes were increased in ADC and SqCC compared to normal and dysplasia cells (p=0.05). Consistent with the immunohistochemical analyses, low amounts of hyaluronan and USP17 were observed in SqCC by confocal analysis, coincident with less colocalization as determined by confocal microscopy. In contrast, a high expression of hyaluronan (48% of positive index) and high USP17 expression (78% of positive index) in ADC was consistent with a higher degree of colocalization.Conclusions: HAS2, hyaluronan and USP17 were expressed at higher levels in particular in preneoplastic lesions and ADC, suggesting a role in NSCLC oncogenic transformation, possibly by promoting cellular division by USP17-mediated. Elucidation of the mechanism of how USP17 and HAS2 cooperate in the regulation of the cell cycle might be of therapeutic importance.
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| 10. |
- Aaltonen, Kirsimari, et al.
(författare)
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Familial breast cancers without mutations in BRCA1 or BRCA2 have low cyclin E and high cyclin D1 in contrast to cancers in BRCA mutation carriers
- 2008
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 14:7, s. 1976-83
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: We analyzed the expression of critical cell cycle regulators cyclin E and cyclin D1 in familial breast cancer, focusing on BRCA mutation-negative tumors. Cyclin E expression in tumors of BRCA1 or BRCA2 carriers is higher, and cyclin D1 expression lower, than in sporadic tumors. In familial non-BRCA1/2 tumors, cyclin E and cyclin D1 expression has not been studied. EXPERIMENTAL DESIGN: Cyclin E and cyclin D1 immunohistochemical expression was studied in tissue microarrays consisting of 53 BRCA1, 58 BRCA2, 798 familial non-BRCA1/2, and 439 sporadic breast tumors. RESULTS: In univariate analysis, BRCA1 tumors had significantly more frequently high cyclin E (88%) and low cyclin D1 (84%) expression than sporadic (54% and 49%, respectively) or familial non-BRCA1/2 (38% and 45%, respectively) tumors. BRCA2 tumors had significantly more frequently low cyclin D1 expression (68%) than sporadic or familial non-BRCA1/2 tumors and significantly more frequently high cyclin E expression than familial non-BRCA1/2 tumors. In a logistic regression model, cyclin expression, early age of onset, and estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) status were the independent factors most clearly distinguishing tumors of BRCA1 mutation carriers from other familial breast cancers. High cyclin E and low cyclin D1 expression were also independent predictors of BRCA2 mutation when compared with familial non-BRCA1/2 tumors. Most interestingly, lower frequency of high cyclin E expression independently distinguished familial non-BRCA1/2 tumors also from sporadic ones. CONCLUSIONS: Cyclin E and cyclin D1 expression distinguishes non-BRCA1/2 tumors from both sporadic and BRCA1- and BRCA2-associated tumors and may reflect different predisposition and pathogenesis in these groups.
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