| 1. |
- Brand, Judith S, et al.
(författare)
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Chemotherapy, genetic susceptibility, and risk of venous thromboembolism in breast cancer patients
- 2016
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Ingår i: Clinical Cancer Research. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 1078-0432. ; 22:21, s. 5249-5255
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Venous thromboembolism (VTE) is highly heritable and a serious complication of cancer and its treatment. We examined the individual and joint effects of chemotherapy and genetic susceptibility on VTE risk in patients with breast cancer. Experimental design: A Swedish population-based study including 4,261 women diagnosed with primary invasive breast cancer between 2001 and 2008 in Stockholm, followed until 2012. Risk stratification by chemotherapy and genetic susceptibility [a polygenic risk score (PRS), including nine established VTE loci] was assessed using Kaplan-Meier and flexible parametric survival analyses, adjusting for patient, tumor, and treatment characteristics. Results: In total, 276 patients experienced a VTE event during a median follow-up of 7.6 years. Patients receiving chemotherapy [HR (95% CI) = 1.98; 1.40-2.80] and patients in the highest 5% of the PRS [HR (95% CI) = 1.90; 1.24-2.91] were at increased risk of developing VTE. Chemotherapy and PRS acted independently on VTE risk and the 1-year cumulative incidence in patients carrying both risk factors was 9.5% compared with 1.3% in patients not having these risk factors (P < 0.001). Stratified analyses by age showed that the risk-increasing effect of PRS was stronger in older patients (P interaction = 0.04), resulting in an excess risk among genetically susceptible patients receiving chemotherapy aged ≥ 60 years (1-year cumulative incidence = 25.0%). Conclusions: Risk stratification by chemotherapy and genetic susceptibility identifies patients with breast cancer at high VTE risk, who could potentially benefit from thromboprophylaxis. Our results further suggest that genetic testing is more informative in older patients with breast cancer.
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| 2. |
- Arbajian, Elsa, et al.
(författare)
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In-depth genetic analysis of sclerosing epithelioid fibrosarcoma reveals recurrent genomic alterations and potential treatment targets
- 2017
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 23:23, s. 7426-7434
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Sclerosing epithelioid fibrosarcoma (SEF) is a highly aggressive soft tissue sarcoma closely related to low-grade fibromyxoid sarcoma (LGFMS). Some tumors display morphological characteristics of both SEF and LGFMS, so called hybrid SEF/LGFMS. Despite the overlap of gene fusion variants between these two tumor types, SEF is much more aggressive. The present study aimed to further characterize SEF and hybrid SEF/LGFMS genetically in order to better understand the role of the characteristic fusion genes and possible additional genetic alterations in tumorigenesis.EXPERIMENTAL DESIGN: We performed whole exome sequencing, single nucleotide polymorphism (SNP) array analysis, RNA-sequencing (RNA-seq), global gene expression analyses and/or IHC on a series of 13 SEFs and 6 hybrid SEF/LGFMS. We also expressed the FUS-CREB3L2 and EWSR1-CREB3L1 fusion genes conditionally in a fibroblast cell line; these cells were subsequently analyzed by RNA-seq and expression of the CD24 protein was assessed by FACS analysis.RESULTS: The SNP array analysis detected a large number of structural aberrations in SEF and SEF/LGFMS, many of which were recurrent, notably DMD microdeletions. RNA-seq identified FUS-CREM and PAX5-CREB3L1 as alternative fusion genes in one SEF each. CD24 was strongly upregulated, presumably a direct target of the fusion proteins. This was further confirmed by the gene expression analysis and FACS analysis on Tet-On 3G cells expressing EWSR1-CREB3L1.CONCLUSIONS: While gene fusions are the primary tumorigenic events in both SEF and LGFMS, additional genomic changes explain the differences in aggressiveness and clinical outcome between the two types. CD24 and DMD constitute potential therapeutic targets.
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| 3. |
- 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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| 4. |
- Candido-dos-Reis, Francisco J, et al.
(författare)
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Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer
- 2015
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 21:3, s. 7-652
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis.EXPERIMENTAL DESIGN: We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model.RESULTS: The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%-31%] for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer-specific mortality.CONCLUSIONS: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.
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| 5. |
- Gruvberger, Sofia, et al.
(författare)
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Estrogen receptor beta expression is associated with tamoxifen response in ER alpha-negative breast carcinoma
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 13:7, s. 1987-1994
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Endocrine therapies, such as tamoxifen, are commonly given to most patients with estrogen receptor (ERalpha)-positive breast carcinoma but are not indicated for persons with ERalpha-negative cancer. The factors responsible for response to tamoxifen in 5% to 10% of patients with ERalpha-negative tumors are not clear. The aim of the present study was to elucidate the biology and prognostic role of the second ER, ERbeta, in patients treated with adjuvant tamoxifen.EXPERIMENTAL DESIGN: We investigated ERbeta by immunohistochemistry in 353 stage II primary breast tumors from patients treated with 2 years adjuvant tamoxifen, and generated gene expression profiles for a representative subset of 88 tumors.RESULTS: ERbeta was associated with increased survival (distant disease-free survival, P = 0.01; overall survival, P = 0.22), and in particular within ERalpha-negative patients (P = 0.003; P = 0.04), but not in the ERalpha-positive subgroup (P = 0.49; P = 0.88). Lack of ERbeta conferred early relapse (hazard ratio, 14; 95% confidence interval, 1.8-106; P = 0.01) within the ERalpha-negative subgroup even after adjustment for other markers. ERalpha was an independent marker only within the ERbeta-negative tumors (hazard ratio, 0.44; 95% confidence interval, 0.21-0.89; P = 0.02). An ERbeta gene expression profile was identified and was markedly different from the ERalpha signature.CONCLUSION: Expression of ERbeta is an independent marker for favorable prognosis after adjuvant tamoxifen treatment in ERalpha-negative breast cancer patients and involves a gene expression program distinct from ERalpha. These results may be highly clinically significant, because in the United States alone, approximately 10,000 women are diagnosed annually with ERalpha-negative/ERbeta-positive breast carcinoma and may benefit from adjuvant tamoxifen.
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| 6. |
- 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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| 7. |
- Gustafsson, Anna, et al.
(författare)
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Differential expression of Axl and Gas6 in renal cell carcinoma reflecting tumor advancement and survival
- 2009
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Ingår i: Clinical Cancer Research. - : American association for cancer research. - 1078-0432 .- 1557-3265. ; 15:14, s. 4742-4749
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Overexpression of the receptor tyrosine kinase Axl is implicated in several cancers. Therefore, we conducted this study to determine the expression of Axl and its ligand Gas6 in various renal cell carcinoma (RCC) types and in oncocytoma. EXPERIMENTAL DESIGN: Real-time quantitative reverse transcription-PCR was used to quantify tumor mRNA levels for Axl and Gas6 in a cohort (n = 221) of RCC patients. Serum levels of soluble sAxl and Gas6 proteins were measured using specific ELISA assays (n = 282). The presence of Axl protein in tumor tissue was evaluated by immunohistochemistry (n = 294). Results were correlated to tumor-associated variables, clinical biochemical tests, and patient survival. RESULTS: Tumor Axl mRNA levels correlated independently to survival when assessed against tumor stage and grade. In the study group, the median cancer-specific survival of all RCC patients during 307 months of follow-up was 55 months (confidence interval, +/-40.4). The 25% of patients with lowest tumor Axl mRNA levels had significantly better survival than the rest (P = 0.0005), with 70% of the patients still alive at the end of follow-up. In contrast, in patients with medium-high Axl mRNA, only 25% were alive at the end of follow-up. Tumor Gas6 mRNA levels correlated to survival, tumor-associated variables, and disease severity as did serum levels of soluble sAxl and Gas6 protein. However, no correlation between Axl protein in tumor tissue and survival was found. CONCLUSIONS: Axl and Gas6 expression in RCC are associated with tumor advancement and patient survival. In particular, low tumor Axl mRNA levels independently correlated with improved survival.
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| 8. |
- Harbst, Katja, et al.
(författare)
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Molecular profiling reveals low- and high-grade forms of primary melanoma.
- 2012
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1557-3265. ; 18:15, s. 4026-4036
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Tidskriftsartikel (refereegranskat)abstract
- For primary melanomas, tumor thickness, mitotic rate, and ulceration are well-laid cornerstones of prognostication. However, a molecular exposition of melanoma aggressiveness is critically missing. We recently uncovered a four-class structure in metastatic melanoma, which predicts outcome and informs biology. This raises the possibility that a molecular structure exists even in the early stages of melanoma and that molecular determinants could underlie histophenotype and eventual patient outcome.We subjected 223 archival primary melanomas to a horizontally integrated analysis of RNA expression, oncogenic mutations at 238 lesions, histomorphometry, and survival data.Our previously described four-class structure that was elucidated in metastatic lesions was evident within the expression space of primary melanomas. Because these subclasses converged into two larger prognostic and phenotypic groups, we used the metastatic lesions to develop a binary subtype-based signature capable of distinguishing between "high" and "low" grade forms of the disease. The two-grade signature was subsequently applied to the primary melanomas. Compared with low-grade tumors, high-grade primary melanomas were significantly associated with increased tumor thickness, mitotic rate, ulceration (all P < 0.01), and poorer relapse-free (HR = 4.94; 95% CI, 2.84-8.59), and overall (HR = 3.66; 95% CI, 2.40-5.58) survival. High-grade melanomas exhibited elevated levels of proliferation and BRCA1/DNA damage signaling genes, whereas low-grade lesions harbored higher expression of immune genes. Importantly, the molecular-grade signature was validated in two external gene expression data sets.We provide evidence for a molecular organization within melanomas, which is preserved across all stages of disease.
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| 9. |
- Rastegar, Bahar, et al.
(författare)
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Resolving the Pathogenesis of Anaplastic Wilms Tumors through Spatial Mapping of Cancer Cell Evolution
- 2023
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 29:14, s. 2668-2677
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: While patients with intermediate-risk (IR) Wilms tumors now have an overall survival (OS) rate of almost 90%, those affected by high-stage tumors with diffuse anaplasia have an OS of only around 50%. We here identify key events in the pathogenesis of diffuse anaplasia by mapping cancer cell evolution over anatomic space in Wilms tumors.EXPERIMENTAL DESIGN: We spatially mapped subclonal landscapes in a retrospective cohort of 20 Wilms tumors using high-resolution copy-number profiling and TP53 mutation analysis followed by clonal deconvolution and phylogenetic reconstruction. Tumor whole-mount sections (WMS) were utilized to characterize the distribution of subclones across anatomically distinct tumor compartments.RESULTS: Compared with non-diffuse anaplasia Wilms tumors, tumors with diffuse anaplasia showed a significantly higher number of genetically distinct tumor cell subpopulations and more complex phylogenetic trees, including high levels of phylogenetic species richness, divergence, and irregularity. All regions with classical anaplasia showed TP53 alterations. TP53 mutations were frequently followed by saltatory evolution and parallel loss of the remaining wild-type (WT) allele in different regions. Morphologic features of anaplasia increased with copy-number aberration (CNA) burden and regressive features. Compartments demarcated by fibrous septae or necrosis/regression were frequently (73%) associated with the emergence of new clonal CNAs, although clonal sweeps were rare within these compartments.CONCLUSIONS: Wilms tumors with diffuse anaplasia display significantly more complex phylogenies compared with non-diffuse anaplasia Wilms tumors, including features of saltatory and parallel evolution. The subclonal landscape of individual tumors was constrained by anatomic compartments, which should be considered when sampling tissue for precision diagnostics.
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| 10. |
- Solta, Anna, et al.
(författare)
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Entinostat Enhances the Efficacy of Chemotherapy in Small Cell Lung Cancer Through S-phase Arrest and Decreased Base Excision Repair
- 2023
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 29:22, s. 4644-4659
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Acquired chemoresistance is a frequent event in small cell lung cancer (SCLC), one of the deadliest human malignancies. Histone deacetylase inhibitors (HDACi) have been shown to synergize with different chemotherapeutic agents including cisplatin. Accordingly, we aimed to investigate the dual targeting of HDAC inhibition and chemotherapy in SCLC.EXPERIMENTAL DESIGN: The efficacy of HDACi and chemotherapy in SCLC was investigated both in vitro and in vivo. Synergistic drug interactions were calculated based on the HSA model (Combenefit software). Results from the proteomic analysis were confirmed via ICP-MS, cell-cycle analysis, and comet assays.RESULTS: Single entinostat- or chemotherapy significantly reduced cell viability in human neuroendocrine SCLC cells. The combination of entinostat with either cisplatin, carboplatin, irinotecan, epirubicin, or etoposide led to strong synergy in a subset of resistant SCLC cells. Combination treatment with entinostat and cisplatin significantly decreased tumor growth in vivo. Proteomic analysis comparing the groups of SCLC cell lines with synergistic and additive response patterns indicated alterations in cell-cycle regulation and DNA damage repair. Cell-cycle analysis revealed that cells exhibiting synergistic drug responses displayed a shift from G1 to S-phase compared with cells showing additive features upon dual treatment. Comet assays demonstrated more DNA damage and decreased base excision repair in SCLC cells more responsive to combination therapy.CONCLUSIONS: In this study, we decipher the molecular processes behind synergistic interactions between chemotherapy and HDAC inhibition. Moreover, we report novel mechanisms to overcome drug resistance in SCLC, which may be relevant to increasing therapeutic success.
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