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1.	Brand, Judith S, et al. (författare) Chemotherapy, genetic susceptibility, and risk of venous thromboembolism in breast cancer patients 2016 Ingår i: Clinical Cancer Research. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 1078-0432. ; 22:21, s. 5249-5255 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.
2.	Arbajian, Elsa, et al. (författare) In-depth genetic analysis of sclerosing epithelioid fibrosarcoma reveals recurrent genomic alterations and potential treatment targets 2017 Ingår i: Clinical Cancer Research. - 1078-0432. ; 23:23, s. 7426-7434 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.
3.	Badn, Wiaam, et al. (författare) Low-dose combretastatin A4 phosphate enhances the immune response of tumor hosts to experimental colon carcinoma 2006 Ingår i: Clinical Cancer Research. - 1078-0432. ; 12:15, s. 4714-4719 Tidskriftsartikel (refereegranskat)abstract Purpose: Although there is a need to enhance the therapeutic efficiency in cancer by combining immunotherapeutic procedures with other therapy, combination with chemotherapy is complicated due to immunosuppressive effects of most chemotherapeutic drugs. The purpose of this investigation was to study whether combining tumor cell immunization with the vascular targeting drug combretastatin A4 phosphate (CA4P) would enhance tumor retardation and/or affect the antitumor immune response. Experimental Design: Rats with intrahepatic colon carcinoma were immunized weekly with IL-18/IFN gamma-transfected tumor cells, starting day 9, and were treated with a low-dose CA4P (2 mg/kg, 5 days a week starting day 7). The effect of CA4P was studied on tumor growth and on immune reactivity in vitro. Results: Rats with preexisting tumor, immunized and treated with low-dose CA4P, had a significantly retarded tumor growth compared with rats receiving CA4P or immunization alone. Splenocytes from rats treated with this combination had a significantly enhanced antitumor immune response compared with splenocytes from control rats. Exposure of nonadherent splenocytes to CA4P in vitro did not enhance their proliferation. However, 3-hour pretreatment of adherent splenocytes with 0.3 mu g/mL CA4P significantly enhanced proliferation and IFN gamma production of admixed nonadherent splenocytes, partly due to nitric oxide reduction. Combining the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester with CA4P and immunization further retarded tumor growth. Conclusion: Concomitant treatment of rats with progressively growing tumor with immunization and low-dose CA4P significantly enhances the therapeutic effect as compared with either treatment alone and results in an enhanced antitumor immune reactivity.
4.	Bai, Yalai, et al. (författare) An Open Source, Automated Tumor Infiltrating Lymphocyte Algorithm for Prognosis in Triple-Negative Breast Cancer 2021 Ingår i: Clinical Cancer Research. - 1078-0432. ; 27:20, s. 5557-5565 Tidskriftsartikel (refereegranskat)abstract Purpose: Although tumor infiltrating lymphocytes (TIL) assessment has been acknowledged to have both prognostic and predictive importance in triple negative breast cancer (TNBC), it is subject to inter and intra-observer variability that has prevented widespread adoption. Here we constructed a machine-learning based breast cancer TIL scoring approach and validated its prognostic potential in multiple TNBC cohorts. Experimental Design: Using the QuPath open source software, we built a neural-network classifier for tumor cells, lymphocytes, fibroblasts and “other” cells on hematoxylin-eosin (H&E) stained sections. We analyzed the classifier-derived TIL measurements with five unique constructed TIL variables. A retrospective collection of 171 TNBC cases was used as the discovery set to identify the optimal association of machine-read TIL variables with patient outcome. For validation we evaluated a retrospective collection of 749 TNBC patients comprised of four independent validation subsets. Results: We found that all five machine TIL variables had significant prognostic association with outcomes (p≤0.01 for all comparisons) but showed cell specific variation in validation sets. Cox regression analysis demonstrated that all five TIL variables were independently associated with improved overall survival after adjusting for clinicopathological factors including stage, age and histological grade (p≤0.003 for all analyses). Conclusions: Neural net driven cell classifier defined TIL variables were robust and independent prognostic factors in several independent validation cohorts of TNBC patients. These objective, open source TIL variables are freely available to download and can now be considered for testing in a prospective setting to assess clinical utility.
5.	Bjarnadottir, Olöf, et al. (författare) Global transcriptional changes following statin treatment in breast cancer. 2015 Ingår i: Clinical Cancer Research. - 1078-0432. ; 21:15, s. 3402-3411 Tidskriftsartikel (refereegranskat)abstract Statins purportedly exert anti-tumoral effects, but the underlying mechanisms are currently not fully elucidated. The aim of this study was to explore potential statin-induced effects on global gene expression profiles in primary breast cancer.
6.	Bjartell, Anders, et al. (författare) Association of cysteine-rich secretory protein 3 and beta-microseminoprotein with outcome after radical prostatectomy 2007 Ingår i: Clinical Cancer Research. - 1078-0432. ; 13:14, s. 4130-4138 Tidskriftsartikel (refereegranskat)abstract Purpose: It has been suggested that cysteine-rich secretory protein 3 (CRISP-3) and p-microseminoprotein (MSP) are associated with outcome in prostate cancer. We investigated whether these markers are related to biochemical recurrence and whether addition of the markers improves prediction of recurring disease. Experimental Design: Tissue microarrays of radical prostatectomy specimens were analyzed for CRISP-3 and MSP by immunohistochemistry. Associations between marker positivity and postprostatectomy biochemical recurrence [prostate-specific antigen (PSA) > 0.2 ng/mL with a confirmatory level] were evaluated by univariate and multivariable Cox proportional hazards regression. Multivariable analyses controlled for preoperative PSA and pathologic stage and grade. Results: Among 945 patients, 224 had recurrence. Median follow-up for survivors was 6.0 years. Patients positive for CRISP-3 had smaller recurrence-free probabilities, whereas MSP-positive patients had larger recurrence-free probabilities. On univariate analysis, the hazard ratio for patients positive versus negative for CRISP-3 was 1.53 (P =0.010) and for MSP was 0.63 (P = 0.004). On multivariable analysis, both CRISP-3 (P = 0.007) and MSP (P = 0.002) were associated with recurrence. The hazard ratio among CRISP-3-positive/MSP-negative patients compared with CRISP-3-negative/MSP-positive patients was 2.38. Adding CRISP-3 to a base model that included PSA and pathologic stage and grade did not enhance the prediction of recurrence, but adding MSP increased the concordance index minimally from 0.778 to 0.781. Conclusion: We report evidence that CRISP-3 and MSP are independent predictors of recurrence after radical prostatectomy for localized prostate cancer. However, addition of the markers does not importantly improve the performance of existing predictive models. Further research should aim to elucidate the functions of CRISP-3 and MSP in prostate cancer cells.
7.	Bjartell, Anders (författare) New Hope in Prostate Cancer Precision Medicine? miRNA Replacement and Epigenetics 2019 Ingår i: Clinical Cancer Research. - 1078-0432. ; 25:9, s. 2679-2681 Tidskriftsartikel (refereegranskat)abstract SPINK1+/ETS- prostate cancer is an aggressive disease with poor clinical outcome. New data suggest a novel treatment by upregulating the expression of miR-338-5p/-421 through epigenetic modulation or by miRNA replacement. This is a new and interesting concept that warrants further exploration in clinical trials.See related article by Bhatia et al., p. 2755.
8.	Bremer, Troy, et al. (författare) A Biological Signature for Breast Ductal Carcinoma In Situ to Predict Radiotherapy Benefit and Assess Recurrence Risk 2018 Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 24:23, s. 5895-5901 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.
9.	Brennan, Donal J, et al. (författare) Altered cytoplasmic-to-nuclear ratio of survivin is a prognostic indicator in breast cancer 2008 Ingår i: Clinical Cancer Research. - 1078-0432. ; 14:9, s. 2681-2689 Tidskriftsartikel (refereegranskat)abstract Purpose: Survivin (BIRC5) is a promising tumor biomarker. Conflicting data exist on its prognostic effect in breast cancer. These data may at least be partly due to the manual interpretation of immunohistochemical staining, especially as survivin can be located in both the nucleus and cytoplasm. Quantitative determination of survivin expression using image analysis offers the opportunity to develop alternative scoring models for survivin immunohistochemistry. Here, we present such a model. Experimental Design: A breast cancer tissue microarray containing 102 tumors was stained with an anti-survivin antibody. Whole-slide scanning was used to capture high-resolution images. These images were analyzed using automated algorithms to quantify the staining. Results: Increased nuclear, but not cytoplasmic, survivin was associated with a reduced overall survival (OS; P = 0.038) and disease-specific survival (P = 0.0015). A high cytoplasmicto-nuclear ratio (CNR) of survivin was associated with improved OS (P = 0.005) and disease-specific survival (P = 0.05). Multivariate analysis revealed that the survivin CNR was an independent predictor of CIS (hazard ratio, 0.09; 95% confidence interval, 0.01-0.76; P = 0.027). A survivin CNR of >5 correlated positively with estrogen receptor (P = 0.019) and progesterone receptor (P = 0.033) levels, whereas it was negatively associated with Ki-67 expression (P = 0.04), p53 status (P = 0.005), and c-myc amplification (P = 0.016). Conclusion: Different prognostic information is supplied by nuclear and cytoplasmic survivin in breast cancer. Nuclear survivin is a poor prognostic marker in breast cancer. Moreover, CNR of survivin, as determined by image analysis, is an independent prognostic factor.
10.	Brennan, Donal J., et al. (författare) CA IX is an independent prognostic marker in premenopausal breast cancer patients with one to three positive lymph nodes and a putative marker of radiation resistance 2006 Ingår i: Clinical Cancer Research. - 1078-0432. ; 12:21, s. 6421-6431 Tidskriftsartikel (refereegranskat)abstract Purpose: Hypoxia in breast cancer is associated with poor prognosis and down-regulation of the estrogen receptor. Carbonic anhydrase IX (CA IX) is a hypoxia-inducible gene that has been associated with poor outcome in many epithelial cancers. Previous studies of CA IX in breast cancer have been carried out on mixed cohorts of premenopausal and postmenopausal patients with locally advanced disease and varying treatment regimens. We examined the potential prognostic and predictive role of CA IX in premenopausal breast cancer patients. Experimental Design: Using tissue microarrays, we analyzed CA IX expression in 400 stage 11 breast cancers from premenopausal women. The patients had previously participated in a randomized control trial comparing 2 years of tamoxifen to no systemic adjuvant treatment. Median follow-up was 13.9 years. Results: CA IX expression correlated positively with tumor size, grade, hypoxia-inducible factor 1 alpha Ki-67, cyclin E, and cyclin A2 expression. CA IX expression correlated negatively with cyclin D1, estrogen receptor, and progesterone receptor. CA IX expression was associated with a reduced relapse-free survival (P = 0.032), overall survival (P = 0.022), and breast cancer specific survival (P = 0.005). Multivariate analysis revealed that CA IX was an independent prognostic marker in untreated patients with one to three positive lymph nodes (hazard ratio, 3.2; 95% confidence interval, 1.15-9.13; P = 0.027). Conclusion: CA IX is marker of poor prognosis in premenopausal breast cancer patients and it is an independent predictor of survival in patients with one to three positive lymph nodes. As all these patients received locoregional radiation therapy, CA IX may be associated with resistance to radiotherapy.
11.	Broselid, Stefan, et al. (författare) G protein-coupled estrogen receptor is apoptotic and correlates with increased distant disease-free survival of estrogen receptor-positive breast cancer patients. 2013 Ingår i: Clinical Cancer Research. - 1078-0432. ; 19:7, s. 1681-1692 Tidskriftsartikel (refereegranskat)abstract G protein-coupled estrogen receptor 1 (GPER1), previously named GPR30, is a membrane receptor reported to mediate nongenomic estrogen responses. We investigated if GPER1 expression correlates with any clinicopathologic variables and distant disease-free survival (DDFS) in patients with breast cancer, if any prognostic impact of the receptor is dependent on estrogen receptor-α (ER-α) status, and if the receptor impacts apoptotic signaling in ER-positive breast cancer cells.
12.	Buddingh, Emilie P., et al. (författare) Tumor-Infiltrating Macrophages Are Associated with Metastasis Suppression in High-Grade Osteosarcoma: A Rationale for Treatment with Macrophage Activating Agents 2011 Ingår i: Clinical Cancer Research. - 1078-0432. ; 17:8, s. 2110-2119 Tidskriftsartikel (refereegranskat)abstract Purpose: High-grade osteosarcoma is a malignant primary bone tumor with a peak incidence in adolescence. Overall survival (OS) of patients with resectable metastatic disease is approximately 20%. The exact mechanisms of development of metastases in osteosarcoma remain unclear. Most studies focus on tumor cells, but it is increasingly evident that stroma plays an important role in tumorigenesis and metastasis. We investigated the development of metastasis by studying tumor cells and their stromal context. Experimental Design: To identify gene signatures playing a role in metastasis, we carried out genome-wide gene expression profiling on prechemotherapy biopsies of patients who did (n = 34) and patients who did not (n = 19) develop metastases within 5 years. Immunohistochemistry (IHC) was performed on pretreatment biopsies from 2 additional cohorts (n = 63 and n = 16) and corresponding postchemotherapy resections and metastases. Results: A total of 118/132 differentially expressed genes were upregulated in patients without metastases. Remarkably, almost half of these upregulated genes had immunological functions, particularly related to macrophages. Macrophage-associated genes were expressed by infiltrating cells and not by osteosarcoma cells. Tumor-associated macrophages (TAM) were quantified with IHC and associated with significantly better overall survival (OS) in the additional patient cohorts. Osteosarcoma samples contained both M1-(CD14/HLA-DR alpha positive) and M2-type TAMs (CD14/CD163 positive and association with angiogenesis). Conclusions: In contrast to most other tumor types, TAMs are associated with reduced metastasis and improved survival in high-grade osteosarcoma. This study provides a biological rationale for the adjuvant treatment of high-grade osteosarcoma patients with macrophage activating agents, such as muramyl tripeptide. Clin Cancer Res; 17(8); 2110-9. (C) 2011 AACR.
13.	Candido-dos-Reis, Francisco J, et al. (författare) Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer 2015 Ingår i: Clinical Cancer Research. - 1078-0432. ; 21:3, s. 7-652 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.
14.	Costa, Carlotta, et al. (författare) The strategy of piking a target : What is aktually most effective? 2018 Ingår i: Clinical Cancer Research. - 1078-0432. ; 24:9, s. 2029-2031 Tidskriftsartikel (refereegranskat)abstract Breast and gynecologic cancers harboring PIK3CA mutations showed no significant responses to AZD5363, a pan-AKT catalytic inhibitor, in contrast with previous in vitro data showing activity of the drug in this subset of cancers. These results raise the question of how to select the most accurate predictive biomarkers of response.
15.	Coward, Jermaine, et al. (författare) Interleukin-6 as a Therapeutic Target in Human Ovarian Cancer 2011 Ingår i: Clinical Cancer Research. - 1078-0432. ; 17:18, s. 6083-6096 Tidskriftsartikel (refereegranskat)abstract Purpose: We investigated whether inhibition of interleukin 6 (IL-6) has therapeutic activity in ovarian cancer via abrogation of a tumor-promoting cytokine network. Experimental Design: We combined preclinical and in silico experiments with a phase 2 clinical trial of the anti-IL-6 antibody siltuximab in patients with platinum-resistant ovarian cancer. Results: Automated immunohistochemistry on tissue microarrays from 221 ovarian cancer cases showed that intensity of IL-6 staining in malignant cells significantly associated with poor prognosis. Treatment of ovarian cancer cells with siltuximab reduced constitutive cytokine and chemokine production and also inhibited IL-6 signaling, tumor growth, the tumor-associated macrophage infiltrate and angiogenesis in IL-6-producing intraperitoneal ovarian cancer xenografts. In the clinical trial, the primary endpoint was response rate as assessed by combined RECIST and CA125 criteria. One patient of eighteen evaluable had a partial response, while seven others had periods of disease stabilization. In patients treated for 6 months, there was a significant decline in plasma levels of IL-6-regulated CCL2, CXCL12, and VEGF. Gene expression levels of factors that were reduced by siltuximab treatment in the patients significantly correlated with high IL-6 pathway gene expression and macrophage markers in microarray analyses of ovarian cancer biopsies. Conclusion: IL-6 stimulates inflammatory cytokine production, tumor angiogenesis, and the tumor macrophage infiltrate in ovarian cancer and these actions can be inhibited by a neutralizing anti-IL-6 antibody in preclinical and clinical studies. Clin Cancer Res; 17(18); 6083-96. (C) 2011 AACR.
16.	Danila, DC, et al. (författare) Circulating Tumor Cell Number and Prognosis in Progressive Castration-Resistant Prostate Cancer 2007 Ingår i: Clinical Cancer Research. - 1078-0432. ; 13:23, s. 7053-7058 Tidskriftsartikel (refereegranskat)abstract PURPOSE: The development of tumor-specific markers to select targeted therapies and to assess clinical outcome remains a significant area of unmet need. We evaluated the association of baseline circulating tumor cell (CTC) number with clinical characteristics and survival in patients with castrate metastatic disease considered for different hormonal and cytotoxic therapies. EXPERIMENTAL DESIGN: CTC were isolated by immunomagnetic capture from 7.5-mL samples of blood from 120 patients with progressive clinical castrate metastatic disease. We estimated the probability of survival over time by the Kaplan-Meier method. The concordance probability estimate was used to gauge the discriminatory strength of the informative prognostic factors. RESULTS: Sixty-nine (57%) patients had five or more CTC whereas 30 (25%) had two cells or less. Higher CTC numbers were observed in patients with bone metastases relative to those with soft tissue disease and in patients who had received prior cytotoxic chemotherapy relative to those who had not. CTC counts were modestly correlated to measurements of tumor burden such as prostate-specific antigen and bone scan index, reflecting the percentage of boney skeleton involved with tumor. Baseline CTC number was strongly associated with survival, without a threshold effect, which increased further when baseline prostate-specific antigen and albumin were included. CONCLUSIONS: Baseline CTC was predictive of survival, with no threshold effect. The shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease, and provides unique information relative to prognosis.
17.	Dihge, Looket, et al. (författare) Prediction of lymph node metastasis in breast cancer by gene expression and clinicopathological models: Development and validation within a population based cohort. 2019 Ingår i: Clinical Cancer Research. - 1078-0432. ; 25:21, s. 6368-6381 Tidskriftsartikel (refereegranskat)abstract Purpose: More than 70% of patients with breast cancer present with node-negative disease, yet all undergo surgical axillary staging. We aimed to define predictors of nodal metastasis using clinicopathological characteristics (CLINICAL), gene expression data (GEX), and mixed features (MIXED) and to identify patients at low risk of metastasis who might be spared sentinel lymph node biopsy (SLNB).Experimental Design: Breast tumors (n = 3,023) from the population-based Sweden Cancerome Analysis Network–Breast initiative were profiled by RNA sequencing and linked to clinicopathologic characteristics. Seven machine-learning models present the discriminative ability of N0/N+ in development (n = 2,278) and independent validation cohorts (n = 745) stratified as ER+HER2−, HER2+, and TNBC. Possible SLNB reduction rates are proposed by applying CLINICAL and MIXED predictors.Results: In the validation cohort, the MIXED predictor showed the highest area under ROC curves to assess nodal metastasis; AUC = 0.72. For the subgroups, the AUCs for MIXED, CLINICAL, and GEX predictors ranged from 0.66 to 0.72, 0.65 to 0.73, and 0.58 to 0.67, respectively. Enriched proliferation metagene and luminal B features were noticed in node-positive ER+HER2− and HER2+ tumors, while upregulated basal-like features were observed in node-negative TNBC tumors. The SLNB reduction rates in patients with ER+HER2− tumors were 6% to 7% higher for the MIXED predictor compared with the CLINICAL predictor accepting false negative rates of 5% to 10%.Conclusions: Although CLINICAL and MIXED predictors of nodal metastasis had comparable accuracy, the MIXED predictor identified more node-negative patients. This translational approach holds promise for development of classifiers to reduce the rates of SLNB for patients at low risk of nodal involvement.
18.	Dolled-Filhart, Marisa, et al. (författare) Classification of breast cancer using genetic algorithms and tissue microarrays 2006 Ingår i: Clinical Cancer Research. - 1078-0432. ; 12:21, s. 6459-6468 Tidskriftsartikel (refereegranskat)abstract PURPOSE: A multitude of breast cancer mRNA profiling studies has stratified breast cancer and defined gene sets that correlate with outcome. However, the number of genes used to predict patient outcome or define tumor subtypes by RNA expression studies is variable, nonoverlapping, and generally requires specialized technologies that are beyond those used in the routine pathology laboratory. It would be ideal if the familiarity and streamlined nature of immunohistochemistry could be combined with the rigorously quantitative and highly specific properties of nucleic acid-based analysis to predict patient outcome. EXPERIMENTAL DESIGN: We have used AQUA-based objective quantitative analysis of tissue microarrays toward the goal of discovery of a minimal number of markers with maximal prognostic or predictive value that can be applied to the conventional formalin-fixed, paraffin-embedded tissue section. RESULTS: The minimal discovered multiplexed set of tissue biomarkers was GATA3, NAT1, and estrogen receptor. Genetic algorithms were then applied after division of our cohort into a training set of 223 breast cancer patients to discover a prospectively applicable solution that can define a subset of patients with 5-year survival of 96%. This algorithm was then validated on an internal validation set (n=223, 5-year survival=95.8%) and further validated on an independent cohort from Sweden, which showed 5-year survival of 92.7% (n=149). CONCLUSIONS: With further validation, this test has both the familiarity and specificity for widespread use in management of breast cancer. More generally, this work illustrates the potential for multiplexed biomarker discovery on the tissue microarray platform.
19.	Elebro, Karin, et al. (författare) Combined Androgen and Estrogen Receptor Status in Breast Cancer: Treatment Prediction and Prognosis in a Population-based Prospective Cohort. 2015 Ingår i: Clinical Cancer Research. - 1078-0432. ; 21:16, s. 3640-3650 Tidskriftsartikel (refereegranskat)abstract To evaluate whether tumor androgen receptor (AR) expression was prognostic and/or predictive for endocrine treatment alone or in combination with estrogen receptor (ER). The AR has been hypothesized to have differential prognostic roles in breast cancer depending on tumor ER-status, and to influence endocrine treatment response.
20.	Elebro, Karin, et al. (författare) High Estrogen Receptor β Expression Is Prognostic among Adjuvant Chemotherapy-Treated Patients-Results from a Population-Based Breast Cancer Cohort 2017 Ingår i: Clinical Cancer Research. - 1078-0432. ; 23:3, s. 766-777 Tidskriftsartikel (refereegranskat)abstract PURPOSE: Isoform-specific tumor estrogen receptor β (ERβ) expression may hold prognostic information in breast cancer, especially among endocrine-treated breast cancer patients. The study's purpose was to evaluate ERβ isoform 1 (ERβ1) expression in relation to tumor characteristics, ESR2 genotypes, and prognosis in different treatment groups.EXPERIMENTAL DESIGN: A population-based prospective cohort of 1,026 patients diagnosed with primary invasive breast cancer in Lund, Sweden, between October 2002 and June 2012 was followed until June 2014 (median 5 years). Associations between immunohistochemical ERβ1 expression, patient and tumor characteristics, as well as outcome within treatment groups were analyzed.RESULTS: Tumor ERβ1 expression was available for 911 patients (89%) and was not associated with ESR2 genotypes. ERβ1 positivity, defined as >75% (ERβ175(+), 72.7%), was positively associated with established favorable tumor characteristics. Overall, ERβ175(+) was associated with lower risk of breast cancer events [HRadj = 0.60; 95% confidence interval (CI), 0.41-0.89]. The magnitude of the association was larger in patients with ERα(-) tumors (HRadj = 0.30; 95% CI, 0.12-0.76), compared with ERα(+) tumors (HRadj = 0.66; 95% CI, 0.42-1.03). Among the 232 chemotherapy-treated patients, ERβ175(+) tumors were associated with lower risk of breast cancer events compared with ERβ175(-) tumors (HRadj = 0.31; 95% CI, 0.15-0.64). Among the 671 chemonaïve patients, ERβ175 status was not associated with the outcome.CONCLUSION: High ERβ1 expression was a favorable prognostic marker in this breast cancer cohort, especially in chemotherapy-treated patients, but not in endocrine therapy-treated patients. These results warrant confirmation, preferably via a biomarker study in a previously conducted randomized trial. Clin Cancer Res; 1-12. ©2016 AACR.
21.	Faedo, Margaret, et al. (författare) Mouse mammary tumor-like virus is associated with p53 nuclear accumulation and progesterone receptor positivity but not estrogen positivity in human female breast cancer 2004 Ingår i: Clinical Cancer Research. - 1078-0432. ; 10:13, s. 4417-4419 Tidskriftsartikel (refereegranskat)abstract PURPOSE: The purpose is to compare the presence of proteins with known associations with breast cancer-progesterone receptor (PgR), estrogen receptor, and p53, with the prevalence of mouse mammary tumor virus (MMTV)-like DNA sequences in human female breast cancers. EXPERIMENTAL DESIGN: A cohort of 128 Australian female breast cancers were screened for MMTV-like DNA sequences using PCR. The presence of PgR, estrogen receptor, and nuclear accumulation of p53 protein was assessed in the same samples using immunohistochemical staining. RESULTS: Nuclear accumulation of p53 was significantly more prevalent (P = 0.05) in archival human breast cancers containing MMTV-like DNA sequences. The presence of progesterone receptor was significantly higher in MMTV-positive than MMTV-negative breast cancers (P = 0.01). No correlation between estrogen receptor and MMTV-like DNA sequences was found. CONCLUSIONS: MMTV causes breast cancer in mice, and hormones up-regulate expression of virus in mice mammary tissue. It is unknown if this is the case in human breast cancers shown to contain DNA of MMTV-like viruses. The positive association between MMTV-like DNA sequences and PgR indicates hormones and MMTV may play a role in human breast cancer. Mutations of the tumor suppressor gene p53 are common in human breast cancer and are associated with higher grades of cancer. The association of MMTV-like DNA sequences with higher grades of cancer, and the positive association between p53 and MMTV-like DNA sequences clearly warrant additional investigation.
22.	Flores-Morales, Amilcar, et al. (författare) Proteogenomic characterization of patient-derived xenografts highlights the role of REST in neuroendocrine differentiation of castration-resistant prostate cancer 2019 Ingår i: Clinical Cancer Research. - 1078-0432. ; 25:2, s. 595-608 Tidskriftsartikel (refereegranskat)abstract Purpose: An increasing number of castration-resistant prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) features. NE prostate cancer (NEPC) has poor prognosis, and its development is poorly understood. Experimental Design: We applied mass spectrometry–based proteomics to a unique set of 17 prostate cancer patient–derived xenografts (PDX) to characterize the effects of castration in vivo, and the proteome differences between NEPC and prostate adenocarcinomas. Genome-wide profiling of REST-occupied regions in prostate cancer cells was correlated to the expression changes in vivo to investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation. Results: An average of 4,881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell-cycle regulation, and DNA repair were found upregulated and elevated in NEPC, while the reduced levels of proteins involved in mitochondrial functions suggested a prevalent glycolytic metabolism of NEPC tumors. Integration of the REST chromatin bound regions with expression changes indicated a direct role of REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell-cycle arrest in G1, which could be rescued by p53 knockdown. Finally, the expression of the REST-regulated gene secretagogin (SCGN) correlated with an increased risk of suffering disease relapse after radical prostatectomy. Conclusions: This study presents the first deep characterization of the proteome of NEPC and suggests that concomitant inhibition of REST and the p53 pathway would promote NEPC. We also identify SCGN as a novel prognostic marker in prostate cancer.
23.	Ford, Caroline, et al. (författare) Mouse mammary tumor virus-like RNA transcripts and DNA are found in affected cells of human breast cancer 2004 Ingår i: Clinical Cancer Research. - 1078-0432. ; 10:21, s. 7284-7284 Tidskriftsartikel (refereegranskat)abstract Identifiable risk factors for the development of breast cancer include age, diet, family history, and lifetime estrogen exposure. An infectious agent (mouse mammary tumor virus; MMTV) is known to cause murine breast tumors and may be involved in the pathogenesis of human disease. Multiple studies have detected MMTV-like sequences in 30 to 60% of breast cancer samples and up to 1.8% of samples from normal breast. Using in situ PCR of MMTV-like sequences of formalin-fixed, paraffin-embedded breast tissue, viral sequences have been located in cancerous epithelial cells in breast acini of male and female breast tumors, but not in adjacent nonmalignant cells. MMTV-like sequences were also located in the epithelial cells of male gynecomastia samples. Using reverse transcriptase in situ PCR, RNA transcripts from the env gene were also detected within cancerous epithelial cells of 78% of DNA-positive tumors, 80% of gynecomastia samples, and 0% of normal tissues screened. This suggests the virus may be replicating in these cells. The epidemiologic and histopathological data are consistent with the association of an MMTV-like virus with breast cancers in men and women. The association with gynecomastia, a benign, possibly premalignant condition suggests hormonal influences, rather than cancer per se, may be the dominant factor in determining viral presence and replication.
24.	Gaedcke, Jochen, et al. (författare) The Rectal Cancer microRNAome - microRNA Expression in Rectal Cancer and Matched Normal Mucosa. 2012 Ingår i: Clinical Cancer Research. - 1078-0432. ; 18:18, s. 4919-4930 Tidskriftsartikel (refereegranskat)abstract PURPOSE: miRNAs play a prominent role in a variety of physiologic and pathologic biologic processes, including cancer. For rectal cancers, only limited data are available on miRNA expression profiles, whereas the underlying genomic and transcriptomic aberrations have been firmly established. We therefore, aimed to comprehensively map the miRNA expression patterns of this disease. EXPERIMENTAL DESIGN: Tumor biopsies and corresponding matched mucosa samples were prospectively collected from 57 patients with locally advanced rectal cancers. Total RNA was extracted, and tumor and mucosa miRNA expression profiles were subsequently established for all patients. The expression of selected miRNAs was validated using semi-quantitative real-time PCR. RESULTS: Forty-nine miRNAs were significantly differentially expressed (log(2)-fold difference >0.5 and P < 0.001) between rectal cancer and normal rectal mucosa. The predicted targets for these miRNAs were enriched for the following pathways: Wnt, TGF-beta, mTOR, insulin, mitogen-activated protein kinase, and ErbB signaling. Thirteen of these 49 miRNAs seem to be rectal cancer-specific, and have not been previously reported for colon cancers: miR-492, miR-542-5p, miR-584, miR-483-5p, miR-144, miR-2110, miR-652, miR-375, miR-147b, miR-148a, miR-190, miR-26a/b, and miR-338-3p. Of clinical impact, miR-135b expression correlated significantly with disease-free and cancer-specific survival in an independent multicenter cohort of 116 patients. CONCLUSION: This comprehensive analysis of the rectal cancer miRNAome uncovered novel miRNAs and pathways associated with rectal cancer. This information contributes to a detailed view of this disease. Moreover, the identification and validation of miR-135b may help to identify novel molecular targets and pathways for therapeutic exploitation. Clin Cancer Res; 1-12. ©2012 AACR.
25.	Gallagher, David J., et al. (författare) Susceptibility Loci Associated with Prostate Cancer Progression and Mortality 2010 Ingår i: Clinical Cancer Research. - 1078-0432. ; 16:10, s. 2819-2832 Tidskriftsartikel (refereegranskat)abstract Purpose: Prostate cancer is a heterogenous disease with a variable natural history that is not accurately predicted by currently used prognostic tools. Experimental Design: We genotyped 798 prostate cancer cases of Ashkenazi Jewish ancestry treated for localized prostate cancer between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to clinical data. The survival analysis was adjusted for Gleason score and prostate-specific antigen. We investigated associations between 29 single nucleotide polymorphisms (SNP) and biochemical recurrence, castration-resistant metastasis, and prostate cancer-specific survival. Subsequently, we did an independent analysis using a high-resolution panel of 13 SNPs. Results: On univariate analysis, two SNPs were associated (P < 0.05) with biochemical recurrence, three SNPs were associated with clinical metastases, and one SNP was associated with prostate cancer specific mortality. Applying a Bonferroni correction (P < 0.0017), one association with biochemical recurrence (P = 0.0007) was significant. Three SNPs showed associations on multivariable analysis, although not after correcting for multiple testing. The secondary analysis identified an additional association with prostate cancer-specific mortality in KLK3 (P < 0.0005 by both univariate and multivariable analysis). Conclusions: We identified associations between prostate cancer susceptibility SNPs and clinical end points. The rs61752561 in KLK3 and rs2735839 in the KLK2-KLK3 intergenic region were strongly associated with prostate cancer-specific survival, and rs10486567 in the 7JAZF1 gene were associated with biochemical recurrence. A larger study will be required to independently validate these findings and determine the role of these SNPs in prognostic models. Clin Cancer Res; 16(10); 2819-32. (C) 2010 AACR.
26.	Gruvberger, Sofia, et al. (författare) Estrogen receptor beta expression is associated with tamoxifen response in ER alpha-negative breast carcinoma 2007 Ingår i: Clinical Cancer Research. - 1078-0432. ; 13:7, s. 1987-1994 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.
27.	Grövdal, Michael, et al. (författare) 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 Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:23, s. 7107-7112 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.
28.	Gustafsson, Anna, et al. (författare) Differential expression of Axl and Gas6 in renal cell carcinoma reflecting tumor advancement and survival 2009 Ingår i: Clinical Cancer Research. - : American association for cancer research. - 1078-0432 .- 1557-3265. ; 15:14, s. 4742-4749 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.
29.	Hallor, Karolin H, et al. (författare) Genomic profiling of chondrosarcoma: chromosomal patterns in central and peripheral tumors. 2009 Ingår i: Clinical Cancer Research. - 1078-0432. ; 15:8, s. 2685-2694 Tidskriftsartikel (refereegranskat)abstract PURPOSE: Histologic grade is currently the best predictor of clinical course in chondrosarcoma patients. Grading suffers, however, from extensive interobserver variability and new objective markers are needed. Hence, we have investigated DNA copy numbers in chondrosarcomas with the purpose of identifying markers useful for prognosis and subclassification. EXPERIMENTAL DESIGN: The overall pattern of genomic imbalances was assessed in a series of 67 chondrosarcomas using array comparative genomic hybridization. Statistical analyses were applied to evaluate the significance of alterations detected in subgroups based on clinical data, morphology, grade, tumor size, and karyotypic features. Also, the global gene expression profiles were obtained in a subset of the tumors. RESULTS: Genomic imbalances, in most tumors affecting large regions of the genome, were found in 90% of the cases. Several apparently distinctive aberrations affecting conventional central and peripheral tumors, respectively, were identified. Although rare, recurrent amplifications were found at 8q24.21-q24.22 and 11q22.1-q22.3, and homozygous deletions of loci previously implicated in chondrosarcoma development affected the CDKN2A, EXT1, and EXT2 genes. The chromosomal imbalances in two distinct groups of predominantly near-haploid and near-triploid tumors, respectively, support the notion that polyploidization of an initially hyperhaploid/hypodiploid cell population is a common mechanism of chondrosarcoma progression. Increasing patient age as well as tumor grade were associated with adverse outcome, but no copy number imbalance affected metastasis development or tumor-associated death. CONCLUSION: Despite similarities in the overall genomic patterns, the present findings suggest that some regions are specifically altered in conventional central and peripheral tumors, respectively.
30.	Hansson, Jennifer, et al. (författare) Overexpression of functional SLC6A3 in clear cell renal cell carcinoma 2017 Ingår i: Clinical Cancer Research. - 1078-0432. ; 23:8, s. 2105-2115 Tidskriftsartikel (refereegranskat)abstract PURPOSE: Renal cell carcinoma (RCC) is derived from a tissue with a remarkable capacity for vectorial transport. We therefore performed an unbiased exploration of transporter proteins in normal kidney and kidney cancer in order to discover novel clinical targets.EXPERIMENTAL DESIGN: Using the TCGA database we investigated differences in membrane transporter expression in ccRCC and normal kidney. We identified the dopamine transporter SLC6A3 as a specific biomarker for ccRCC. To investigate the functionality of SLC6A3 we used a [3H]-dopamine uptake assay on ccRCC cells. We further explored the effect of HIF proteins on SLC6A3 expression by introducing siRNA in ccRCC cells and by hypoxic treatment of non-malignant cells.RESULTS: We show that ccRCC express very high transcript levels of SLC6A3 in contrast to normal kidney tissue and other tumor types, which do not express appreciable levels of this transporter. Importantly, we demonstrate that the elevated expression of SLC6A3 in ccRCC cells is associated with specific uptake of dopamine. By targeting the expression of HIF-1α and HIF-2α we could show that SLC6A3 expression is primarily influenced by HIF-2α, and that hypoxia can induce SLC6A3 expression in normal renal cells.CONCLUSIONS: We conclude that the dopamine transporter SLC6A3 constitute a novel biomarker that is highly specific for ccRCC. We further postulate that the protein can be exploited for diagnostic or therapeutic purposes for detection or treatment of ccRCC.
31.	Hansson, Markus, et al. (författare) A phase 1 dose-escalation study of antibody BI-505 in relapsed/refractory multiple myeloma. 2015 Ingår i: Clinical Cancer Research. - 1078-0432. ; 21:12, s. 2730-2736 Tidskriftsartikel (refereegranskat)abstract Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients. Experimental design: BI-505 was given intravenously, every two weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses. Results: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate and those attributed to study medication were mostly limited to the first dose, and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505's half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at 10 mg/kg doses. Using the International Myeloma Working Group criteria, seven patients on extended therapy had stable disease for more than two months. Conclusion: BI-505 can be safely administered at doses that saturate myeloma cell ICAM-1 receptors in patients. This study was registered at www.clinicaltrials.gov (NCT01025206).
32.	Harbst, Katja, et al. (författare) Molecular profiling reveals low- and high-grade forms of primary melanoma. 2012 Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1557-3265. ; 18:15, s. 4026-4036 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.
33.	Henic, Emir, et al. (författare) Cleaved forms of the urokinase plasminogen activator receptor in plasma have diagnostic potential and predict postoperative survival in patients with ovarian cancer. 2008 Ingår i: Clinical Cancer Research. - 1078-0432. ; 14:18, s. 5785-5793 Tidskriftsartikel (refereegranskat)abstract PURPOSE: To evaluate the plasma level of different forms of soluble urokinase plasminogen activator receptor (suPAR) as discriminators between malignant, borderline, and benign ovarian tumors and as prognostic markers in patients with ovarian cancer. EXPERIMENTAL DESIGN: The different suPAR forms were measured in preoperative plasma samples obtained from 335 patients with adnexal lesions using three different time-resolved fluoresence assays (TR-FIA): TR-FIA 1 measuring intact suPAR, suPAR(I-III), TR-FIA 2 measuring the total amount of suPAR(I-III) and the cleaved form, suPAR(II-III), and TR-FIA 3 measuring the liberated uPAR(I). Tumors were classified as benign (n = 211), borderline (possibly malignant; n = 30), and well (n = 19), moderately (n = 15), and poorly (n = 60) differentiated malignant. RESULTS: All uPAR forms as well as CA125 were statistically significant in univariate analysis discriminating between benign, borderline, and invasive tumors. Restricting the analysis of invasive tumors to early stage (I and II) showed similar results. A combination of CA125 and suPAR(I-III) + suPAR(II-III) discriminated between malignant (all stages) and benign tumors [AUC, 0.94; 95% confidence interval (95% CI), 0.90-0.98] as well as borderline and benign tumors (AUC, 0.78; 95% CI, 0.67-0.89). All suPAR forms were markers for poor prognosis in univariate analyses, and high preoperative plasma level of uPAR(I) is an independent predictor of poor prognosis (hazard ratio, 1.84; 95% CI, 1.15-2.95; P = 0.011) in multivariate analyses including age and CA125. CONCLUSIONS: High concentration of plasma uPAR(I) is an independent preoperative marker of poor prognosis in patients with ovarian cancer. The combination of plasma suPAR(I-III) + suPAR(II-III) and CA125 discriminates between malignant and benign tumors with an AUC of 0.94.
34.	Hinrichsen, Inga, et al. (författare) Expression Defect Size among Unclassified MLH1 Variants Determines Pathogenicity in Lynch Syndrome Diagnosis 2013 Ingår i: Clinical Cancer Research. - 1078-0432. ; 19:9, s. 2432-2441 Tidskriftsartikel (refereegranskat)abstract Purpose: Lynch syndrome is caused by a germline mutation in a mismatch repair gene, most commonly the MLH1 gene. However, one third of the identified alterations are missense variants with unclear clinical significance. The functionality of these variants can be tested in the laboratory, but the results cannot be used for clinical diagnosis. We therefore aimed to establish a laboratory test that can be applied clinically. Experimental Design: We assessed the expression, stability, and mismatch repair activity of 38 MLH1 missense variants and determined the pathogenicity status of recurrent variants using clinical data. Results: Four recurrent variants were classified as neutral (K618A, H718Y, E578G, V716M) and three as pathogenic (A681T, L622H, P654L). All seven variants were proficient in mismatch repair but showed defects in expression. Quantitative PCR, pulse-chase, and thermal stability experiments confirmed decreases in protein stability, which were stronger in the pathogenic variants. The minimal cellular MLH1 concentration for mismatch repair was determined, which corroborated that strongly destabilized variants can cause repair deficiency. Loss of MLH1 tumor immunostaining is consistently reported in carriers of the pathogenic variants, showing the impact of this protein instability on these tumors. Conclusions: Expression defects are frequent among MLH1 missense variants, but only severe defects cause Lynch syndrome. The data obtained here enabled us to establish a threshold for distinguishing tolerable (clinically neutral) from pathogenic expression defects. This threshold allows the translation of laboratory results for uncertain MLH1 variants into pathogenicity statements for diagnosis, thereby improving the targeting of cancer prevention measures in affected families. (C) 2013 AACR.
35.	Hofvander, Jakob, et al. (författare) Recurrent PRDM10 Gene Fusions in Undifferentiated Pleomorphic Sarcoma. 2015 Ingår i: Clinical Cancer Research. - 1078-0432. ; 21:4, s. 864-869 Tidskriftsartikel (refereegranskat)abstract Purpose: Undifferentiated pleomorphic sarcoma (UPS) is defined as a sarcoma with cellular pleomorphism and no identifiable line of differentiation. It is typically a high-grade lesion with a metastatic rate of about 1/3. No tumor-specific rearrangement has been identified and genetic markers that could be used for treatment stratification are lacking. We performed transcriptome sequencing (RNA-Seq) to search for novel gene fusions. Experimental design: RNA-Seq, fluorescence in situ hybridization, and/or various PCR methodologies were used to search for gene fusions and rearrangements of the PRDM10 gene in 84 soft tissue sarcomas. Results: Using RNA-Seq, two cases of UPS were found to display novel gene fusions, both involving the transcription factor PRDM10 as the 3'-partner and either MED12 or CITED2 as the 5'-partner gene. Further screening of 82 soft tissue sarcomas for rearrangements of the PRDM10 locus, revealed one more UPS with a MED12/PRDM10 fusion. None of these genes has been implicated in neoplasia-associated gene fusions before. Conclusions: Our results suggest that PRDM10-fusions are present in around 5% of UPS. Although the fusion-positive cases in our series showed the same nuclear pleomorphism and lack of differentiation as other UPS, it is noteworthy that all three were morphologically low-grade and that none of the patients developed metastases. Thus, PRDM10 fusion-positive sarcomas may constitute a clinically important subset of UPS.
36.	Humphries, Matthew P., et al. (författare) A case-matched gender comparison transcriptomic screen identifies eIF4E and eIF5 as potential prognostic markers in male breast cancer 2017 Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 23:10, s. 2575-2583 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.
37.	Indira Chandran, Vineesh, et al. (författare) Ultrasensitive Immunoprofiling of Plasma Extracellular Vesicles Identifies Syndecan-1 as a Potential Tool for Minimally Invasive Diagnosis of Glioma 2019 Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 25:10, s. 3115-3127 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.
38.	Ji, Zhenyu, et al. (författare) Vemurafenib Synergizes with Nutlin-3 to Deplete Survivin and Suppresses Melanoma Viability and Tumor Growth 2013 Ingår i: Clinical Cancer Research. - 1078-0432. ; 19:16, s. 4383-4391 Tidskriftsartikel (refereegranskat)abstract Purpose: For patients with advanced melanoma, primary and secondary resistance to selective BRAF inhibition remains one of the most critically compelling challenges. One rationale argues that novel biologically informed strategies are needed to maximally cripple melanoma cells up front before compensatory mechanisms emerge. As p53 is uncommonly mutated in melanoma, restoration of its function represents an attractive adjunct to selective BRAF inhibition. Experimental Design: Thirty-seven BRAF(V600E)-mutated melanoma lines were subjected to synergy studies in vitro using a combination of vemurafenib and nutlin-3 (Nt-3). In addition, cellular responses and in vivo efficacy were also determined. We also analyzed changes in the levels of canonical apoptotic/survival factors in response to vemurafenib. Results: Dual targeting of BRAF(V600E) and Hdm2 with vemurafenib and Nt-3, respectively, synergistically induced apoptosis and suppressed melanoma viability in vitro and tumor growth in vivo. Suppression of p53 in melanoma cells abrogated Nt-3's effects fully and vemurafenib's effects partially. A survey of canonical survival factors revealed that both vemurafenib and Nt-3 independently attenuated levels of the antiapoptotic protein, survivin. Genetic depletion of survivin reproduces the cytotoxic effects of the combination strategy. Conclusion: These results show preclinical feasibility for overcoming primary vemurafenib resistance by restoring p53 function. Moreover, it identifies survivin as one downstream mediator of the observed synergism and a potential secondary target. (C)2013 AACR.
39.	Jin, Yuesheng, et al. (författare) Distinct mitotic segregation errors mediate chromosomal instability in aggressive urothelial cancers. 2007 Ingår i: Clinical Cancer Research. - 1078-0432. ; 13:6, s. 1703-1712 Tidskriftsartikel (refereegranskat)abstract Purpose: Chromosomal instability (CIN) is believed to have an important role in the pathogenesis of urothelial cancer (UC). The aim of this study was to evaluate whether disturbances of mitotic segregation contribute to CIN in UC, if these processes have any effect on the course of disease, and how deregulation of these mechanisms affects tumor cell growth. Experimental Design: We developed molecular cytogenetic methods to classify mitotic segregation abnormalities in a panel of UC cell lines. Mitotic instabilities were then scored in biopsies from 52 UC patients and compared with the outcome of tumor disease. Finally, UC cells were exposed in vitro to a telomerase inhibitor to assess how this affects mitotic stability and cell proliferation. Results: Three distinct chromosome segregation abnormalities were identified: (a) telomere dysfunction, which triggers structural rearrangements and loss of chromosomes through anaphase bridging; (b) sister chromatid nondisjunction, which generates discrete chromosomal copy number variations; and (c) supernumerary centrosomes, which cause dramatic shifts in chromosome copy number through multipolar cell division. Chromosome segregation errors were already present in preinvasive tumors and a high rate mitotic instability was an independent predictor of poor survival. However, induction of even higher levels of the same segregation abnormalities in UC cells by telomerase inhibition in vitro led to reduced tumor cell proliferation and clonogenic survival. Conclusion: Several distinct chromosome segregation errors contribute to CIN in UC, and the rate of such mitotic errors has a significant effect on the clinical course. Efficient tumor cell proliferation may depend on the tight endogenous control of these processes.
40.	Joensuu, Heikki, et al. (författare) KIT and PDGFRA Mutations and Survival of Gastrointestinal Stromal Tumor Patients Treated with Adjuvant Imatinib in a Randomized Trial 2023 Ingår i: Clinical Cancer Research. - 1078-0432. ; 29:17, s. 3313-3319 Tidskriftsartikel (refereegranskat)abstract Purpose: Limited data are available about the influence of KIT and PDGFRA mutations on overall survival (OS) of patients with gastrointestinal stromal tumor (GIST) treated with adjuvant imatinib. Patients and Methods: The Scandinavian Sarcoma Group XVIII/AIO multicenter trial accrued 400 patients with a high risk for GIST recurrence after macroscopically complete surgery between February 4, 2004, and September 29, 2008. The patients received adjuvant imatinib 400 mg/day for either 1 year or 3 years based on random allocation. We analyzed using conventional sequencing KIT and PDGFRA mutations centrally from 341 (85%) patients who had localized, centrally confirmed GIST, and correlated the results with recurrence-free survival (RFS) and OS in exploratory analyses. Results: During a median follow-up time of 10 years, 164 RFS events and 76 deaths occurred. Most patients were re-treated with imatinib when GIST recurred. Patients with KIT exon 11 deletion or indel mutation treated with 3 years of adjuvant imatinib survived longer than patients treated for 1 year [10-year OS 86% versus 64%, respectively; HR, 0.34; 95% confidence interval (CI), 0.15-0.72; P 0.007], and also had longer RFS (10-year RFS 47% versus 29%; HR, 0.48; 95% CI, 0.31-0.74; P < 0.001). Patients with KIT exon 9 mutation had unfavorable OS regardless of the duration of adjuvant imatinib. Conclusions: Compared with 1 year of imatinib, 3 years of adjuvant imatinib led to 66% reduction in the estimated risk of death and a high 10-year OS rate in the subset of patients with a KIT exon 11 deletion/indel mutation.
41.	Jönsson, Göran B, et al. (författare) Gene Expression Profiling-Based Identification of Molecular Subtypes in Stage IV Melanomas with Different Clinical Outcome. 2010 Ingår i: Clinical Cancer Research. - 1078-0432. ; 16:13, s. 3356-3367 Tidskriftsartikel (refereegranskat)abstract PURPOSE: The incidence of malignant melanoma is increasing worldwide in fair-skinned populations. Melanomas respond poorly to systemic therapy, and metastatic melanomas inevitably become fatal. While spontaneous regression, likely due to immune defense activation, rarely occurs, we lack a biological rationale and predictive markers selecting patients for immune therapy. Experimental design: We performed unsupervised hierarchical clustering of global gene expression data from stage IV melanomas in 57 patients. For further characterization we used immunohistochemistry of selected markers, genome-wide DNA copy number analysis, genetic and epigenetic analysis of the CDKN2A locus and NRAS/BRAF mutation screening. RESULTS: The analysis revealed four distinct subtypes with gene signatures characterized by expression of immune response, pigmentation differentiation, proliferation or stromal composition genes. Even though all subtypes harbored NRAS and BRAF mutations, there was a significant difference between subtypes (p<0.01), with no BRAF/NRAS wild-type samples in the proliferative subtype. Additionally, the proliferative subtype was characterized by high frequency of CDKN2A homozygous deletions (p<0.01). We observed different prognosis between the subtypes (p=0.01), with a particularly poor survival for patients harboring tumors of the proliferative subtype compared to the others (p = 0.003). Importantly, the clinical relevance of the subtypes was validated in an independent cohort of 44 stage III/IV melanomas. Moreover, low expression of an a priori-defined gene set associated to immune response signaling was significantly associated to poor outcome (p=0.001). CONCLUSIONS: Our data reveal a biologically-based taxonomy of malignant melanomas with prognostic impact and support an influence of the anti-tumoral immune response on outcome.
42.	Karlsson, Anna K, et al. (författare) Genome-wide DNA methylation analysis of lung carcinoma reveals one neuroendocrine and four adenocarcinoma epitypes associated with patient outcome. 2014 Ingår i: Clinical Cancer Research. - 1078-0432. ; 20:23, s. 6127-6140 Tidskriftsartikel (refereegranskat)abstract Purpose: Lung cancer is the worldwide leading cause of death from cancer. DNA methylation in gene promoter regions is a major mechanism of gene expression regulation that may promote tumorigenesis. However, whether clinically relevant subgroups based on DNA methylation patterns exist in lung cancer remains unclear. Experimental Design: Whole-genome DNA methylation analysis using 450K Illumina BeadArrays was performed on 12 normal lung tissues and 124 tumors including 83 adenocarcinomas, 23 squamous cell carcinomas (SqCC), one adenosquamous cancer, five large cell carcinomas, nine large cell neuroendocrine carcinomas (LCNEC), and three small cell carcinomas (SCLC). Unsupervised bootstrap clustering was performed to identify DNA methylation subgroups, which were validated in 695 adenocarcinomas and 122 SqCCs. Subgroups were characterized by clinicopathological factors, whole-exome sequencing data, and gene expression profiles. Results: Unsupervised analysis identified five DNA methylation subgroups (epitypes). One epitype was distinctly associated with neuroendocrine tumors (LCNEC and SCLC). For adenocarcinoma, remaining four epitypes were associated with unsupervised and supervised gene expression phenotypes, and differences in molecular features including global hypomethylation, promoter hypermethylation, genomic instability, expression of proliferation-associated genes, and mutations in KRAS, TP53, KEAP1, SMARCA4, and STK11. Furthermore, these epitypes were associated with clinicopathological features such as smoking history, and patient outcome. Conclusions: Our findings highlight one neuroendocrine and four adenocarcinoma epitypes associated with molecular and clinicopathological characteristics, including patient outcome. This study highlights the possibility to further subgroup lung cancer, and more specifically adenocarcinomas, based on epigenetic/molecular classification that could lead to more accurate tumor classification, prognostication, and tailored patient therapy.
43.	Karlsson, Anna K, et al. (författare) Genomic and transcriptional alterations in lung adenocarcinoma in relation to smoking history. 2014 Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 20:18, s. 4912-4924 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.
44.	Karlsson, Jenny, et al. (författare) Arsenic trioxide-induced death of neuroblastoma cells involves activation of Bax and does not require p53. 2004 Ingår i: Clinical Cancer Research. - 1078-0432. ; 10:9, s. 3179-3188 Tidskriftsartikel (refereegranskat)
45.	Kimbung, Siker, et al. (författare) Transcriptional Profiling of Breast Cancer Metastases Identifies Liver Metastasis-Selective Genes Associated with Adverse Outcome in Luminal A Primary Breast Cancer 2016 Ingår i: Clinical Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 22:1, s. 146-157 Tidskriftsartikel (refereegranskat)abstract Purpose: The complete molecular basis of the organ-specificity of metastasis is elusive. This study aimed to provide an independent characterization of the transcriptional landscape of breast cancer metastases with the specific objective to identify liver metastasis-selective genes of prognostic importance following primary tumor diagnosis. Experimental Design: A cohort of 304 women with advanced breast cancer was studied. Associations between the site of recurrence and clinicopathologic features were investigated. Fine-needle aspirates of metastases (n = 91) were subjected to whole-genome transcriptional profiling. Liver metastasis-selective genes were identified by significance analysis of microarray (SAM) analyses and independently validated in external datasets. Finally, the prognostic relevance of the liver metastasis-selective genes in primary breast cancer was tested. Results: Liver relapse was associated with estrogen receptor (ER) expression (P = 0.002), luminal B subtype (P = 0.01), and was prognostic for an inferior postrelapse survival (P = 0.01). The major variation in the transcriptional landscape of metastases was also associated with ER expression and molecular subtype. However, liver metastases displayed unique transcriptional fingerprints, characterized by down-regulation of extracellular matrix (i.e., stromal) genes. Importantly, we identified a 17-gene liver metastasis-selective signature, which was significantly and independently prognostic for shorter relapse-free (P < 0.001) and overall (P = 0.001) survival in ER-positive tumors. Remarkably, this signature remained independently prognostic for shorter relapse-free survival (P = 0.001) among luminal A tumors. Conclusions: Extracellular matrix (stromal) genes can be used to partition breast cancer by site of relapse and may be used to further refine prognostication in ER positive primary breast cancer. (C)2015 AACR.
46.	Klintman, Marie, et al. (författare) Changes in expression of genes representing key biologic processes after neoadjuvant chemotherapy in breast cancer, and prognostic implications in residual disease 2016 Ingår i: Clinical Cancer Research. - 1078-0432. ; 22:10, s. 2405-2416 Tidskriftsartikel (refereegranskat)abstract Purpose: The primary aim was to derive evidence for or against the clinical importance of several biologic processes in patients treated with neoadjuvant chemotherapy (NAC) by assessing expression of selected genes with prior implications in prognosis or treatment resistance. The secondary aim was to determine the prognostic impact in residual disease of the genes' expression. Experimental Design: Expression levels of 24 genes were quantified by NanoString nCounter on formalin-fixed paraffinembedded residual tumors from 126 patients treated with NAC and 56 paired presurgical biopsies. The paired t test was used for testing changes in gene expression, and Cox regression and penalized elastic-net Cox Regression for estimating HRs. Results: After NAC, 12 genes were significantly up- and 8 downregulated. Fourteen genes were significantly associated with time to recurrence in univariable analysis in residual disease. In a multivariable model, ACACB, CD3D, MKI67, and TOP2A added prognostic value independent of clinical ER-, PgR-, and HER2- status. In ER+/HER2- patients, ACACB, PAWR, and ERBB2 predicted outcome, whereas CD3D and PAWR were prognostic in ER-/HER2- patients. By use of elastic-net analysis, a 6-gene signature (ACACB, CD3D, DECORIN, ESR1, MKI67, PLAU) was identified adding prognostic value independent of ER, PgR, and HER2. Conclusions: Most of the tested genes were significantly enriched or depleted in response to NAC. Expression levels of genes representing proliferation, stromal activation, metabolism, apoptosis, stemcellness, immunologic response, and Ras-ERK activation predicted outcome in residual disease. Themultivariable gene models identified could, if validated, be used to identify patients needing additional post-neoadjuvant treatment to improve prognosis.
47.	Koch, Raphael, et al. (författare) Zoledronic Acid Add-on Therapy for Standard-Risk Ewing Sarcoma Patients in the Ewing 2008R1 Trial 2023 Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 29:24, s. 5057-5068 Tidskriftsartikel (refereegranskat)abstract PURPOSE: The phase III, open-label, prospective, multicenter, randomized Ewing 2008R1 trial (EudraCT2008-003658-13) was conducted in 12 countries to evaluate the effect of zoledronic acid (ZOL) maintenance therapy compared with no add-on regarding event-free survival (EFS, primary endpoint) and overall survival (OS) in standard-risk Ewing sarcoma (EWS). PATIENTS AND METHODS: Eligible patients had localized EWS with either good histologic response to induction chemotherapy and/or small tumors (<200 mL). Patients received six cycles of VIDE induction and eight cycles of VAI (male) or eight cycles of VAC (female) consolidation. ZOL treatment started parallel to the sixth consolidation cycle. Randomization was stratified by tumor site (pelvis/other). The two-sided adaptive inverse-normal four-stage design (planned sample size 448 patients, significance level 5%, power 80%) was changed after the first interim analysis using the Müller-Schäfer method. RESULTS: Between April 2010 and November 2018, 284 patients were randomized (142 ZOL/142 no add-on). With a median follow-up of 3.9 years, EFS was not significantly different between ZOL and no add-on group in the adaptive design (HR, 0.74; 95% CI, 0.43-1.28, P = 0.27, intention-to-treat). Three-year EFS rates were 84.0% (95% CI, 77.7%-90.8%) for ZOL vs. 81.7% (95% CI, 75.2%-88.8%) for no add-on. Results were similar in the per-protocol collective. OS was not different between groups. The 3-year OS was 92.8% (95% CI, 88.4%-97.5%) for ZOL and 94.6% (95% CI, 90.9%-98.6%) for no add-on. Noticeable more renal, neurologic, and gastrointestinal toxicities were observed for ZOL (P < 0.05). Severe renal toxicities occurred more often in the ZOL arm (P = 0.003). CONCLUSIONS: In patients with standard-risk localized EWS, there is no additional benefit from maintenance treatment with ZOL.
48.	Kumar, Rakesh, et al. (författare) Extranuclear Coactivator Signaling Confers Insensitivity to Tamoxifen. 2009 Ingår i: Clinical Cancer Research. - 1078-0432. ; 15, s. 4123-4130 Tidskriftsartikel (refereegranskat)abstract PURPOSE: Tamoxifen is one of many standard therapeutic options currently available for estrogen receptor-alpha-positive breast cancer patients. Emerging data have suggested that levels of estrogen receptor coregulatory proteins play a significant role in acquiring resistance to antiestrogen action. It has been suggested that high levels of estrogen receptor coactivators and its mislocalization may enhance the estrogen agonist activity of tamoxifen and contribute to tamoxifen resistance.EXPERIMENTAL DESIGN: In an effort to understand the impact of nongenomic signaling and its contribution to hormone resistance in a whole-animal setting, we generated a transgenic mouse expressing a cytoplasmic version of proline-, glutamic acid-, and leucine-rich protein-1 (PELP1) mutant defective in its nuclear translocation (PELP1-cyto) and implanted these mice with tamoxifen pellets to assess its responsiveness.RESULTS: We show that mammary glands from these mice developed widespread hyperplasia with increased cell proliferation and enhanced activation of mitogen-activated protein kinase and AKT as early as 12 weeks of age. Treatment with tamoxifen did not inhibit this hyperplasia; instead, such treatment exaggerated hyperplasia with an enhanced degree of alteration, indicative of hypersensitivity to tamoxifen. Analysis of molecular markers in the transgenic mammary glands from the tamoxifen-treated transgenic mice showed higher levels of proliferation markers proliferating cell nuclear antigen and activated mitogen-activated protein kinase than in untreated PELP1-cyto cell-derived mice. We also found that nude mice with MCF-7/PELP1-cyto cell-derived tumor xenografts did not respond to tamoxifen. Using immunohistochemical analysis, we found that 43% of human breast tumor samples had high levels of cytoplasmic PELP1, which shows a positive correlation between tumor grade and proliferation. Patients whose tumors had high levels of cytoplasmic PELP1 exhibited a tendency to respond poorly to tamoxifen compared with patients whose tumors had low levels of cytoplasmic PELP1.CONCLUSIONS: These findings suggest that PELP1 localization could be used as a determinant of hormone sensitivity or vulnerability. The establishment of the PELP1-cyto transgenic mouse model is expected to facilitate the development of preclinical approaches for effective intervention of breast tumors using cytoplasmic coregulators and active nongenomic signaling.
49.	Laakso, Mervi, et al. (författare) Basoluminal carcinoma: A new biologically and prognostically distinct entity between basal and luminal breast cancer 2006 Ingår i: Clinical Cancer Research. - 1078-0432. ; 12:14, s. 4185-4191 Tidskriftsartikel (refereegranskat)abstract Purpose: Breast carcinomas expressing basal epithelium cytokeratins constitute a tumor subgroup that is typically hormone receptor negative and shows a distinct gene expression profile. Based on variable basal cytokeratin immunostaining patterns, we hypothesized that the "basal phenotype" tumor group may comprise more than one biological entity. Experimental Design: Basal cytokeratins 5 and 14 (CK5/14) were stained by immunohistochemistry and the percentage of positive cells was defined by image analysis. The results thus obtained were compared with clinicopathologic characteristics and relapse-free survival. Results: Of the 506 breast tumors, 53 (10.5%) showed immunoreactivity for CK5/14. Basal cytokeratin expression showed up as two microscopically distinguishable subtypes, i.e., a uniformly positive type ("basal") and a partially positive type ("basoluminal") often displaying a checkerboard-type intratumoral heterogeneity. These subgroups could also be separated with a third basal cytokeratin (CK17, P < 0,0001). Both basal and basoluminal subtypes were hormone receptor negative and of high grade, but differed with respect to the Ki-67 labeling index (P = 0.0014), vimentin (P = 0.005), and c-kit (P = 0.02), which were more frequently expressed in basal than in basoluminal tumors. In contrast, the amplification of HER-2 was found almost exclusively in the basoluminal subgroup (P = 0.009). Compared with the basal tumors, basoluminal tumors associated with significantly shorter relapse-free survival (P = 0.01), which was not explained by their more frequent HER-2 amplification. Conclusions: We conclude that the intratumoral heterogeneity in basal cytokeratin expression can be used to define two distinct breast cancer subtypes, basal and basoluminal, with distinctive features related to proliferation activity, oncogene and biomarker status, and patient survival.
50.	Labbé, David P., et al. (författare) TOP2A and EZH2 provide early detection of an aggressive prostate cancer subgroup 2017 Ingår i: Clinical Cancer Research. - 1078-0432. ; 23:22, s. 7072-7083 Tidskriftsartikel (refereegranskat)abstract Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer–associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer–derived murine cell lines. Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches.

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