The 70‐gene signature (MammaPrint™) has been developed on retrospective series of breast cancer patients to predict the risk of breast cancer distant metastases. The ...microarRAy‐prognoSTics‐in‐breast‐cancER (RASTER) study was the first study designed to prospectively evaluate the performance of the 70‐gene signature, which result was available for 427 patients (cT1–3N0M0). Adjuvant systemic treatment decisions were based on the Dutch CBO 2004 guidelines, the 70‐gene signature and doctors' and patients' preferences. Five‐year distant‐recurrence‐free‐interval (DRFI) probabilities were compared between subgroups based on the 70‐gene signature and Adjuvant! Online (AOL) (10‐year survival probability <90% was defined as high‐risk). Median follow‐up was 61.6 months. Fifteen percent (33/219) of the 70‐gene signature low‐risk patients received adjuvant chemotherapy (ACT) versus 81% (169/208) of the 70‐gene signature high‐risk patients. The 5‐year DRFI probabilities for 70‐gene signature low‐risk (n = 219) and high‐risk (n = 208) patients were 97.0% and 91.7%. The 5‐year DRFI probabilities for AOL low‐risk (n = 132) and high‐risk (n = 295) patients were 96.7% and 93.4%. For 70‐gene signature low‐risk–AOL high‐risk patients (n = 124), of whom 76% (n = 94) had not received ACT, 5‐year DRFI was 98.4%. In the AOL high‐risk group, 32% (94/295) less patients would be eligible to receive ACT if the 70‐gene signature was used. In this prospective community‐based observational study, the 5‐year DRFI probabilities confirmed the additional prognostic value of the 70‐gene signature to clinicopathological risk estimations such as AOL. Omission of adjuvant chemotherapy as judged appropriate by doctors and patients and instigated by a low‐risk 70‐gene signature result, appeared not to compromise outcome.
What's new?
The “MammaPrint” is a 70‐gene signature developed to predict the risk of breast cancer metastases. This study, the RASTER study, provides the first prospective data looking at this 70‐gene signature to evaluate it's performance. For 427 patients, treatment decisions were based on standard guidelines, the 70‐gene signature, and doctors' and patients' preferences. Here, 124 patients were categorized as “low‐risk” by the 70‐gene signature, but high‐risk by other measures, such as age, tumor size, nodal status, and other clinicopathological factors. Of these, 76% did not receive adjuvant chemotherapy, and 98% survived 5 years with no recurrence of disease. Thus, withholding chemotherapy based on the low‐risk gene signature result, and in accordance with doctors' and patients' preferences, did not negatively impact recurrence rate, confirming the prognostic value of this new tool.
Triple negative breast cancers (TNBCs) have a relatively poor prognosis and cannot be effectively treated with current targeted therapies. We searched for genes that have the potential to be ...therapeutic targets by identifying genes consistently overexpressed when amplified. Fifty-six TNBCs were subjected to high-resolution microarray-based comparative genomic hybridization (aCGH), of which 24 were subjected to genome-wide gene expression analysis. TNBCs were genetically heterogeneous; no individual focal amplification was present at high frequency, although 78.6% of TNBCs harboured at least one focal amplification. Integration of aCGH and expression data revealed 40 genes significantly overexpressed when amplified, including the known oncogenes and potential therapeutic targets, FGFR2 (10q26.3), BUB3 (10q26.3), RAB20 (13q34), PKN1 (19p13.12) and NOTCH3 (19p13.12). We identified two TNBC cell lines with FGFR2 amplification, which both had constitutive activation of FGFR2. Amplified cell lines were highly sensitive to FGFR inhibitor PD173074, and to RNAi silencing of FGFR2. Treatment with PD173074 induced apoptosis resulting partly from inhibition of PI3K-AKT signalling. Independent validation using publicly available aCGH data sets revealed FGFR2 gene was amplified in 4% (6/165) of TNBC, but not in other subtypes (0/214, P=0.0065). Our analysis demonstrates that TNBCs are heterogeneous tumours with amplifications of FGFR2 in a subgroup of tumours.
Background. The role of environmental contamination in nosocomial cross-transmission of antibiotic-resistant bacteria has been unresolved. Using vancomycin-resistant enterococci (VRE) as a marker ...organism, we investigated the effects of improved environmental cleaning with and without promotion of hand hygiene adherence on the spread of VRE in a medical intensive care unit. Methods. The study comprised a baseline period (period 1), a period of educational intervention to improve environmental cleaning (period 2), a “washout” period without any specific intervention (period 3), and a period of multimodal hand hygiene intervention (period 4). We performed cultures for VRE of rectal swab samples obtained from patients at admission to the intensive care unit and daily thereafter, and we performed cultures of environmental samples and samples from the hands of health care workers twice weekly. We measured patient clinical and demographic variables and monitored intervention adherence frequently. Results. Our study included 748 admissions to the intensive care unit over a 9-month period. VRE acquisition rates were 33.47 cases per 1000 patient-days at risk for period 1 and 16.84, 12.09, and 10.40 cases per 1000 patient-days at risk for periods 2, 3, and 4, respectively. The mean (±SD) weekly rate of environmental sites cleaned increased from 0.48 ± 0.08 at baseline to 0.87 ± 0.08 in period 2; similarly high cleaning rates persisted in periods 3 and 4. Mean (±SD) weekly hand hygiene adherence rate was 0.40 ± 0.01 at baseline and increased to 0.57 ± 0.11 in period 2, without a specific intervention to improve adherence, but decreased to 0.29 ± 0.26 in period 3 and 0.43 ± 0.1 in period 4. Mean proportions of positive results of cultures of environmental and hand samples decreased in period 2 and remained low thereafter. In a Cox proportional hazards model, the hazard ratio for acquiring VRE during periods 2–4 was 0.36 (95% confidence interval, 0.19–0.68); the only determinant explaining the difference in VRE acquisition was admission to the intensive care unit during period 1. Conclusions. Decreasing environmental contamination may help to control the spread of some antibiotic-resistant bacteria in hospitals.
Earlier, mapping of the 9p23-24 amplicon in esophageal cancer cell lines led us to the positional cloning of gene amplified in squamous cell carcinoma 1 (GASC1), which encodes a nuclear protein with ...a Jumonji C domain that catalyzes lysine (K) demethylation of histones. However, the transforming roles of GASC1 in breast cancer remain to be determined. In this study, we identified GASC1 as one of the amplified genes for the 9p23-24 region in breast cancer, particularly in basal-like subtypes. The levels of GASC1 transcript expression were significantly higher in aggressive, basal-like breast cancers compared with nonbasal-like breast cancers. Our in vitro assays demonstrated that GASC1 induces transformed phenotypes, including growth factor-independent proliferation, anchorage-independent growth, altered morphogenesis in Matrigel, and mammosphere forming ability, when overexpressed in immortalized, nontransformed mammary epithelial MCF10A cells. Additionally, GASC1 demethylase activity regulates the expression of genes critical for stem cell self-renewal, including NOTCH1, and may be linked to the stem cell phenotypes in breast cancer. Thus, GASC1 is a driving oncogene in the 9p23-24 amplicon in human breast cancer and targeted inhibition of GASC1 histone demethylase in cancer could provide potential new avenues for therapeutic development.
The OVHIPEC-1 trial previously showed that the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery resulted in improved progression-free and overall ...survival compared with cytoreductive surgery alone at 4·7 years of follow-up in patients with stage III epithelial ovarian cancer who were ineligible for primary cytoreduction. We report the final survival outcomes after 10 years of follow-up.
In this open-label, randomised, controlled, phase 3 trial, patients with primary epithelial stage III ovarian cancer were recruited at eight HIPEC centres in the Netherlands and Belgium. Patients were eligible if they were aged 18–76 years, had not progressed during at least three cycles of neoadjuvant carboplatin plus paclitaxel, had a WHO performance status score of 0–2, normal blood counts, and adequate renal function. Patients were randomly assigned (1:1) to undergo interval cytoreductive surgery without HIPEC (surgery group) or with HIPEC (100 mg/m2 cisplatin; surgery-plus-HIPEC group). Randomisation was done centrally by minimisation with a masked web-based allocation procedure at the time of surgery when residual disease smaller than 10 mm diameter was anticipated, and was stratified by institution, previous suboptimal cytoreductive surgery, and number of abdominal regions involved. The primary endpoint was progression-free survival and a secondary endpoint was overall survival, analysed in the intention-to-treat population (ie, all randomly assigned patients). This study is registered with ClinicalTrials.gov, NCT00426257, and is closed.
Between April 1, 2007, and April 30, 2016, 245 patients were enrolled and followed up for a median of 10·1 years (95% CI 8·4–12·9) in the surgery group (n=123) and 10·4 years (95% CI 9·5–13·3) in the surgery-plus-HIPEC group (n=122). Recurrence, progression, or death occurred in 114 (93%) patients in the surgery group (median progression-free survival 10·7 months 95% CI 9·6–12·0) and 109 (89%) patients in the surgery-plus-HIPEC group (14·3 months 12·0–18·5; hazard ratio HR 0·63 95% CI 0·48–0·83, stratified log-rank p=0·0008). Death occurred in 108 (88%) patients in the surgery group (median overall survival 33·3 months 95% CI 29·0–39·1) and 100 (82%) patients in the surgery-plus-HIPEC group (44·9 months 95% CI 38·6–55·1; HR 0·70 95% CI 0·53–0·92, stratified log-rank p=0·011).
These updated survival results confirm the long-term survival benefit of HIPEC in patients with primary stage III epithelial ovarian cancer undergoing interval cytoreductive surgery.
Dutch Cancer Foundation (KWF Kankerbestrijding).
Purpose The 70-gene prognosis signature (van't Veer et al., Nature 415(6871):530-536, 2002) may improve the selection of lymph node-negative breast cancer patients for adjuvant systemic therapy. ...Optimal validation of prognostic classifiers is of great importance and we therefore wished to evaluate the prognostic value of the 70-gene prognosis signature in a series of relatively recently diagnosed lymph node negative breast cancer patients. Methods We evaluated the 70-gene prognosis signature in an independent representative series of patients with invasive breast cancer (N = 123; <55 years; pT1-2N0; diagnosed between 1996 and 1999; median follow-up 5.8 years) by classifying these patients as having a good or poor prognosis signature. In addition, we updated the follow-up of the node-negative patients of the previously published validation-series (Van de Vijver et al., N Engl J Med 347(25):1999-2009, 2002; N = 151; median follow-up 10.2 years). The prognostic value of the 70-gene prognosis signature was compared with that of four commonly used clinicopathological risk indexes. The endpoints were distant metastasis (as first event) free percentage (DMFP) and overall survival (OS). Results The 5-year OS was 82 ± 5% in poor (48%) and 97 ± 2% in good prognosis signature (52%) patients (HR 3.4; 95% CI 1.2-9.6; P = 0.021). The 5-years DMFP was 78 ± 6% in poor and 98 ± 2% in good prognosis signature patients (HR 5.7; 95% CI 1.6-20; P = 0.007). In the updated series (N = 151; 60% poor vs. 40% good), the 10-year OS was 51 ± 5% and 94 ± 3% (HR 10.7; 95% CI 3.9-30; P < 0.01), respectively. The DMFP was 50 ± 6% in poor and 86 ± 5% in good prognosis signature patients (HR 5.5; 95% CI 2.5-12; P < 0.01). In multivariate analysis, the prognosis signature was a strong independent prognostic factor in both series, outperforming the clinicopathological risk indexes. Conclusion The 70-gene prognosis signature is also an independent prognostic factor in node-negative breast cancer patients for women diagnosed in recent years.
Visceral organ metastasis is associated with poor survival outcomes in terms of metastasis free- and overall survival in breast carcinomas. Identification of a gene expression profile in tumours that ...selects a subpopulation of patients that is more likely to develop visceral organ metastases will help elucidate mechanisms for the development of distant metastases and could be of clinical value. With this study we aimed to determine genomic predictors that would help to distinguish breast cancer patients with more likelihood to develop visceral metastasis.
Gene expression profiling data of 157 primary tumours from breast cancer patients who developed distant metastases were analyzed and differentially expressed genes between the group of tumours with visceral metastasis and the those without visceral metastases were identified. Published data were used to validate our findings. Multivariate logistic regression tests were applied to further investigate the association between the gene-expression-signature and clinical variables. Survival analyses were performed by the Kaplan-Meier method.
Fourteen differentially expressed genes (WDR6, CDYL, ATP6V0A4, CHAD, IDUA, MYL5, PREP, RTN4IP1, BTG2, TPRG1, ABHD14A, KIF18A, S100PBP and BEND3) were identified between the group of tumours with and without visceral metastatic disease. Five of these genes (CDYL, ATP6V0A4, PREP, RTN4IP1 and KIF18A) were up-regulated and the other genes were down-regulated. This gene expression signature was validated in the training and in the independent data set (p 2.13e- 08 and p 9.68e- 06, respectively). Multivariate analyses revealed that the 14-gene-expression-signature was associated with visceral metastatic disease (p 0.001, 95% CI 1.43-4.27), independent of other clinicopathologic features. This signature has been also found to be associated with survival status of the patients (p < .001).
We have identified an unique gene expression signature which is specific to visceral metastasis. This 14-gene-expression-signature may play a role in identifying the subgroup of patients with potential to develop visceral metastasis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Breast cancer cells deficient for BRCA1 are hypersensitive to agents inducing DNA double-strand breaks (DSB), such as bifunctional alkylators and platinum agents. Earlier, we had developed a ...comparative genomic hybridisation (CGH) classifier based on BRCA1-mutated breast cancers. We hypothesised that this BRCA1-likeCGH classifier could also detect loss of function of BRCA1 due to other causes besides mutations and, consequently, might predict sensitivity to DSB-inducing agents.
We evaluated this classifier in stage III breast cancer patients, who had been randomly assigned between adjuvant high-dose platinum-based (HD-PB) chemotherapy, a DSB-inducing regimen, and conventional anthracycline-based chemotherapy. Additionally, we assessed BRCA1 loss through mutation or promoter methylation and immunohistochemical basal-like status in the triple-negative subgroup (TN subgroup).
We observed greater benefit from HD-PB chemotherapy versus conventional chemotherapy among patients with BRCA1-likeCGH tumours 41/230 = 18%, multivariate hazard ratio (HR) = 0.12, 95% confidence interval (CI) 0.04–0.43 compared with patients with non-BRCA1-likeCGH tumours (189/230 = 82%, HR = 0.78, 95% CI 0.50–1.20), with a significant difference (test for interaction P = 0.006). Similar results were obtained for overall survival (P interaction = 0.04) and when analyses were restricted to the TN subgroup. Sixty-three percent (20/32) of assessable BRCA1-likeCGH tumours harboured either a BRCA1 mutation (n = 8) or BRCA1 methylation (n = 12).
BRCA1 loss as assessed by CGH analysis can identify patients with substantially improved outcome after adjuvant DSB-inducing chemotherapy when compared with standard anthracycline-based chemotherapy in our series.
Motivation: Genetic analysis of HIV-1 is important not only for vaccine development, but also to guide treatment strategies, track the emergence of new viral variants and ensure that diagnostic ...assays are contemporary and fully optimized. However, most genotyping methods are laborious and complex, and involve the use of multiple software applications. Here, we describe the development of an automated genotyping system that can be easily applied to HIV-1 and other rapidly evolving viral pathogens. Results: The new REGA subtyping tool, developed using Java programming and PERL scripts, combines phylogenetic analyses with bootscanning methods for the genetic subtyping of full-length and subgenomic fragments of HIV-1. When used to investigate the subtype of previously published reference datasets that were analysed using manual phylogenetic methods, the automated method correctly identified 97.5–100% of non-recombinant and circulating recombinant forms of HIV-1, including 108 full-length, 108 gag and 221 env sequences downloaded from the Los Alamos database. Availability: The tool, which can be easily downloaded and installed on either a UNIX or Linux-based computer system, is available at http://www.bioafrica.net/subtypetool/html/ Contact: tulio.deoliveira@zoology.oxford.ac.uk
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