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Optimized outcome prediction in breast cancer by combining the 70-gene signature with clinical risk prediction algorithms.

ABSTRACT: Clinical guidelines for breast cancer treatment differ in their selection of patients at a high risk of recurrence who are eligible to receive adjuvant systemic treatment (AST). The 70-gene signature is a molecular tool to better guide AST decisions. The aim of this study was to evaluate whether adding the 70-gene signature to clinical risk prediction algorithms can optimize outcome prediction and consequently treatment decisions in early stage, node-negative breast cancer patients. A 70-gene signature was available for 427 patients participating in the RASTER study (cT1-3N0M0). Median follow-up was 61.6 months. Based on 5-year distant-recurrence free interval (DRFI) probabilities survival areas under the curve (AUC) were calculated and compared for risk estimations based on the six clinical risk prediction algorithms: Adjuvant! Online (AOL), Nottingham Prognostic Index (NPI), St. Gallen (2003), the Dutch National guidelines (CBO 2004 and NABON 2012), and PREDICT plus. Also, survival AUC were calculated after adding the 70-gene signature to these clinical risk estimations. Systemically untreated patients with a high clinical risk estimation but a low risk 70-gene signature had an excellent 5-year DRFI varying between 97.1 and 100 %, depending on the clinical risk prediction algorithms used in the comparison. The best risk estimation was obtained in this cohort by adding the 70-gene signature to CBO 2012 (AUC: 0.644) and PREDICT (AUC: 0.662). Clinical risk estimations by all clinical algorithms improved by adding the 70-gene signature. Patients with a low risk 70-gene signature have an excellent survival, independent of their clinical risk estimation. Adding the 70-gene signature to clinical risk prediction algorithms improves risk estimations and therefore might improve the identification of early stage node-negative breast cancer patients for whom AST has limited value. In this cohort, the PREDICT plus tool in combination with the 70-gene signature provided the best risk prediction.

SUBMITTER: Drukker CA

PROVIDER: S-EPMC4031388 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionMutations in BRCA1 and BRCA2 confer high risks of breast cancer and ovarian cancer. The risk prediction algorithm BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) may be used to compute the probabilities of carrying mutations in BRCA1 and BRCA2 and help to target mutation screening. Tumours from BRCA1 and BRCA2 mutation carriers display distinctive pathological features that could be used to better discriminate between BRCA1 mutation carriers, BRCA2 mutation carriers and noncarriers. In particular, oestrogen receptor (ER)-negative status, triple-negative (TN) status, and expression of basal markers are predictive of BRCA1 mutation carrier status.MethodsWe extended BOADICEA by treating breast cancer subtypes as distinct disease end points. Age-specific expression of phenotypic markers in a series of tumours from 182 BRCA1 mutation carriers, 62 BRCA2 mutation carriers and 109 controls from the Breast Cancer Linkage Consortium, and over 300,000 tumours from the general population obtained from the Surveillance Epidemiology, and End Results database, were used to calculate age-specific and genotype-specific incidences of each disease end point. The probability that an individual carries a BRCA1 or BRCA2 mutation given their family history and tumour marker status of family members was computed in sample pedigrees.ResultsThe cumulative risk of ER-negative breast cancer by age 70 for BRCA1 mutation carriers was estimated to be 55% and the risk of ER-positive disease was 18%. The corresponding risks for BRCA2 mutation carriers were 21% and 44% for ER-negative and ER-positive disease, respectively. The predicted BRCA1 carrier probabilities among ER-positive breast cancer cases were less than 1% at all ages. For women diagnosed with breast cancer below age 50 years, these probabilities rose to more than 5% in ER-negative breast cancer, 7% in TN disease and 24% in TN breast cancer expressing both CK5/6 and CK14 cytokeratins. Large differences in mutation probabilities were observed by combining ER status and other informative markers with family history.ConclusionsThis approach combines both full pedigree and tumour subtype data to predict BRCA1/2 carrier probabilities. Prediction of BRCA1/2 carrier status, and hence selection of women for mutation screening, may be substantially improved by combining tumour pathology with family history of cancer.

Project description:Endometrial carcinoma (EC) is one of the common gynecological cancers with increasing incidence and revived mortality recently. Given the heterogeneity of tumors and the complexity of lncRNAs, a panel of lncRNA biomarkers might be more precise and stable for prognosis. In the present study, we developed a new lncRNA model to predict the prognosis of patients with EC. EC-associated differentially expressed long noncoding RNAs (lncRNAs) were identified from The Cancer Genome Atlas (TCGA). Univariate COX regression and least absolute shrinkage and selection operator (LASSO) model were selected to find the 8-independent prognostic lncRNAs of EC patient. Furthermore, the risk score of the 3-lncRNA signature for overall survival (OS) was identified as CTD-2377D24.6 expression × 0.206 + RP4-616B8.5 × 0.341 + RP11-389G6.3 × 0.343 by multivariate Cox regression analysis. According to the median cutoff value of this prognostic signature, the EC samples were divided into two groups, high-risk set (3-lncRNAs at high levels) and low-risk set (3-lncRNAs at low levels), and the Kaplan-Meier survival curves demonstrated that the low-risk set had a higher survival rate than the high-risk set. In addition, the 3-lncRNA signature was closely linked with histological subtype (p = 0.0001), advanced clinical stage (p = 0.011), and clinical grade (p < 0.0001) in EC patients. Our clinical samples also confirmed that RP4-616B8.5, RP11-389G6.3, and CTD-2377D24.6 levels were increased in tumor tissues by qRT-PCR and in situ hybridization. Intriguingly, the p-value of combined 3-lncRNAs was lower than that of each lncRNA, indicating that the 3-lncRNA signature also showed higher performance in EC tissue than paracancerous. Functional analysis revealed that cortactin might be involved in the mechanism of 3-lncRNA signatures. These findings provide the first hint that a panel of lncRNAs may play a critical role in the initiation and metastasis of EC, indicating a new signature for early diagnosis and therapeutic strategy of uterine corpus endometrial carcinoma.

Project description:PurposeTo develop and internally validate a nomogram combining radiomics signature of primary tumor and fibroglandular tissue (FGT) based on pharmacokinetic dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and clinical factors for preoperative prediction of sentinel lymph node (SLN) status in breast cancer patients.MethodsThis study retrospectively enrolled 186 breast cancer patients who underwent pretreatment pharmacokinetic DCE-MRI with positive (n = 93) and negative (n = 93) SLN. Logistic regression models and radiomics signatures of tumor and FGT were constructed after feature extraction and selection. The radiomics signatures were further combined with independent predictors of clinical factors for constructing a combined model. Prediction performance was assessed by receiver operating characteristic (ROC), calibration, and decision curve analysis. The areas under the ROC curve (AUCs) of models were corrected by 1,000-times bootstrapping method and compared by Delong's test. The added value of each independent model or their combinations was also assessed by net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indices. This report referred to the "Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis" (TRIPOD) statement.ResultsThe AUCs of the tumor radiomic model (eight features) and the FGT radiomic model (three features) were 0.783 (95% confidence interval [CI], 0.717-0.849) and 0.680 (95% CI, 0.604-0.757), respectively. A higher AUC of 0.799 (95% CI, 0.737-0.862) was obtained by combining tumor and FGT radiomics signatures. By further combining tumor and FGT radiomics signatures with progesterone receptor (PR) status, a nomogram was developed and showed better discriminative ability for SLN status [AUC 0.839 (95% CI, 0.783-0.895)]. The IDI and NRI indices also showed significant improvement when combining tumor, FGT, and PR compared with each independent model or a combination of any two of them (all p < 0.05).ConclusionFGT and clinical factors improved the prediction performance of SLN status in breast cancer. A nomogram integrating the DCE-MRI radiomics signature of tumor and FGT and PR expression achieved good performance for the prediction of SLN status, which provides a potential biomarker for clinical treatment decision-making.

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Optimized outcome prediction in breast cancer by combining the 70-gene signature with clinical risk prediction algorithms.

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