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Kaplan-Meier plots for 10 year distant recurrence for CTS and CTS+OMclin2 composite continuous score split by the score median in node-negative and node-positive patients, respectively. *Due to the distribution of CTS score, dividing the cohort by the score median resulted in slightly uneven groups. The numbers of patients at risk in each group at various time points are given below each graph. CTS, clinical treatment score; med, median; CI, confidence interval

Added prognostic information to NPI. Likelihood (χ²) for distant recurrence for all prognostic scores in all patients and subgroups. DR, distant recurrence; OMm, OncoMasTR Molecular Score; OMclin2, OncoMasTR Risk Score; NPI, Nottingham Prognostic Index.

Supplementary Legend

Main clinical and laboratory parameters of trial patients with or without tumor blocks

Purpose:To test the validity of OncoMasTR Molecular Score (OMm), OMclin1, and OncoMasTR Risk Score (OMclin2) prognostic scores for prediction of distant recurrence (DR) in estrogen receptor (ER)-positive/HER2-negative breast cancer treated with 5 years' endocrine therapy only and compare their performance with the Oncotype DX Recurrence Score (RS).Experimental Design:OMm incorporates three master transcription regulator genes. OMclin1 combines OMm, tumor size, grade, and nodal status; OMclin2 incorporates OMm, tumor size, and nodal status. OMclin1 and OMclin2 were evaluated for 646 postmenopausal patients with ER-positive/HER2-negative primary breast cancer with 0–3 involved lymph nodes in TransATAC. Patients were randomized to 5 years' anastrozole or tamoxifen without chemotherapy. RS was available in all cases. We used likelihood ratio-χ2, C-index, and Kaplan–Meier analyses to assess prognostic information.Results:OMm, OMclin1, and OMclin2 were highly prognostic for prediction of DR in years 0–10 among all patients [likelihood ratio (LR)-χ2 = 25.4, 48.7, and 45.0, respectively, all P < 0.001; C-index = 0.67, 0.71, and 0.71, respectively], compared with RS (LR-χ2 = 18.8; P < 0.001; C-index = 0.63). All three scores provided significant additional prognostic value beyond clinical treatment score, Nottingham Prognostic Index, and Ki67. OMclin1 and OMclin2 categorized 190 and 267 node-negative patients as low risk (DR rates: 2.9% and 4.9%, respectively). In comparison, RS categorized 296 node-negative patients as low-risk and 128 patients as intermediate-risk (DR rate: 6.6% and 17.3%, respectively).Conclusions:OMm, OMclin1, and OMclin2 were highly prognostic for early and late DR in women with early-stage ER-positive breast cancer receiving 5 years' endocrine therapy. In TransATAC, OMclin1 and the OncoMasTR Risk Score (OMclin2) were superior to RS in identifying patients at increased risk of DR.

Purpose:To validate the clinical performance of the OncoMasTR Risk Score in the biomarker cohort of Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8.Experimental Design:We evaluated the OncoMasTR test in 1,200 formalin-fixed, paraffin-embedded (FFPE) surgical specimens from postmenopausal women with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative primary breast cancer with 0 to 3 involved lymph nodes in the prospective, randomized ABCSG Trial 8. Time to distant recurrence (DR) was analyzed by Cox models.Results:The OncoMasTR Risk Score categorized 850 of 1,087 (78.2%) evaluable patients as “low risk”. At 10 years, the DR rate for patients in the low-risk group was 5.8% versus 21.1% for patients in the high-risk group (P < 0.0001, absolute risk reduction 15.3%). The OncoMasTR Risk Score was highly prognostic for prediction of DR in years 0 to 10 in all patients [HR 1.91, 95% confidence interval (CI) 1.62–2.26, P < 0.0001; C-index 0.73], in patients that were node negative (HR 1.79, 95% CI, 1.43–2.24, P < 0.0001; C-index 0.72), and in patients with 1 to 3 involved lymph nodes (HR 1.93, 95% CI, 1.44–2.58, P < 0.0001; C-index 0.71). The OncoMasTR Risk Score provided significant additional prognostic information beyond clinical parameters, Ki67, Nottingham Prognostic Index, and Clinical Treatment Score.Conclusions:OncoMasTR Risk Score is highly prognostic for DR in postmenopausal women with ER-positive, HER2-negative primary breast cancer with 0 to 3 involved lymph nodes. In combination with prior validation studies, this fully independent validation in ABCSG Trial 8 provides level 1B evidence for the prognostic capability of the OncoMasTR Risk Score.

374 Background: Prostate cancer (PCa) is diagnosed in over 1.2 million men worldwide annually, making it the second-most common non-cutaneous cancer in men. Most men have indolent PCa and can safely defer treatment with active surveillance. However, many patients are commonly treated with surgery (radical prostatectomy, RP) or radiation therapy, which are associated with a significant reduction in quality of life. Molecular signatures have been developed to assist clinicians in stratifying patients based on their risk of aggressive PCa; while these have shown promise, there remains a significant opportunity for improving prognostic capacity. Methods: A panel of fourteen prognostic genes was identified from The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA PRAD) database. Gene expression was measured by reverse-transcription quantitative polymerase chain reaction in RP samples from an Irish cohort of men diagnosed with PCa and treated with RP (PCRC, n=426). Cross-validated logistic regression analysis identified a six-gene molecular risk score (MRS) with strong prognostic performance to predict aggressive PCa, i.e., adverse pathology (AP) at RP or biochemical recurrence (BCR). The MRS was combined with the Cancer of the Prostate Risk Assessment (CAPRA) score to create a molecular plus clinical risk score (MCRS). The MRS and MCRS were clinically validated in biopsy samples from an independent Swedish cohort of men diagnosed with PCa and treated by RP (UPCA, n=100). Results: We identified a six-gene signature, consisting of four prognostic and two reference genes, with improved prognostic value over clinical features. In the clinical biopsy validation study univariable analysis, the AUC of the signature for AP was 0.72 (MRS) and 0.82 (MCRS) versus 0.72 for EAU risk categories and 0.82 for CAPRA. The C-index for BCR was 0.62 (MRS) and 0.74 (MCRS) versus 0.65 for EAU risk categories and 0.73 for CAPRA. Furthermore, in bivariable analysis, the six-gene signature added statistically significant (p < 0.001) prognostic value to EAU risk categories and CAPRA. Conclusions: The six-gene prognostic signature has strong performance for AP and BCR in an independent clinical biopsy validation study. MCRS can provide improved prognostic stratification and inform optimal patient management post-diagnosis.

Background OncoMasTR is a recently developed multigene prognostic test for early-stage breast cancer. The test has been developed in a kit-based format for decentralized deployment in molecular pathology laboratories. The analytical performance characteristics of the OncoMasTR test are described in this study. Methods Expression levels of 6 genes were measured by 1-step reverse transcription-quantitative PCR on RNA samples prepared from formalin-fixed, paraffin-embedded (FFPE) breast tumor specimens. Assay precision, reproducibility, input range, and interference were determined using FFPE-derived RNA samples representative of low and high prognostic risk scores. A pooled RNA sample derived from 6 FFPE breast tumor specimens was used to establish the linear range, limit of detection, and amplification efficiency of the individual gene expression assays. Results The overall precision of the OncoMasTR test was high with an SD of 0.16, which represents less than 2% of the 10-unit risk score range. Test results were reproducible across 4 testing sites, with correlation coefficients of 0.94 to 0.96 for the continuous risk score and concordance of 86% to 96% in low-/high-risk sample classification. Consistent risk scores were obtained across a > 100-fold RNA input range. Individual gene expression assays were linear up to quantification cycle values of 36.0 to 36.9, with amplification efficiencies of 80% to 102%. Test results were not influenced by agents used during RNA isolation, by low levels of copurified genomic DNA, or by moderate levels of copurified adjacent nontumor tissue. Conclusion The OncoMasTR prognostic test displays robust analytical performance that is suitable for deployment by local pathology laboratories for decentralized use.

Purpose: To validate the clinical performance of the OncoMasTR Risk Score in the biomarker cohort of Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8. Experimental Design: We evaluated the OncoMasTR test in 1,200 formalin-fixed, paraffin-embedded (FFPE) surgical specimens from postmenopausal women with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative primary breast cancer with 0 to 3 involved lymph nodes in the prospective, randomized ABCSG Trial 8. Time to distant recurrence (DR) was analyzed by Cox models. Results: The OncoMasTR Risk Score categorized 850 of 1,087 (78.2%) evaluable patients as “low risk”. At 10 years, the DR rate for patients in the low-risk group was 5.8% versus 21.1% for patients in the high-risk group (P < 0.0001, absolute risk reduction 15.3%). The OncoMasTR Risk Score was highly prognostic for prediction of DR in years 0 to 10 in all patients [HR 1.91, 95% confidence interval (CI) 1.62–2.26, P < 0.0001; C-index 0.73], in patients that were node negative (HR 1.79, 95% CI, 1.43–2.24, P < 0.0001; C-index 0.72), and in patients with 1 to 3 involved lymph nodes (HR 1.93, 95% CI, 1.44–2.58, P < 0.0001; C-index 0.71). The OncoMasTR Risk Score provided significant additional prognostic information beyond clinical parameters, Ki67, Nottingham Prognostic Index, and Clinical Treatment Score. Conclusions: OncoMasTR Risk Score is highly prognostic for DR in postmenopausal women with ER-positive, HER2-negative primary breast cancer with 0 to 3 involved lymph nodes. In combination with prior validation studies, this fully independent validation in ABCSG Trial 8 provides level 1B evidence for the prognostic capability of the OncoMasTR Risk Score.

The aim of the study was to assess the prognostic performance of a 6-gene molecular score (OncoMasTR Molecular Score [OMm]) and a composite risk score (OncoMasTR Risk Score [OM]) and to conduct a within-patient comparison against four routinely used molecular and clinicopathological risk assessment tools: Oncotype DX Recurrence Score, Ki67, Nottingham Prognostic Index and Clinical Risk Category, based on the modified Adjuvant! Online definition and three risk factors: patient age, tumour size and grade.Biospecimens and clinicopathological information for 404 Irish women also previously enrolled in the Trial Assigning Individualized Options for Treatment [Rx] were provided by 11 participating hospitals, as the primary objective of an independent translational study. Gene expression measured via RT-qPCR was used to calculate OMm and OM. The prognostic value for distant recurrence-free survival (DRFS) and invasive disease-free survival (IDFS) was assessed using Cox proportional hazards models and Kaplan-Meier analysis. All statistical tests were two-sided ones.OMm and OM (both with likelihood ratio statistic [LRS] P 0.001; C indexes = 0.84 and 0.85, respectively) were more prognostic for DRFS and provided significant additional prognostic information to all other assessment tools/factors assessed (all LRS P ≤ 0.002). In addition, the OM correctly classified more patients with distant recurrences (DRs) into the high-risk category than other risk classification tools. Similar results were observed for IDFS.Both OncoMasTR scores were significantly prognostic for DRFS and IDFS and provided additional prognostic information to the molecular and clinicopathological risk factors/tools assessed. OM was also the most accurate risk classification tool for identifying DR. A concise 6-gene signature with superior risk stratification was shown to increase prognosis reliability, which may help clinicians optimise treatment decisions.

This abstract was withdrawn by the authors. Citation Format: Loughman T, Wang C-JA, Dynoodt P, Fender B, Lopez-Ruiz C, Barron S, Stapleton S, O'Leary D, Fabre A, Quinn C, Nodin B, Jirström K, Bracken A, Gallagher WM. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-31.

Background Multigene prognostic signatures (MGPS) enable identification of candidate patients for treatment de-escalation in early stage breast cancer (BC). Here we present OncoMasTR, a MGPS for classifying the risk of distant metastasis (DM) in ER-positive, HER2-negative BC patients with up to 3 involved lymph nodes (LNs). OncoMasTR was discovered via a novel transcriptional network analysis methodology that identified genes that regulate previously identified prognostic biomarkers. These upstream genes, termed master transcriptional regulators (MTRs), were shown to provide improved prognostic performance compared with downstream genes. OncoMasTR has been mechanistically verified by RT-qPCR, immunohistochemistry and chromatin immunoprecipitation. OncoMasTR has been further trained to include clinicopathological information (CPI) to maximise its prognostic performance. Methods Two independent sample sets: 225 patients from Malmö University Hospital and 100 patients from Skåne University Hospital were used for training, cross-validation and refinement of OncoMasTR. RNA extracted from 225 archived tissues was analysed by RT-qPCR to measure the expression levels of the MTRs. Statistical models of all possible combinations of MTRs were trained and cross-validated (1,000 times x 2-fold) using the first set of 225 samples. Statistical models with the best cross-validated performance were further evaluated on RT-qPCR data from the second independent set of 100 samples. Robustness of the data was verified by assessing the reproducibility of OncoMasTR across 6 days, using 6 unique kit lots, conducted by 4 operators on 3 RT-qPCR instruments. Results In the first training set of 225 patients, OncoMasTR classified up to 72% of LN0 patients and 58% of LN0-3 patients as low risk, with ≤ 5.0% DM within each group. When incorporating CPI, its prognostic performance further improved to a c (concordance) index > 0.8. Results showed that the OncoMasTR molecular score and CPI add statistically significant prognostic value to each other. In the independent verification set, all patients with DM were correctly classified as high risk (p2000-fold RNA input range and PCR efficiencies ranged from 92% to 101%. Conclusions OncoMasTR development and verification results show analytical robustness and clinically accurate risk stratification. Furthermore, OncoMasTR's binary classification of risk avoids an ambiguous intermediate risk classification and has potential to provide clinicians with useful, actionable information to support treatment decisions. The OncoMasTR test is now ready for large-scale clinical validation. Citation Format: Barron S, Jirström K, Jernström H, Ingvar C, Moran B, Wang C-JA, Loughman T, Fender B, Dynoodt P, Lopez-Ruiz C, Russell N, Gallagher WM. Prognostic value of OncoMasTR: A novel multigene signature based on master transcriptional regulators [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-08-06.

Purpose: To test the validity of OncoMasTR Molecular Score (OMm), OMclin1, and OncoMasTR Risk Score (OMclin2) prognostic scores for prediction of distant recurrence (DR) in estrogen receptor (ER)-positive/HER2-negative breast cancer treated with 5 years' endocrine therapy only and compare their performance with the Oncotype DX Recurrence Score (RS). Experimental Design: OMm incorporates three master transcription regulator genes. OMclin1 combines OMm, tumor size, grade, and nodal status; OMclin2 incorporates OMm, tumor size, and nodal status. OMclin1 and OMclin2 were evaluated for 646 postmenopausal patients with ER-positive/HER2-negative primary breast cancer with 0–3 involved lymph nodes in TransATAC. Patients were randomized to 5 years' anastrozole or tamoxifen without chemotherapy. RS was available in all cases. We used likelihood ratio-χ2, C-index, and Kaplan–Meier analyses to assess prognostic information. Results: OMm, OMclin1, and OMclin2 were highly prognostic for prediction of DR in years 0–10 among all patients [likelihood ratio (LR)-χ2 = 25.4, 48.7, and 45.0, respectively, all P < 0.001; C-index = 0.67, 0.71, and 0.71, respectively], compared with RS (LR-χ2 = 18.8; P < 0.001; C-index = 0.63). All three scores provided significant additional prognostic value beyond clinical treatment score, Nottingham Prognostic Index, and Ki67. OMclin1 and OMclin2 categorized 190 and 267 node-negative patients as low risk (DR rates: 2.9% and 4.9%, respectively). In comparison, RS categorized 296 node-negative patients as low-risk and 128 patients as intermediate-risk (DR rate: 6.6% and 17.3%, respectively). Conclusions: OMm, OMclin1, and OMclin2 were highly prognostic for early and late DR in women with early-stage ER-positive breast cancer receiving 5 years' endocrine therapy. In TransATAC, OMclin1 and the OncoMasTR Risk Score (OMclin2) were superior to RS in identifying patients at increased risk of DR.

A novel type of biosensor was assessed for application to the qualitative determination of circulating antibodies to herpes simplex virus type 2 (HSV-2). The device utilises a high activity HSV-2 type specific gG2 antigen for antibody capture and commercially available ELISA reagents. The study compares the diagnostic performance of a prototype HSV-2 biochip to well-established in vitro tests routinely applied in clinical procedures. A panel of human serum samples (n = 60) previously characterised for HSV-2 serological status using the DiaSorin LIAISON® HSV-2 chemiluminescent immunoassay were assayed on the HSV-2 biochip and the Focus Diagnostics HerpeSelect® 2 ELISA IgG kit to determine concordance with the predicate test method. Sensitivity and specificity of the HSV-2 biochip were found comparable to both the DiaSorin and Focus test methods. Sample index values calculated from the immunoassay response of the biochip's coulometric sensors indicated a high degree of linear correlation of the dataset with the corresponding index values from the DiaSorin LIAISON® test (r2 0.8799) and Focus HerpeSelect® test (r2 0.8794). The HSV-2 biochip demonstrated excellent diagnostic performance in qualitative and semi-quantitative measurements, matching closely the performance of two diagnostic industry standard predicate methods.

535 Background: Multigene prognostic signatures (MGPS) can identify early stage breast cancer patients who may require less aggressive treatment. To be clinically useful, MGPSs must provide additional prognostic information to clinicopathological information routinely used by clinicians. The OncoMasTR MGPS was discovered via a novel bioinformatic transcriptional network analysis. OncoMasTR consists of genes – Master Transcription Regulators (MTRs) – that regulate previously known prognostic genes and have identified functional roles in several hallmarks of cancer including proliferation, invasion and metastasis. The OncoMasTR Molecular Score (OM) consists of just 3 MTRs. The OncoMasTR Risk Score (OncoMasTR) combines OM with lymph node status and tumour size, and categorises patients as low or high risk. The OncoMasTR Test has been analytically and clinically validated. Methods: MTR expression was measured by RT-qPCR in tissue from 404 patients enrolled in an independent translational trial (NCT02050750) that collected tissue and clinical data from patients enrolled in TAILORx in Ireland. OM, OncoMasTR and Oncotype DX Recurrence Score (RS) were compared on the additional prognostic value they provided to Ki67, Nottingham Prognostic Index (NPI) and other clinicopathological information for distant recurrence (DR) and invasive disease (ID). Results: OM (LRχ2 = 20.3, p < 0.00001, c-index = 0.84) and OncoMasTR (LRχ2 = 22.6, p < 0.00001, c-index = 0.85) were significantly prognostic, and more prognostic than RS (LRχ2 = 8.4, p = 0.004, c-index = 0.73) for DR. OM and OncoMasTR provided more additional prognostic information than RS to Ki67, NPI, tumour size, tumour grade, and age for DR. Similar results were found when OM, OncoMasTR and RS were compared on prognostic performance for ID. Conclusions: OM and OncoMasTR were significantly prognostic for DR and ID and added significant prognostic value to Ki67, NPI, and other clinicopathological information. Furthermore, OM and OncoMasTR showed superior prognostic performance to RS.

Background: OncoMasTR is a new multigene prognostic test that was discovered via a novel transcriptional network analysis method that identified upstream Master Transcription Regulators (MTRs), which regulate previously identified prognostic biomarkers. The optimised OncoMasTR signature incorporating clinicopathological information has been shown to be significantly prognostic for predicting distant recurrence in two independent cohorts (TransATAC & a subset of TAILORx from participating Irish centres). The analytical performance characteristics of the OncoMasTR test, comprising solely three prognostic MTRs, were determined. Methods: Relative gene expression levels were measured by RT-qPCR. Assay precision and input ranges were determined using a panel of samples representative of low and high recurrence risk tested across a number of runs incorporating different sources of variation. Serial dilutions of a pooled patient RNA sample was used to establish the linear range and efficiency of the individual gene assays. Results: The overall standard deviation of the OncoMasTR risk score was 0.15, which represents less than 2% of the 10-unit risk score range. The majority of the variability in OncoMasTR results was related to within-run variation (78.2%) with other between-run variation sources contributing relatively little (PCR instrument (0.6%), assay operator (5.2%), reagent lots (7.3%) or loading position (8.7%)). Consistent risk scores were measured for individual samples from 40ng down to 500-fold RNA input range corresponding to CT values of 23 – 36, demonstrating the ability of the test to reliably detect low level expression of the OncoMasTR panel. Importantly, PCR efficiencies were similar for the individual MTR and reference gene assays which ranged from 79 – 95%. Conclusions: The OncoMasTR prognostic test displays robust analytical and clinical performance and is being launched as a CE-marked test. The concise nature of the three gene signature and a simplified workflow that can be readily adopted using standard laboratory equipment will enable convenient qualification by local laboratories for decentralised use. (Less)

12074Background: Multigene prognostic signatures (MGPS) enable identification of early stage breast cancer (BC) patients requiring less aggressive treatment. OncoMasTR is a new MGPS found via a nov...

553Background: The assessment of distant recurrence (DR) risk in patients with early estrogen receptor (ER) positive breast cancer receiving adjuvant endocrine therapy is essential in making decisi...

OBJECTIVE Recent studies have suggested that circulating levels of the tumor necrosis factor-α receptor 1 (sTNFαR1) may be a useful predictor for the risk of end-stage renal disease (ESRD) in patients with diabetes. However, its potential utility as a biomarker has not been formally quantified. RESEARCH DESIGN AND METHODS Circulating levels of sTNFαR1 were assessed in 429 patients with type 1 diabetes and overt nephropathy from the Finnish Diabetic Nephropathy (FinnDiane) cohort study. Predictors of incident ESRD over a median of 9.4 years of follow-up were determined by Cox regression and Fine-Gray competing risk analyses. The added value of sTNFαR1 was estimated via time-dependent receiver operating characteristic curves, net reclassification index (NRI), and integrated discrimination improvement (IDI) for survival data. RESULTS A total of 130 individuals developed ESRD (28%; ESRD incidence rate of 3.4% per year). In cause-specific modeling, after adjusting for baseline renal status, predictors of increased incidence of ESRD in patients with overt nephropathy were an elevated HbA1c, shorter duration of diabetes, and circulating levels of sTNFαR1. Notably, sTNFαR1 outperformed estimated glomerular filtration rate in terms of R2. Circulating levels of the sTNFαR1 also remained associated with ESRD after adjusting for the competing risk of death. A prediction model including sTNFαR1 (as a −0.5 fractional polynomial) was superior to a model without it, as demonstrated by better global fit, an increment of R2, the C index, and area under the curve. Estimates of IDI and NRI(>0) were 0.22 (95% CI 0.16–0.28; P < 0.0001) and 0.98 (0.78–1.23; P < 0.0001), respectively. The median increment in the risk score after including sTNFαR1 in the prediction model was 0.18 (0.12–0.30; P < 0.0001). CONCLUSIONS Circulating levels of sTNFαR1 are independently associated with the cumulative incidence of ESRD. This association is both significant and biologically plausible and appears to provide added value as a biomarker, based on the absolute values of NRI and IDI.