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Distribution of RS results in T3 patients in the gene signature cohort. Abbreviations: RS, recurrence score; T3, stage III tumor.

Purpose: Adjuvant sunitinib prolonged disease-free survival (DFS; HR, 0.76) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov NCT00375674). The 16-gene Recurrence Score (RS) assay was previously developed and validated to estimate risk for disease recurrence in patients with RCC after nephrectomy. This analysis further validated the prognostic value of RS assay in patients from S-TRAC and explored the association of RS results with prediction of sunitinib benefit.Patients and Methods: The analysis was prospectively designed with prespecified genes, algorithm, endpoints, and analytical methods. Primary RCC was available from 212 patients with informed consent; primary analysis focused on patients with T3 RCC. Gene expression was quantitated by RT-PCR. Time to recurrence (TTR), DFS, and renal cancer–specific survival (RCSS) were analyzed using Cox proportional hazards regression.Results: Baseline characteristics were similar between patients with and those without RS results, and between the sunitinib and placebo arms among patients with RS results. RS results predicted TTR, DFS, and RCSS in both arms, with the strongest results observed in the placebo arm. When high versus low RS groups were compared, HR for recurrence was 9.18 [95% confidence interval (CI), 2.15–39.24; P < 0.001) in the placebo arm; interaction of RS results with treatment was not significant.Conclusions: The strong prognostic performance of the 16-gene RS assay was confirmed in S-TRAC, and the RS assay is now supported by level IB evidence. RS results may help identify patients at high risk for recurrence who may derive higher absolute benefit from adjuvant therapy. Clin Cancer Res; 24(18); 4407–15. ©2018 AACR.

Patient baseline characteristics in the placebo versus sunitinib arm: all T3 patients in the gene signature cohort. aN0 or NX, any Fuhrman grade, ECOG PS 0 or Fuhrman grade 1 and ECOG PS ï,³1. bN0 or NX, Fuhrman grade {greater than or equal to}2, ECOG PS {greater than or equal to}1. cAny Fuhrman grade, any ECOG PS. Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; SD, standard deviation; RS, Recurrence Score.

Background Early cancer detection could identify tumors at a time when outcomes are superior and treatment is less morbid. This prospective case-control sub-study (from NCT02889978 and NCT03085888) assessed the performance of targeted methylation analysis of circulating cell-free DNA (cfDNA) to detect and localize multiple cancer types across all stages at high specificity. Participants and methods The 6689 participants [2482 cancer (>50 cancer types), 4207 non-cancer] were divided into training and validation sets. Plasma cfDNA underwent bisulfite sequencing targeting a panel of >100 000 informative methylation regions. A classifier was developed and validated for cancer detection and tissue of origin (TOO) localization. Results Performance was consistent in training and validation sets. In validation, specificity was 99.3% [95% confidence interval (CI): 98.3% to 99.8%; 0.7% false-positive rate (FPR)]. Stage I–III sensitivity was 67.3% (CI: 60.7% to 73.3%) in a pre-specified set of 12 cancer types (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile-duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach), which account for ∼63% of US cancer deaths annually, and was 43.9% (CI: 39.4% to 48.5%) in all cancer types. Detection increased with increasing stage: in the pre-specified cancer types sensitivity was 39% (CI: 27% to 52%) in stage I, 69% (CI: 56% to 80%) in stage II, 83% (CI: 75% to 90%) in stage III, and 92% (CI: 86% to 96%) in stage IV. In all cancer types sensitivity was 18% (CI: 13% to 25%) in stage I, 43% (CI: 35% to 51%) in stage II, 81% (CI: 73% to 87%) in stage III, and 93% (CI: 87% to 96%) in stage IV. TOO was predicted in 96% of samples with cancer-like signal; of those, the TOO localization was accurate in 93%. Conclusions cfDNA sequencing leveraging informative methylation patterns detected more than 50 cancer types across stages. Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies.

To examine the extent of the evaluation required to achieve diagnostic resolution and the test performance characteristics of a targeted methylation cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test, ~6200 participants ≥50 years with (cohort A) or without (cohort B) ≥1 of 3 additional specific cancer risk factors will be enrolled in PATHFINDER (NCT04241796), a prospective, longitudinal, interventional, multi-center study. Plasma cfDNA from blood samples will be analyzed to detect abnormally methylated DNA associated with cancer (i.e., cancer “signal”) and a cancer signal origin (i.e., tissue of origin). Participants with a “signal detected” will undergo further diagnostic evaluation per guiding physician discretion, those with a “signal not detected” will be advised to continue guideline-recommended screening. The primary objective will be to assess the number and types of subsequent diagnostic tests needed for diagnostic resolution. Based on microsimulations (using estimates of cancer incidence and dwell times) of the typical risk profiles of anticipated participants, the median (95% CI) number of participants with a “signal detected” result is expected to be 106 (87–128). Subsequent diagnostic evaluation is expected to detect 52 (39–67) cancers. The positive predictive value of the MCED test is expected to be 49% (39–58%). PATHFINDER will evaluate the integration of a cfDNA-based MCED test into existing clinical cancer diagnostic pathways. The study design of PATHFINDER is described here.

3070 Background: A multi-cancer early detection (MCED) test that uses targeted methylation-based cfDNA technology to detect cancer and predict cancer signal origin (CSO) has potential to efficiently identify malignancies for which effective screening modalities do not exist. A previous version of a blood-based MCED test demonstrated favorable classification and test characteristics. Samples from the ongoing PATHFINDER study were reanalyzed in a prespecified interim analysis to evaluate performance of a more recent version of the test with an updated classifier (eg, updated CSO localization, hematological signal threshold) that is planned for clinical implementation as a general multi-cancer screening tool. Methods: PATHFINDER (NCT04241796) is an interventional, prospective study in which results (cancer signal detected/not detected and predicted CSO) using a previous version of the MCED test are returned to investigators, and those with a signal detected undergo further diagnostic testing. In this prespecified interim analysis, samples from those enrolled as of October 6, 2020 were reanalyzed with the more recent version of the MCED test (these results were not returned to investigators). The positive predictive value (PPV) for cancer detection, overall CSO accuracy, and concordance between the two test versions were assessed. Results: A total of 4011/4047 (99%) participants (pts) were analyzable (mean [SD] age 63.9 [8.7] years, 62% female, 92% white, 24% with prior cancer history, 39% ever smoker [4% current], 6% with genetic cancer predisposition). Cancer signal was detected in 0.95% (38/4011). A total of 27/38 also had signal detected by the previous version of the MCED test, including 19 who reached diagnostic resolution (13 with cancer diagnosis and 6 without); 11/38 were discordant positives. Nine different cancer types were detected in the 13 pts (2 stage I, 3 stage II, 2 stage III, and 3 stage IV); 1 had no AJCC stage expected, 1 metastatic recurrence and 1 stage evaluation underway. A conservative minimal PPV assuming all discordant positives are false positives, was 43.3% (13/30, 95% CI 27.4-60.8%) based on 19 pts with diagnostic resolution and 11 discordant positives. High negative percent agreement (PA) 99.7% (99.5-99.8%) between the two test versions was observed. Positive PA of 43.5% (95% CI, 31.9-55.9%) was consistent with the more stringent threshold for hematologic signal in the recent MCED version, as most discrepant cases had hematologic CSO with the previous MCED test. Among 13 detected cancers, accuracy of the top CSO prediction was 92.3% (12/13, 95% CI 66.7-99.6%). Conclusions: In this prespecified interim analysis, the more recent version of the MCED test detected cancers with high PPV and high accuracy of CSO prediction, supporting readiness for use in clinical practice. Full enrollment cohort data will be available at the meeting. Clinical trial information: NCT04241796.

3010 Background: PATHFINDER (NCT04241796) is an interventional, prospective study evaluating implementation of a blood-based multi-cancer early detection (MCED) test that uses targeted methylation-based cfDNA analysis to detect multiple cancer types and simultaneously predict cancer signal origin (CSO). We present a prespecified interim analysis of PATHFINDER evaluating an MCED test in a clinical setting. Methods: Participants (pts; ≥50y) were enrolled into 2 risk cohorts: non-elevated and elevated (smoking history, prior cancer [ > 3y post treatment], or genetic predisposition). MCED test results (cancer signal detected/not detected) were returned to investigators; pts with a signal detected also received a CSO prediction and underwent further diagnostic testing by their medical team. The primary objective was to assess the extent of diagnostic testing needed to achieve diagnostic resolution (eg, time to resolution, number/type of tests). Secondary endpoints included positive predictive value (PPV) and a measure of test satisfaction (following diagnostic resolution [signal detected] and post test [signal not detected]). Results: PATHFINDER consented 6796 pts before closing accrual on 12/4/20; as of October 6, 2020, 4086 consented, 4047 enrolled, and 4033 analyzable pts were included in the interim analysis (62.4% female, 92.1% white). Two study-related adverse events (anxiety of mild severity) were reported. Cancer signal was detected in 1.5% (62/4033) of pts; 40/62 reached diagnostic resolution to date. Kaplan-Meier estimate of median time to resolution was 78 (95% CI, 54-151) days. Among 40 pts that reached diagnostic resolution, ≥1 imaging test was performed in 93% (37/40); ≥1 invasive procedure was performed in 72% (13/18) versus 18% (4/22) of pts with diagnostic resolution of cancer versus no cancer, respectively. Based on results to date, PPV was 45% (95% CI, 30.7-60.2%; 18/40). Of 18 cancer diagnoses, 11 were solid tumors (3 stage IV, 6 stages I-III, 1 metastatic recurrence, 1 missing stage), and 7 were hematologic malignancies (1 stage IV, 4 stages I-III, 2 without AJCC stage). Accuracy of the top CSO prediction in true positives was 82.4% (95% CI, 59.0-93.8%; 14/17). Most pts were satisfied with the test (43.7% extremely satisfied, 30.7% very satisfied, 14.6% satisfied). Signal detection rate and test satisfaction were similar in the 2 risk cohorts; PPV tended to be higher in the elevated risk cohort, as expected. Conclusions: An interim analysis of this return of results study demonstrated promising MCED test results. Of 40 pts achieving diagnostic resolution, nearly half had a diagnostic workup confirming cancer; CSO was predicted with high accuracy for detected cancers. Taken together with the rarity of adverse events and high test satisfaction, these results support the feasibility of clinical implementation. Full enrollment cohort data will be available at the meeting. Clinical trial information: NCT04241796.

Background: Early detection decreases patient mortality for many cancers, but prevailing paradigms focus on distinct screening modalities for each cancer type. A minimally invasive test that detects multiple tumor types could substantially reduce cancer mortality and improve screening efficiency. In preliminary studies, we showed that a targeted methylation cell-free DNA (cfDNA) test can detect cancer and determine the tissue of origin (TOO) of abnormally methylated cfDNA with high sensitivity and specificity; however, blood was collected at the time of diagnosis and results were not disclosed to inform care. The current study includes disclosure of results to the study investigator to understand the care pathways prompted by a “signal detected” test result, and the benefits, harms, and burdens associated with a multi-cancer detection test. Methods: PATHFINDER (NCT04241796) is a prospective, longitudinal, multi-center clinical study. Approximately 6,200 participants with varying levels of cancer risk will be enrolled at 5-10 clinical sites in the United States. Participants must be ≥50 years of age. If participants have at least 1 of the following–a smoking history of ≥100 cigarettes, a genetic cancer predisposition, or a history of invasive or hematologic malignancy with definitive treatment completed >3 years prior to enrollment–they are eligible for the Elevated Risk Cohort (n = 4340); otherwise, they are eligible for the Non-Elevated Risk Cohort (n = 1860). Individuals being evaluated for cancer or who have a history of invasive or hematologic malignancy within 3 years of enrollment will be excluded. Blood drawn at study sites will be analyzed at GRAIL, Inc. (Menlo Park, CA). Participants and study investigators will be informed of the test results. Participants with “signal not detected” results will be advised to continue routine clinical care, including age- and risk-based cancer screening. Those with “signal detected” test results will be informed of the predicted origin and undergo diagnostic evaluation. The primary study objective is to determine the extent of diagnostic testing required to achieve diagnostic resolution following a “signal detected” test result, defined as the date when the study investigator determines to end diagnostic evaluation triggered by a “signal detected” test result. Health resource utilization, the number and types of tests and time required to reach this point, is the primary endpoint. Secondary objectives include evaluation of test performance (specificity, positive predictive value, and TOO accuracy), and assessment of participants' perceptions about the test and changes in anxiety and health-related quality of life. Exploratory aims include assessment of the number and types of invasive cancer diagnoses among participants with “signal not detected” test results and changes in attitude toward adherence to guideline-recommended screening. Citation Format: Lincoln Nadauld, Charles H. McDonnell III, Minetta C. Liu, Eric Klein, Tomasz M. Beer, Deborah Schrag, Andrew G. Hudnut, Richard Whittington, Bruce Taylor, Joanna Tierney, Catherine Marinac, Jafi Lipson, Margarita Lopatin, Karen C. Chung, Eric Fung, Anne-Renee Hartman, Geoffrey R. Oxnard. The PATHFINDER Study: Assessment of the implementation of an investigational multi-cancer early detection test into clinical practice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT291.

Purpose: Adjuvant sunitinib prolonged disease-free survival (DFS; HR, 0.76) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov NCT00375674). The 16-gene Recurrence Score (RS) assay was previously developed and validated to estimate risk for disease recurrence in patients with RCC after nephrectomy. This analysis further validated the prognostic value of RS assay in patients from S-TRAC and explored the association of RS results with prediction of sunitinib benefit. Patients and Methods: The analysis was prospectively designed with prespecified genes, algorithm, endpoints, and analytical methods. Primary RCC was available from 212 patients with informed consent; primary analysis focused on patients with T3 RCC. Gene expression was quantitated by RT-PCR. Time to recurrence (TTR), DFS, and renal cancer–specific survival (RCSS) were analyzed using Cox proportional hazards regression. Results: Baseline characteristics were similar between patients with and those without RS results, and between the sunitinib and placebo arms among patients with RS results. RS results predicted TTR, DFS, and RCSS in both arms, with the strongest results observed in the placebo arm. When high versus low RS groups were compared, HR for recurrence was 9.18 [95% confidence interval (CI), 2.15–39.24; P < 0.001) in the placebo arm; interaction of RS results with treatment was not significant. Conclusions: The strong prognostic performance of the 16-gene RS assay was confirmed in S-TRAC, and the RS assay is now supported by level IB evidence. RS results may help identify patients at high risk for recurrence who may derive higher absolute benefit from adjuvant therapy. Clin Cancer Res; 24(18); 4407–15. ©2018 AACR.

Summary Background The likelihood of tumour recurrence after nephrectomy in localised clear cell renal cell carcinoma is well characterised by clinical and pathological parameters. However, these assessments can be improved and personalised by the addition of molecular characteristics of each patient's tumour. We aimed to develop and validate a prognostic multigene signature to improve prediction of recurrence risk in clear cell renal cell carcinoma. Methods In the development stage, we investigated the association between expression of 732 genes, measured by reverse-transcription PCR, and clinical outcome in 942 patients with stage I–III clear cell renal cell carcinoma who had undergone a nephrectomy at the Cleveland Clinic (OH, USA). 516 genes were associated with recurrence-free interval. 11 of these genes were selected by further statistical analyses, and were combined with five reference genes (ie, 16 genes in total), from which a recurrence score algorithm was developed. The recurrence score was then validated in an independent cohort of 626 patients from France with stage I–III clear cell renal cell carcinoma who had also undergone nephrectomy. The association between the recurrence score and the risk of recurrence and cancer-specific survival in the first 5 years after surgery was assessed using Cox proportional hazard regression, stratified by tumour stage (stage I vs stage II vs III). Findings In our primary univariate analysis, the continuous recurrence score (median 37, IQR 31–45) was significantly associated with recurrence-free interval (hazard ratio 3·91 [95% CI 2·63–5·79] for a 25-unit increase in score, p Interpretation Our findings validate the recurrence score as a predictor of clinical outcome in patients with stage I–III clear cell renal cell carcinoma, providing a more accurate and individualised risk assessment beyond existing clinical and pathological parameters. Funding Genomic Health Inc and Pfizer Inc.

Purpose. The Oncotype DX colon cancer assay is a clinically validated predictor of recurrence risk in stage II colon cancer patients. This prospective study evaluated the impact of recurrence score (RS) results on physician recommendations regarding adjuvant chemotherapy in T3, mismatch repair-proficient (MMR-P) stage II colon cancer patients. Patients and Methods. Stage IIA colon cancer patients were enrolled in 17 centers. Patient tumor specimens were assessed by the RS test (quantitative reverse transcription-polymerase chain reaction) and mismatch repair (immunohistochemistry). For each patient, the physician's recommended postoperative treatment plan of observation, fluoropyrimidine monotherapy, or combination therapy with oxaliplatin was recorded before and after the RS and mismatch repair results were provided. Results. Of 221 enrolled patients, 141 patients had T3 MMR-P tumors and were eligible for the primary analysis. Treatment recommendations changed for 63 (45%; 95% confidence interval: 36%–53%) of these 141 T3 MMR-P patients, with intensity decreasing for 47 (33%) and increasing for 16 (11%). Recommendations for chemotherapy decreased from 73 patients (52%) to 42 (30%), following review of RS results by physician and patient. Increased treatment intensity was more often observed at higher RS values, and decreased intensity was observed at lower values (p = .011). Conclusion. Compared with traditional clinicopathological assessment, incorporation of the RS result into clinical decision making was associated with treatment recommendation changes for 45% of T3 MMR-P stage II colon cancer patients in this prospective multicenter study. Use of the RS assay may lead to overall reduction in adjuvant chemotherapy use in this subgroup of stage II colon cancer patients.

Purpose Accurate assessments of recurrence risk and absolute treatment benefit are needed to inform colon cancer adjuvant therapy. The 12-gene Recurrence Score assay has been validated in patients with stage II colon cancer from the Cancer and Leukemia Group B 9581 and Quick and Simple and Reliable (QUASAR) trials. We conducted an independent, prospectively designed clinical validation study of Recurrence Score, with prespecified end points and analysis plan, in archival specimens from patients with stage II and III colon cancer randomly assigned to fluorouracil (FU) or FU plus oxaliplatin in National Surgical Adjuvant Breast and Bowel Project C-07. Methods Recurrence Score was assessed in 892 fixed, paraffin-embedded tumor specimens (randomly selected 50% of patients with tissue). Data were analyzed by Cox regression adjusting for stage and treatment. Results Continuous Recurrence Score predicted recurrence (hazard ratio for a 25-unit increase in score, 1.96; 95% CI, 1.50 to 2.55; P < .001), as well as disease-free and overall survival (both P < .001). Recurrence Score predicted recurrence risk (P = .001) after adjustment for stage, mismatch repair, nodes examined, grade, and treatment. Recurrence Score did not have significant interaction with stage (P = .90) or age (P = .76). Relative benefit of oxaliplatin was similar across the range of Recurrence Score (interaction P = .48); accordingly, absolute benefit of oxaliplatin increased with higher scores, most notably in patients with stage II and IIIA/B disease. Conclusion The 12-gene Recurrence Score predicts recurrence risk in stage II and stage III colon cancer and provides additional information beyond conventional clinical and pathologic factors. Incorporating Recurrence Score into the clinical context may better inform adjuvant therapy decisions in stage III as well as stage II colon cancer.

Purpose A greater understanding of the biology of tumor recurrence should improve adjuvant treatment decision making. We conducted a validation study of the 12-gene recurrence score (RS), a quantitative assay integrating stromal response and cell cycle gene expression, in tumor specimens from patients enrolled onto Cancer and Leukemia Group B (CALGB) 9581. Patients and Methods CALGB 9581 randomly assigned 1,713 patients with stage II colon cancer to treatment with edrecolomab or observation and found no survival difference. The analysis reported here included all patients with available tissue and recurrence (n = 162) and a random (approximately 1:3) selection of nonrecurring patients. RS was assessed in 690 formalin-fixed paraffin-embedded tumor samples with quantitative reverse transcriptase polymerase chain reaction by using prespecified genes and a previously validated algorithm. Association of RS and recurrence was analyzed by weighted Cox proportional hazards regression. Results Continuous RS was significantly associated with risk of recurrence (P = .013) as was mismatch repair (MMR) gene deficiency (P = .044). In multivariate analyses, RS was the strongest predictor of recurrence (P = .004), independent of T stage, MMR, number of nodes examined, grade, and lymphovascular invasion. In T3 MMR-intact (MMR-I) patients, prespecified low and high RS groups had average 5-year recurrence risks of 13% (95% CI, 10% to 16%) and 21% (95% CI, 16% to 26%), respectively. Conclusion The 12-gene RS predicts recurrence in stage II colon cancer in CALGB 9581. This is consistent with the importance of stromal response and cell cycle gene expression in colon tumor recurrence. RS appears to be most discerning for patients with T3 MMR-I tumors, although markers such as grade and lymphovascular invasion did not add value in this subset of patients.

Background The Oncotype DX colon cancer assay is a validated predictor of recurrence risk in patients with resected stage II colon cancer. We previously reported that Oncotype DX led to a change in treatment recommendations for 45% of patients with T3 mismatch repair proficient (MMR-P) stage II tumors in a prospective study. In the present study, we report the assay's influence on patient treatment decisions, physician confidence, concordance between physicians and patients, and patient decisional conflict. Patients and Methods Consecutive patients with resected stage IIA colon cancer were enrolled. The tumor specimens were assessed using a 12-gene assay (reverse transcription-polymerase chain reaction) and by immunohistochemistry for MMR. Before and after receiving the results, the patients completed surveys that included their treatment preference, their current and preferred roles in treatment decision-making, and indicators of decisional conflict. Physicians completed similar pre- and postassay surveys. Results Of 221 patients enrolled, 139 T3 MMR-P patients were evaluable for the patient-reported analyses and 150 patients were evaluable for the physician-reported analyses. Before the assay, 46% of the patients chose observation, 3% 5-fluorouracil, 7% oxaliplatin, 4% other, and 41% were undecided. After the assay, 75% chose observation, 12% 5-fluorouracil, 11% oxaliplatin, and 2% other. After the assay, 94% of the defined treatment decisions were concordant between patients and physicians compared with 60% before the assay. Physicians reported the assay influenced their treatment decisions and increased confidence in their treatment recommendations for 69% and 84% of patients, respectively. Most patients (86%) reported that the assay influenced their treatment decisions. Patient decisional conflict was significantly lower after learning the assay results (P Conclusion In the present prospective study, knowledge of the 12-gene assay results influenced treatment decisions for most patients and physicians, increased physician confidence, improved the concordance between patients and physicians, and decreased patient decisional conflict.

Purpose The 12-gene Recurrence Score assay has been validated in resected stage II colon cancer treated with or without chemotherapy and resected stage III disease treated with chemotherapy. This study evaluated the 12-gene Recurrence Score assay for stage II and III colon cancer without chemotherapy to reveal the natural course of recurrence risk in stage III disease. Methods A cohort-sampling design was used. From 1,487 consecutive patients with stage II to III disease who had surgery alone, 630 patients were sampled for inclusion with a 1:2 ratio of recurrence and nonrecurrence. Sampling was stratified by stage (II v III). The assay was performed on formalin-fixed, paraffin-embedded primary cancer tissue. Association of the Recurrence Score result with recurrence-free interval (RFI) was assessed by using weighted Cox proportional hazards regression. Results Overall, 597 of 630 patients were analyzable—247 patients had stage II, and 350 had stage III colon cancer. The continuous Recurrence Score was significantly associated with RFI after adjustment for disease stage (hazard ratio for a 25-unit increase in Recurrence Score, 2.05; 95% CI, 1.47 to 2.86; P < .001). With respect to prespecified subgroups, as defined by low (< 30), intermediate (30 to 40), and high (≥ 41) Recurrence Score risk groups, patients with stage II disease in the high-risk group had a 5-year risk of recurrence similar to patients with stage IIIA to IIIB disease in the low-risk group (19% v 20%), whereas patients with stage IIIA to IIIB disease in the high-risk group had a recurrence risk similar to that of patients with stage IIIC disease in the low-risk group (approximately 38%). Conclusion To our knowledge, this study provides the first validation of the 12-gene Recurrence Score assay in stage III colon cancer without chemotherapy and showed the heterogeneity of recurrence risks in stage III as well as in stage II colon cancer.

Purpose We developed quantitative gene expression assays to assess recurrence risk and benefits from chemotherapy in patients with stage II colon cancer. Patients and Methods We sought validation by using RNA extracted from fixed paraffin-embedded primary colon tumor blocks from 1,436 patients with stage II colon cancer in the QUASAR (Quick and Simple and Reliable) study of adjuvant fluoropyrimidine chemotherapy versus surgery alone. A recurrence score (RS) and a treatment score (TS) were calculated from gene expression levels of 13 cancer-related genes (n = 7 recurrence genes and n = 6 treatment benefit genes) and from five reference genes with prespecified algorithms. Cox proportional hazards regression models and log-rank methods were used to analyze the relationship between the RS and risk of recurrence in patients treated with surgery alone and between TS and benefits of chemotherapy. Results Risk of recurrence was significantly associated with RS (hazard ratio [HR] per interquartile range, 1.38; 95% CI, 1.11 to 1.74; P = .004). Recurrence risks at 3 years were 12%, 18%, and 22% for predefined low, intermediate, and high recurrence risk groups, respectively. T stage (HR, 1.94; P < .001) and mismatch repair (MMR) status (HR, 0.31; P < .001) were the strongest histopathologic prognostic factors. The continuous RS was associated with risk of recurrence (P = .006) beyond these and other covariates. There was no trend for increased benefit from chemotherapy at higher TS (P = .95). Conclusion The continuous 12-gene RS has been validated in a prospective study for assessment of recurrence risk in patients with stage II colon cancer after surgery and provides prognostic value that complements T stage and MMR. The TS was not predictive of chemotherapy benefit.

The optimal use of diuretics in decompensated heart failure remains uncertain. We analyzed data from the ADHERE registry to look at the impact of diuretic dosing. 62,866 patients receiving

Objectives: Continuous or bilevel positive airway pressure ventilation, called noninvasive ventilation (NIV), is a controversial therapy for acute decompensated heart failure (ADHF). While NIV is considered safe and effective in patients with chronic obstructive pulmonary disease (COPD), clinical trial data that have addressed safety in ADHF patients are limited, with some suggestion of increased mortality. The objective of this study was to assess mortality outcomes associated with NIV and to determine if a failed trial of NIV followed by endotracheal intubation (ETI) (NIV failure) is associated with worse outcomes, compared to immediate ETI. Methods: This was a retrospective analysis of the Acute Decompensated Heart Failure National Registry (ADHERE), which enrolls patients with treatment for, or with a primary discharge diagnosis of, ADHF. The authors compared characteristics and outcomes in four groups: no ventilation, NIV success, NIV failure, and ETI. One-way analysis of variance or Wilcoxon testing was performed for continuous data, and chi-square tests were used for categorical data. In addition, multivariable logistic regression was used to adjust mortality comparisons for risk factors. Results: Entry criteria were met by 37,372 patients, of which 2,430 had ventilation assistance. Of the ventilation group, 1,688 (69.5%) were deemed NIV success, 72 (3.0%) were NIV failures, and 670 (27.6%) required ETI. The NIV failure group had the lowest O2 saturation (SaO2) (84 ± 16%), compared to either NIV success (89.6 ± 10%) or ETI (88 ± 13%; p = 0.017). ETI patients were more likely to receive vasoactive medications (p 0.05); other than that the NIV failure group more often received vasodilators (68.1% vs. 54.3%; p = 0.026). In-hospital mortality was 7.9% with NIV, 13.9% with NIV failure, and 15.4% with ETI. After risk adjustment, the mortality odds ratio for NIV failure versus ETI increased to 1.43, although this endpoint was not statistically significant. Conclusions: In this analysis of ADHF patients receiving NIV to date, patients placed on NIV for ADHF fared better than patients requiring immediate ETI. Patients who failed NIV and required ETI still experienced lower mortality than those initially placed on ETI. Thus, while the ETI group may be more severely ill, starting therapy with NIV instead of immediate ETI will likely not harm the patient. When ETI is required, mortality and length of stay may be adversely affected. Since a successful trial of NIV is associated with improved outcomes in patients with ADHF, application of this therapy may be a reasonable treatment option. ACADEMIC EMERGENCY MEDICINE 2008; 15:355‐362 a 2008 by the Society for Academic Emergency Medicine

B-type natriuretic peptide (BNP) and cardiac troponin (Tn) I or T have been demonstrated to provide prognostic information in patients with acute coronary syndromes. Whether admission BNP and Tn levels provide additive prognostic value in acutely decompensated heart failure (HF) has not been well studied. Hospitalizations for HF from April 2003 to December 2004 entered into ADHERE were analyzed. BNP assessment on admission was performed in 48,629 (63%) of 77,467 hospitalization episodes. Tn assessment was performed in 42,636 (88%) of these episodes. In-hospital mortality was assessed using logistic regression models adjusted for age, gender, blood urea nitrogen, systolic blood pressure, creatinine, sodium, pulse, and dyspnea at rest. Median BNP was 840 pg/ml (interquartile range 430 to 1,730). Tn was increased in 2,370 (5.6%) of 42,636 HF episodes. BNP above the median and increased Tn were associated with significantly increased risk of in-hospital mortality (odds ratios [OR] 2.09 and 2.41 respectively, each p value0.0001). Mortality was 10.2% in patients with BNPor=840/Tn increased compared with 2.2% with BNP840/Tn not increased (OR 5.10, p0.0001). After covariate adjustment, mortality risk remained significantly increased with BNPor=840/Tn not increased (adjusted OR 1.56, 95% confidence interval 1.40 to 1.79, p0.0001), BNP840/Tn increased (adjusted OR 1.69, 95% confidence interval 1.17 to 2.45, p = 0.006), and BNPor=840/Tn increased (adjusted OR 3.00, 95% confidence interval 2.47 to 3.66, p0.0001). Admission BNP and cardiac Tn levels are significant, independent predictors of in-hospital mortality in acutely decompensated HF. Patients with BNP levelsor=840 pg/ml and increased Tn levels are at particularly high risk for mortality. In conclusion, a multimarker strategy for the assessment of patients hospitalized with HF adds incremental prognostic information.

ObjectivesThis study was designed to determine whether admission B-type natriuretic peptide (BNP) levels are predictive of in-hospital mortality in acute decompensated heart failure (HF).BackgroundLevels of BNP have been demonstrated to facilitate the diagnosis of HF and predict mortality in chronic systolic HF.MethodsB-type natriuretic peptide levels within 24 h of presentation were obtained in 48,629 (63%) of 77,467 hospitalization episodes entered in ADHERE (Acute Decompensated Heart Failure National Registry). In-hospital mortality was assessed by BNP quartiles in the entire cohort and in patients with reduced (n = 19,544) as well as preserved (n = 18,164) left ventricular systolic function using chi-square and logistic regression models.ResultsQuartiles (Q) of BNP were Q1 (

Clinical Presentation, Management, and In-Hospital Outcomes of Patients Admitted With Acute Decompensated Heart Failure With Preserved Systolic Function: A Report From the Acute Decompensated Heart...

Skin irritation due to iontophoresis may limit the frequency of use of devices for drug delivery or transdermal extraction of analytes of clinical interest. This study examined whether preapplication of corticosteroid preparations could reduce skin irritation from iontophoresis used by the GlucoWatch G2 Biographer (Cygnus, Inc., Redwood City, CA) in monitoring interstitial glucose levels frequently and automatically. Numerous corticosteroid preparations were screened to identify formulations that did not interfere with adhesion of the Biographer to the skin or glucose sensing. Kenalog (Westwood-Squibb Pharmaceuticals, Inc., Buffalo, NY) (triamcinolone acetonide) and Cortizone-10 Quick Shot (Pfizer, Inc., New York, NY) (hydrocortisone) sprays were selected and, in a double-masked, randomized, controlled trial, were applied to the forearms of 66 subjects with diabetes and allowed to dry. Biographers were applied and worn for 15 h, and home blood glucose measurements were taken every 30 min to assess accuracy. Irritation was assessed periodically by trained observers and study subjects. Skin irritation was reduced by both corticosteroid sprays, with the fraction of subjects who experienced moderate irritation reduced by 57% and 43% for the Kenalog and Cortizone-10 Quick Shot sprays, respectively. The treatment effect persisted at the 1-week assessment. Preapplication of these preparations did not affect the clinical utility of interstitial glucose readings. Preapplication of Kenalog or Cortizone-10 Quick Shot sprays significantly reduced skin irritation due to iontophoresis, and did not interfere with glucose measurements. This approach may enable the minority of users who experience moderate to severe skin irritation to use the Biographer more frequently for diabetes management.

Objective: This study was done to evaluate the accuracy and safety of measuring glucose with the GlucoWatch® biographer in children and adolescents with diabetes. Methods: Accuracy was assessed by comparing biographer glucose measurements with hourly blood glucose measurements using the HemoCue (Aktiebolaget Leo, Helsingborg, Sweden) Photometer for up to 12 h of monitoring. Safety was evaluated by examining the biographer application sites immediately upon removal of the devices, and then at regular intervals. Results: Sixty-six subjects each wore three biographers at sites including the forearm, upper arm, leg, and torso. For forearm biographers, the mean absolute relative difference between biographer readings and blood glucose was 21%. Ninety-five per cent of biographer readings fell into the A or B regions of the Clarke error grid, and 97.3% into the A or B regions of the consensus error grid. Data from biographers worn at the alternative sites were similar to data from the forearm biographers. Two strong reactions to the adhesive pad of the biographer AutoSensor were observed. Most skin reactions were mild. Conclusions: The GlucoWatch biographer is well tolerated by children and adolescents with diabetes. Performance is similar when the device is worn at different anatomical sites, and is similar to the performance on the forearm, previously reported in adults.

4508 Background: Adjuvant therapy with sunitinib (SU) compared with placebo (PBO) prolonged disease-free survival (DFS) in 615 patients (pts) with high-risk RCC (hazard ratio [HR] 0.76; P= 0.03) in the S-TRAC trial. The 16-gene Recurrence Score (RS) was developed and validated to predict risk of recurrence of RCC after nephrectomy in 2 cohorts of stage I–III pts (Rini et al., Lancet Oncol 2015;16:676-85). We present further validation of RS results in high-risk stage III pts from S-TRAC. Methods: The study was prospectively designed with prespecified genes, algorithm, endpoints, analytical methods, and analysis plan using primary RCC tissues from 212 evaluable pts with informed consent. Gene expression was quantitated by RT-PCR; primary analysis focused on stage III (n = 193 pts). Time to recurrence (TTR) and DFS were analyzed using Cox proportional hazard regression. Results: Baseline characteristics were similar in SU and PBO arms and in pts with and without gene expression data; effect of SU was numerically similar to that in the entire trial (DFS HR 0.78, 95% CI 0.48–1.24; P= 0.29). RS predicted TTR and DFS in both treatment arms with the strongest results observed in PBO arm where high RS group had significantly higher risk (Table). Interaction of RS with treatment was not significant (TTR P= 0.192; DFS P= 0.219); however, the number of events was relatively low. Conclusions: The prognostic value of the 16-gene assay was confirmed in S-TRAC. RS is now validated with consistent results in 2 separate studies (level IB evidence). RS results may help identify patients at high risk who could derive higher absolute benefit from adjuvant treatment. The predictive value of RS to select patients for adjuvant SU requires further investigation in independent adjuvant trials. [Table: see text]

The 12-gene Recurrence Score assay is a validated predictor of recurrence risk in stage II and III colon cancer patients. We conducted a prospectively designed study to validate this assay for prediction of recurrence risk in stage II and III rectal cancer patients from the Dutch Total Mesorectal Excision (TME) trial.RNA was extracted from fixed paraffin-embedded primary rectal tumor tissue from stage II and III patients randomized to TME surgery alone, without (neo)adjuvant treatment. Recurrence Score was assessed by quantitative real time-polymerase chain reaction using previously validated colon cancer genes and algorithm. Data were analysed by Cox proportional hazards regression, adjusting for stage and resection margin status. All statistical tests were two-sided.Recurrence Score predicted risk of recurrence (hazard ratio [HR] = 1.57, 95% confidence interval [CI] = 1.11 to 2.21, P = .01), risk of distant recurrence (HR = 1.50, 95% CI = 1.04 to 2.17, P = .03), and rectal cancer-specific survival (HR = 1.64, 95% CI = 1.15 to 2.34, P = .007). The effect of Recurrence Score was most prominent in stage II patients and attenuated with more advanced stage (P(interaction) ≤ .007 for each endpoint). In stage II, five-year cumulative incidence of recurrence ranged from 11.1% in the predefined low Recurrence Score group (48.5% of patients) to 43.3% in the high Recurrence Score group (23.1% of patients).The 12-gene Recurrence Score is a predictor of recurrence risk and cancer-specific survival in rectal cancer patients treated with surgery alone, suggesting a similar underlying biology in colon and rectal cancers.

Noninvasive detection of urine tumor DNA (utDNA) has the potential to augment the diagnosis and management of bladder cancer. We sought to identify whether patient specific molecular events identified initially in the primary tumor could be detected in their utDNA. We interrogated both genetic and epigenetic events by a number of different technologies. Single nucleotide variants (SNVs) were analyzed by Next Generation Sequencing (NGS) on both the Ion Torrent platform (using amplicon enrichment) and the Illumina platform (via hybridization capture). Thirteen differentially methylated regions (DMRs) in the genome were analyzed by methylation-specific quantitative polymerase chain reaction (MS-qPCR). The cohort included patients with newly diagnosed NMIBC and those undergoing surveillance cystoscopy following a prior diagnosis of NMIBC. DNA was isolated from fixed paraffin embedded (FPE) primary tumors, matched blood buffy coat (BC), urine sediment (US) and, in some cases, clarified urine (CU-a.k.a. urine supernatant). Tumor specific molecular events were identified by comparing primary tumor tissue to BC (for SNVs with NGS) or to pooled data from urine DNA from healthy controls (for DMRs with MS-qPCR). Initially, 8 patients were evaluated with all three technologies. A larger cohort of 66 patients undergoing surveillance for NMIBC was then analyzed using MS-qPCR and a subset was also analyzed using NGS on the Ion Torrent platform. Tumor specific DMRs and/or SNVs were detected in tumor tissue from 73 of 74 patients. In the 8 patients assessed using both NGS platforms, SNVs were found in the primary tumor for 8/8 (Ion Torrent) and 6/8 (Illumina) patients, and both NGS platforms identified utDNA in 4 of 5 biopsy confirmed NMIBC patients. In patients with sufficient DNA to be assessed with all three technologies, in both US and CU, there was 100% agreement for all positive/negative calls for utDNA. Targeted genomic regions methylated in NMIBC tissue were seen to be methylated in the corresponding utDNA at the time of diagnosis or recurrence. In the cohort of 66 patients undergoing surveillance for NMIBC using MS-qPCR, a negative predictive value for high risk recurrences of 95% (with a prevalence of 10%) was achievable. These results provide evidence that both genetic and epigenetic events are evident in utDNA and reflect the presence and genetics of the NMIBC. This proof of concept study demonstrates the potential for a personalized non-invasive means to detect and monitor bladder cancer, thus making a valuable contribution to the field of precision medicine. Citation Format: Matthew J. Resnick, Margarita Lopatin, Neal D. Shore, Po N. Lam, Brian Helfand, Richard D. Abramson, Michael Crager, Michael Bonham, Haluk Tezcan, Kim M. Clark-Langone, Chris Silk, Seth Michelson, Gregory Alexander, Phillip G. Febbo. Analysis of tumor DNA in urine as a highly sensitive liquid biopsy for patients with non-muscle invasive bladder cancer (NMIBC). [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 14.

Purpose These studies were conducted to determine the relationship between quantitative tumor gene expression and risk of cancer recurrence in patients with stage II or III colon cancer treated with surgery alone or surgery plus fluorouracil (FU) and leucovorin (LV) to develop multigene algorithms to quantify the risk of recurrence as well as the likelihood of differential treatment benefit of FU/LV adjuvant chemotherapy for individual patients. Patients and Methods We performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) on RNA extracted from fixed, paraffin-embedded (FPE) tumor blocks from patients with stage II or III colon cancer who were treated with surgery alone (n = 270 from National Surgical Adjuvant Breast and Bowel Project [NSABP] C-01/C-02 and n = 765 from Cleveland Clinic [CC]) or surgery plus FU/LV (n = 308 from NSABP C-04 and n = 508 from NSABP C-06). Overall, 761 candidate genes were studied in C-01/C-02 and C-04, and a subset of 375 genes was studied in CC/C-06. Results A combined analysis of the four studies identified 48 genes significantly associated with risk of recurrence and 66 genes significantly associated with FU/LV benefit (with four genes in common). Seven recurrence-risk genes, six FU/LV-benefit genes, and five reference genes were selected, and algorithms were developed to identify groups of patients with low, intermediate, and high likelihood of recurrence and benefit from FU/LV. Conclusion RT-qPCR of FPE colon cancer tissue applied to four large independent populations has been used to develop multigene algorithms for estimating recurrence risk and benefit from FU/LV. These algorithms are being independently validated, and their clinical utility is being evaluated in the Quick and Simple and Reliable (QUASAR) study.

Vasoactive therapy is often used to treat acute decompensated heart failure (ADHF). The authors sought to determine whether clinical outcomes are temporally associated with time to vasoactive therapy (vasoactive time) in ADHF. Using the Acute Decompensated Heart Failure (ADHERE) Registry, the authors examined the relationship between vasoactive time and inpatient mortality within 48 hours of hospitalization. Vasoactive agents were used early (defined as

Morphine is a long-standing therapy in acute decompensated heart failure (ADHF), despite few supporting data. A study was undertaken to compare the outcomes of patients who did and did not receive morphine for ADHF.The study was a retrospective analysis of the Acute Decompensated Heart Failure National Registry (ADHERE) which enrols hospitalised patients with treatment for, or a primary discharge diagnosis of, ADHF. Patients were stratified into cohorts based on whether or not they received intravenous morphine. ANOVA, Wilcoxon and chi(2) tests were used in univariate analysis, followed by multivariate analysis controlling for parameters previously associated with mortality. Analyses were repeated for ejection fraction subgroups and in patients not on mechanical ventilation.There were 147 362 hospitalisations in ADHERE at December 2004, 20 782 of whom (14.1%) received morphine and 126 580 (85.9%) did not. There were no clinically relevant differences between the groups in the initial age, heart rate, blood pressure, blood urea nitrogen, creatinine, haemoglobin, ejection fraction or atrial fibrillation. A higher prevalence of rest dyspnoea, congestion on chest radiography, rales and raised troponin occurred in the morphine group. Patients on morphine received more inotropes and vasodilators, were more likely to require mechanical ventilation (15.4% vs 2.8%), had a longer median hospitalisation (5.6 vs 4.2 days), more ICU admissions (38.7% vs 14.4%), and had greater mortality (13.0% vs 2.4%) (all p0.001). Even after risk adjustment and exclusion of ventilated patients, morphine was an independent predictor of mortality (OR 4.84 (95% CI 4.52 to 5.18), p0.001).Morphine is associated with increased adverse events in ADHF which includes a greater frequency of mechanical ventilation, prolonged hospitalisation, more ICU admissions and higher mortality.

Heart failure (HF) with normal ejection fraction (EF) is an increasingly common presentation of acute decompensated heart failure (ADHF). Differences between patients with HF and truly normal EF and those with mildly impaired EF have not been described. The Acute Decompensated Heart Failure Registry (ADHERE) contains information on over 100,000 heart failure hospitalizations and may provide insight into this distinction. The ADHERE database was used to investigate differences between patients hospitalized with heart failure and severely (EF < 25%), moderately (EF 25–40%) and mildly reduced ejection fraction (EF 40–55%) vs. those with normal ejection fraction (EF ≥ 55%). The group with normal EF was 69% female with a mean age of 74 (p

The purpose of this study was to assess temporal trends in clinical characteristics, treatments, quality indicators, and outcomes for heart failure (HF) hospitalizations.Characteristics, treatments, quality measures, and inhospital outcomes were measured over 12 consecutive quarters (January 2002 to December 2004) using data from 159,168 enrollments from 285 ADHERE hospitals.Baseline characteristics were similar or showed only modest changes, and severity of illness by logistic regression was unchanged over all 12 quarters. Inhospital treatment changed significantly over time with inotrope use decreasing from 14.7% to 7.9% (P.0001). Discharge instructions increased 133%; smoking counseling, 132%; left ventricular function measurement, 8%; and beta-blocker use, 29% (all P.0001). Clinical outcomes improved over time, including need for mechanical ventilation, which decreased 5.3% to 3.4% (relative risk 0.64, P.0001); length of stay (mean), 6.3 to 5.5 days; and mortality, 4.5% to 3.2% (relative risk 0.71, P.0001).Over a 3-year period, demographics and clinical characteristics were relatively similar, but significant changes in intravenous therapy, enhancements in conformity to quality-of-care measures, increased administration of evidence-based HF medications, and substantial improvements in inhospital morbidity and mortality were observed during hospitalization for HF.

Background Prior studies on chronic systolic heart failure (HF) have demonstrated that body mass index (BMI) is inversely associated with mortality, the so-called obesity paradox. The aim of this study was to determine whether BMI influences the mortality risk in acute decompensated HF, a subject not previously studied. Methods The Acute Decompensated Heart Failure National Registry was analyzed for acute HF hospitalizations in 263 hospitals in the United States from October 2001 through December 2004. Patients with documented height and weight were divided into BMI (measured in kilograms per square meter) quartiles. Inhospital mortality by BMI quartile for all the patients and for those with reduced (n = 43255) and preserved (n = 37901) systolic function was assessed. Results Body mass index quartiles in the 108927 hospitalizations were QI (16.0-23.6 kg/m 2 ), QII (23.7-27.7 kg/m 2 ), QIII (27.8-33.3 kg/m 2 ), and QIV (33.4-60.0 kg/m 2 ). Patients in the higher BMI quartiles were younger, had more diabetes, and had a higher left ventricular ejection fraction. Inhospital mortality rates decreased in a near-linear fashion across successively higher BMI quartiles. After adjustments for age, sex, blood urea nitrogen, blood pressure, creatinine, sodium, heart rate, and dyspnea at rest, BMI quartile still predicted mortality risk. For every 5-U increase in BMI, the odds of risk-adjusted mortality was 10% lower (95% CI 0.88-0.93, P Conclusions In this cohort of hospitalized patients with HF, higher BMI was associated with lower inhospital mortality risk. The relationship between BMI and adverse outcomes in HF appears to be complex and deserving of further study.

Approximately 50% of patients hospitalized for heart failure have preserved systolic function. These patients are more likely to be older, women, and hypertensive. Their duration of hospitalization is similar to that of heart failure patients with systolic dysfunction, but their in-hospital mortality risk is lower. This mortality risk is increased in the setting of renal insufficiency, and the two most important risk predictors are elevated blood urea nitrogen and systolic blood pressureor = 125 mm Hg. Medical treatment strategies for patients with preserved systolic function are inconsistent and reflect the need for efficacious evidence-based treatment regimens.The aims of this analysis were to describe the clinical characteristics, management, and outcomes of patients hospitalized for acute decompensated heart failure (HF) with preserved systolic function (PSF).Clinically meaningful characteristics of these patients have not been fully studied in a large database.Data from100,000 hospitalizations from the Acute Decompensated Heart Failure National Registry (ADHERE) database were analyzed.Heart failure with PSF was present in 50.4% of patients with in-hospital assessment of left ventricular function. When compared with patients with systolic dysfunction, patients with PSF were more likely to be older, women, and hypertensive and less likely to have had a prior myocardial infarction or be receiving an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. In-hospital mortality was lower in patients with PSF compared with patients with systolic dysfunction (2.8% vs. 3.9%; adjusted odds ratio [OR]: 0.86; p = 0.005), but duration of intensive care unit stay and total hospital length of stay were similar. Serum creatinine2 mg/dl was associated with increased in-hospital mortality in both systolic function groups (PSF: 4.8%; systolic dysfunction: 8.4%; p0.0001), and the most powerful predictors of in-hospital mortality in both groups were blood urea nitrogen37 mg/dl (OR: 2.53; 95% confidence interval [CI]: 2.22 to 2.87) and systolic blood pressureor =125 mm Hg (OR: 2.58; 95% CI: 2.33 to 2.86).Heart failure with PSF is common and is characterized by a unique patient profile. Event rates are worrisome and reflect a need for more effective management strategies.

Objective. To evaluate usability, accuracy, and hypoglycemia detection of the GlucoWatch G2 Biographer (GW2B) in children aged 1 to 17 years. Methods. After a 15-hour study of device accuracy, 46 children (15 Results. A total of 531 paired GW2B/meter readings were available for accuracy assessment. The correlation coefficients were 0.58 and 0.74 (ages Conclusion. The GW2B is usable and safe in children who are

This study was done to evaluate the accuracy and safety of measuring glucose with the GlucoWatch biographer in children and adolescents with diabetes.Accuracy was assessed by comparing biographer glucose measurements with hourly blood glucose measurements using the HemoCue (Aktiebolaget Leo, Helsingborg, Sweden) Photometer for up to 12 h of monitoring. Safety was evaluated by examining the biographer application sites immediately upon removal of the devices, and then at regular intervals.Sixty-six subjects each wore three biographers at sites including the forearm, upper arm, leg, and torso. For forearm biographers, the mean absolute relative difference between biographer readings and blood glucose was 21%. Ninety-five per cent of biographer readings fell into the A or B regions of the Clarke error grid, and 97.3% into the A or B regions of the consensus error grid. Data from biographers worn at the alternative sites were similar to data from the forearm biographers. Two strong reactions to the adhesive pad of the biographer AutoSensor were observed. Most skin reactions were mild.The GlucoWatch biographer is well tolerated by children and adolescents with diabetes. Performance is similar when the device is worn at different anatomical sites, and is similar to the performance on the forearm, previously reported in adults.

Objective. To determine whether use of the GlucoWatch biographer improves glucose control in children and adolescents with type 1 diabetes. Methods. Forty children in poor glucose control (glycohemoglobin [HbA1c] >8%) were randomized to diabetes management with or without glucose monitoring using the biographer. Conventional glucose monitoring was performed 4 times daily in both groups. Those randomized to the biographer group were asked to wear the device 4 times per week for 3 months (intervention phase) and to perform blood glucose monitoring if the biographer alerted them that glucose was ≤70 mg/dL (3.9 mmol/L) or ≥300 mg/dL (16.7 mmol/L). After 3 months, all patients received biographers and were followed for 6 months (observation phase). HbA1c values were determined at baseline and after 1, 3, 6, and 9 months. Results. The median HbA1c was 8.6% and 8.9% (control versus biographer) at baseline and was significantly lower in the biographer group after 3 months (8.4% vs 9%). More hypoglycemia was detected when subjects were wearing the biographer, especially at night. No severe hypoglycemia occurred. During the observation phase, HbA1c values at 6 months were 8.5% and 8.3% and at 9 months were 8.6% and 8.4% in the control and biographer groups, respectively. Two children dropped out of the study, 1 because of skin irritation from using the device. Conclusions. The GlucoWatch biographer was well tolerated by children and adolescents and significantly improved glucose control compared with standard therapy. The use of the biographer with an alarm to detect nocturnal hypoglycemia has the potential to increase the safety of diabetes management in children.

Background Standardized tools which accurately quantify recurrence risk are needed for optimal adjuvant treatment of colon cancer. The 12-gene RS has been validated in stage II colon cancer pts from QUASAR and CALGB 9581. We conducted a large prospectively-designed clinical validation study of RS, w/ pre-specified endpoints, methods, and analysis plan, in stage II and III colon cancer pts randomized to FU or FU + Ox in C-07. Methods 50% of C-07 pts w/ tissue were randomly selected, stratified on stage and recurrence. Gene expression was quantitated by RT-PCR on 25 µm manually microdissected fixed tumor tissue. Data were analyzed by Cox regression controlling for stage and treatment (TRT). Results RT-PCR was successful in 892/921 pts (97%): 449 FU, 443 FU + Ox; 264 st II, 409 st IIIA/B, 219 st IIIC. The primary endpoint was met: RS predicted recurrence (HR/25 units = 1.96, 95% CI 1.50-2.55 p Conclusions RS predicts recurrence risk in stage II and III colon cancer, capturing underlying biology and providing risk information beyond conventional factors. RS is not predictive of relative Ox benefit but enables better discrimination of absolute Ox benefit as a function of risk. Incorporating RS into the clinical context may better inform adjuvant therapy decisions for pts w/ stage III as well as stage II colon cancer. Disclosure M. Lee: I am an employee and stockholder of Genomic Health, Inc. M. Lopatin: I am an employee and stockholder of Genomic Health, Inc. K.M. Clark-Langone: I am an employee and stockholder of Genomic Health, Inc. C. Millward: I am an employee and stockholder of Genomic Health, Inc. S. Shak: I am Chief Medical Officer and a stockholder of Genomic Health, Inc. All other authors have declared no conflicts of interest.

Aim: New clinical tools are needed to improve risk assessment in ccRCC. The 16-gene (11 cancer related, 5 reference) Recurrence Score (RS) was developed in a cohort of 931 stage I-III ccRCC patients (pts) from Cleveland Clinic. A large prospectively-designed clinical validation study of the RS in stage I-III ccRCC pts diagnosed from 1995 to 2007 at the French consortium was recently reported. The present analysis assesses the performance of the score in clinically relevant subgroups. Methods: The genes, algorithm, endpoints, methods, and analysis plan were pre-specified prior to merging clinical and molecular data. RT-PCR in fixed paraffin-embedded primary ccRCC tissue was performed without knowledge of clinical data. Recurrence-free interval was analyzed using Cox regression stratified by stage with data censored at 5 years, and Kaplan-Meier methods. Results: RS was successfully generated in 626/645 pts (97%): 398 stage I, 54 stage II, 174 stage III. Most (71%) patients were male, 29% were 70 years or older, 36% with partial nephrectomy, 46% with tumors ≤4 cm, 65% with Fuhrman grade 3-4, and 27% with invasion. Median follow-up was 5.5 yrs. The continuous RS predicted recurrence risk (HR per 25 point increase in RS (HR/25) =3.9, 95% CI 2.6-5.8, p 7cm), Fuhrman grade, and presence/absence of invasion (all interaction p > 0.29). Conclusions: The 16-gene RS is validated as a predictor of clinical outcome in pts with stage I-III ccRCC and provides significant information beyond conventional pathologic measures. The performance of the score was similar across a wide range of clinically relevant covariates indicating potential broad utility. Disclosure: B. Escudier: has an interest in relation with Genomich Health for sponsored research; M. Lopatin: is an employee of Genomic Health; C. Svedman: I am an employee of Genomic Health; T. Tsiati, M. Bonham, D. Knezevic and A. Goddard: Employee of Genomic Health; T. Lebret: Part of research grant from Genomic Health to perform the study (with the IGR institution, not personally); A. Mejean: Part of research grant from Genomic Health to perform the study (with the IGR institution, not personally). All other authors have declared no conflicts of interest.

4502 Background: New molecular diagnostics are needed to improve assessment of recurrence risk after nephrectomy in ccRCC. The 16-gene (11 cancer-related, 5 reference) Recurrence Score (RS) was pre...

396 Background: The 12-gene Oncotype DXColon Cancer Assay is clinically validated as a predictor of recurrence risk in stage II colon cancer patients following surgery. We previously reported that the 12-gene assay led to 45% change in physician treatment (Tx) recommendations in a prospective study in MMR-P stage IIA colon cancer patients. Here, from the same prospective study, we report the influence of the 12-gene assay on patient Tx decisions, physician confidence, concordance in Tx choice between physicians and patients, and patient decisional conflict. Methods: Consecutive patients with resected stage IIA colon cancer who were candidates for adjuvant chemotherapy were enrolled by 105 physicians from 17 sites. Patient's tumor specimens were assessed by the 12-gene assay (RT-PCR) and MMR (IHC). Prior to and after receiving these results, patients completed surveys including (1) their Tx decisions (observation (Obs) vs. 5FU-monotherapy (5FU) vs. 5FU + oxaliplatin (Oxal)) and (2) indicators of decisional conflict. Results: 190 of 221 patients enrolled were evaluable including 139 who were MMR-P. Pre-assay: 46% of patients chose Obs, 3% 5FU, 7% Oxal, 2% other and 41% were undecided. Post-assay: 75% chose Obs, 12% 5FU, 11% Oxal, 3% other (undecided was not a possible response). Post-assay 129 (96%) of 135 definitive Tx decisions (Obs, 5FU, or Oxal) were concordant between patients and physicians compared to 49 (66%) of 74 definitive decisions pre-assay. In the majority of cases, patients (85%) and physicians (69%) reported that the assay influenced their Tx decisions. Assay results increased physician confidence in Tx recommendations in 126 (84%) and provided additional clinically relevant information to physicians in 129 (86%) of cases. Patient decisional conflict was significantly lower after assay results (p

523 Background: The 12-gene colon cancer assay is the first commercially available molecular assay to predict the risk of recurrence in stage II/III colon and rectal cancer. Rigorous evidence for clinical validity and utility of an assay is imperative since the result is used for treatment decision-making. This summary outlines the studies that meet an established definition of clinical validation and additional studies that support the utility of the assay. Methods: Prospectively designed studies using archival tissue with pre-specified methods, clinical outcomes, and analysis plan were considered clinical validation studies (Simon et al. JNCI 2009). Additional studies that demonstrated the utility of the assay in a clinical setting were considered supportive. Results: The assay has been clinically validated in four independent studies with 3315 patients (2390 stage II/628 stage III colon and 130 stage II/167 stage III rectal). All four studies demonstrated a significant association (p

Improved glycemic control significantly reduces long-term microvascular complications of diabetes mellitus associated with chronic hyperglycemia. The GlucoWatch biographer is designed to facilitate intensive diabetes management by providing automatic, frequent, and noninvasive glucose readings up to three times per hour for as long as 12 hours.The device extracts glucose through intact skin using reverse iontophoresis and measures the extracted glucose with an electrochemical biosensor. A clinical trial was performed to assess the effect of acetaminophen, a potential interference for traditional blood glucose meters, on the accuracy of the GlucoWatch biographer in adult subjects with diabetes (n = 18). One thousand milligram doses of acetaminophen were administered to subjects in two groups: one to achieve Cmax (peak acetominophen concentration) at the time of biographer calibration and the other to achieve Cmax during the measurement period. The biographer readings were compared to serial fingerstick blood glucose measurements.Time profiles over 9 hours show close tracking of the biographer glucose results with fingerstick blood glucose measurements for all groups. The mean difference between the two measurements is between 8 and 12 mg/dL for all groups. The mean absolute value of the relative difference is less than 20%, and more than 93% of the points were in the clinically acceptable (A+B) region of the Clarke Error Grid. No statistically significant differences were found for any accuracy measurement across all groups.The GlucoWatch Biographer provides frequent measurements of glucose over a 12-hour period with high accuracy. No effect of therapeutic dosage of acetaminophen on the accuracy of the glucose readings was found.

e14569 Background: Appropriate use of prognostic and predictive markers depends on quality of evidence for clinical utility in addition to clinical validity. In stage II CC, RR assessment is based traditionally on clinicopathologic factors (CP) with limited clinical validation and varies substantially across providers. We hypothesized that the validated Oncotype DX Colon Cancer RS and MMR tests may impact clinical decision-making by decreasing variation in RR assessment across MDs. We conducted a survey to compare the level of MD agreement on stage II CC RR assessment using CP alone vs CP+RS+MMR (CP+). Methods: A clinical trial database was randomly sampled for 100 cases of stage II CC stratified on T-stage, MMR and RS groups. Anonymous internet surveys asked each MD to assess 3-year RR for 10 cases with CP and 10 different cases with CP+. MDs were divided into panels of 5; all members of each panel reviewed the same cases. Agreement in RR among MDs was assessed using within-panel mean squared difference in RR assessments and analyzed using generalized linear models. Results: 30 community (C) and 20 university-based (U) MDs (Assoc of Northern California Oncologists or NCCN, respectively) completed evaluable surveys April-June 2012. For C vs U, median years in practice were 5 and 2; prior use of RS 13% vs 25%; and routine MMR use 21% vs 55%. The standard deviation of the differences (SDD) in RR assessments for CP alone was high overall (7%), and greater for U vs C MDs (8.2% vs 6.4%). CP+ produced higher agreement in RR assessments vs CP for both C (p

3512 Background: Standardized clinical tools which accurately quantify recurrence risk are needed for optimal adjuvant treatment of colon cancer. The 12-gene RS has been validated in stage II colon cancer pts from QUASAR and CALGB 9581. We conducted a large prospectively-designed clinical validation study of RS, w/ pre-specified endpoints, methods, and analysis plan, in stage II and III colon cancer pts randomized to FU or FU+Ox in NSABP C-07. Methods: 50% of C-07 pts w/ tissue were randomly selected, stratified on stage (AJCC 6th) and recurrence. Gene expression was quantitated by RT-PCR on 25 µm manually microdissected fixed colon tumor tissue. Data were analyzed by Cox regression controlling for stage and treatment (TRT). Results: RT-PCR was successful in 892/921 pts (97%): 449 FU, 443 FU + Ox; 264 st II, 409 st IIIA/B, 219 st IIIC. The primary endpoint was met: RS predicted recurrence (HR/25 units=1.96, 95% CI 1.50-2.55 p

3626 Background: The Oncotype DX Colon Cancer Recurrence Score (RS) has been clinically validated as an independent predictor of individual recurrence risk in stage II colon cancer patients following surgery. As a result, physicians have been ordering the Oncotype DX assay for stage II colon cancer patients since January 2010, yet no data exist on the assay’s impact on adjuvant treatment planning in clinical practice. We performed a survey to characterize the impact of the assay on adjuvant treatment recommendations in stage II colon cancer. Methods: U.S. medical oncologists (n=346) who ordered Oncotype DX for ≥3 patients with stage II colon cancer were contacted and asked to complete a web-based survey regarding the single most recent stage II colon cancer patient for whom the assay was ordered. The survey was developed through cognitive interviews with four medical oncologists, and the protocol was institutional review board approved. Results: We analyzed survey results from 116 eligible physicians. Physicians were more often in community (86%) than academic or other practices, and had a median of 14.5 years (range, 2-40) of practice experience. The median patient age was 62 years (range, 32–85). Most patients (81%) had T3 disease. Patients had ≤8, 9-11 and ≥12 nodes examined 3%, 13% and 84% of the time and 38% had comorbidities. Of the 76 patients tested for MMR/MSI, 13 (17%) were MMR-D or MSI-H and 46 (61%) were MMR-P or MSI-L; 17 (22%) unknown. Median RS was 20 (range, 1-77). Before obtaining the RS, chemotherapy was planned in 52 (45%) patients, observation in 40 (34%), and there was no recommendation in 24 (21%). For the 92 patients with pre-assay recommendations, recommended treatment changed after obtaining the RS for 27 patients (29%). Treatment intensity decreased for 18 (67%) and increased for 9 (33%) of 27 changed recommendations. A significant trend of decreasing treatment intensity with lower RS values was observed (p=.0035). Conclusions: These findings indicate that for stage II colon cancer patients, treatment recommendations were changed by RS results in 29% of patients. Use of the Oncotype DX assay may lead to reductions in treatment intensity, contributing to the assay’s cost effectiveness.

398 Background: The Oncotype DX Colon Cancer Recurrence Score (RS) has been clinically validated as an independent predictor of individual recurrence risk in stage II colon cancer patients following surgery. As a result, physicians have been ordering the Oncotype DX assay for stage II colon cancer patients since January 2010, yet no data exist on the assay’s impact on adjuvant treatment planning in practice. We performed a survey to characterize the impact of the assay on adjuvant treatment recommendations in stage II colon cancer. Methods: U.S. medical oncologists (N=277) who ordered Oncotype DX for ≥3 patients with stage II colon cancer were contacted and asked to complete a web-based survey regarding the single most recent stage II colon cancer patient for whom the assay was ordered. The survey was developed through cognitive interviews with four medical oncologists, and the protocol was institutional review board approved. Results: As a planned preliminary analysis, we analyzed surveys from 92 eligible physicians. Physicians were more often in community (85%) than academic or other practices, and had a median of 14.5 years (range, 2-40) of practice experience. The median patient age was 62 years (range, 34–81). 84% of patients had T3 disease. Patients had ≤8, 9-11 and ≥12 nodes examined 2%, 14% and 84% of the time and 36% had comorbidities. Of the 60 patients tested for MMR/MSI, 9 (15%) were MMR-D or MSI-high and 37 (62%) were MMR-P or MSI-low; 14 (23%) unknown. Median RS was 20 (range, 1-77). Before obtaining the RS, chemotherapy was planned in 38 (41%) patients, observation in 35 (38%), and there was no recommendation in 19 (21%). For the 73 patients with pre-assay recommendations, recommended treatment changed after obtaining the RS for 23 patients (32%), including changes from chemotherapy to observation and vice-versa. Conclusions: These preliminary findings indicate that for stage II colon cancer patients, treatment recommendations were changed by RS results approximately one-third of the time. Final results will be reported to include accrual through December 2011.