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Evaluating the merits of a genomic assay includes measuring analytic and clinical validity, and establishing clinical utility—a property that is not consistently defined. One definition of clinical utility that has gained traction is “the balance of benefits and harms associated with the use of the test in practice” [Genet Med. 2015; doi:10.1038/gim.2015.173]. The 21-gene RS assay is the only assay clinically validated for both prognosis and prediction of chemotherapy (CT) benefit in patients with node-negative (N0) or node-positive (N+), ER+, HER2− EBC. The original clinical validation studies were prospectively designed using archived tissue from legacy trials that had long-term outcomes (NSABP B-14 and B-20, TransATAC, and SWOG 8814). With 10+ years of the RS assay in clinical use, we now have real-world, prospective outcomes for patients with N0 or N+ disease that meet the aforementioned definition of clinical utility. Here we summarize the growing body of clinical evidence including the original validation studies, prospective outcomes-based trials, and analyses from two large, real-world registries in which patients were treated based on RS results: the US SEER and Clalit Health Services registries. The US SEER registry is a population-based cancer surveillance program that covers 30% of the US population and includes 40,134 N0 and 4,691 N+ patients with RS results. The Clalit Health Services registry, from the largest HMO in Israel, has 2,028 N0 and micrometastatic (Nmi) patients who were uniformly tested and had complete treatment information. In the SEER and Clalit cohorts, the distribution of RS results were similar for N0/Nmi and N+ patients: 54% and 57% low ( 5-y BC-specific Mortality (95% CI) SEER RegistriesClalit Registry N0a (N=38,568)Known CT use (% of N)N+b (N=4,691)Known CT use (% of N)N0/Nmic (N=2,028)Known CT use (% of N)RS In summary, after 10+ years of clinical use, the 21-gene RS assay has now amassed a body of clinical evidence from >50,000 patients that confirms the original clinical validation results and supports its clinical utility. The assay identifies patients with low RS results who can be safely and effectively treated with hormonal therapy alone and spared the toxicity of CT exposure. In aggregate, these data support the clinical utility of the 21-gene RS assay and its value to physicians and patients by providing information based on individual tumor biology that they can use to tailor treatment. Citation Format: Sing AP, Rothney M, Svedman C, Shak S, Baehner FL. Real-world clinical experience and outcomes in patients with early-stage breast cancer (EBC) treated according to the 21-gene recurrence score® (RS) result [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-08.

Background: The 21-Gene Recurrence Score® Assay (Oncotype DX®) has been validated as a prognostic and predictive tool in estrogen receptor (ER)+ breast cancer in multiple studies using archival specimens of clinical trials with long term follow up. Prospective outcome data from patients where treatment decisions incorporated the Recurrence Score results have not been reported. We evaluated treatments and clinical outcomes in patients undergoing Recurrence Score testing in 9 medical centers within Clalit Health Services (CHS), the largest HMO in Israel. Methods: Medical records of patients with N0/Nmic ER+ HER2-negative disease undergoing testing from 12/2004 to 12/2010 in 9 medical centers (Rabin, Lin, Soroka, Meir, Kaplan, Hadassah, Ha'emek, Rambam, and Shaare Zedek) within CHS were individually reviewed to verify treatments given, recurrence, and survival status. 5-year Kaplan-Meier (KM) and standard error estimates for distant recurrence and breast cancer specific survival were determined. Results: 1594 patients were evaluated with 5.9 years median follow-up. Median age, 61 (25-85) years; N0/Nmic (90%/10%); Grade I (16%), II (48%), III (16%), N/A (19%); histology, IDC (80%), lobular (13%), other (7%). Distribution of Recurrence Score risk groups (Recurrence Score results of Conclusions: These are the first prospective long term clinical outcome data from approximately 1600 patients for whom the 21-gene Recurrence Score assay has been incorporated in real-life clinical decision making. The documented use of CT was appropriately based on the Recurrence Score result, and the outcomes for recurrence and survival are consistent with previously reported prospective-retrospective studies of the 21-gene assay. The 5 year KM estimates for distant recurrence rate in patients with low and intermediate Recurrence Score results who were treated based upon their Recurrence Score results were very low (0.5% and 1.2%, respectively). Citation Format: Stemmer SM, Steiner M, Rizel S, Soussan-Gutman L, Geffen DB, Nisenbaum B, Ben-Baruch N, Isaacs K, Fried G, Rosengarten O, Uziely B, Svedman C, Rothney M, Klang SH, Ryvo L, Kaufman B, Evron E, Zidan J, Shak S, Liebermann N. Real-life analysis evaluating 1594 N0/Nmic breast cancer patients for whom treatment decisions incorporated the 21-gene recurrence score result: 5-year KM estimate for breast cancer specific survival with recurrence score results ≤30 is >98%. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-02.

ObjectivesTo evaluate the impact of the 12-gene Colon Cancer Recurrence Score Assay—a clinically validated prognosticator in stage II colon cancer after surgical resection—on adjuvant treatment decisions in T3 mismatch repair proficient (MMR-P) stage II colon cancer in clinical practice.MethodsThis retrospective analysis included all patients with T3 MMR-P stage II colon cancer (Clalit Health Services members) with Recurrence Score results (time frame January 2011 to May 2012). Treatment recommendations pretesting were compared with the treatments received. Changes were categorized as decreased (to observation alone/removing oxaliplatin from the therapy) or increased (from observation alone/adding oxaliplatin to the therapy) intensity.ResultsThe analysis included 269 patients; 58%, 32%, and 10% of the values were in the low (

Introduction The 21-gene Recurrence Score® assay (Oncotype DX®, Genomic Health, Inc.) is a validated predictor of recurrence risk/chemotherapy benefit in patients with estrogen receptor-positive (ER+) early-stage breast cancer treated with endocrine therapy. The Prosigna® assay (NanoString Technologies Inc.) is a validated prognosticator in postmenopausal patients with low-risk ER+ early-stage breast cancer treated with endocrine therapy. The assays were analytically/clinically developed and validated differently. This study focused on comparing recurrence risk estimates as determined by these assays and is the first blinded comparison of these assays on matched patient samples. Methods Sequential breast cancer specimens from postmenopausal, node-negative, ER+ patients treated at the Marin General Hospital were analyzed: first by the 21-gene assay then by the Prosigna assay in an independent lab blinded to the Recurrence Score results. Results The final analysis included 52 patients. Correlation between the Recurrence Score and the Prosigna assay results was poor (r = 0.08). Agreement between risk classifications based on these assays was 54%; 4/7 of patients classified as high risk by the Prosigna assay had low Recurrence Score results. Two tumors with high Recurrence Score results had low ER expression (close to positivity threshold); both of which had a low/intermediate Prosigna assay result. The Prosigna assay classified 73.1% and 23.1% of samples as luminal A and luminal B, respectively. A range of Recurrence Score results was observed within the subtypes; 83% of luminal B samples had a low Recurrence Score result. Conclusion Consistent with prior comparisons between the 21-gene and other genomic assays, our study demonstrated substantial differences in the way patients are risk stratified, suggesting that the different assays are not interchangeable. Funding Genomic Health, Inc. Electronic supplementary material The online version of this article (doi:10.1007/s12325-015-0269-2) contains supplementary material, which is available to authorized users.

Introduction The biopsy based 17-gene GPS was clinically validated to predict the likelihood of adverse surgical pathology in men with NCCN ® very low, low or low-intermediate risk prostate cancer. We performed a prospective study to assess the impact of incorporating GPS into treatment recommendations in 3 high volume urology practices. Methods Men with newly diagnosed prostate cancer meeting specific NCCN criteria were prospectively enrolled in the trial. Biopsy tissue was analyzed. Urologists indicated treatment recommendations on questionnaires administered before and after GPS. The primary study objectives were to assess all changes in treatment modality and/or treatment intensity after GPS. Results A total of 158 men were included in analysis, including 35, 71 and 52 at NCCN very low, low and low-intermediate risk. Biological risk predicted by GPS differed from NCCN clinical risk alone in 61 men (39%). Overall 18% of recommendations between active surveillance and immediate treatment changed after GPS. The relative increase in recommendations for active surveillance was 24% (absolute change 41% to 51%). In 41 of 158 men (26%) modality and/or intensity recommendations changed after GPS, including 25, 14 and 2 in whom recommendation intensity decreased, increased and were equivocal, respectively. All changes were directionally consistent with GPS. The NCCN low risk group showed the greatest absolute recommendation change after GPS (37%). In 17 of 57 men (30%) the initial recommendation of radical prostatectomy was changed to active surveillance after GPS. Urologists indicated greater confidence and found that incorporating GPS was useful in 85% and 79% of cases, respectively, including when biological risk confirmed the clinical risk category. Conclusions This study demonstrates that the 17-gene GPS influenced treatment recommendations among urologists and provided increased confidence in these recommendations in patients at NCCN very low to low-intermediate risk.

Intro Accurate measurement of ER in early stage invasive breast cancer (EBC) is important to identify patients likely to benefit from HT. While immunohistochemistry (IHC) is the most common method to quantify ER, other methods can also accurately measure ER, such as RT-PCR. ER is one of the genes included in the RT-PCR based 21-gene Recurrence Score assay (Oncotype DX®, Genomic Health, Redwood City, CA) and is also reported separately as a single gene expression. Additionally, the association between ER expression by RT-PCR (ER-PCR) and tamoxifen benefit has been reported by Kim, et al (2011). A recent study reported that patients with ER levels Aim The study aims are: (1) To correlate quantification of ER in EBC as assessed by Allred Score (AS) and ER as measured by RT-PCR in the 21-gene assay; (2) To describe changes in ER, Recurrence Score, and measures of proliferation after 2wks of an aromatase inhibitor (AI); (3) To perform exploratory analyses of factors associated with changes in proliferation. Methods 55 postmenopausal EBC patients with lower ER (AS 2-7) were treated with 2wks of an AI followed by wide excision. All patients had a 21-gene assay on a pre-and post-treatment (Tx) sample. Proliferation was measured by both Ki67 by IHC (in 45 patients) and by the proliferation gene group score (PGS) in the RT-PCR based 21-gene assay (in all patients). Proliferation response was defined by a 20% relative decrease in Ki67 or a decrease in PGS. Changes in proliferation were correlated with AS, ER-PCR and Recurrence Score result. Results The Table shows the correlation of AS with ER-PCR measured in the pre-Tx (r=0.83) samples. 94% of AS (2-3) patients and 56% of AS (4-5) were ER(-) by RT-PCR There was a significant change (pre to post) in the average Ki67 level (18% to 11%; p Pre-Tx ASER-PCR Status (Pre-Tx)NegativePositiveTotalAS 2-317 (94%)1(6%)18AS 4-59(56%)7(44%)6AS 6-70 (0%)21(100%)21Total262955 Conclusions • Results confirm earlier reports showing substantial disagreement in ER measured by IHC vs RT-PCR in patients with lower ER-expressing tumors • The clinical implications are that a substantial number of patients with low ER by IHC may have little to no benefit from HT • The 21-gene assay may be useful in selecting patients likely to benefit from HT • Further studies in larger cohorts are required to confirm these findings. Citation Format: J Michael Dixon, Arran Turnbull, Lorna Renshaw, Megan P Rothney, Cynthia A Loman, Laura Arthur, Jeremy S Thomas, Oliver Young, Juliette Murray, Linda Williams, Amy P Sing, David Cameron. Association of estrogen receptor (ER) levels and prediction of antiproliferative effect of hormone therapy (HT) in lower ER-expressing tumors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-35.

Introduction Breast cancer in young women (

Background: Abdominal visceral fat, typically measured by computer tomography (CT) or magnetic resonance imaging (MRI), has been shown to correlate with cardiometabolic risks. The purpose of this study was to examine whether a newly developed and validated visceral fat measurement from dual-energy X-ray absorptiometry (DXA) provides added predictive value to the cross-sectional differences of cardiometabolic parameters beyond the traditional anthropometric and DXA adiposity parameters. Method: A heterogeneous cohort of 194 adults (81 males and 113 females) with a BMI of 19 to 54 kg/m2 participated in this cross-sectional study. Body composition was measured with a DXA densitometer. Visceral fat was then computed with a proprietary algorithm. Insulin sensitivity index (SI, measured by intravenous glucose tolerance test), blood pressures, and lipid profiles, and peak oxygen uptake were also measured as cardiometabolic risk parameters. Results: DXA-estimated visceral fat mass was associated with HDL cholesterol (regression coefficient [β] = −5.15, P < .01, adjusted R2 = .21), triglyceride (β = 26.01, P < .01, adjusted R2 = .14), and peak oxygen uptake (β = −3.15, P < .01, adjusted R2 = .57) after adjusting for age, gender, and ethnicity. A subanalysis stratifying gender-specific BMI tertiles showed visceral fat, together with ethnicity, was independently associated with SI in overweight men and moderately obese women (second tertile). Conclusions: Without requiring additional CT or MRI-based measurements, visceral fat detected by DXA might offer certain advantages over the traditional DXA adiposity parameters as means of assessing cardiometabolic risks.

54 Background: Active surveillance (AS) is a recommended management approach for low risk prostate cancer (PCa). Studies have shown high rates of AS in the Veterans Administration (VA), but concerns about missing aggressive disease lead to variation between centers. The 17-gene Genomic Prostate Score (GPS) has been validated to predict likelihood of favorable pathology (LFP) in men with clinically low risk PCa. This study compared treatment patterns before and after introduction of the GPS to determine if the assay influenced treatment patterns. Methods: Men newly diagnosed with PCa who met NCCN criteria for very low (VL), low (L), or intermediate (INT) risk PCa were eligible. Chart review of men across 6 VA medical centers (VAMCs) established treatment in untested patients in 2013-2014. In 2015, Veterans at the same VAMCs were offered the assay in a prospective study measuring treatment recommendations before and after the assay and treatment implemented based on chart review. Results: There were 200 men in the untested cohort. Characteristics: age (median = 66, range:43-83), Gleason Score (GS) (3+3:64%, 3+4:37%), PSA (mean = 6.6, range:0.7-20), NCCN risk (VL:18%, L:37%, INT:46%). There were 190 men in the prospective study with complete data. NCCN risk group: age (median = 66, range:50-85), GS (3+3:74%, 3+4:26%), PSA (mean = 6.4, range:0.4-18.1), VL:22%, L:43%, INT:35%. GPS ranged from 0-61 and LFP ranged from 38%-91%. GPS identified 24 patients who had more favorable pathology and 13 patients who had less favorable pathology than would be expected using NCCN alone. 62% of untested Veterans pursued AS compared to 74% of tested Veterans. AS increases between untested and tested cohorts were 1% in VL, 16% in L, and 3% in INT. Conclusions: Both untested and tested patients had clinical characteristics representative of low risk PCa in the VA. Use of AS increased in tested Veterans compared to untested, with the largest increases observed in NCCN low risk patients. The 17-gene assay used biological information to provide refined risk estimates in tested Veterans, assisting physicians in appropriately identifying candidates for AS or immediate treatment.

Physical activity is essential to health. Accelerometry-based activity monitors are widely used in clinical and epidemiological research settings; however, only measuring body movement may prohibit accurate prediction of energy expenditure. Recent technological advancements allow synchronous measurements of heart rate, body temperature, acceleration, and other physiological responses and record them in detail (every minute or finer precision). Current multisensor devices are small, wireless, and capable of continuously recording data over several days or weeks, making them readily applicable in the free-living environment. Future studies should focus on developing strategies to optimize sensor data for accurate and robust predictions of clinically pertinent outcome parameters, such as total daily energy expenditure and physical activity energy expenditure. There is also a need for calibration instruments to allow users to standardize devices in their own laboratory or clinic. We also call for more transparency in publishing sensor properties and modeling algorithms, rather than proprietary or "black-box" prediction approaches.

Objective To examine the association between cardiometabolic risk factors and visceral adipose tissue (VAT) measurements using a dual-energy X-ray absorptiometry (DXA) based approach. Design and Methods An analysis of cross-sectional relationships between DXA VAT measured using CoreScan (GE Healthcare) and cardiometabolic indicators was conducted on a sample of 939 subjects (541 females and 398 males; average age, 56 years; average BMI, 26 kg/m2) who had previously undergone a total body DXA scan as well as measurements of key cardiometabolic risk factors. Results Sex-specific, age-adjusted multivariable regression analysis showed that for both men and women, DXA VAT was significantly associated with increased odds of hypertension, impaired fasting glucose, metabolic syndrome, and type 2 diabetes (P < 0.001). After additional model adjustment for BMI and waist circumference, the odds ratio (per SD change in VAT) for type 2 diabetes was 2.07 for women and 2.25 for men. Similarly, the odds ratio for metabolic syndrome for women was 3.46 and for men was 1.75. Conclusions VAT measured using DXA showed a significant association with cardiometabolic risk factors and disease. These relationships persist after statistical adjustment for age, BMI, and waist circumference. DXA VAT may provide a new accessible option for quantifying VAT-related cardiometabolic risk.

e16570Background: The overtreatment of prostate cancer and underutilization of active surveillance in men with Gleason 6 (GS6) cancer stems from uncertainty with current risk instruments such as vo...

e16611Background: Active surveillance (AS) is a recommended treatment option for low risk prostate cancer (PCa). Studies have shown high rates of AS in the Veterans Administration (VA) yet treatmen...

e16124 Background: The 17-gene prostate cancer assay is clinically validated as a biopsy-based gene expression assay that, combined with clinical features, provides an estimate of PCa disease aggre...

101 Background: A 17-gene biopsy-based RT-PCR assay (Oncotype DX Prostate Assay) has been validated as a predictor of adverse pathology and biochemical recurrence (BCR) in clinically very low to intermediate-risk prostate cancer patients. The assay measures expression of 12 cancer and 5 reference genes that are combined to calculate a Genomic Prostate Score (GPS; scaled 0-100), providing a biologic measure of tumor aggressiveness. The cancer genes represent four biological pathways: androgen signaling, stromal response, cellular organization and proliferation. We examined the effects of variation in quantitative expression of individual gene groups on GPS results and prediction of clinical risk. Methods: The first 3,500 tumor specimens processed in the Genomic Health Inc.’s reference laboratory were included. Expression of individual genes was measured and expression of the four gene groups and GPS calculated. For each gene group, GPS of patients with the lowest 5% expression levels were contrasted with GPS of patients with highest 5% expression levels. Results: Percentages of NCCN very low, low and intermediate patients were 28%, 37%, 30%; median age was 65. Mean and median GPS were 24.6 (SD 12.0) and 23 (range 0-90). Individual gene groups exhibited wide expression ranges (e.g. proliferation-16-fold difference (FD) vs. cellular organization > 8000 FD). Large differences in expression of each gene group were reflected in GPS values and, based on a prior clinical validation study, translate into large differences in BCR risk (Table). Conclusions: Each of the four gene groups show large variations in expression, meaningfully affect the GPS, and contribute to the prediction of PCa aggressiveness. [Table: see text]

33 Background: Tumor size is a clinicopathologic factor often used in early stage breast cancer (EBC) management to estimate prognosis and make decisions about therapy. While in general, small tumors have a lower chance of recurring than large tumors, some patients with small tumors have poor outcomes. The 21-gene breast cancer assay (OncotypeDX) yields a Recurrence Score result that predicts the 10-yr risk of distant recurrence (DR) and the likelihood of chemotherapy (CT) benefit in patients (pts) with ER+ EBC. This study reviews the clinical evidence and experience of the 21-gene assay in subcentimeter (subCM) tumors and shows that the Recurrence Score is more reflective of the underlying tumor biology. Methods: A meta-analysis of Genomic Health validation and supportive studies reporting Recurrence Score result and tumor size was conducted in order to describe the distribution of Recurrence Score results. Results: There were 10 GHI-sponsored studies (7,094 pts) that presented Recurrence Score results as a function of tumor size. The studies varied in the recorded tumor sizes, ranging from < = 0.5 cm to > 5 cm. Four studies specifically examined the distribution of Recurrence Score results in subCM tumors and identified a total of 629 pts out of 2,912 pts (21.6%) that fit the size criteria of < 1cm. A broad distribution of score results was observed in subCM tumors in the four studies combined: 61% low, 25% int, 15% high. Conclusions: These results demonstrate that not all pts with subCM tumors have low risk disease, and that the 21-gene assay can help inform the risk of DR more precisely as well as predict the likelihood of CT benefit. Approximately 40% of pts had intermediate or high score results, suggesting an increased potential for DR and CT benefit. The clinical implications of this meta-analysis are that size doesn’t tell the whole story. There is underlying biology reflected in the Recurrence Score that can better inform the treatment decision for pts with ER+ EBC. [Table: see text]

11003 Background: The Oncotype DX 21-gene Recurrence Score assay was developed in endocrine-treated patients (pts) and validated as a predictor of 10-yr distant recurrence risk and chemotherapy ben...

Visceral adiposity is increasingly recognized as a key condition for the development of obesity related disorders, with the ratio between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) reported as the best correlate of cardiometabolic risk. In this study, using a cohort of 40 obese females (age: 25-45 y, BMI: 28-40 kg/m(2)) under healthy clinical conditions and monitored over a 2 weeks period we examined the relationships between different body composition parameters, estimates of visceral adiposity and blood/urine metabolic profiles. Metabonomics and lipidomics analysis of blood plasma and urine were employed in combination with in vivo quantitation of body composition and abdominal fat distribution using iDXA and computerized tomography. Of the various visceral fat estimates, VAT/SAT and VAT/total abdominal fat ratios exhibited significant associations with regio-specific body lean and fat composition. The integration of these visceral fat estimates with metabolic profiles of blood and urine described a distinct amino acid, diacyl and ether phospholipid phenotype in women with higher visceral fat. Metabolites important in predicting visceral fat adiposity as assessed by Random forest analysis highlighted 7 most robust markers, including tyrosine, glutamine, PC-O 44∶6, PC-O 44∶4, PC-O 42∶4, PC-O 40∶4, and PC-O 40∶3 lipid species. Unexpectedly, the visceral fat associated inflammatory profiles were shown to be highly influenced by inter-days and between-subject variations. Nevertheless, the visceral fat associated amino acid and lipid signature is proposed to be further validated for future patient stratification and cardiometabolic health diagnostics.