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Several passive surveillance systems reported increased risks of myocarditis or pericarditis, or both, after COVID-19 mRNA vaccination, especially in young men. We used active surveillance from large health-care databases to quantify and enable the direct comparison of the risk of myocarditis or pericarditis, or both, after mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech) vaccinations.We conducted a retrospective cohort study, examining the primary outcome of myocarditis or pericarditis, or both, identified using the International Classification of Diseases diagnosis codes, occurring 1-7 days post-vaccination, evaluated in COVID-19 mRNA vaccinees aged 18-64 years using health plan claims databases in the USA. Observed (O) incidence rates were compared with expected (E) incidence rates estimated from historical cohorts by each database. We used multivariate Poisson regression to estimate the adjusted incidence rates, specific to each brand of vaccine, and incidence rate ratios (IRRs) comparing mRNA-1273 and BNT162b2. We used meta-analyses to pool the adjusted incidence rates and IRRs across databases.A total of 411 myocarditis or pericarditis, or both, events were observed among 15 148 369 people aged 18-64 years who received 16 912 716 doses of BNT162b2 and 10 631 554 doses of mRNA-1273. Among men aged 18-25 years, the pooled incidence rate was highest after the second dose, at 1·71 (95% CI 1·31 to 2·23) per 100 000 person-days for BNT162b2 and 2·17 (1·55 to 3·04) per 100 000 person-days for mRNA-1273. The pooled IRR in the head-to-head comparison of the two mRNA vaccines was 1·43 (95% CI 0·88 to 2·34), with an excess risk of 27·80 per million doses (-21·88 to 77·48) in mRNA-1273 recipients compared with BNT162b2.An increased risk of myocarditis or pericarditis was observed after COVID-19 mRNA vaccination and was highest in men aged 18-25 years after a second dose of the vaccine. However, the incidence was rare. These results do not indicate a statistically significant risk difference between mRNA-1273 and BNT162b2, but it should not be ruled out that a difference might exist. Our study results, along with the benefit-risk profile, continue to support vaccination using either of the two mRNA vaccines.US Food and Drug Administration.

Objectives Third-generation tyrosine kinase inhibitors (TKIs) have proven effective in patients with the acquired EGFR T790M resistance mutation who progress on prior EGFR TKI therapy. Median progression-free survival (PFS) on a 3rd-gen TKI was 9–10 months for T790M+ patients compared to 2.8 months for T790M- patients. PFS is similar regardless of the specimen used to assess T790M, such as tissue, plasma, or urine ctDNA. This study aimed to assess the total cost of care of a urine-testing strategy (UTS) versus a tissue-testing strategy (TTS) for T790M detection, in patients with EGFR-mutation positive lung adenocarcinoma and progression on prior TKI therapy. Materials and methods Long-term outcomes and economic implications were assessed from a US payer perspective. Endpoints were PFS, overall survival (OS), medical resource use and related costs. Data sources We included published randomized drug trials and Medicare fee schedules. A state-transition analysis and Markov model tracked patients from stable disease to progression and death. Univariate and multivariate sensitivity analyses were performed to assess the robustness of findings and identify factors that most influenced outcomes and costs. Results UTS increased the rate of detection of patients with T790M mutation eligible for treatment with 3rd generation TKI by 7% compared with TTS; urine ctDNA testing detected T790M mutation in some patients for whom biopsy could not be performed or when tissue testing yielded indeterminate results. Due to enhanced targeting of TKI therapy, UTS increased PFS and OS by 0.44 and 0.35 months, respectively. UTS yields a savings of $1243-$1680 per patient due to avoidance of biopsy, potential biopsy-associated complications, and tissue-based molecular testing in approximately 55.6% of patients. Probability of T790M detection by tissue and cost of biopsy procedure were the most influential factors. Conclusion UTS prolonged PFS/OS due to increased detection of T790M mutation and decreased biopsies and complication-related costs.

Aim: To assess multi-gene assay (MGA) effects on chemotherapy use, toxicities, recurrences, and costs in estrogen receptor-positive early breast cancer. Methods: Meta-analysis performed using data from public databases. Results: Studies included 12,202 women. Relative to no testing, chemotherapy use was higher with 12-gene and 70-gene and lower with PAM50 (commercial) and 21-gene MGAs. Overall, 1643 distant recurrences occurred with no testing, declining by 231 (21-gene), 121 (70-gene), 54 (12-gene) and 94 (PAM50); only the 21-gene assay resulted in no risk of increasing the number of distant recurrences. Relative to ‘no testing’, total cost of care declined only with 21-gene MGA. Conclusion: MGAs differ in chemotherapy use and related outcomes for women with estrogen receptor-positive early breast cancer.

Randomized, controlled trials can provide high-quality, unbiased evidence for therapeutic interventions but are not always a practical or viable study design for certain healthcare decisions, such as those involving prognostic or predictive testing. Studies using large, real-world databases may be more appropriate and more generalizable to the intended target population of physicians and patients to answer these questions but carry potential for hidden bias. We illustrate several emerging methods of analyzing observational studies using propensity score matching (PSM) and coarsened exact matching (CEM). These advanced statistical methods are intended to reveal a “hidden experiment” within an observational database, and so refute or confirm a potential causal effect of assignment to an intervention and study outcome. We applied these methods to the Optum™ Research Database (ORD; Eden Prairie, MN) of electronic health records and administrative claims data to assess the effect of the 17-gene Genomic Prostate Score® (GPS™; Genomic Health, Redwood City, CA) assay on use of active surveillance (AS). In a traditional multivariable logistic regression, the GPS assay increased the use of AS by 29% (95% CI, 24%-33%). Upon applying the matching methods, the effect of the GPS assay on AS use varied between 27% and 80% and the matched data were significant among all algorithms. All matching algorithms performed well in identifying matched data that improved the imbalance in baseline covariates. By using different matching methods to assess causal inference in an observational database, we provide further confidence that the effect of the GPS assay on AS use is statistically significant and unlikely to be a result of confounding due to differences in baseline characteristics of the patients or the settings in which they were seen.

The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) is a key venue for members from private industry, government, and academia to collaborate and share advances in regulatory, clinical, and reimbursement science for drugs, devices, and diagnostics. In parallel, the US Food and Drug Administration (FDA) “is responsible for advancing the public health by helping to speed innovations that make medical products more effective, safer, and more affordable.” In 2012, the Medical Device Innovation Consortium (MDIC) was formed as a public-private partnership bringing together government, industry, and nonprofit organizations to advance approaches that promote patient access to safe, innovative medical technologies. With a focus on regulatory science, the MDIC has been assessing how to apply real-world evidence (RWE) regulatory science to medical devices. A key goal of this project is to review the history of RWE regulatory science, define terms, and explain why and how RWE is being considered across the total product life cycle, including regulatory assessment. Unique considerations of real-world data for in vitro diagnostics are also taken into account. We envision that these activities will help ensure a high level of rigor and integrity of RWE necessary for regulatory use cases and demonstrate where RWE can be successfully used for regulatory decision making. The ISPOR, FDA, and MDIC are providing the needed leadership in ensuring that diverse stakeholders share a meaningful voice in determining RWE use and, by so doing, are improving the quality and efficiency of care, enhancing health outcomes, and addressing broader societal concerns of reducing health disparities and costs.

Each year, ineffective medical management of patients with mental illness compromises the health and well-being of individuals, and also impacts communities and our society. A variety of interrelated factors have impeded the health system's ability to treat patients with behavior health conditions adequately. A key contributing factor is a lack of objective markers to help predict patient response to specific drugs that has led to patterns of “trial and error” prescribing. For many years, clinicians have sought objective data (eg, a laboratory or imaging test) to assist them in selecting appropriate treatments for individual patients. Electroencephalogram (EEG) findings coupled with medication outcomes data may provide a solution. “Crowdsourced” physician registries that reference clinical outcomes to individual patient physiology have been used successfully for cancers. These techniques are now being explored in the context of behavioral health care. The Psychiatric EEG Evaluation Registry (PEER) is one such approach. PEER is a clinical phenotypic database comprising more than 11,000 baseline EEGs and more than 39,000 outcomes of medication treatment for a variety of mental health diagnoses. Collective findings from 45 studies (3130 patients) provide compelling evidence for PEER as a relatively simple, inexpensive predictor of likely patient response to specific antidepressants and likely treatment-related side effects (including suicidal ideation).

Importance A recently described noninvasive gene expression test (the pigmented lesion assay [PLA]) with adhesive patch–based sampling has the potential to rule out melanoma and the need for surgical biopsy of pigmented lesions suggestive of melanoma with a negative predictive value of 99% compared with 83% for the histopathologic standard of care. The cost implications of using this molecular test vs visual assessment followed by biopsy and histopathologic assessment (VAH) have not been evaluated. Objective To determine potential cost savings of PLA use vs the VAH pathway. Design, Setting, and Participants This health economic analysis performed from a US payer perspective was based on consensus treatment guidelines and fee schedules from the Centers for Medicare & Medicaid Services. Data for model input were derived from routine use of the test in US dermatology practices and literature. Participants included patients with primary cutaneous pigmented lesions suggestive of melanoma. Data were analyzed from February 8 to December 1, 2017. Main Outcomes and Measures The primary analysis consisted of the relative reduction in costs of diagnostic surgical procedures for PLA vs VAH management. Additional analyses included stage-related treatment costs associated with delays in diagnosis. Results In the cost analysis for this economic model, the relative reduction in surgical procedure costs (biopsy and subsequent excision), assuming $0 for the PLA to facilitate multiple comparison scenarios, was −$395 compared with VAH. The relative reduction in stage-related treatment costs associated with the PLA was −$433 compared with VAH, primarily associated with avoidance of delays due to false-negative diagnoses. Surveillance costs were reduced by −$119 with the PLA. The total cost of fully adjudicating a lesion suggestive of melanoma by VAH was $947. At a mean selling price reference point for PLA of $500, cost savings of $447 (47%) per lesion tested could be realized. Conclusions and Relevance The results of this analysis suggest that the PLA reduces cost and may improve the care of patients with primary pigmented skin lesions suggestive of melanoma.

Many men with low-risk prostate cancer (PCa) receive definitive treatment despite recommendations that have been informed by two large, randomized trials encouraging active surveillance (AS). We conducted a retrospective cohort study using the Optum™ Research Database (Eden Prairie, MN) of electronic health records and administrative claims data to assess AS use for patients tested with a 17-gene Genomic Prostate Score™ (GPS; Genomic Health, Redwood City, CA) assay and/or prostate magnetic resonance imaging (MRI). De-identified records were extracted on health plan members enrolled from June 2013 to June 2016 who had ≥1 record of PCa (n 5 291,876). Inclusion criteria included age ≥18 years, new diagnosis, American Urological Association low-risk PCa (stage T1-T2a, prostate-specific antigen ≤10 ng/mL, Gleason score 5 6), and clinical activity for at least 12 months before and after diagnosis. Data included baseline characteristics, use of GPS testing and/or MRI, and definitive procedures. GPS or MRI testing was performed in 17% of men (GPS, n 5 375, 4%; MRI, n 5 1174, 13%). AS use varied from a low of 43% for men who only underwent MRI to 89% for GPStested men who did not undergo MRI (P

Summary Background The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution. Methods Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk–outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990–2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian metaregression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol. Findings All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8–58·5) of deaths and 41·6% (40·1–43·0) of DALYs. Risks quantified account for 87·9% (86·5−89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa. Interpretation Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks. Funding Bill & Melinda Gates Foundation. Background The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the fi rst of a series of annual updates of the GBD. Risk factor quantifi cation, particularly of modifi able risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution. Methods Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk–outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990–2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the fi rst level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular fi ltration rate. For most risks, data for exposure were synthesised with a Bayesian metaregression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol. Findings All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8–58·5) of deaths and 41·6% (40·1–43·0) of DALYs. Risks quantified account for 87·9% (86·5−89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa. Interpretation Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks. Funding Bill & Melinda Gates Foundation.

To evaluate how a genomic classifier (GC) that predicts the risk of metastasis after prostatectomy would impact adjuvant treatment recommendations made by radiation oncologists and urologists. The 2 specialties often disagree about postprostatectomy adjuvant treatment recommendations.Twenty-six radiation oncologists and 20 urologists with genitourinary oncology expertise reviewed de-identified clinical results from 11 patients after radical prostatectomy and made adjuvant treatment recommendations. The same cases were later randomized and reassigned, and treatment recommendations were made using the clinical information and GC test results together.Using clinical information alone, observation was recommended in 42% of decisions made by urologists vs 23% by radiation oncologists (P.0001). The GC test results altered 35% and 45% of treatment recommendations made by radiation oncologists and urologists, respectively. Multivariate analysis showed GC risk was the strongest factor influencing treatment recommendations by both specialties, with an adjusted odds ratio of 4.17 (95% confidence interval [CI], 2.26-7.70) and 6.51 (95% CI, 4.29-9.88) for radiation oncologists and urologists, respectively. GC results indicating high metastatic risk resulted in intensification of treatment, whereas low metastatic risk resulted in less aggressive recommendations. The GC results increased interdisciplinary agreement in treatment recommendations, as the odds of a recommendation for adjuvant treatment by urologists vs radiation oncologists increased from 0.27 (95% CI, 0.17-0.44) to 0.46 (95% CI, 0.29-0.75) after results of the GC test were available.The GC test significantly influenced adjuvant postprostatectomy treatment recommendations, reduced disagreement between radiation oncologists and urologists, and has the potential to enhance personalization of postprostatectomy care.

Objectives Lung cancer accounts for a significant number of new cancer cases and deaths, with the majority of patients presenting with non-small cell lung cancer (NSCLC). Although epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors are recommended as an alternative to chemotherapy for certain patients, challenges exist for clinical utilization. The objective of this analysis was to assess the outcome and economic implications of a clinically validated serum-based proteomic test to guide treatment decisions in patients with advanced NSCLC, who are EGFR-negative or status unknown, and have progressed following at least one chemotherapy regimen. Methods This analysis was conducted from a US payer perspective. Clinical outcomes were evaluated over the lifetime of a patient, based on data from randomized trials and clinical studies. The clinical endpoints included treatment utilization, adverse events, survival, and a composite measure of length and quality of life, referred to as the quality-adjusted life year (QALY). Costs for testing, treatment, surveillance, and management of adverse events were analyzed based on publicly available costs of the related procedures. The economic endpoints were cumulative lifetime direct medical costs and cost per QALY gained. Results In the base case, treatment recommendation for 27.3% of the patient population changed from erlotinib to chemotherapy after using the proteomic test. Overall survival increased by 0.091 year and QALYs increased by 0.050 year. The total lifetime direct medical cost per patient decreased by $135 with test-guided treatment. The findings were robust over a wide range of variation in the input parameters. Conclusion The serum-based proteomic test informed treatment selection for patients with advanced NSCLC who failed previous chemotherapy regimen(s), improving QALYs and saving costs.

Objective. The multibiomarker disease activity (MBDA) blood test has been clinically validated as a measure of disease activity in patients with RA. We aimed to estimate the effect of the MBDA test on physical function for patients with RA (based on HAQ), quality-adjusted life years and costs over 10 years. Methods. A decision analysis was conducted to quantify the effect of using the MBDA test on RA-related outcomes and costs to private payers and employers. Results of a clinical management study reporting changes to anti-rheumatic drug recommendations after use of the MBDA test informed clinical utility. The effect of treatment changes on HAQ was derived from 5 tight-control and 13 treatment-switch trials. Baseline HAQ scores and the HAQ score relationship with medical costs and quality of life were derived from published National Data Bank for Rheumatic Diseases data. Results. Use of the MBDA test is projected to improve HAQ scores by 0.09 units in year 1, declining to 0.02 units after 10 years. Over the 10 year time horizon, quality-adjusted life years increased by 0.08 years and costs decreased by US$457 (cost savings in disability-related medical costs, US$659; in productivity costs, US$2137). The most influential variable in the analysis was the effect of the MBDA test on clinician treatment recommendations and subsequent HAQ changes. Conclusion. The MBDA test aids in the assessment of disease activity in patients with RA by changing treatment decisions, improving the functional status of patients and cost savings. Further validation is ongoing and future longitudinal studies are warranted.

Background: Prosigna is a standardized test measuring expression levels of 50 classifier genes (PAM50) in breast tumor tissue using nCounter® Technology (Nanostring Technologies, Inc.). It provides intrinsic subtype and risk of recurrence (ROR) score predicting 10-year recurrence probability. WSG prospectively evaluated Prosigna's impact on therapy decisions in EBC and the quality assurance at its implementation in clinical routine. Methods: The study recruited 201 consecutive postmenopausal patients in 11 centers with ER+ HER- N0 EBC (10/2013 to 10/2014). Its primary objective was to assess the extent to which the Prosigna (Breast Cancer Intrinsic Subtype Test (BCIST)) affects the oncologists' treatment recommendations regarding adjuvant chemotherapy (CT) and actual treatments received for EBC patients. Changes in treatment recommendations include (1) endocrine therapy alone, (2) endocrine therapy plus CT, and (3) changes in types of CT before/after the test and confidence in this treatment decision from physician and patient at a 6-month follow up. Secondary objectives included information on (1) physicians' confidence in the recommendations before/after the test, and by cancer recurrence risk groups, (2) rate of CT related adverse events stratified by administration of CT, and (3) patients' decisional conflict status, anxiety levels, and functional status before/after Prosigna's results. As a secondary endpoint for quality assurance, we repeated Prosigna in a second decentralized pathology laboratory in Germany for inter-observation control. Results: In the total evaluable cohort (n=198), 114 (57.6%) of tumors were classified by Prosigna as Luminal A, 79 (39.9%) Luminal B, 3 (1.5%) Basal-like and 2 (1%) HER2-E. Median Prosigna ROR score was 45 (0-94). There was a 29.3% discordance in intrinsic subtyping between Prosigna and IHC. Concordance between central pathology and the second lab regarding molecular subtype was 95.5% with only 9 discordant samples, all within the luminal group. Concordance regarding ROR risk group classification was 92.9%; no clinically relevant differences (low-high or vice versa) were seen. Overall, there was a change of treatment choice (change in CT indication and change in regimens) in 18.2% compared to the pre-Prosigna decision. Post-Prosigna, 87.8% of physicians felt more confident with their prognostic assessment and 89.4% with their intended treatment. 94.8% of the patients expected to stick to their decision after discussing the Prosigna results. Six-month follow up (actual CT administered, its morbidity, perceptions by physicians and patients) will be presented at SABC. Conclusion: Overall, there was a change of treatment choice (change in CT indication and change in CT regimens) in 18.2% compared to the pre-Prosigna decision. Substantial discordance between Prosigna (PAM50) and local IHC underlines the importance of molecular subtyping prior adjuvant treatment decisions. High concordance of Prosigna results between central and decentralized lab testing were found. Results of WSG study can be pooled with two similar European studies and may thus help to improve our understanding of treatment decision making and adherence in EBC. Citation Format: Wuerstlein R, Sotlar K, Gluz O, Hofmann D, Otremba B, Von Schumann R, Witzel I, Schindlbeck C, Janni W, Schem C, Bauerfeind I, Hasmueller S, Tesch H, Paulenz A, Morel P, Cowens W, Hornberger J, Kates RE, Pelz E, Harbeck N. Prosigna® results impact on adjuvant decision making in early breast cancer (EBC): Final analysis of the prospective WSG study. [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 P5-07-03.

Purpose The Prosigna® breast cancer prognostic gene signature assay identifies a gene-expression profile that permits the classification of tumors into subtypes and gives a score for the risk of recurrence (ROR) at 10 years. The primary objective of this multicenter study was to evaluate the impact of Prosigna’s assay information on physicians’ adjuvant treatment decisions in patients with early-stage breast cancer. Secondary objectives were to assess confidence of practitioners in their therapeutic recommendations before and after the added information provided by the Prosigna assay; and to evaluate the emotional state of patients before and after the Prosigna test results. Methods Consecutive patients with invasive early-stage breast cancer were enrolled in a prospective, observational, multicenter study carried out in 8 hospitals in France. The Prosigna test was carried out on surgical specimens using the nCounter® Analysis System located at the Institut Curie. Both before and after receiving the Prosigna test results, physicians completed treatment confidence questionnaires and patients completed questionnaires concerning their state of anxiety, the difficulties felt in face of the therapy and quality of life. Information was also collected at 6 months regarding the physicians’ opinion on the test results and the patients’ degree of anxiety, difficulties with therapy and quality of life. Results Between March 2015 and January 2016, 8 study centers in France consecutively enrolled 210 postmenopausal women with estrogen receptor (ER) positive, human epidermal growth hormone-2 (HER-2) negative, and node negative tumors, either stage 1 or stage 2. Intrinsic tumor subtypes as assessed by the Prosigna test were 114 (58.2%) Luminal A, 79 (40.3%) Luminal B, 1 (0.5%) HER-2 enriched (HER-2E), and 2 (1.0%) basal-like. Before receiving the Prosigna test results, physicians categorized tumor subtypes based on immunohistochemistry (IHC) as Luminal A in 126 (64%) patients and Luminal B in 70 (36%) patients, an overall discordance rate of 25%. The availability of Prosigna assay results was significantly associated with the likelihood of change in treatment recommendations, with 34 patients (18%) having their treatment plan changed from Adjuvant Chemotherapy to No Adjuvant Chemotherapy or vice versa (p

The KAST (Kiva Safety and Efficacy) investigation device exempt (IDE) study indicated that the majority of patients responded equally well to vertebral augmentation using either an implant-based approach or balloon kyphoplasty (BK). Additional investigation has suggested that a subset of patients may benefit further by avoiding repeated readmissions due to serious adverse events (SAEs) if they receive one vertebral augmentation approach over another.The primary aim was to assess the effect of 2 different augmentation procedures on readmission rates for SAEs.The KAST trial is a pivotal, multicenter, randomized, controlled trial conducted to evaluate an implant-based vertebral augmentation approach (implant) against BK. Post-hoc analysis was performed to evaluate SAEs and readmission rates.Twenty-one sites in North America and Europe.The treatment effect of vertebral implant versus BK on SAEs requiring unplanned readmission was evaluated by estimating the risk of SAEs associated with readmissions in KAST while controlling for key baseline covariates using multivariate Poisson regression modeling.Forty (27.8%) patients with implants had 69 SAEs associated with readmission compared to 44 (31.2%) patients with BK having 103 events. The risk for all SAEs leading to readmission was 34.4% lower with the implant than for BK (95% confidence interval = 11.1%, 51.7%; P0.01). Multivariate analysis showed that the risk of SAEs associated with readmission was decreased in subjects treated with the implant compared to BK, and increased in patients with prior histories of vertebral compression fractures (VCFs) or significant osteoporosis.The power of the KIVA study was based on clinical efficacy criteria to meet FDA requirements and recommendations for equivalency or noninferiority. The primary endpoint in this post-hoc analysis is SAEs associated with readmissions; as a result, the sample size is underpowered, although the results remain significant.The augmentation approaches compared here have similar pain relief and quality of life effects; the implant showed a lower risk of readmissions.ClinicalTrials.gov Identifier: NCT01123512. Key words: Vertebral compression fracture, kiva implant, balloon kyphoplasty, vertebroplasty, health economics, osteoporosis.

Improved understanding of risk of recurrence (ROR) is needed to reduce cases of recurrence and more effectively treat breast cancer patients. The purpose of this study was to examine how a gene-expression profile (GEP), identified by Prosigna, influences physician adjuvant treatment selection for early breast cancer (EBC) and the effects of this influence on optimizing adjuvant treatment recommendations in clinical practice. A prospective, observational, multicenter study was carried out in 15 hospitals across Spain. Participating medical oncologists completed pre-assessment, post-assessment, and follow-up questionnaires recording their treatment recommendations and confidence in these recommendations, before and after knowing the patient’s ROR. Patients completed questionnaires on decision-making, anxiety, and health status. Between June 2013 and January 2014, 217 patients enrolled and a final 200 were included in the study. Patients were postmenopausal, estrogen receptor positive, human epidermal growth hormone factor negative, and node negative with either stage 1 or stage 2 tumors. After receiving the GEP results, treatment recommendations were changed for 40 patients (20%). The confidence of medical oncologists in their treatment recommendations increased in 41.6% and decreased in 6.5% of total cases. Patients reported lower anxiety after physicians made treatment recommendations based on the GEP results (p Though this study does not include evaluation of the impact of GEP on long-term outcomes, it was found that GEP results influenced the treatment decisions of medical oncologists and their confidence in adjuvant therapy selection. Patients’ anxiety about the selected adjuvant therapy decreased with use of the GEP.

Objective: Amyloid beta (Aβ) positron emission tomography (PET) imaging helps estimate Aβ neuritic plaque density in patients with cognitive impairment who are under evaluation for Alzheimer’s disease (AD). This study aims to evaluate the cost-effectiveness of the Aβ-PET scan as an adjunct to standard diagnostic assessment for diagnosis of AD in France, using florbetapir as an example. Methods: A state-transition probability analysis was developed adopting the French Health Technology Assessment (HTA) perspective per guidance. Parameters included test characteristics, rate of cognitive decline, treatment effect, costs, and quality of life. Additional scenarios assessed the validity of the analytical framework, including: (1) earlier evaluation/treatment; (2) cerebrospinal fluid (CSF) as a comparator; and (3) use of other diagnostic procedures. Outputs included differences in quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). All benefits and costs were discounted for time preferences. Sensitivity analyses were performed to assess the robustness of findings and key influencers of outcomes. Results: Aβ-PET used as an adjunct to standard diagnostic assessment increased QALYs by 0.021 years and 10 year costs by €470 per patient. The ICER was €21,888 per QALY gained compared to standard diagnostic assessment alone. When compared with CSF, Aβ-PET costs €24,084 per QALY gained. In other scenarios, Aβ-PET was consistently cost-effective relative to the commonly used affordability threshold (€40,000 per QALY). Over 95% of simulations in the sensitivity analysis were cost-effective. Conclusion: Aβ-PET is projected to affordably increase QALYs from the French HTA perspective per guidance over a range of clinical scenarios, comparators, and input parameters.

Guideline panels recognize the need to increase the accuracy of identifying women at high risk of developing breast cancer who would benefit from prevention strategies. The characterization of proliferative epithelial disease found in nipple aspirate fluid (PED-NAF) may be a relevant risk factor.To comprehensively review the published literature to characterize and summarize abnormal cytology detected by NAF and the association of PED-NAF with subsequent risk of developing breast cancer.Literature identified by systematic searches in MEDLINE PubMed and the Cochrane Library was screened for articles containing primary data on NAF cytology based on predefined inclusion and exclusion criteria.Study characteristics, cytological group distribution, and incidence of breast cancer.Thirty articles were included after full-text review, of which 16 were analyzed, containing data on 20,808 unique aspirations from over 17,378 subjects. Seven (44%) of the studies used the King cytological classification system. Among aspirations from women free of breast cancer, 51.5% contained fluid, in which over 27.7% had PED on cytology. In the two prospective studies of 7850 cancer-free women, abnormal cytology by NAF carried a 2.1-fold higher risk (95% CI, 1.6-2.6; p 0.001) of developing breast cancer, compared with women from whom no fluid could be obtained.PED-NAF among women free of breast cancer, compared with no fluid being obtained, has an independent risk of developing breast cancer comparable to the risk of a woman with a positive family history of breast cancer. These findings have implications for augmenting risk prediction and clinical decisions concerning breast cancer surveillance and chemoprevention. As with all reviews, heterogeneity across studies may have influenced the results. The limited literature calls for prospective studies on asymptomatic women with long-term follow-up.

Objectives To evaluate the impact of a genomic classifier (GC) test for predicting metastasis risk after radical prostatectomy (RP) on urologists' decision-making about adjuvant treatment of patients with high-risk prostate cancer. Subjects and Methods Patient case history was extracted from the medical records of each of the 145 patients with pT3 disease or positive surgical margins (PSMs) after RP treated by six high-volume urologists, from five community practices. GC results were available for 122 (84%) of these patients. US board-certified urologists (n = 107) were invited to provide adjuvant treatment recommendations for 10 cases randomly drawn from the pool of patient case histories. For each case, the study participants were asked to make an adjuvant therapy recommendation without (clinical variables only) and with knowledge of the GC test results. Recommendations were made without knowledge of other participants' responses and the presentation of case histories was randomised to minimise recall bias. Results A total of 110 patient case histories were available for review by the study participants. The median patient age was 62 years, 71% of patients had pT3 disease and 63% had PSMs. The median (range) 5-year predicted probability of metastasis by the GC test for the cohort was 3.9 (1–33)% and the GC test classified 72% of patients as having low risk for metastasis. A total of 51 urologists consented to the study and provided 530 adjuvant treatment recommendations without, and 530 with knowledge of the GC test results. Study participants performed a mean of 130 RPs/year and 55% were from community-based practices. Without GC test result knowledge, observation was recommended for 57% (n = 303), adjuvant radiation therapy (ART) for 36% (n = 193) and other treatments for 7% (n = 34) of patients. Overall, 31% (95% CI: 27–35%) of treatment recommendations changed with knowledge of the GC test results. Of the ART recommendations without GC test result knowledge, 40% (n = 77) changed to observation (95% CI: 33–47%) with this knowledge. Of patients recommended for observation, 13% (n = 38 [95% CI: 9–17%]) were changed to ART with knowledge of the GC test result. Patients with low risk disease according to the GC test were recommended for observation 81% of the time (n = 276), while of those with high risk, 65% were recommended for treatment (n = 118; P < 0.001). Treatment intensity was strongly correlated with the GC-predicted probability of metastasis (P < 0.001) and the GC test was the dominant risk factor driving decisions in multivariable analysis (odds ratio 8.6, 95% CI: 5.3–14.3%; P < 0.001). Conclusions Knowledge of GC test results had a direct effect on treatment strategies after surgery. Recommendations for observation increased by 20% for patients assessed by the GC test to be at low risk of metastasis, whereas recommendations for treatment increased by 16% for patients at high risk of metastasis. These results suggest that the implementation of genomic testing in clinical practice may lead to significant changes in adjuvant therapy decision-making for high-risk prostate cancer.

To assess the effect of an individualized genomic classifier (GC) test, for predicting metastasis following radical prostatectomy (RP), on urologists' adjuvant treatment decisions when caring for high-risk patients.Data were submitted by US board-certified urologists in community practices (n = 15), who ordered the GC test for 146 prostate cancer patients with adverse pathologic features following RP (i.e., pathologic stage pT3 or positive surgical margins). Treatment recommendations were reported using an electronic data collection instrument, before and after reviewing the GC test report. Physicians also completed a Decision Conflict Scale (DCS), a decisional conflict measure, to assess their confidence with their treatment recommendations.Over 60% of high-risk patients were re-classified as low risk after review of the GC test results. Overall, adjuvant treatment recommendations were modified for 30.8% (95% CI = 23-39%) of patients. With GC test results, 42.5% of patients who were initially recommended adjuvant therapy were subsequently recommended observation. Although the number of patients recommended adjuvant therapy remained the same before and after review of the GC test results, it did influence patient treatment strategies. Multivariable analysis confirmed GC risk was the only significant predictor of treatment recommendations (OR = 4.04; 95% CI = 2.36, 6.92; p 0.0001). Decisional conflict with regard to adjuvant treatment decisions was significantly less with the use of the GC test (p 0.0001).Information on individualized metastasis risk based on a patient's tumor biology, with use of the GC test, significantly changed urologists' adjuvant treatment recommendations for post-operative patients with prostate cancer, who were at high risk of metastasis. Namely, the results of this study provide evidence for the utility of the GC test, and show it may guide use of adjuvant radiation.

Background: Prosigna™ (PAM50) is a standardized test that measures the expression levels of 50 classifier genes in formalin-fixed paraffin-embedded (FFPE) breast tissue tumor samples. It provides subtype classification based on the fundamental biology of an individual patient’s tumor (referred to as "intrinsic subtyping"), as well as a prognostic score (referred to as "risk of recurrence [ROR] score") that predicts the probability of distant recurrence over 10 years. This decision impact study examines whether the Prosigna™ test influences both physician and patient adjuvant treatment selection, beyond standard immunohistochemistry (IHC) testing. Methods: The analytic sample was comprised of postmenopausal women with node-negative, estrogen-receptor positive (ER+), HER2 negative (HER2-), early-stage breast cancer with tumors Results: A total of 200 patients met eligibility criteria and were enrolled in the study between June 2013 and January 2014. According to Prosigna™ results, intrinsic tumor subtypes of these patients were distributed as follows: 129 Luminal A (64.5%), 66 Luminal B (33.0%), 3 HER2-enriched (1.5%) and 2 basal-like (1.0%). Modifications to the adjuvant treatment recommendations by ROR score can be seen in the following table: Change in physician pre- to post- Prosigna recommendation Low ROR (N=101), N (%)Intermediate ROR (N=66), N (%)High ROR (N=33), N (%)TOTAL (N=200), N (%)HT to CHT0 (0.0)8 (12.1)10 (30.3)18 (9.0)CHT to HT11 (10.9)9 (13.6)0 (0.0)20 (10.0)TOTAL11 (10.9)17 (25.7)10 (30.3)38 (19.0) Treatment decisions changed for 19.0% of all patients: 10.0% and 9.0% of patients went from CHT to HT and HT to CHT, respectively. The percentage of patients who received chemotherapy in the low, intermediate and high risk groups was 5%, 36% and 88%, respectively. Both the central and each local laboratory analyzed the samples using IHC. We found 60% concordance between central IHC and Prosigna™ intrinsic subtypes (Kappa=0.2365). Prosigna™ results were consistent across labs (Kappa = 0.89). Conclusions: The Prosigna™ test can be reliably performed in hospital laboratories to provide useful information beyond standard clinical-pathological variables that oncologists can use to optimize adjuvant treatment decisions in clinical practice. Subtype determined using IHC is not an interchangeable proxy for subtype determined by Prosigna™. *Two last authors have contributed equally to the study. Citation Format: Miguel Martín, Milagros González-Rivera, Serafín Morales, Juan de la Haba, Lucía González-Cortijo, Luis Manso, Joan Albanell, Antonio González-Martín, Sónia González, Angels Arcusa, Luis de la Cruz-Merino, Federico Rojo, Maria Vidal, Uxue Goicoechea, Patricia Galván, Rosalía Caballero, Eva Carrasco, Steven Michalopoulos, John Hornberger, Aleix Prat. Prospective study of the impact of the Prosigna™ assay on adjuvant clinical decision-making in women with estrogen receptor-positive, HER2-negative, node-negative breast cancer: A GEICAM study [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 P6-08-10.

Adverse events, response failures and medication non-compliance are common in patients receiving medications for the treatment of mental illnesses. A systematic literature review assessed whether pharmacokinetic (PK) or pharmacodynamic (PD) responses to 26 commonly prescribed antipsychotic and antidepressant medications, including efficacy or side effects, are associated with nucleotide polymorphisms in eight commonly studied genes in psychiatric pharmacotherapy: CYP2D6, CYP2C19, CYP2C9, CYP1A2, CYP3A4, HTR2C, HTR2A, and SLC6A4. Of the 294 publications included in this review, 168 (57%) showed significant associations between gene variants and PK or PD outcomes. Other studies that showed no association often had insufficient control for confounding variables, such as co-medication use, or analysis of medications not substrates of the target gene. The strongest gene-outcome associations were for the PK profiles of CYP2C19 and CYP2D6 (93% and 90%, respectively), for the PD associations between HTR2C and weight gain (57%), and for SLC6A4 and clinical response (54%), with stronger SLC6A4 response associations for specific drug classes (60-83%). The preponderance of evidence supports the validity of analyzing nucleotide polymorphisms in CYP and pharmacodynamic genes to predict the metabolism, safety, or therapeutic efficacy of psychotropic medications commonly used for the treatment of depression, schizophrenia, and bipolar illness.

Genomic algorithms are typically multiple variable, mathematical equations that assign a score or probability to an event of clinical interest. Debate about the valuation of multianalyte algorithm assays highlights the gaps in best practices for valuing technologies. Decisions about valuation are partly about resolving scientific uncertainty, but also involve issues of social norms and political processes. More transparent discussion and understanding of beliefs about the valuation of algorithms would help reduce uncertainty and drive optimal investment in development and adoption of algorithms that improve social welfare; that is, affordably improving population health. Techniques have been evolving for greater public participation and engagement in such deliberations, which are to be encouraged in determining the valuation of genomic algorithms.

To assess the impact of a serum-based proteomic test for non-small-cell lung cancer (NSCLC) on physician treatment recommendations.A multivariate, serum-based proteomic test (VeriStrat) is commercially available to assist physicians when determining treatment using epidermal growth factor receptor inhibitor (EGFRi) therapy, such as erlotinib (Tarceva), by stratifying patients into two categories: those with significantly better ('good') and those with significantly worse ('poor') outcomes following treatment with EGFRi therapy. All tests ordered from August 9, 2011 to November 26, 2012, were considered for this study. Pre- and post-test treatment recommendations were prospectively collected from ordering physicians on a voluntary basis. Only those tests that had both pre- and post-test treatment information were included in the analysis group.Proportional change and correlation of treatment recommendations before and after receipt of the test results.Over the duration of the study, 724 physicians ordered 2854 tests. The analysis group comprised the 226 physicians who provided pre- and post-test treatment information (n = 403 tests). Following receipt of the test results, 90.3% (95% CI: 86.4-93.3%) of patients who tested as 'good' received erlotinib recommendations versus 9.6% (95% CI: 4.5-17.4%, p0.0001) of patients who tested as 'poor'. Ninety percent of post-test treatment recommendations positively correlated with test results, with 40% showing a change from pre-test considerations.Data based on physicians willing to submit recommendations and endpoint limited to therapy recommendations.Among test orderers, serum-based proteomic mass spectrometry testing significantly influenced therapy recommendations in NSCLC. Usage patterns should be monitored as use expands.

Purpose: The West German Study Group (WSG) Breast Cancer Intrinsic Subtype (BCIST) study was designed to assess the influence of Prosigna gene signature assay results on physicians’ adjuvant treatment recommendations by determining the extent of change in pre-test treatment recommendations following assay results. Secondary objectives were to assess the influence of Prosigna results on physicians’ confidence in their therapeutic recommendations and on patients’ decisional conflict status, anxiety levels, and functional status. Methods: This prospective, observational, decision impact study enrolled consecutive postmenopausal patients with estrogen-receptor (ER)-positive, HER2-negative, lymph-node-negative early-stage breast cancer in 11 centers in Germany. Physicians based their pre-test adjuvant treatment recommendations on standard clinico-pathological parameters. Tumor specimens were assayed using the Prosigna test in a WSG central pathology laboratory following manufacturer’s guidelines. An independent pathology laboratory performed subsequent Prosigna assays on tumor sections to assess assay result concordance with the central laboratory. Physicians completed treatment confidence questionnaires prior to and after receiving Prosigna test results. Patients completed standardized questionnaires on decisional conflict, anxiety, and health status both before and after Prosigna testing. Results: The present study population consisted predominantly of low-to-intermediate risk patients (N = 198). Prosigna had 29.3% discordance in intrinsic subtyping with local immunohistochemistry test results. After Prosigna test results, a change in the adjuvant therapy recommendation occurred in 36 (18.2%) patients; 22 (11.1%) patients switched from no chemotherapy to chemotherapy. After Prosigna test results, physicians expressed increased confidence in their prognostic assessment in 87.9% of patients, and increased confidence in their treatment recommendation in 89.4%. Patients reported improved anxiety and emotional/functional well-being after receiving Prosigna test results. Conclusions: Use of the Prosigna assay led to a change in 18.2% of adjuvant treatment decisions. Prosigna testing was associated with increased patient and physician confidence in treatment decisions, and with decreased patient anxiety and improved well-being. Any comparison of the therapeutic decision-making impacts of different genomic assays must account for potential confounding factors.

Background: Breast cancer incidence and breast-cancer mortality have been increasing in Japan. In estrogen-receptor-positive breast cancer, adding chemotherapy as adjuvant treatment is not definitive benefit for all women. Primary data on the clinical validity and decision impact of the 21-gene Recurrence Score for guiding the use of adjuvant chemotherapy has been studied among a Japanese population. Objective: The cost-effectiveness of the clinically validated 21-gene Recurrence Score for estrogen-receptor-positive, lymph-node-negative, early-stage breast cancer (ESBC) was assessed from a Japanese societal perspective. Method: The proportion of patients with low, intermediate, and high risk of recurrence by the 21-gene Recurrence Score and the influence of the Recurrence Score on use of adjuvant chemotherapy were obtained in a study of 104 patients. A Markov model was used to track time until distant recurrence and time from distant recurrence to death. Effect of adjuvant chemotherapy based on 21-gene Recurrence Score was based on published clinical validation studies. Direct and indirect medical costs were obtained from the referral center. Utilities associated with progression and adverse events associated with chemotherapy were extracted from the literature. Sensitivity analyses were performed to assess the key drivers of cost-effectiveness and the robustness of the findings to variations in the input estimates. Results: Forty-eight percent of patients were identified by the 21-gene Recurrence Score as low-risk, 36% as intermediate-risk, and 16% as high-risk. In treatment decision by using the 21-gene Recurrence Score, chemotherapy use overall decreased by 19%, resulting in an average increase of 0.235 QALYs. Testing with the 21-gene Recurrence Score cost ¥350,000 per patient with ¥153,490 lower acute costs because fewer women were treated with adjuvant chemotherapy. Eighteen percent more women who were identified as high risk were recommended adjuvant chemotherapy, which results in longer progression-free survival. On average across all risk groups, cost of monitoring until recurrence per patient increased by ¥3,572 and costs associated with recurrence declined by ¥43,687. Use of the 21-gene Recurrence Score resulted in a net cost of ¥665,455 ($8,386) per QALY gained. Conclusions: The change in decisions resulting from use of the 21-gene Recurrence Score in women with estrogen-receptor-positive, lymph-node-negative, ESBC is projected to be societally cost-effective in Japan. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-15-06.

J. Scott Nystrom 1 , John C. Hornberger 2,3 , Gauri R. Varadhachary 4 , Richard J. Hornberger 3 , Hialy R. Gutierrez 3 , W. David Henner 5 , Shawn H. Becker 5 , Mahul B. Amin 6 , and Michael G. Walker 2 1 Department of Medicine, Tufts Medical Center, Boston, MA, USA 2 Department of Medicine, Stanford University, Stanford, CA, USA 3 Cedar Associates LLC, Menlo Park, CA, USA 4 Department of Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Pathwork Diagnostics, Inc., Redwood City, CA, USA 6 Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA Received: May 22, 2012; Accepted: June 08, 2012; Published: June 9, 2012; Keywords: cancer of unknown primary, diagnosis, genomics, clinical utility, tissue of origin Correspondence: John Hornberger, email: // // Abstract PURPOSE: The primary tissue-site origin in over 4% of cancers remains uncertain despite thorough clinicopathological evaluation. This study assessed the effect of a Food and Drug Administration-cleared 2,000-gene–expression-profiling (GEP) test on primary tissue-site working diagnoses and management for metastatic and poorly differentiated cancers. METHODS: Clinical information was collected from physicians ordering the GEP test for patients with difficult to diagnose cancers. Endpoints included diagnostic procedures, physicians’ working diagnoses and treatment recommendations before and after GEP result availability, and physician reports of the test’s usefulness for clinical decision making. Patient date of death was obtained, with a minimum of one year follow-up from date of biopsy. RESULTS: Sixty-five physicians participated in the study (n=107 patients). Before GEP, patients underwent 3.2 investigations on average (e.g., radiology, endoscopy). Ten immunohistochemistry tests were used per biopsy (SD 5.2). After GEP testing, physicians changed the primary working diagnosis for 50% of patients (95% CI: 43%,58%) and management for 65% of patients (95% CI: 58%,73%). With GEP results, the recommendation for guideline-consistent chemotherapy increased from 42% to 65% of patients, and the recommendation for non-guideline-consistent regimens declined from 28% to 13%. At last follow-up, 69 patients had died, and median survival was 14.0 months (95% CI: 10.2,18.6). Thirty-three percent of patients were alive at 2 years. CONCLUSION: In patients with difficult-to-diagnose cancers, GEP changed the working diagnosis and management for the majority of patients. Patients for whom the GEP test was ordered had longer median survival than that historically reported for patients enrolled in treatment trials for cancer of unknown primary.

Since the late 1990 s, there has been an unprecedented growth in the development of new molecular and proteomic assays for clinical decision making. Despite the thousands of tests available, a standardized, well-defined, and coherent evaluation framework for these molecular assays is still lacking. We aim to summarize the publicly available appraisal criteria and to develop a succinct and accessible set of criteria that can provide a roadmap for the appraisal of gene-based laboratory developed tests (LDTs). We conducted a systematic literature review of the available molecular diagnostic framework in PubMed MD and CINAHL and identified 91 articles on existing appraisal criteria. We provided a summary of the historical appraisal system and developed an analysis of these appraisal systems, LDT-SynFRAME, which details the major criteria for evaluating molecular diagnostics in the clinical setting. Our goal with the LDT-SynFRAME system is to promote a well-informed dialog among all the stakeholders responsible for the development, approval, reimbursement, and use of new molecular classifiers.

A recent phase III trial demonstrated improved progression-free survival (PFS) and overall survival (OS) associated with adding rituximab to fludarabine and cyclophosphamide (R-FC) compared to FC in treatment of previously untreated chronic lymphocytic leukemia (CLL). A cost-effectiveness analysis of R-FC over FC was performed from a US third-party payer perspective over a lifetime horizon in the base case. One-way, two-way and probabilistic sensitivity analyses were conducted to assess the robustness of the results. A secondary analysis was performed by also considering a societal perspective. R-FC was associated with an incremental 1.15 quality-adjusted life-years (QALYs) compared to FC and resulted in an incremental cost-effectiveness ratio of $23 530 per QALY in the base case and $31 513 per QALY considering a societal perspective. Results were most sensitive to time horizon, discount rate and unit drug cost for rituximab. Within the limitations of modeling long-term outcomes, R-FC is cost-effective for previously untreated CLL.

Objectives: To estimate the cost-effectiveness of bortezomib (BTZ) compared with dexamethasone (DEX) and lenalidomide plus dexamethasone (LEN ⁄DEX) for the treatment of relapsed ⁄refractory multiple myeloma in Sweden. Methods: We used partitioned survival analysis to assess survival data decomposed into three states: (i) alive before disease progression; (ii) alive after progression; and (iii) dead. The effects of treatment on time to progression and overall survival (OS) were obtained from published reports of the APEX, MM-009, and MM-010 randomized clinical trials. Costs included drug and administration costs, adverse events, treatment of relapses, and end-of-life costs. Utility estimates were derived from the literature. Results: BTZ mean OS was 57.4 months compared with 44.6 and 54.1 months for DEX and LEN ⁄DEX, respectively. Mean lifetime direct medical costs per patient were approximately 2010 SEK 1 904 462, 1 278 854, and 2 450 588 for BTZ, DEX, and LEN ⁄DEX, respectively. Mean incremental cost per quality-adjusted life-year of BTZ compared to DEX was 2010 SEK 902,874 (€95 073) (95% CI: 514 791, 962 416) and was dominant with respect to LEN ⁄DEX. Conclusion: BTZ and LEN ⁄DEX are projected to prolong survival relative to DEX. From a Swedish perspective, BTZ is cost-effective compared to DEX and LEN ⁄DEX.

Several national and international guidelines recommend the use of antiretroviral therapy containing a protease inhibitor (PI) with ritonavir (RTV) boosting for human immunodeficiency virus (HIV)-infected treatment-naïve patients. RTV-boosted PIs such as lopinavir (LPV/r), atazanavir (ATV + RTV), darunavir (DRV + RTV), fosamprenavir (FPV + RTV), and saquinavir (SQV + RTV) are usually recommended in regimens for initial therapy. The guideline recommendations are generally based on the clinical efficacy of the regimens. A broadened perspective of assessing the evidence related to selection of a PI for optimal first-line therapy might consider additional factors for evaluation, such as effectiveness in actual clinical practice and cost-effectiveness of individual drugs in formulating recommendations. Among the guideline-recommended PIs, LPV/r is one of the earliest PIs approved, has been a well-recognized boosted PI for treatment-naïve patients in all guidelines, and demonstrates the most evidence on long-term clinical and economic effectiveness. Studies have shown its efficacy in various controlled and real-world settings in different populations, the relationship of adherence to virologic efficacy, and the implications of resistance when used in sequence with other PI regimens. In the absence of published evidence for other guideline-recommended PIs that will greatly facilitate a fully transparent, comparative effectiveness evaluation, the cumulative evidence from this broader perspective indicates all PIs should not be viewed as equally safe and effective across all patients for initial therapy, nor should any single PI within the class be considered preferred for all treatment-naïve patients.

Objective Onco type DX, a 21-gene assay, was clinically validated as a predictor of 10-year recurrence-free survival and treatment response in patients with early-stage estrogen-receptor-positive, lymph-node negative breast cancer (ER+ LN- ESBC). This study determined "real-life" alteration in treatment decision and economic implications of Onco type DX use in women with ER+ LN- ESBC. Methods Clalit Health Services (CHS, Tel Aviv, Israel), determined the proportion of women in low, intermediate and high-risk groups in the first 368 Onco type DX assays performed, the change of adjuvant therapy recommendation following the recurrence (RS) results from Onco type DX use, and associated chemotherapy costs. The risk of recurrence-free survival was derived from prespecified statistical protocols of NCI-sponsored trials conducted by NSABP (B-14 and B-20). Utilities were literature based. A 3% discount rate was employed. Results Onco type DX altered recommendations of 40% of patients, 84% of whom were changed from hormone + chemotherapy to hormonal therapy alone. Among high-risk women, 8% switched actual treatment from hormonal therapy to hormone + chemotherapy. By reducing the chemotherapy disutility, quality-adjusted life-years (QALY) increased 0.170 years. Use of Onco type DX costs $10,770 per QALY gained. Sensitivity analyses revealed that risk reduction in the low-risk population, the cost of adverse events, and the relative risk reduction of recurrence were the most influential variables. Conclusion Onco type DX resulted in net QALY gain and increased overall costs, with an incremental cost-effectiveness ratio of $10,770. For CHS, Onco type DX represents an effective and affordable approach to favorably affect the lives of women with ESBC.

e12519Background: Therapy de-escalation aims to optimize care with less treatment. Available MGAs aid decisions on CT use for women with N0, ER+ ESBC. Comparative analysis of effects on CT de-escal...

The addition of rituximab to cyclophosphamide, vincristine and prednisolone (CVP) for advanced follicular lymphoma increases median time to progression by 17 months. A US societal cost-effectiveness of R-CVP versus CVP is estimated for a representative 50-year-old patient. Progression-free survival (PFS) and overall survival are based on a randomized Phase III trial. Costs are estimated using Medicare reimbursement rates and published drug price data, and include drug and administration costs, adverse events, treatment of relapses, and end-of-life care. Utility estimates are derived from the literature and a 3% discount rate is employed. Mean overall survival is projected to be 1.51 years longer for patients assigned to R-CVP versus CVP. The cost per quality-adjusted year of life gained is $28,565. The utility associated with stable or progressive disease and the unit drug cost of rituximab most influence the findings. The cost-effectiveness ratio of R-CVP compared with CVP is projected to be cost-effective in the United States under a range of sensitivity analyses.

BACKGROUND The prognostic accuracy for distant recurrence-free survival using a 21-gene reverse-transcriptase polymerase chain reaction (RT-PCR) assay underwent validation in 668 lymph node-negative, estrogen receptor-positive women with early-stage breast cancer receiving tamoxifen on National Surgical Adjuvant Breast Program (NSABP) B-14. The predictive accuracy for treatment efficacy also underwent validation in 651 patients randomized on NSABP B-20 and 645 patients on NSABP B-14. METHODS Patients were classified as high (recurrence score [RS] ≥ 31), intermediate (RS 18–30), or low (RS < 18) risk for distant recurrence at 10 years. Cost-effectiveness ratios were estimated for RS-guided treatment compared with either tamoxifen alone or the combined chemotherapy and tamoxifen. RESULTS Distant recurrence was reported in RS low-risk, intermediate-risk, and high-risk patients at 10 years in 3.7%, 17.8%, and 38.3% receiving tamoxifen alone and 5.0%, 10.1%, and 11.1% receiving the chemotherapy and tamoxifen. RS-guided therapy is associated with a gain in individual life expectancy of 2.2 years compared with tamoxifen alone, whereas it is associated with similar life expectancy to that seen with the chemotherapy and tamoxifen strategy. RS-guided therapy is estimated to provide a net cost savings of $2256 compared with chemotherapy and tamoxifen with an incremental cost-effectiveness ratio of $1944 per life year saved compared with tamoxifen alone. CONCLUSIONS Treatment decisions based on RS-guided therapy compared with tamoxifen alone are associated with greater efficacy with acceptable cost-effectiveness ratios, and associated with similar efficacy and lower cost compared with chemotherapy and tamoxifen for patients with lymph node-negative, estrogen receptor-positive early-stage breast cancer. Cancer 2007 © 2007 American Cancer Society.

To evaluate the cost-effectiveness of the multivariate index assay (MIA) for use in triaging women with an adnexal mass relative to modified American College of Obstetricians and Gynecologists (mACOG) referral guidelines and CA-125 testing alone.The MIA triage algorithm was based on qualitative serum testing of five biomarkers: transthyretin, apolipoprotein, A-1, 2-microglobulin, transferrin, and CA-125. An economic analysis was developed to evaluate the clinical and cost implications of adopting MIA in clinical practice versus the mACOG referral guidelines and CA-125 alone, over a lifetime horizon, from the perspective of the public payer. Clinical parameters used to characterize patients' disease status, quality of life, and treatment decisions were estimated using the results of published studies; costs were approximated using reimbursement rates from CMS fee schedules. Model endpoints included overall survival (OS), costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). The cost-effectiveness threshold was set to $50,000 per QALY. One-way sensitivity analysis was performed to assess uncertainty of individual parameters included in the analysis. All costs were reported in 2014 US dollars.Use of MIA was cost-effective, resulting in fewer re-operations and pre-treatment CT scans. Overall MIA resulted in an ICER of $35,094/QALY gained. MIA was also cost-saving and QALY-increasing compared to use of CA-125 alone with an ICER of $12,189/QALY gained. One-way sensitivity analysis showed the ICER was most affected by the following parameters: (1) sensitivity of MIA; (2) sensitivity of mACOG; and (3) percentage of patients, not referred to a gynecologic oncologist, who were correctly diagnosed with advanced epithelial ovarian cancer (EOC).Use of MIA is a more cost-effective triage strategy than mACOG or CA-125. It is expected to increase the percentage of women with ovarian cancer that are referred to gynecologic oncologists, which is shown to improve clinical outcomes. Limitations include the use of assumptions when published data was unavailable, and the use of multiple sources for survival data.

The Department of Veterans Affairs (VA) recognized the need to balance patient-centered care with responsible creation of generalizable knowledge on the effectiveness of molecular medicine tools. Embracing the principles of the rapid learning healthcare system, a new clinical program called the Precision Oncology Program (POP) was created in New England. The POP integrates generalized knowledge about molecular medicine in cancer with a database of observations from previously treated veterans. The program assures access to modern genomic oncology practice in the veterans affairs (VA), removes disparities of access across the VA network of clinical centers, disseminates the products of learning that are generalizable to non-VA settings, and systematically presents opportunities for patients to participate in clinical trials of targeted therapeutics.

To describe the lifetime outcomes and economic implications of combinatorial pharmacogenomic (CPGx) testing versus treatment as usual (TAU) psychopharmacologic medication selection for a representative major depressive disorder patient who has not responded to previous treatment(s).Markov state-transition analysis based on clinical studies.Clinical validity and utility were based on published findings in prospective clinical studies of a commercially available CPGx test. Data for quality of life, direct costs, and indirect costs were extracted from meta-analyses of published literature on clinical studies and claims databases. Outcomes were assessed from a societal perspective, and included differences between the CPGx and the TAU strategies in quality-adjusted life-years (QALYs), cumulative direct and indirect costs, and cost per QALY gained.CPGx improved the treatment response rate by 70% (1.7 times as high as that with TAU), increasing QALYs by 0.316 years. With these health benefits, CPGx is expected to save $3711 in direct medical costs per patient and $2553 in work productivity costs per patient over the lifetime. The cost-effectiveness of CPGx testing was robust over a wide range of variation in the input parameters, including the scenario when testing efficacy was set to its lower limit.CPGx testing has been shown by prospective studies to modify treatment decisions for patients nonresponsive to previous treatment(s), with increased rates of treatment response. These effects are projected to increase quality-adjusted survival, and to save both direct and indirect costs to individual patients and society generally.

Background: Vertebral compression fractures (VCFs) are the most common osteoporotic fractures and cause persistent pain, kyphotic deformity, weight loss, depression, reduced quality of life, and even death. Current surgical approaches for the treatment of VCF include vertebroplasty (VP) and balloon kyphoplasty (BK). The Kiva® VCF Treatment System (Kiva System) is a next-generation alternative surgical intervention in which a percutaneously introduced nitinol Osteo Coil guidewire is advanced through a deployment cannula and subsequently a PEEK Implant is implanted incrementally and fully coiled in the vertebral body. The Kiva System’s effectiveness for the treatment of VCF has been evaluated in a large randomized controlled trial, the Kiva Safety and Effectiveness Trial (KAST). The Kiva System was non-inferior to BK with respect to pain reduction (70.8% vs. 71.8% in Visual Analogue Scale) and physical function restoration (38.1 % vs. 42.2% reduction in Oswestry Disability Index) while using less bone cement. The economic impact of the Kiva system has yet to be analyzed. Objective: To analyze hospital resource use and costs of the Kiva System over 2 years for the treatment of VCF compared to BK. Setting: A representative US hospital. Study Design: Economic analysis of the KAST randomized trial, focusing on hospital resource use and costs. Methods: The analysis was conducted from a hospital perspective and utilized clinical data from KAST as well as unit-cost data from the published literature. The cost of initial VCF surgery, reoperation cost, device market cost, and other medical costs were compared between the Kiva System and BK. The relative risk reduction rate in adjacent-level fracture with Kiva [31.6% (95% CI: -22.5%, 61.9%)] demonstrated in KAST was used in this analysis. Results: With 304 vertebral augmentation procedures performed in a representative U.S. hospital over 2 years, the Kiva System will produce a direct medical cost savings of $1,118 per patient and $280,876 per hospital. This cost saving with the Kiva System was attributable to 19 reduced adjacent-level fractures with the Kiva System. Limitations: This study does not compare the Kiva System with VP or any other non-surgical procedures for the treatment of VCF. Conclusion: This first-ever economic analysis of the KAST data showed that the Kiva System for vertebral augmentation is hospital resource and cost saving over BK in a hospital setting over 2 years. These savings are attributable to reduced risk of developing adjacent-level fractures with the Kiva System compared to BK. Key words: Vertebral compression fracture, vertebral augmentation, osteoporosis, adjacent-level fractures, kyphoplasty, balloon kyphoplasty, Kiva System