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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.

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.

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.

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

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.

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.

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.

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.

Objective Analyze the economic value of replacing conventional fetal aneuploidy screening approaches with non-invasive prenatal testing (NIPT) in the general pregnancy population. Methods Using decision-analysis modeling, we compared conventional screening to NIPT with cell-free DNA (cfDNA) analysis in the annual US pregnancy population. Sensitivity and specificity for fetal aneuploidies, trisomy 21, trisomy 18, trisomy 13, and monosomy X, were estimated using published data and modeling of both first- and second trimester screening. Costs were assigned for each prenatal test component and for an affected birth. The overall cost to the healthcare system considered screening costs, the number of aneuploid cases detected, invasive procedures performed, procedure-related euploid losses, and affected pregnancies averted. Sensitivity analyses evaluated the effect of variation in parameters. Costs were reported in 2014 US Dollars. Results Replacing conventional screening with NIPT would reduce healthcare costs if it can be provided for $744 or less in the general pregnancy population. The most influential variables were timing of screening entry, screening costs, and pregnancy termination rates. Of the 13,176 affected pregnancies undergoing screening, NIPT detected 96.5% (12,717/13,176) of cases, compared with 85.9% (11,314/13,176) by conventional approaches. NIPT reduced invasive procedures by 60.0%, with NIPT and conventional methods resulting in 24,596 and 61,430 invasive procedures, respectively. The number of procedure-related euploid fetal losses was reduced by 73.5% (194/264) in the general screening population. Conclusion Based on our analysis, universal application of NIPT would increase fetal aneuploidy detection rates and can be economically justified. Offering this testing to all pregnant women is associated with substantial prenatal healthcare benefits.

Enfuvirtide (ENF) is the first of a new class of antiretrovirals (ARVs) known as the HIV fusion inhibitors. Two phase III studies of ENF, TORO 1 and TORO 2, demonstrated that ENF given in combination with optimized background (OB) therapy significantly improved virological response, increased the time to virological failure, and increased CD4-cell count compared with OB alone among highly treatment-experienced patients. The present study investigated the long-term clinical outcomes, costs, and cost-effectiveness of ENF. Outcomes, costs, and cost-effectiveness were estimated using a Markov model. Viral suppression and immune reconstitution were determined from the outcomes of the clinical trials. Time to immunological failure, time to AIDS-defining event (ADE), and time to death were estimated based on published mathematical models of disease progression. Costs were based on published estimates of the use and costs of ARVs, cost of managing ADEs, and cost of laboratory and other outpatient services. Cost-effectiveness was calculated as the incremental cost per year of life gained, adjusted for quality of life. The combined effects of an increase in CD4 count and delayed time to virological and immunological failure with ENF + OB were predicted to produce a mean life expectancy of 7.4 years from initiation of therapy, which was 1.8 years (1.5 quality-adjusted lifeyears [QALYs]) greater than the life expectancy associated with OB alone. The incremental cost-effectiveness of ENF + OB was estimated to be Dollars 24,604 per QALY. ENF is projected to increase time to immunological failure, delay onset of new AIDS-defining events, and increase life expectancy by more than 1.5 years among treatment-experienced HIV-infected patients. The cost-effectiveness of ENF is comparable to many existing treatment and prevention management strategies for HIV.

Clinical and pharmacokinetic studies have shown that target hemoglobin or hematocrit levels can be maintained using a reduced recombinant human erythropoietin (epoetin) dosage by switching from intravenous (IV) to subcutaneous (SC) administration.We conducted a meta-analysis of comparative studies of epoetin administered IV versus SC to assess the relative costs of these administration routes. Twenty-seven prospective clinical studies involving 916 patients were included in the analysis. The average difference between IV and SC doses of epoetin and average difference in drug costs between administration routes were determined.The average reduction in dose in patients treated with SC versus IV epoetin was 48 IU/kg/wk (P0.001), representing an average annual cost savings with SC administration of US $1,761 +/- $1,080 (SD) per patient. The difference between SC and IV doses was similar in both parallel- and crossover-design studies. A retrospective US survey showed a dose reduction of 26 IU/kg/wk (P0.001) with SC administration, translating to an annual savings of $946 per patient.This study indicates that the cost of epoetin is reduced substantially when administered SC in comparison to IV. Recommendations of current US and European guidelines, which encourage the use of SC administration, not only have a sound rationale in terms of efficacy and safety, but also have a sound economic basis.

Not AvailableDisclosure: Study supported by DermTech.

Inaccurate diagnoses of prostate cancer can result from transposition or contamination of patient biopsy specimens, which are known as specimen provenance complications. We assessed the clinical and economic burden of specimen provenance complications in prostate biopsies in the United States.We performed a comprehensive, systematic review of the literature to approximate the effect of specimen provenance complications on direct medical costs, patient QALYs and medicolegal costs. Data were extracted from published studies on specimen provenance complications rates, prostate cancer treatment efficacy, treatment cost, litigation/settlement costs after false diagnoses of prostate biopsies and patient quality of life. Sensitivity analysis was done to identify factors that most influenced the outcomes and assess the robustness of the findings.Of the estimated 806,251 primary and secondary prostate biopsies performed annually in the United States 20,322 specimen provenance complications were projected to result in 4,570 clinically meaningful false diagnoses and an expected loss of 634 QALYs. The total burden of specimen provenance complications was projected to exceed $879.9 million or $3,776 per positive cancer diagnosis. This estimate was most sensitive to the indemnity cost per false-positive case and the rate of transpositions at independent reference laboratories.The societal burden of specimen provenance complications in patients who undergo prostate biopsy exceeds $880 million annually in the United States. This analysis framework may be useful as policy makers, health organizations and researchers seek to decrease false diagnoses of prostate cancer and the consequent effects of delayed or unnecessary treatment. Further study is warranted to quantify the economic burden among additional diseases.

Background Breast-cancer incidence and mortality have been increasing in Japan. Japanese-specific clinical validity and utility data for the 21-gene assay (Oncotype DX® Breast Cancer Assay; Genomic Health, Inc., Redwood City, USA) are now available. The objective of this study was to evaluate the cost-effectiveness of the 21-gene assay for the guidance of adjuvant chemotherapy decisions in estrogen-receptor–positive, lymph-node–negative, early-stage breast cancer patients, from the Japanese societal perspective. Methods The recurrence risk group distribution by the 21-gene assay result and the assay’s influence on adjuvant chemotherapy recommendations were obtained from a study of 104 patients. A state-transition cohort (Markov) model tracked time from surgery until distant recurrence and from distant recurrence to death. Adjuvant chemotherapy benefit by 21-gene assay risk group was based on published clinical validation studies. Direct and indirect medical costs were obtained from the referral centers. Utilities associated with progression and chemotherapy-related adverse events were extracted from literature. Sensitivity analyses assessed the key drivers and robustness of the primary outcomes. Results The 21-gene assay identified 48% of patients as low-risk, 36% as intermediate-risk, and 16% as high-risk. Total acute chemotherapy-related costs decreased by ¥154,066 due to less adjuvant chemotherapy usage. In the high-risk group, adjuvant chemotherapy use increased 18%, leading to survival benefits. Chemotherapy use overall decreased by 19%. Monitoring costs increased by ¥3,744 but recurrence costs declined by ¥46,113 per patient. Use of the 21-gene assay increased quality-adjusted–life-years (QALYs) by 0.241 per patient on average; the net cost per QALY gained was ¥636,752 ($6,368). Conclusions The 21-gene assay for women with estrogen-receptor–positive, lymph-node–negative, early-stage breast cancer is projected to be cost-effective in Japan.

BACKGROUND: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration.METHODS: To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets.FINDINGS: Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990.INTERPRETATION: Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS's estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action.FUNDING: Bill & Melinda Gates Foundation.

This literature review assessed the burden of treatment-resistant depression in the United States by compiling published data about the clinical, societal, and economic outcomes associated with failure to respond to one or more adequate trials of drug therapy.PubMed and the Tufts Cost-Effectiveness Analyses Registry were searched for English-language articles published between January 1996 and August 2013 that collected primary data about treatment-resistant depression. Two researchers independently assessed study quality and extracted data.Sixty-two articles were included (N=59,462 patients). Patients with treatment-resistant depression had 3.8±2.1 prior depressive episodes and illness duration of 4.4±3.3 years and had completed 4.7±2.7 unsuccessful drug trials involving 2.1±.3 drug classes. Response rates for treatment-resistant depression were 36%±1%. A total of 17%±6% of patients had prior suicide attempts (1.1±.2 attempts per patient). Quality-of-life scores (scale of 0-1, with 0 indicating death and 1 indicating perfect health) for patients with treatment-resistant depression were .41±.8 and .26±.8 points lower, respectively, than for patients who experienced remission or response. Annual costs for health care and lost productivity were $5,481 and $4,048 higher, respectively, for patients with treatment-resistant versus treatment-responsive depression.Treatment-resistant depression exacts a substantial toll on patients' quality of life. At current rates of 12%-20% among all depressed patients, treatment-resistant depression may present an annual added societal cost of $29-$48 billion, pushing up the total societal costs of major depression by as much as $106-$118 billion. These findings underscore the need for research on the mechanisms of depression, new therapeutic targets, existing and new treatment combinations, and tests to improve the efficacy of and adherence to treatments for treatment-resistant depression.

Background This study was performed to assess patient preferences for consequences of 3 coronary revascularization procedures: angioplasty, conventional coronary bypass surgery, and minimally invasive coronary bypass surgery. Method A nationwide sample of 3 types of respondents was recruited: respondents with no heart disease (n = 89), respondents with heart disease who had not undergone cardiac surgery (n = 97), and respondents with heart disease who had undergone cardiac surgery (n = 118). Results Sixty-two percent ranked the risk of repeat revascularization as the most important concern, followed by postprocedure pain (22%), time to recovery of physical functioning (8%), time in hospital (4%), and body appearance (4%). Respondents preferred angioplasty to conventional and minimally invasive cardiac surgery if the 3-year risk of repeat revascularization with angioplasty were to decline to less than 28% and 21%, respectively. Conclusion These data suggest that patient preference should influence individual and policy recommendations when choosing among coronary revascularization procedures. (Am Heart J 1999;137:1153-62.)

Objectives. To estimate the risks and costs of end-stage renal disease (ESRD) after heart transplantation. Background. Previous studies have shown high rates of ESRD among solid-organ transplant patients, but the relevance of these studies for current transplant practices and policies is unclear. Limitations of prior studies include relatively small, single-center samples and estimates made before implementing suggested practice changes to reduce ESRD risk. Methods. Medicare beneficiaries who underwent heart transplantation between 1989 and 1994 were eligible for study inclusion (n=2088). Thirty-four patients undergoing dialysis or who had the diagnosis of ESRD before or at transplantation were excluded from the study. ESRD was defined as any patient undergoing renal transplantation or requiring dialysis for more than 3 months. Mortality and ESRD events were recorded up to 1995. ESRD risk was estimated using the Kaplan-Meier product-limit estimator and logistic regression analyses. Linear regression was performed to determine expenditures for treating ESRD, and we developed long-term models of the risk and direct medical costs of ESRD care. Results. The annual risk of ESRD was 0.37% in the first year after transplant and increased to 4.49% by the sixth posttransplant year. There was no significant trend in the risk of ESRD based on the year of transplantation, even after adjusting for patient characteristics. The average cumulative 10-year direct cost of ESRD per patient undergoing heart transplantation exceeded $13,000. Conclusions. In a large, national sample of patients undergoing heart transplantation, ESRD is not rare, even for patients undergoing transplant after the development of new practices intended to reduce its occurrence. ESRD remains an important component of the costs of heart transplantation.

OBJECTIVE: The purpose was to determine the optimal treatment protocol for women with a cervical vaginal diagnosis of atypical squamous cells of undetermined significance. STUDY DESIGN: By means of decision analysis, 8 strategies were compared in terms of cost, life expectancy, cost-effectiveness, and the number of cancers and complications from treatment. Data were obtained from the medical literature and the University of Iowa Hospitals and Clinics. RESULTS: Compared with more aggressive strategies, such as those that use immediate colposcopy, strategies featuring repeated smears were less expensive and carried fewer complications but had lower life expectancies per patient and more cancers. The strategy of repeating a smear annually had a lower cost per patient than did the other strategies, ranging from $112 to $989, and had a similar discounted life expectancy to that of the strategy with the longest discounted life expectancy. CONCLUSIONS: In most clinical scenarios strategies that used repeated smears were the most cost-effective. (Am J Obstet Gynecol 1998;179:411-20.)

Study objective To assess the potential health and cost effects of initial testing with sputum cytology to diagnose lung cancer. Design Cost-effectiveness analysis. Data sources Surveillance Epidemiology and End Results (SEER) program; cost data from Northern California Kaiser Permanente Hospitals and Universities of Stanford and Iowa; National Center for Health Statistics; and a MEDLINE search. Interventions The use of sputum cytologies preceding other tests (ie, fine-needle aspiration, bronchoscopy, thoracoscopy) in patients with suspected lung cancer. Main outcome measures Mortality associated with testing and initial surgical treatment (eg, performance of thoracoscopy to remove a local-stage, centrally located cancer), cost of testing and initial treatment, life expectancy, lifetime cost of medical care, and cost-effectiveness. Results In central lesions, sputum cytology as the first test was the dominant strategy because it both lowers medical-care costs ($2,516 per patient) and lowers the mortality risk (19 deaths in 100,000 patients) of the evaluation without adversely affecting long-term survival. In peripheral lesions, sputum cytology costs less then $25,000 per year of life saved if the pretest probability of cancer exceeds 50%. The estimated annual savings of adopting sputum cytology as the first test for diagnosing lung cancer in the United States is at least $30 million. Conclusions Experience in regional centers indicates that sputum cytologic testing is infrequently ordered before implementing invasive diagnostic techniques, even in patients with central lung masses. The study findings suggest that sputum cytology as the first test in suspected lung cancer is likely to be cost saving without adversely affecting patient outcomes.

Patients with schizophrenia often fail to respond to an initial course of therapy. This study systematically reviewed the societal and economic burden of treatment-resistant schizophrenia (TRS). Studies that described patients with TRS published 1996-2012 were included if they collected primary data on clinical, social, or economic outcomes. All studies were independently reviewed and extracted by at least two investigators. Sixty-five studies were identified. Almost 60% (SD 18%) of patients failed to achieve response after 23 weeks on antipsychotic drug therapy. Patients with TRS had high rates of smoking (56%), alcohol abuse (51%), substance abuse (51%), and suicide ideation (44%). The incidence of severe adverse events to treatment was 4% (SD 7%). Mean quality of life for patients who were unresponsive or intolerant to treatment was ∼20% lower than that of patients in remission. Annual costs for patients with schizophrenia are $15 500-$22 300 and are 3-11-fold higher for patients with TRS. TRS remains common and costly, despite availability of many treatment options, and contributes to a significant loss in patient quality of life. Although estimates in the literature vary greatly, TRS conservatively adds more than $34 billion in annual direct medical costs in the USA.

The United Network for Organ Sharing system of allocating cadaveric kidneys for transplantation permits only minimal involvement of patients in the selection process. The system ignores potential variations in the importance that patients may attach to outcomes associated with the transplant decision. For instance, some patients may prefer only kidneys that will give them a very favorable chance to achieve a successful transplant. We designed a decision model in which patients are surveyed about their preferences for health states that in turn affect decisions about the type of donor kidneys that would be acceptable for transplantation. Our analyses show that patients with favorable transplant characteristics (e.g., young age, good health, good immunologic match between the donor kidney and the recipient) or who expect a minimal improvement in quality of life after successful transplantation can afford to be selective when considering which kidneys to accept for transplantation. Involving patients in selecting the optimal donor-kidney should improve patients' quality and duration of life with end-stage renal disease, and thereby improve the overall efficiency of the U.S. kidney transplantation program.

Involving patients in their health care decisions improves patient satisfaction and outcomes, but can be costly because of the materials and time needed to discuss the many issues that constitute a medical problem. The authors present a framework for identifying the minimum data needed on patient preferences for accurate medical decision making. The method is illustrated for the decision of whether patients with end-stage renal disease should undergo short or long hemodialysis treatments. The value of health states to patients was modeled as a function of six outcomes: survival, uremic symptoms, hospital days per year, the inconvenience associated with long dialysis treatment duration, presence of hypotension during dialysis, and presence of other symptoms during dialysis. The relative importance of each outcome was characterized in a value function by weights referred to as preference-scaling factors. These factors were varied at random over a uniform distribution to simulate different patterns of patient preferences on the six outcomes. The decision model's recommendation was recorded for each simulation. Classification and regression-tree (CART) and stepwise logistic regression analyses were applied to these recommendations to determine the scaling-factor levels that predict short or long treatments. Knowledge of scaling factors on only the inconvenience of long dialysis treatment duration, the worst alive state of health on hemodialysis, and presence of hypotension identified the correct treatment in more than 97% of simulations. Fifty-five patients undergoing hemodialysis were then surveyed for their scaling factors on the six dimensions of well-being. When patients' scaling factors were applied to the predictive rule generated by CART using simulated scaling factors, more than 94% of treatment decisions were classified correctly--sensitivity and specificity of predicting long dialysis were 89% and 100%, respectively. These statistical techniques applied to results of a decision model help identify the minimum data needed on patient preferences to involve patients in efficient and accurate decisions about their health care.

A recent phase III trial demonstrated that maintenance rituximab® therapy after response to first-line treatment with rituximab plus chemotherapy (R-chemo) increases progression-free survival (PFS) for follicular non-Hodgkin lymphoma (f-NHL). A cost-effectiveness analysis of R-maintenance versus observation was conducted from a US payer perspective to estimate PFS and overall survival (OS) over a representative patient's lifetime. Primary outcomes were cost per life-year gained (LYG) and cost per quality-adjusted life-year (QALY) gained. Compared with observation, R-maintenance increased mean PFS by 1.50 years, OS by 1.21 years and QALYs gained by 1.11 years. The incremental cost of maintenance therapy was $38,545. The costs per LYG and QALY gained were $31,934 and $34,842, respectively. Within the limitations of modeling long-term outcomes, R-maintenance therapy in patients who received R-chemo for previously untreated f-NHL compared with observation alone after R-chemo for first-line treatment for f-NHL is cost-effective from the US payer perspective.

National guidelines recommend a 21-gene recurrence score (RS) to aid in adjuvant treatment decision in patients with estrogen receptor (ER) -positive, lymph node (LN) -negative early-stage breast cancer (ESBC). This study was performed to assess the economic implication of the assay in community practices from the perspective of a US payer.The study analyzed 952 women with ESBC enrolled with Humana (Louisville, KY) who were tested with the 21-gene RS between June 2006 and June 2010. The proportion of women classified by the assay according to RS risk category, use, and costs of chemotherapy regimens and supportive care, and costs of adverse events were obtained from Humana. We adopted a validated Markov model to compute the cost implications of RS for a representative patient. The probability of risk of recurrence, the chemotherapy benefit, and the decision impact of RS were derived from published studies.Two hundred fifty-five patients within the tested population received adjuvant chemotherapy. Adjuvant chemotherapy was administered to 10% of women at low risk, 36% of women at intermediate risk, and 72% of women at high risk of recurrence. On the basis of a meta-analysis in the reduction of chemotherapy after RS, the model estimated an average test saving of $1,160 per patient. The immediate direct savings for chemotherapy drugs, supportive care, and management of adverse events were $1,885, $2,578, and $472, respectively. Prevention of recurrence through appropriate treatment of patients at high risk resulted in additional savings of $199.The adoption of the 21-gene RS led to targeted management of women with ER-positive, LN-negative ESBC and consequently directed savings to the payer.

What comprises an optimal prescription for uremictoxin clearance in the chronic hemodialysis setting is a much disputed issue. The dispute is underscored by the rise in mortality of the U.S. dialysis population during the 1980s and reports of significant noncompliance with minimal treatment standards recommended from the National Cooperative Dialysis Study. A decision model was developed to summarize and test assumptions about the effect of various dialytic-treatment options on patient outcomes. Treatment options included delivered fractional urea clearance (Kt/V), dialysis-treatment duration, dialysis membrane (high flux versus conventional), dialysate (bicarbonate versus acetate), and ultrafiltration (controlled versus uncontrolled). The expected outcome for any set of treatment options was calculated as a function of a representative patient's life expectancy, adjusted for the probability and assumed importance of avoiding uremia- and treatment-related complications, referred to as quality-adjusted life expectancy (QALE). QALE increased by 59 days for each 0.1-U increase in Kt/V and by 187 days with high-flux dialysis. Controlled ultrafiltration with bicarbonate dialysis increased QALE by 30 days compared with uncontrolled ultrafiltration with acetate dialysis. Sensitivity analyses showed that, under conservative assumptions, QALE increased 11 days for every 0.1 increment in Kt/V. The model afforded a framework for reviewing the literature and testing assumptions about the expected benefits of dialytic-treatment options for the development of a clinical guideline on the adequacy of dialysis.

More than 3 million people were receiving antiretroviral therapy (ART) at the end of 2007, but this number represents only 31% of people clinically eligible for ART in resource-limited settings. The primary objective of this study is to summarize the key obstacles that impede the goal of universal access prevention, care, and treatment. We performed a systematic literature search to review studies that reported barriers to diagnosis and access to treatment of HIV/AIDS in resource-limited countries. Persons living with HIV/ AIDS commonly face economic, sociocultural, and behavioral obstacles to access treatment and care for HIV. A variety of programs to overcome these barriers have been implemented, including efforts to destigmatize HIV/AIDS, enhance treatment literacy, provide income-generation skills, decentralize HIV services, promote gender equality, and adopt a multisectoral approach to optimize limited resources. An understanding of these obstacles and suggested methods to overcome them must be addressed by global policy makers before universal ART access can be achieved.

Objectives . To determine whether gaps exist in published cost-utility analyses as measured by their coverage of topics addressed in current HIV guidelines from the Department of Health and Human Services (DHHS). Design . A systematic review of US-based cost-effectiveness analyses of HIV/AIDS prevention and management strategies, based on original, published research. Methods . Predefined criteria were used to identify all analyses pertaining to prevention and management of HIV/AIDS; information was collected on type of strategy, patient demographics, study perspective, quality of the study, effectiveness measures, costs, and cost-effectiveness ratios. Results . One hundred and six studies were identified; 62 described strategies for averting new HIV infections, and 44 dealt with managing persons who are HIV positive. The quality of studies was generally high, but gaps were found in all studies. Especially common were omissions in reporting data abstraction methodology and discussions of direction and magnitude of potential biases. Among the 22 most highly rated papers (score of 90 or higher), only 1 was cited in the guidelines, and 3 papers reported on interventions that were superseded by newer approaches. Using a $100,000 threshold, the guidelines usually endorsed interventions found to be cost-effective. Exceptions included recommending postexposure prophylaxis (PEP) for populations in which PEP is unlikely to be cost-effective and not recommending primary resistance testing in treatment-naive persons, although the intervention was reported to have a cost-effectiveness ratio of less than $50,000. Conclusions . Despite an abundant literature on the cost-utility of HIV/AIDS-targeted strategies, guidelines cite relatively few of these papers, and gaps exist regarding assessments of some strategies and special populations.

The Shingles Prevention Study showed that a varicella-zoster virus (VZV) vaccine administered to adults 60 years of age or older reduced the incidence of herpes zoster from 11.12 to 5.42 cases per 1000 person-years. Median follow-up was 3.1 years, and relative risk reduction was 51.3% (95% CI, 44.2% to 57.6%).To assess the extent to which clinical and cost variables influence the cost-effectiveness of VZV vaccination for preventing herpes zoster in immunocompetent older adults.Decision theoretical model.English-language data published to March 2006 identified from MEDLINE on herpes zoster rates, vaccine effectiveness, quality of life, medical resource use, and unit costs.Immunocompetent adults 60 years of age or older with a history of VZV infection.Lifetime.U.S. societal.Varicella-zoster virus vaccination versus no vaccination.Incremental quality-adjusted survival and cost per quality-adjusted life-year (QALY) gained.By reducing incidence and severity of herpes zoster, vaccination can increase quality-adjusted survival by 0.6 day compared with no vaccination. One scenario in which vaccination costs less than 100,000 dollars per QALY gained is when 1) the unit cost of vaccination is less than 200 dollars, 2) the age at vaccination is less than 70 years, and 3) the duration of vaccine efficacy is more than 30 years.Vaccination would be more cost-effective in "younger" older adults (age 60 to 64 years) than in "older" older adults (ageor =80 years). Longer life expectancy and a higher level of vaccine efficacy offset a lower risk for herpes zoster in the younger group. Other factors influencing cost-effectiveness include quality-of-life adjustments for acute zoster, unit cost of the vaccine, risk for herpes zoster, and duration of vaccine efficacy.The effectiveness of VZV vaccination remains uncertain beyond the median 3.1-year duration of follow-up in the Shingles Prevention Study.Varicella-zoster virus vaccination to prevent herpes zoster in older adults would increase QALYs compared with no vaccination. Resolution of uncertainties about the average quality-of-life effects of acute zoster and the duration of vaccine efficacy is needed to better determine the cost-effectiveness of zoster vaccination in older adults.

BACKGROUND Findings from the Groupe d'Etude des Lymphomes Adultes LNH 98-5 study showed that rituximab added to combined cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) prolonged progression-free survival and overall survival in adults age ≥ 60 years with diffuse large B-cell non-Hodgkin lymphoma (DLBCL). The current study was conducted to investigate the incremental cost utility of the addition of rituximab to CHOP (R-CHOP) compared with CHOP alone. METHODS Clinical prognosis of the time to disease progression and death was estimated using published evidence from the LNH 98-5 study (n = 399 patients) that was linked mathematically to published long-term outcome data on patients with DLBCL. Drug-acquisition costs were based on published data from formulary pricing sources, and the costs of cancer surveillance and end-of-life care were based on published literature sources. The authors assessed cost utility as the difference in costs between R-CHOP and CHOP divided by the increase in expected overall survival adjusted for quality of life. RESULTS Over 5 years, it was projected that R-CHOP would prolong overall survival by 1.04 years. The mean cumulative cost of CHOP was $3358, and the mean cost of R-CHOP was $17,225, resulting in a cumulative net increase of $13,867. The posttreatment cancer surveillance cost for CHOP was $3950, compared with $5202 for R-CHOP. It was estimated that R-CHOP would have a cost-utility ratio of $19,297 per year of life gained compared with CHOP when adjusted for quality of life. R-CHOP remained cost effective over wide ranges of variables in sensitivity analyses. CONCLUSIONS Compared with CHOP alone, it was predicted that R-CHOP would be cost effective in elderly patients with DLBCL. Cancer 2005. © 2005 American Cancer Society.