A Cost-Effectiveness Analysis of Lung Cancer Screening With Low-Dose Computed Tomography and a Diagnostic Biomarker.

Background: The Lung Computed Tomography Screening Reporting and Data System (Lung-RADS) reduces the false-positive rate of lung cancer screening but introduces prolonged periods of uncertainty for indeterminate findings. We assess the cost-effectiveness of a screening program that assesses indeterminate findings earlier via a hypothetical diagnostic biomarker introduced in place of Lung-RADS 3 and 4A guidelines. Methods: We evaluated the performance of the US Preventive Services Task Force (USPSTF) recommendations on lung cancer screening with and without a hypothetical noninvasive diagnostic biomarker using a validated microsimulation model. The diagnostic biomarker assesses the malignancy of indeterminate nodules, replacing Lung-RADS 3 and 4A guidelines, and is characterized by a varying sensitivity profile that depends on nodules' size, specificity, and cost. We tested the robustness of our findings through univariate sensitivity analyses. Results: A lung cancer screening program per the USPSTF guidelines that incorporates a diagnostic biomarker with at least medium sensitivity profile and 90% specificity, that costs $250 or less, is cost-effective with an incremental cost-effectiveness ratio lower than $100 000 per quality-adjusted life year, and improves lung cancer-specific mortality reduction while requiring fewer screening exams than the USPSTF guidelines with Lung-RADS. A screening program with a biomarker costing $750 or more is not cost-effective. The health benefits accrued and costs associated with the screening program are sensitive to the disutility of indeterminate findings and specificity of the biomarker, respectively. Conclusions: Lung cancer screening that incorporates a diagnostic biomarker, in place of Lung-RADS 3 and 4A guidelines, could improve the cost-effectiveness of the screening program and warrants further investigation.

Real-World Utilization of Biomarker Testing for Patients with Advanced Non-Small Cell Lung Cancer in a Tertiary Referral Center and Referring Hospitals.

The continued introduction of biomarkers and innovative testing methods makes already complex diagnosis in patients with stage IV non-small-cell lung cancer (NSCLC) even more complex. This study primarily analyzed variations in biomarker testing in clinical practice in patients referred to a comprehensive cancer center in the Netherlands. The secondary aim was to compare the cost of biomarker testing with the cost of whole-genome sequencing. The cohort included 102 stage IV NSCLC patients who received biomarker testing in 2017 or 2018 at the comprehensive cancer center. The complete biomarker testing history of the cohort was identified using linked data from the comprehensive cancer center and the nationwide network and registry of histopathology and cytopathology in the Netherlands. Unique biomarker-test combinations, costs, turnaround times, and test utilization were examined. The results indicate substantial variation in test utilization and sequences. The mean cost per patient of biomarker testing was 2259.92 ± 1217.10 USD, or 1881.23 ± 1013.15 EUR. Targeted gene panels were most frequently conducted, followed by IHC analysis for programmed cell death protein ligand 1. Typically, the most common biomarkers were assessed within the first tests, and emerging biomarkers were tested further down the test sequence. At the cost of current biomarker testing, replacing current testing with whole-genome sequencing would have led to cost-savings in only two patients (2%).

Inappropriate requests for tumor markers in patients aged 50 years and older: lessons not learned / Solicitação inapropriada de marcadores tumorais em pacientes com 50 anos ou mais: lições não aprendidas

OBJECTIVE: To investigate, within a private health insurance, the ordering frequency and the costs related to inappropriate tumor markers test orders. METHODS: This study analyzed data regarding tumor markers requests within a private health insurance between 2010 and 2017. Patients included in this analysis were ≥ 50 years old, had available medical records, and had at least 1 tumor markers tested within the study period. Tests were considered inappropriate when tumor markers were used in screening for neoplasms, ie, when there was no previous diagnosis. We evaluated data regarding age, sex, the ordering physician's medical specialty, and test costs. RESULTS: Between 2010 and 2017, 1112 tumor markers tests were performed and increased from 52 to 262 per year. Our sample consisted mostly of women (69.50%) with a mean age of 59.40 (SD 8.20) years. Most orders were inappropriate (87.80%) and represented 79.40% of all expenses with tumor markers tests. Cardiology professionals were the medical specialty that requested the most tumor markers tests (23.90%), followed by internal medicine specialists (22.70%) and gynecologists (19.20%). CONCLUSIONS: We observed a high percentage of inappropriate test orders in the study period, resulting in elevated costs. Studies of this nature deserve the attention of health care managers, and interventions should be performed in order to reduce the inappropriate use of tumor markers tests in clinical practice.

OBJETIVO: investigar no âmbito de um plano de saúde privado a frequência de solicitação e os custos relacionados à solicitação inapropriada de marcadores tumorais. METODOLOGIA: Utilizou-se a base de dados de um plano de saúde privado entre os anos de 2010 a 2017. Foram incluídos na pesquisa, sujeitos com idade ≥ 50 anos, que apresentavam prontuários médicos acessíveis e que havia realizado a dosagem de algum marcadores tumorais no período. Considerou-se como "exame inapropriado" quando o marcador tumoral foi utilizado como rastreio de neoplasia, ou seja, quando não havia o diagnóstico prévio. Foram avaliados os dados referentes à idade, sexo, especialidade do médico solicitante e informações sobre os custos desses exames. RESULTADOS: Foram realizados um total 1.112 testes no período, representando um aumento de 52 para 262 exames/ano. A amostra foi composta na maioria pelo sexo feminino (69,50%), com média de idade de 59,40 ± 8,20 anos. A maioria das solicitações foram inapropriadas (87,80%). Notou-se que a solicitação desses exames, impactaram cerca de 79,40% dos gastos totais do plano de saúde com marcadores tumorais. Os cardiologistas foram a especialidade que mais solicitaram marcadores tumorais em 23,90% das ocasiões, seguidos pelos especialistas em clínica médica (22,70%) e ginecologistas (19,20%). CONCLUSÕES: Observamos um alto percentual de pedidos de exames inadequados no período do estudo, resultando em custos elevados. Estudos dessa natureza merecem a atenção dos gestores de saúde e intervenções devem ser realizadas a fim de reduzir o uso inadequado de testes de marcador tumoral na prática clínica.

Butyrylcholinesterase: An economical marker of disease activity in oral squamous cell carcinoma before and after therapy.

INTRODUCTION: Biomarkers which can predict disease progression and serve as prognostic indicators are necessary for better management of oral cancer. Studies have shown that Cholinesterase plays an important role in cellular proliferation, differentiation and may have a possible involvement in tumor growth. AIM AND OBJECTIVE: The present study is aimed to determine the utility of serum Butyrylcholinesterase (BChe) levels as a marker for progression of oral squamous cell carcinoma (OSCC) in relation to the grade of the tumor and to determine if any variation occurred in the levels of BChe before and after therapy. MATERIALS AND METHODS: A total of 120 patients were included in the study and divided into two groups as Group A-30 patients (healthy individuals) and Group B-90 cases of histopathologically diagnosed OSCC. The blood sample was collected before surgery, re-collected after the completion of radiotherapy (i.e., 3 and 6 months postsurgery) and analyzed biochemically for the concentration of BCh. STATISTICAL ANALYSIS: Paired t-test, ANOVA, and post hoc test (Bonferroni) were used for determining the statistical significance. RESULTS: BChe levels were lower in OSCC (2940.32-1405.50 u/l when compared with controls (11149.60-11243.07 unit/l) and this difference was statistically significant. Postoperatively at 3 months, the serum BChe levels of OSCC patients increased almost two-fold compared to the preoperative values, and this difference was also statistically significant (P = 0.000) After 6 months, these levels further increased but did not reach those of controls. CONCLUSION: BChe can be used as an inexpensive, easy to use, noninvasive biomarker for the evaluation of disease-free survival in OSCC patients.

Are there socio-economic inequalities in utilization of predictive biomarker tests and biological and precision therapies for cancer? A systematic review and meta-analysis.

BACKGROUND: Novel biological and precision therapies and their associated predictive biomarker tests offer opportunities for increased tumor response, reduced adverse effects, and improved survival. This systematic review determined if there are socio-economic inequalities in utilization of predictive biomarker tests and/or biological and precision cancer therapies. METHODS: MEDLINE, Embase, Scopus, CINAHL, Web of Science, PubMed, and PsycINFO were searched for peer-reviewed studies, published in English between January 1998 and December 2019. Observational studies reporting utilization data for predictive biomarker tests and/or cancer biological and precision therapies by a measure of socio-economic status (SES) were eligible. Data was extracted from eligible studies. A modified ISPOR checklist for retrospective database studies was used to assess study quality. Meta-analyses were undertaken using a random-effects model, with sub-group analyses by cancer site and drug class. Unadjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed for each study. Pooled utilization ORs for low versus high socio-economic groups were calculated for test and therapy receipt. RESULTS: Among 10,722 citations screened, 62 papers (58 studies; 8 test utilization studies, 37 therapy utilization studies, 3 studies on testing and therapy, 10 studies without denominator populations or which only reported mean socio-economic status) met the inclusion criteria. Studies reported on 7 cancers, 5 predictive biomarkers tests, and 11 biological and precision therapies. Thirty-eight studies (including 1,036,125 patients) were eligible for inclusion in meta-analyses. Low socio-economic status was associated with modestly lower predictive biomarker test utilization (OR 0.86, 95% CI 0.71-1.05; 10 studies) and significantly lower biological and precision therapy utilization (OR 0.83, 95% CI 0.75-0.91; 30 studies). Associations with therapy utilization were stronger in lung cancer (OR 0.71, 95% CI 0.51-1.00; 6 studies), than breast cancer (OR 0.93, 95% CI 0.78-1.10; 8 studies). The mean study quality score was 6.9/10. CONCLUSIONS: These novel results indicate that there are socio-economic inequalities in predictive biomarker tests and biological and precision therapy utilization. This requires further investigation to prevent differences in outcomes due to inequalities in treatment with biological and precision therapies.

Cost-effectiveness analysis comparing "PARP inhibitors-for-all" to the biomarker-directed use of PARP inhibitor maintenance therapy for newly diagnosed advanced stage ovarian cancer.

OBJECTIVES: Clinical trials evaluating universal PARP inhibitor (PARPi) frontline maintenance therapy for advanced stage ovarian cancer have reported progression-free survival (PFS) benefit. It is unclear whether PARPi maintenance therapy will universally enhance value (clinical benefits relative to cost of delivery). We compared a "PARPi-for-all" to a biomarker-directed frontline maintenance therapy approach as a value-based care strategy. METHODS: The cost of two frontline PARPi maintenance strategies, PARPi-for-all and biomarker-directed maintenance, was compared using modified Markov decision models simulating the study designs of the PRIMA, VELIA, and, PAOLA-1 trials. Outcomes of interest included overall costs and incremental cost-effectiveness ratios (ICERs) reported in US dollars per quality adjusted progression-free life-year (QA-PFY) gained. RESULTS: PARPi-for-all was more costly and provided greater PFS benefit than a biomarker-directed strategy for each trial. The mean cost per patient for the PARPi-for-all strategy was $166,269, $286,715, and $366,506 for the PRIMA, VELIA, and PAOLA-1 models, respectively. For the biomarker-directed strategy, the mean cost per patient was $98,188, $167,334, and $260,671 for the PRIMA, VELIA, and PAOLA-1 models. ICERs of PARPi-for-all compared to biomarker-directed maintenance were: $593,250/QA-PFY (PRIMA), $1,512,495/QA-PFY (VELIA), and $3,347,915/QA-PFY (PAOLA-1). At current drug pricing, there is no PFS improvement in a biomarker negative cohort that would make PARPi-for-all cost-effective compared to biomarker-directed maintenance. CONCLUSIONS: This study highlights the high costs of universal PARPi maintenance treatment, compared with a biomarker-directed PARPi strategy. Maintenance therapy in the front-line setting should be reserved for those with germline or somatic HRD mutations until the cost of therapy is significantly reduced.

Can Biomarkers Guide the Use of Neoadjuvant Chemotherapy in T2 Bladder Cancer?

Current guidelines recommend cisplatin-based neoadjuvant chemotherapy prior to radical cystectomy as the preferred treatment of muscle-invasive bladder cancer. Nevertheless, for multiple reasons compliance with this guideline recommendation is low. This is particularly evident in clinical T2 bladder cancer, where controversy exists regarding the role of proceeding with radical cystectomy alone. Novel biomarkers such as molecular phenotype and DNA damage repair and response gene alterations may be able to predict who will respond to cisplatin-based neoadjuvant chemotherapy. This clinical problem is discussed, and a recommendation is made given the current state of the art. PATIENT SUMMARY: Neoadjuvant chemotherapy improves survival for patients with muscle-invasive bladder cancer. In the future, perhaps validated biomarkers may predict who should and should not receive this treatment.

Cost-Effectiveness of Urinary Biomarker Panel in Prostate Cancer Risk Assessment.

PURPOSE: SelectMDx (MDxHealth®) is a panel of urinary biomarkers used in conjunction with traditional risk factors to individualize risk prediction for clinically significant prostate cancer. In this study we sought to characterize the effectiveness of SelectMDx in a population of American men with elevated prostate specific antigen. MATERIALS AND METHODS: We developed a Markov decision analytical model to simulate the chain of events and downstream outcomes associated with ultrasound guided prostate biopsy and a strategy in which the biomarker panel is implemented prior to biopsy. The primary outcome was health outcomes, measured in QALYs (quality-adjusted life years). The secondary outcome was health care costs from the Medicare payer perspective. Multiple 1-way sensitivity analyses were performed to characterize model robustness. RESULTS: The expected mean QALYs per patient under the current standard was 10.796 at a cost of $11,060 during an 18-year horizon. Incorporating the urinary biomarker panel resulted in an expected mean of 10.841 QALYs per patient and a mean cost of $9,366, representing an average of 0.045 QALYs gained at a cost savings of $1,694 per patient. When extrapolating these data to a conservative estimate of 311,879 men per year undergoing biopsy, one would expect that the biomarker panel would result in an incremental 14,035 QALYs gained at a cost savings of $528,323,026 in each yearly cohort. The biomarker panel strategy dominated the current standard across a wide range of sensitivity analyses. CONCLUSIONS: Routine use of the SelectMDx urinary biomarker panel to guide biopsy decision making improved health outcomes and lowered costs in American men at risk for prostate cancer. This strategy may optimize the value of prostate cancer risk assessment in an era of increasing financial accountability.

Incorporating Biomarkers into the Primary Prostate Biopsy Setting: A Cost-Effectiveness Analysis.

PURPOSE: We performed a cost-effectiveness analysis using the PHI (Prostate Health Index), 4Kscore®, SelectMDx™ and the EPI (ExoDx™ Prostate [IntelliScore]) in men with elevated prostate specific antigen to determine the need for biopsy. MATERIALS AND METHODS: We developed a decision analytical model in men with elevated prostate specific antigen (3 ng/ml or greater) in which 1 biomarker test was used to determine which hypothetical individuals required biopsy. In the current standard of care strategy all individuals underwent biopsy. Model parameters were derived from a comprehensive review of the literature. Costs were calculated from a health sector perspective and converted into 2017 United States dollars. RESULTS: The cost and QALYs (quality adjusted life-years) of the current standard of care, which was transrectal ultrasound guided biopsy, was $3,863 and 18.085, respectively. Applying any of the 3 biomarkers improved quality adjusted survival compared to the current standard of care. The cost of SelectMDx, the PHI and the EPI was lower than performing prostate biopsy in all patients. However, the PHI was more costly and less effective than the SelectMDx strategy. The EPI provided the highest QALY with an incremental cost-effectiveness ratio of $58,404 per QALY. The use of biomarkers could reduce the number of unnecessary biopsies by 24% to 34% compared to the current standard of care. CONCLUSIONS: Applying biomarkers in men with elevated prostate specific antigen to determine the need for biopsy improved quality adjusted survival by decreasing the number of biopsies performed and the treatment of indolent disease. Using SelectMDx or the EPI following elevated prostate specific antigen but before proceeding to biopsy is a cost-effective strategy in this setting.

Modelling cost-effectiveness of a biomarker-based approach to neoadjuvant chemotherapy for muscle-invasive bladder cancer.

OBJECTIVES: To model the cost-effectiveness of a biomarker-based approach to select patients for neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC). PATIENTS AND METHODS: We obtained data from the most recent clinical studies on patients with locally advanced MIBC treated by RC, including stage distributions, overall survival (OS) estimates, associated costs, and utilisation/response to NAC. Additionally, we estimated the putative efficacy of three biomarkers to select patients for NAC: DNA-repair gene panel [ataxia telangiectasia mutated (ATM), retinoblastoma 1 (RB1), and Fanconi anaemia complementation group C (FANCC)], excision repair cross-complementation group 2 (ERCC2), and ribonucleic acid (RNA) subtypes. A decision analysis model was developed to evaluate the cost-effectiveness of biomarker-based approaches to select patients with MIBC for NAC. Comparison of cost-effectiveness included RC alone, unselected NAC plus RC, and NAC based on the three aforementioned biomarkers. RESULTS: The DNA-repair gene panel-based approach to NAC was the most cost-effective strategy (mean OS of 3.14 years, $31 482/life year). Under this approach, 38% would undergo NAC, about twice the number of patients who are currently receiving NAC for MIBC. Such an approach would improve mean OS by 5.2, 1.6, and 4.4 months compared to RC alone, a hypothetical scenario where all patients received NAC, and compared to current estimates of NAC utilisation, respectively. CONCLUSIONS: A biomarker-based strategy to identify patients with MIBC who should undergo NAC was more cost-effective than unselected use of NAC or RC alone. As further data becomes available, such a model may serve as a basis for incorporating biomarkers into clinical decision making.

Potential therapeutic and economic value of risk-stratified treatment as initial treatment of multiple myeloma in Europe.

Biomarkers associated with prognosis in multiple myeloma (MM) can be used to stratify patients into risk categories. An attractive alternative to uniform treatment (UT), risk-stratified treatment (RST) is proposed where high-risk patients receive bortezomib-based regimens while standard-risk patients receive alternative less costly regimens. An early Markov-type decision analytic model evaluated the potential therapeutic and economic value of different RST strategies compared with UT in MM patients in key European countries. Results suggest RST strategies were both cheaper and more effective than UT across all countries, with the molecular marker-only strategy RST-SKY92 producing maximum health gains (0.031-0.039 QALYs). The conclusions remained consistent in the univariate sensitivity analyses. These findings should encourage stakeholders to support the adoption of RST approaches in MM.

Perspectives on the integration of Immuno-Oncology Biomarkers and drugs in a Health Care setting.

Immunotherapies, specifically checkpoint inhibitors, are becoming an important component in cancer care with the most application now in melanoma and lung cancer patients. Some drawbacks that converge with this new evolution are the rather low response rates to these drugs and their high cost with a significant economic impact on the health care system. These major challenges can likely be circumvented by implementing a "personalized immuno-oncology" approach to accomplish a selection of optimal responders based on biomarkers. In this paper we first discuss the legal framework for the development of valuable in vitro diagnostics. Based on a case study in lung cancer, the clinical validity and utility requirements of predictive immuno-oncology biomarkers is highlighted and an overview is given on the evolution towards multiplex or omics-based assays together with its challenges and pitfalls. Finally, some initiatives between the public and private sector are pinpointed to sustain the future access to innovative medicines in cancer therapy at a reasonable cost.

Biomarker Testing for Personalized Therapy in Lung Cancer in Low- and Middle-Income Countries.

There have been many important advances in personalized therapy for patients with lung cancer, particularly for those with advanced disease. Molecular testing is crucial for implementation of personalized therapy. Although the United States and many Western countries have come far in the implementation of personalized therapy for lung cancer, there are substantial challenges for low- and middle-income countries (LMICs). Globally, the LMICs display great heterogeneity in the pattern of implementation of molecular testing and targeted therapy. The current review presents an attempt to identify the challenges and obstacles for the implementation of molecular testing and the use of targeted therapies in these areas. Lack of infrastructure, lack of technical expertise, economic factors, and lack of access to new drugs are among the substantial barriers.

Use of Tumor Markers in Gastrointestinal Cancers: Surgeon Perceptions and Cost-Benefit Trade-Off Analysis.

BACKGROUND: Gastrointestinal cancers constitute the third most common cancers worldwide. Tumor markers have long since been used in the postoperative surveillance of these malignancies; however, the true value in clinical practice remains undetermined. OBJECTIVE: This study aimed to evaluate the clinical utility of three tumor markers in colorectal and esophagogastric cancer. METHODS: A systematic review of the literature was undertaken to elicit the sensitivity, specificity, statistical heterogeneity and ability to predict recurrence and metastases for carcinoembryonic antigen (CEA), cancer antigen (CA) 19-9 and CA125. European surgeons were surveyed to assess their current practice and the characteristics of tumor markers they most valued. Data from the included studies and survey were combined in a cost-benefit trade-off analysis to assess which tumor markers are of most use in clinical practice. RESULTS: Diagnostic sensitivity and specificity were ranked the most desirable characteristics of a tumor marker by those surveyed. Overall, 156 studies were included to inform the cost-benefit trade-off. The cost-benefit trade-off showed that CEA outperformed both CA19-9 and CA125, with lower financial cost and a higher sensitivity, and diagnostic accuracy for metastases at presentation (area under the curve [AUC] 0.70 vs. 0.61 vs. 0.46), as well as similar diagnostic accuracy for recurrence (AUC 0.46 vs. 0.48). CONCLUSIONS: Cost-benefit trade-off analysis identified CEA to be the best performing tumor marker. Further studies should seek to evaluate new tumor markers, with investigation tailored to factors that meet the requirements of practicing clinicians.

Biopsy Procedures and Molecular Testing Utilization and Related Costs in Patients with Metastatic Lung Cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) gene mutations and anaplastic lymphoma kinase (ALK) gene rearrangements are key therapeutic targets for biomarker-driven treatment with an EGFR or ALK tyrosine kinase inhibitor (TKI) in patients with metastatic non-small cell lung cancer (NSCLC). To appropriately guide treatment decisions, since 2011, the National Comprehensive Cancer Network and the American Society of Clinical Oncology therefore recommend EGFR and ALK analysis in tumor samples obtained at the time of diagnosis in patients with non-squamous NSCLC. Currently, there are limited data on utilization patterns and cost of biopsy procedures and biomarker tests in patients with metastatic NSCLC who receive an EGFR or ALK TKI. OBJECTIVES: To (a) describe utilization patterns and costs associated with biopsy procedures and biomarker testing in patients with NSCLC who received erlotinib or crizotinib between 2009 and 2012 and (b) investigate the timing of these procedures relative to the erlotinib or crizotinib index date. METHODS: Adult patients with metastatic lung cancer were identified by ICD-9-CM diagnostic codes within the Truven Health Analytic MarketScan database. Patients were included in the analysis if they had an index erlotinib or crizotinib claim between January 1, 2009, and September 30, 2012 (index period) and were continuously enrolled for ≥ 12 months before the index claim. Because there is no specific ICD-9-CM diagnostic code for NSCLC, patients with metastatic lung cancer who received erlotinib or crizotinib were considered to have metastatic NSCLC. Using CPT and ICD-9-CM codes, lung biopsy procedures performed during the 24 months before or 12 months after the index claim date were identified. For every patient, biomarker testing claims for EGFR and ALK were identified using the molecular pathology stacked CPT code during the 2 months before or 1 month after the index date. The frequency of claims for biopsy procedures and biomarker testing was analyzed descriptively. The overall summary measures for biomarker testing, especially frequency of EGFR testing in patients receiving erlotinib, was also described as before and after 2011, the year when biomarker testing became part of the guidelines. Per patient and overall costs for biopsy procedures and biomarker testing were calculated from payer and patient perspectives. RESULTS: Of the 4,926 identified patients, 4,801 (97.5%) received erlotinib, and 125 (2.5%) received crizotinib. Biopsy procedure claims were identified for 3,579 (72.7%) patients, including 3,503 (73.0%) erlotinib recipients and 76 (60.8%) crizotinib recipients. Biomarker testing claims were identified for 675 (13.7%) patients, including 634 (13.2%) erlotinib recipients and 41 (32.8%) crizotinib recipients. Overall, most biomarker testing procedures (476 of 741) were identified in 435 (of 675) patients after year 2011. Also, among erlotinib recipients, percentage of patients receiving EGFR testing was increased over the index period. Per patient mean (SD) numbers of biopsy procedures and biomarker tests were 1.2 (1.1) and 0.2 (0.4), respectively. In the outpatient setting, per patient mean (SD) cost per biopsy procedure was $1,223 ($1,899) from the payer perspective and $60 ($147) from the patient perspective, whereas in the inpatient setting, it was $8,163 ($18,712) and $180 ($691), respectively. Among patients receiving at least 1 biomarker test, the per patient mean (SD) cost for the overall population was $891 ($1,062) and $43 ($229); for erlotinib recipients, it was $906 ($1,084) and $42 ($228); and for crizotinib recipients, it was $664 ($576) and $55 ($243) in payer and patient perspectives, respectively. CONCLUSIONS: This study provides insight into the use and cost of biopsy and biomarker testing procedures in patients with metastatic NSCLC. The low frequency of biomarker testing highlights the need for more awareness of testing to guide treatment decisions in these patients. Costs associated with biopsy procedures and biomarker testing provide insight into the economic impact on metastatic NSCLC patients treated with targeted therapy. DISCLOSURES: This study was sponsored by Merck & Co. Shinde is a study manager working for Merck under contract with AllSourcePPS, an Agile 1 company in Huntington Beach, California. Cao and Kothari are employees of Merck & Co., Kenilworth, New Jersey. Study concept and design were contributed primarily by Shinde and Kothari. Data analysis was performed by Cao. Data interpretation was performed by Shinde, Cao, and Kothari. Shinde wrote the manuscript with assistance from Cao and Kothari. The revision was completed primarily by Shinde and Kothari.

European cost-effectiveness study of uPA/PAI-1 biomarkers to guide adjuvant chemotherapy decisions in breast cancer.

BACKGROUND: This study investigated the cost effectiveness of guideline-recommended (American Society of Clinical Oncology, European Society of Medical Oncology) urokinase plasminogen activator (uPA)/plasminogen activator inhibitor-1 (PAI-1) biomarkers to guide adjuvant chemotherapy decisions for hormone receptor-positive, node-negative early breast cancer patients at intermediate risk of relapse, in France, Germany, and The Netherlands. METHODS: uPA/PAI-1 testing was compared to chemotherapy for all patients and to no chemotherapy in two age-related subgroups (35-49 and 50-75 years). A partitioned survival analysis was performed using patient-level data for survival outcomes and secondary sources. Mean quality-adjusted life years (QALYs) and costs were estimated over a lifetime horizon to calculate the incremental net monetary benefit (INMB) at a willingness-to-pay of €50,000/QALY. Uncertainty was explored through bootstrap and probabilistic sensitivity analysis using 5000 replicates. RESULTS: In the 35-49 year age group, INMBs were negative when uPA/PAI-1 testing was compared to chemotherapy for all patients but positive when it was compared to no chemotherapy for the three countries. In the 50-75 year age group, INMBs of uPA/PAI-1 testing compared to both reference strategies were positive in the three countries, with cost-effectiveness probabilities for the uPA/PAI-1 strategy of 65%, 70%, and 59% for France, Germany, and the Netherlands, respectively, compared with chemotherapy for all patients, and 64%, 58%, and 65%, respectively, compared with no chemotherapy. CONCLUSIONS: uPA/PAI-1 testing could allow the selection of patients older than 50 years requiring chemotherapy in this population, but the cost effectiveness of this strategy is uncertain. Chemotherapy for all patients is the most cost-effective strategy for patients younger than 50 years.

Decisions on Further Research for Predictive Biomarkers of High-Dose Alkylating Chemotherapy in Triple-Negative Breast Cancer: A Value of Information Analysis.

OBJECTIVES: To inform decisions about the design and priority of further studies of emerging predictive biomarkers of high-dose alkylating chemotherapy (HDAC) in triple-negative breast cancer (TNBC) using value-of-information analysis. METHODS: A state transition model compared treating women with TNBC with current clinical practice and four biomarker strategies to personalize HDAC: 1) BRCA1-like profile by array comparative genomic hybridization (aCGH) testing; 2) BRCA1-like profile by multiplex ligation-dependent probe amplification (MLPA) testing; 3) strategy 1 followed by X-inactive specific transcript gene (XIST) and tumor suppressor p53 binding protein (53BP1) testing; and 4) strategy 2 followed by XIST and 53BP1 testing, from a Dutch societal perspective and a 20-year time horizon. Input data came from literature and expert opinions. We assessed the expected value of partial perfect information, the expected value of sample information, and the expected net benefit of sampling for potential ancillary studies of an ongoing randomized controlled trial (RCT; NCT01057069). RESULTS: The expected value of partial perfect information indicated that further research should be prioritized to the parameter group including "biomarkers' prevalence, positive predictive value (PPV), and treatment response rates (TRRs) in biomarker-negative patients and patients with TNBC" (€639 million), followed by utilities (€48 million), costs (€40 million), and transition probabilities (TPs) (€30 million). By setting up four ancillary studies to the ongoing RCT, data on 1) TP and MLPA prevalence, PPV, and TRR; 2) aCGH and aCGH/MLPA plus XIST and 53BP1 prevalence, PPV, and TRR; 3) utilities; and 4) costs could be simultaneously collected (optimal size = 3000). CONCLUSIONS: Further research on predictive biomarkers for HDAC should focus on gathering data on TPs, prevalence, PPV, TRRs, utilities, and costs from the four ancillary studies to the ongoing RCT.

Use and Costs of Disease Monitoring in Women With Metastatic Breast Cancer.

PURPOSE: The optimal frequency of monitoring patients with metastatic breast cancer (MBC) is unknown; however, data suggest that intensive monitoring does not improve outcomes. We performed a population-based analysis to evaluate patterns and predictors of extreme use of disease-monitoring tests (serum tumor markers [STMs] and radiographic imaging) among women with MBC. METHODS: The SEER-Medicare database was used to identify women with MBC diagnosed from 2002 to 2011 who underwent disease monitoring. Billing dates of STMs (carcinoembryonic antigen and/or cancer antigen 15-3/cancer antigen 27.29) and imaging tests (computed tomography and/or positron emission tomography) were recorded; if more than one STM or imaging test were completed on the same day, they were counted once. We defined extreme use as > 12 STM and/or more than four radiographic imaging tests in a 12-month period. Multivariable analysis was used to identify factors associated with extreme use. In extreme users, total health care costs and end-of-life health care utilization were compared with the rest of the study population. RESULTS: We identified 2,460 eligible patients. Of these, 924 (37.6%) were extreme users of disease-monitoring tests. Factors significantly associated with extreme use were hormone receptor-negative MBC (odds ratio [OR], 1.63; 95% CI, 1.27 to 2.08), history of a positron emission tomography scan (OR, 2.92; 95% CI, 2.40 to 3.55), and more frequent oncology office visits (OR, 3.14; 95% CI, 2.49 to 3.96). Medical costs per year were 59.2% higher in extreme users. Extreme users were more likely to use emergency department and hospice services at the end of life. CONCLUSION: Despite an unknown clinical benefit, approximately one third of elderly women with MBC were extreme users of disease-monitoring tests. Higher use of disease-monitoring tests was associated with higher total health care costs. Efforts to understand the optimal frequency of monitoring are needed to inform clinical practice.

The path to routine use of genomic biomarkers in the cancer clinic.

It has been almost 15 years since the first microarray-based studies creating multigene biomarkers to subtype and predict survival of cancer patients. This Perspective looks at why only a handful of genomic biomarkers have reached clinical application and what advances are needed over the next 15 years to grow this number. I discuss challenges in creating biomarkers and reproducing them at the genomic and computational levels, including the problem of spatio-genomic heterogeneity in an individual cancer. I then outline the challenges in translating newly discovered genome-wide or regional events, like trinucleotide mutation signatures, kataegis, and chromothripsis, into biomarkers, as well as the importance of incorporating prior biological knowledge. Lastly, I outline the practical problems of pharmaco-economics and adoption: Are new biomarkers viewed as economically rational by potential funders? And if they are, how can their results be communicated effectively to patients and their clinicians? Genomic-based diagnostics have immense potential for transforming the management of cancer. The next 15 years will see a surge of research into the topics here that, when combined with a stream of new targeted therapies being developed, will personalize the cancer clinic.