Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays.

Cancer patients with an aberrant regulation of the protein phosphorylation networks are often treated with the tyrosine kinase inhibitors. Response rates approaching 85% are common. Unfortunately, patients often become refractory to the treatment by altering their signal transduction pathways. An implementation of the expression profiling with microarrays can identify the overall mRNA-level changes, and proteomics can identify the overall changes in protein levels or can identify the proteins involved, but the activity of the signal transduction pathways can only be established by interrogating post-translational modifications of the proteins. As a result, the ability to identify whether a drug treatment is successful or whether resistance arose, or the ability to characterize any alterations in the signaling pathways, is an important clinical challenge. Here, we provide a detailed explanation of antibody arrays as a tool which can identify system-wide alterations in various post-translational modifications (e.g., phosphorylation). One of the advantages of using antibody arrays includes their accessibility (an array does not require either an expert in proteomics or costly equipment) and speed. The availability of arrays targeting a combination of post-translational modifications is the primary limitation. In addition, unbiased approaches (phosphoproteomics) may be more suitable for the novel discovery, whereas antibody arrays are ideal for the most widely characterized targets.

Health insurer policies toward risk-stratified colorectal cancer screening: a survey of health plan medical directors.

OBJECTIVES: We sought to determine whether health insurance coverage of colorectal cancer (CRC) screening varied based on risk. BACKGROUND: Population-wide screening guidelines for cancer often incorporate risk information, with modified screening recommendations for those at higher risk due to family history or other factors. METHODS: In a nationwide Internet- and mail-based survey of health insurance plan medical directors, respondents were asked about their organization's policies towards coverage of CRC screening for persons at average and higher risk of CRC. Additional questions asked about whether the insurer had a definition of increased risk, and coverage of genetic testing for familial CRC syndromes. RESULTS: Survey invitations were sent to 1158 medical directors; 133 (11%) completed the survey. All plans covered screening for average and high-risk persons. The onset of screening was earlier and intervals were more frequent for higher risk compared to average risk persons, with most respondents stating coverage was determined by "physician discretion." While 75% had a definition of high risk, only 55% covered genetic testing. CONCLUSIONS: Most insurers offer enhanced coverage of CRC screening, most commonly following the discretion of the physician. Whether this coverage results in earlier, more frequent, or more complete screening of higher risk persons remains uncertain.

Online tool to guide decisions for BRCA1/2 mutation carriers.

PURPOSE: Women with BRCA1 or BRCA2 (BRCA1/2) mutations must choose between prophylactic surgeries and screening to manage their high risks of breast and ovarian cancer, comparing options in terms of cancer incidence, survival, and quality of life. A clinical decision tool could guide these complex choices. METHODS: We built a Monte Carlo model for BRCA1/2 mutation carriers, simulating breast screening with annual mammography plus magnetic resonance imaging (MRI) from ages 25 to 69 years and prophylactic mastectomy (PM) and/or prophylactic oophorectomy (PO) at various ages. Modeled outcomes were cancer incidence, tumor features that shape treatment recommendations, overall survival, and cause-specific mortality. We adapted the model into an online tool to support shared decision making. RESULTS: We compared strategies on cancer incidence and survival to age 70 years; for example, PO plus PM at age 25 years optimizes both outcomes (incidence, 4% to 11%; survival, 80% to 83%), whereas PO at age 40 years plus MRI screening offers less effective prevention, yet similar survival (incidence, 36% to 57%; survival, 74% to 80%). To characterize patients' treatment and survivorship experiences, we reported the tumor features and treatments associated with risk-reducing interventions; for example, in most BRCA2 mutation carriers (81%), MRI screening diagnoses stage I, hormone receptor-positive breast cancers, which may not require chemotherapy. CONCLUSION: Cancer risk-reducing options for BRCA1/2 mutation carriers vary in their impact on cancer incidence, recommended treatments, quality of life, and survival. To guide decisions informed by multiple health outcomes, we provide an online tool for joint use by patients with their physicians (http://brcatool.stanford.edu).

Health care use and primary prophylaxis with colony-stimulating factors.

OBJECTIVES: We examined health care use in conjunction with primary prophylaxis use of colony stimulating factors (CSF) during patients' initial course of chemotherapy. METHODS: This retrospective cohort study identified adults aged 25 years and older with a diagnosis of breast, colorectal, or nonsmall cell lung cancer between 2002 and 2005 from the Western Washington Surveillance Epidemiology and End Results Puget Sound registry. We linked these records to health insurance claims from four payers representing 75% of those insured in the state. Claims records were used to determine chemotherapy regimen type, CSF use, febrile neutropenia occurrences, and supportive care. Chemotherapy regimens were categorized as conferring high, intermediate, or low risk of myelosuppression according to the National Comprehensive Cancer Network guidelines. CSF use was described as primary prophylaxis, other, or none. Antibiotics and antifungal and antiviral agents per National Comprehensive Cancer Network guidelines for supportive care for cancer infection were categorized using Healthcare Common Procedure Coding System and National Drug Code assignments. RESULTS: Use of CSF as primary prophylaxis is not significantly associated with a reduction in antibiotic use or inpatient or outpatient visits. Primary prophylactic CSF use was associated with less use of antiviral drugs. CONCLUSIONS: CSF use is not associated with a reduction in health care use, with the exception of antiviral drug use. Given the expense associated with CSF use, pragmatic trials and additional research are needed to further assess the affects of CSF on health care use.

An economic evaluation of atorvastatin for primary prevention of cardiovascular events in type 2 diabetes.

OBJECTIVE: The CARDS trial, a multicentre, randomized, controlled trial, found that atorvastatin 10 mg/day for patients with type 2 diabetes mellitus and normal low-density lipoprotein (LDL)-cholesterol significantly reduced cardiovascular (CV) events, including stroke. We estimated the cost effectiveness of atorvastatin as primary prevention against CV disease from the short-term and lifetime US payer perspectives. RESEARCH DESIGN AND METHODS: We constructed a decision analytic (Markov) model to evaluate long-term costs and outcomes for atorvastatin 10 mg/day versus no HMG-CoA reductase inhibitor (statin) therapy for patients with type 2 diabetes and no history of a CV event. CV event rates and survival were based on risk equations calibrated to CARDS and applied to a US type 2 diabetes population; the atorvastatin effect on CV events was based on hazard ratios from CARDS; direct medical care costs were based on US treatment patterns and published costs analyses of patients with diabetes. Costs were valued in $US, year 2005 values; costs and benefits were discounted at 3% per annum. RESULTS: Within the time horizon of the trial (5 years), the cost effectiveness of atorvastatin was $US137 276 per QALY. At 10 years, the incremental cost per QALY improved to $US3640 per QALY. At 25 years, overall costs were lower and QALYs higher in the atorvastatin arm. Costs of managing CV events were lower after 5 years for patients treated with atorvastatin. CONCLUSIONS: For patients with type 2 diabetes and one additional risk factor for CV disease, normal LDL-cholesterol and no history of a CV event, primary prevention with atorvastatin appears to be cost saving and improve outcomes over 25 years, although it is costly from a short-term US payer perspective. From both a medical and an economic viewpoint, primary prevention is desirable in this patient population.

Cost effectiveness of entecavir versus lamivudine with adefovir salvage in HBeAg-positive chronic hepatitis B.

OBJECTIVE: To evaluate the cost effectiveness of treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) with entecavir compared with lamivudine with adefovir salvage, based primarily on the results of a recent 2-year, randomised, multicentre, clinical trial (n = 709). Previous economic analyses have been limited by the lack of comparative clinical data for entecavir and lamivudine beyond 1-year duration and for salvage therapy. METHODS: We conducted a cost-utility analysis using a Markov model from a US-payer perspective over a lifetime time horizon. The hypothetical cohort was 35-year-old patients with HBeAg-positive CHB. We evaluated 2 years of treatment with entecavir 0.5mg/day versus lamivudine 100mg/day, plus addition of adefovir 10mg/day for patients who developed virologic breakthrough due to resistance to either drug. In a scenario analysis, we considered adefovir plus lamivudine combination therapy for treatment-naive patients. Clinical and economic inputs ($US, year 2006 values) were derived from publicly available data, and probabilistic sensitivity analyses were conducted to evaluate uncertainty in the results. RESULTS: The estimated 10-year cumulative incidence of cirrhosis for patients initiated on entecavir was 2.3% lower than for those on lamivudine (20.5% vs 22.8%). The discounted incremental cost per QALY gained was $US7600 in the base-case analysis, and the 95% central range from probabilistic sensitivity analysis was $US2500-$US19 100. Combination therapy for treatment-naive patients led to an increase in costs without improvement in patient outcomes compared with entecavir monotherapy. CONCLUSIONS: Our analysis suggests entecavir improves health outcomes in a cost-effective manner compared with lamivudine with adefovir salvage or combination therapy, and highlights the importance of using evidence-based effectiveness estimates in economic studies of CHB therapies.

Evaluation of erlotinib in advanced non-small cell lung cancer: impact on the budget of a U.S. health insurance plan.

BACKGROUND: Lung cancer is the most common non-skin cancer and the leading cause of cancer death among men and women in North America. More than half of all patients diagnosed with lung cancer are diagnosed with advanced disease. Most cases of lung cancer are non-small cell lung cancer (NSCLC). Erlotinib monotherapy is indicated for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy regimen. OBJECTIVE: To assess the budgetary impact, from the health plan perspective, of covering erlotinib for treating patients with NSCLC stage IIIb/IV who have failed at least 1 prior chemotherapy regimen. METHODS: An Excel-based model was developed to evaluate costs for U.S. Food and Drug Administration-approved and National Comprehensive Cancer Network guideline-recommended treatment options for second- and third-line NSCLC from the perspective of a U.S. health insurer. In particular, the model compares a formulary with erlotinib and a formulary without erlotinib, including the costs of treatment, drug administration, and adverse effects. The incidence of advanced NSCLC is based on the Surveillance, Epidemiology, and End Results Cancer Registry and adverse effects related to treatment (all agents) in published results of clinical trials. Drug and treatment costs were obtained from publicly available sources in 2005. RESULTS: The base case considers a health plan of 500,000 enrollees. Assuming that erlotinib comprises 30% of second-line treatments and 90% for third-line, total costs of treating stage IIIb/IV NSCLC patients over 1 year are Dollars 382,418 with erlotinib and Dollars 380,968 without erlotinib (difference: Dollars 1,450; 90% confidence interval, -Dollars 61,376 to Dollars 29,855), less than Dollars 0.01 per member per month (PMPM) in 2005. Erlotinib direct cost is offset by reductions in standard chemotherapy-related infusion costs and adverse events. CONCLUSIONS: Based on the analysis, the inclusion of erlotinib on a formulary appears to have a relatively small impact on the annual health care budget or PMPM expenditures if it is used consistent with the product label indications.

Family history assessment to detect increased risk for colorectal cancer: conceptual considerations and a preliminary economic analysis.

BACKGROUND: Although the rationale for earlier screening of persons with a family history of colorectal cancer is plausible, there is no direct evidence that earlier assessment is either effective or cost-effective. OBJECTIVE: To estimate the clinical and economic effect of using family history assessment to identify persons for colorectal cancer screening before age 50. METHODS: We developed a decision model to compare costs and outcomes for two scenarios: (a) standard population screening starting at age 50; (b) family history assessment at age 40, followed by screening colonoscopy at age 40 for those with a suggestive family history of colorectal cancer. The analysis was conducted using the health insurer perspective. RESULTS: Using U.S. population estimates, 22 million would be eligible for family history assessment, and one million would be eligible for early colonoscopy; 2,834 invasive cancers would be detected, and 29,331 life years would be gained. The initial program cost would be USD $900 million. The discounted cost per life year gained of family history assessment versus no assessment equals USD $58,228. The results were most sensitive to the life expectancy benefit from earlier screening, the cost of colonoscopy, and the relative risk of colon cancer in those with a family history. CONCLUSIONS: The cost-effectiveness of family history assessment for colorectal cancer approaches that of other widely accepted technologies; yet, the results are sensitive to several assumptions where better data are needed. Because of the relatively high prevalence of family history in the population, careful analysis and empirical data are needed.

Is combined androgen blockade with bicalutamide cost-effective compared with combined androgen blockade with flutamide?

OBJECTIVES: To determine the cost-effectiveness of combined androgen blockade (CAB) with bicalutamide versus CAB with flutamide in men with Stage D2 prostate cancer. Both bicalutamide and flutamide are commonly used in CAB for prostate cancer. Although the cost of bicalutamide is more than that of flutamide, it is important that the efficacy, quality of life, and side effects are also considered when determining whether CAB with bicalutamide is a cost-effective option. METHODS: A decision model was created to compare treatment strategies. Survival and side-effect information was based on a randomized trial that directly compared bicalutamide and flutamide. The costs and quality-of-life effects related to therapy were determined from published sources. RESULTS: The incremental cost per quality-adjusted life year gained for bicalutamide versus flutamide was 22,000 dollars and 16,000 dollars at 5 and 10 years, respectively. If a quality adjustment was not included, the incremental cost-effectiveness ratio for CAB with bicalutamide compared with CAB with flutamide was even more favorable (20,000 dollars/life year gained at 5 years). One-way sensitivity analysis demonstrated that the cost-effectiveness estimates were most sensitive to drug costs and survival (baseline survival was not significantly different between therapies). Multi-way uncertainty analysis revealed that the median value of the incremental cost-effectiveness ratio at 5 years was 13,637 dollars/quality-adjusted life year when all the parameters were varied over a clinically reasonable range. CONCLUSIONS: Bicalutamide is cost-effective compared with flutamide when used for androgen blockade as part of CAB for men with advanced prostate cancer.

The cost-effectiveness of combined androgen blockade with bicalutamide and luteinizing hormone releasing hormone agonist in men with metastatic prostate cancer.

PURPOSE: Combined androgen blockade therapy (CAB) has been shown to have a small survival advantage over luteinizing hormone releasing hormone LH-RH agonists (LH-RHa) alone in men with metastatic prostate cancer. The goal of this study was to assess the cost-effectiveness of CAB with bicalutamide and LH-RH agonist therapy to LH-RH agonist therapy alone. MATERIALS AND METHODS: A macro-simulation model was developed to compare the cost-effectiveness of 2 interventions for stage D2 prostate cancer, 1) CAB with bicalutamide 50 mg per day and monthly dosing of an LH-RHa or 2) monthly LH-RH agonist therapy. Cost and outcomes are tabulated in 5 and 10-year time horizons. Model assumptions were taken from the published literature. Appropriate 1-way and multi-way sensitivity analyses were performed. RESULTS: At 5 years, the incremental cost-effectiveness ratio (ICER) for CAB, when compared with LH-RHa monotherapy, was US dollars 33,677 per quality-adjusted life-year. In other words, for every additional quality-adjusted life year that a patient lived because he received CAB, it cost US dollars 33,677. At 10 years the ICER for CAB was US dollars 20,053 (well within the accepted cost-effectiveness threshold). If quality adjustment was not included, the ICER for CAB was even more favorable (US dollars 20,489 at 5 years and US dollars 13,313 at 10 years). The model was most sensitive to the estimates of effectiveness (survival) of LH-RHa therapy alone and CAB therapy. The model was also fairly sensitive to the quality of life effect of having late stage prostate cancer and the cost of bicalutamide. CONCLUSIONS: CAB with bicalutamide is cost-effective when compared with LH-RH monotherapy in men with stage D2 prostate cancer.

An economic viewpoint on alternative strategies for identifying persons with hereditary nonpolyposis colorectal cancer.

PURPOSE: There is uncertainty regarding the optimal strategy for identifying mutation carriers among those with hereditary nonpolyposis colorectal cancer (HNPCC). METHODS: We used decision analysis to compare the cost-effectiveness of 4 strategies among those with newly diagnosed colon cancer: (1) clinical and family history followed by microsatellite instability testing and germline testing (Bethesda guidelines); (2) universal microsatellite instability testing; (3) germline testing of those who meet clinical and family history criteria; and (4) universal germline testing. RESULTS: The added cost per year of life saved (YLS) for each strategy was as follows: (1) 11,865 US dollars/YLS, (2) 35,617 US dollars/YLS, (3) 49,702 US dollars/YLS, and (4) 267,548 US dollars/YLS. CONCLUSIONS: The Bethesda guidelines are the most cost-effectiveness approach to screen persons for HNPCC.