Longitudinal adherence to breast cancer surveillance following cancer genetic testing in an integrated health care system.

PURPOSE: Screening with mammography and breast magnetic resonance imaging (MRI) is an important risk management strategy for individuals with inherited pathogenic variants (PVs) in genes associated with increased breast cancer risk. We describe longitudinal screening adherence in individuals who underwent cancer genetic testing as part of usual care in a vertically integrated health system. METHODS: We determined the proportion time covered (PTC) by annual mammography and breast MRI for individuals with PVs in TP53, BRCA1, BRCA2, PALB2, NF1, CHEK2, and ATM. We determined time covered by biennial mammography beginning at age 50 years for individuals who received negative results, uncertain results, or with PVs in genes without specific breast cancer screening recommendations. RESULTS: One hundred and forty individuals had PVs in TP53, BRCA1, BRCA2, PALB2, NF1, CHEK2, or ATM. Among these individuals, average PTC was 48% (range 0-99%) for annual screening mammography and 34% (range 0-100%) for annual breast MRI. Average PTC was highest for individuals with PVs in CHEK2 (N = 14) and lowest for individuals with PVs in TP53 (N = 3). Average PTC for biennial mammography (N = 1,027) was 49% (0-100%). CONCLUSION: Longitudinal screening adherence in individuals with PVs in breast cancer associated genes, as measured by the proportion of time covered, is low; adherence to annual breast MRI falls below that of annual mammography. Additional research should examine screening behavior in individuals with PVs in breast cancer associated genes with a goal of developing interventions to improve adherence to recommended risk management.

Risk-reducing surgery in unaffected individuals receiving cancer genetic testing in an integrated health care system.

BACKGROUND: Germline genetic testing enables primary cancer prevention, including through prophylactic surgery. We examined risk-reducing surgeries in unaffected individuals tested for hereditary cancer susceptibly between 2010 and 2018 in the Kaiser Permanente Northwest health system. METHODS: We used an internal genetic testing database to create a cohort of individuals who received tests including one or more high-penetrance hereditary cancer susceptibility gene. We then identified, after testing, bilateral mastectomy, bilateral salpingo-oophorectomy (BSO), and total hysterectomy procedures in electronic health record and claims data through 2019. We describe surgery utilization by genetic test results and National Comprehensive Cancer Network (NCCN) guidelines. RESULTS: The cohort included 1020 individuals, 16% with pathogenic/likely pathogenic (P/LP) variants in one or more of the following genes: BRCA1, BRCA2, CHEK2, APC, MUTYH, ATM, MSH2, PALB2, BRIP1, MLH1, MSH6, EPCAM, FLCN, RAD51C, RAD51D, or TP53. Among individuals with P/LP variants making them candidates for mastectomy, BSO, or hysterectomy per NCCN guidelines, 34% (33/97), 24% (23/94), and 8% (1/12), respectively, underwent surgery during follow-up. Fifty-three percent (18/37) of hysterectomies were among APC, BRCA1, and BRCA2 P/LP variant heterozygotes, typically concurrent with BSO. Three individuals with variants of uncertain significance (only) and 22 with negative results had prophylactic surgery after genetic testing. CONCLUSIONS: Uptake of risk-reducing surgery following usual care genetic testing appears to be lower than in studies that actively recruit high-risk patients and provide testing and follow-up care in specialized settings. Factors in addition to genetic test results and NCCN guidelines motivate prophylactic surgery use and deserve further study.

Cost-Effectiveness of Targeted Pharmacotherapy for Moderate to Severe Plaque Psoriasis.

BACKGROUND: Newer classes of targeted drugs for moderate to severe plaque psoriasis are more effective and more expensive than older classes, posing a difficult and potentially costly decision about whether to use them as initial targeted treatments. OBJECTIVE: To estimate the clinical and economic outcomes of initial targeted treatment for the following drugs: adalimumab, etanercept, and infliximab (TNFα inhibitors); apremilast (PDE4 inhibitor); ustekinumab (IL-12/23 inhibitor); and ixekizumab, secukinumab, and brodalumab (IL-17 inhibitors). METHODS: We developed a Markov model to simulate patient outcomes as measured by quality-adjusted life-years (QALYs) and health care costs over a 10-year period. We assumed that patients who fail initial targeted treatment either proceed to subsequent therapy or discontinue targeted treatment. Effectiveness estimates for initial treatment were defined as improvement in Psoriasis Area and Severity Index (PASI) from baseline and derived from a 2018 network meta-analysis. Wholesale acquisition drug costs were discounted by a class-specific, empirically derived rebate percentage off of 2016 costs. We conducted one-way and probabilistic sensitivity analyses to assess uncertainty in results. RESULTS: The incremental benefits compared with no targeted treatment were, in descending order: ixekizumab 1.68 QALYs (95% credible range [CR] = 1.11-2.02), brodalumab 1.64 QALYs (95% CR = 1.08-1.98), secukinumab 1.51 QALYs (95% CR = 1.00-1.83), ustekinumab 1.43 QALYs (95% CR=0.94-1.74), infliximab 1.27 QALYs (95% CR = 0.89-1.55), adalimumab 1.15 QALYs (95% CR = 0.76-1.44), etanercept 0.97 QALYs (95% CR = 0.61-1.25), and apremilast 0.87 QALYs (95% CR = 0.52-1.17). Costs of care without targeted treatment totaled $66,451, and costs of targeted treatment ranged from $137,080 (apremilast) to $255,422 (ustekinumab). Probabilistic sensitivity analysis results indicated that infliximab and apremilast are likely to be the most cost-effective initial treatments at willingness-to-pay thresholds around $100,000 per QALY, while IL-17 drugs are more likely to be cost-effective at thresholds approaching $150,000 per QALY. Acquisition cost of the initial targeted drug and utility of clinical response were the most influential parameters. CONCLUSIONS: Our findings suggest that initial targeted treatment with IL-17 inhibitors is the most effective treatment strategy for plaque psoriasis patients who have failed methotrexate and phototherapy. Apremilast, brodalumab, infliximab, ixekizumab, and secukinumab are cost-effective at different willingness-to-pay thresholds. Additional research is needed on whether the effectiveness of targeted agents changes when used after previously targeted agents. DISCLOSURES: Funding for this study was contributed by the Institute for Clinical and Economic Review (ICER). Ollendorf, Chapman, Pearson, and Kumar are current employees, and Loos and Liu are former employees, of ICER, an independent organization that evaluates the evidence on the value of health care interventions, which is funded by grants from the Laura and John Arnold Foundation, Blue Shield of California Foundation, and the California HealthCare Foundation. ICER's annual policy summit is supported by dues from Aetna, AHIP, Anthem, Alnylam, AstraZeneca, Blue Shield of California, Cambia Health Solutions and MedSavvy, CVS Caremark, Editas, Express Scripts, Genentech, GlaxoSmithKline, Harvard Pilgrim Health Care, Health Care Service Corporation, OmedaRx, United Healthcare, Johnson & Johnson, Kaiser Permanente, Premera Blue Cross, Merck, National Pharmaceutical Council, Takeda, Pfizer, Novartis, Lilly, Humana, Prime Therapeutics, Sanofi, and Spark Therapeutics. Linder owns stock in Amgen, Biogen, and Eli Lilly; has contingent value rights in Sanofi Genzyme (related to alemtuzumab for multiple sclerosis); has received grant support from Astellas Pharma not related to this study and Clintrex, which was supported by AstraZeneca on an unrelated topic; and has received an honorarium from the Society of Healthcare Epidemiology of America (SHEA) as part of the SHEA Antimicrobial Stewardship Research Workshop Planning Committee, an educational activity supported by Merck. No other authors have potential conflicts of interest.

Impact of Body Mass Index and Genetics on Warfarin Major Bleeding Outcomes in a Community Setting.

BACKGROUND: Several studies have demonstrated an association between body mass index (BMI) and warfarin therapeutic dose, but none evaluated the association of BMI with the clinically important outcome of major bleeding in a community setting. To address this evidence gap, we conducted a case-control study to evaluate the association between BMI and major bleeding risk among patients receiving warfarin. METHODS: We used a case-control study design to evaluate the association between obesity (BMI >30.0 kg/m2) and major bleeding risk among 265 cases and 305 controls receiving warfarin at Group Health, an integrated healthcare system in Washington State. Multivariate logistic regression was used to adjust for potential confounders derived from health plan records and a self-report survey. In exploratory analyses we evaluated the interaction between genetic variants potentially associated with warfarin bleeding (CYP2C9, VKORC1, and CYP4F2) and obesity on the risk of major bleeding. RESULTS: Overall, the sample was 55% male, 94% Caucasian, and mean age was 70 years. Cases and controls had an average of 3.4 and 3.7 years of warfarin use, respectively. Obese patients had significantly lower major bleeding risk relative to non-obese patients (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.39-0.92). The OR was 0.56 (95% CI 0.35-0.90) in patients with ≥1 year of warfarin use, and 0.78 (95% CI 0.40-1.54) in patients with <1 year of warfarin use. An exploratory analysis indicated a statistically significant interaction between CYP4F2*3 genetic status and obesity (P = .049), suggesting a protective effect of obesity on the risk of major bleeding among those wild type for CYP4F2*3, but not among variants. CONCLUSIONS: Our findings suggest that BMI is an important clinical factor in assessing and managing warfarin therapy. Future studies should confirm the major bleeding associations, including the interaction between obesity and CYP4F2*3 status identified in this study, and evaluate potential mechanisms.

Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND: High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to guide best practices. METHODS: The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS: Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also address anticoagulation management services and intensive patient education. CONCLUSIONS: We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have not been adequately studied.

Budget impact of erlotinib for maintenance therapy in advanced non-small cell lung cancer.

OBJECTIVE: Assess the budgetary impact of adding erlotinib for maintenance therapy (MTx) in advanced non-small cell lung cancer (NSCLC) from a US health plan perspective. METHODS: A budget impact model was developed to analyze the costs (drug, administration, adverse events) associated with adding erlotinib MTx to a hypothetical 500,000 member US health plan. Treatment durations and dosing were derived from randomized controlled trials, FDA labeling, and National Comprehensive Cancer Network guidelines. Treatment patterns and assumptions were based on market research data, the SEER registry, and published literature. Cost data were obtained from Centers for Medicare and Medicaid Services payment rates and a drug pricing database. Sensitivity analyses were conducted to assess uncertainty. RESULTS: Overall health plan expenditures increased by $0.010 per member per month (PMPM). The main driver of additional cost was the erlotinib drug cost (∼$66,000) with the administration ($464) and side-effect ($47) costs being relatively modest. One-way sensitivity analyses showed that the results were most sensitive to the proportion of members receiving MTx; however, the PMPM did not exceed $0.013. CONCLUSIONS: The overall budget impact to a health plan of expanding the use of erlotinib from the 2nd/3rd-line advanced NSCLC setting to include the maintenance setting was relatively small. This was primarily due to the proportion of patients who would receive erlotinib MTx, the low cost of side-effects and minimal cost of drug administration. Additional research may be warranted to estimate the relative clinical and economic impacts of erlotinib MTx versus alternative MTx treatments.

HBeAg-negative chronic hepatitis B: cost-effectiveness of peginterferon alfa-2a compared to lamivudine in Taiwan.

OBJECTIVE: In Taiwan, the carrier rate of hepatitis B surface antigen is 15% to 20%, one of the highest in the world. Among chronic hepatitis B (CHB) patients, hepatitis B e antigen (HBeAg)-negative accounts for approximately 40% to 50% of these patients. A recent study found that peginterferon alfa-2a (40 KD) is more effective than lamivudine in treating HBeAg-negative CHB, but its cost-effectiveness has not been evaluated. Our objective is to evaluate the incremental cost-effectiveness of 48 weeks of peginterferon alfa-2a compared to 48 weeks of lamivudine, from the perspective of the Taiwan Bureau of National Health Insurance. METHODS: A Markov model was used to simulate the natural history of HBeAg-negative CHB in a cohort of 40-year-old patients. Efficacy, disease progression, economic, and quality-of-life data were derived from published literature and a survey of clinical experts in Taiwan. Life expectancy, quality-adjusted life expectancy, lifetime costs in New Taiwan Dollars (NTD) (1 USD = 31.96 NTD), and incremental cost-effectiveness ratios (ICERs) were calculated. RESULTS: The gain in quality-adjusted life-years (QALYs) for 48 weeks of peginterferon alfa-2a compared to 48 weeks of lamivudine was 0.45 at an additional cost of 157,000 NTD (4900 USD), resulting in an ICER of 347,000 NTD (10,900 USD) per QALY gained. The 95% central range for the ICER from a probabilistic sensitivity analysis was 228,000-566,000 NTD (7100-17,700 USD). CONCLUSIONS: In HBeAg-negative CHB, 48 weeks of treatment with peginterferon alfa-2a compared to 48 weeks of lamivudine appears to offer life expectancy and quality-of-life improvements at an acceptable cost-effectiveness ratio.

Comparative clinical and economic outcomes of treatments for refractory non-small cell lung cancer (NSCLC).

BACKGROUND: Various drug therapies are available for treatment of refractory stage IIIB/IV non-small cell lung cancer (NSCLC), but their comparative economic value is unclear. METHODS: We developed a decision analytic model to evaluate the incremental costs and quality-adjusted life-years (QALYs) of erlotinib, docetaxel, or pemetrexed in a cohort of refractory advanced stage NSCLC patients 60 years of age from a US payer perspective. Mean progression-free and overall survival were assumed equal for the three treatments based on published clinical trials, from which adverse event rates were also derived. Costs and utilities were obtained from publicly available sources. We performed sensitivity analyses to evaluate uncertainty in the results. RESULTS: Treatment with erlotinib, docetaxel, and pemetrexed yielded 0.42, 0.41, and 0.41 quality-adjusted life-years (QALYs), respectively. The slightly increased QALYs for erlotinib compared to docetaxel and pemetrexed resulted from less severe treatment complications and oral vs. IV administration. Total costs were US$ 37,000, US$ 39,100 and US$ 43,800 for erlotinib, docetaxel and pemetrexed, respectively. In the probabilistic sensitivity analyses, erlotinib was cost-saving in 65 and 87% of the simulations compared to docetaxel and pemetrexed, respectively, and had improved QALYs and decreased costs or was cost-effective in 42 and 55% of simulations. Estimates of treatment duration were among the most influential parameters in the analyses. CONCLUSIONS: The results of our analysis suggest treatment of refractory NSCLC with erlotinib is less costly compared with alternative treatments, and suggested improvements in QALYs should be confirmed in controlled clinical trials.

Gene expression profiling and breast cancer care: what are the potential benefits and policy implications?

PURPOSE: Gene expression profiling has been proposed as an alternative to clinical guidelines to identify high-risk patients for adjuvant chemotherapy. However, the outcomes associated with gene expression profiling are not clear, and guidelines for the appropriate use of genomic technologies have not been established. METHODS: We developed a decision analytic model to evaluate the incremental cost and quality-adjusted life years of gene expression profiling versus NIH clinical guidelines in a hypothetical cohort of premenopausal early stage breast cancer patients 44 years of age. We conducted empirical analyses and identified literature-based data to inform the model, and performed probabilistic sensitivity analyses to evaluate uncertainty in the results. We interpreted the implications of our findings for treatment guidelines and policies. RESULTS: Use of gene expression profiling resulted in an absolute 5% decrease in the proportion of cases of distant recurrence prevented, 0.21 fewer quality-adjusted life years, and a cost savings of USD 2882. The chosen test cutoff value to identify a tumor as poor prognosis and the cost of adjuvant chemotherapy were the most influential parameters in the analysis, but our findings did not change substantially in sensitivity analyses. Regardless of the test cutoff used to identify a poor prognosis tumor, the gene expression profiling assay studied in our analysis, at its current level of performance, did not attain the threshold sensitivity (95%) necessary to produce equal or greater quality-adjusted life years than NIH guidelines. CONCLUSION: Although the use of gene expression profiling in breast cancer care holds great promise, our analysis suggests additional refinement and validation are needed before use in clinical practice.

Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.

BACKGROUND: The management of warfarin therapy is complicated by a wide variation among patients in drug response. Variants in the gene encoding vitamin K epoxide reductase complex 1 (VKORC1) may affect the response to warfarin. METHODS: We conducted a retrospective study of European-American patients receiving long-term warfarin maintenance therapy. Multiple linear-regression analysis was used to determine the effect of VKORC1 haplotypes on the warfarin dose. We determined VKORC1 haplotype frequencies in African-American, European-American, and Asian-American populations and VKORC1 messenger RNA (mRNA) expression in human liver samples. RESULTS: We identified 10 common noncoding VKORC1 single-nucleotide polymorphisms and inferred five major haplotypes. We identified a low-dose haplotype group (A) and a high-dose haplotype group (B). The mean (+/-SE) maintenance dose of warfarin differed significantly among the three haplotype group combinations, at 2.7+/-0.2 mg per day for A/A, 4.9+/-0.2 mg per day for A/B, and 6.2+/-0.3 mg per day for B/B (P<0.001). VKORC1 haplotype groups A and B explained approximately 25 percent of the variance in dose. Asian Americans had a higher proportion of group A haplotypes and African Americans a higher proportion of group B haplotypes. VKORC1 mRNA levels varied according to the haplotype combination. CONCLUSIONS: VKORC1 haplotypes can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups and may explain differences in dose requirements among patients of different ancestries. The molecular mechanism of this warfarin dose response appears to be regulated at the transcriptional level.

Cost comparison of surgery vs organ preservation for laryngeal cancer.

OBJECTIVE: To perform a cost minimization analysis of total laryngectomy with postoperative radiotherapy vs induction chemotherapy with subsequent radiotherapy in patients with advanced (stage III or IV) squamous cell carcinoma of the larynx. DESIGN: Decision-analysis model using data from peer-reviewed trials, case series, meta-analyses, and Medicare diagnosis related group reimbursement rates. SETTING AND PATIENTS: A hypothetical cohort of patients with stage III or IV laryngeal cancer. The perspective is that of a health care payer. INTERVENTIONS: The hypothetical patient cohort could receive (1) surgery (total laryngectomy) with postoperative radiotherapy or (2) induction chemotherapy (fluorouracil and cisplatin) with radiotherapy followed by salvage surgery for patients failing to respond to chemotherapy. MAIN OUTCOME MEASURE: Overall difference in direct medical costs in 2003 US dollars between the 2 treatment arms from initiation to completion of treatment. RESULTS: In the baseline analysis, the direct medical costs for the surgical arm were 30,138 US dollars per patient. For the organ preservation arm, the direct medical costs were 33,052 US dollars per patient. The finding that the surgical arm costs were lower was robust to all sensitivity analyses except for the extreme low estimate for the cost of chemotherapy. CONCLUSIONS: Our results suggest that total laryngectomy with postoperative radiotherapy costs nearly 3000 US dollars less than organ preservation treatment for advanced laryngeal cancer. Given that survival appears equivalent between the 2 modalities, cost consideration and patient preference may be important factors in decision making for the treatment of advanced laryngeal cancer.