Health economic impact of a biopsy-based cell cycle gene expression assay in localized prostate cancer.

Background: Prior studies have established that broader incorporation of active surveillance, guided by additional prognostic tools, may mitigate the growing economic burden of localized prostate cancer in the USA. This study sought to further explore the potential of a particular gene expression-based prognostic tool to address this unmet need. Materials & methods: A deterministic, decision-analytic model was developed to estimate the economic impact of the Prolaris® test on a US commercial health plan. Results & conclusion: When adopted in patients classified by the American Urological Association as low or intermediate risk, the assay was projected to reduce costs by $1894 and $2129 per patient over 3 and 10 years, respectively, largely through the increased use of active surveillance.

Economic burden of illness associated with localized prostate cancer in the United States.

Aim: Prior studies have established the economic burden of prostate cancer on society. However, changes to screening, novel therapies and increased use of active surveillance (AS) create a need for an updated analysis. Methods: A deterministic, decision-analytic model was developed to estimate medical costs associated with localized prostate cancer over 10 years. Results: 10-year costs averaged $45,957, $99,445 and $188,928 for low-, intermediate- and high-risk patients, respectively. For low-risk patients, AS 10-year costs averaged $33,912/patient, whereas definitive treatment averaged $49,667/patient. Despite higher failure rates in intermediate-risk patients, AS remained less costly than definitive treatment, with 10-year costs averaging $90,614/patient and $99,394/patient, respectively. Conclusion: Broader incorporation of AS, guided by additional prognostic tools, may mitigate this growing economic burden.

Budget impact analysis of a novel gene expression assay for the diagnosis of malignant melanoma.

BACKGROUND: Traditional pathology techniques alone can be insufficient to reliably distinguish between malignant melanoma, dysplastic nevi, and benign nevi in biopsies of suspicious pigmented lesions. Numerous studies have shown high rates of ambiguity when assessing such samples. A novel gene expression assay has been developed to objectively differentiate malignant melanoma from benign nevi. OBJECTIVE: The purpose of this study was to quantify the economic impact of the gene expression assay on a US commercial health plan. METHODS: The clinical paradigm of care was modeled for a hypothetical cohort of patients with suspicious pigmented lesions that are difficult-to-diagnose. Costs were assigned to each unit of care provided based on 2013 Medicare fee-for-service rates. Patients were followed for 10 years and were modeled to progress according to the natural history of their disease. The total cost of care was calculated for two scenarios: a Reference Scenario, representing current clinical practice, and a Test Scenario, in which each lesion was tested with the gene expression assay and diagnosed. Total cost of care was compared between the two scenarios to determine overall budget impact. Sensitivity analyses were performed to test the robustness of the model. RESULTS: The gene expression assay reduces costs by $1268 per patient tested over 10 years, a decrease of 8.3%, after accounting for the cost of the assay. For a health plan with 10 million members, this would translate to over $8 million in savings. The largest portion of this saving comes from reducing the number of missed melanomas, which would otherwise progress to advanced disease. In sensitivity analyses, no single model input changed within a reasonable range of values caused the model to show that the assay was not cost-saving. CONCLUSION: In addition to improving the diagnosis of melanoma, this gene expression assay would likely reduce costs for health plans that choose to cover it.

Clinical utility of a biopsy-based cell cycle gene expression assay in localized prostate cancer.

OBJECTIVE: The CCP signature test (Prolaris) quantifies a patient's risk of disease progression and prostate cancer specific mortality using a gene-expression-based cell cycle progression (CCP) score. This study evaluated the potential clinical utility of the CCP test in a US-based clinical setting. METHODS: Urologists who participated in a prospective clinical study were sent a retrospective questionnaire to assess the value of the CCP test result. Fifteen board-certified urologists participated in the study, representing 15 distinct community urology group practices. Questionnaires were received for 294 evaluable patients. All patients had localized prostate cancer (T1-T3b, N0, M0). RESULTS: Physicians found the CCP score valuable and indicated that 55% of tests generated a mortality risk that was either higher or lower than expected. Physicians also indicated that 32% of test results would lead to a definite or possible change in treatment. The data suggest that the test would have the net effect of shifting patients from more aggressive treatment to more conservative treatment. This was evidenced by the significant association between change in treatment and lower CCP scores (p < 0.002) and by the fact that 62% of tests likely to lead to a definite or possible change in treatment had mortality risks lower than the physician expected versus only 10% with risks higher than expected. STUDY LIMITATIONS: This study measured the retrospectively assessed likelihood of change in treatment as estimated by the physician, not the actual change in treatment. CONCLUSIONS: The CCP score adds meaningful new information to risk assessment for localized prostate cancer patients. Real-world use of the test is likely to lead to a change in treatment in a significant portion of tested patients, particularly by shifting patients towards more conservative management. This could reduce overtreatment of patients with less aggressive disease, decreasing patient morbidity and costs for payers and the healthcare system.

Differential use of CCR5 by HIV-1 clinical isolates resistant to small-molecule CCR5 antagonists.

How HIV-1 resistant to small-molecule CCR5 antagonists uses the coreceptor for entry has been studied in a limited number of isolates. We characterized dependence on the N terminus (NT) and the second extracellular loop (ECL2) of CCR5 of three vicriviroc (VCV)-resistant clinical isolates broadly cross-resistant to other CCR5 antagonists. Pseudoviruses were constructed to assess CCR5 use by VCV-sensitive and -resistant envelopes of subtype B and C viruses. We determined the extent of entry inhibition by monoclonal antibodies (MAbs) directed against the NT and ECL2 in the presence and absence of VCV and the capacity of these pseudoviruses to use CCR5 mutants that contained scanning alanine substitutions in the CCR5 NT and ECL2 domains. Sensitive and resistant viruses were completely and competitively inhibited by the ECL2-specific MAb 2D7, whereas the NT-specific MAb CTC5 led to partial noncompetitive inhibition. VCV-resistant clones showed greater sensitivity to 2D7 than VCV-sensitive clones, but in the presence of saturating VCV concentrations, the 2D7 susceptibilities of two VCV-resistant viruses were similar to that of VCV-sensitive virus. The entry of VCV-sensitive and -resistant isolates was impaired to differing degrees by alanine mutations in CCR5; substitutions in NT had the greatest effect on viral entry. HIV-1 clinical isolates broadly resistant to CCR5 antagonists demonstrated significant heterogeneity in their use of CCR5. This heterogeneity makes it difficult to draw general conclusions about the relationship between patterns of CCR5 antagonist resistance and the use of specific CCR5 domains for entry.

Evolution of CCR5 antagonist resistance in an HIV-1 subtype C clinical isolate.

OBJECTIVES: We previously reported vicriviroc (VCV) resistance in an HIV-infected subject and used deep sequencing and clonal analyses to track the evolution of V3 sequence forms over 28 weeks of therapy. Here, we test the contribution of gp120 mutations to CCR5 antagonist resistance and investigate why certain minority V3 variants emerged as the dominant species under drug pressure. METHODS: Nineteen site-directed HIV-1 mutants were generated that contained gp120 VCV resistance mutations. Viral sensitivities to VCV, maraviroc, TAK-779, and HGS004 were determined. RESULTS: Three patterns of susceptibilities were observed as follows: sigmoid inhibition curves with 50% inhibitory concentration similar to pretreatment virus [07J-week 0 (W0)], single mutants with decreased 50% inhibitory concentrations compared with 07J-W0, and mutants that contained ≥5 of 7 VCV resistance mutations with flattened inhibition curves and decreased or negative percent maximal inhibition. Substitutions such as S306P, which sensitized virus to CCR5 antagonists when present as single mutations, were not detected in the baseline virus population but were necessary for maximal resistance when incorporated into V3 backbones that included preexisting VCV resistance mutations. CONCLUSIONS: CCR5 antagonist resistance was reproduced only when a majority of V3 mutations were present. Minority V3 loop variants may serve as a scaffold upon which additional mutations lead to complete VCV resistance.