Rajesh R. Kaldate

Cell cycle progression score and treatment decisions in prostate cancer: results from an ongoing registry

Abstract Objective: The cell cycle progression (CCP) test (Prolaris) is a novel prognostic assay that provides accurate risk of prostate cancer-specific disease progression and disease specific mortality when combined with standard clinicopathologic parameters. This prospective study evaluated the impact of the CCP report on physician treatment recommendations for prostate cancer. Methods: Physicians ordering the CCP test in clinical practice completed surveys regarding treatment recommendations before and after they received and discussed the test results with patients. Clinicians also rated the influence of the test result on treatment decisions. Treatment selections were confirmed via third-party audit of patient charts following final survey responses. Results: Overall, 65% of cases showed a change between intended treatment pre- and post-CCP test reporting. Pre-CCP testing, 164 of 305 cases received a recommendation for interventional treatment. Post-CCP test, interventional therapy was recommended for 103 of these cases, a reduction of 37.2%. Conversely, 141 of 305 cases were recommended pre-CCP testing for non-interventional treatment; 108 of these remained with non-interventional treatment while 33 shifted to interventional options, a 23.4% increase. There was a 49.5% reduction in surgical interventions and a 29.6% reduction in radiation treatment. A third-party audit identified 80.2% concordance between the post-CCP testing treatment recommendation and actual treatment. Re-assignment to intervention or non-intervention generally correlated with the result of the CCP report. Study limitations included physician selection of patients for testing, no evaluation of patient input in therapeutic choice, and other potential treatment decision factors not queried by the survey. Conclusion: Based on responses of ordering physicians, the CCP report adds meaningful new information to risk assessment for localized prostate cancer patients. Test results led to changes in treatment with reductions and increases in interventional treatment that were directionally aligned with prostate cancer risk specified by the test.

Modeling the 5-Fluorouracil Area Under the Curve Versus Dose Relationship to Develop a Pharmacokinetic Dosing Algorithm for Colorectal Cancer Patients Receiving FOLFOX6

BACKGROUND 5-Fluorouracil (5-FU) is administered based on standard body surface area (BSA) dosing. BSA administration results in highly variable exposure, measured as the area under the concentration-time curve (AUC). An immunoassay (OnDose®; Myriad Genetic Laboratories, Inc., Salt Lake City, UT) that measures plasma 5-FU concentration and reports an AUC in mg · h/L has been developed to optimize therapy using pharmacokinetic (PK) dosing. The results of an analysis to model the 5-FU AUC-dose relationship are presented. METHODS A set of 589 sequential patients from a clinical database receiving 5-FU, leucovorin, and oxaliplatin (the FOLFOX6 regimen) for colorectal cancer (CRC) treatment was analyzed. A subset including only patients who had at least two consecutive cycles tested, received 1,600-3,600 mg/m2 of continuous infusion 5-FU during the initial test cycle, and had a blood sample collected after ≥18 hours, was used to conduct regression modeling of the change in AUC versus change in dose. RESULTS A simple regression model with R(2) = 0.51 developed over n = 307 cycle-pair observations characterizes the AUC-Dose relationship as: change in AUC = 0.02063 * dose change. The model suggests that dose changes in the range of 145-727 mg/m2 would be sufficient to adjust the AUC to a potential therapeutic threshold of >20 mg · h/L for most patients. CONCLUSIONS 5-FU is an ideal candidate for PK dose optimization. Because individual factors other than dose change may also affect the change in AUC, longitudinal PK monitoring in all cycles and dose adjustment to ensure AUC in the desired range of 20-30 mg · h/L are recommended.

Impact of the Cell Cycle Progression Test on Physician and Patient Treatment Selection for Localized Prostate Cancer

PURPOSE The cell cycle progression test is a validated molecular assay that assesses prostate cancer specific disease progression and mortality risk when combined with clinicopathological parameters. We present the results from PROCEDE-1000, a large, prospective registry designed to evaluate the impact of the cell cycle progression test on shared treatment decision making for patients newly diagnosed with prostate cancer. MATERIALS AND METHODS Untreated patients with newly diagnosed prostate adenocarcinoma were enrolled in the study and the cell cycle progression test was performed on the initial prostate biopsy tissue. A set of 4 sequential surveys tracked changes relative to initial therapy recommendations (before cell cycle progression) based on clinicopathological parameters following physician review of the cell cycle progression test result, physician/patient review of the cell cycle progression test results and a minimum of 3 months of clinical followup (actual treatment). RESULTS Of the 1,596 patients enrolled in this registry 1,206 were eligible for analysis. There was a significant reduction in the treatment burden recorded at each successive evaluation (p <0.0001), with the mean number of treatments per patient decreasing from 1.72 before the cell cycle progression test to 1.16 in actual followup. The cell cycle progression test caused a change in actual treatment in 47.8% of patients. Of these changes 72.1% were reductions and 26.9% were increases in treatment. For each clinical risk category there was a significant change in treatment modality (intervention vs nonintervention) before vs after cell cycle progression testing (p=0.0002). CONCLUSIONS The cell cycle progression test has a significant impact in assisting physicians and patients reach personalized treatment decisions.

Hereditary Cancer-Associated Mutations in Women Diagnosed with Two Primary Cancers: An Opportunity to Identify Hereditary Cancer Syndromes after the First Cancer Diagnosis

Objectives: Patients with hereditary cancer syndromes are at high risk for a second primary cancer. Early identification of these patients after an initial cancer diagnosis is the key to implementing cancer risk-reducing strategies. Methods: A commercial laboratory database was searched for women with a history of both breast and ovarian or colorectal and endometrial cancer who underwent genetic testing for hereditary breast and ovarian cancer (HBOC) or Lynch syndrome (LS). Results: Among women with both breast and ovarian cancer, 22.4% (2,237/9,982) had a BRCA1 or BRCA2 mutation. Among women with both colorectal and ovarian cancer, 28.1% (264/941) had a mutation associated with LS. In 66.6% of BRCA1 or BRCA2 mutation carriers and in 58.3% of LS mutation carriers, >5 years passed between the cancer diagnoses. Of patients with HBOC and LS, 56 and 65.2%, respectively, met the National Comprehensive Cancer Network guidelines for hereditary cancer testing after their initial diagnosis based on their personal cancer history alone. Conclusions: A substantial number of women tested for LS or HBOC after being diagnosed with two successive primary cancers were diagnosed with a hereditary cancer syndrome. In many cases, the time interval between the diagnoses was long enough to allow for the implementation of surveillance and/or prophylactic measures.

Cost-Utility of a Prognostic Test Guiding Adjuvant Chemotherapy Decisions in Early-Stage Non-Small Cell Lung Cancer

BACKGROUND A prognostic test was developed to guide adjuvant chemotherapy (ACT) decisions in early-stage non-small cell lung cancer (NSCLC) adenocarcinomas. The objective of this study was to compare the cost-utility of the prognostic test to the current standard of care (SoC) in patients with early-stage NSCLC. MATERIALS AND METHODS Lifetime costs (2014 U.S. dollars) and effectiveness (quality-adjusted life-years [QALYs]) of ACT treatment decisions were examined using a Markov microsimulation model from a U.S. third-party payer perspective. Cancer stage distribution and probability of receiving ACT with the SoC were based on data from an academic cancer center. The probability of receiving ACT with the prognostic test was estimated from a physician survey. Risk classification was based on the 5-year predicted NSCLC-related mortality. Treatment benefit with ACT was based on the prognostic score. Discounting at a 3% annual rate was applied to costs and QALYs. Deterministic one-way and probabilistic sensitivity analyses examined parameter uncertainty. RESULTS Lifetime costs and effectiveness were

Stratification of risk for patients with prostate cancer at biopsy using CCP score.

137,403 and 5.45 QALYs with the prognostic test and

Assessment of proteomic measures across serious psychiatric illness

127,359 and 5.17 QALYs with the SoC. The resulting incremental cost-effectiveness ratio for the prognostic test versus the SoC was

Prevalence of DPYD gene mutations among patients receiving 5-FU therapy.

35,867/QALY gained. One-way sensitivity analyses indicated the model was most sensitive to the utility of patients without recurrence after ACT and the ACT treatment benefit. Probabilistic sensitivity analysis indicated the prognostic test was cost-effective in 65.5% of simulations at a willingness to pay of

Abstract B08: Predictors of delay to single-site confirmatory testing for familial BRCA1/2 mutations

50,000/QALY. CONCLUSION The study suggests using a prognostic test to guide ACT decisions in early-stage NSCLC is potentially cost-effective compared with using the SoC based on globally accepted willingness-to-pay thresholds. IMPLICATIONS FOR PRACTICE Providing prognostic information to decision makers may help some patients with high-risk early stage non-small cell lung cancer receive appropriate adjuvant chemotherapy while avoiding the associated toxicities and costs in patients with low-risk disease. This study used an economic model to assess the effectiveness and costs associated with using a prognostic test to guide adjuvant chemotherapy decisions compared with the current standard of care in patients with non-small cell lung cancer. When compared with current standard care, the prognostic test was potentially cost effective at commonly accepted thresholds in the U.S. This study can be used to help inform decision makers who are considering using prognostic tests.

The effect of cell cycle progression (CCP) score on treatment decisions in prostate cancer: Results of an ongoing registry trial.

127 Background: In the US, most prostate cancers are treated with surgery or radiation, despite many having low malignant potential. If low cancer progression risk can be established, some men can be spared treatment. PSA, Gleason score and clinical stage work well for population risk assessment but lack precision for individuals. Molecular analysis can refine risk assessment as demonstrated by a cell cycle progression score (CCP) predictive of prostate cancer aggressiveness in 4 separate cohorts. In these studies, CCP typically ranged from -2 to +3 with each 1-unit increase corresponding to approximately a doubling of risk. We characterized the CCP distribution using recent samples from a typical US urology multi-centered clinical setting and determined the analytic success rate of the assay. METHODS Formalin fixed, prostate biopsy tissue from 300 patients diagnosed with adenocarcinoma within the last 12 months was analyzed. CCP is calculated by measuring the relative RNA expression of 31 cell cycle progression genes. Patients were recruited from 15 geographically diverse community urology practices. RESULTS CCP could be measured for 98% of samples (294/300). This study showed a normal distribution for the CCP ranging from -2 to 3.2 (median = -0.3, SD=0.92). There was little correlation of CCP with PSA, age, or body mass index. Correlation with Gleason score was similar to those in prior studies (r=0.494). A relative classification of cancer aggressiveness based on CCP of ~ 1200 patients from multiple cohorts has been developed. The 294 evaluable patients were cross-classified by AUA risk and cancer aggressiveness (see table). CCP further stratified patients within each AUA risk classification. CONCLUSIONS CCP is a novel assay that can facilitate risk stratification for men with prostate adenocarcinoma. [Table: see text].