Risk of Subsequent Breast Cancer in Women with Early Stage HER2-Positive Breast Cancer in a Large Community Health Plan.

Purpose: Clinical outcomes have improved for women with early stage, HER2-positive breast cancer following the FDA approval of adjuvant trastuzumab use in 2006. However, only limited information exists on such patients' outcomes in real-world settings outside of clinical trials. We examined the risk of subsequent breast cancer in women with HER-2 positive disease, and the impact of trastuzumab use, in a large California community-based health plan. Patients and Methods: A cohort of 3550 women with HER2-positive breast cancer (stages I-III) from 2009-2017 were followed through December 2018. We calculated subsequent breast cancer (SBC) rates overall and by trastuzumab use. Multivariable Cox proportional hazards modeling was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for SBC by trastuzumab use. Results: Within the cohort diagnosed with HER2-positive disease, 81% received adjuvant trastuzumab. After 4.1 mean years follow-up (maximum 10 years), the risk of SBC was 22% lower with adjuvant trastuzumab use (hazard ratio [HR] = 0.78, 95% confidence interval [CI]: 0.66-0.92) compared with non-use. The cumulative incidence of SBC precipitously rose two years after diagnosis and by the 10th year, the cumulative incidence was 31% among those who had trastuzumab therapy versus 34% without this therapy. Conclusion: In community practice settings, the cumulative incidence of SBC in patients with early stage HER2-positive BC was 31% at 10 years in a cohort treated with adjuvant trastuzumab. Trastuzumab use was associated with a 22% reduced risk of developing SBC. This residual disease burden suggests breast cancer outcomes may be improved with further treatment given the advent of next-generation HER2-targeted therapies.

Residual Disease Burden After Neoadjuvant Therapy Among US Patients With High-Risk HER2-positive Early-Stage Breast Cancer: A Population Effectiveness Model.

BACKGROUND: Approximately half of patients with high-risk HER2-positive early-stage breast cancer (ESBC) do not have pathologic complete response (pCR) after neoadjuvant therapy. The residual burden of disease among this population has not been previously quantified. MATERIALS AND METHODS: We used decision-modeling techniques to simulate recurrence, progression from locoregional to distant cancer, breast cancer-related mortality, and mortality from other causes over a 10-year period in a hypothetical cohort. We derived progression probabilities primarily from the KATHERINE trial of T-DM1 (ado-trastuzumab emtansine) and mortality outcomes from the published literature. Modeled outcomes included recurrences, breast cancer deaths, deaths from other causes, direct medical costs, and costs due to lost productivity. To estimate the residual disease burden, we compared outcomes from a cohort of patients treated with T-DM1 versus a hypothetical cohort with no disease recurrence. RESULTS: We estimated that 9,300 people would experience incident high-risk HER2-positive ESBC in the United States in 2021 based on cancer surveillance databases, clinical trial data, and expert opinion. We estimated that, in this group, 2,118 would experience disease recurrence, including 1,576 distant recurrences, and 1,358 would experience breast cancer deaths. This residual disease burden resulted in 6,435 life-years lost versus the recurrence-free cohort, and healthcare-related costs totaling $644 million, primarily associated with treating distant cancers. CONCLUSION: Patients with HER2-positive ESBC who do not achieve pCR after neoadjuvant therapy are at ongoing risk of recurrence despite the effectiveness of neoadjuvant treatment. There is substantial clinical and economic value in further reducing the residual disease burden in this population.

Health Care Resource Utilization and Costs for Metastatic Breast Cancer Patients Newly Treated with Human Epidermal Growth Factor Receptor 2 (HER2)-Targeted Agents.

INTRODUCTION: HER2-positive metastatic breast cancer (mBC) is an incurable disease associated with years of chronic therapy and excess cost. HER2-targeted therapies have shown survival benefit for early-stage and mBC; however, the economic impact of these therapies has not been fully assessed. We evaluated health care resource use (HCRU) and costs of mBC patients treated with HER2-targeted therapy. METHODS: This was a retrospective cohort study using the IQVIA Real-World Data Adjudicated Claims Database (July 1, 2014 to July 31, 2019). Female patients aged ≥18 years with mBC who initiated HER2-targeted therapy in the prior year were identified. The index date was the initiation date of the HER2-targeted agent, after which patients were required to have ≥12 months of follow-up. Annual and cumulative all-cause and BC-related costs (2019 USD) and annual BC-related HCRU were computed in years 1, 2, and 3 following the index date. RESULTS: Following the initiation of HER2-targeted therapy, the mean annual total all-cause costs per patient in years 1 (n = 423), 2 (n = 357), and 3 (n = 166) were $320,892 (SD: $224,343), $235,159 (SD: $185,287), and $226,254 (SD: $197,901), respectively. The mean annual total BC-related costs were $240,048 (SD: $151,230), $175,631 (SD: $148,058), and $165,506 (SD: $159,374) in years 1, 2, and 3, respectively. A major portion of BC-related costs were costs associated with HER2-targeted treatment. The 3-year cumulative all-cause and BC-related total costs were $769,573 (SD: $456,920) and $624,455 (SD: $401,319), respectively. CONCLUSION: Treatment of HER2-positive mBC is a substantial economic burden. A potential approach to minimizing cost and HCRU is to prevent recurrence.

Neratinib + capecitabine sustains health-related quality of life in patients with HER2-positive metastatic breast cancer and ≥ 2 prior HER2-directed regimens.

PURPOSE: To characterize health-related quality of life (HRQoL) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) from the NALA phase 3 study. METHODS: In NALA (NCT01808573), patients were randomized 1:1 to neratinib + capecitabine (N + C) or lapatinib + capecitabine (L + C). HRQoL was assessed using seven prespecified scores from the European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire core module (QLQ-C30) and breast cancer-specific questionnaire (QLQ-BR23) at baseline and every 6 weeks. Descriptive statistics summarized scores over time, mixed models evaluated differences between treatment arms, and Kaplan-Meier methods were used to assess time to deterioration in HRQoL scores of ≥ 10 points. RESULTS: Of the 621 patients randomized in NALA, patients were included in the HRQoL analysis if they completed baseline and at least one follow-up questionnaire. The summary, global health status, physical functioning, fatigue, constipation, and systemic therapy side effects scores were stable over time with no persistent differences between treatment groups. There were no differences in time to deterioration (TTD) for the QLQ-C30 summary score between treatment arms; the hazard ratio (HR) for N + C vs. L + C was 0.94 (95% CI 0.63-1.40). Only the diarrhea score worsened significantly more in the N + C arm as compared to the L + C arm, and this remained over time (HR for TTD for N + C vs. L + C was 1.71 [95% CI 1.32-2.23]). CONCLUSION: In NALA, patients treated with N + C maintained their global HRQoL over time, despite a worsening of the diarrhea-related scores. These results may help guide optimal treatment selection for HER2-positive MBC.

Real-World Assessment of Health Care Costs for Patients with Metastatic Pancreatic Cancer Following Initiation of First-Line Chemotherapy.

BACKGROUND: Management of metastatic pancreatic ductal adenocarcinoma (mPDA) places a significant financial burden on the U.S. health care system because of such factors as treatment with multidrug chemotherapy regimens, management of chemotherapy-related adverse events, and disease- or treatment-related hospitalizations. Depending on functional status, first-line chemotherapy regimens that are guideline recommended include nab-paclitaxel with gemcitabine (AG) and FOLFIRINOX (FFX), the combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin. However, few previous studies have examined overall health care costs associated with mPDA management. OBJECTIVE: To describe health care costs following initiation of first-line treatment with AG or FFX among patients with mPDA. METHODS: Retrospective cohorts of first-line AG and FFX initiators were constructed from the MarketScan database (2014-2017). The index date was the date of first-line AG or FFX initiation. Included patients had insurance enrollment for 6 months before the index date. Total cumulative health care costs and costs from outpatient services, inpatient admissions, emergency department visits, chemotherapy administrations, and pharmacy dispensing were assessed within 12 months after the index date (i.e., 0-1, 0-2, …, 0-12 months). Patient-level cost data began accruing from the first paid claim and continued accruing until the censoring date. RESULTS: A total of 2,199 patients with mPDA initiated first-line AG (n = 1,352) or FFX (n = 847). Compared with AG initiators, FFX patients were younger (mean age 59 vs. 63 years) and had better baseline health status, with fewer having diabetes (43% vs. 57%) or coronary artery disease (12% vs. 22%). Median follow-up was 5.4 and 7.2 months for AG and FFX, respectively. Median first-line treatment duration was 2.1 months with AG and 2.3 months with FFX. Six months following first-line treatment initiation, total cumulative health care costs (median) were $85,714 (95% CI = $79,683-$91,788) and $114,116 (95% CI = $105,816-$119,591) for AG and FFX initiators, respectively. Outpatient services contributed the largest fractional cost for both groups. CONCLUSIONS: Total health care costs for patients with mPDA who initiated FFX or AG are driven mostly by outpatient rather than inpatient costs. Further research, using comparative methodology, is warranted to fully understand cost drivers and whether higher costs for FFX patients relate primarily to use of FFX or higher underlying use of outpatient care among FFX patients. DISCLOSURES: This study was funded by Halozyme Therapeutics. Oestreicher and Yeganegi were employees of Halozyme Therapeutics at the time of the study and were involved in study design, data interpretation, and the decision to submit the data for publication. Bullock reports advisory board fees from Eisai, Exelixis, Bayer, and Taiho and consulting fees from Halozyme Therapeutics, outside the submitted work. Rowan reports consulting fees from Halozyme Therapeutics, during the conduct of the study. Chiorean reports grants and consulting fees from Celgene and Halozyme Therapeutics; grants from Lilly, Stemline, Ignyta, Roche, Merck, Boehringer-Ingelheim, Bristol Meyer Squibb, Incyte, Macrogenics, Rafael, and AADi; and consulting fees from Astra Zeneca, Array, Eisai, Ipsen, Five Prime Therapeutics, Seattle Genetics, Vicus, and Legend, outside the submitted work.

Correction to: Cost-Effectiveness Analysis of Patiromer and Spironolactone Therapy in Heart Failure Patients with Hyperkalemia.

Correction to Bounthavong M, Butler J, Dolan CM, Dunn JD, Fisher KA, Oestreicher N, Pitt B, Hauptman PJ, Veenstra DL.

Real-World Evaluation of Patiromer for the Treatment of Hyperkalemia in Hemodialysis Patients.

INTRODUCTION: Patiromer is a potassium (K+) binding polymer indicated for treating hyperkalemia. Among patients receiving chronic hemodialysis (HD), this study aimed to identify patient characteristics associated with patiromer initiation, describe patiromer utilization, and analyze serum K+ pre- and post-patiromer initiation. METHODS: In a retrospective cohort study, using electronic health record data from a large dialysis provider in the United States (study period: December 21, 2015, to December 20, 2016), HD patients were included who had a medication order for patiromer, sodium polystyrene sulfonate (SPS), or laboratory evidence of hyperkalemia (no K+ binder [NoKb] cohort). The index date was the first order for patiromer/SPS, or the first K+ ≥5.0 mEq/l (NoKb cohort), respectively. Using multivariable logistic regression, we identified patient characteristics associated with patiromer initiation. We evaluated patiromer utilization using Kaplan-Meier methodology and proportion of days covered. Serum K+ concentrations were assessed pre- versus post-patiromer initiation. RESULTS: Study cohorts included 527 (patiromer), 852 (SPS), and 8747 (NoKb) HD patients. Median follow-up was 141 days. Patiromer initiators were 2.6 times more likely to have had multiple prior episodes of hyperkalemia (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.8-3.7). Most (61%) commenced patiromer on 8.4 g once daily; 60% of patients' first patiromer order remained open after 180 days. Statistically significant reductions in K+, averaging approximately -0.5 mEq/l, were observed post-patiromer initiation (48% pre-patiromer vs. 22% post-patiromer had K+ ≥6.0 mEq/l [P < 0.001]). CONCLUSION: Patiromer initiators receiving chronic hemodialysis had comparatively more severe, uncontrolled baseline hyperkalemia. Medication order data show long-term patiromer use was associated with significantly reduced K+.

Cost-Effectiveness Analysis of Patiromer and Spironolactone Therapy in Heart Failure Patients with Hyperkalemia.

BACKGROUND AND OBJECTIVE: Certain patients with heart failure (HF) are unable to tolerate spironolactone therapy due to hyperkalemia. Patiromer is a novel agent used to treat hyperkalemia and has been shown to be efficacious, safe, and well-tolerated. The potential clinical outcomes and economic value of using patiromer and spironolactone in patients with HF unable to otherwise tolerate spironolactone due to hyperkalemia are unclear. The objective of this analysis was to model the potential pharmacoeconomic value of using patiromer and spironolactone in patients with a history of hyperkalemia that prevents them from utilizing spironolactone. METHODS: We performed a cost-effectiveness analysis of treatment with patiromer, spironolactone, and an angiotensin-converting enzyme inhibitor (ACEI) in patients with New York Heart Association (NYHA) class III-IV HF compared with ACEI alone. A Markov model was constructed to simulate a cohort of 65-year-old patients diagnosed with HF from the payer perspective across the lifetime horizon. Clinical inputs were derived from the RALES and OPAL-HK randomized trials of spironolactone and patiromer, respectively. Utility estimates and costs were derived from the literature and list prices. Outcomes assessed included hospitalization, life expectancy, and quality-adjusted life-years (QALYs), costs, and the incremental cost-effectiveness ratio (ICER). One-way and probability sensitivity analyses were performed to test the robustness of the model findings. RESULTS: Treatment with patiromer-spironolactone-ACEI was projected to increase longevity compared with ACEI alone (5.29 vs. 4.62 life-years gained, respectively), greater QALYs (2.79 vs. 2.60), and costs (US$28,200 vs. US$18,200), giving an ICER of US$52,700 per QALY gained. The ICERs ranged from US$40,000 to US$85,800 per QALY gained in 1-way sensitivity analyses. CONCLUSION: Our results suggest that the use of spironolactone-patiromer-ACEI may provide clinical benefit and good economic value in patients with NYHA class III-IV HF unable to tolerate spironolactone due to hyperkalemia.

Serum-to-dialysate potassium gradient and its association with short-term outcomes in hemodialysis patients.

Background: A high serum-to-dialysate potassium (K+) gradient at the start of dialysis leads to rapid lowering of serum K+ and may confer a greater risk of adverse events. Here, we examined the near-term association of K+ gradient with clinical outcomes. Methods: This retrospective (2010-11) event-based study considered 830 741 patient-intervals, each defined by a pre-dialysis measurement of serum K+ made among adult Medicare Parts A and B enrollees who received in-center hemodialysis on a Monday/Wednesday/Friday schedule at a large US dialysis organization. K+ gradient was considered based on the difference in K+ concentration (serum-dialysate) on the date of measurement; analyses accounted for multiple observations per patient. Outcomes considered were: all-cause and cardiovascular hospital admissions, emergency department (ED) visits and deaths. Results: Higher K+ gradient was associated with younger age, greater fistula use, lower comorbidity scores and better nutritional indices. Adjusting for patient differences, there was a dose-response relationship between higher K+ gradient and greater risks of all-cause hospitalization and ED visit. A similar trend was seen for cardiovascular hospitalization but did not achieve statistical significance. No associations were observed with mortality, potentially due to a low number of events. Conclusions: Higher K+ gradient is independently associated with greater risk of all-cause hospitalizations and ED visits. Further research is needed to determine whether interventions that reduce the K+ gradient ameliorate this risk.

Clinical and Economic Impact of Hyperkalemia in Patients with Chronic Kidney Disease and Heart Failure.

BACKGROUND: Hyperkalemia (HK) is a concern for patients with chronic kidney disease (CKD) and heart failure (HF), and for those receiving treatments that inhibit the renin-angiotensin-aldosterone system (RAASi). An analysis of 1.7 million medical records of patients in the United States revealed that among individuals with more than 2 potassium values during 2007 to 2012, HK was detected in 34.6% of patients with CKD and 30.0% of patients with HF. OBJECTIVE: To evaluate the association of HK and use of RAASi therapies at optimal and suboptimal doses in patients with CKD and/or HF with health care resource utilization and overall cost of care in a diverse cohort of commercially insured patients. METHODS: This retrospective cohort study was conducted using medical and pharmacy claims from multiple regional health plans. Qualifying patients were ≥ 18 years old, continuously enrolled for 6 months before and throughout the study period (January 1, 2014, to December 31, 2015) and had an ICD-9-CM or ICD-10-CM diagnosis code of CKD and/or HF. Health care resource utilization, including hospital visits, length of stay, office visits, and associated medical and pharmacy costs, were assessed according to the 3 cohorts (CKD alone, HF alone, and concomitant CKD and HF). For the 3 cohorts, the results were also compared between patients with and without HK and between patients with and without RAASi use at optimal and suboptimal doses. Generalized linear models were used to further examine the predictors of medical and overall costs. RESULTS: In this study, 15,999 patients met inclusion criteria. Among patients using RAASi therapy, 26.8% received the optimal dose. Optimal dosing of RAASi was associated with decreased median outpatient office visits (8, 10, and 15, respectively, for patients with CKD, HF, and both CKD and HF) compared with suboptimal dosing of RAASi (12, 15, and 23, respectively). Similarly, optimal dosing of RAASi was associated with decreased overall median medical costs ($2,092, $4,144, and $7,762, respectively, for patients with CKD, HF, and both CKD and HF) compared with suboptimal dosing of RAASi ($3,121, $8,289, and $12,749, respectively). Patients with CKD, HF, or both CKD and HF, all in combination with HK, had higher overall costs, compared with those without HK. CONCLUSIONS: The results of this real-world analysis suggest that HK and suboptimal dosing of RAASI were associated with a median increase in outpatient office visits as well as increased overall medical costs among patients with CKD and/or HF. This evaluation of median costs suggests effective HK management may potentially reduce costs in patients with CKD and/or HF, including those currently receiving RAASi therapy. DISCLOSURES: This study was conducted by Magellan Rx Management and funded by Relypsa. Brenner, Alvarez, and Oestreicher were employed by Relypsa during the development of this study and the writing of this manuscript. Polson, Lord, Kangethe, Speicher, and Farnum are employees of Magellan Rx Management, which received funding from Relypsa for conducting the retrospective study and writing the manuscript. Study concept and design were contributed by Lord, Polson, Brenner, Alvarez, and Oestreicher. Data collection and interpretation were performed by Polson and Kangethe, with assistance from Lord. The manuscript was written by Farnum, with assistance from Kangethe and Speicher and revised by all authors.

Clinical and Economic Impact of Hyperkalemia in Patients with Chronic Kidney Disease and Heart Failure.

BACKGROUND: Hyperkalemia (HK) is a concern for patients with chronic kidney disease (CKD) and heart failure (HF), and for those receiving treatments that inhibit the renin-angiotensin-aldosterone system (RAASi). An analysis of 1.7 million medical records of patients in the United States revealed that among individuals with more than 2 potassium values during 2007 to 2012, HK was detected in 34.6% of patients with CKD and 30.0% of patients with HF. OBJECTIVE: To evaluate the association of HK and use of RAASi therapies at optimal and suboptimal doses in patients with CKD and/or HF with health care resource utilization and overall cost of care in a diverse cohort of commercially insured patients. METHODS: This retrospective cohort study was conducted using medical and pharmacy claims from multiple regional health plans. Qualifying patients were ≥ 18 years old, continuously enrolled for 6 months before and throughout the study period (January 1, 2014, to December 31, 2015) and had an ICD-9-CM or ICD-10-CM diagnosis code of CKD and/or HF. Health care resource utilization, including hospital visits, length of stay, office visits, and associated medical and pharmacy costs, were assessed according to the 3 cohorts (CKD alone, HF alone, and concomitant CKD and HF). For the 3 cohorts, the results were also compared between patients with and without HK and between patients with and without RAASi use at optimal and suboptimal doses. Generalized linear models were used to further examine the predictors of medical and overall costs. RESULTS: In this study, 15,999 patients met inclusion criteria. Among patients using RAASi therapy, 26.8% received the optimal dose. Optimal dosing of RAASi was associated with decreased median outpatient office visits (8, 10, and 15, respectively, for patients with CKD, HF, and both CKD and HF) compared with suboptimal dosing of RAASi (12, 15, and 23, respectively). Similarly, optimal dosing of RAASi was associated with decreased overall median medical costs ($2,092, $4,144, and $7,762, respectively, for patients with CKD, HF, and both CKD and HF) compared with suboptimal dosing of RAASi ($3,121, $8,289, and $12,749, respectively). Patients with CKD, HF, or both CKD and HF, all in combination with HK, had higher overall costs, compared with those without HK. CONCLUSIONS: The results of this real-world analysis suggest that HK and suboptimal dosing of RAASI were associated with a median increase in outpatient office visits as well as increased overall medical costs among patients with CKD and/or HF. This evaluation of median costs suggests effective HK management may potentially reduce costs in patients with CKD and/or HF, including those currently receiving RAASi therapy. DISCLOSURES: This study was conducted by Magellan Rx Management and funded by Relypsa. Brenner, Alvarez, and Oestreicher were employed by Relypsa during the development of this study and the writing of this manuscript. Polson, Lord, Kangethe, Speicher, and Farnum are employees of Magellan Rx Management, which received funding from Relypsa for conducting the retrospective study and writing the manuscript. Study concept and design were contributed by Lord, Polson, Brenner, Alvarez, and Oestreicher. Data collection and interpretation were performed by Polson and Kangethe, with assistance from Lord. The manuscript was written by Farnum, with assistance from Kangethe and Speicher and revised by all authors.

Serum Potassium and Short-term Clinical Outcomes Among Hemodialysis Patients: Impact of the Long Interdialytic Interval.

BACKGROUND: Hyperkalemia is common among hemodialysis patients and is associated with morbidity and mortality. The long interdialytic interval is likewise associated with adverse outcomes. However, the interplay among serum potassium, dialysis cycle phase, and clinical outcomes has not been examined. STUDY DESIGN: Retrospective observational study. SETTING & PARTICIPANTS: 52,734 patients receiving in-center hemodialysis at a large dialysis organization during 2010 and 2011 contributed 533,889 potassium measurements (230,634 on Monday; 285,522 on Wednesday; 17,733 on Friday). PREDICTOR: Serum potassium concentration, day of the week of potassium measurement. OUTCOMES: Death, hospitalization, emergency department (ED) visit. RESULTS: There was a significant association between higher serum potassium and risk of hospitalization within 96 hours that was of greater magnitude on Fridays (389 hospitalizations) than Mondays or Wednesdays (4,582 and 4,629 hospitalizations, respectively; P for interaction = 0.008). Serum potassium of 5.5 to <6.0 (vs the referent category of 4.0-<4.5 mEq/L) was associated with increased risk of hospitalization on Fridays, with an adjusted OR of 1.68 (95% CI, 1.22-2.30). However, serum potassium of 5.5 to <6.0 mEq/L was associated with only mild elevation of risk on Mondays and no significantly increased risk on Wednesdays (adjusted ORs of 1.12 [95% CI, 1.00-1.24] and 1.04 [95% CI, 0.94-1.16], respectively). Associations of elevated serum potassium (6.0-<6.5 mEq/L or greater) with death and ED visit were significant, but did not differ based on day of the week. LIMITATIONS: There were insufficient observations to detect effect modification by day of the week for deaths, ED visits, and specific causes of hospitalizations. Confounding may have influenced results. CONCLUSIONS: Higher serum potassium is associated with increased short-term risk of hospitalization, ED visit, and death. The association between serum potassium and hospitalization risk is modified by day of the week, consistent with a contribution of accumulated potassium to adverse outcomes following the long interdialytic interval. Further work is needed to determine whether directed interventions ameliorate this risk.

Budget Impact of Enzalutamide for Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Prostate cancer is expected to account for approximately one quarter of all new diagnoses of cancer in American men in 2015. The cost of prostate cancer care is expected to reach $15.1 billion by the year 2020, up from $11.9 billion in 2010. Given the high burden of prostate cancer, health care payers are interested in quantifying the potential budget impact of new therapies. OBJECTIVE: To estimate the budget impact of enzalutamide for the treatment of chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) from a U.S. payer perspective. METHODS: A model was developed to assess the budget impact of enzalutamide for treatment of chemotherapy-naïve mCRPC patients in a hypothetical 1-million-member U.S. health plan over a 1-year time horizon. Comparators included abiraterone acetate, sipuleucel-T, radium Ra 223 dichloride, and docetaxel. Epidemiologic data, including National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) incidence rates, were used to estimate the number of chemotherapy-naïve mCRPC patients. Dosing, administration, duration of therapy, and adverse event rates were based on package inserts and pivotal studies. Drug costs were obtained from RED BOOK and Centers for Medicare & Medicaid Services (CMS) average sales price pricing files, costs of administration and monitoring from the CMS physician fee schedule, and adverse events from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project and published literature. Market shares were estimated for each comparator before and after adoption of enzalutamide. The incremental aggregate budget impact, per patient per year (PPPY), per patient per month (PPPM), and per member per month (PMPM), was calculated. One-way sensitivity analyses were performed. RESULTS: In a population of 115 chemotherapy-naïve mCRPC patients, adopting enzalutamide had an annual incremental budget impact of $510,641 ($4,426 PPPY, $369 PPPM, and $0.04 PMPM). Results were most sensitive to enzalutamide drug cost, size of the chemotherapy-naïve mCRPC patient population, and enzalutamide adoption rate. CONCLUSIONS: Results indicate a modest 1-year budget impact of adopting enzalutamide for chemotherapy-naïve mCRPC patients, partly because of the cost offset of a moderate incidence of adverse events and lack of additional required monitoring.

Evaluation of the treatment gap between clinical guidelines and the utilization of renin-angiotensin-aldosterone system inhibitors.

OBJECTIVES: This study examined renin-angiotensin-aldosterone system (RAAS) inhibitor dose levels in a US patient population and investigated the impact of hyperkalemia on RAAS inhibitor dose and the association between dose levels and clinical outcomes. STUDY DESIGN: De-identified medical records from a large database of electronic health records (Humedica) for patients 5 years of age or older with at least 2 serum potassium readings were analyzed (N = 205,108 patients; 1.7 million records). METHODS: Inclusion criteria required 1 RAAS inhibitor prescription and 12 months' data prior to July 1, 2009 (index date). Patients were classified by comorbidities (chronic kidney disease, heart failure, or diabetes) and RAAS inhibitor dose level at index date, as determined by prescription information. Additional analyses examined RAAS inhibitor dose changes following hyperkalemia and the frequency of cardiorenal adverse outcome/mortality or mortality alone by post index dose level. RESULTS: Dose level was similarly distributed irrespective of patient comorbidity status, with RAAS inhibitors prescribed at maximum dose in 19% to 26% of patients and submaximum dose in 58% to 65% of patients; RAAS inhibitors were discontinued in 14% to 16% of patients. RAAS inhibitor dose was down-titrated after 16% to 21% of hyperkalemia events and discontinued after 22% to 27% of hyperkalemia events. Cardiorenal adverse event/mortality and mortality occurred in 34.3% and 11.0% of patients who discontinued RAAS inhibitors, 24.9% and 8.2% of patients on submaximum doses, and 24.9% and 4.1% of patients on maximum doses, respectively. CONCLUSIONS: Relatively few patients were prescribed maximum doses of RAAS inhibitors, and dose and usage declined following hyperkalemia. Patients on submaximum doses or who discontinued RAAS inhibitors had worse outcomes than patients on maximum doses.

Physical activity and change in mammographic density: the Study of Women's Health Across the Nation.

One potential mechanism by which physical activity may protect against breast cancer is by decreasing mammographic density. Percent mammographic density, the proportion of dense breast tissue area to total breast area, declines with age and is a strong risk factor for breast cancer. The authors hypothesized that women who were more physically active would have a greater decline in percent mammographic density with age, compared with less physically active women. The authors tested this hypothesis using longitudinal data (1996-2004) from 722 participants in the Study of Women's Health Across the Nation (SWAN), a multiethnic cohort of women who were pre- and early perimenopausal at baseline, with multivariable, repeated-measures linear regression analyses. During an average of 5.6 years, the mean annual decline in percent mammographic density was 1.1% (standard deviation = 0.1). A 1-unit increase in total physical activity score was associated with a weaker annual decline in percent mammographic density by 0.09% (standard error = 0.03; P = 0.01). Physical activity was inversely associated with the change in nondense breast area (P < 0.01) and not associated with the change in dense breast area (P = 0.17). Study results do not support the hypothesis that physical activity reduces breast cancer through a mechanism that includes reduced mammographic density.

Active, but not passive cigarette smoking was inversely associated with mammographic density.

PURPOSE: The opposing carcinogenic and antiestrogenic properties of tobacco smoke may explain why epidemiologic studies have not consistently reported positive associations for active smoking and breast cancer risk. A negative relation between mammographic density, a strong breast cancer risk factor, and active smoking would lend support for an antiestrogenic mechanism. METHODS: We used multivariable linear regression to assess the associations of active smoking and secondhand smoke (SHS) exposure with mammographic density in 799 pre- and early perimenopausal women in the Study of Women's Health Across the Nation (SWAN). RESULTS: We observed that current active smoking was associated with 7.2% lower mammographic density, compared to never active smoking and no SHS exposure (p = 0.02). Starting to smoke before 18 years of age and having smoked > or =20 cigarettes/day were also associated with statistically significantly lower percent densities. Among nulliparous women having smoked > or =20 cigarettes/day was associated with 23.8% lower density, compared to having smoked < or = 9 cigarettes/day (p<0.001). CONCLUSIONS: Our findings support the hypothesis that tobacco smoke exerts an antiestrogenic effect on breast tissue, but counters the known increased risk of breast cancer with smoking prior to first full-term birth. Thus, our data suggest that the antiestrogenic but not the carcinogenic effects of smoking may be reflected by breast density.

Physical activity and mammographic density in a cohort of midlife women.

PURPOSE: Physical activity (PA) is one of few modifiable breast cancer risk factors. There have been few studies of the relation between PA and mammographic density, especially in multiethnic populations. METHODS: In a cohort of pre- and early perimenopausal women of non-Hispanic white (N = 373), African American (N = 55), Chinese (N = 178), and Japanese (N = 166) ethnicity, we used multivariable linear regression to examine the association between two measures of mammographic density (percent density and area of density) and mutually exclusive components of recent physical activity (sports, household/caregiving and work activity, active living). RESULTS: After adjusting for race/ethnicity, menopausal status, parity, past use of hormones, body mass index, waist circumference and education, we observed nonsignificant inverse associations for percent mammographic density and the highest versus the lowest category of each of our PA domains. For example, the adjusted beta for active living = -2.62, 95% confidence interval (CI) (-5.84, 0.60). Nonsignificant inverse associations also were observed for area of density and each PA domain except work activity. However, most associations were nonlinear. CONCLUSION: Our results are consistent with a modest inverse association between multiple domains of PA and mammographic density, although findings may have been attributable to chance alone.

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.

Menstrual and reproductive factors in relation to mammographic density: the Study of Women's Health Across the Nation (SWAN).

Menstrual and reproductive factors may increase breast cancer risk through a pathway that includes increased mammographic density. We assessed whether known or suspected menstrual and reproductive breast cancer risk factors were cross-sectionally associated with mammographic density, by measuring area of radiographic density and total breast area on mammograms from 801 participants in the Study of Women's Health Across the Nation (SWAN), a multi-ethnic cohort of pre- and early perimenopausal women. From multivariable linear regression, the following menstrual or reproductive factors were independently associated with percent mammographic density (area of dense breast/breast area): older age at menarche (beta=10.3, P<0.01, for >13 vs. <12 years), premenstrual cravings and bloating (beta=-3.36, P=0.02), younger age at first full-term birth (beta=-8.12, P<0.01 for or=3 births versus no births), and premenopausal status (beta=3.78, P<0.01 versus early perimenopausal). Only number of births remained associated with percent density after adjustment for age, race/ethnicity, study site, body mass index (BMI), and smoking. In addition, stratified analyses revealed that the association with number of births was confined to women within the lowest BMI tertile (beta=-12.2, P<0.01 for >or=3 births versus no births). Our data support a mechanism for parity and breast cancer that involves mammographic density among pre- and early perimenopausal women that may be modified by body size.