Real-world outcomes in metastatic HR+/HER2-, HER2+ and triple negative breast cancer after start of first-line therapy.

Aim: We evaluated outcomes of first-line (1L) treatment of metastatic breast cancer by biomarker subtype in the community setting over the last decade. Methods: Eligible patients (n = 1518) were female, ≥18 years, diagnosed with metastatic breast cancer 2010 or later, had documented HR+/HER2-, HER2+, or triple negative breast cancer (TNBC); and initiated 1L therapy. Kaplan-Meier and Cox methods were used to evaluate 1L real-world progression-free survival and overall survival from start of 1L. Results: TNBC was diagnosed at an earlier stage and had higher tumor grade at initial diagnosis. 1L real-world progression-free survival and overall survival from start of 1L were shorter for TNBC than HR+/HER2- or HER2+. Conclusion: Overall prognosis for patients with metastatic TNBC remains poor, and new therapies are needed to improve clinical outcomes.

What is this article about? This study looked at how well women with metastatic breast cancer did after starting treatment. It compared three groups. The first group had tumors that respond to hormone therapy. The second group had tumors that respond to treatment that works on a specific protein. A third group had tumors that don't respond to either of those ­ called triple negative. The study looked at women 18 and older who had metastatic breast cancer in 2010 or later. They had all been treated at a community oncology practice. We looked at how long it took for the cancer to get worse, and how long until patients died, for each of the three groups. What were the results? There were 1518 patients in the study. Most (62.5%) were in the group that responds to hormone therapy. The rest had tumors that respond to treatment that works on the specific protein (23.4%), or had triple negative tumors (14.1%). Patients with triple negative tumors were diagnosed earlier, but they had worse tumor characteristics. They also had shorter time until their cancer got worse, and they did not live as long, compared with the other groups. What do the results of the study mean? This builds on other studies by showing that, even in a modern era, outcomes are poor for patients with triple negative breast cancer. It shows that new treatments are needed for patients with triple negative breast cancer.

Treatment and disease management patterns for bacillus Calmette-Guérin unresponsive nonmuscle invasive bladder cancer in North America, Europe and Asia: A real-world data analysis.

Background: This study examined real-world treatment and management of bacillus Calmette-Guérin (BCG)-unresponsive patients across 3 continents, including patients unable or unwilling to undergo cystectomy. Materials and methods: Physicians actively involved in managing patients with nonmuscle invasive bladder cancer completed online case report forms for their 5 consecutive patients from the broad BCG-unresponsive population and a further 5 consecutive BCG-unresponsive patients who did not undergo cystectomy (in Japan, physicians provided a total of 5 patients across both cohorts). Results: Most patients had received 1 (37%) or 2 (24%) maintenance courses of BCG. Five or more maintenance BCG courses were received by patients in Japan (59%) and China (31%), while in Germany 76% of patients received only 1 course. Most patients became BCG-unresponsive during their first (44%) or second (22%) treatment course; in Germany, 77% became BCG-unresponsive during their first treatment course. Most countries did not provide another course of BCG after a patient first became unresponsive, whereas unresponsive patients in Japan and China were most likely to be retreated with BCG. "Untreated - on watch and wait" was the main treatment/management approach received post-BCG treatment for 42% or more of patients in most countries except China (39%) and the United States (36%). "Following treatment guidelines" was consistently the top reason for post-BCG treatment selection across all treatment options. Conclusions: This study confirmed the global unmet need for patients with nonmuscle invasive bladder cancer, and found that many patients experienced periods of no treatment after not responding to BCG therapy.

Multi-country clinical practice patterns, including use of biomarkers, among physicians' treatment of BCG-unresponsive non-muscle invasive bladder cancer (NMIBC).

BACKGROUND: Intravesical bacillus Calmette-Guérin (BCG) fails in a considerable proportion of non-muscle invasive bladder cancer (NMIBC) patients despite treatment per recommended protocol. This real-world study aimed to understand the current patterns of treatment and disease management for the broad BCG-unresponsive NMIBC patient population, alongside collecting sufficient data on patients who do not undergo cystectomy. METHODS: This was a multicenter, retrospective survey of physicians treating BCG-unresponsive NMIBC patients. Data were collected in eight countries - France, Germany, Spain, Italy, United Kingdom, United States, China, and Japan - between January and May 2019. The study consisted of a short online physician survey and a retrospective chart review of eligible BCG-unresponsive NMIBC patients. Physicians abstracted chart data for the last 10 (five patients in Japan) eligible BCG-unresponsive NMIBC patients meeting the inclusion criteria, and the data were analysed for all countries combined using descriptive statistics. Country-specific analyses were also carried out, as appropriate. RESULTS: Overall, 508 physicians participated in the study. Almost one-quarter (22.9%) of physicians' current NMIBC patient caseload was BCG-unresponsive, whereby BCG therapy was no longer considered an option. Half of physicians (49.4%) did not regularly use biomarker tests in their practice, with particularly few physicians undertaking biomarker testing in Spain and Japan. Biomarker testing varied considerably, with the proportions of physicians selecting 'none' ranging from 11.4% in China to 70.3% in Japan. Physicians reported transurethral resection of the bladder tumor (TURBT) and BCG as the most common current treatments received by their patients. Chemotherapy and anti-PD-L1 treatment options were considered impactful new therapies by 94.7% and 90.0% of physicians surveyed in this study, respectively. CONCLUSIONS: The most common treatments received by patients in this study were TURBT and BCG. Emerging new treatments are driven by exploring biomarkers, but in real-world clinical practice only half of physicians or fewer regularly tested their NMIBC patients for biomarkers; PD-1/PD-L1 was the most common biomarker test used. Most physicians reported that, in addition to chemotherapy, anti-PD-L1 was an impactful new therapy.

Comparison of Approaches for Measuring Adherence and Persistence to Oral Oncologic Therapies in Patients Diagnosed with Metastatic Renal Cell Carcinoma.

BACKGROUND: Adherence and persistence studies face several methodologic difficulties, including short-term mortality. We compared approaches to quantify adherence and persistence to first line (1L) oral targeted therapy (TT) in patients diagnosed with metastatic renal cell carcinoma (mRCC). METHODS: Patients with mRCC ages 66 years or more who initiated TTs within 4 months of diagnosis were identified in the Surveillance, Epidemiology, and End Results Medicare-linked database (2007-2015). Adherence [proportion of days covered (PDC) >80%] was calculated using (i) PDC with a fixed 6-month denominator including then excluding patients who died within the 6 months and (ii) PDC with a denominator measuring time on treatment. Risk of nonpersistence was obtained by censoring death or treating death as a competing risk using cumulative incidence functions. RESULTS: Among 485 patients with mRCC initiating a 1L oral TT (sunitinib, 64%; pazopanib, 25%; other, 11%), 40% died within 6 months. Adherence was higher after restricting to patients who survived (60%) compared with including those patients and assigning zero days covered after death (47%). Risk of nonpersistence was higher when censoring patients at death, 0.91 [95% confidence interval (CI), 0.88-0.94], compared with treating death as a competing risk, 0.75 (95% CI, 0.71-0.79). CONCLUSIONS: Different approaches to handling death resulted in different adherence and persistence estimates in the metastatic setting. Future studies should explicitly report the proportion of patient deaths over time and explore appropriate methods to account for death as competing risk. IMPACT: Use of several approaches can provide a more comprehensive picture of medication-taking behavior in the metastatic setting where death is a major competing risk.

Overall survival in the real-world and clinical trials: a case study validating external controls in advanced melanoma.

Aims: We assessed the suitability of real-world data (RWD) as an external control for analysis of overall survival (OS) compared with clinical trial data (CTD) in advanced melanoma. Methods: OS among adults receiving ipilimumab for advanced melanoma was compared between trials (CTD group) and the Flatiron Health database (RWD group) using Cox models. Adjusted analyses accounted for differences in baseline factors; missing data were addressed through multiple imputation. Results: After adjusting for baseline factors and accounting for missingness, OS was similar in the CTD (n = 241) versus RWD groups (n = 816; hazard ratio: 0.98; 95% CI: 0.75-1.26). Conclusion: Flatiron Health data is suitable to construct external control groups for OS in advanced melanoma trials after adjusting for baseline factors and missing data.

Clinical trials are the gold standard for measuring the efficacy and safety of new treatments. Comparisons between clinical trials and external controls drawn from real-world data are potentially valuable ­ especially when randomized trials are not available or feasible ­ but carry important risks of bias stemming from differences across populations, care settings and measurement of patient characteristics and outcomes. As a case study, we assessed the suitability of a particular real-world database (the Flatiron Health Database) for analyzing overall survival among patients in clinical trials of treatments for metastatic melanoma. Challenges included differences in patient baseline prognostic factors across populations, including high proportions with missing information in real-world data. After accounting for these differences, we observed similar survival between patients receiving ipilimumab monotherapy in clinical trials and in real-world data. We conclude that real-world external controls can be suitable for metastatic melanoma.

Indirect treatment comparison of nivolumab versus placebo for the adjuvant treatment of melanoma.

INTRODUCTION: Until recently, adjuvant treatment options for stage III and IV resectable melanoma have been limited. Patients were often managed through routine surveillance. The phase III randomised controlled trial (RCT) CheckMate 238 (238) demonstrated the safety and efficacy of nivolumab as an adjuvant treatment for melanoma in patients with stage IIIB/C or IV disease (American Joint Committee on Cancer [AJCC], 7th edition) versus ipilimumab. The study objective was to estimate the relative efficacy, safety and health-related quality of life (HRQoL) between nivolumab and routine surveillance. METHODS: Indirect treatment comparisons (ITCs) of nivolumab versus placebo were constructed using data from 238 and EORTC 18071. EORTC 18071 is a phase III RCT comparing ipilimumab with placebo in patients with resected stage IIIA-IIIC melanoma (AJCC, 6th edition). ITCs were performed using the Bucher comparison method and patient-level data for efficacy, safety and HRQoL. RESULTS: For the efficacy outcomes, nivolumab performed significantly better than placebo for recurrence-free survival (hazard ratio [HR]: 0.53 [95% confidence interval {CI}: 0.41, 0.68]) and distant metastases-free survival (HR: 0.59 [95% CI: 0.44, 0.78]). Safety ITCs indicated that patients receiving nivolumab had a greater hazard of experiencing an adverse event (AE) and AEs leading to treatment discontinuation, whereas there was a non-significant increased hazard of experiencing a serious AE. HRQoL ITCs showed comparable time to deterioration in 14 of the 15 QLQ-C30 domains; only the dyspnoea domain significantly favoured placebo. CONCLUSION: Nivolumab was associated with significantly improved efficacy outcomes versus placebo, whereas maintaining patient's overall HRQoL. Across the different analysis and populations, there was a high level of consistency in the effect size.

Modelling Survival of Patients Treated with Adjuvant Nivolumab Who Have Melanoma with Lymph Node Involvement or Metastatic Disease After Complete Resection.

INTRODUCTION: Nivolumab demonstrated significant recurrence-free survival (RFS) gains versus ipilimumab in the CheckMate-238 trial, whereas the CA184-029 trial showed superior RFS gains for ipilimumab versus placebo. No head-to-head trial data were available to compare the efficacy of nivolumab to that of observation, so indirect treatment comparisons were required. Additionally, overall survival (OS) data were not available from CheckMate-238, and the clinical pathway for melanoma has changed significantly over the last decade. Four modelling options were developed using different methods and evidence sources to estimate OS and the impact of nivolumab on predicted life-years in the adjuvant setting; however, this article focuses on two primary methods. METHODS: RFS for nivolumab and observation were informed by a patient-level data meta-regression. The first model was a partitioned survival model, where the parametric OS curve for observation was derived from CA184-029 and nivolumab OS was based on a surrogacy relationship between RFS and OS specific to adjuvant melanoma. The other option used a state-transition model to estimate post-recurrence survival using different data sources. RESULTS: The modelling options estimated different OS for both nivolumab and observation but demonstrated at least a 32% increase in life-years gained for nivolumab versus observation. CONCLUSION: This analysis demonstrated the difficulties in modelling within the adjuvant setting. Each model produced different survival projections, showing the need to explore different techniques to address the extent of uncertainty. This also highlighted the importance of understanding the impact of RFS in the long term in a setting where the aim of treatment is to remain disease free.

Nivolumab in patients with unresectable locally advanced or metastatic urothelial carcinoma: CheckMate 275 2-year global and Japanese patient population analyses.

BACKGROUND: Nivolumab has demonstrated antitumor activity and manageable safety in the single-arm, phase II CheckMate 275 study in patients with unresectable locally advanced or metastatic platinum-resistant urothelial carcinoma. We report updated results of the global population and a subanalysis of Japanese patients from this study. METHODS: Patients received nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) confirmed by blinded independent review committee (BIRC) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included progression-free survival (PFS) by BIRC and overall survival (OS). Safety was also reported. The minimum follow-up was 21 months. RESULTS: Overall, 270 patients were treated with nivolumab globally; 23 patients were Japanese. In the global and Japanese populations, respectively, ORR per BIRC was 20.4% and 21.7%; median PFS was 1.9 (95% confidence interval [CI] 1.9-2.3) and 3.8 months (95% CI 1.9-7.2); and median OS was 8.6 (95% CI 6.1-11.3) and 21.0 months (95% CI 7.2-not reached). The most common any grade treatment-related adverse events were fatigue (18.1%) and diarrhea (12.2%) in the global population; the most common in the Japanese population were diarrhea (26.1%) and pyrexia (13.0%). Grade 3 or 4 treatment-related adverse events occurred in 61 (22.6%) and seven (30.4%) of the global and Japanese patients, respectively. CONCLUSIONS: Nivolumab continues to show antitumor activity and survival in the global population of CheckMate 275. Meaningful clinical benefit was also observed in Japanese patients. No new safety signals were identified.

Evaluation of cardiovascular ischemic event rates in dasatinib-treated patients using standardized incidence ratios.

With high survival rates for chronic myeloid leukemia (CML) patients treated with BCR-ABL1 tyrosine kinase inhibitors (TKIs), emerging consequences, such as arterial ischemic events, require consideration when evaluating treatment options. Cardiovascular ischemic event incidence in clinical trials was evaluated in 2712 dasatinib-treated patients with Philadelphia chromosome-positive (Ph+) leukemias from 11 first- and second-line trials (pooled), newly diagnosed CML patients treated with dasatinib or imatinib (DASISION), and prostate cancer patients treated with dasatinib or placebo plus docetaxel/prednisone (READY). Overall, 2-4% of dasatinib-treated patients had cardiovascular ischemic events. Most dasatinib-treated patients with an event had a history of and/or risk factor for atherosclerosis (pooled 77 with history/risk and event/96 with events; DASISION 8/10; READY 15/18). Most cardiovascular ischemic events occurred within 1 year of initiating dasatinib (pooled 69/96; DASISION 7/10; READY 16/18). Comparison of observed and expected event rates through standardized incidence ratios indicates that dasatinib does not increase risk for cardiovascular ischemic events compared with external reference populations.

Incidence of type 2 diabetes among patients exposed to the combination of pravastatin and paroxetine.

PURPOSE: This study evaluated the effects of concomitant pravastatin and paroxetine use on the incidence of Type 2 Diabetes Mellitus (T2DM). METHODS: A new-user retrospective cohort design was employed using data selected from US health insurance claims databases (OptumInsight and MarketScan) between July 1, 2002, and December 31, 2009. Patients included were of age ≥18; newly prescribed pravastatin or paroxetine; and enrolled in the database for ≥180 days prior to the index date (i.e., first prescription of incident drug). Patients were assigned to either incident pravastatin or incident paroxetine user groups. Patients were followed until the study endpoint (T2DM), discontinuation of incident drug, second drug, or end of study/patient data. Cox proportional hazards models compared T2DM in users of pravastatin who were also taking paroxetine at index the date (combination users) versus pravastatinonly users. A similar analysis among users of paroxetine evaluated the use or non-use of pravastatin at index date. RESULTS: OptumInsight yielded 288,678 incident users of pravastatin or paroxetine; 443,137 were identified in MarketScan. The risk of T2DM among combination users compared to incident pravastatin only users was 1.05 (95% CI: 0.76, 1.44) and 0.94 (95% CI: 0.90, 0.97) in OptumInsight and MarketScan, respectively. The risk of T2DM among combination users compared to incident paroxetine only users was 1.03 (95% CI: 0.69, 1.54) in OptumInsight and 1.02 (95% CI: 0.97, 1.07) in MarketScan. CONCLUSION: The results indicate no increase in the risk of T2DM due to combined use of pravastatin and paroxetine compared to individual use of the two drugs; however, this study is limited by short mean follow-up.

The effect of hospital and surgeon volume on racial differences in recurrence-free survival after radical prostatectomy.

OBJECTIVE: This study investigates associations between hospital and surgeon volume, and racial differences in recurrence after surgery for prostate cancer. METHODS: Data from the 1991 to 2002 Surveillance, Epidemiology, and End-Results-Medicare database were examined for 962 black and 7387 white men who received surgery for prostate cancer within 6 months of diagnosis during 1993-1999. Cox regression models were used to estimate the relationships between volume (grouped in tertiles), recurrence or death, and race, controlling for age, Gleason grade, and comorbidity score. RESULTS: Prostate cancer recurrence-free survival rates improved with hospital and surgical volume. Black men were more likely to experience recurrence than white men [hazard ratio (HR) = 1.34; 95% confidence interval (CI): 1.20-1.50]. Stratification by hospital volume revealed that racial differences persisted for medium and high volume hospitals, even after covariate adjustments (medium HR = 1.30, 95% CI: 1.04-1.61; high HR = 1.36, 95% CI: 1.07-1.73). Racial differences persisted within medium and high levels of surgeon volume as well (medium HR = 1.43, 95% CI: 1.10-1.85; high HR = 1.57, 95% CI: 1.14-2.16). CONCLUSIONS: High hospital and physician volumes were not associated with reduced racial differences in recurrence-free survival after prostate cancer surgery, contrary to expectation. This study suggests that social and behavioral characteristics, and some aspects of access, may play a larger role than organizational or systemic characteristics with regard to recurrence-free survival for this population.

Val153Met polymorphism of catechol-O-methyltransferase and prevalence of uterine leiomyomata.

The catechol-O-methyltransferase (COMT) gene encodes enzymes that inactivate catechol estrogens and may have a protective role in estrogen-induced tumorigenesis, such as uterine leiomyoma (fibroids). Val158Met is a common single-nucleotide polymorphism of the COMT gene (Ex4-12 G>A; rs4680) that results in a lower activity enzyme, increasing susceptibility to tumorigenesis. The purpose of this study was to evaluate the relation between the COMTVal158Met polymorphism and uterine fibroids. Participants were 972 premenopausal African American (n = 576) and white (n = 396) women from a cross-sectional sample of women in the National Institute of Environmental Health Science's Uterine Fibroid Study. Blood was collected from participants for DNA, and telephone interviews and questionnaires were completed to gather demographic and reproductive history. Prevalence ratios and 95% confidence intervals were estimated using race-specific log-risk regression models. Effect measure modification by age, body mass index, oral contraceptive use, full-term births, smoking, and alcohol use were also evaluated. Distributions of genotypes and fibroid prevalence varied by race. No associations between fibroids and Val158Met were observed among African American or white participants. This study suggests that variation in this polymorphism alone does not affect fibroid prevalence. Additional research is needed to examine other variations and haplotypes within the COMT gene.

Differences in resident characteristics and prevalence of urinary incontinence in nursing homes in the southeastern United States.

BACKGROUND: Relatively little is known about differences in the prevalence of urinary incontinence (UI) by race and region in the United States. OBJECTIVES: To use the 1999-2002 Centers for Medicare and Medicaid Services (CMS) Minimum Data Set (MDS), Atlanta Region, to investigate the prevalence of UI among African American and Caucasian residents of nursing homes (NH) in the southeastern United States. METHODS: A repeated-measures, two time-period design was employed. Data for 95,911 residents in 7,640 NH were extracted using the study's inclusion and exclusion criteria. Residents' admission and annual assessment records were accessed; UI presence and relevant indicators were captured; and admission and postadmission UI prevalence rates were determined by region, state, race, and gender. Logistic regression, adjusting for residents' demographics, morbidity status, bed mobility, and cognitive and functional statuses, was conducted also. RESULTS: The majority of residents were Caucasian (82.4%) and women (76.5%) with mean (+/-SD) age of 82.7 +/- 7.58 years. Regional UI prevalence was 65.4% at admission and 74.3% postadmission. Postadmission, 73.5% of Caucasian and 78.1% of African Americans were incontinent. Similarly, 72.2% of men and 75% of women were incontinent. For African Americans postadmission, adjusted odds of UI were OR = 1.07 (95% CI: 1.01, 1.14). DISCUSSION: Prevalence of UI was high in this region and the odds of UI was significantly higher among African Americans in two of eight states, suggesting racial disparity in this condition in these states. Factors contributing to this disparity should be explored to increase quality care to vulnerable populations.

Perceptions of participation in an observational epidemiologic study of cancer among African Americans.

PURPOSE: Recruitment and retention of African Americans in cancer research studies has become increasingly important. However, little is known about factors bearing on recruitment and retention in etiologic observational studies of cancer. We assessed perceptions and attitudes of African Americans towards participation in an observational epidemiologic study of cancer, and attitudes toward the data collection process. METHODS: Five focus groups, each lasting approximately 2 hours, were conducted. Participants were comprised of men and women between 41-65 years of age. A total of 35 adults from three rural and two urban counties in North Carolina participated. Data were analyzed using NVivo software. RESULTS: Four key themes emerged on the perception of participation and retention in an epidemiologic study of cancer: (1) fear of cancer prognosis; (2) conflicts between mistrust and trust in researchers; (3) comprehension of prospective study purpose, structure, and participation strategies; and (4) the necessity for and obligation to provide feedback. CONCLUSION: Results indicate that African Americans would be willing to participate in epidemiologic studies to identify etiologic risk factors for cancer. However, culturally appropriate efforts to thoroughly inform them of study process and progress are deemed essential for successful recruitment and retention.