Risk of seizures in a population of women with BRCA-positive metastatic breast cancer from an electronic health record database in the United States.

BACKGROUND: Incidence and risk factors for seizures among women with advanced breast cancer (BC) and brain metastases are not well characterized across treatment-related or clinical subtypes. This study leveraged a large real-world dataset to describe incidence and risk factors for seizures in BRCA-associated metastatic breast cancer. METHODS: The Optum® de-identified electronic health records database was used. Females with a BC diagnoses between 2008 and 2018, with clinic visits 12 months before BC index date, evidence of BRCA mutation (BRCA+), evidence of metastasis, and no previous cancers were included. Analyses were stratified by the overall BRCA+ cohort and 4 molecular phenotypes: HER2+/HR- (human epidermal growth factor 2/hormone receptor), HER2-/HR+, HER2+/HR+, and triple negative BC (TNBC; HER2-/HR-). Seizures were identified using diagnosis codes and natural language processing. Incidence, occurrence rates, and cumulative incidence of seizures from the diagnosis of metastasis to the end of follow up were calculated. Comparisons were made between phenotypes and stratified on PARP inhibitor use, diagnosed brain metastases, history of seizures, and anticonvulsants use before BC. All comparisons included age at metastasis, number of prior lines of treatment, and metastasis location as covariates. RESULTS: 27.8% of 7941 BRCA+ patients had ≥1 seizure over a mean follow-up time of 2.35 years. Incidence and occurrence rates were 11.83 (95% CI: 11.35-12.33) and 201.3 (95% CI: 198.05-204.50), respectively, per 100 person-years. HER2-/HR+ and TNBC patients had the lowest and highest seizure incidence rates, respectively (10.94 [95% CI: 10.23-11.71] and 16.83 [95% CI: 15.34-18.46]). With HER2-/HR+ as the reference group in a competing risk analysis, TNBC (hazard ratio, HR = 1.35; 95%CI: 1.21, 1.52; p < 0.001) and HER2+/HR- (HR = 1.29; 95%CI: 1.07, 1.56; p < 0.01) patients had a greater risk of seizures. Patients with diagnosed brain metastases or a history of seizures had higher seizure rates. Incidence trended higher with PARP inhibitor use, but patient numbers were low. CONCLUSIONS: This study provides novel real-world evidence on seizure incidence rates in BRCA+ BC patients, even those without diagnosed brain metastases, and underscores the need to understand patients' tumor phenotypes when assessing seizure risk. These findings may have implications for clinical practice and assessment of benefit-risk ratios of new therapeutic agents.

BRCA testing and outcomes in women with breast cancer.

MAIN PURPOSE: Germline BRCA mutations (BRCAm) strongly influence the risk of developing breast cancer. This study aimed to understand the role of BRCAm testing in affected individuals and to assess its impact on the outcome of BRCAm carriers compared to non-carriers (BRCAwt) with breast cancer. RESEARCH QUESTION: The research question is "Does standard of care testing for BRCAm improve survival outcomes of breast cancer patients?" METHODS: In a single institution observational cohort study, demographic and clinical characteristics were compared between breast cancer patients with and without BRCAm. Frequency of BRCA testing was assessed. Survival outcomes were assessed by initial treatment setting stratified by BRCA status. RESULTS: Of 5712 identified women with breast cancer, 14.6% (n = 835) were tested for a BRCA mutation and had a documented result. The total number and proportion of women tested for a BRCAm increased between 2000 and 2014, resulting in an increased number of BRCAm carriers identified. However, the proportion of women who underwent testing and had a BRCAm decreased during the study period from 27.5% in 2000-2004 to 13.3% in 2010-2014. Disease-free survival was similar in the adjuvant and neoadjuvant treatment settings between BRCAm and BRCAwt patients. Progression-free survival on first line treatment and overall survival for patients with metastatic disease was also similar between BRCAm and BRCAwt patients. CONCLUSIONS: The proportion of women tested and the number of BRCAm identified increased during the study period despite a decreasing proportion of positive results among women tested.

Impact of primary platinum-free interval and BRCA1/2 mutation status on treatment and survival in patients with recurrent ovarian cancer.

OBJECTIVE: To understand the relationship between primary platinum-free interval (PFI), BRCA mutation status, and overall survival (OS) in patients with recurrent ovarian cancer receiving multiple lines of therapy in a multicenter, community-based, retrospective observational cohort study of adult patients with stage III-IV high-grade ovarian cancer. METHODS: Data were retrospectively obtained from the electronic health record (EHR) of a US community oncology network, including patient characteristics, subsequent treatments, primary PFI, and BRCA status. OS was analyzed by the Kaplan-Meier method, stratified by primary PFI and BRCA status. RESULTS: 750 patient charts were reviewed. BRCA testing status was known in 267 patients (16% BRCA mutation). Among patients with identified recurrent disease, 41% had a primary PFI <6months and 59% had a primary PFI ≥6months. Of second-line patients, 59% received third-line therapy, and 60% of third-line patients received fourth-line therapy within the period of observation. Median OS from the start of primary treatment for the entire population was 41.4months (95% CI, 39.0-48.3months). Median OS was significantly increased in patients with primary PFI ≥6months at second-line and third-line (P<0.0001 and P=0.002, respectively). Survival was observed to be increased among patients with BRCA mutations across multiple treatment lines, although this was not statistically significant. CONCLUSIONS: Patients with a primary PFI ≥6months demonstrated improved outcomes over multiple lines of therapy. BRCA status was known in 36% of patients, and those patients with a BRCA mutation demonstrated a trend toward delayed primary recurrence and improved clinical outcomes.

Comparison Between Health Insurance Claims and Electronic Health Records (EHRs) for Metastatic Non-small-cell Lung Cancer (NSCLC) Patient Characteristics and Treatment Patterns: A Retrospective Cohort Study.

BACKGROUND: The clinical landscape in non-small-cell lung cancer (NSCLC) treatment has rapidly evolved in recent years. Real-world data (RWD) can provide insights into current clinical practice. OBJECTIVE: This study examined the patient characteristics and treatment patterns of patients with metastatic NSCLC using RWD sources. METHODS: This was a retrospective cohort study using health insurance claims and electronic health records (EHRs). Adult patients treated for metastatic NSCLC during the period 2017 to September 2020 were followed from the earliest treatment date until a censoring event. RESULTS: The claims cohort included 7917 patients with a mean age of 70 years and a mean follow-up period of 373 days. The EHR cohort included 7087 patients with a mean age of 67 years and a mean follow-up period of 362 days. The five most common first-line therapies (LoT1) were the same for both cohorts: carboplatin + paclitaxel, pembrolizumab, carboplatin + pemetrexed + pembrolizumab, cisplatin + pemetrexed, and nivolumab. Mean LoT1 durations were 146 and 147 days in the claims and EHR cohorts, respectively. For patients who received a second LoT (LoT2), the five most common LoT2 were also the same in both cohorts: durvalumab, nivolumab, pembrolizumab, carboplatin + pembrolizumab + pemetrexed, and carboplatin + pemetrexed. Mean LoT2 durations were 157 and 158 days in the claims and EHR cohorts, respectively. CONCLUSIONS: LoTs between the claims and EHR cohorts were comparable and showed similar treatment patterns. Traditional platinum-containing chemotherapy was most common in LoT1, whereas programmed cell death protein-1 inhibitors became the most common choices in LoT2. Our findings suggest that RWD can reliably provide up-to-date insight into current treatment modalities and indicate that new clinical evidence is rapidly adopted in patients with NSCLC.

Incidence and Risk Factors of Pneumonitis in Patients with Non-Small Cell Lung Cancer: An Observational Analysis of Real-World Data.

INTRODUCTION: The incidence of pneumonitis, a treatment-related adverse event (AE) in non-small cell lung cancer (NSCLC) patients, has been studied in the United States mostly through clinical trials and retrospective chart reviews. Few analyses of real-world data have been published. This study of a large nationally representative health records database estimated the incidence and predictors of pneumonitis among treated NSCLC patients between 2008 and 2018. METHODS: The Optum® electronic health records (EHR) database includes data on over 80 million patients from more than 50 healthcare plans. The cohort of primary NSCLC patients was identified using ICD-9/10 codes. Natural language processing of unstructured data from physicians' notes facilitated extraction of biomarker (epidermal growth factor receptor [EGFR] and programmed death ligand-1 [PD-L1]) status. Cumulative incidence was estimated as the proportion with pneumonitis overall, by clinical characteristics, and line of therapy (LOT) after diagnosis and treatment. Univariate analysis of incidence rates (cases/1000 person-years) enabled the identification of significant predictors of risk. Competing risk regression identified predictors of pneumonitis. RESULTS: The cohort included 81,628 patients. Overall, 19.0% developed pneumonitis during any LOT, with a cumulative incidence of 33.7% and 17.0% for patients with a prior history of pneumonitis and those without, respectively. Univariate analyses revealed several factors associated with pneumonitis (p < 0.05). While factors varied between LOTs, common factors included male gender, squamous histology, history of diabetes or pneumonitis, EGFR-negative status, monotherapy immunomodulatory drugs, or history of radiation therapy. Multivariable competing risk regression showed that male gender, history of pneumonitis, EGFR-negative status, use of other targeted therapies, use of immunomodulatory drugs, and history of radiation therapy predicted pneumonitis. CONCLUSION: Pneumonitis is significantly associated with NSCLC treatment. Knowledge of its predictors identified in this study may help devise strategies to mitigate its impact, enhancing treatment adherence and improving outcomes.

Pneumonitis is a side effect of non-small cell lung cancer (NSCLC) treatment. Real-world data on its incidence in the United States is not extensive. In this study, the Optum^® electronic health records database with data on over 80 million patients from more than 50 healthcare plans across the United States was used to estimate the incidence and predictors of pneumonitis in NSCLC patients treated between 2008 and 2018. A total of 81,628 NSCLC patients were identified using disease-specific codes. Physicians' notes in their health records were subjected to natural language processing to identify presence of epidermal growth factor receptor (EGFR) and programmed death ligand-1 (PD-L1) receptors in tumors. Proportions of patients with pneumonitis overall, by clinical characteristics, and line of therapy (LOT) were calculated. Univariate analysis of incidence (cases per 1000 person-years) a multivariable competing risk regression helped identify risk predictors. Overall, 19.0% of patients developed pneumonitis during any LOT. Incidence was 33.7% and 17.0% in patients with and without prior pneumonitis, respectively. Univariate analysis revealed factors associated with pneumonitis, including male gender, squamous histology, history of diabetes or pneumonitis, EGFR-negative status, monotherapy immunomodulatory drugs, or history of radiation therapy. Multivariable competing risks regression analysis showed that male gender, history of pneumonitis, EGFR-negative status, use of other targeted therapies, use of immunomodulatory drugs, and history of radiation therapy were significantly associated with pneumonitis. Pneumonitis is significantly associated with NSCLC treatment. Knowledge of its predictors may help design interventions to lessen its impact, promoting compliance with treatment and improving outcomes.

Risk Minimization of Antibody-Drug Conjugates in Oncology: A Review.

Antibody-drug conjugates (ADCs) are new treatment options for certain cancers, especially those in advanced states with limited treatment options. Their unique design provides targeted therapy with toxins that otherwise would not be available, but they manifest toxicities that require risk minimization interventions to optimize their tolerability. We summarize selected toxicities for ADCs that have been approved through the end of 2020 and three investigational ADCs, which include both payload and linker, as described in the US Prescribing Information, the European Summary of Product Characteristics, and study protocols. These toxicities include peripheral neuropathy; pulmonary, skin, hepatic, and ocular toxicities; hyperglycemia; left ventricular dysfunction; and fluid-related events. We also review the risk minimization approaches to managing these toxicities as described in the product labels and study protocols. Our general observation suggests that the selected toxicities of the approved ADCs are primarily associated with off-target effects of the drug payloads. We also observed that the risk minimization approaches used to manage the selected toxicities are similar across product labels and study protocols. ADCs provide a unique treatment approach that is currently focused on advanced or refractory cancers. The risk minimization approaches for the selected toxicities for the approved ADCs per product label, or the study protocol for those in clinical investigation, are similar to those of standard chemotherapy agents and other pharmaceutical agents for the treatment of advanced malignancies. These risk minimization measures align with standard medical practice and are likely familiar to and feasible for physicians who prescribe for, and to other healthcare practitioners who care for, patients treated with ADCs.

Clinical outcomes of female breast cancer according to BRCA mutation status.

BACKGROUND: To investigate breast cancer prognosis (disease-free (DFS) and overall survival (OS)) among carriers of germline BRCA mutations (BRCAm) in Denmark. METHODS: We identified all women in Central and Northern Denmark diagnosed with breast cancer during 2004-2011. We retrieved information on germline BRCAm testing from Clinical Genetics departments and clinical/treatment characteristics from population-based medical registries. Follow-up for recurrence, new primary cancer, and mortality extended from 180days after diagnosis until 31/12/2012. We estimated median DFS and OS and five-year cumulative incidence and incidence rates (IR/1000 person-years), and 95% confidence intervals (95% CI), for each outcome. RESULTS: Among 9874 patients, 523 (5%) underwent BRCA testing-90 were BRCAm carriers, 433 were BRCA wildtype (BRCAwt). Compared with BRCAwt women, BRCAm carriers were younger, had lower stage, and ER- and HER2- tumors. Median time from diagnosis to BRCA testing was 0.91 years and 1.3 years in BRCAm and BRCAwt women; median follow-up to first event was 3.9 and 3.4 years, respectively. Five-year DFS and OS were higher in BRCAm than BRCAwt women: 88% (95%CI=78.3-93.5) vs. 75.3% (95%CI=70.2-79.6) and 97.8% (95%CI=91.4-99.4) vs 92.2% (95%CI=88.5-94.7), respectively. Five-year IRs of recurrence were 36.7/1000 person-years (95%CI=15.8-72.2) in the BRCAm cohort vs. 58.4 (95%CI=42.9-77.6) in the BRCAwt cohort. CONCLUSIONS: BRCAm carriers may have a better prognosis than BRCAwt women. However, limited testing conducted mainly during follow-up, yielded low numbers for precise estimations, and may be attributable to selection bias.

Why do postmenopausal African-American women not benefit from overall breast cancer mortality decline?

BACKGROUND: An overall decline in U.S. female breast cancer mortality in the 1990s has been reported. However, several studies have shown that mortality trends are different for White women and African-American (AA) women. The purpose of this study was to assess differences in time trends and patterns of female breast cancer mortality among women by race and age in Ohio. MATERIAL AND METHODS: Joinpoint regression (JR) and age-period-cohort (APC) approaches were used to evaluate temporal changes in mortality and to assess period and birth generation impacts on observed patterns. Logistic regression was used to assess racial differences in tumor staging and grading among women diagnosed with breast cancer in Ohio from 1996 to 2000. Mortality data were obtained from NCHS (National Center for Health Statistics) via Surveillance Research Program, National Cancer Institute SEER*Stat software; Ohio incidence data were provided by the Ohio Cancer Incidence Surveillance System. RESULTS: Among women aged 30-74, a significant decline of 2.8% was noted since 1988 for White women. AA women in this age group have experienced significant decline (by 0.9%) since 1983. White women aged 30-39 years experienced a decline in mortality of 3.5% per year in the period 1986-2001, while decline by 2.3% was observed among Black women of that age since 1984. Among the age categories 40-49, 50-59, and 60-74, a decline in mortality rates was observed among White women in the 1990s. The decline was observed also among AA women aged 40-49, beginning in the mid 1980s, but not in the older AA age groups. Specifically, in AA women 60-74 and 75+, a mortality increase was observed within the entire study period (0.9% and 1.4%, respectively). CONCLUSIONS: Analysis of the data for Ohio suggests that AA women do not equally benefit from the overall decline in breast cancer mortality that is often sited. This is especially true for AA postmenopausal women who continue to experience an increase in breast cancer mortality. In light of existing literature and this analysis of data from the state of Ohio, we conclude that the reason for these differences lies mostly in disparities in access to care, as well as in differences in stage at diagnosis and biological determinants (grading) between White and Black women.

BRCA testing, treatment patterns and survival in platinum-sensitive recurrent ovarian cancer - an observational cohort study.

BACKGROUND: Breast cancer associated (BRCA) genes are critical for DNA repair. Mutations in BRCA1 and BRCA2 (BRCAm) result in loss of these repair mechanisms and potential carcinogenesis. Germline BRCAm are common in ovarian carcinomas, particularly in platinum-sensitive disease. The increased prevalence of BRCAm in platinum-sensitive disease is likely due to enhanced responsiveness to platinum chemotherapy from homologous recombination repair deficiency. The purpose of this study was to explore BRCA testing, treatment patterns and survival in platinum-sensitive recurrent (PSR) ovarian cancer. METHODS: This was an observational cohort analysis of PSR ovarian cancer treated at the Huntsman Cancer Institute from 1995 to 2012. Germline BRCA status was ascertained through chart review and categorized as BRCAm (BRCA1/2 positive), BRCAwt (BRCA wild type or variant of uncertain significance), and untested. Treatment patterns and survival were assessed from recurrence until death or last follow-up. The Kaplan-Meier method was used to evaluate survival from recurrence by BRCA status. Logistic regression and COX proportional hazard model was used to estimate predictors of BRCA testing and survival, respectively. RESULTS: Of the 168 PSR patients, 15 (9 %) were BRCAm, 25 (15 %) were BRCAwt, and 128 (76 %) were untested. Median age at PSR was 56 years for BRCAm and BRCAwt (p = 0.90) and 63 years for those untested (p = 0.033 vs BRCAm). Overall survival was similar between BRCAm and BRCAwt (median 50.4 vs 67.5 months, p = 0.86) and was 24.9 months in untested patients. Significant predictors for the likelihood of BRCA testing were age (OR = 0.93, 95 % CI 0.89, 0.97, p = 0.002), family history of breast or ovarian cancer (OR = 8.33, 95 % CI: 3.08, 22.59, p < 0.001), and cancer diagnosis year (OR = 10.02, 95 % CI: 3.22, 31.21, p < 0.001). BRCA-tested patients had a lower risk of death versus untested (HR 0.35, 95 % CI 0.17, 0.68, p = 0.001). CONCLUSIONS: BRCAwt patients had similar outcomes to BRCAm patients, potentially owing to similar age at diagnosis, representing a BRCA testing channeling bias. Younger patients, those with a family history of breast or ovarian cancer, and those diagnosed more recently were more likely to be BRCA tested. BRCA tested patients had a lower risk of death.

Selecting Patients with Ovarian Cancer for Germline BRCA Mutation Testing: Findings from Guidelines and a Systematic Literature Review.

INTRODUCTION: One of the most significant risk factors for the development of ovarian cancer (OC) is a genetic mutation in BRCA1 (breast cancer gene 1) or BRCA2. Here we describe the impact of previous and current guidance on BRCA testing practices and provide evidence about which characteristics best identify patients with OC and an underlying germline BRCA mutation. METHODS: A search was conducted for guidelines recommending genetic testing to identify constitutional pathogenic mutations in the BRCA genes. In addition, a systematic literature search of studies published in 2003-2015 was performed to assess BRCA mutation frequency in population-based OC patients unselected for patient characteristics (personal history, family history, and Ashkenazi Jewish ethnicity) and to describe the association of patient characteristics with BRCA mutation. Exclusively, studies assessing epithelial OC or invasive epithelial OC with full-gene screening of both BRCA1 and BRCA2 mutations were evaluated. RESULTS: Of 15 guidelines recommending genetic testing for OC patients, only 5 do not require co-occurrence of specific patient or family characteristics. Twenty-two full publications were identified that assessed germline BRCA mutation frequency in women with OC, utilizing a range of different full mutation detection methods. Germline BRCA mutation prevalence in patients with OC was 5.8-24.8%. Using criteria recommended in guidelines that are yet to be updated, we estimated that 27.5% of all germline BRCA mutations present in patients with OC may be missed because patients do not meet appropriate criteria. CONCLUSION: With the availability of BRCA mutation-targeted therapies, identification of patients with OC with germline BRCA mutations has potential therapeutic consequences. For identified gene carriers, predictive testing to allow cancer prevention strategies, including bilateral salpingo-oophorectomy, provides wider benefit to identifying such gene carriers. Updating guidelines will increase the opportunity for targeted treatment among patients and risk reduction in relatives. FUNDING: AstraZeneca.

Mortality from lung cancer and tobacco smoking in Ohio (U.S.): will increasing smoking prevalence reverse current decreases in mortality?

BACKGROUND: Despite significant changes in smoking patterns within the past few decades, lung cancer remains a major cause of cancer deaths in many developed countries in people of each sex, and one of the most important public health issues. The study aims to analyze the possible impact of changes in tobacco smoking practices in the state of Ohio (U.S.) on current and future trends and patterns of lung cancer mortality. MATERIALS AND METHODS: Mortality rates from lung cancer were calculated for the period 1970 to 2001 on the basis of data from the National Center for Health Statistics. The Joinpoint regression approach was used to evaluate changes in time trends by sex, age, and race. Data on smoking prevalence in Ohio were retrieved from the Centers for Disease Control and Prevention website. RESULTS: Lung cancer mortality rates in Ohio have declined among men of all ages as well as in specific age groups in the 1990s, and the rate of increase among middle-aged and elderly women has dropped over time. The mortality rate among young women (ages 20-44) began to increase during the early 1990s. The prevalence of smoking in Ohio has increased since the early 1990s, especially among young persons. CONCLUSIONS: Recent trends in tobacco smoking in Ohio indicate that the declining trends in lung cancer mortality might be reversed in the future. An early indicator of possible change is the recent increase in mortality among young women. Implementation of the Ohio Comprehensive Tobacco Use Prevention Strategic Plan might help to disseminate proven prevention strategies among the inhabitants of Ohio and might thus prevent future increases in lung cancer mortality rates in the state.

Comparison of male and female breast cancer incidence trends, tumor characteristics, and survival.

PURPOSE: To compare male and female breast cancer and to determine the predictors of tumor characteristics and survival in both genders. METHODS: Male (n = 2923) and female breast cancer cases (n = 442,500) from the Surveillance, Epidemiology and End Results (SEER) registry were analyzed. Joinpoint regression was performed to detect changes in incidence trends from 1973 to 2001. Multiple logistic regression was used to regress each of four outcome variables (STAGE, LATERALITY, ESTROGEN, and PROGESTERONE RECEPTOR STATUS) on four demographic variables. Cox proportional hazards regression modeling was used to determine significant predictors of death of breast cancer after adjusting for demographic factors. RESULTS: Both men and women aged less than 50 years were at higher risk for advanced breast cancers. Males were at higher risk than females for advanced tumors among non-whites. The risk of breast cancer death among all cases was lower for each 10-year increase in age by 2%, higher for those who are unmarried than for those who are married by 12% and 13% higher for non-whites than for whites. CONCLUSIONS: Some important gender differences were detected with respect to factors associated with tumor characteristics, but gender was not a significant predictor of survival after adjusting for the other demographic variables.

Long-term all-sites cancer mortality time trends in Ohio, USA, 1970-2001: differences by race, gender and age.

BACKGROUND: There were significant changes in cancer mortality in the USA over the last several decades, in the whole country and in particular states. However, no in depth analysis has been published so far, dealing with changes in mortality time trends in the state of Ohio. Since the state of Ohio belongs to the states of relatively high level of all-sites mortality in both males and females, it is of interest to analyze recent changes in mortality rates, as well as to compare them with the situation in the rest of the USA. The main aim of this study was to analyze, describe and interpret all-sites cancer mortality time trends in the population of the State of Ohio. METHODS: Cancer mortality data by age, sex, race and year for the period 1970-2001 were obtained from the Surveillance Research Program of the National Cancer Institute SEER*Stat software. A joinpoint regression methodology was used to provide estimated annual percentage changes (EAPCs) and to detect points in time where significant changes in the trends occurred. RESULTS: In both, males and females mortality rates were higher in blacks compared with whites. The difference was bigger in males (39.9%) than in women (23.3%). Mortality rates in Ohio are generally higher than average USA rates--an overall difference was 7.5% in men in 1997-2001, and 6.1% in women. All-sites mortality trends in Ohio and in the whole USA are similar. However, in general, mortality rates in Ohio remained elevated compared with the USA rates throughout the entire analyzed period. The exceptions are the rates in young and middle-aged African Americans. CONCLUSION: Although direction of time trends in Ohio are similar in Ohio and the whole US, Ohio still have cancer mortality rates higher than the US average. In addition, there is a significant discrepancy between white and black population of Ohio in all-sites mortality level, with disadvantage for Blacks. To diminish disparities in cancer mortality between African Americans and white inhabitants of Ohio efforts should be focused on increasing knowledge of black people regarding healthy lifestyle and behavioral risk factors, but also on diminishing socioeconomic differences, and last but not least, on better access to medical care.

Epidemiology of Patients with Ovarian Cancer with and Without a BRCA1/2 Mutation.

Ovarian cancer survival rates have improved only slightly in recent decades; however, treatment of this disease is expected to undergo rapid change as strategies incorporating molecular-targeted therapies enter clinical practice. Carriers of deleterious mutations (defined as a harmful mutation) in either the BRCA1 or BRCA2 gene (BRCAm) have a significantly increased risk of developing ovarian cancer. Epidemiology data in large (>500 patients) unselected ovarian cancer populations suggest that the expected incidence rate for BRCAm in this population is 12-14 %. Patients with a BRCAm are typically diagnosed at a younger age than those without a BRCAm. Associations with BRCAm vary according to ethnicity, with women of Ashkenazi Jewish descent being 10 times more likely to have a BRCAm than the general population. In terms of survival, patients with invasive epithelial ovarian cancer who have a BRCAm may have improved overall survival compared with patients who do not carry a BRCAm. Although genetic testing for BRCAm remains relatively uncommon in ovarian cancer patients, testing is becoming cheaper and increasingly accessible; however, this approach is not without numerous social, ethical and policy issues. Current guidelines recommend BRCAm testing in specific ovarian cancer patients only; however, with the emergence of treatments that are targeted at patients with a BRCAm, genetic testing of all patients with high-grade serous ovarian cancer may lead to improved patient outcomes in this patient population. Knowledge of BRCAm status could, therefore, help to inform treatment decisions and identify relatives at increased risk of developing cancer.

Testicular cancer incidence in eight northern European countries: secular and recent trends.

OBJECTIVE: Striking geographic variation and marked increasing secular trends characterize the incidence of testicular cancer. However, it is not known whether these patterns have attenuated in recent years and whether they are similar for seminomas and nonseminomas, the two main histologic groups of testicular cancer. METHOD: Cancer registry data, including 27,030 testicular cancer cases, were obtained from Denmark, Estonia, Finland, Latvia, Lithuania, Norway, Poland, and Sweden. Between 57 (Denmark) and 9 (Poland) years of registration were covered. Country-specific temporal trends were estimated, with focus on the last decade and seminomas and nonseminomas. Data from the Nordic countries were further analyzed using an age-period-cohort approach. RESULTS: Age-standardized incidence rates increased annually by 2.6% to 4.9% during the study period, with marginal differences between seminomas and nonseminomas. In the last decade, the increasing trend attenuated only in Denmark (annual change, -0.3%; 95% confidence interval, -1.5 to 0.9). In 1995, the highest and the lowest age-standardized incidence rates (per 10(5)) were 15.2 in Denmark and 2.1 in Lithuania. Incidence rates (i.e., for all cancers and for seminomas and nonseminomas, separately) depended chiefly on birth cohort rather than on calendar period of diagnosis (although both birth cohort and period determined the Danish incidence rates). CONCLUSIONS: Testicular cancer incidence is still increasing, with the exception of Denmark, and a large geographic difference exists. The increasing trend is mainly a birth cohort phenomenon also in recent cohorts. Temporal trends for seminomas and nonseminomas are similar, which suggests that they share important causal factors.

Safety assessment of an anti-obesity drug (sibutramine): a retrospective cohort study.

BACKGROUND: Obesity is a serious and rapidly growing health problem worldwide. Few therapies are available beyond diet, exercise and bariatric surgery. A previously approved medication, sibutramine, has been withdrawn from the market due to concerns over the potential of increased risk of cardiovascular (CV) events, based on a phase IV clinical trial that included only individuals at high risk for CV events. OBJECTIVE: The aim of the study was to compare sibutramine users and matched non-users on rates of CV events, both overall and stratified by whether the patient qualified for on-label sibutramine use, using data from real-life clinical practice. METHODS: A retrospective cohort was constructed from electronic medical record data from physician office practices (mostly primary care) in the UK and Germany, using the LifeLink™ database from IMS Health Incorporated. For patients with at least one physician visit in which sibutramine was prescribed between 1 April 1999 and 31 October 2008, the date of their first such prescription was their index date. Users and non-users were matched 1 : 1 on index date (within 30 days), sex, age group (six categories), Charlson Comorbidity Index and evidence of obesity (high body mass index [BMI] or, if BMI was missing, diagnosis of obesity or very high weight relative to height). The resultant total samples analysed were 6186 in Germany and 7264 in the UK. User and non-user cohorts in the samples were compared according to the ratio of their crude incidence rates of acute myocardial infarction (AMI), stroke and either AMI or stroke per 1000 patient-years of follow-up. Cox regression analysis was used to compare the risk of CV events as a hazard ratio (HR) with 95% confidence intervals (CIs) between sibutramine user and non-user cohorts, controlling for label status and/or history of prior CV disease at baseline. RESULTS: The risk of AMI, stroke and either AMI or stroke was not higher among sibutramine users than comparable non-users of sibutramine in both Germany and the UK [Germany: HR 0.47 (95% CI 0.17, 1.26), 0.43 (0.23, 0.81) and 0.44 (0.26, 0.75), respectively; UK: HR 0.44 (0.15, 1.31), 0.63 (0.25, 1.60) and 0.54 (0.27, 1.10), respectively]. Regardless of whether or not the model controlled for prior CV disease (CVD), the direction and statistical significance of the differences did not change. In the sensitivity analyses including only those without a history of CVD in the 365 days prior to the index date there was no increased risk of CV events in either Germany or the UK. CONCLUSION: This study offers a framework for the safety assessment of anti-obesity drugs using an observational epidemiological study design. Large electronic health databases were used to construct retrospective cohorts to examine the risk in a population using one specific anti-obesity drug. Use of sibutramine in general practice settings was not found to increase the risk of acute CV events.

Lung cancer in Europe in 2000: epidemiology, prevention, and early detection.

Lung cancer is the most common cancer in the world. In men, the highest incidence rates are seen in Europe (especially eastern Europe) and North America. In women, high incidence rates are found in North America and in Europe, particularly in northern and western Europe. It is estimated that there were about 375000 cases of lung cancer in Europe in 2000; 303000 in men and 72000 in women. The number of resulting deaths was about 347000 (280000 in men and 67000 in women). Tobacco smoking is well established as the main cause of lung cancer and about 90% of cases are thought to be tobacco related. There is a clear dose-response relation between lung-cancer risk and the number of cigarettes smoked per day, degree of inhalation, and age at initiation of smoking. Someone who has smoked all their life has a lung-cancer risk 20-30 times greater than a non-smoker. However, risk of lung cancer decreases with time since smoking cessation. Recently, there has been renewed interest in screening because spiral computerised tomography can detect small asymptomatic lesions more effectively than conventional radiography. Although cure rates for such lesions are very good, there is to date no evidence for effectiveness of mass-screening strategies.

Breast cancer mortality patterns and time trends in 10 new EU member states: mortality declining in young women, but still increasing in the elderly.

Breast cancer is the cancer diagnosed most frequently in women worldwide. In Europe it is the most common cancer in the female population, with approximately 350,000 new cases diagnosed each year including 130,000 deaths. Incidence rates are increasing in the majority of European countries, whereas a decline in mortality rates has been observed in many West European countries since the late 1980s and early 1990s. Our study examines breast cancer mortality patterns and time trends in the new European Union (EU) member states and compares them with the situation in current EU member states. A Joinpoint regression analysis was used to assess temporal changes in mortality rates and the trends examined in the light of known risk factors, screening programs and advances in treatment. In the majority of the countries analyzed, a deceleration in the increase of mortality rates appeared, followed by a decrease of mortality in many of them in the second half of the 1990s. The declining tendency was visible primarily in young women, and to a lesser extent in middle-aged women, whereas in elderly women a continuing increase of mortality was observed. Analysis of mortality data, information from previous publications, as well as analysis of known factors influencing breast cancer risk suggest that changes observed are due mainly to recent advances in treatment rather than changes in lifestyle risk factors or the result of screening programs. Early detection and a shift toward more favorable stage distribution could have played the leading role for mortality decline in younger patients.

Lung cancer mortality patterns in selected Central, Eastern and Southern European countries.

Significant changes in the prevalence of tobacco smoking have been observed in many European countries. EU candidate countries have also experienced major changes with respect to tobacco smoking, which have resulted in changes in the frequency of lung cancer. In men in the majority of these countries, a reduction of mortality rates has been observed recently, while in Hungary and Poland a deceleration of mortality increase was observed in the 1990s. The situation is much less favorable in females, where in the majority of countries a continuous increase of mortality rates has been observed, the only exceptions being Latvia, Lithuania and, to a lesser extent, Estonia. In Hungarian women, an acceleration of the increase rate was observed in the 1980s and 1990s (compared with the 1970s). Patterns of lung cancer mortality in analyzed countries are somewhat similar to those observed in EU member states. Recent analyses of time trends of lung cancer in EU countries showed, in general, a decreasing risk in the majority of male populations and an increase in several countries in women. If the decrease of mortality is to be achieved and maintained in the longer term, efforts have to be focused on young generations (entering adulthood now or in the near future). Despite all the difficulties present in reducing tobacco smoking in youth, it seems that one of the most important ways to reduce the future lung cancer burden in current and new EU member states is to strengthen efforts toward changing smoking attitudes in young generations.