Ana F. Best

Trends in premature mortality in the USA by sex, race, and ethnicity from 1999 to 2014: an analysis of death certificate data

BACKGROUND Reduction of premature mortality is a UN Sustainable Development Goal. Unlike other high-income countries, age-adjusted mortality in the USA plateaued in 2010 and increased slightly in 2015, possibly because of rising premature mortality. We aimed to analyse trends in mortality in the USA between 1999 and 2014 in people aged 25-64 years by age group, sex, and race and ethnicity, and to identify specific causes of death underlying the temporal trends. METHODS For this analysis, we used cause-of-death and demographic data from death certificates from the US National Center for Health Statistics, and population estimates from the US Census Bureau. We estimated annual percentage changes in mortality using age-period-cohort models. Age-standardised excess deaths were estimated for 2000 to 2014 as observed deaths minus expected deaths (estimated from 1999 mortality rates). FINDINGS Between 1999 and 2014, premature mortality increased in white individuals and in American Indians and Alaska Natives. Increases were highest in women and those aged 25-30 years. Among 30-year-olds, annual mortality increases were 2·3% (95% CI 2·1-2·4) for white women, 0·6% (0·5-0·7) for white men, and 4·3% (3·5-5·0) and 1·9% (1·3-2·5), respectively, for American Indian and Alaska Native women and men. These increases were mainly attributable to accidental deaths (primarily drug poisonings), chronic liver disease and cirrhosis, and suicide. Among individuals aged 25-49 years, an estimated 111 000 excess premature deaths occurred in white individuals and 6600 in American Indians and Alaska Natives during 2000-14. By contrast, premature mortality decreased substantially across all age groups in Hispanic individuals (up to 3·2% per year), black individuals (up to 3·9% per year), and Asians and Pacific Islanders (up to 2·6% per year), mainly because of declines in HIV, cancer, and heart disease deaths, resulting in an estimated 112 000 fewer deaths in Hispanic individuals, 311 000 fewer deaths in black individuals, and 34 000 fewer deaths in Asians and Pacific Islanders aged 25-64 years. During 2011-14, American Indians and Alaska Natives had the highest premature mortality, followed by black individuals. INTERPRETATION Important public health successes, including HIV treatment and smoking cessation, have contributed to declining premature mortality in Hispanic individuals, black individuals, and Asians and Pacific Islanders. However, this progress has largely been negated in young and middle-aged (25-49 years) white individuals, and American Indians and Alaska Natives, primarily because of potentially avoidable causes such as drug poisonings, suicide, and chronic liver disease and cirrhosis. The magnitude of annual mortality increases in the USA is extremely unusual in high-income countries, and a rapid public health response is needed to avert further premature deaths. FUNDING US National Cancer Institute Intramural Research Program.

Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort.

Li‐Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome characterized by a very high lifetime cancer risk and an early age at diagnosis of a wide cancer spectrum. Precise estimates for the risk of first and subsequent cancers are lacking.

Baseline Surveillance in Li-Fraumeni Syndrome Using Whole-Body Magnetic Resonance Imaging: A Meta-analysis

Importance Guidelines for clinical management in Li-Fraumeni syndrome, a multiple-organ cancer predisposition condition, are limited. Whole-body magnetic resonance imaging (WBMRI) may play a role in surveillance of this high-risk population. Objective To assess the clinical utility of WBMRI in germline TP53 mutation carriers at baseline. Data Sources Clinical and research surveillance cohorts were identified through the Li-Fraumeni Exploration Research Consortium. Study Selection Cohorts that incorporated WBMRI for individuals with germline TP53 mutations from January 1, 2004, through October 1, 2016, were included. Data Extraction and Synthesis Data were extracted by investigators from each cohort independently and synthesized by 2 investigators. Random-effects meta-analysis methods were used to estimate proportions. Main Outcomes and Measures The proportions of participants at baseline in whom a lesion was detected that required follow-up and in whom a new primary malignant neoplasm was detected. Results A total of 578 participants (376 female [65.1%] and 202 male [34.9%]; mean [SD] age, 33.2 [17.1] years) from 13 cohorts in 6 countries were included in the analysis. Two hundred twenty-five lesions requiring clinical follow-up were detected by WBMRI in 173 participants. Sixty-one lesions were diagnosed in 54 individuals as benign or malignant neoplasms. Overall, 42 cancers were identified in 39 individuals, with 35 new localized cancers treated with curative intent. The overall estimated detection rate for new, localized primary cancers was 7% (95% CI, 5%-9%). Conclusions and Relevance These data suggest clinical utility of baseline WBMRI in TP53 germline mutation carriers and may form an integral part of baseline clinical risk management in this high-risk population.

Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia

PurposeTo characterize the spectrum of germline mutations in BRCA1, BRCA2, and PALB2 in population-based unselected breast cancer cases in an Asian population.MethodsGermline DNA from 467 breast cancer patients in Sarawak General Hospital, Malaysia, where 93% of the breast cancer patients in Sarawak are treated, was sequenced for the entire coding region of BRCA1; BRCA2; PALB2; Exons 6, 7, and 8 of TP53; and Exons 7 and 8 of PTEN. Pathogenic variants included known pathogenic variants in ClinVar, loss of function variants, and variants that disrupt splice site.ResultsWe found 27 pathogenic variants (11 BRCA1, 10 BRCA2, 4 PALB2, and 2 TP53) in 34 patients, which gave a prevalence of germline mutations of 2.8, 3.23, and 0.86% for BRCA1, BRCA2, and PALB2, respectively. Compared to mutation non-carriers, BRCA1 mutation carriers were more likely to have an earlier age at onset, triple-negative subtype, and lower body mass index, whereas BRCA2 mutation carriers were more likely to have a positive family history. Mutation carrier cases had worse survival compared to non-carriers; however, the association was mostly driven by stage and tumor subtype. We also identified 19 variants of unknown significance, and some of them were predicted to alter splicing or transcription factor binding sites.ConclusionOur data provide insight into the genetics of breast cancer in this understudied group and suggest the need for modifying genetic testing guidelines for this population with a much younger age at diagnosis and more limited resources compared with Caucasian populations.

Premature mortality projections in the USA through 2030: a modelling study

BACKGROUND Although life expectancy has been projected to increase across high-income countries, gains for the USA are anticipated to be among the smallest, and overall US death rates actually increased from 2014 to 2015, with divergence for specific US populations. Therefore, projecting future premature mortality is essential for clinical and public health service planning, curbing rapidly increasing causes of death, and sustaining progress in declining causes of death. We aimed to project premature mortality (here defined as deaths of individuals aged 25-64 years) trends through 2030, and to estimate the total number of projected deaths, the projected number of potential years of life lost due to premature mortality, and the effect of reducing projected accidental death rates by 2% per year. METHODS We obtained death certificate data for the US population aged 25-64 years for 1990-2015 from the US Centers for Disease Control and Prevention (CDC) National Center for Health Statistics. We obtained US mortality data for 2016 for non-American Indian or Alaska native groups from CDC WONDER; data for 2016 were not available for American Indians or Alaska natives. Our analysis focused on all-cause premature mortality and the commonest causes of premature death (cancer, heart disease, accidents, suicide, and chronic liver disease or cirrhosis) among white, black, Hispanic, Asian or Pacific islanders, and American Indian or Alaska native men and women. We estimated age-standardised premature mortality and corresponding annual percentage changes for 2017-30 by sex and race or ethnic origin by use of age-period-cohort forecasting models. We also did a sensitivity analysis projecting future mortality from cross-sectional mortality and a JoinPoint of the (log) period rate ratio curve. We calculated absolute death counts by use of corresponding age-specific and year-specific US census population projections, and estimated years of potential life lost. FINDINGS During 2017-30, all-cause deaths are projected to increase among white women and American Indians or Alaska natives, resulting in 239 700 excess premature deaths relative to 2017 rates (a 10% increase). Mortality declines in white men and black, Hispanic, and Asian or Pacific islander men and women will result in 945 900 fewer deaths (a 14% reduction). Cancer mortality rates are projected to decline among white, black, Hispanic, and Asian or Pacific islander women and men, with the largest declines among black women (age-standardised premature mortality rate 2016: 104·5 deaths per 100 000 woman-years; 2030: 77·1 per 100 000 woman-years) and men (2016: 116·8 per 100 000 man-years; 2030: 81·6 per 100 000 man-years). Heart disease death rates are projected to increase in American Indian or Alaska native men (2015: 150·9 per 100 000 man-years; 2030: 175·9 per 100 000 man-years) and decline in other groups, albeit only slightly in white (2016: 35·6 per 100 000 woman-years; 2030: 31·1 per 100 000 woman-years) and American Indian or Alaska native women (2015: 64·4 per 100 000 woman-years; 2030: 62·8 per 100 000 woman-years). Accidental death rates are projected to increase in all US populations except Asian or Pacific islander women, and will increase most rapidly among white women (2030: 60·5 per 100 000 woman-years) and men (2030: 101·9 per 100 000 man-years) and American Indian or Alaska native women (2030: 97·5 per 100 000 woman-years) and men (2030: 298·7 per 100 000 man-years). Suicide rates are projected to increase for all groups, and chronic liver disease and cirrhosis deaths are projected to increase for all groups except black men. A 2% per year reduction in projected accidental deaths would eliminate an estimated 178 700 deaths during 2017-30. INTERPRETATION To reduce future premature mortality, effective interventions are needed to address rapidly rising mortality rates due to accidents, suicides, and chronic liver disease and cirrhosis. FUNDING National Cancer Institute Intramural Research Program.

Infant and Youth Mortality Trends by Race/Ethnicity and Cause of Death in the United States

Importance The United States has higher infant and youth mortality rates than other high-income countries, with striking disparities by racial/ethnic group. Understanding changing trends by age and race/ethnicity for leading causes of death is imperative for focused intervention. Objective To estimate trends in US infant and youth mortality rates from 1999 to 2015 by age group and race/ethnicity, identify leading causes of death, and compare mortality rates with Canada and England/Wales. Design, Setting, and Participants This descriptive study analyzed death certificate data from the US National Center for Health Statistics, Statistics Canada, and the UK Office of National Statistics for all deaths among individuals younger than 25 years. The study took place from January 1, 1999, to December 31, 2015, and analyses started in September 2017. Exposures Race/ethnicity. Main Outcomes and Measures Average annual percent changes in mortality rates from 1999 to 2015 and absolute rate change between 1999 to 2002 and 2012 to 2015 for each age group, race/ethnicity, and cause of death. Results Among individuals from birth to age 24 years, 1 169 537 deaths occurred in the United States, 80 540 in Canada, and 121 183 in England/Wales from 1999 to 2015. In the United States, 64% of deaths occurred in male individuals and 52.6% occurred in white individuals (25.1% deaths occurred in black individuals and 17.9% in Latino individuals). All-cause mortality declined for all age groups (infants younger than 1 year [38.5% of deaths], children aged 1-9 years [10.6%], early adolescents aged 10-14 years [5%], late adolescents aged 15-19 years [17.7%], and young adults aged 20-24 years [28.1%]) in the United States, Canada, and England/Wales from 1999 to 2015. However, rates were highest in the United States. Within the United States, annual declines in all-cause mortality rates occurred among all age groups of black, Latino, and white individuals, except for white individuals aged 20 to 24 years, whose rates remained stable. Mortality rates declined across most major causes of death from 1999 to 2002 and 2012 to 2015, with notable declines observed for sudden infant death syndrome, unintentional injury death, and homicides. Among infants, unintentional suffocation and strangulation in bed increased (difference between 2012-2015 and 1999-2002 range, 6.11-29.03 per 100 000). Further, suicide rates among Latino and white individuals aged 10 to 24 years (range, 0.21-2.63 per 100 000) and black individuals aged 10 to 19 years (range, 0.10-0.45 per 100 000) increased, as did unintentional injury deaths in white young adults (0.79 per 100 000). The rise in unintentional injury deaths is attributed to increases in drug poisonings and was also observed in black and Latino young adults. Conclusions and Relevance Mortality rates in the United States have generally declined for infants and youths from 1999 to 2015 owing to reductions in sudden infant death syndrome, unintentional injury death, and homicides. However, US mortality rates remain higher than Canada and England/Wales, with particularly elevated rates among black and American Indian/Alaskan Native youth. Further, there is a concerning increase in suicide and drug poisoning death rates among US adolescents and young adults.

Abstract 5231: Multiple myeloma will become a common cancer in the era of modern therapy

INTRODUCTION: Multiple myeloma (MM) is the second most common hematological malignancy in the United States (US), representing 1.4% of all newly diagnosed cancers. The annual number of new MM patients is expected to increase primarily because the population is ageing. In parallel, several new drugs with unprecedented efficacy have been approved by the FDA. We were motivated to use data from the Surveillance, Epidemiology, and End Results (SEER) Program and statistical models to estimate future numbers of MM survivors in the era of modern therapy. METHODS: We estimated future MM incidence using age-period-cohort forecasting models. We estimated all-cause mortality rates by years-since-MM-diagnosis, for cohorts of incident cases defined by age-at-diagnosis and year-of-diagnosis; here we used a proportional hazards absolute risk model with age, year, and duration effects specified using linear splines. We calculated current and future prevalence rates based on observed and extrapolated SEER incidence and mortality. We calculated corresponding numbers of MM survivors in the US by multiplying prevalence rates by official observed and projected population counts. We projected life year gains among persons with MM from prevalence forecasts incorporating more and less favorable assumptions about MM prognosis. RESULTS: We analyzed MM among black and white men and women using 1992 - 2010 SEER data and forecast to 2022. Qualitative patterns were similar in each group. As previously reported, incidence was stable or slightly increasing and highest among black men. However, survival improved in all groups between 1992 through 2010. For example, among white men aged 60-69 years at diagnosis, median survival after MM increased from 2.6 to 5.0 years. If progress continues at the same rate - a conservative assumption in light of recent advances - the projected median will increase to 7.6 years circa 2022. Among black and white men and women ages 40 - 79 years combined, the number of new MM cases is expected to increase by 28%, from 16,000 to 21,000, primarily because of population growth. However, the number of persons living with MM is conservatively expected to increase by 55%, from 76,000 to 119,000, because of improvements in prognosis as well as population growth. The cumulative life year gain between 2011 through 2022 is around 50,000 life years. If recent treatments are as promising as they appear, these estimates will be conservative. CONCLUSION: Driven by access to modern therapies with unprecedented efficacy, overall survival for patients with MM will continue to improve significantly. Consequently, our forecast is MM will become much more common in the era of modern therapy. The numbers of patients living with MM are expected to increase more quickly than the corresponding numbers of new cases. Citation Format: Philip S. Rosenberg, Ana Best, William F. Anderson, Ola Landgren. Multiple myeloma will become a common cancer in the era of modern therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5231.