Human papillomavirus-positive oropharynx cancer incidence has increased rapidly in cohorts of US white men born during the 1930s to 1950s. It is unknown how the trajectory of the oropharynx cancer ...epidemic may be changing in the United States.
Using US cancer registry information, we investigated whether increases in oropharynx cancer have continued into recent birth cohorts and forecasted the future burden across age, sex, and race/ethnicity subgroups. Log-linear Joinpoint regression and age-period-cohort models were used to evaluate incidence trends during 1992 to 2015 and projections through 2029.
Among white men, oropharynx cancer incidence increased rapidly in individuals born during 1939 to 1955 (5.3% per 2-year birth cohort; 95% CI, 4.8% to 5.7%), but this rate of increase significantly moderated in individuals born during 1955 to 1969 (1.7% per 2-year birth cohort; 95% CI, 1.0% to 2.4%). Should these birth-cohort trends continue, from 2016 to 2029 we forecast that incidence will increase dramatically in older white men 65 to 74 years of age (from 40.7 to 71.2 per 100,000) and 75 to 84 years of age (from 25.7 to 50.1 per 100,000), moderately in white men 55 to 64 years of age (from 40.3 to 52.0 per 100,000), and remain stable in white men 45 to 54 years of age (approximately 18 per 100,000). Accounting for population growth, we project an increase in annual number of cases in the United States from 20,124 (95% CI, 19,779 to 20,469) in 2016 to 30,629 (95% CI, 29,413 to 31,845) in 2029, primarily driven by older individuals (age ≥ 65 years; from 7,976 95% CI, 7,782 to 8,172 to 18,072 95% CI, 17,271 to 18,895) and white men (from 14,453 95% CI, 14,142 to 14,764 to 22,241 95% CI, 21,119 to 23,364).
The exponential increase in oropharynx cancer incidence in young white US men has ebbed, and modest increases are occurring/anticipated in cohorts born after 1955. Continued strong increases in incidence in cohorts born before 1955, and an approximate 50% increase in size of the US population age 65 years or older through 2029, portend a substantial shift in burden to elderly white men.
Summary 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.
Fanconi anemia (FA) is a genomic instability syndrome with predisposition to congenital abnormalities, bone marrow failure, and cancer. Classical and most frequent congenital abnormalities include ...all those seen in VACTERL-H association and those described under the PHENOS acronym. Pathogenic variants in at least 22 genes are associated with FA, which code for proteins that comprise the FA/BRCA DNA repair pathway. We reviewed 187 publications and 1101 cases of FA in which the gene or complementation group was identified and analyzed those in whom physical findings were sought. We conducted genotype-phenotype analyses considering the specific gene, the location in the FA/BRCA DNA repair pathway, and the type of variant (null or hypomorphic) as exposures. The outcomes were the presence of any physical abnormality or specific categories of abnormalities. Seventy-nine percent of the patients had at least one physical abnormality. Pathogenic variants in FANCB, FANCD2, the ID complex and downstream genes were associated with several specific anomalies. Patients with biallelic or hemizygous null variants had a higher proportion of at least one abnormality, renal malformations, microcephaly, short stature and the combination of VACTERL-H compared with those with hypomorphic genotypes. VACTERL-H alone or in combination with PHENOS is highly associated with FA, but the absence of those features does not rule out the diagnosis of FA.
Background
Family history may inform risks of gastric cancer and preneoplastic lesions.
Methods
We examined associations with history of cancer in first-degree relatives for 307 incident gastric ...cancer cases among 20,720 male smokers in a prospective study in Finland. Cox regression was used to calculate gastric cancer hazard ratios (HR) and 95% confidence intervals (95% CI). Logistic regression was used to estimate odds ratios (OR) and 95% CIs for low serum pepsinogen, a marker of gastric atrophy.
Results
Gastric cancer risk was associated with gastric cancer history in first-degree relatives overall (HR 1.56, 95% CI 1.15–2.12), in fathers (HR 1.67, 95% CI 1.09–2.55) and in siblings (HR 2.05, 95% CI 1.25–3.38). Associations were significant for noncardia (HR 1.83, 95% CI 1.30–2.57) but not cardia (HR 0.93, 95% CI 0.46–1.87) cancers, and marginal for both intestinal—(HR 1.53, 95% CI 0.92–2.55) and diffuse-type (HR 1.47, 95% CI 0.72–3.03) histologies. Family history of other cancer types was not associated with gastric cancer risk. Family history of gastric cancer was associated with low pepsinogen (OR 1.29, 95% CI 1.11–1.50).
Conclusions
Family history of gastric cancer is strongly associated with specific subtypes of gastric cancer as well as with gastric atrophy, a risk factor for developing this malignancy.
Li-Fraumeni syndrome, caused primarily by pathogenic or likely pathogenic germline TP53 variants, is a rare, variably penetrant, cancer predisposition syndrome with very high risks of cancer starting ...in childhood, including the risk of multiple primary malignancies over an individual's lifespan. We aimed to characterise and quantify cancer incidence, patterns, and genotype–phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants.
This observational cohort study was done in 480 carriers of pathogenic or likely pathogenic germline TP53 variants enrolled in the National Cancer Institute's referral-based longitudinal Li-Fraumeni syndrome study between Aug 1, 2011, and March 24, 2020. Data on personal and family history of cancer were obtained through study questionnaires and validated by medical records. Variants were categorised on the basis of both loss-of-function (LOF) and dominant-negative effect (DNE) properties. Cancer incidence associated with Li-Fraumeni syndrome was compared with that of the general population using the Surveillance, Epidemiology, and End Results (SEER) 1975–2017 registry. Cancer incidence was evaluated with family-clustered Cox regression models and competing risk methods. This study is registered with ClinicalTrials.gov, NCT01443468.
Individuals with Li-Fraumeni syndrome had a nearly 24 times higher incidence of any cancer than the general population (standardised incidence ratio 23·9; 95% CI 21·9–26·0), with the highest comparative incidence from childhood to 30 years of age. The overall cancer incidence remained 10·3 (95% CI 7·9–13·2) times higher than that of the general population after age 50 years. In women, when considering breast cancer as a competing risk, the probability of a first diagnosis of a non-breast cancer malignancy was substantially lower than that of any first cancer (24·4% 95% CI 19·6–30·5 vs 50·4% 43·5–56·5 by age 33·7 years). Overall, DNE_LOF and notDNE_LOF variants were associated with earlier age at first and second cancer compared with notDNE_notLOF and DNE_notLOF variants. The time interval from first to second cancer was shorter among carriers whose first cancer diagnoses were later in life. Multiple cancers were diagnosed within a short timeframe in some individuals, regardless of the order of cancer occurrence.
This study adds granularity to the understanding of cancer incidence and patterns in individuals with pathogenic or likely pathogenic germline TP53 variants. Integration of age range-specific cancer incidence estimates, cancer-free survival by functional variant group, the potential impact of risk-reducing mastectomy on female cancer incidence, and data on subsequent malignancies will be important for the development of strategies to optimise cancer screening and management for these individuals.
Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Institutes of Health.
Background
Participation of adolescents and young adults (AYAs) in oncology clinical trials is important to ensure adequate opportunities for AYA patients to contribute to, and benefit from, advances ...in cancer treatment.
Methods
Accrual data for National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) cooperative group‐led treatment trials were examined to assess enrollment of newly diagnosed AYA patients (15–39 years) during the period 2004–2019, with particular interest in comparing enrollment before launch of the NCI National Clinical Trials Network (NCTN) to after. All phase 2, 2/3, and 3 trials activated during the period between January 1, 2004, and December 31, 2019, were identified (n = 1568) and reduced to a set of 304 that met predetermined criteria to focus on cooperative group‐led trials that involved therapy for newly diagnosed cancer and had age eligibility overlapping the AYA range. The proportion of AYA patients relative to total accrual, along with 95% bootstrapped CI was calculated for patients enrolled pre‐NCTN and post‐NCTN.
Results
AYA accrual comprised 9.5% (95% CI, 7.6–11.8) pre‐NCTN compared with 14.0% (95% CI, 9.9–18.3) post‐NCTN. The mean difference in proportions post‐NCTN compared with pre‐NCTN was 4.4% (0.7%–8.3%).
Conclusions
These results indicate an increase in AYA participation in trials conducted within the NCTN relative to the pre‐NCTN period. This suggests an awareness and utilization of NCTN trials for AYAs with cancer.
Lay summary
Five‐year relative survival for newly diagnosed adolescent and young adult (AYA) patients (15–39 years) with cancer is estimated at approximately 85% overall. However, outcomes tend to be worse for certain high‐risk AYA subsets, and AYAs remain challenged by multiple issues that could be addressed effectively through improved enrollment of AYAs onto clinical trials.
This study assessed participation of AYA patients newly diagnosed with cancer in National Cancer Institute (NCI) Cancer Therapy Evaluation Program‐sponsored clinical trials before and after launch of the NCI National Clinical Trials Network.
Trends in enrollment of adolescent and young adult (AYA) patients participating in National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP)‐sponsored cancer treatment trials during the period 2004–2019 are examined. Comparing enrollment prior to the launch of the NCI National Clinical Trials Network in 2014 to that after, a proportionate increase in enrollment of AYA patients is observed.
DICER1 syndrome is an autosomal-dominant, pleiotropic tumor-predisposition disorder caused by pathogenic germline variants in DICER1. We sought to quantify risk, hazard rates, and the probability of ...neoplasm incidence accounting for competing risks ("cumulative incidence") of neoplasms (benign and malignant) and standardized incidence ratios for malignant tumors in individuals with DICER1 pathogenic variation.
We combined data from three large cohorts of patients who carry germline pathogenic variation in DICER1. To reduce ascertainment bias, we distinguished probands from nonprobands. Neoplasm diagnoses were confirmed by review of pathology reports and/or central review of surgical pathology materials. Standardized cancer incidence ratios were determined relative to the SEER program, which does not capture all DICER1-associated neoplasms. For all malignancies and benign tumors ("neoplasms," excluding type Ir pleuropulmonary blastoma and thyroid nodules), we used the Kaplan-Meier method and nonparametric cumulative incidence curves to estimate neoplasm-free survival.
We calculated the age at first neoplasm diagnosis (systematically ascertained cancers plus DICER1-associated neoplasms pleuropulmonary blastoma, cystic nephroma, and nasal chondromesenchymal hamartoma) in 102 female and male nonproband DICER1 carriers. By age 10 years, 5.3% (95% CI, 0.6% to 9.7%) of nonproband DICER1 carriers had developed a neoplasm (females, 4.0%; males, 6.6%). By age 50 years, 19.3% (95% CI, 8.4% to 29.0%) of nonprobands had developed a neoplasm (females, 26.5%; males, 10.2%). After age 10 years, female risk was elevated compared with male risk. Standardized cancer incidence ratio analysis of 102 nonproband DICER1 carriers, which represented 3,344 person-years of observation, showed significant cancer excesses overall, particularly of gynecologic and thyroid cancers.
This work provides the first quantitative analysis of site-specific neoplasm risk and excess malignancy risk in 102 systematically characterized nonproband DICER1 carriers. Our findings inform DICER1 syndrome phenotype, natural history, and genetic counseling.
The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007, provide standardized definitions of adjuvant breast cancer clinical trial end points. Given the evolution ...of breast cancer clinical trials and improvements in outcomes, a panel of experts reviewed the STEEP criteria to determine whether modifications are needed.
We conducted systematic searches of ClinicalTrials.gov for adjuvant systemic and local-regional therapy trials for breast cancer to investigate if the primary end points reported met STEEP criteria. On the basis of common STEEP deviations, we performed a series of simulations to evaluate the effect of excluding non-breast cancer deaths and new nonbreast primary cancers from the invasive disease-free survival end point.
Among 11 phase III breast cancer trials with primary efficacy end points, three had primary end points that followed STEEP criteria, four used STEEP definitions but not the corresponding end point names, and four used end points that were not included in the original STEEP manuscript. Simulation modeling demonstrated that inclusion of second nonbreast primary cancer can increase the probability of incorrect inferences, can decrease power to detect clinically relevant efficacy effects, and may mask differences in recurrence rates, especially when recurrence rates are low.
We recommend an additional end point, invasive breast cancer-free survival, which includes all invasive disease-free survival events except second nonbreast primary cancers. This end point should be considered for trials in which the toxicities of agents are well-known and where the risk of second primary cancer is small. Additionally, we provide end point recommendations for local therapy trials, low-risk populations, noninferiority trials, and trials incorporating patient-reported outcomes.
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