Trends in Cancer Incidence in US Adolescents and Young Adults, 1973-2015

This cross-sectional population-based study characterizes the epidemiology of cancer in US adolescents and young adults aged 15 to 39 years with respect to (1) patient demographic characteristics, (2) cancer type frequencies, and (3) cancer incidence trends over time.


Introduction
The National Cancer Institute has identified adolescents and young adults (AYAs) as a patient population with cancer distinct from children and older adults. 1 Adolescents and young adults are defined as individuals aged 15 to 39 years at cancer diagnosis. 1,2 As of 2006, approximately 70 000 AYAs were diagnosed with cancer in the US every year, and cancer was much more common in this age group than in those aged 0 to 14 years. 1,3 Although accidents are the overall leading cause of death in adolescents, cancer is the leading cause of disease-related death in this age group. 3,4 Despite the significant cancer burden in the AYA population, much is still unknown about the epidemiology of AYA cancers.
Although recently there has been a dramatic increase in research focused specifically on AYA cancers, historically, research has focused on childhood and adult cancers, leaving cancer in AYAs an inadequately studied problem. 2,5 This gap has prevented the development of diagnosis, treatment, and monitoring guidelines specific to this age group. 3 Instead, treatment and management of AYA patients often falls somewhere between pediatric and adult medical oncology frameworks, which are not ideally suited to the complex and distinct biological, social, and economic needs of AYA patients. 2,6 In addition, subgroups of the AYA population may be at increased risk for poor outcomes. 3,7 All of these factors make it essential to broaden the understanding of cancer epidemiology in this age group.
Although existing research has described epidemiological characteristics at a specific time and trends for limited periods (5-20 years), there remains a lack of research into the long-term trends and characteristics of cancer in AYAs. 2,[8][9][10] Our present work expands on these studies because it contains data not presented in these previous works, including incidence rates over time, mean annual percentage change (APC) values, and incidence trends for subgroups of cancer diagnoses. The objectives of this work were to characterize the epidemiology of cancer in AYAs with respect to (1) patient demographic characteristics, (2) distribution (age subgroup and primary cancer anatomical site), and (3) incidence trends from 1973 to 2015. The results of this study may be useful in identifying the evolving epidemiological characteristics and trends in cancer incidence in AYAs, a necessary next step in understanding cancer in this distinct age group.

Data Availability
The data used in this cross-sectional study are provided in the Surveillance, Epidemiology, and End Results (SEER) database, which is publicly accessible (https://seer.cancer.gov/). The relevant session information from the present work and abbreviated data sets (from SEER) are available elsewhere. To access the data in this study, we provide a data availability statement in the eMethods in the Cancer Institute) was used for this analysis. 12 Patients diagnosed only through autopsy or death certificate were excluded. All incidence rates were age adjusted to the 2000 US standard population and reported per 100 000 persons. 12 An overview and limitations of the database and the methods are described in the eMethods in the Supplement. 13

Statistical Analysis
For objective 1, patient demographic characteristics were summarized by age at diagnosis, sex, and race/ethnicity. The χ 2 test was used to determine whether significant differences exist between male and female patients and between races/ethnicities. Demographic data from patients diagnosed from 1973 to 2015 were collected from SEER 9 regions to provide an overarching picture of the AYA landscape in the US during a 42-year window. Data limited to diagnoses from 2005 to 2015 were also collected from SEER 18 regions to provide a more contemporary description of AYA cancer demographics.
For objective 2, age at diagnosis, primary cancer site, and patient count data were obtained.
Disease sites were categorized based on AYA site recode/World Health Organization 2008 definition (eTable 1 in the Supplement). 17 The SEER AYA site recode is a classification scheme for tumors specific to those aged 15 to 39 years. Because of the large number of cancer subtypes affecting AYAs, the data presented below were restricted to the 12 cancers with the highest incidence for both female and male patients.
For objective 3, incidence rates by year of diagnosis were analyzed for a statistically significant change from 1973 to 2015 using linear regression models. The APC values were comparable across scales, allowing for comparisons between incidence rate changes in rare and common cancers. 12 Percentage change calculations were completed using 1 year as each end point, and the weighted least squares method was used to calculate APCs. 12 A Bonferroni correction was applied to adjust for multiple hypothesis testing (n = 78 tests); 1-sided P < .001 was considered significant.  Carcinomas were the most frequently diagnosed type of cancer for all male (n = 54 414) and female (n = 196 700) AYAs (eFigure 1 and eTable 2 in the Supplement). The relative number of carcinoma diagnoses compared with other cancer types increased as age at diagnosis increased for both male and female patients. Table 3 shows the incidence of cancer among AYAs diagnosed from 1973 to 2015 by disease site and age subgroup. eTable 2 and eFigure 2 in the Supplement show incidence data for disease sites not included in Table 3.

Age Subgroups and Specific Disease Site
For male AYAs, testicular cancer (germ cell and trophoblastic neoplasms of gonads) had the highest incidence (n = 37 597), followed by melanoma (n = 20 850) and non-Hodgkin lymphoma

AYA Cancer Incidence Trends
The Figure and Table 4 show the incidence trends by disease sites for those with the 12 highest incidences for male and female AYAs from 1973 to 2015. eTable 3 in the Supplement shows changes b Sorted by decreasing absolute incidence for males and females combined and taken from the 12 disease sites with the highest absolute incidence for males and females .  Year of diagnosis

Discussion
This cross-sectional study found that AYAs are affected by a wide variety of cancers, and the diagnosis of these cancers has been increasing from 1973 to 2015. During this period, the rate of cancer in AYAs increased by 29.6%, from 57.2 to 74.2 invasive cancer diagnoses per 100 000 AYAs per year. In contrast, previous findings assessed trends in cancer incidence for different age ranges. 18 In addition, from 1975 to 1995, most pediatric cancers did not significantly increase or decrease in incidence, and from 1992 to 2004, there was no significant increase in the incidence rate for pediatric cancers. 19,20 The 29.6% increase in the rate of cancer in AYAs reflects the increasing rates of many cancer types. Carcinoma of the kidney, thyroid, and gastrointestinal tract (eg, carcinoma of the colon and rectum), germ cell and trophoblastic neoplasms (eg, testicular cancer), and melanoma, among other cancer sites, have been increasing in AYAs during this period (eTable 3 in the Supplement). Although carcinoma of the kidney has been increasing at the greatest rate, its contribution to the overall increased incidence may be minimal owing to its relatively low absolute incidence during 1973 to 2015. Cancer sites with larger absolute incidences contribute more to the overall increase in cancers among AYAs. These sites include carcinoma of the gastrointestinal tract, thyroid carcinoma, melanoma, non-Hodgkin lymphoma, and germ cell and trophoblastic neoplasms of the gonads.
The increasing rates of diagnosis at many of the disease sites identified in this work have been observed in previous analyses of data from more historical and limited periods. 21-26 The present study demonstrates that the rate of diagnosis of cancer at these sites has increased from 1973 through 2015.
Environmental factors, dietary and obesity trends, and changes in screening practices are 3 major categories that likely played a role in the increasing rate of cancer in AYAs from 1973 to 2015.
For example, factors that may be involved in the increasing rate of testicular cancer include exposure to estrogens and progesterone (prenatally and via dairy consumption), increased prevalence of maternal risk factors (increasing age at first birth, having fewer children, and increasing survival of

JAMA Network Open | Oncology
Trends in Cancer Incidence in US Adolescents and Young Adults, 1973 premature infants), and exposure to cannabis. 21, [27][28][29] Diet and obesity may play a role in the development of thyroid carcinoma and carcinoma of the kidney. 9,30,31 In addition, cancer screening and overdiagnosis are thought to account for much of the increasing rates of thyroid and kidney carcinoma, among others. 32 Worsening diet (less vegetables and more fats and processed meats), increasing rates of childhood and adolescent obesity, lack of exercise, and human papillomavirus infections have been implicated as potential risk factors contributing to the increasing rate of gastrointestinal tract cancers among AYAs. 9,22,[33][34][35] The increasing rate of diagnosis of melanoma in female AYAs may be associated with increasing intensity of UV exposure, including the use of artificial UV sources. 36 Increasing exposure to chemotherapy and ionizing radiation may be another factor contributing to the overall increase in AYA cancers. 37 This study also found a decrease in incidence in 7 disease sites in male patients and 5 disease sites in female patients (eTable 3 in the Supplement). Potential explanations for the decreasing rates for some AYA disease sites include increased oral contraceptive use, laws restricting exposure to environmental toxins (eg, benzene), and decreased smoking initiation. 9,38,39 Lung, breast, colorectal, bladder, and endometrial cancers are among those most influenced by lifestyle and environmental factors. 40 As shown in the Figure Table 4). This pattern of incidence for these cancers has been shown to be associated with the onset and consequent decrease of the HIV/AIDS epidemic in the 1980s and 1990s. 41 Adolescents and young adults are a heterogenous group. They are affected by a wide variety of cancers, and the distribution of the type of cancer diagnoses shifts throughout the AYA age range.
As AYAs age, there is generally a decrease in the relative incidence of leukemias, lymphomas, germ cell and trophoblastic neoplasms, and neoplasms of the central nervous system and an increase in the relative incidence of carcinomas (Table 3 and

Limitations
A limitation of this study is that the data from SEER is limited to people living in the US, and therefore our results may not be generalizable to other countries. In addition, data from SEER are limited to collection at the time of diagnosis and do not include information about recurrence. Finally, reporting of race/ethnicity may contain errors, resulting in underestimates of cancer in some subpopulations.

JAMA Network Open | Oncology
Trends in Cancer Incidence in US Adolescents and Young Adults, 1973-2015

Conclusions
Despite cancer in AYAs being a significant and growing problem, data on the epidemiology of cancer in AYAs are limited. 5,10 Previous research has shown that AYA cancers have distinct features from cancers in other age groups, and subgroups of the AYA population may be at increased risk for poor outcomes. 7,[43][44][45][46] In this cross-sectional, US population-based study using cancer registry data from 497 452 AYAs, the rate of cancer increased by 29.6% from 1973 to 2015, with kidney carcinoma increasing at the greatest rate. Breast carcinoma and testicular cancer were the most common cancer diagnoses for female and male AYAs, respectively. This study demonstrated that cancer in AYAs has a distinct distribution and is a growing problem and that continued research in this area is necessary to address the unique needs of this population. Specifically, there is a need to use the expanded knowledge about AYA cancers to target diagnosis and treatment options specific to the unique patterns and characteristics of cancer in this age group.