Discussion
The study systematically evaluated the global burden of 29 cancers with early onset in 2019. The analysis of incidence, death and DALYs by location, country and sex revealed that the spectrum of early-onset cancer varied significantly among the regions and nations across the world. Although the global early-onset cancer incidence surpassed 3.26 million in 2019, a 79.1% increase of the incidence in 1990, the mortality number of early-onset cancer only increased by 27.7%. Notably, the prediction model indicated that the age brackets of 40–44 and 45–49 will represent a significant proportion of the population affected by early-onset cancer morbidity and mortality in the next 10 years.
Significant regional variations in the early-onset cancer spectrum can be ascribed to the local environment, lifestyle and level of available medical treatment. For example, in high-income North America, Australasia and Western Europe with high degree of development, the ASIRs in 2019 were higher than 125 per 100k, while the lowest were in Western Sub-Saharan Africa and Central Sub-Saharan Africa (<50 per 100k), which were similar to the ASIR of all-age cancer.14 At present, cancer control efforts, preventive measures and strategies in Africa are inadequate, and the majority of Africa countries have limited cancer registries, and their cancer reporting systems are poorly organised.17 Besides, most countries in Africa do not have well established health insurance systems to cover the cost of cancer screening.18 The afore-mentioned factors could be contributing factors to the Africa’s low ASIRs for early-onset cancer. On the whole, the more developed the country and region, the higher the incidence of early-onset cancer. The rising incidence of early-onset cancers may partially attribute to increasing uptake of screening and early detection in developed regions and countries2; however, only a small number of countries and certain types of cancer (including cervical cancer, breast cancer and CRC19) have implemented a screening strategy for individuals with cancer who are under the age of 50. Beyond this, western diet risk and lifestyle risk factors promoted the incidence rate of early-onset cancers.1 However, as SDI values increased, there was a sharp decrease in ASDR for early-onset cancer in Western Europe, high-income Asia Pacific and high-income North America regions. Furthermore, the projections indicated that the global morbidity and ASIR from early-onset cancer would increase over the next 10 years, while there would be a slight increase in mortality and ASDR compared to 2019 due to changing demographics over the following 10 years. Our results suggested that the incidences of early-onset nasopharynx cancer and prostate cancer displayed the most rapid upward trends in morbidity from 1990 to 2019. Despite the regional clustering and ethnic susceptibility of nasopharynx cancer, its underlying causes are currently unknown. While genetic factors, Epstein-Barr virus (EBV) infection and environmental factors are thought to be significant contributors to the development of nasopharynx cancer, more research is required to establish exact aetiological roles of early-onset nasopharynx cancer.20 Prostate-specific antigen (PSA) screening, which began in developed countries in the 1990s, contributed to the incidence of early-onset prostate cancer.20 However, it would be incorrect to solely attribute the entire increase in early-onset prostate cancer since 1986 to PSA screening. Besides advancements in screenings and diagnostics, other possible reasons for variations in health outcomes could be differences in age demographics and the presence of genetic and lifestyle risk factors.20
Among 29 early-onset cancers, breast cancer had the highest morbidity, mortality and DALYs. In 1990, North America regions with high-income levels had the highest rate of early-onset breast cancer (30.6 per 100k), but by 2019, the incidence of early-onset breast cancer (23.1 per 100k) had decreased, although it still remained in third place. It may benefit from the application of early screening programmes of breast cancer in North America regions. In contrast, over the same time period, Asia regions experienced a significant increase in the incidence of early-onset breast cancer, rising from 4.9 to 13.1 per 100k in 1990 to 8.7–15.6 per 100k in 2019. The growing prevalence of a westernised lifestyle could be among the factors contributing to the upward trend observed in Asian countries.21 22 Recently, a case–control study of Asian American women (diagnosed at age≤55 years) from the San Francisco Bay Area found that breast cancer risk was marginally increased among foreign-born women (OR=1.40) and twofold among foreign-born Chinese women.23 Thus, the factors (including genetic susceptibility) driving the increasing burden of breast cancer in women of Asian are still unclear. Furthermore, the death of early-onset breast cancer accounted for 32% and 20% among all early-onset cancers in the Oceania and Southeast Asia, respectively. The extensive application and promotion of mammography screening worldwide from 2005 to 201524 has led to an earlier age of breast cancer screening and higher rates of early-onset breast cancer detection. The most typical country is the USA,25 which began to introduce and promote mammography screening from 1980s. The ACS suggests that women be given the chance to commence yearly screening between the ages of 40–44, and to undergo routine screening mammography from the age of 45 onwards.20 More importantly, it is noteworthy that the incidence of early-onset breast cancer also increased in some countries without the introduction of routine screening,26 suggesting that the change of reproductive factors (younger age at menarche, oral contraceptive use, nulliparity, older age at first birth and never breast feeding), physical indicators (higher BMI) and behaviour factors (physical inactivity and alcohol consumption) during recent decades may have contributed to the increasing incidence of early-onset breast cancer.2 Globally, we found that alcohol use and tobacco were always the leading risk factors for early-onset breast cancer DALYs during 1990–2019. Several previous studies also found that both tobacco use and alcohol consumption increase the risk of developing breast cancer, with tobacco use specifically linked to premenopausal breast cancer27 and alcohol consumption linked to increased risk regardless of menopausal status.28 The above evidences highlights that limiting and quitting alcohol and tobacco may serve as a promising strategy to reduce the growing burden of early-onset breast cancer.
Early-onset TBL cancer had the highest burden in men and secondary cause of death for the overall population. Generally, the incidence of early-onset TBL cancer dropped during 1990–2019, which benefited from tobacco control in recent decades.29 In 1990, the regions of Central Europe, Eastern Europe, Central Asia, high-income North America and East Asia had the highest ASIR of early-onset TBL cancer among all regions. However, ASIR of early-onset TBL cancer in these regions decreased by 2019. Notedly, lung adenocarcinoma in East Asia, especially among those who have never smoked, tends to have an early onset, which sets it apart from cases observed in other regions.30 The differences in incidence rates may be due to various risk factors, such as genetics and exposure to environmental pollution.31 32 Thus, by examining the molecular characteristics and defining the hallmarks of tumour progression in early-onset TBL cancer, precision medicine and prevention may be a viable approach for managing non-smoking early-onset TBL cancer in East Asia. Globally, the morbidity and mortality of early-onset TBL cancer in men was 1.7 and 1.8 times higher than that of women, respectively, which was mainly attributed to the higher tobacco consumption in men.33 Notably, between 1990 and 2019, smoking continued to be the most significant risk factor for lung cancer among men. Currently, the definition of high-risk or moderate-risk individuals in National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for lung cancer screening was restricted to those aged 50 years or older.34 However, it is still to be assessed if lung cancer screening is necessary for populations with a history of long-term and high-dose smoking who are younger than 50 years old. TBL cancer is similarly caused by passive exposure to tobacco smoking, environmental pollution and indoor lampblack pollution,35 particularly in women. And outdoor air pollution may be emerging as an important risk factor for early-onset TBL cancer.36 37 In addition to tobacco, we identified two risk factors for early-onset TBL cancer: high fasting plasma glucose and a diet low in fruits. Recently, a meta-analysis of prospective cohort studies demonstrated high glycaemic index diet increased risks of lung cancer.38 Therefore, it is necessary to implement a planned programme of measures, including preventing indoor and outdoor air pollution, promoting balanced diet and blood glucose control for diabetic, to further reduce the burden of early-onset TBL cancer.
Early-onset CRC also had high DALYs for both sexes and was the most common form of digestive system early-onset cancer in 2019 globally, accounting for 36.8%. It was reported that greater proportions of patients younger than 50 years were diagnosed with advanced-stage tumours than older patients, thus promoting diagnosis of early-onset CRC patients and identification of potential risk factor were important to improving prevention and therapy of early-onset CRC.39 In 1990, Australasia had the highest occurrence of early-onset CRC. By 2019, this incidence had further increased. However, it is important to highlight that in East Asia, the ASIR of early-onset CRC rose from 4.2 per 100k in 1990 to 10.0 per 100k in 2019, making it the top-ranked region. Besides, the results of risk factors analysis indicated that a diet low in milk, low in whole grains and low in calcium were the top risk factors for early-onset CRC in both women and men. Although diet low in calcium were the top risk factors for early-onset CRC in 2019, its risk proportion showed a general downward trend from 1990 to 2019 across all SDI regions, which may benefit from calcium fortification programme since 1990.40 Interestingly, as one source of calcium intake, an obvious downward trend of risk proportion of diet low in milk of early-onset CRC from 1990 to 2019 was only observed in high SDI region, but an upward or flat trend in other SDI regions. For a diet low in whole grains, the risk proportion in high SDI region has been on an upward trend from 1990 to 2019. The above results suggest that calcium and milk fortification should be taken into reducing the risk of early-onset CRC in the population, especially in non-high SDI regions. Furthermore, diet in whole grains should be promoted, especially in high SDI regions. Except for dietary risk factors, alcohol use, high BMI, tobacco consumption, high fasting plasma glucose and low physical activity contributed to early-onset CRC. Of these risk factors, high BMI, particularly obesity, has been identified as a strong risk factor for early-onset CRC. The increasing prevalence of obesity in younger generations has led to a substantial increase in early-onset CRC cases.41 According to research, obesity is associated with an OR of 1.4 for early-onset CRC.42 Besides, individuals with high fasting plasma glucose and diabetes have a higher risk of developing early-onset CRC, as demonstrated by previous studies,43 and it was recommended to conduct CRC screening earlier for those with diabetes than for the general population.44 Taken together, in addition to focusing on traditional lifestyle risk factors, dietary modifications will have a positive impact on lowering the incidence burden of early-onset CRC.
The ASIR of early-onset stomach cancer in 2019 was highest in East Asia, high-income Asia Pacific, and Eastern Europe, whereas Oceania had the highest ASDR. Generally, stomach non-cardia cancer was common in Eastern Asia and Eastern Europe where the prevalence of Helicobacter pylori infection is quite high.45 Overall, the morbidity and mortality of early-onset stomach cancer in the most regions showed a downward trend from 1990 to 2019, which suggests that the prevention and treatment of stomach cancer has achieved a remarkable success in recent decades. Undoubtedly, the decrease in mortality of early-onset stomach cancer mainly attributed to the control of risk factors, screening, and treatment methods. For instance, the prevalence of H. pylori infection, associated with early-onset stomach cancer, has declined in the USA, most European countries and several East Asian countries.46 More importantly, surgical resection combined with neoadjuvant/perioperative chemotherapy is a highly effective treatment for stomach cancer in early stage, which gives a substantial support to the prevention and treatment of early stomach cancer. Additionally, our result indicated that tobacco and a diet high in sodium were the main risk factors for early-onset stomach cancer. Therefore, the morbidity of early-onset stomach cancer might benefit from the decrease in salt intake and tobacco control.
As the SDI increased, there was a rise in the ASIR of early-onset cancer; yet in regions with a high SDI (>0.7), there was a reduction in both early-onset cancer ASDR and DALYs rate as the SDI increased. The high of ASDR and DALYs rate concentrated on middle and middle-high SDI regions. Despite the fact that the ASIR remained elevated in high SDI regions, advancements in medical technology and treatments had substantially alleviated the mortality and overall impact of early-onset cancer. Conversely, it appeared that the middle SDI region was afflicted by the issue of early-onset cancer with high deaths and DALYs. Meanwhile, our findings indicated that the relationship between the HDI and the EAPC of incidence and death rates for early-onset breast cancer, TBL cancer, CRC and stomach cancer follows an inverted U-shaped curve, and the highest EAPC was observed in regions with low-middle and middle HDI, ranging from 0.5 to 0.7. Therefore, it could be concluded that in countries with a low-middle and middle HDI, burdensome early-onset cancers were displaying the most rapid increase in incidence, mortality and DALYs rates. As a result, enhancing the monitoring and prevention of early-onset cancers in these regions is crucial.
Genetic screening has become an indispensable tool due to its emphasis on the prevention of early-stage cancer. For example, current research indicated that breast and ovarian cancer were associated with variants in the BRCA1 and BRCA2 genes.47 Besides, approximately 10% of CRC cases have been found to be associated with pathogenic variants according to research studies.20 Research studies have revealed that these pathogenic variants were detected in 15%–33% of individuals who were diagnosed with CRC before the age of 50, regardless of their family history of the disease.20 More importantly, next-generation sequencing has led to improvements in the accessibility and affordability of genetic testing for cancer susceptibility genes. Therefore, genetic screening is expected to have a significant impact on the identification and anticipation of early-onset cancers in the near future.
However, the study still has several limitations due to GBD 2019’s intrinsic drawbacks. First, the accuracy of GBD data was compromised by the quality of cancer registry data in different countries. Thus, the under-reporting and under-diagnosis in undeveloped countries may result in underestimation of the incidences and deaths of early-onset cancer. Second, the increasing trend of early-onset cancer burden is still unclear, which may be related to early screening intervention and early-life exposures. Third, the estimation of risk factor exposure was conducted on data with sparse investigation time nodes and different sources, which may affect influence accuracy and introduce potential measurement bias. Fourth, it is inevitable that implementing a dichotomy at 50 years of age has drawbacks because pathological, molecular and biological characteristics are unlikely to change considerably at that age.
