The rise in early-onset cancers is reshaping public health priorities as scientists pinpoint environmental and lifestyle factors driving the epidemic, and call for innovative treatments and preventive measures.

Review: Early-onset cancers: Biological bases and clinical implications. Image Credit: Lightspring / Shutterstock

A recent study published in the journal Cell Reports Medicine discussed early-onset (EO) cancers and their implications.

Cancer epidemiology has remarkably changed due to the growing incidence of sporadic EO cancers. Conventionally detected in older adults (> 65 years), these cancers are increasingly diagnosed in people under 50, even in those aged 15–39. This shift was first observed in the United States (US) in the 1980s and later confirmed worldwide in the 1990s.

Therefore, understanding why it has happened and defining treatment for young adults with cancers remain top research priorities.

The study emphasizes the urgent need for global, large-scale research collaborations and the integration of data from epidemiological, clinical, and biological sources.

The authors formulated hypotheses and suggested translational comprehensive approaches to address this epidemic.

Clinical observations and hypotheses

The emergence of EO cancers as the primary mortality cause in people aged 15–49 underscores the clinical relevance of their upsurge.

The global incidence of EO cancers has increased by about 80% between 1990 and 2019. Projections suggest that breast, gastrointestinal, and kidney cancers will be the most common cancers in people aged 20–49 in the next 15 years.

By 2030, it is estimated that one-third of all colorectal cancer cases will be diagnosed in individuals younger than 50.

Consequently, EO-CRC is the first cause of cancer mortality in US males aged 20–49. Identifying the biological features of EO cancers is pivotal to determining effective prophylactic and therapeutic options.

The rise in EO cancer incidence has promoted investigations into underlying mechanisms, focusing on the exposome. The exposome refers to the totality of environmental exposures individuals experience, beginning prenatally.

The authors list the following testable hypotheses in relation to the unprecedented surge in EO cancers.

Which environmental substances have millennials and later generations been exposed to have changed in the past decades that potentially escalated EO cancer incidence since the 1990s?

Further, does EO-CRC diverge from the accepted colorectal tumorigenesis path (the adenoma-carcinoma cascade)?

Moreover, do these tumors follow the same (established) path more rapidly than in older people, or do they have distinct evolutionary trajectories?

Further, if these tumors and their microenvironments are different, could the response and resistance of EO cancers to existing anticancer agents be different from cancers in older patients?

Answering these will have profound implications for secondary prevention strategies and enable the development of more effective and personalized treatments.

This may necessitate the development of new screening strategies, such as more frequent and non-invasive methods like blood-based tests tailored to detect these rapidly progressing cancers.

Impact of exposome changes

Most EO cancers are attributed to inherited genetic changes, and the prevalence of hereditary cases has been stable over time.

Nevertheless, only 20% to 30% of EO pancreatic cancers and EO-CRC are hereditary, while the remainder are sporadic. The underlying causes are likely associated with the exposome.

The unprecedented industrialization in the last century has significantly improved life expectancy and welfare. As such, there has been an exponential surge in the substances that humans and animals interact with from the prenatal period.

Consequently, potential carcinogens have also increased. Recent data suggest that specific carcinogens, such as 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a compound found in grilled meats, and food dyes like Red40, might contribute to EO cancers.

However, the carcinogen potential of most commercial substances, including those used in foods and beverages, is unknown.

Chronic sub-clinical metabolic inflammation and mutagenesis induced by Western lifestyle might have contributed to cancers in the young population.

Diet Westernization has increased exposure to known carcinogens, such as polycyclic aromatic hydrocarbons, N-nitroso compounds, etc., widely used in frozen meals, fast foods, and cured meats, especially in metropolitan areas.

Additionally, air pollution, particularly PM2.5, has been implicated in the development of lung cancers by promoting oxidative stress and immune downregulation. These molecules, accompanied by protective nutrient deficits, might have contributed to the increase in EO cancers by promoting oxidative stress and inducing DNA adducts.

Further, obesity, low physical activity, diabetes, metabolic syndrome, and less favorable socioeconomic conditions associated with higher intake of low-quality and processed foods have been correlated with elevated EO cancer risk.

The study also draws attention to emerging concerns about plastic micro- and nanofibers, which may act as vectors for other carcinogens and are linked to long-term health risks, including cancer. Besides, using fertilizers, antibiotics, hormones, and pesticides in agriculture and livestock could be associated with the increasing incidence of EO cancers.

Of note, exposome changes are not limited to exercise and dietary habits. The indiscriminate use of common medicines could be linked to EO cancers due to their genotoxicity to human cells and impact on the gut microbiota.

In addition, exposure to specific pathogens could be carcinogenic to human cells. The study suggests that the increased use of antibiotics, particularly in childhood, may disrupt gut microbiota, increasing the risk for EO gastrointestinal cancers.  

Recently, air pollution was reported to drive the development of non-small cell lung cancer.

Improvements in EO cancer management

Whether EO cancers are biologically distinct relative to later-onset cancers may have implications for the effectiveness of medical and surgical therapeutic modalities.

Clinicians are prone to overtreat EO cancer patients with more intensive approaches despite the lack of evidence of improved survival benefits.

It has been speculated that (specific) EO cancers may have a different response to treatments typically effective in standard-onset cancers.

The authors advocate for more targeted therapeutic approaches, supported by multi-omics profiling, to uncover specific molecular alterations in EO cancers.

Developing tailored therapies will require comprehensive (multi-omics) profiling of EO cancers to uncover molecular features underlying druggable alterations.

Besides, exploring novel treatment regimens may include combinations of novel/existing targeted therapies, immunotherapies, and conventional chemotherapies.

Such research efforts should also focus on minimizing adverse effects and improving the overall quality of life.

EO cancer integrome

Unraveling the interactions and effects of exposures, predispositions, evolutionary trajectories, and tumorigenesis of EO cancers will be challenging.

However, effectively integrating epidemiological and cohort studies, dedicated EO cancer specimen biobanks, clinicopathological and exposure data, and preclinical model platforms will be pivotal to success.

This integrated approach has been coined the “EO cancer integrome” by the authors, representing a comprehensive framework to study EO cancers.

The authors believe this would eventually lead to the development of the EO cancer integrome. Initial steps have been taken in this direction, suggesting feasibility.

The increasing availability of artificial intelligence tools will be crucial in integrating omics with clinical and epidemiological data.

Preclinical models will be instrumental in functionally and mechanistically testing the specified hypotheses.

Concluding remarks

Taken together, disentangling the causes of EO cancers is necessary to protect future generations from this epidemic.

As such, the study illustrated how epidemiological, clinical, and experimental translational results should be integrated to develop a comprehensive knowledge base of EO cancer biology.

The researchers stress that addressing the EO cancer epidemic will require a global, coordinated effort, leveraging emerging technologies like AI and multi-omics to uncover new biological insights.