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Although rates of colorectal cancer (CRC) are on the decline, the incidence among younger people continues to rise.

Data show that the incidence of early-onset CRC, diagnosed in people younger than 50, has increased globally by as much as 2% to 4% a year since the 1990s, with even steeper increases among those younger than 30.

“We know rates are increasing in young people, but it’s alarming to see how rapidly the whole patient population is shifting younger, despite shrinking numbers in the overall population, yasmin birth control pill and alcohol ” Rebecca Siegel, MPH, of the American Cancer Society and lead author of a new report published earlier this month that highlights this trend, said in a statement.

But gaining a more granular understanding of why this shift is occurring remains a challenge. Studies attempting to unravel the causes of early-onset CRC have been limited in scope, often focusing on single aspects of the etiology, while the causes are likely multifactorial, according to Marios Giannakis, MD, PhD, and Kimmie Ng, MD, PhD, of the Young-Onset Colorectal Cancer Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston.

That is why “a multidisciplinary path forward is needed to expand the understanding of this increasingly prevalent problem,” Giannakis and Ng write in a perspective, published this month in Science  in which they summarize the current state of our understanding.

Early-Onset CRC Patterns

In their perspective, Giannakis and Ng highlight several patterns that have emerged among individuals with early-onset CRC.

Younger patients are often diagnosed at more advanced stages of disease, despite having fewer comorbidities. This pattern could stem from a lack of screening to detect early lesions, but it “also raises the question of a more aggressive biology,” Giannakis and Ng write.

This idea is supported by the fact that survival rates among younger patients with metastatic early-onset CRC are similar to those among older patients, despite the fact that younger patients are often healthier overall, they undergo more intensive therapy, and they experience fewer side effects from treatment.

What might be happening on a genetic level in younger patients?

The evidence to date suggests that factors that predispose to cancer are more prevalent among younger patients. The most common such factor is Lynch syndrome. However, underdiagnosis of Lynch syndrome and high-penetrance pathogenic germline variants “do not explain the observed rise of early-onset CRC,” the perspective authors note.

Tumors also tend to present on the left side of the colon and rectum. Symptoms include abdominal pain and rectal bleeding. Left-sided tumors have different embryologic origins and may provide clues to the mutational profiles of early-onset tumors.

But large, genome-wide association studies dedicated to early-onset CRC as well as “analyses of gene-environment interactions are needed to further refine any genetic contribution that is specific to young-onset presentation,” the authors note.

On the environmental and lifestyle fronts, Giannakis and Ng highlight the roles obesity and other metabolic conditions, as well as physical inactivity and diet, may play in early-onset CRC risk.

One 2019 study, for instance, found that obesity during adolescence and adulthood was associated with a higher risk of early-onset CRC. Another study, published the same year, revealed that being more sedentary may increase the risk of early-onset CRC. Consumption of sugar-sweetened beverages and red and processed meat have been implicated in the early emergence of CRC as well.

These factors can affect an individual’s gut microbiome, which is yet another probable player in early-onset CRC. There is a “compelling body of evidence supporting a role of the gut microbiota in CRC pathogenesis and progression, which include species such as Fusobacterium nucleatum, Bacteroidetes fragilis, and pks+ E coli, the authors say.

Although complex, understanding the interactions between lifestyle and dietary elements, the tumor microenvironment, and the host “will be fundamental to uncovering the root causes of the rise in early-onset CRC,” Giannakis and Ng explain.

What steps can help map out a path forward?

Recent recommendations by the American Cancer Society and the US Preventive Services Task Force to start CRC screening for the average population at age 45 represent a step in the right direction, but the path forward “is neither short nor straightforward.”

To meet the challenges, Giannakis and Ng propose developing specialized centers of excellence that are focused on patients with early-onset disease to provide and model comprehensive clinical care and conduct multidisciplinary research.

Global collaborations and prospective cohort studies of healthy individuals and patients with early-onset CRC are needed as well. The Count Me In Colorectal Cancer Project, for instance, partners with patients in the US and Canada and makes data available for research.

“The urgency of navigating this path, which goes beyond unidimensional perspectives and considers the multifactorial nature of early-onset CRC, is paramount, particularly for the youngest patients who do not meet the recommended screening age,” Giannakis and Ng conclude.

Giannakis has received research funding from Janssen and Servier. Ng has received institutional research funding from Pharmavite, the Evergrande Group, Janssen, and Revolution Medicines and advisory or consulting fees from Bayer, GlaxoSmithKline, and Pfizer.

Science. Published March 16, 2023. Full text

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