Rising Incidence, Unclear Drivers: Knowledge Gaps Persist in Early-Onset CRC

Colorectal cancer (CRC) incidence among adults younger than 50 years has nearly doubled since the 1990s, transforming what was once a projected trend into a present-day clinical crisis.¹ By 2030, CRC is projected to increase in incidence by 90%, and recent data show that the disease is already the leading cause of cancer-related death among men and women younger than 50 years.^1,2

Unlike average-onset CRC, early-onset cases are predominantly sporadic, often affecting fit, healthy individuals without a family history of the disease.¹ Moreover, although therapeutic advances in CRC have translated into measurable overall survival (OS) gains for older adults, mortality continues to rise in the younger subset, implicating a host of contributing factors such as delayed diagnosis, distinct tumor biology, and hereditary or environmental factors.^1,2

Whether this represents the emergence of a new subtype or the acceleration of an existing disease is still unclear. Likewise, addressing the rising rates of early-onset CRC (EO-CRC) requires more than a revision of screening guidelines; it necessitates deep microbiome research, global collaborative clinical trials, and a multidisciplinary approach to survivorship, according to John L. Marshall, MD, and Christopher Lieu, MD, who sat down with OncLive to discuss what we know about this troubling trend and what can be done to reverse it.

Marshall is the chief of hematology and oncology, director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers, and a professor of medicine and oncology at Georgetown University Lombardi Comprehensive Cancer Center in Washington, DC. Lieu is codirector of gastrointestinal medical oncology, associate director for clinical research, and a professor of medicine in the Department of Medical Oncology at the University of Colorado Anschutz Cancer Center in Aurora.

How has the epidemiology of CRC shifted across generations?

The landscape of CRC is undergoing a fundamental shift in both timing and patient demographics. According to a research letter published in JAMA Oncology, CRC mortality in adults younger than 50 years has increased by approximately 1.1% (95% CI, 0.9%-1.3%) annually since 2005, reversing decades of decline.² Over the same period, CRC moved from the fifth-leading cause of cancer death in this age group to the leading cause in 2023.

At the same time, CRC incidence in the US is moving in 2 directions. Among adults aged 20 to 49 years and 50 to 64 years, rates are increasing by approximately 3% and 0.4% per year, respectively.¹ In contrast, among adults 65 years or older, the incidence is decreasing by approximately 2.5% per year.

Lieu emphasized that the epidemiologic signal extends beyond age cutoffs. “What we’re also seeing is this birth cohort effect. If you are a 40- or 50-year-old born in 1960, your risk [of developing CRC] was fairly average. Now our 40-, 50-, and 60-year-olds are carrying [an increased] risk.” Accordingly, as these high-risk younger cohorts move into older age brackets, incidence in the 50- to 65-year age group has begun to plateau rather than decline.

Why is CRC increasing in younger patients, and how much is hereditary vs environmental?

A central question is whether EO-CRC reflects inherited risk, modifiable exposures, or a complex interaction between the 2. Multigene panel testing has identified pathogenic germline variants in approximately 16% to 20% of patients younger than 50 years, which Lieu stated is a higher percentage of genetic syndromes than that typically seen in older patients.¹ However, this leaves the majority of EO-CRC cases unexplained by known hereditary predispositions such as Lynch syndrome or familial adenomatous polyposis, prompting attention to shift to cumulative environmental, dietary, microbial, and metabolic exposures in a patient’s lifetime.

“What you inherit from your parents only explains part of the story,” Lieu said. “The issue here is that there’s something that our patients are either being exposed to,…[which] actually begins in utero and goes all the way up until the moment they are diagnosed.” However, there is an inherent difficulty in reconstructing 30 to 40 years of exposure to environmental risk factors when trying to identify causative factors, Lieu noted.

Early evidence and associated public health messaging frequently attributed the rising rates of EO-CRC to obesity, poor diet, sedentary behavior, and family history, Marshall stated. Although these are established CRC risk factors, they do not adequately explain the rapid generational shift on their own, and clinical experience paints a more nuanced picture.

“The American Cancer Society [ACS] came out with an official position paper that said this was because [individuals] were eating badly, they were overweight, or they had a family history of the disease, and that wasn’t what I was seeing in my clinic,” Marshall said. “It was healthy, fit, young people [who had] no family history [and were] careful [about] what they ate. We had this misconception early on, [which resulted in] barriers to recognition and interventions in both the health care system and [patient] populations that [are] only now starting to roll into broader awareness.”

Lieu similarly underscored the need for caution when interpreting these causal relationships. “As a society, we want to be able to point to one [driving factor],” he said. “It’s got to be McDonald’s, or it’s got to be microplastics. But this is so incredibly complex. There are so many things that we’re not only exposed to, but [that affect which] genes are turned on or off…and [so many] lifestyle [changes we experience]. It’s not going to be just one simple answer.”

Could the microbiome contribute to increased left-sided tumor predominance?

Anatomic distribution provides an additional clue. Data from multiple studies have demonstrated a disproportionate increase in distal, or left-sided, colon and rectal cancers in younger adults.¹ Rectal cancer incidence, in particular, has risen more steeply than colon cancer incidence in individuals younger than 50 years.

“When I hear a presentation now of a 40-year-old [with CRC], I can already tell you that it’s going to be in the rectosigmoid junction,” Marshall said. “[Approximately] 90% of these tumors are in the left side distal colon.”

“I believe the location is striking,” Lieu said. “Why are these cancers developing in a very specific area? That points to microbiome.”

Accumulating data support a role for gut microbial dysbiosis in colorectal carcinogenesis. Specific bacterial species, including Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis, have been implicated in promoting inflammation, DNA damage, and tumor progression.³ Additional data suggest that specific microbiome configurations or environmental triggers may be concentrated in this area of the colon.⁴

Marshall framed the phenomenon in evolutionary terms. “We are seeing this scientific observation of these young [individuals] with these colon cancers in the same location, but [we don’t have] the tools at hand to explain or find that one thing that we could alter or influence so that we could turn this off. Is this ‘unnatural’ selection? Have we done something to our diets…that is somehow reversing progress?” He added that parallel increases of other cancers in young adults, including breast cancer, suggest broader environmental or biologic pressures.

Is a new CRC subtype emerging?

Whether EO-CRC represents a biologically distinct subtype remains a matter of debate. Clinically, younger patients tend to have left-sided tumors, poorly differentiated histology, and synchronous metastatic disease.⁵ Molecular analyses have also suggested that EO-CRC tumors may harbor distinct epigenetic and transcriptomic profiles, including a higher rate of RAS mutations, a specific pattern of TP53 and APC alterations, Wnt pathway alterations, and other promoter methylation events that may mediate the effects of diet or the microbiome on tumor development. However, no single defining molecular signature has been established.

Additionally, there are conflicting reports regarding the prognosis of patients with EO-CRC vs average-onset CRC due to a limited number of survival studies.^1,5,6 For example, the ACS report states that individuals younger than 50 years have similar or higher 5-year relative survival than older patients, with the largest gap seen in distant-stage disease at 23% vs 17% in patients aged 50 to 64 years vs 10% in those 65 years or older.¹

However, data from a 2022 landmark analysis found that young patients with EO-CRC experienced an increase in early mortality in the first 25 months after treatment but would have superior long-term survival outcomes if they survived for more than 25 months. The study also confirmed that young patients tended to be overtreated; however, unlike in older patients, this overuse of chemotherapy led to no meaningful survival benefit.⁶ Similarly, findings from a 2024 study showed that younger patients exhibit worse progression-free survival and OS rates regardless of molecular subgroup, indicating an inherently aggressive presentation.⁵

“We used to think when we first started seeing this that these young people would do better, and we could be more aggressive [in our treatment approach]….” Marshall said. “That’s turned out not to be true. It feels like a more aggressive, less responsive kind of cancer.”

“There [is also this] question of [whether] our younger patients respond equally as well to therapies,” Lieu said. “There are some studies that suggest that our younger patients [experience worse outcomes because they] have more resistant disease. That doesn’t make any sense to me, because our younger patients should be younger, fitter, have [fewer] comorbid conditions, and should be able to tolerate more therapy.”

The location of most early-onset tumors also contradicts this conclusion, as left-sided tumors typically confer a more favorable prognosis and responsiveness to anti–EGFR therapy in RAS wild-type disease.⁷

“This phenomenon seems to have drifted past the 50-year-olds, mainly because [EO-CRC appears to have an] independent biology,” Marshall said. “It’s got its own location, its own behavior. To me, [this is] the emergence of a new CRC subtype taking us all by storm.”

Do current screening guidelines adequately address barriers to early detection in EO-CRC?

In 2021, the US Preventive Services Task Force lowered the recommended starting age for average-risk screening from 50 to 45 years, in response to epidemiologic data demonstrating a 15% rise in cases among younger adults over approximately 15 years and modeling data supporting benefit in the 45- to 49-year age group (Table).⁸ Despite this, significant barriers to early detection remain. In Lieu’s experience, younger adults are still typically not screened before age 45 unless they have a known genetic predisposition or family history of CRC. Moreover, symptoms present in younger adults, such as rectal bleeding, are frequently dismissed by patients and primary care physicians as benign issues, such as hemorrhoids. These delays in diagnosis allow tumors to progress to metastatic disease before treatment begins.

Systemic barriers also persist, Lieu pointed out. Younger adults are less likely to have established relationships with primary care providers who are familiar enough with their medical history to flag subtle changes in bowel habits or unexplained weight loss. Additionally, insurance authorization of diagnostic procedures such as colonoscopies for symptomatic 30-year-olds often requires more effort and “escalating care” than for older patients.

“How do we change culture with a screening process that already had barriers, even in the ‘proper’ age group, and shift that down to a younger patient population?” Lieu asked. “The big thing is raising awareness. Unfortunately, we’ve had some high-profile deaths [from CRC recently, including] James Van Der Beek, who died of a cancer that he should have never had. He was just too young. [This shows that] earlier detection does matter [for] overall prognosis.”

How does the clinical framework change when treating younger patients with CRC?

With this rising incidence of CRC in young adults comes a fundamental shift in treatment goals. Lieu and Marshall agreed that for a 30- or 40-year-old patient, factors such as fertility preservation, sexual function, bowel function, career stability, and long-term toxicity are important to focus on over tumor eradication.

“They care about having renal function more,” Marshall said of younger patients. “If we [cure] them [but they lose renal function], they have to live with that for 40 more years.” He described a shift toward total neoadjuvant therapy and nonoperative management strategies in select rectal cancer cases, informed by trial data demonstrating that a subset of patients achieving clinical complete response after chemoradiation can avoid immediate surgery.

Disease management for younger patients accordingly required increased multidisciplinary integration. “Every one of these patients requires care that [covers] oncofertility, social work, financial considerations, et cetera,” Lieu said. “We’re dealing with things that we have never dealt with in our 70- or 80-year-olds. Our patients are raising young children, they’re in school, they’re developing their careers, and [treatment can be] a tremendous interruption to all of that.“

Long-term toxicities of systemic therapy are also of even greater importance, Lieu noted. In a patient expected to live decades after cure, even low-grade chronic neuropathy or bowel dysfunction may substantially affect someone’s quality of life and occupational functioning.

“What [does] having neuropathy look like when you’re not just living with it for 5 or 10 years, but you’re living with it for 30 or 40 years?” Lieu asked. “They have to live with whatever it is that we had to do to get rid of the cancer. [That’s why it is] important to keep the consideration for survivorship [front and center].”

How can we reverse this trend?

To change the current trajectory of EO-CRC, the field of oncology must employ a more collaborative mindset and substantially improve the general understanding of disease biology.

“When we think about how we treat cancer, how…we cure cancer, how…we find better treatments of cancer, [it comes down to] understanding the disease better,” Lieu said. “We all need to become microbiome experts, and we need to collaborate not only within the US but globally.” Lieu also advocated for partnerships with microbiologists, epidemiologists, and computational biologists, as well as global data-sharing initiatives to increase statistical power in studying relatively uncommon age-defined subsets.

Marshall also pointed to stagnation in adjuvant therapy advances as a current source of frustration. “We’ve talked about our lack of progress with adjuvant therapy and early intervention. We have seen that occur in other cancers, so we are…trying to learn lessons from those [studies and] apply them [in our own CRC research] to ensure progress.”

Leveraging emerging tools such as circulating tumor DNA assays for minimal residual disease detection also could enable more appropriate treatment de-escalation vs intensification for patients with EO-CRC.⁹

“My hope is that this phenomenon will be the spark that allows us to uncover secrets that will not just help these young people with CRC but many other diseases,” Marshall said.

References

1. Siegel RL, Wagle NS, Star J, Kratzer TB, Smith RA, Jemal A. Colorectal cancer statistics, 2026. CA Cancer J Clin. 2026;76(2):e70067. doi:10.3322/caac.70067
2. Siegel RL, Wagle NS, Jemal A. Leading cancer deaths in people younger than 50 years. JAMA. 2026;335(7):632-634. doi:10.1001/jama.2025.25467
3. Gomes de Sousa R, Guerreiro CS, Santos I, Cravo M. The knowledge gap in gut microbiome characterization in early-onset colorectal cancer patients: a systematic scoping review. Cancers (Basel). 2025;17(11):1863. doi:10.3390/cancers17111863
4. Zhong M, Xiong Y, Ye Z, et al. Microbial community profiling distinguishes left-sided and right-sided colon cancer. Front Cell Infect Microbiol. 2020;10:498502. doi:10.3389/fcimb.2020.498502
5. Pretta A, Nasca V, Marmorino F, et al. Early-onset colorectal cancer patients exhibit a distinct molecular fingerprint: insights from a large-scale NGS study of 1209 patients. ESMO Open. 2025;10(9):105756. doi:10.1016/j.esmoop.2025.105756
6. Wang S, Yuan Z, Ni K, et al. Young patients with colorectal cancer have higher early mortality but better long-term survival. Clin Transl Gastroenterol. 2022;13(12):e00543. doi:10.14309/ctg.0000000000000543
7. Jones V. Cancer in the sigmoid colon: what it means when colon cancer is on the left side. The University of Texas MD Anderson Cancer Center. February 14, 2024. Accessed March 4, 2026. https://www.mdanderson.org/cancerwise/cancer-in-the-sigmoid-colon--what-it-means-when-colon-cancer-is-on-the-left-side.h00-159695178.html
8. US Preventive Services Task Force; Davidson KW, Barry MJ, Mangione CM, et al. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965-1977. doi:10.1001/jama.2021.6238