The Rising Incidence of Early-Onset CRC: What Do We Know and What Can We Do?

John L. Marshall, MD

Historically, colorectal cancer (CRC) has been considered a disease of aging. The median age at diagnosis for colon cancer is 68 years in men and 72 years in women, and the median age at diagnosis for rectal cancer is 63 years in both sexes.¹ However, an American Cancer Society (ACS) study published in 2017 reported that although CRC incidence in the United States is declining overall due to improved screening, it is rapidly increasing among young and middleaged adults (<50 years).² The study found that CRC rates have increased by 1.0% to 2.4% annually since the mid-1980s among adults aged 20 to 39 years and by 0.5% to 1.3% since the mid-1990s among adults aged 40 to 54 years.2 Subsequently, the proportion of CRC cases diagnosed in individuals younger than 50 years increased from 6% in 1990 to 11% in 2013, with the majority (72%) being in individuals in their 40s.¹

During an OncLive Peer Exchange^® program on individualizing treatment and improving outcomes for patients with CRC, a panel of experts shared their insights on early-onset CRC, which has been observed to occur as early as adolescence. “I’ve got a 17-year-old now and 20-, 30-, and 40-yearolds,” said John L. Marshall, MD, who served as moderator. Another panelist reported treating a patient as young as 16 years.

Tumor Features

Table 1. Clinicopathologic and Molecular Features More Commonly Observed in Early-Onset CRC³

Since early-onset CRC is a relatively recently recognized phenomenon, particularly among adolescents and very young adults, data on this population are still limited. However, the panelists shared their experiences treating early-onset CRC, discussing tumor features, CRC screening, patient characteristics, treatment approaches, and special considerations for younger patients as part of a broader conversation about individualizing care for patients with the disease.Early-onset CRC, like CRC in older adults, is considered a heterogenous disease. Some cases appear to have a hereditary component (~15%- 20%), although the majority appear to be sporadic.³ Clinicopathologic and molecular features that have been more commonly observed in earlyversus late-onset CRC have been reported previously (Table 1).³“The biology appears to be much more aggressive in quite a few of these patients, much more so than in our older patients, and they’re not responding to the therapies that we’ve been giving as a standard to all of our other patients,” Cathy Eng, MD, FACP, said. “It seems like a different cancer,” Marshall chimed in.

Screening Recommendations

The panel discussed rightand left-sided CRCs, the latter of which have generally been associated with an improved prognosis. “I think we all know [that patients with early-onset CRC are] presenting more often with left-sided tumors and rectal tumors. We’re told the left-sided tumors have better survival, but this seems a little bit different in this unique young patient population,” Eng said, adding that peritoneal disease is another common presentation. The panel acknowledged that the later stage at diagnosis is likely a major contributing factor to these patients’ worse outcomes, making improved screening essential.Based on the finding that CRC rates are increasing in younger populations, particularly those in their 40s, the ACS recently lowered the age at which to begin CRC screenings in average-risk persons, from age 50 years to 45 years.4 However, this move may be insufficient, since it does not improve detection among adolescents, young adults, and those in their early 40s, the group that may be at greatest risk.

“I’m thinking that maybe we should start screening at 40 or having more awareness that when a younger patient presents with gastrointestinal symptoms, don’t just send them away and say it’s not [CRC],” Johanna C. Bendell, MD, said.

Eng concurred. “I think that it’s really important that people recognize that young patients can develop CRC and when they have symptoms, they need to be investigated. I think that’s being completely underrecognized, and a lot of people tell individuals, ‘It’s just a change in bowel habits,’ ‘You ate something wrong,’ or ‘It’s due to a hemorrhoid.’”

The panel agreed that if the cause of the underlying problem is not obvious, such as a clearly visible hemorrhoid or anal fissure on physical examination, the patient should be scoped. Per the ACS, recommended CRC screening options include fecal immunochemical testing; high-sensitivity, guaiac-based fecal occult blood testing; multitarget stool DNA testing; colonoscopy; computed tomography colonography; and flexible sigmoidoscopy.⁴ Because most earlyonset CRCs are in the distal colon and rectum (83% in a study of 739 patients with CRC aged 18 to 49 years), when direct visualization is preferred, it has been suggested that flexible sigmoidoscopy might be a good choice for younger patients (<50 years).⁵ This modality has been reported to be more cost effective than colonoscopy while providing similar benefits, including reduced CRC mortality and a reduced risk of incident cancers of the rectum and sigmoid colon, a benefit observed to last at least 10 years for patients aged 55 to 64 years.^5,6

The reason for the rise in early-onset CRC remains unclear, which has led to interest in understanding clinical and molecular differences between younger and older cohorts. “There’s data that suggest they’re very similar to older patients. They certainly do not have more obesity. Their body mass index [BMI], for example, is the same between the different age groups,” Michael A. Morse, MD, said.

The data Morse referenced came from a poster that Iyer et al presented at the 2018 Gastrointestinal Cancers Symposium.⁷ In this retrospective study of patients with CRC treated at the University of Colorado between 2008 and 2015, molecular differences were compared between younger (<50 years; n = 58) and older patients (≥50 years; n = 183). The researchers observed that a higher percentage of the younger cohort was nonsmokers and that younger patients had significantly lower rates of APC and BRAF mutations, with no mutations found to be more prevalent in the younger versus older cohort. Younger patients also had similar BMI compared with older patients (27.0 vs 25.7, respectively; P = .35). These findings suggest that neither mutational differences nor obesity play a major role in the development of early-onset CRC.

“[Based on these data,] I think that you would want to look for something environmental or something habit based. It seems like that would be the obvious thing, but until we can collect enough data from a large enough number of people, I just don’t see how we’re going to tease it out,” Morse said.

One key area that is actively being explored is the gut microbiome, since the concept of microbe-driven cancers is well recognized across the cancer spectrum. In CRC, there is already some evidence to suggest that specific bacteria may serve as potentiators of tumorigenesis, such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and colibactinproducing Escherichia coli.⁸

Treatment Approaches

Marshall and Eng reported being involved in research aimed at determining which factors may be contributing to the dramatic rise in CRC among younger patients. “Maybe, just maybe, we’ll figure out some science that brings new stuff to the table that might affect screening or might tell us which yogurt to eat or whatever it will be to prevent the disease,” Marshall suggested.Determining how best to treat younger patients has been challenging. “As we’ve suggested, the biology is so much different; it has to be. Tumors are mostly left sided, which we think is better, but they are more aggressive. They don’t seem to respond as well. But we just don’t have good information on the biology to know what to do differently, so I think we’re kind of forced into doing what we do with everyone else until we know better,” Dale R. Shepard, MD, PhD, FACP, said.

Special Considerations

Although there are no special treatment regimens for younger patients, some panelists indicated being a bit more aggressive in their approach. “In the metastatic disease setting, I will be more aggressive than normal on these young patients because their performance status is usually fairly good,” Eng said, noting she particularly favors using FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) in these patients. When deciding on the duration of adjuvant therapy (eg, 6 vs 3 months), she said she looks at all the usual data to make her decision.The panelists agreed that it is important to discuss fertility preservation with young patients with CRC. “We don’t discuss that very much with our patients because usually they’re past those ages. But it’s becoming an increasing issue with banking, whether it’s for sperm [or eggs],” said Marshall.

The costs of fertility preservation can be high. Sperm banking is estimated to cost $500 to $1000 up front, with additional storage charges of $150 to $400 annually; egg or embryo freezing costs can be more than $10,000 per cycle, with storage charges of up to $600 annually.⁹ Several resources are available that can help patients access fertility preservation information and resources and to subsidize costs (Table 2).

The panel also recommended performing next-generation sequencing in young patients with CRC. “Know as much as you can about their disease walking into it, because if something is there, you might be able to help treat it. You might find something that’s more genetically linked. So that way you’re able to both take care of them and their families better,” Bendell said.

Regardless of patient age, the panel members concurred that knowing RAS, KRAS, and NRAS mutational status is important, with extended RAS testing being ideal. BRAF mutational status and microsatellite instability were also considered important. There was some debate about HER2 testing, which is still emerging as a biomarker in the CRC space.

Table 2. Oncology Patient and Clinician Resources for Fertility Preservation

Conclusions

“I think of HER2 as what BRAF used to be. It’s a small percentage of patients, but this is a patient population that likely has another treatment option available to them,” Bendell said, noting that clinical trials with targeted agent combinations are showing response rates of 35% to 40%. As an example, in the phase II MyPathway trial, which included 37 patients with HER2-amplified/overexpressed metastatic CRC who had exhausted all standard treatments, use of a combination of trastuzumab (Herceptin) and pertuzumab (Perjeta) led to an objective response rate of 38%.¹⁰Because drivers of early-onset CRC remain unclear, there are no CRC screening guidelines for younger patients. Subsequently, many patients with early-onset CRC are being diagnosed at later stages, many times because their signs and symptoms are dismissed as innocuous conditions. The panelists encouraged clinicians to take any signs and symptoms of CRC seriously, regardless of the patient’s age. “There are so many people who don’t get the necessary screening. We know that survival is so much greater if you find an early tumor instead of a late tumor,” Shepard concluded.

Reference

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4. Wolf AMD, Fontham ETH, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society [published online May 30, 2018]. CA Cancer J Clin. doi: 10.3322/caac.21457.
5. Segev L, Kalady MF, Church JM. Left-sided dominance of early-onset colorectal cancers: a rationale for screening flexible sigmoidoscopy in the young [published online May 15, 2018]. Dis Colon Rectum. doi: 10.1097/DCR.0000000000001062.
6. Hilsden RJ, Rostom A. Colorectal cancer screening using flexible sigmoidoscopy: United Kingdom study demonstrates significant incidence and mortality benefit. Can J Gastroenterol. 2010;24(8):479-480.
7. Iyer P, Wong K, Lieu CH, et al. Clinical and molecular characteristics of young versus older patients with colorectal cancer. Poster presented at: Gastrointestinal Cancer Symposium; January 18-20, 2018; San Francisco, CA. Abstract 630. meetinglibrary.asco.org/ record/155677/abstract.
8. Brennan CA, Garrett WS. Gut microbiota, inflammation, and colorectal cancer. Annu Rev Microbiol. 2016;70:395-411. doi: 10.1146/annurev- micro-102215-095513.
9. Paying for treatments. How much does fertility preservation cost? Alliance for Fertility Preservation website. allianceforfertilitypreservation. org/costs/paying-for-treaments. Accessed June 20, 2018.
10. Hainsworth JD, Meric-Bernstam F, Swanton C, et al. Targeted therapy for advanced solid tumors on the basis of molecular profiles: results from MyPathway, an open-label, phase IIa multiple basket study. J Clin Oncol. 2018;36(6):536-542. doi: 10.1200/JCO.2017.75.3780.