The Young: Early-Onset Colon Cancer

Abstract

Early-onset colorectal cancer (EO-CRC), characterized by diagnosis before the age of 50 years, has emerged as a significant healthcare challenge with increasing global incidence. While traditional risk factors such as family history and inherited syndromes contribute to EO-CRC, a substantial proportion of cases remain sporadic, necessitating further investigation into additional etiological factors. Molecular studies reveal heterogeneity in EO-CRC, with distinct mutational profiles compared to late-onset CRC. Clinical management presents unique considerations, including challenges in early detection and treatment strategies tailored to younger patients. Addressing EO-CRC requires a multidisciplinary approach integrating epidemiological, molecular, and clinical insights to improve prevention, diagnosis, and therapeutic outcomes. Emerging research avenues explore novel biomarkers and therapeutic targets, offering promise for advancing understanding and management of this disease in contemporary oncology practice.

In recent years, the landscape of colorectal cancer has undergone a significant shift with a concerning rise in diagnosis among younger populations. The term “early-onset colorectal cancer” (EO-CRC) has emerged, defining a distinct subset characterized by diagnosis occurring before the age of 50 years. This phenomenon, once an anomaly, has become increasingly prevalent, posing a substantial challenge to healthcare systems worldwide. In this article, we delve into the comprehensive literature surrounding EO-CRC, exploring the burgeoning significance it holds within oncology and the escalating concerns that accompany this disturbing trend. As this enigmatic disease pattern continues to perplex medical communities, understanding its nuances becomes paramount for effective prevention, diagnosis, and treatment.

Epidemiology

Over the past 30 years, colorectal cancer (CRC) incidence and mortality have been steadily decreasing in those who are 50 and older (late-onset CRC [LO-CRC]). Nevertheless, the incidence of EO-CRC has been increasing globally over the past several decades. In the United States, EO-CRC incidence increased from 8.6 to 12.9 per 100,00 from 1992 to 2018. ¹ A similar trend has been seen across Europe, where the incidence of CRC across 20 European countries increased by 7.9% in individuals aged 20 to 29, 4.9% in individuals aged 30 to 39, and 1.6% in individuals aged 40 to 49 from 2004 to 2016. ² Of note, prevailing literature on EO-CRC focuses on individuals of European descent, a trend attributed to the limited sample size derived from non-white patients. ³ This discrepancy will be expanded upon further, later in this article.

Rectal cancers initially drove the increase in EO-CRC in the United States with an average annual percentage change in the incidence of rectal cancer of 4.3% in individuals younger than 50 years from 1995 to 2010. ⁴ However, in the last decade, the increase in incidence of rectal cancer has slowed down to 2% per year versus 0.5 and 1.6% per year for tumors in the proximal and descending colon, respectively. ⁵ Approximately 10% of all new diagnoses of CRC in the United States are now early onset, and following this trend in the next 10 years, early-onset CRC will make up 25% of rectal cancers and 10 to 12% of colon cancers. ^{6 7 8}

Risk Factors

Nonmodifiable

There are several well-known risk factors associated with EO-CRC, including a positive family history of CRC, inherited syndromes, such as Lynch syndrome or familial adenomatous polyposis (FAP), as well as inflammatory bowel disease (IBD). However, the rise of EO-CRC cannot be fully explained by only these factors. In fact, up to 80% of EO-CRC cases are sporadic, or not inherited, with only 26% of cases having a familial component and 20% of cases with an identifiable germline mutation. ^{9 10} Similarly, IBD has been implicated in less than 5% of EO-CRC cases. ¹¹

Cohort Effect

The rise of EO-CRC since the 1980s can be explained by a birth-cohort effect, wherein distinct groups of individuals born in the same generation exhibit a heightened risk of CRC with advancing age. ^{2 12 13 14} Siegel et al evaluated age-specific trends by birth cohort from 1974 to 2013 and found that people born after the 1950s have a significantly higher age-specific risk of colon cancer compared with those born before them. ¹² This is in stark contrast to the declining risk of CRC in successive cohorts from the late 1800s to 1950. Specifically, compared with people born around 1950, those born in the late 1800s had double the age-specific risk of colon cancer (incidence rate ratio [IRR] = 2.12, 95% confidence interval [CI] = 1.91–2.36) and triple the risk of rectal cancer (IRR = 2.12, 95% CI = 2.71–3.47). This risk decreased in successive generations born through the early 1900s, until around 1950. Since 1950, successive generations have increased age-specific risk of colon cancer to the point where the relative risks in the youngest birth cohort (those born in the 2010s) are similar to those born in the 1890s for both colon (IRR = 2.12, 95% CI = 1.91–2.36) and rectal cancer (IRR = 4.32, 95% CI = 2.19–8.51). ¹²

Modifiable

The association between the escalation of EO-CRC within contemporary birth cohorts and the escalating presence of obesity has been well documented. O'Sullivan et al performed a meta-analysis of all studies investigating nongenetic risk factors for EO-CRC through 2020. Twenty studies were included in their review, which found a significant risk of EO-CRC with obesity (relative risk [RR]: 1.54, 95% CI: 1.01–2.35). ¹⁵ This substantiates the direct implication of lifestyle components, such as dietary patterns and physical activity, in modulating the age of onset (Li et al., 2022 ¹⁶ ). Supplementary contributing factors include hyperlipidemia (RR: 1.62, 95% CI: 1.22–2.13) and alcohol consumption (RR: 1.71, 95% CI: 1.62–1.80). ¹⁵ Although smoking is posited as a potential influencing factor, empirical findings did not reveal statistically significant associations.

Molecular Characteristics and Pathophysiology

Evidence points to sporadic EO-CRC representing a genetically and pathologically heterogeneous group of cancers. While familial syndromes and germline mutations account for some proportion of EO-CRC, they do not fully explain the rise we are seeing. Approximately 30% of EO-CRC cases report a family history of related cancers, yet only 10 to 20% of these patients have a known genetic risk factor, like FAP, Lynch syndrome, or IBD. ^{3 16 17} Only 15 to 20% of EO-CRCs are reported as microsatellite instability-high (MSI-H), reflecting Lynch syndrome and Lynch-like syndromes, compared to 10 to 15% of CRC reported in age-agnostic studies of CRC. ^{13 17 18} If a rise in MSI-H tumors were driving EO-CRC, we would predictably see an increased prevalence of less aggressive, right-sided tumors, which has not been the case. ^{18 19}

Sporadic cancers, in which patients have no known familial predisposition, represent the vast majority of EO-CRC. As such, significant efforts have been made to identify any unique mutational signatures of sporadic EO-CRC. Individual studies have found EO-CRC to have significantly decreased prevalence of adenomatous polyposis coli (APC) gene and Wnt pathway mutations compared to LO-CRC. ^{3 20 21 22} APC mutations are the hallmark first step of the traditional canonical “adenoma–carcinoma sequence.” The APC gene is a tumor-suppressor gene that helps regulate the Wnt signaling pathway involved in cell growth and differentiation. ²³ APC mutations lead to activation of the Wnt pathway, promoting uncontrolled cell growth. A decrease in the prevalence of BRAF mutations has also been noted in EO-CRC. ^{3 24} The BRAF gene encodes a protein kinase involved in cell signaling pathways. Mutations in the BRAF gene can lead to abnormal activation of these pathways, resulting in the development of CRC. BRAF mutations are often found in MSI-H CRC, are implicated in the serrated neoplasia pathway, and portend a poor prognosis. ²⁵

Epigenetic alterations have also been explored, with sporadic EO-CRC having increased prevalence of long-interspersed nucleotide element 1 hypomethylation but a lower prevalence of the CpG island methylator phenotype than LO-CRC. ^{3 13 18 26} CRC is often categorized into consensus molecular subtypes (CMS). CMS1 is characterized by MSI-H status and strong immune reaction; CMS2 involves in the activation of WNT and MYUC signaling pathways; CMS3 shows a specific metabolic signature; and CMS4 is associated with the epithelial–mesenchymal transition and immunosuppression. ^{3 21 27} Willauer et al. found that patients younger than 40 years were more likely to exhibit CMS1, whereas CMS3 and CMS4 were relatively uncommon. ²¹ These findings did not distinguish between familial and sporadic EO-CRC cases and likely reflect the high proportion of MSI-H EO-CRC cases associated with Lynch syndrome. Several studies have identified unique pathologic characteristics of EO-CRC, such as poor tumor cell differentiation and the presence of signet ring pathology. ¹³ Signet ring carcinoma accounts for less than 2% of CRC in patients older than 40 years but accounts for 6.1 to 6.4% of CRCs in patients <30 years of age and for 2.3 to 2.4% of CRCs in patients aged 30 to 39 years. ^{13 21}

Clinical Presentation and Diagnosis

In 2018, The American Cancer Society lowered the recommended screening age for average-risk individuals from 50 to 45 years, citing that this would lead to up to 50% of EO-CRC cases being identified at non-advanced stages. ²⁸ While this has aided in addressing those aged 45 to 50 years, patients younger than 45 years are still left out of routine screening protocols and there are still significant barriers for patients to receive diagnostic imaging or procedures, even when they present with typical CRC-related symptoms. Moreover, it should be noted that while screening colonoscopies are considered gold standard in many Western countries, other options, including stool-based testing are available and are a part of screening guidelines, which might lower the barrier to improve colon cancer screening in many communities. ²⁹

Patients with EO-CRC frequently present to their physicians with distinct cancer-related symptoms, often preceding the formal diagnosis date by 3 months to 2 years. ³⁰ These symptoms are often attributed to more common diagnoses in younger populations, such as hemorrhoids, IBD, or IBS and therefore appropriate diagnostics are forgone or significantly delayed. In an attempt to identify specific symptoms that should prompt further oncologic evaluation, Fritz et al performed a matched case–control study of 5,075 EO-CRC patients. ³⁰ They identified four “red-flag” signs and symptoms, including abdominal pain, rectal bleeding, diarrhea, and iron-deficiency anemia associated with a significant increased risk of EO-CRC. ^{30 31 32 33} Rectal bleeding in particular had the strongest association with CRC, with an odds ratio (OR) of 5.13% (95% CI 4.36–6.04). ^{30 34} Multiple “red flag” symptoms were also found to correlate with increased risk. For each additional “red-flag” sign or symptom, the risk of EO-CRC increased by 91% (OR: 1.91, CI: 1.78–2.05). ³⁰ Improving physician and patient awareness of these “red flag” symptoms and emphasizing thorough evaluations can help decrease the diagnostic interval and improve patient outcomes.

Racial Differences and Disparities

It is important to understand differences in the presentation of EO-CRC in different racial and ethnic groups, as these differences may lead to disparities in outcomes. For example, investigations have revealed notable trends regarding the influence of race on tumor localization. Notably, rectal cancer has emerged as the predominant subtype of EO-CRC. However, when looking at the racial demographics, there is a significantly higher incidence of rectal cancers in Caucasian populations (64.2%) compared to African Americans (39.1%). ³⁵ Conversely, African Americans exhibit a 37.5% higher likelihood of developing right colon cancer compared to Caucasians (18%). ³⁵ This demographic distinction holds substantial implications and warrants careful consideration. If a young patient presents with rectal bleeding, many practitioners may consider sigmoidoscopy as a reasonable next step given the predominance of left-sided tumors in young patients and ability to rule out other anorectal pathology. However, this modality would miss tumors in certain groups who are more prone to right-sided tumors. This example highlights the need for better diversity in scientific research and the potential for improved personalized medicine.

While existing research primarily compares Caucasian and African American populations, further investigation is also warranted to discern distinct patterns among Hispanic and non-Hispanic white ethnic/racial groups. Notably, a significant limitation in this research lies in access to screening and compliance, which correlates with factors such as educational attainment, socioeconomic status, and societal attitudes toward healthcare interventions. Many studies have demonstrated higher compliance to screening recommendations in older patient populations, as well as in white populations compared to younger or under-represented minorities. ^{36 37 38} Addressing these systemic obstacles to screening as well as other barriers, such as insurance companies withholding ethnicity and race data from research endeavors, is imperative for progress. ³⁰

Treatment Considerations

Younger patients with cancer present with unique challenges associated with treatment. In general, EO-CRC patients tend to have more preoperative treatment, aggressive surgical resections, and postoperative therapy than LO-CRC patients. ³⁹ The cause for this is likely multifactorial, including better preoperative health and fitness, as well as a desire to maximize outcomes and reduce the risk of recurrence. Gonadotoxicity and sexual dysfunction are well documented for patients with cancer, and patients with CRC are at a heightened risk for these side effects due to CRC-specific therapies, including pelvic radiation, pelvic surgical dissection, and cytotoxic chemotherapies. ^{40 41} As such, EO-CRC patients are at a uniquely heightened risk for sexual and reproductive consequences as a result of their pathology and treatment. In one study of 276 EO-CRC patients, erectile dysfunction was reported in 94.5% of males and female sexual dysfunction was reported in 81.6% of females. Only half of these patients reported having a discussion with their physician about sexual issues during or after treatment, despite the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) recommendations to have discussions about sexual function for patients with CRC at regular intervals, including at the time of diagnosis. ^{42 43 44}

Gonadotoxicity and infertility should also be addressed early in the treatment process. Adjunctive chemotherapy with infusion of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) has been shown to induce amenorrhea in women and cause temporary reduction in male fertility. ^{40 45 46} Additionally, pelvic radiation induces premature menopause in greater than 90% of patients and is one of the highest risks for acute ovarian failure in female patients. ^{40 47 48 49} As such, embryo and oocyte cryopreservation are considered standard of care for women desiring fertility preservation. ⁴⁹

Ovarian and uterine transposition surgeries are emerging as alternative solutions for fertility preservation prior to radiation treatment. In regions lacking infrastructure for long-term oocyte/embryo cryopreservation, these relatively simple procedures offer a technically easy and relatively cheap solutions. Large prospective studies are lacking, particularly in the United States; however, small cohort studies have demonstrated up to 90% preserved ovarian function after pelvic radiation with these procedures. ^{50 51 52} In one prospective study evaluating uterine transposition, eight patients (seven with rectal cancer) underwent uterine transposition followed by radiation therapy. The uterus was successfully preserved in six patients and two patients achieved spontaneous pregnancies and healthy cesarean deliveries without complication. Cervical ischemia was the most common postsurgical complication, occurring in three patients, and one patient presented with uterine necrosis 4 days after transposition, requiring hysterectomy. ⁵² It is important to note that ovarian and uterine transposition procedures are primarily meant to preserve hormonal function, not fertility. While natural pregnancy is possible, it remains quite rare after these procedures. In addition, the risk of ovarian metastasis is estimated to be between 3 and 14%. ^{53 54 55} For these reasons, pre-radiation oocyte extraction remains the mainstay of fertility preservation for those who have access and means. Further prospective trials must be completed to further evaluate efficacy and oncologic safety of these surgical procedures.

Unfortunately, only 19 states have laws that require some health coverage for infertility treatment as part of their state insurance statue as of 2023. ⁵⁶ Only half of these states have benchmark plans that require individual and small group plans to provide some form of infertility treatment coverage. Mandated coverage varies considerably across states with many not covering in vitro fertilization or medications, while some have specific diagnosis requirements or lifetime benefit maximums. ⁵⁶ Further epidemiologic studies to investigate fertility and sexual health specifically among patients with EO-CRC are essential to address this gap and help change the landscape of fertility coverage among young patients with cancer. ⁴⁰

Emerging Areas of Research

EO-CRC is hypothesized to have a distinct etiology and malignant transformation from LO-CRC. While individual studies have demonstrated unique mutational signatures in small cohorts, these findings are difficult to reproduce and often contradict each other from study to study. As a result, researchers have started exploring non-mutational alterations, including the tumor microenvironment, to explain the steady rise of EO-CRC. Preliminary studies suggest that an immune-cold microenvironment with impaired T cell infiltrate may promote tumorigenesis in EO-CRC. ^{57 58} Gardner et al demonstrated upregulation of complement genes C7 and CFD and the inflammatory gene SAA1 in EO-CRC compared with LO-CRC. ⁵⁸ While the exact role of these three genes is not yet fully understood, their upregulation suggests that EO-CRC may be associated with a unique tumor permissive immune phenotype. ^{58 59} Further studies are needed to test this hypothesis, and novel technologies, such as spatial transcriptomics, may better characterize the immune profile of EO-CRC compared to LO-CRC. Understanding the unique immune signature of EO-CRC may lead to the identification of biomarkers for early detection and unique dependences that can be exploited for therapeutics.

Conclusion

The surge in EO-CRC has emerged as a critical challenge in contemporary oncology, prompting a reevaluation of our understanding of this enigmatic disease. While several studies have found mutational differences in EO-CRC compared with LO-CRC, the general consensus is that EO-CRC is a heterogeneous group of cancers, molecularly similar to LO-CRC. Further research is ongoing into possible modifiable risk factors involved in early tumorigenesis as well as the unique immune signature of EO-CRC that may lead to improved testing and treatment modalities. Moving the screening age to 45 years for average-risk individuals has improved our ability to detect these cancers at an earlier stage, but significant work must be done to improve patient's and physician's awareness to “alarm symptoms” that would warrant diagnostic testing. When treating EO-CRC patients, it is important to understand the implications of chemo and radiation therapy on sexual function and fertility. Early discussions are imperative to address these problems and take steps to minimize the side effects of treatment.