The Rise of Early-Onset Colorectal Cancer: Clinical Characteristics an

Introduction

Colorectal cancer (CRC) remains a major global health challenge, ranking as the third most commonly diagnosed cancer and the second leading cause of cancer-related mortality worldwide.1,2 While incidence in older adults has stabilized or declined in many high-income countries, largely due to screening and preventive strategies, there is growing concern about the rising incidence of CRC among individuals aged ≤50 years, a group classified as having EOCRC.3,4

EOCRC often presents with distinct clinical and pathological features, including a higher likelihood of left-sided or rectal tumors, mucinous or signet ring histology, and more advanced stage at diagnosis.5,6 Despite emerging data, the etiologic drivers remain poorly understood. Lifestyle changes, increasing prevalence of obesity, and rising exposure to ultra-processed foods (UPFs) have been implicated, particularly in rapidly developing countries.7,8

Prompted by these trends, multiple professional societies now recommend initiating CRC screening before age 50, with modeling studies supporting the cost-effectiveness and survival benefits of starting as early as age 40.9,10 However, most existing data originate from Western populations, and the presentation and outcomes of EOCRC in non-Western settings remain underexplored.

In Saudi Arabia, CRC is the most common malignancy in men and the second most common in women, with a steadily increasing incidence over recent decades.11 National registry data indicate a rising incidence of EOCRC, particularly among individuals aged 40–49, with women demonstrating slightly higher rates than men.12 Recent institutional findings further highlight a higher prevalence of aggressive histologic subtypes and adverse prognostic features among young Saudi patients.13

Given this growing burden, understanding the clinical behavior, treatment patterns, and survival outcomes of EOCRC in Saudi Arabia is critical. This study aims to describe the clinicopathologic characteristics and real-world outcomes of EOCRC patients treated at a tertiary cancer center in Saudi Arabia and to identify key prognostic factors influencing survival.

MethodsStudy Design and Population

This retrospective cohort study included all patients aged 50 years or younger who were diagnosed with histologically confirmed colorectal adenocarcinoma at King Abdullah Medical City (KAMC), Makkah, Saudi Arabia, between January 2015 and December 2021. Eligible patients were identified from a prospectively maintained institutional oncology registry and supplemented by electronic medical record review.

Inclusion criteria were age ≤50 years at diagnosis, confirmed colorectal adenocarcinoma, including mucinous and signet ring subtypes and diagnosis and/or treatment at KAMC during the study period. Only patients with complete clinical, treatment, and survival data were included. Exclusion criteria included non-adenocarcinoma histologies (eg, neuroendocrine tumors, lymphomas), secondary colorectal involvement from non-colorectal primaries, or incomplete medical records precluding analysis of key outcomes.

Due to the retrospective design, no formal sample size calculation was performed. All eligible patients within the study period were included, yielding a total cohort of 97 patients.

Data Sources and Measurement

Clinical, pathological, and treatment-related data were extracted from the institutional electronic health record system and the KAMC oncology registry. Data were cross-validated using multiple sources, including pathology reports, chemotherapy order systems, and clinician documentation. Information bias was minimized by cross-referencing these data and performing manual chart reviews by senior oncology staff, with discrepancies resolved through consensus. Tumor staging was determined using the American Joint Committee on Cancer (AJCC) criteria at diagnosis. When available, molecular data, including microsatellite instability (MSI) status and rat sarcoma viral oncogene (RAS) and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations, were obtained from institutional or outsourced panel testing. Comprehensive next-generation sequencing was not uniformly performed, and extended sequencing data were not included in the analysis. Germline testing, now guideline-recommended for EOCRC, was not systematically performed during the study period due to limited access to genetic counseling and testing infrastructure at our institution.

Data Collection and Variables

Collected variables included demographic information (age, sex, body mass index [BMI]), Eastern Cooperative Oncology Group (ECOG) performance status, carcinoembryonic antigen (CEA) level at diagnosis, tumor site, clinical stage, histologic subtype, molecular profile (MSI, RAS, BRAF), and metastatic distribution. Treatment variables included surgical intervention, surgical intent (curative vs palliative), receipt of adjuvant therapy, and systemic therapy regimens stratified by line and class (eg, oxaliplatin-based regimens such as capecitabine plus oxaliplatin [XELOX] or folinic acid, fluorouracil, and oxaliplatin [FOLFOX]; irinotecan-based regimens such as folinic acid, fluorouracil, and irinotecan [FOLFIRI] or capecitabine plus irinotecan [XELIRI]; capecitabine-based monotherapy; and late-line agents such as trifluridine/tipiracil [TAS-102] or regorafenib).

Tumor site classification followed anatomical groupings: right-sided colon cancer (cecum to transverse colon), left-sided colon cancer (splenic flexure to sigmoid colon), and rectal cancer. BMI was categorized as underweight (2.

Outcomes

The primary outcome was OS, defined as the interval from diagnosis to death from any cause or last known follow-up. PFS was measured from the start of each systemic therapy line to documented clinical or radiologic progression or death. Treatment exposure and PFS were reported by line of therapy and regimen class.

This manuscript was prepared in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for cohort studies.14

Statistical Analysis

All statistical analyses were performed using R software (version 4.3.2). Categorical variables were summarized as frequencies and percentages, while continuous variables were presented as means with standard deviations or medians with interquartile ranges, as appropriate.

Subgroup analyses were conducted for key clinical variables, including tumor stage, primary tumor site, ECOG, and treatment exposure. OS and PFS were estimated using the Kaplan–Meier method, and survival differences across subgroups were compared using the Log rank test.

Univariable and multivariable Cox proportional hazards regression models were used to identify predictors of OS. Variables with a p-value

Missing data were managed through case-wise deletion (complete-case analysis), with no imputation applied.

ResultsPatient Characteristics

Ninety-seven patients with EOCRC were included (Table 1). The median age at diagnosis was 43 years, and 55.7% were male. Nearly half were overweight or obese, and most had favorable ECOG performance status. Tumors predominantly arose in the rectum and left colon, with one-third of patients presenting with metastatic disease. Mucinous histology was observed in 13.4%, and RAS/BRAF mutations were identified in 14.5%. The liver was the most frequent metastatic site.

Table 1 Summary of Baseline Demographic, Clinical, and Tumor Characteristics of Patients Aged ≤50 Years with CRC

Treatment Patterns

Surgery was performed in 79.4% of patients, with curative intent in 71.1% (Table 2). Adjuvant chemotherapy was administered in less than half of eligible cases, most commonly with XELOX.

Table 2 Summary of Treatment Patterns in Young CRC Patients (n = 97)

Systemic Therapy by Line and Regimen

Of the entire cohort, 39.2% received first-line systemic therapy, 27.8% proceeded to second-line, and 13.4% proceeded to third-line. (Table 3). Oxaliplatin-based regimens predominated in first line, while irinotecan-based regimens were more frequent in second line. Use of late-line agents (TAS-102 or regorafenib) was limited to 8.2%.

Table 3 Systemic Therapy Regimen Categories by Line of Treatment (n = 97)

Survival Outcomes

Median overall survival (OS) was 20.2 months, while the 5-year OS probability was 55%, reflecting a skewed survival distribution driven by a subset of long-term survivors (Figure 1). Median progression-free survival (PFS) declined across successive lines (8.2, 6.4, and 4.1 months), underscoring the limited durability of current systemic therapy (Table 4).

Table 4 Survival and Progression-Free Outcomes

Figure 1 Kaplan–Meier overall survival (OS) curve for the entire cohort (n = 97). Shaded area represents the 95% confidence interval. The survival curve illustrates a skewed distribution, with a subset of long-term survivors accounting for the observed 5-year OS of ~55% despite the earlier median of 20.2 months.

Prognostic Factors

On univariable analysis, metastatic stage at diagnosis and lack of surgery or adjuvant therapy were significantly associated with poorer OS (Table 5). On multivariable analysis, obesity independently predicted worse OS (HR 6.63, 95% CI 1.14–38.50; p = 0.035), alongside metastatic stage at diagnosis (HR 10.92, 95% CI 1.42–83.70; p = 0.021). Other factors, including ECOG, primary tumor site, and adjuvant therapy, were not independently significant (Table 6). Non-significant p-values were reported to two decimals.

Table 5 Univariable Cox Proportional Hazards Regression for Overall Survival

Table 6 Multivariable Cox Proportional Hazards Regression for Overall Survival

Discussion

This single-institution analysis provides novel insights into early-onset colorectal cancer (EOCRC) in a Middle Eastern cohort, an underrepresented population in the global EOCRC literature. We identified four major findings: (i) a substantial proportion of patients presented with advanced or metastatic disease, (ii) obesity emerged as an independent adverse prognostic factor for overall survival (OS), (iii) adjuvant therapy was underutilized despite curative resections, and (iv) systemic therapy demonstrated limited durability across successive lines. Together, these findings highlight the aggressive clinical behavior and unique care gaps in EOCRC within non-Western settings.

Over one-third of our patients presented with de novo metastatic disease, consistent with meta-analyses showing EOCRC is more often diagnosed at advanced stages than late-onset CRC.15 The liver was the predominant metastatic site, consistent with classical dissemination patterns and findings by Sharma et al.16 This figure is higher than typically observed in late-onset CRC but consistent with EOCRC cohorts such as Saraste et al,17 and Georgiou et al.18 Such patterns emphasize persistent diagnostic delays and low clinical suspicion in this age group, reducing opportunities for curative treatment.19

Tumor sidedness in our cohort favored left-sided and rectal primaries, while right-sided tumors, typically linked with adverse biology were less common, consistent with Angelakas et al and Baran et al20,21 RAS and BRAF mutations were detected at lower frequencies than in older-onset CRC, possibly reflecting distinct EOCRC biology or limited testing access. Akkus et al,22 linked higher RAS mutation rates to with recurrence risk, underscoring the value of routine molecular profiling in younger patients. By contrast, Cercek et al,23 reported no major genomic differences between EOCRC and older-onset CRC in microsatellite-stable tumors, suggesting that treatment should be guided by molecular features rather than age.

Surgery was undertaken in 79% of patients, with curative intent in 71%. Nevertheless, fewer than half of eligible patients received adjuvant chemotherapy, most often XELOX. In contrast, Western cohorts report adjuvant uptake rates exceeding 85%.17 This underutilization may reflect patient-level factors (toxicity concerns, treatment acceptance), physician decision-making, or system-level barriers to access. Given the high relapse risk in EOCRC despite aggressive therapy, suboptimal use of adjuvant chemotherapy represents a modifiable gap in care.

The sharp decline in PFS across successive lines underscores the limited long-term effectiveness of standard regimens in EOCRC, despite patients’ young age and preserved fitness. The minimal use of later-line agents (≤8%) highlights restricted therapeutic options and reflects either tolerance issues or access barriers. These findings mirror attrition patterns in other EOCRC cohort reported by Georgiou et al,18 and emphasize the urgent need for novel strategies such as biomarker-guided intensification, immunotherapy combinations, and broader clinical trial participation to extend survival beyond early treatment lines.

Despite their younger age and presumed better fitness, patients in our cohort experienced poor survival, with only a modest difference between localized and metastatic disease. This narrow separation underscores the biological aggressiveness of EOCRC and mirrors similarly unfavorable outcomes reported by Georgiou et al.18 By contrast, studies showing longer survival in resected, left-sided, or rectal primaries highlight the prognostic importance of tumor site and surgical resectability.24

Our analysis identified obesity as an independent adverse prognostic factor, emerging alongside advanced stage as a key driver of poor outcomes. This observation challenges the so-called “obesity paradox” described in older CRC populations, where excess body weight has sometimes been associated with improved outcomes. Instead, our findings align with growing evidence that metabolic dysregulation accelerates EOCRC risk and fuels its biological aggressiveness. The high prevalence of overweight and obese individuals in our cohort reflects regional lifestyle patterns and underscores the importance of metabolic health in shaping disease trajectory. Conventional markers including performance status, tumor location, and adjuvant therapy, did not retain significance after adjustment, highlighting obesity as a biologically distinct determinant of prognosis. Taken together, these findings reinforce EOCRC as a unique clinical and biologic entity, echoing Xu et al,25 who emphasized the need for integrative models that combine clinical, genomic, and metabolic dimensions. They also support Chen et al,26 who linked metabolic dysregulation to increased EOCRC risk, underscoring obesity not merely as a comorbidity but as a central factor in the pathogenesis and outcomes of this rising disease.

This real-world analysis provides a comprehensive dataset encompassing clinical, molecular, and treatment-related variables across the EOCRC continuum. The inclusion of data on multi-line systemic therapy, adjuvant utilization, and survival outcomes enhances the clinical applicability of our findings.

Nevertheless, the retrospective design introduces important limitations, including documentation inconsistencies and potential selection bias. Details of surgery and radiotherapy, particularly for rectal cancer, were not systematically captured, limiting assessment of local control strategies. Similarly, treatment adherence, toxicity, and reasons for adjuvant omission were unavailable, constraining insight into therapeutic decision-making. The absence of extended molecular profiling (eg, MSI, tumor mutational burden, germline testing) and family history data restricts biologic interpretation. Germline testing, now guideline-recommended for all EOCRC patients,27 was not uniformly available during our study period, limiting our ability to assess hereditary contributions. Its systematic integration is critical for identifying hereditary syndromes, refining risk stratification, and guiding management in this young population.28 Moreover, the lack of a late-onset comparator arm precluded direct age-based comparisons. Finally, the relatively small sample size, interdependence of variables, and small subgroup numbers increase the risk of chance findings, limiting the robustness of multivariable Cox regression results. These prognostic associations should therefore be interpreted with caution.

Our results are consistent with global observations of late-stage EOCRC presentation, including among individuals without overt risk factors, reinforcing the call to revisit screening approaches in high-incidence populations.29 Patterns of adjuvant therapy underutilization and treatment sequencing, even among patients with favorable performance status, highlight an opportunity to optimize care delivery. The modest prevalence of RAS/BRAF mutations and predominance of distal tumors further underscore the need for subtype-specific research. Early therapeutic intensification and personalized care pathways may help improve outcomes in this distinct patient group.

Future multicenter studies with larger sample sizes, integrated molecular profiling, and age-matched comparators are essential to unravel the heterogeneity of EOCRC and refine age-specific treatment strategies. Expanding biomarker-driven and immunotherapy research in this population will guide the development of novel therapeutic approaches. Beyond treatment, research must address the psychosocial and economic challenges unique to younger patients. Embedding survivorship care, fertility preservation, and quality-of-life measures into clinical pathways is critical. Given its rising incidence, EOCRC warrants urgent integration into clinical guidelines, research priorities, and public health strategies.

In conclusion, this study underscores the aggressive clinical behavior and unique management challenges of EOCRC. Despite their younger age and favorable fitness, many patients presented with advanced-stage disease, adjuvant therapy was underutilized, and systemic regimens showed limited durability. Obesity, alongside metastatic presentation, emerged as a distinct adverse prognostic factor, reinforcing the need to integrate metabolic health into risk stratification. Together, these findings highlight EOCRC as a biologically aggressive and clinically unique entity that requires earlier detection strategies, optimized treatment pathways, and molecularly informed precision care. As incidence continues to rise, EOCRC warrants prioritization in clinical guidelines, research agendas, and public health policies.

Data Access and Responsibility

Emad Tashkandi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Abbreviations

AJCC, American Joint Committee on Cancer; BMI, body mass index; CEA, carcinoembryonic antigen; CI, confidence interval; CRC, colorectal cancer; ECOG, Eastern Cooperative Oncology Group; EOCRC, early-onset colorectal cancer; HR, hazard ratio; IQR, interquartile range; IRB, Institutional Review Board; KAMC, King Abdullah Medical City; MSI, microsatellite instability; OS, overall survival; PFS, progression-free survival; RAS, rat sarcoma viral oncogene; BRAF, v-raf murine sarcoma viral oncogene homolog B1; TMB, tumor mutational burden; UPF, ultra-processed foods; XELOX, capecitabine plus oxaliplatin; FOLFOX, folinic acid, fluorouracil, and oxaliplatin; FOLFIRI, folinic acid, fluorouracil, and irinotecan; TAS-102, trifluridine/tipiracil.

Data Sharing Statement

The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.

Ethics Statement

The study protocol was approved by the IRB of KAMC, Makkah, Saudi Arabia (IRB no. 22-965). The need for informed consent was waived because de-identified data was used. All procedures were performed in accordance with the principles outlined in the Declaration of Helsinki.

Acknowledgments

The author gratefully acknowledges Ms. Ruqqaya Azhar for her contributions to data handling and statistical coordination. The author also recognizes the assistance of senior oncology staff who supported blinded data extraction and chart review; their contributions did not meet the authorship criteria of the International Committee of Medical Journal Editors (ICMJE) and are therefore appropriately acknowledged here. This study was conducted using data from the Cancer Center at KAMC in Makkah, Saudi Arabia. The study protocol was approved by the Institutional Review Board (IRB) at KAMC (IRB no. 25-1413). As Umm Al-Qura University does not have a hospital or cancer center for clinical research, IRB approval from KAMC was essential to access patient data and conduct this study. The author also acknowledges the support of the KAMC Cancer Center in facilitating this research.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Disclosure

The authors declare no conflicts of interest.

References

1. Duan B, Zhao Y, Bai J, et al. Colorectal cancer: an overview. Gastrointest Cancers. 2022;2022:1–12.

2. Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023;73(3):233–254. doi:10.3322/caac.21772

3. Patel SG, Karlitz JJ, Yen T, Lieu CH, Boland CR. The rising tide of early-onset colorectal cancer: a comprehensive review of epidemiology, clinical features, biology, risk factors, prevention, and early detection. Lancet Gastroenterol Hepatol. 2022;7(3):262–274. doi:10.1016/S2468-1253(21)00426-X

4. Saad El Din K, Loree JM, Sayre EC, et al. Trends in the epidemiology of young-onset colorectal cancer: a worldwide systematic review. BMC Cancer. 2020;20(1). doi:10.1186/s12885-020-06766-9

5. Gausman V, Dornblaser D, Anand S, et al. Risk factors associated with early-onset colorectal cancer. Clin Gastroenterol Hepatol. 2020;18(12):2752–2759.e2. doi:10.1016/j.cgh.2019.10.009

6. Patel SG, Boland CR. Genetic testing use and expectations in early onset colorectal cancer. Curr Treat Options Gastroenterol. 2020;18(4):589–603. doi:10.1007/s11938-020-00308-9

7. Baker P, Machado P, Santos T, et al. Ultra-processed foods and the nutrition transition: global, regional and national trends, food systems transformations and political economy drivers. Obes Rev. 2020;21(12). doi:10.1111/obr.13126

8. Faienza MF, Chiarito M, Molina-Molina E, et al. Childhood obesity, cardiovascular and liver health: a growing epidemic with age. World J Pediatr. 2020;16(5):438–445. doi:10.1007/s12519-020-00341-9

9. Knudsen AB, Rutter CM, Peterse EFP, et al. Colorectal cancer screening: an updated modeling study for the US preventive services task force. JAMA. 2021;325(19):1998–2011. doi:10.1001/jama.2021.5746

10. Azad NS, Leeds IL, Wanjau W, Shin EJ, Padula WV. Cost-utility of colorectal cancer screening at 40 years old for average-risk patients. Prev Med. 2020;2020:133.

11. Elwali NE, Jarrah O, Alzahrani SG, et al. Colorectal cancer in saudi arabia: the way forward. Asian Pac J Cancer Prev. 2023;24(1):13. doi:10.31557/APJCP.2023.24.1.13

12. Alyabsi M, Algarni M, Alshammari K. Trends in colorectal cancer incidence rates in Saudi Arabia (2001–2016) using Saudi national registry: early- versus late-onset disease. Front Oncol. 2021;11:730689. doi:10.3389/fonc.2021.730689

13. Aldriwesh MG, Aljaian AR, Alorf KM, et al. Comparative analysis of the clinical aspects of colorectal cancer in young adult and older adult patients in Saudi Arabia. Front Oncol. 2024;14:1460636. doi:10.3389/fonc.2024.1460636

14. Vandenbroucke JP, von Elm E, Altman DG, et al. Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration. Int J Surg. 2014;12(12):1500–1524. doi:10.1016/j.ijsu.2014.07.014

15. Carbone F, Spinelli A, Ciardiello D, et al. Prognosis of early-onset versus late-onset sporadic colorectal cancer: systematic review and meta-analysis. Eur J Cancer. 2025;2025:215.

16. Sharma V, Sharma A, Raina V, et al. Metastatic colo-rectal cancer: real life experience from an Indian tertiary care center. BMC Cancer. 2021;21(1):1–12. doi:10.1186/s12885-021-08398-z

17. Saraste D, Järås J, Martling A. Population-based analysis of outcomes with early-age colorectal cancer. Br J Surg. 2020;107(3):301–309. doi:10.1002/bjs.11333

18. Georgiou A, Khakoo S, Edwards P, et al. Outcomes of patients with early onset colorectal cancer treated in a UK specialist cancer center. Cancers. 2019;11(10):1558. doi:10.3390/cancers11101558

19. Mauri G, Patelli G, Crisafulli G, Siena S, Bardelli A. Tumor “age” in early-onset colorectal cancer. Cell. 2025;188(3):589–593. doi:10.1016/j.cell.2024.12.003

20. Angelakas A, Christodoulou T, Kamposioras K, et al. Is early-onset colorectal cancer an evolving pandemic? Real-world data from a tertiary cancer center. Oncologist. 2024;29(12):e1680. doi:10.1093/oncolo/oyae239

21. Baran B, Ozupek NM, Tetik NY, Acar E, Bekcioglu O, Baskin Y. Difference between left-sided and right-sided colorectal cancer: a focused review of literature. Gastroenterol Res. 2018;11(4):264. doi:10.14740/gr1062w

22. Akkus E, Karaoğlan BB, Kayaalp M, Turmuş U, Akyol C, Utkan G. Stage-specific characterization of “early-onset colorectal cancer”: localized and synchronous metastatic disease. Int J Cancer. 2025;156(12):2340–2351. doi:10.1002/ijc.35336

23. Cercek A, Chatila WK, Yaeger R, et al. A comprehensive comparison of early-onset and average-onset colorectal cancers. J Natl Cancer Inst. 2021;113(12):1683–1692. doi:10.1093/jnci/djab124

24. Zaborowski AM, Murphy B, Creavin B, et al. Clinicopathological features and oncological outcomes of patients with young-onset rectal cancer. Br J Surg. 2020;107(5):606–612. doi:10.1002/bjs.11526

25. Xu P, Tao Z, Yang H, Zhang C. Obesity and early-onset colorectal cancer risk: emerging clinical evidence and biological mechanisms. Front Oncol. 2024;14:1366544. doi:10.3389/fonc.2024.1366544

26. Chen H, Zheng X, Zong X, et al. Metabolic syndrome, metabolic comorbid conditions and risk of early-onset colorectal cancer. Gut. 2021;70(6):1147–1154. doi:10.1136/gutjnl-2020-321661

27. Cavestro GM, Mannucci A, Balaguer F, et al. Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) international management guidelines. Clin Gastroenterol Hepatol. 2023;21(3):581–603.e33. doi:10.1016/j.cgh.2022.12.006

28. Zinkeng A, Taylor FL, Cheong SH, Song H, Merchant JL. Early onset colorectal cancer: molecular underpinnings accelerating occurrence. CMGH. 2025;19(2). doi:10.1016/j.jcmgh.2024.101425

29. Sung H, Siegel RL, Laversanne M, et al. Colorectal cancer incidence trends in younger versus older adults: an analysis of population-based cancer registry data. Lancet Oncol. 2025;26(1):51–63. doi:10.1016/S1470-2045(24)00600-4