A Comprehensive Comparison of Early-Onset and Average-Onset Colorectal Cancers

Abstract

Background: The causative factors for the recent increase in early-onset colorectal cancer (EO-CRC) incidence are unknown. We sought to determine if early-onset disease is clinically or genomically distinct from average-onset colorectal cancer (AO-CRC).

Methods: Clinical, histopathologic, and genomic characteristics of EO-CRC patients (2014-2019), divided into age 35 years and younger and 36-49 years at diagnosis, were compared with AO-CRC (50 years and older). Patients with mismatch repair deficient tumors, CRC-related hereditary syndromes, and inflammatory bowel disease were excluded from all but the germline analysis. All statistical tests were 2-sided.

Results: In total, 759 patients with EO-CRC (35 years, n = 151; 36-49 years, n = 608) and AO-CRC (n = 687) were included. Left-sided tumors (35 years and younger = 80.8%; 36-49 years = 83.7%; AO = 63.9%; P < .001 for both comparisons), rectal bleeding (35 years and younger = 41.1%; 36-49 years = 41.0%; AO = 25.9%; P = .001 and P < .001, respectively), and abdominal pain (35 years and younger = 37.1%; 36-49 years = 34.0%; AO = 26.8%; P = .01 and P = .005, respectively) were more common in EO-CRC. Among microsatellite stable tumors, we found no differences in histopathologic tumor characteristics. Initially, differences in TP53 and Receptor Tyrosine Kinase signaling pathway (RTK-RAS)alterations were noted by age. However, on multivariate analysis including somatic gene analysis and tumor sidedness, no statistically significant differences at the gene or pathway level were demonstrated. Among advanced microsatellite stable CRCs, chemotherapy response and survival were equivalent by age cohorts. Pathogenic germline variants were identified in 23.3% of patients 35 years and younger vs 14.1% of AO-CRC (P = .01).

Conclusions: EO-CRCs are more commonly left-sided and present with rectal bleeding and abdominal pain but are otherwise clinically and genomically indistinguishable from AO-CRCs. Aggressive treatment regimens based solely on the age at CRC diagnosis are not warranted.

Figure 1.

Overview of comparison groups. The figure shows the comparisons made between patients with EO-CRC and AO-CRC. AO = average onset; CRC= colorectal cancer; EO = early-onset; MSS = microsatellite stable.

Figure 2.

Clinical and tumor characteristics. Cancer-specific features of early-onset colorectal EO-CRC and AO-CRC by age at diagnosis: 35 years and younger, 36-49 (EO-CRC) and 50 years and older AO-CRC. A) Comparison of demographic, clinical, and tumor characteristics demonstrates that there is no significant difference in several characteristics, including sex and tumor grade distribution. Median body mass index was lower in the 35 years and younger cohort than in the AO-CRC cohort. B) Frequency of cancer-related presenting symptoms. C) Colorectal primary tumor location. AO = average onset; CRC = colorectal cancer; EO = early-onset; NOS = not otherwise specified.

Figure 3.

Somatic mutation analyses. Comparison of somatic tumor mutation analyses between EO-CRC and AO-CRC. A) Frequency of oncogenic alterations by age group (35 years and younger, 36-49, 50 years and older [AO-CRC]). B) Frequency of oncogenic alterations adjusted for primary tumor location (left vs right vs rectum) between the 35 years and younger and AO cohorts. C) Frequency of oncogenic alterations adjusted for primary tumor location (left vs right vs rectum) between the 36-49 and AO cohorts. D) Response to first-line chemotherapy. E) Survival outcomes by age groups. F) Multivariate survival analysis incorporating clinical and genomic characteristics that were statistically significant on univariate analysis, as well as age. All statistical tests were 2-sided. AIC = Akaike information criterion; AO = average onset; CI = confidence interval; CRC = colorectal cancer; EO = early-onset; FSM = first sites of metastasis; HAI = hepatic arterial infusion; Dif = differentiated; Mod = moderately; Pw = Pathway.

Figure 4.

Germline mutation analyses. A) Germline mutations by age group. B) Distribution of germline mutations by gene and penetrance by age group. An asterisk (*) next to a gene name designates the following: MUTYH, under low penetrance, represents the presence of monoallelic MUTYH variant; APC, under low penetrance, represents the APC p. Ile130Lys germline variant, not associated with classical or attenuated familial adenomatous polyposis; CHEK2, under uncertain penetrance, represents the CHEK2 p. Ile15Thr germline variant of uncertain clinical actionability; FH, under uncertain or recessive penetrance, represents the FH p. Lys477dup variant, not associated with the high-penetrance hereditary leiomyomatosis and renal cell carcinoma syndrome; VHL, under recessive penetrance, represents VHL p. Arg200Trp, associated with a recessive form of VHL-dependent polycythemia and not Von Hippel-Lindau syndrome; EPCAM, deletion exons 2-7, under recessive penetrance, represents variant possibly associated with autosomal recessive congenital tufting enteropathy, but not Lynch syndrome.