Real-World Molecular Testing in European Early-Onset Colorectal Cancer

Abstract

Purpose: The global incidence and mortality of early-age onset colorectal cancer (EOCRC, or CRC diagnosed under 50 years) has increased in recent decades. High-risk surveillance and personalised oncological treatment may improve patients' outcomes. This study aims to characterise real-world somatic and germline molecular profiles in European EOCRC patients.

Patients and methods: Consecutive patients across the UK, Spain, Germany and Italy from the GEOCODE and SECOC consortia were identified using electronic patient records. Clinicopathological, somatic and germline testing data were collected on EOCRC patients. Tests included mismatch repair (MMR), somatic next generation sequencing (NGS) and germline multi-gene panels.

Results: Eight hundred ninety-three EOCRC patients were identified from 23 European centres (45.7% female, median age 42, range 14-49), predominantly in the distal colorectum: 205/893 (22.9%) patients with right-sided tumours, 302/893 (33.8%) left-sided tumours, 288/893 (32.2%) rectal tumours and 97/893 (10.8%) unknown. On somatic analysis, 735/893 (82.3%) of patients had pMMR tumours and 148/893 (16.5%) dMMR. Although 534/893 (59.7%) did not receive NGS somatic testing, somatic variants were detected in 233/359 (64.9%) of those tested. Germline variants were detected in 133/210 (63.3%) patients tested. Lynch syndrome was diagnosed in 93/210 (44.2%), of whom 17/93 (18.2%) presented with pMMR tumours. Systematic recording of family history in these real-world data was variable. In all patients with family history recorded, 153/484 (31.4%) patients reported a relative with CRC.

Conclusions: Our results support universal and paired somatic and germline multi-gene panels for all EOCRC patients, regardless of MMR status or family history. Systematic molecular testing approaches are necessary to address disparities in people with EOCRC. Larger unselected cohort studies would support validation of testing prediction models and estimates of clinically relevant variant actionability.

Keywords: colorectal cancer; early onset; germline; lynch syndrome; mismatch repair; real‐world data; somatic.

Flowchart 1

Molecular testing strategies for Lynch syndrome in people with colorectal cancer.

FIGURE 1

(a) Number of patients receiving germline testing and variants detected. Of the entire cohort of patients 893, a total of 210 received germline testing, of whom 112 tested positive for a pathogenic variant, 98 tested negative and 683 were not tested. (b) Germline variants detected. (c) Germline testing and results per country. (d) Germline variant heatmap per stage.

FIGURE 2

(a) Number of patients tested for mismatch repair (MMR) with immunohistochemistry and result whether dMMR (mismatch repair deficient) or pMMR (proficient). (b) Proportion of patients with dMMR status having Lynch syndrome on germline testing. (c) Proportion of patients with pMMR status having Lynch syndrome on germline testing.

FIGURE 3

(a) Number of patients receiving somatic (tumour) testing and variants detected. Of the entire cohort of 893, a total of 331 patients received somatic testing. (b) Somatic variants detected.

FIGURE 4

Tumour location for dMMR tumours n = 148 with right colon n = 71 (50.0%), left colon n = 41 (27.7%), rectum n = 41 (27.7%) and unknown n = 10 (6.8%) and for pMMR tumours n = 735 with 258 (35.4%) rectal disease, 257 (35.0%) in the left colon, 132 (18.0%) in the right colon, 1 (0.1%) in other area and 87 (11.8%) unknown.

FIGURE 5

(a) TNM stage for dMMR tumours n = 148 with 26 (17.6%) patients stage I disease, 42 (28.4%) with stage II disease, 58 (39.2%) with stage III disease, 19 (12.8%) stage IV disease and 3 (2%) unknown. (b) and for all tumours n = 893 with 144 (16.1%) patients having stage I disease, 185 (20.7%) with stage II disease, 334 (37.4%) with stage III disease and 198 (22.1%) with stage IV disease and 32 (3.6%) unknown.