Patients with early-onset metastatic colorectal cancer as an emerging distinctive clinical and molecular phenomenon

Background: Despite a reduction of both incidence and mortality from CRC in the elderly population, several studies published in the last decade have shown an increase in the incidence of early-onset CRC (EO-CRC), conventionally defined as cancer that occurs in adults between the ages of 18 and 49. Clinical and prognostic data on this setting are limited and conflicting. The aim of our study was to evaluate the clinical, prognostic, and molecular profiles of metastatic EO-CRC patients (age at diagnosis # 50) in order to identify potentially relevant differences compared to a control group late-onset CRC (LO-CRC). Methods: We retrospectively collected data from 1272 metastatic colorectal cancers from 5 different Italian Institutions: 693 (54.5%) EO-CRC and 579 (45.5%) LO-CRC as control group. All patients had one or more metastatic sites, molecular profiling available (including RAS, BRAF, and MSI status), and underwent at least one line of treatment for metastatic disease. The main objective of the study was to the evaluate clinical outcome for the global population of EO-CRC patients in different clinical and molecular subgroups according to RAS and BRAF status and in comparison to patients included in the control group. Results: In the EO-CRC group median age was 42.8 (20.0-50.9) and 66.7 (51.0-86.2) in the control group. M/F ratios were 1:1 and 2:1, respectively. In the overall population, mOS was 34,7 in EO-CRC pts vs 43,0 months (mo) (p , 0,0001) in the control group. In the RAS/BRAF mutated subgroup mOS in EO-CRC pts was 30,3 vs 34,0 mo in the control group (p = 0,0156). In RAS/BRAF wild-type subgroup mOS in EO-CRC pts was 43,0 vs 50,0mo(p = 0,0290). Finally, in the BRAF V600E mutated subgroup EO-CRC pts showed a 16mo mOS vs 26mo (p = 0,04). In the overall population, mPFS was 11,0 in EO-CRC pts vs 14,0 mo (p, 0,0001) in the control group. Furthermore, the overall response rate (ORR) was 63% in EO-CRC and 67% in LO-CRC. Conclusions: Findings from a large population of EO-CRC patients indicate a general worse prognosis for patients with early-onset colorectal cancer compared to late-onset patients. Interestingly this seems to occur regardless of the molecular status. These observations might have a considerable impact on clinical practice and research. Subsequent investigations will be needed to further understand the specific clinical and molecular characteristics of this growing group of patients to better define the more appropriate treatment strategy