Younger age may be a poor prognostic factor in patients with metastatic colon cancer

1. In this retrospective cohort study, patients younger than 50 with metastatic colorectal cancer (mCRC) had significantly shorter progression-free survival and overall survival rates compared with those aged 50 to 65 years old.

2. The younger cohort of patients also had unique treatment-related adverse events and distinct genomic profiles compared with their older counterparts.

Evidence Rating Level: 2 (Good)

Study Rundown: Colorectal cancer (CRC) is the third most common cancer and the second deadliest cancer worldwide. The incidence of early-onset colorectal cancer (EO-CRC), CRC diagnosed in individuals under 50 years of age, has steadily increased by 2% per year since the 1990s. The etiology and the underlying biology of EO-CRC are poorly understood. Furthermore, there is a paucity of literature elucidating the differences in treatment-related adverse events and survival outcomes from mCRC between EO disease and its older counterparts. To address this gap, individual patient data from 3 clinical trials and a contemporary patient cohort was analyzed to evaluate the differences in treatment outcomes and adverse events among three distinct age groups of mCRC patients. Overall, this retrospective cohort study found that mCRC patients younger than 50 years had worse progression-free survival (PFS) and overall survival (OS), than those aged 50 – 65 years. This younger cohort of patients was also found to have a unique pattern of adverse events, for example, a higher incidence and onset of nausea and vomiting among others. Finally, patients younger than 50 had a distinct genomic profile. They exhibited a higher prevalence of CTNNB1 mutation, ERBB2 amplification, CREBBP mutation, and a lower incidence of BRAF mutation. 

Click to read the study in JAMA Network Open

 In-Depth [randomized control trial]:  Individualized patient data from three multicenter randomized phase 3 studies were utilized and divided into study 1 (NCT00272051, NCT 00305188) and study 2 (NCT00364013).  Only patients from the control arm of these studies, mCRC patients treated with FOLFOX, were included. Studies 1 and 2 comprised 1223 patients for analysis of OS, defined as the time from randomization to death, PFS, defined as the time from randomization to disease progression, and treatment-related adverse events, in EO-mCRC patients compared to their older counterparts. Study 1 and 2 patients were treated in a clinical trial setting before 2010, therefore a contemporary cohort that included 736 patients diagnosed with mCRC at Moffitt Cancer Center (MCC) from 2006 to 2022 was also analyzed to provide external validation of OS and assess tumor genetic alterations. In both studies 1 and 2, patients younger than 50 years had shorter median OS and median PFS compared with their older counterparts. After adjustment for sex, race, and Eastern Cooperative Oncology Group Performance status, age <50 years was identified as an independent factor for significantly shorter OS (age <50 vs 50-65 years: HR, 1.48; 95% CI, 1.19-1.84; P < .001) and PFS (age <50 vs 50-65 years: HR, 1.46; 95% CI, 1.22-1.76; P < .001). This finding was confirmed in the contemporary MCC cohort, in which patients younger than 50 years also had worse median OS compared with those aged 50 to 65 years (39.2 vs 51.3; P = .02). Patients younger than 50 years exhibited higher incidences of nausea and vomiting, severe abdominal pain, severe anemia, and severe rash, but lower incidences of fatigue, neutropenia, and severe diarrhea. They also experienced an earlier onset of nausea and vomiting, mucositis, and neutropenia, as well as a shorter duration of mucositis. When examining treatment-related adverse events, patients younger than 50 years had a higher incidence of nausea and vomiting (< 50 years vs. 50-65 years vs. >65 years: 69.3% vs 57.6% 60.4%; P = .02), severe abdominal pain (8.4% vs 3.4% vs 3.5%; P = .02), severe anemia  (6.1% vs 1.0% vs 1.5%; P < .001), and severe rash (2.8% vs 1.2% vs 0.4%; P = .047), but a lower incidence of fatigue  (44.1% vs 46.9% vs 55.6%; P = .005), neutropenia (38.5% vs 39.7% vs 49.8%; P = .002), and severe diarrhea (6.1% vs 9.1% vs 13.0%; P = .02). They also experienced an earlier onset of nausea and vomiting, mucositis, and neutropenia, as well as a shorter duration of mucositis.  Analysis of the next-generation genetic sequencing data from the MCC cohort revealed that the 3 age groups had similar but distinct genetic alterations. Compared with mCRC patients aged 50-65 years and older than 60 years, the tumors of patients younger than 50 years had a higher prevalence of CTNNB1 mutation (6.6% vs 3.1% vs 2.3%; P = .047), ERBB2 amplification (5.1% vs 0.6% vs 2.3%; P = .005), and CREBBP mutation (3.1% vs 0.9% vs 0.5%; P = .05), with a varying incidence of BRAF mutation (7.7% vs 8.5% vs 16.7%; P = .002). Overall, these findings suggest worse survival outcomes and unique adverse event patterns for those with EO-mCRC, though the study’s retrospective nature prevent causal conclusions being drawn. 

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