Objective : Molecular signatures and other markers have been identified as predictors of response and prognosis in colorectal cancer (CRC) patients. The aim of this study is to evaluate molecular and other markers that can predict prolonged survival in CRC chemo-refractory patients with liver predominant metastases (CRLM) treated with Y-90 radioembolization (RE).
Methods : In a retrospective single-institution study, patients with unresectable, chemo-refractory (at least 1 line) CRLM who underwent Y-90 therapy from 2013 to 2018 were identified. Patients with genomic information including MAPK pathway (including KRAS and BRAF genes), PI3K pathway, and microsatellite stability were included in this study. Baseline demographics, Eastern Cooperative Oncology Group (ECOG) performance status, laterality of primary tumor (right vs. left), carcinoembryonic antigen (CEA) level, and MELD scores (as a surrogate marker for baseline liver function) were evaluated as potential predictors of survival. Additionally, the relationship between timing of receiving Y-90 after diagnosis of CRLM and outcome was studied. Survival from first Y-90 therapy was measured using Kaplan-Meier estimation and predictors of outcome were identified using log-rank analysis.
Results : A total of 58 patients (38 males) were identified with mean age of 67 years. The median overall survival (OS) after first Y-90 RE was 12.9 months. Overall, 26/58 (44.8%) had MAPK pathway mutations, 2/58 (3.5%) had PI3K pathway mutations, and 5/58 (8.6%) microsatellite instability. Twenty-one (36%) patients underwent Y-90 within 9 months of CRLM diagnosis. Oncogenic mutation status and laterality of the primary tumor were not found to predict survival in the entire cohort (p>0.05). On the other hand, baseline CEA ≤20 ng/ml was a significant predictor of prolonged survival (median OS of 17.7 months vs. 10.3 months for others; p<0.001). Baseline MELD sore of ≤7 was also a predictor of prolonged OS (median OS of 15.1 month vs. 6.5 months for others; p=0.002). Additionally, there was a significant prolonged OS if Y-90 therapy was received within 9 months of initial CRLM diagnosis (16.9 vs. 11.4 months for others; p=0.023).
When stratifying the cohort based on the timing of receipt of Y-90 after CRLM diagnosis, patients with WT-MAPK (n=8) had significantly prolonged median OS if they underwent Y-90 within 9 months of metastatic diagnosis (22.3 months vs. 12.9 months for others; p=0.019). Similarly, patients with WT-PI3K (n=19) undergoing Y-90 within 9 months of CRLM diagnosis showed prolonged median OS of 16.9 months vs. 12 months for others (p=0.037). Y-90 treatment within 9 months of CRLM diagnosis for patients with ECOG 0 (n=6) also resulted in improved survival median OS of 14.4 months vs 12.1 months for others (p=0.03). Any decreasing CEA (n=9) level post Y-90 in patients who were treated within 9 months was associated with increased survival rates (30.2 months vs. 11.4 months; p=0.003). In those with left-sided primary tumors, being treated with Y-90 within 9 months also demonstrated prolonged survival 23 months vs. 12.2 months for others (p=0.04).
Conclusions : Our results suggest that earlier (<9 months) treatment of patients with chemo-refractory CRLM confers significant prolonged survival especially for WT-MAPK and WT-PI3K pathway oncogenes and left sided primary tumors. Further larger studies are needed to confirm these results.