Abstract 383P
Background
Metastatic colorectal cancer (mCRC) remains the third leading cause of cancer-related deaths worldwide. Wild-type (WT) K-RAS status is a major determinant for the efficacy of anti-EGFR therapy; however, as many as 40-60% patients (pts) even with this genetic background do not benefit from these regimens. While circulating cell-free miRNAs (cf-miRNAs) have emerged as an important class of cancer biomarkers, reent data suggests that miRNAs within the tumor-derived exosomal cargo (exo-miRNAs) might offer higher cancer specificity. Herein, we systematically examine a cf- and exo-miRNA signature in mCRC patients to predict therapeutic response from first-line anti-EGFR plus chemotherapy in prospective clinical trials.
Methods
Small RNA sequencing was performed in matched cell-free and exosomal specimens from 29 mCRC patients ( refractory : 10 pts with PFS ≤9 months (m); sensitive : 19 pts with PFS >9 m) with WT K-RAS who received anti-EGFR therapy in PULSE and POSIBA clinical trials. We prioritized a panel of cf- and exo-miRNAs and evaluated its predictive performance using bioinformatic and machine learning algorithms. Kaplan-Meier analysis was performed by dichotomizing mCRC patients based on their risk scores derived from the miRNA biomarker panels.
Results
The genomewide sequencing analysis identified a panel of 8 cf- and 11 exo-miRNAs, which were differentially expressed between refractory and sensitive mCRC patients, and significantly discriminated patients based on <9 m and >9 m PFS (p<0.001). Kaplan-Meier analysis revealed that the risk scores derived from both miRNA panels was significantly associated with PFS with hazard ratios of 49.16 (5.89-410.3 for cf-miRNAs) and 44.07 (5.281-367.7, for exo-miRNAs). Furthermore, cf- and exo-miRNA panels exhibited Harrell’s concordance indices of 0.77 (0.67–0.87) and 0.78 (0.69 – 0.86), highlighting their ability to accurately predict PFS (p<0.001).
Conclusions
This is the first evidence for an exosomal-based liquid biopsy assay for the prediction of therapeutic benefit to first-line anti-EGFR therapy in mCRC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.