Abstract 348P
Background
The genome-wide DNA methylation status in metastatic colorectal cancer (mCRC) has been reported to be associated with therapeutic sensitivity to anti-epidermal growth factor receptor (EGFR) inhibitors. We recently developed a DNA methylation assay focused on 16 CpG sites that reflect genome-wide DNA methylation status for mCRC based on the modified MethyLight and reported its ability to predict the clinical outcomes of anti-EGFR inhibitors (Ouchi et al. Cancer Sci 2022). Here, we report the predictive performance of a modified MethyLight assay on sensitivity to anti-EGFR inhibitors focused on salvage-line treatment.
Methods
We retrospectively collected 159 mCRC cases that treated with anti-EGFR inhibitors combined with irinotecan after being refractory or intolerable for treatment of fluoropyrimidine, oxaliplatin, and irinotecan as 2nd line or later line chemotherapy. RAS status was checked by direct sequencing and DNA methylation status was measured by our modified MethyLight assay for each case. The correlation between the DNA methylation status and clinical outcomes was analyzed.
Results
One hundred and forty-five cases were identified as RAS wild-type, with 31 cases classified as highly-methylated colorectal cancers (HMCCs) and 114 cases as low-methylated colorectal cancers (LMCCs). There were 14 cases with RAS mutations. Clinical outcomes in the HMCCs were significantly worse than in the LMCCs (response rate [RR]: 3.3% vs. 26.8%, p < 0.01, median progression-free survival [mPFS]: 2.6 vs 6.5 months, p < 0.01, hazard ratio [HR] = 2.66, median overall survival [mOS]: 6.6 vs 15.2 months, p < 0.01, HR = 2.46, respectively) and comparable to those in the RAS mutant group (RR: 0%, mPFS: 2.8 months, mOS: 8.1 months). In both univariate and multivariate Cox regression analyses, the DNA methylation status, independent of primary tumor location, showed the strongest predictive values for PFS and OS.
Conclusions
Similar to the RAS mutation status, the DNA methylation status measured by a modified MethyLight assay is a robust predictor of the effect of anti-EGFR inhibitors with irinotecan for mCRC in salvage line treatment.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
The Japan Agency for Medical Research and Development.
Disclosure
S. Takahashi: Financial Interests, Personal, Research Grant: Merck Biopharma. C. Ishioka: Financial Interests, Personal, Research Grant: Takeda, Daiichi Sankyo, Ono, Asahi-Kasei Pharma, Chugai, Taiho, Eisai. All other authors have declared no conflicts of interest.