Yttrium-90 radioembolization for colorectal cancer liver metastases in KRAS wild-type and mutant patients: Clinical and ccfDNA studies

Abstract

Patients with unresectable, chemo-refractory colorectal cancer liver metastases (CRCLM) have limited local treatment options. We report our institutional experience on the efficacy of resin-based yttrium-90 (90Y) radioembolization for the treatment of CRCLM and our findings on associated circulating cell-free DNA (ccfDNA) studies. A total of 58 patients treated with 90Y for CRCLM at the Medstar Georgetown University Hospital had a median survival of 6 months [95% confidence interval (CI), 4.55‑7.45 months] after treatment, with a 12-month survival rate of 33%. The median survival from treatment stratified by mutational status was longer in the wild-type (WT) as compared to the KRAS mutant patients at 7 vs. 5 months, but did not achieve statistical significance (p=0.059). Median tumor local control duration after 90Y treatment was 2 months (95% CI, 0.34‑3.66 months) for the entire cohort and was longer in the WT vs. the mutant patients (2 vs. 1 month, respectively, p=0.088). Plasma was prospectively collected from a subset of 9 patients both before and after single lobe treatment, and ccfDNA concentration and fragmentation index (FI) were measured using quantitative PCR and atomic-force microscopy (AFM). In the WT and KRAS mutant patients, DNA FI was reduced from a median of 0.73-0.65 after treatment. A reduction in DNA FI after single lobe treatment was associated with an improved overall survival (p=0.046). Analysis by AFM of paired pre- and post-treatment samples from KRAS mutant and WT patients revealed a larger average decrease in fragment size in the WT patients (p=0.013). 90Y radioembolization extends local control for CRCLM, however, KRAS mutant tumors may be more radio-resistant to treatment. Changes in the FI of patients following treatment were noted and may be evaluated in a larger study for relevance as a biomarker of response.

Figure 1.

Representative CT images of DNA in (A and B) wild-type and (C and D) KRAS mutant patients before (A and C) and after (B and D) ⁹⁰Y treatment.

Figure 2.

Progression-free survival in the liver: (A) all patients; (B) patients by mutational status.

Figure 3.

Overall survival: (A) all patients from diagnosis; (B) overall survival from treatment all patients; (C) overall survival of patients by performance status from treatment; (D) overall survival of patients by mutation status from treatment.

Figure 4.

Evaluation of KRAS mutant and wild-type patients for changes in circulating cell-free DNA. (A) Overall survival from treatment according to DNA fragmentation index (FI) changes; (B) overall survival from diagnosis according to DNA FI changes.

Figure 5.

Representative atomic-force microscopy images of DNA in (A and B) wild-type (WT) and (C and D) KRAS mutant patients before (A and C) and after (B and D) yttrium-90 (⁹⁰Y) treatment. ⁹⁰Y treatment appeared to induce significant fragmentation in circulating cell-free DNA for KRAS WT but not in KRAS mutant patients.

Figure 6.

Comparison of the fractional fragment size distribution of circulating cell-free DNA (ccfDNA) from (A) wild-type (WT) and (B) KRAS mutant samples before and after single lobe treatment with yttrium-90 (⁹⁰Y). The estimated amount of each ccfDNA fraction expressed as the percentage of the total ccfDNA estimated as the sum of the ccfDNA amount of the three size fractions in (A) WT and (B) KRAS mutant patients before (blue) and after (red) treatment in (A) four pooled WT samples and (B) two pooled KRAS mutant samples.