Improving selection of patients with metastatic colorectal cancer to benefit from cetuximab based on KIR genotypes

Abstract

Aim: Cetuximab is a standard-of-care treatment for KRAS wild-type metastatic colorectal cancer (mCRC), but it may also be effective in a subgroup of KRAS mutant patients by its immunomodulatory activity. Here, we explore if KIR (killer cell immunoglobulin-like receptor) genotyping can provide a significant added value in the clinical outcome of patients with KRAS mutant mCRC based on cetuximab treatment.

Methods: We included 69 patients with histologically confirmed mCRC and KRAS mutation, positive EGFR expression, and Eastern Cooperative Oncology Group performance status ≤2. Based on KIR gene content, haplotype (A or B) was defined and genotypes (AA or Bx) were grouped for each patient.

Results: We demonstrated with new evidence the immunomodulatory activity of cetuximab in patients with KRAS mutant mCRC. Patients with homozygous genotypes (AA or BB) showed shorter 12-month progression-free survival (PFS12) and poorer overall survival (OS) than those with heterozygotes (AB). Moreover, multivariate analysis confirmed stratification of patients based on genotype was an independent marker of PFS12 (HR 2.16) and the centromeric and telomeric distribution of KIRs was an independent predictor of both PFS12 (HR 2.26) and OS (HR 1.93) in patients with mCRC with KRAS mutation treated with cetuximab.

Conclusions: Selection of patients with mCRC based on their KIR genotypes opens a therapeutic opportunity for patients with KRAS mutation, and it should be tested in clinical trials in comparison with other alternatives with scarce benefit.

Trial registration number: NCT01450319, EudraCT 2010-023580-18.

Keywords: antibodies; biomarkers; natural killer t-cells; neoplasm; translational medical research; tumor.

Figure 1

Kaplan-Meier curve for 12-month progression-free survival (PFS12) according to genotypes or centromeric and telomeric KIR content. Heterozygous individuals (AB) were compared with homozygotes (AA or BB) separately (A) or in combination (AA and BB) (B). The median PFS12 among homozygotes (AA+BB) was 2.21 months and among heterozygous patients 2.59 months (p=0.003, log-rank test). Genotypes (AA and Bx) were assessed based on the centromeric and telomeric regions (C) or only based on the centromeric region (D). The median PFS12 among homozygotes (cAcA-tAtA or cBx-tBx) was 2.28 months, whereas among heterozygotes (cAcA-tBx or cBx-tAtA) was 2.63 months (p=0.002, log-rank test). The median PFS12 among homozygotes (AA) was 2.13 months, whereas among heterozygotes (Bx/cenA) was 2.63 months (p=0.026, log-rank test). cenA (cA) and telA (tA), centromeric and telomeric motifs of the A haplotype; cenB (cB), centromeric motif of the B haplotype; KIR, killer cell immunoglobulin-like receptor; telB (tB), telomeric motif of the B haplotype.

Figure 2

Kaplan-Meier curve for overall survival according to genotypes or centromeric and telomeric KIR content. Heterozygous individuals (AB) were compared with homozygotes (AA or BB) separately (A) or in combination (AA and BB) (B). The median overall survival among homozygotes (AA+BB) was 5.28 months and among heterozygous patients 7.60 months (p=0.015, log-rank test). Genotypes (AA and Bx) were assessed based on the centromeric and telomeric regions (C). The median overall survival among homozygotes (cAcA-tAtA or cBx-tBx) was 5.28 months, whereas among heterozygotes (cAcA-tBx or cBx-tAtA) was 8.17 months (p=0.006, log-rank test). cenA (cA) and telA (tA), centromeric and telomeric motifs of the A haplotype; cenB (cB), centromeric motif B haplotype; KIR, killer cell immunoglobulin-like receptor; telB (tB), telomeric motif of the B haplotype.