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

AIM

Cetuximab is a standard-of-care treatment for wild-type metastatic colorectal cancer (mCRC), but it may also be effective in a subgroup of 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 mutant mCRC based on cetuximab treatment.

METHODS

We included 69 patients with histologically confirmed mCRC and 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 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 mutation treated with cetuximab.

CONCLUSIONS

Selection of patients with mCRC based on their KIR genotypes opens a therapeutic opportunity for patients with 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.