Association between ABCB1 genetic polymorphisms with treatment outcomes in patients with metastatic pancreatic cancer.

ABCB1

Germline ABCB1 variants, encoding P-glycoprotein, altering cytotoxic drug efflux and therefore bone marrow exposure.

Severe neutropenia under gemcitabine plus nanoparticle albumin-bound paclitaxel had already been linked to survival, but its relationship with germline pharmacokinetic polymorphisms remained poorly documented. This prospective multicentre observational study enrolled 122 Japanese patients with metastatic pancreatic cancer on first-line therapy, genotyping 22 polymorphisms related to regimen pharmacokinetics, including those of ABCB1. Patients who developed severe neutropenia within the first fourteen days had longer median overall survival (523 vs 249 days; adjusted HR 0.47; 95% CI 0.26-0.85; p = 0.012). After inverse probability of treatment weighting, the combination of ABCB1 rs2032582 non-GG and rs1045642 non-CC genotypes was associated both with severe neutropenia (adjusted OR 2.75; p = 0.020) and with overall survival (adjusted HR 0.56; p = 0.017).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Twenty-two polymorphisms tested, one significant combination, with no explicit correction for multiple testing: the chance that this association is an artefact is real and the paper gives no way to quantify it. The result is also counter-intuitive for prescribers, since the genotype most at risk of neutropenia is also the one associated with better survival: reducing the dose in these patients might simply remove the marker of effective exposure. This is a signal to replicate in an independent cohort, not data to add to a pre-treatment work-up.

Analysis by Dr Thibaut Benquey