Pharmacogenetic investigation of lapatinib-associated diarrhea in metastatic breast cancer clinical trials.

Abstract

552 Background: Diarrhea is common during lapatinib treatment. Most events are mild to moderate, self-limiting and managed proactively to prevent serious complications, however diarrhea may lead to non-compliance and possibly poor treatment outcomes. Pharmacogenetic associations with diarrhea caused by tyrosine kinase inhibitors have been reported for the functional variants CYP2C19*2 (lapatinib), ABCG2 Q141K (gefitinib) and EGFR −216G>T (erlotinib) in studies with few diarrhea cases (n<40). The present study evaluated these variants and explored additional genetic influences in a larger dataset in metastatic breast cancer (MBC) patients from lapatinib treatment (monotherapy or combination) clinical trials. Methods: In the primary dataset (8 trials), cases (n=285) were defined as patients who experienced NCI CTC AE grades ≥2 for diarrhea during lapatinib treatment. Controls (n=319) were patients who did not experience diarrhea and received lapatinib for at least 9days (median onset for diarrhea). Germline DNA was extracted from peripheral blood and genotypes were determined by standard methods. In addition to the four specified variants, genome wide association screen data (GWAS, 1M SNPs) including ∼500 tagging SNPs selected in 36 candidate genes for lapatinib metabolism or mechanism pathways were also investigated for diarrhea association using penalised logistic regression. Nominally significant associations were evaluated for confirmation in an independent dataset comprising 120 cases and 124 controls from a single MBC trial. Results: The reported variants in CYP2C19, ABCG2 and EGFR did not show significant association (p>0.05) with lapatinib associated diarrhea, despite >80% power to demonstrate similar effects. No GWAS SNPs achieved a genome-wide significance threshold (p=5×10−8), however 57 polymorphisms achieved p<10−4. None of these associations were confirmed in the second independent lapatinib dataset. Conclusions: Previously reported EGFR, ABCG2 and CYP2C19 variants were not found to be associated with lapatinib induced diarrhea. No robust associations were identified following candidate gene and genome-wide evaluation of common variants.