Frequency of certain germline polymorphisms among ethnicities and adverse drug reaction risk associated with colorectal cancer therapies.

12119 Background: Chemotherapy regimens used to treat colorectal cancer (CRC) often include a combination of a fluoropyrimidine (i.e., fluorouracil or capecitabine), folinic acid, irinotecan, and/or oxaliplatin as first-line therapy in metastatic disease. Adverse drug reactions (ADRs) related to these regimens, such as neutropenia, severe diarrhea, and mucositis, can be severe or even life-threatening. Fluoropyrimidine (FP) and irinotecan-related toxicities in CRC are associated with certain germline polymorphisms in DPYD (*2A, *13, HapB3, and c.2846A>T) and UGT1A1 (*28 allele), respectively. Clinically actionable recommendations are available per the FDA and the Clinical Pharmacogenetics Implementation Consortium (CPIC) for DPYD poor metabolizers (PMs) and intermediate metabolizers (IMs) due to increased risk for FP-induced ADRs. The FDA also provides dosing guidance for UGT1A1PMs in an effort to minimize irinotecan-induced toxicities. The objective of this research was to observe the frequency of DPYDvariants (*2A, *13, HapB3, c.2846A>T, c.557A>G), UGT1A1 variants (*6, *28), and associated phenotypes in various racial and ethnic groups. Methods: A retrospective analysis of 8,640 samples genotyped for DPYD and UGT1A1 was conducted (OneOme, Minneapolis, MN). Phenotype and carrier frequencies were analyzed and stratified by self-reported ethnicity and race. Results: DPYD variants with reduced or no function were observed in 6% of all samples tested where 6% of patients having clinically actionable IM or PM status. UGT1A1 carrier frequency was 56% with 12% of patients with clinically actionable PM status. Conclusions: A significant proportion of patients carry DPYD and/or UGT1A1 variants that result in decreased metabolism of FPs and irinotecan, respectively. In this large sample size, a 6% DPYD risk variant carrier frequency is significantly more than an estimated 2%, as previously reported. The FDA and CPIC provide clinically actionable recommendations for these commonly used colorectal and other gastrointestinal cancer therapies in an effort to avoid severe and even life-threatening toxicities that may be potentiated by these germline variations. [Table: see text]