How do you approach a patient with DPD deficiency that experiences severe toxicity on 5-FU despite dose reduction in the setting of metastatic colorectal cancer?

This depends on the mutation. Most patients heterozygous for DPYD mutations can be treated with dose-reduced 5-FU or capecitabine. Guidelines from CPIC (Clinical Pharmacogenomics Implementation Consortium) give recommended dose reductions for specific genotypes - a 50% dose reduction is appropriate for most heterozygous conditions. Patients with two affected DPYD alleles are generally not candidates for further fluoropyrimidine therapy, though at least 1 report of a microdosing approach suggests...

Unfortunately, this represents a contraindication to further 5FU. One would need to either utilize IROX or irinotecan alone in combination with antibody therapy. Further, it is not clear whether TAS-102 is a safe agent in this setting. Thus, this patient's options are very limited given their underlying genetic predisposition to fluoropyrimidine toxicity.