Pharmacogenomic contribution to drug response.

There has been significant progress made in individualizing cancer therapy, especially for colorectal and breast cancer. This has included objective determination of aggressiveness of therapy using molecular predictors of disease recurrence (i.e., Mammaprint, OncotypeDX), identifying altered drug activation for dose modifications (i.e., DPYD, CYP2D6, UGT1A1), or variation in drug targets or components of a pharmacodynamic pathway (TYMS, EGFR, KRAS). With patient-specific molecular characteristics increasingly guiding therapy, this review provides important and timely insights on targeted therapy. Ultimately, integration of both pharmacogenomic and clinical characteristics can provide powerful predictive tools for stratifying responders from nonresponders and identifying patients at increased risk for toxicity.

Amplification of thymidylate synthetase in metastatic colorectal cancer patients pretreated with 5-fluorouracil-based chemotherapy.

Resistance to 5-fluorouracil (5-FU) represents a major contributor to cancer-related mortality in advanced colorectal cancer patients. Genetic variations and expression alterations in genes involved in 5-FU metabolism and effect have been shown to modulate 5-FU sensitivity in vitro, however these alterations do not fully explain clinical resistance to 5-FU-based chemotherapy. To determine if alterations of DNA copy number in genes involved in 5-FU metabolism-impacted clinical resistance to 5-FU-based chemotherapy, we assessed thymidylate synthetase (TYMS) and thymidine phosphorylase (TYMP) copy number in colorectal liver metastases. DNA copy number of TYMS and TYMP was evaluated using real time quantitative PCR in frozen colorectal liver metastases procured from 62 patients who were pretreated with 5-FU-based chemotherapy prior to surgical resection (5-FU exposed) and from 51 patients who received no pretreatment (unexposed). Gain of TYMS DNA copy number was observed in 18% of the 5-FU exposed metastases, while only 4% of the unexposed metastases exhibited TYMS copy gain (p = 0.036). No significant differences were noted in TYMP copy number alterations between 5-FU-exposed and -unexposed metastases. Median survival time was similar in 5-FU-exposed patients with metastases containing TYMS amplification and those with no amplification. However, TYMS amplification was associated with shorter median survival in patients receiving post-resection chemotherapy (hazard ratio = 2.7, 95% confidence interval = 1.1-6.6; p = 0.027). These results suggest amplification of TYMS amplification as a putative mechanism for clinical resistance to 5-FU-based chemotherapy and may have important ramifications for the post-resection chemotherapy choices for metastatic colorectal cancer.