Background
Many patients with rectal cancer undergo preoperative neoadjuvant chemoradiation,
with approximately 70% exhibiting pathologic downstaging in response to treatment.
Currently, there is no accurate test to predict patients who are likely to be complete
responders to therapy. 5-Fluorouracil is used regularly in the neoadjuvant treatment
of rectal cancer. Genetic polymorphisms affect the activity of thymidylate synthase,
an enzyme involved in 5-Fluorouracil metabolism, which may account for observed differences
in response to neoadjuvant treatment between patients. Detection of genetic polymorphisms
might identify patients who are likely to have a complete response to neoadjuvant
therapy and perhaps allow them to avoid operation.
Methods
DNA was isolated from whole blood taken from patients with newly diagnosed rectal
cancer who received neoadjuvant therapy (n = 50). Response to therapy was calculated with a tumor regression score based on
histology from the time of operation. Polymerase chain reaction was performed targeting
the promoter region of thymidylate synthase. Polymerase chain reaction products were
separated using electrophoresis to determine whether patients were homozygous for
a double-tandem repeat (2R), a triple-tandem repeat (3R), or were heterozygous (2R/3R).
A single nucleotide polymorphism, 3G or 3C, also may be present in the second repeat
unit of the triple-tandem repeat allele. Restriction fragment length polymorphism
assays were performed in patients with at least one 3R allele using HaeIII.
Results
Patients with at least 1 thymidylate synthase 3G allele were more likely to have a
complete or partial pathologic response to 5-Fluorouracil neoadjuvant therapy (odds
ratio 10.4; 95% confidence interval, 1.3–81.6; P = .01) than those without at least one 3G allele.
Conclusion
Identification of rectal cancer patients with specific genetic polymorphisms in enzymes
involved in 5-Fluorouracil metabolism seems to predict the likelihood of complete
or partial pathologic response to preoperative neoadjuvant therapy.
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Article info
Publication history
Published online: July 13, 2016
Accepted:
May 13,
2016
Footnotes
Supported by the National Cancer Institute grant R25-CA134283 (Nelson [PI, Hein]) and the John Williamson and Barbara Thurston Atwood Price Family Trust.
The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The authors declare no conflicts of interest.
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© 2016 Elsevier Inc. All rights reserved.
