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Thymidylate synthase genotyping guides therapy in patients with rectal adenocarcinoma
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In 2010, there were 142,570 estimated new cases of colorectal cancer that led to an estimated 51,370 deaths, making it the third-leading cause of cancer death among men and women. Of the 142,570 estimated new cases of colorectal cancer, 27.8% were rectal tumors.
For locally advanced rectal adenocarcinoma, the treatment of choice has been neoadjuvant chemotherapy with fluorouracil and radiation. The goal of treatment is to achieve tumor T-stage down-staging before the patient undergoes surgery. Radiation plus chemotherapy has been shown to be more effective at achieving this goal compared with radiation alone (50% vs. 35%). Down-staging has been linked to increased OS, higher rate of sphincter-preserving surgeries and decreased recurrence. Approximately 45% of patients receiving neoadjuvant chemotherapy and radiation achieve down-staging of their tumor.
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Fluorouracil is a fluoropyrimidine analogue that irreversibly binds to thymidylate synthase. Binding to thymidylate synthase blocks the synthesis of thymidine, thus blocking the replication of DNA and, ultimately, the cell. The overexpression of thymidylate synthase has been associated with poor response in patients with rectal cancer treated with fluoropyrimidine for adjuvant therapy. One study showed a 60% 5-year survival for patients with low thymidylate synthase levels compared with 40% for patients with high thymidylate synthase levels.
Repeated sequences
The gene in the human genome that codes for thymidylate synthase has a tandem repeated sequence in the 5’-untranslated region, which exhibits polymorphism. Most humans express either two or three repeats of this sequence. A correlation was found showing the more repeats present in a patient’s genome, the higher the level of thymidylate synthase.
An increase in tandem repeats in the 5’-untranslated region of the gene coding for thymidylate synthase leads to increased levels of thymidylate synthase and, thus, decreases response of patients with rectal cancer treated with a fluoropyrimidine. A study by Pullarkat and colleagues examined the correlation between the number of tandem sequences and clinical outcomes in colorectal patients treated with fluorouracil. Fifty patients were enrolled in the study. Eight were homozygous for two repeated tandem sequences (*2/*2); 22 were homozygous for three repeated tandem sequences (*3/*3); and 20 were heterozygous for one strain with two repeated tandem sequences and the other strain with three repeated tandem sequences (*2/*3). The response rates were 50%, 9% and 15%, respectively. Although small, this study confirmed that increased tandem repeats led to poor response to therapy.
A second study demonstrated that rectal cancer patients who were homozygous *2/*2 have a higher rate of complete pathological response. Fifty-three percent of patients homozygous for *2/*2 achieved a pathological complete response compared with 22% in the *2/*3 and *3/*3 group. Although this trial only enrolled 60 patients, it provided more evidence linking thymidylate synthase genomics and poor outcomes in patients with rectal cancer.
Treatment based on genotype
Tan and colleagues created a study to assess the use of neoadjuvant chemotherapy and radiation guided by the patient’s thymidylate synthase genotype. The study was a single institution, multidisciplinary, prospective, tandem, phase 2, nonrandomized study. The study enrolled 135 patients with T3/T4, N0-2, M0-1 rectal adenocarcinoma.
Before treatment started, genetic testing was performed, and patients with at least one allele with two repeating tandem sequences were classified as good risk (*2/*2, *2/*3, *2/*4) and patients with two alleles with more than two repeating tandem sequences were classified as poor risk. Of the 135 patients enrolled, 98 were classified as good risk and 37 were classified as poor risk. Two patients in both classifications withdrew consent and were not included in the assessment.
Both the good- and poor-risk groups received radiation and fluorouracil 225 mg/m2/day throughout radiation with no breaks for weekends. Patients in the poor-risk group received irinotecan 50 mg/m 2 every week for 5 weeks. The patients in the poor-risk group were given additional chemotherapy (irinotecan besides the standard fluorouracil) to achieve down-staging at rates similar to the good-risk group.
Dosage adjustments based on toxicities were made following a standard table of study-defined adjustments. Tumors were resected 6 to 10 weeks after therapy and restaged at this time. One patient in the poor-risk group did not receive irinotecan due to physician error.
One patient in each classification died before surgery, two patients in the good-risk classification were found to have unresectable disease, one patient in both classifications had clinical complete response and did not undergo surgery, and one patient from each classification refused surgery. This left 90 good-risk patients evaluable for down-staging and 31 poor-risk patients. Of the 90 patients in the good-risk group, 58 achieved tumor down-staging (64.4%) and 20 of the 31 patients in the poor-risk group achieved tumor down-staging (64.5%). These results were dramatically different than the preliminary study, which showed a 9% response rate in a homozygous group (*3/*3).
Complete tumor response was achieved in 18 patients in the good-risk group (20%) and 13 patients in the poor-risk group (41.9%). Pathological complete response was achieved in 17 patients in the good-risk group (18.9%) and 11 of the patients in the poor-risk group (35.5%). Patients who achieved down-staging were shown to have statistically significant improved relapse-free survival and OS. Results for OS and relapse-free survival are listed in the Table. Relapse-free survival statistics exclude metastatic patients.
Although the addition of irinotecan showed favorable clinical outcomes, it also demonstrated increased toxicities. Hospitalization rates were increased in the poor-risk group compared with the good-risk group (34% vs. 16%). Patients in the poor-risk group also experienced an increased incidence of grade 3 or 4 toxicities (54.3% in the poor-risk group vs. 30.2% in the good-risk group). One patient in the good-risk group died of myocardial infarction and one patient in the poor-risk group died of an aneurysmal bleed.
Overall, the study demonstrated that using a patient’s genotype to direct therapy for patients with rectal adenocarcinoma was beneficial. Patients in the poor-risk group, given the combination of fluorouracil and irinotecan, could achieve similar outcomes as patients with good risk. Genetic testing spared patients in the good-risk group from the side effects of additional chemotherapy that may not have added additional benefit.
Paul Morales, PharmD, is a pharmacy practice resident at the University of Minnesota Medical Center, Minneapolis. He reports no relevant financial disclosures.
For more information:
- Johnson P. The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol. 1994;12:2640-2647.
- Onaitis M. Neoadjuvant chemoradiation for rectal cancer: Analysis of clinical outcomes from a 13-year institutional experience. Ann Surg. 2001; 233:778-785.
- Pullarkart S. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J. 2001;1: 65-70.
- Tan B. Thymidylate synthase genotype-directed neoadjuvant chemoradiation for patients with rectal adenocarcinoma. J Clin Oncol. 2011; 29:875-883.
- Villafranca E. Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J Clin Oncol. 2001;19:1779-1786.