January 4, 2012 — A new way of predicting which patients with colorectal cancer are unlikely to respond to chemotherapy regimens containing fluorouracil is reported in the January 4 issue of the New England Journal of Medicine.
Patients with colorectal or rectal cancer whose tumors show hypermethylation of the gene encoding transcription factor AP-2 epsilon (TFAP2E) are clinically nonresponsive to fluorouracil-based chemotherapy, say the researchers, headed by Matthias Ebert, MD, from the University of Mannheim, Germany.
This genetic alteration was found frequently in the 4 cohorts of patients studied, occurring in 27% to 63% in patients with metastatic colorectal cancer and in 45% to 46% of patients with rectal cancer.
Patients whose tumors showed TFAP2E hypermethylation had a significantly lower response to fluorouracil-based chemotherapy regimens than patients without this alteration, the researchers report.
They suggest that testing for this mutation could be used to predict which patients are unlikely to respond to fluorouracil-based regimens. "However, before our published association between TFAP2E methylation and chemotherapy response can be used for the clinical management of cancer patients, our data need to be confirmed in prospective studies," Dr. Ebert emphasized.
"These studies were done in tissue samples stored from patients treated with chemotherapy or chemoradiation," he explained to Medscape Medical News. "We do not have data from prospective trials, which are required for further validation of our results."
Four Cohorts Studied
Dr. Ebert and colleagues analyzed tumor samples and clinical data from 4 independent cohorts of patients being treated at a number of university hospitals in Germany.
Cohort 1 (in Bochum) consisted of 76 patients with metastatic colorectal cancer who were participating in a trial comparing oral capecitabine and oxaliplatin (CAPOS) with intravenous fluorouracil and oxaliplatin (FUFOX).
Cohort 2 (in Dresden) consisted of 44 patients with metastatic colorectal cancer treated with either leucovorin, fluorouracil, and irinotecan (FOLFIRI) or folinic acid, fluorouracil, and oxaliplatin (FOLFOX).
Cohorts 3 (in Mannheim) consisted of 50 patients with rectal cancer undergoing chemoradiation with fluorouracil in combination with irinotecan and cetuximab.
Cohort 4 (in Munich) consisted of 70 patients with primary rectal cancer who underwent chemoradiation with intravenous fluorouracil and 45 Gy of radiation.
In all 4 cohorts there was a negative association between TFAP2E hypermethylation and treatment response rates, the researchers report.
Patients who had this genetic alteration (hypermethylation) had a significantly lower response to chemotherapy than patients who did not (hypomethylation).
For example, in cohort 2, of the 36 (of 44) patients for whom data were sufficient for analysis, 23 were found to have hypermethylated TFAP2E, and only 1 had a response to chemotherapy; the remaining 22 patients did not respond. The other 13 patients were found to have hypomethylated TFAP2E, and all 13 showed a response to chemotherapy. None of the hypomethylated TFAP2E tumors failed to respond.
There was "a substantial effect size," the researchers note. The probability of response to treatment was 6 times as high in patients with hypomethylation as in those with hypermethylation.
TFAP2E methylation might be valuable for predicting response to chemotherapy in both colorectal and rectal cancer, the researchers suggest. "Overall, our data indicate that fluorouracil-based chemotherapy is largely ineffective in patients with colorectal cancer with TFAP2E hypermethylation," they conclude.
This is the first time that a link between TFAP2E hypermethylation and chemoresistance to fluorouracil-based regimens has been reported, Dr. Ebert noted. However, there have been several previous reports linking such resistance to the gene that encodes for dickkopf homolog 4 protein (DKK4), "which we identified as a potential downstream target of TFAP2E," he added.
The team speculates that targeting this downstream DKK4 gene might be useful in these patients. "It would be an interesting option to make a potentially resistant cancer sensitive again," Dr. Ebert explained. "We are looking into this with cell-culture studies and animal models," he told Medscape Medical News. "Antibodies against DKK4 are available, and we speculate that the development of anti-DKK4 antibodies or other targeted agents would be of interest."
The authors have disclosed no relevant financial relationships.
N Engl J Med. 2012;336:44-53. Abstract
Patients with colorectal or rectal cancer whose tumors show hypermethylation of the gene encoding transcription factor AP-2 epsilon (TFAP2E) are clinically nonresponsive to fluorouracil-based chemotherapy, say the researchers, headed by Matthias Ebert, MD, from the University of Mannheim, Germany.
This genetic alteration was found frequently in the 4 cohorts of patients studied, occurring in 27% to 63% in patients with metastatic colorectal cancer and in 45% to 46% of patients with rectal cancer.
Patients whose tumors showed TFAP2E hypermethylation had a significantly lower response to fluorouracil-based chemotherapy regimens than patients without this alteration, the researchers report.
They suggest that testing for this mutation could be used to predict which patients are unlikely to respond to fluorouracil-based regimens. "However, before our published association between TFAP2E methylation and chemotherapy response can be used for the clinical management of cancer patients, our data need to be confirmed in prospective studies," Dr. Ebert emphasized.
"These studies were done in tissue samples stored from patients treated with chemotherapy or chemoradiation," he explained to Medscape Medical News. "We do not have data from prospective trials, which are required for further validation of our results."
Four Cohorts Studied
Dr. Ebert and colleagues analyzed tumor samples and clinical data from 4 independent cohorts of patients being treated at a number of university hospitals in Germany.
Cohort 1 (in Bochum) consisted of 76 patients with metastatic colorectal cancer who were participating in a trial comparing oral capecitabine and oxaliplatin (CAPOS) with intravenous fluorouracil and oxaliplatin (FUFOX).
Cohort 2 (in Dresden) consisted of 44 patients with metastatic colorectal cancer treated with either leucovorin, fluorouracil, and irinotecan (FOLFIRI) or folinic acid, fluorouracil, and oxaliplatin (FOLFOX).
Cohorts 3 (in Mannheim) consisted of 50 patients with rectal cancer undergoing chemoradiation with fluorouracil in combination with irinotecan and cetuximab.
Cohort 4 (in Munich) consisted of 70 patients with primary rectal cancer who underwent chemoradiation with intravenous fluorouracil and 45 Gy of radiation.
In all 4 cohorts there was a negative association between TFAP2E hypermethylation and treatment response rates, the researchers report.
Patients who had this genetic alteration (hypermethylation) had a significantly lower response to chemotherapy than patients who did not (hypomethylation).
For example, in cohort 2, of the 36 (of 44) patients for whom data were sufficient for analysis, 23 were found to have hypermethylated TFAP2E, and only 1 had a response to chemotherapy; the remaining 22 patients did not respond. The other 13 patients were found to have hypomethylated TFAP2E, and all 13 showed a response to chemotherapy. None of the hypomethylated TFAP2E tumors failed to respond.
There was "a substantial effect size," the researchers note. The probability of response to treatment was 6 times as high in patients with hypomethylation as in those with hypermethylation.
TFAP2E methylation might be valuable for predicting response to chemotherapy in both colorectal and rectal cancer, the researchers suggest. "Overall, our data indicate that fluorouracil-based chemotherapy is largely ineffective in patients with colorectal cancer with TFAP2E hypermethylation," they conclude.
This is the first time that a link between TFAP2E hypermethylation and chemoresistance to fluorouracil-based regimens has been reported, Dr. Ebert noted. However, there have been several previous reports linking such resistance to the gene that encodes for dickkopf homolog 4 protein (DKK4), "which we identified as a potential downstream target of TFAP2E," he added.
The team speculates that targeting this downstream DKK4 gene might be useful in these patients. "It would be an interesting option to make a potentially resistant cancer sensitive again," Dr. Ebert explained. "We are looking into this with cell-culture studies and animal models," he told Medscape Medical News. "Antibodies against DKK4 are available, and we speculate that the development of anti-DKK4 antibodies or other targeted agents would be of interest."
The authors have disclosed no relevant financial relationships.
N Engl J Med. 2012;336:44-53. Abstract
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