Circulating Tumor-Specific DNA: A Marker for Monitoring Efficacy of Adjuvant Therapy in Cancer Patients

Abstract

Adjuvant systemic therapy (a strategy that targets potential disseminated tumor cells after complete removal of the tumor) has clearly improved survival of patients with cancer. To date, no tool is available to monitor efficacy of these therapies, unless distant metastases arise, a situation that unavoidably leads to death. We analyzed RASSF1A DNA methylation in pretherapeutic sera and serum samples collected 1 year after surgery from 148 patients with breast cancer who were receiving adjuvant tamoxifen; 19.6% and 22.3% of patients with breast cancer showed RASSF1A DNA methylation in their pretherapeutic and 1-year-after serum samples, respectively. RASSF1A methylation 1 year after primary surgery (and during adjuvant tamoxifen therapy) was an independent predictor of poor outcome, with a relative risk (95% confidence interval) for relapse of 5.1 (1.3-19.8) and for death of 6.9 (1.9-25.9). Measurement of serum DNA methylation allows adjuvant systemic treatment to be monitored for efficacy: disappearance of RASSF1A DNA methylation in serum throughout treatment with tamoxifen indicates a response, whereas persistence or new appearance means resistance to adjuvant tamoxifen treatment. It remains to be seen whether modifications made in adjuvant therapeutic strategies based on detection of circulating nucleic acids will improve survival as well as quality of life.

RASSF1A hypermethylation in pretreatment serum DNA of neuroblastoma patients: a prognostic marker

“…In patients with malignancies, aberrant methylation of serum DNA has been reported (Müller et al, 2003;Ibanez de Caceres et al, 2004;Fiegl et al, 2005;Mori et al, 2005;Koyanagi et al, 2006). We have detected cell-free tumour DNA in serum of neuroblastoma patients (Gotoh et al, 2005).…”

“…The presence of tumour-derived DNA within the blood stream has been identified earlier (Müller et al, 2003;Fiegl et al, 2005;Mori et al, 2005). Recently, one study showed that the detection of circulating tumour cells was correlated with tumour-related methylated DNA in patients with melanoma (Koyanagi et al, 2006), suggesting that circulating tumour cells are a potential source of circulating methylated DNA.…”

“…Methylation-specific PCR assay is a sensitive and specific assay for tumour-related DNA methylation in serum. Several studies have investigated the prospect of using DNA methylation as a surrogate marker for circulating tumour cells in serum samples from breast cancer or melanoma patients (Fiegl et al, 2005;Koyanagi et al, 2006). However, no studies of neuroblastoma have assayed serum samples for aberrant DNA methylation.…”

Array-Based Multiplex Analysis of DNA Methylation in Breast Cancer Tissues

“…Although analysis of each separate biomarker may not be adequate for diagnosis, combinations of biomarkers can produce accurate assays for cancer detection. Such assays together with the presence of abnormally methylated DNA in the blood of cancer patients 6,7 create a possibility for a minimally invasive diagnostic test.…”

Meth-DOP-PCR: an assay for the methylation profiling of trace amounts of DNA extracted from bodily fluids

“…[1][2][3][4][5] Furthermore, although the identification of DNA methylation markers predictive of the response to chemotherapy is just beginning, several studies have shown the association between specific methylation aberrations and the efficacy of chemotherapy in cancer patients. [6][7][8] Alteration of the methylation status of selected CpG-rich promoter sequences is an early event of cell transformation that influences gene expression and thus is a particularly promising cancer biomarker for early diagnosis (reviewed in Baylin and Herman, 9 Verma and Srivatsava, 10 and Esteller 11 ). In this respect, it must be considered that methylation may act as a relatively simple 'yes or no' signal for the presence of tumor DNA or for tumor recurrence.…”