Abstract
In a previous study, we established a one-step methylation-specific polymerase chain reaction (OS-MSP) assay for the detection of methylated DNA (met-DNA) and total DNA levels in serum. For the present study, this OS-MSP assay was used for patients with breast cancer treated with neoadjuvant chemotherapy (NAC) in order to investigate the prognostic significance of met-DNA and total DNA levels. Following treatment with NAC and prior to surgery, serum samples obtained from 120 patients with stage II/III breast cancer were subjected to the OS-MSP assay for analysis of the glutathione S-transferase pi 1, Ras association (RalGDS/AF-6) domain family member 1 and retinoic acid receptor β2 genes. The detection of methylation in a minimum of one of these genes indicated a positive outcome of the assay. The total DNA content of the serum was also determined. Of the 120 stage II/III patients, seven (6%) were positive for met-DNA in serum and showed a significantly worse overall survival (OS) time compared with patients negative for met-DNA (n=113) (5-year OS, 43 vs. 85%; P=0.002). The patients with high total DNA levels in serum (n=40) also showed a significantly worse OS compared with those with low total DNA levels (n=80) (65 vs. 91%; P<0.001). The presence of met-DNA and high total DNA levels in the serum were found to be significant prognostic factors that are independent of a pathological complete response by multivariate analysis. Following NAC, met-DNA and high total DNA levels in the serum detected with the OS-MSP assay constitute novel prognostic factors for patients with breast cancer; this may be clinically useful for the prognosis prediction for patients who do not achieve a pathological complete response following NAC.
Highlights
In recent years, growing numbers of patients with breast cancer have been treated with neoadjuvant chemotherapy (NAC) to shrink the tumor size for an improved chance of breast conservation
The present study investigated whether the presence of methylated DNA (met‐DNA) in the serum, as detected by one‐step methylation‐specific polymerase chain reaction (PCR) (OS‐MSP), may be associated with a poor prognosis for patients with breast cancer treated with NAC
The present study investigated whether detection of met‐DNA and high total DNA levels in the serum by means of the one‐step methylation‐specific polymerase chain reaction (OS‐MSP) assay could serve as novel prognostic factors for patients with breast cancer treated with NAC
Summary
In recent years, growing numbers of patients with breast cancer have been treated with neoadjuvant chemotherapy (NAC) to shrink the tumor size for an improved chance of breast conservation It has been reported by specific studies that more patients treated with NAC undergo breast‐conserving surgery than those not treated [1,2]. Since prognostic evaluation is extremely important in deciding whether or not further adjuvant therapy should be used, more effective prognostic factors are required for those patients who cannot achieve a pCR It has been hypothesized and is currently accepted that the detection of tumor‐specific DNA methylation in serum is useful for prognosis prediction and for monitoring responses to systemic therapy in patients with breast cancer [5,6,7,8,9,10,11,12,13]. A study by Sharma et al [12] detected methylation of the glutathione S‐transferase pi 1 (GSTP1) and breast cancer 1, early onset (BRCA1) genes in serum more frequently in non‐responders to NAC than in responders, while Avraham et al [13] reported that none of the responders to NAC showed methylated Ras association (RalGDS/AF‐6) domain family member 1 (RASSF1A)
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