Cytokeratin-19 mRNA-Positive CTC's after chemo in early bc

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Cytokeratin-19 mRNA-Positive Circulating Tumor Cells After Adjuvant Chemotherapy in Patients With Early Breast Cancer

J Clin Oncol. 2009 Mar 30;[Online Ahead of Print], N Xenidis, M Ignatiadis, S Apostolaki, M Perraki, K Kalbakis, S Agelaki, E Stathopoulos, G Chlouverakis, E Lianidou, S Kakolyris, V Georgoulias, D Mavroudis


Several studies have identified the presence of circulating tumor cells (CTCs) as an adverse prognostic factor in patients with early-stage breast cancer. However, most studies on the prognostic value of CTCs have been based on detection of CTCs at the time of primary diagnosis. Limited, recent evidence suggests that persistence of CTCs after adjuvant therapy may signify an unfavorable outcome. One of the most sensitive tumor markers for the detection of breast cancer cells in patients with early-stage and metastatic breast cancer is cytokeratin-19 (CK-19). The purpose of the present study was to assess the clinical relevance of CK-19 mRNA−positive CTCs detected by real-time polymerase chain reaction (RT-PCR) following the completion of adjuvant chemotherapy in patients with early-stage breast cancer. The results showed that the presence of CK-19 mRNA−positive CTCs after chemotherapy in these patients was associated with shorter survival.
The study involved 437 patients (mean age, 54 years) who received chemotherapy for stage I to III breast cancer from 1997 to 2004. Patients whose tumors tested positive for estrogen receptors (ER positive), progesterone receptors (PR positive), or both received tamoxifen alone or tamoxifen followed by an aromatase inhibitor. Patients with HER2/neu-expressing tumors did not receive trastuzumab, because the positive results from the adjuvant therapy trials with this agent had not yet been reported.
The main outcome measures were overall survival (OS) and disease-free survival (DFS). The size of the primary tumor was <2.0 cm in 35.2% of the patients, histologic grade 3 tumors were noted in 43%, and at least 1 lymph node was involved in 63.4%. ER-positive and PR-positive tumors were found in 58.6% and 45.8% of patients, respectively. Blood samples were taken prior to and after completion of adjuvant chemotherapy.
CK-19 mRNA in CTCs was detected in 41% of the patients prior to the start of adjuvant chemotherapy and in 32.7% upon completion of such therapy. Among the 258 patients initially testing negative for CK-19 mRNA prior to chemotherapy, 21.7% tested positive at completion. Among the 179 patients initially testing positive for CK-19 mRNA prior to chemotherapy, 51.4% tested negative at completion.
Median follow-up was 53.5 months. Distant and/or locoregional recurrence developed in 21.7% of the patients. Recurrence was significantly more common in patients testing positive for CK-19 mRNA after chemotherapy than in those testing negative after chemotherapy. Patients who experienced relapse also had a higher median number of CTCs positive for CK-19 mRNA than did patients who did not relapse. Patients testing positive for CK-19 mRNA both before and after chemotherapy had a higher relapse rate than did patients who were CK-19 mRNA negative at both time points (39.1% vs 13.9%).
DFS rates in patients who were CK-19 mRNA positive vs those who were CK-19 mRNA negative after chemotherapy were 78% vs 92% at 3 years and 68% vs 84% at 5 years. During follow-up, 42 patients (9.6%) died because of disease progression. The death rate was higher among patients with than among those without detectable CTCs after completion of adjuvant chemotherapy (16.8% vs 6.1%). In addition, more patients with detectable CTCs both before and after adjuvant chemotherapy died compared with patients who did not have measurable CTCs at these same time points (19.5% vs 4.0%). OS rates in patients who were CK-19 mRNA positive vs those who were CK-19 mRNA negative after chemotherapy were 91% vs 97% at 3 years and 82% vs 93% at 5 years. OS was significantly shorter for the patients with detectable CTCs after completion of adjuvant chemotherapy than for those without detectable CTCs.
In univariate analysis, factors that were significantly associated with reduced OS and DFS were CK-19 mRNA−positive CTCs prior to or following adjuvant chemotherapy, or persistently positive CTCs prior to and after chemotherapy; tumor size >2.0 cm; >3 involved axillary lymph nodes; histologic grade 3 tumor; and ER-negative status.
In summary, the presence of CK-19 mRNA−positive CTCs after chemotherapy was independently prognostic for poor OS and DFS in patients with early breast cancer. Based on these findings, the investigators propose that CTCs be measured during or after therapy to better characterize the prognostic risk for each patient and enable individualized treatment. Future well-designed studies are needed to further explore the application of CTC monitoring to improving clinical outcomes.


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