Predictive Value Of Circulating Tumor Cells For Micrometastatic Risk On Surgery And Response To Adjuvant Therapies: Preliminary Results Of A Pilot Study

Breast cancer is by far the most common malignancy in women and it is ranked as theleading cause of cancer death. However,tumor relapse and metastasis are still the primaryreason for mortality, which mainly result from micrometastasis undetected by conventionalapproaches in blood, bone marrow or lymph nodes. Recent clinical research has focused ondetection and exploration of micrometastasis in the form of circulating tumor cells (CTC) inperipheral blood, which significantly contributes to distant metastasis. Results from studieshave showed a clinical value of detecting and monitoring levels of CTC for evaluation ofprognosis and therapeutic regime, as well as providing reference information for clinicaldecision-making. Previous studies have demonstrated surgery can contribute to the seeding ofcancer cells, while there has been no research on difference in different surgical approaches.Meanwhile, there still have been controversies on the role of CTC detection in predicting theeffect of treatment. Accordingly, the aim of this pilot study was to evaluate the effect of thesurgical approach on differentiation of micrometastatic risk correlated to surgery and thepredictive and prognostic value of CTC for assessing response to breast cancer relatedadjuvant therapies.Methods&ResultsPart I. Decreased risk of circulating tumor cells after endoscopic breast surgerythan open surgery for breast cancerMethods:. Pre-and postoperative (12h after surgery) peripheral blood samples (5ml)obtained from110female patients with operable breast cancer (53patients underwentendoscopic breast surgery and57patients underwent open radical mastectomy) were enrichedby density gradient centrifugation for mononuclear cells and then detected by quantitativereal-time reverse transcription-PCR (qPCR) for cytokeratin19mRNA-positive CTC. The difference in detection rate, median levels expressed as MCF-7cell equivalents/2μg RNA ofCK19mRNA-positive CTC, micrometastatic risk on surgery between endoscopic breastsurgery and open surgery were compared and analyzed.Results: There was no significant difference in clinicopathologic characteristics betweenthese two groups. In the open-group, the positive rate of CTC before and after surgery were22.81%(13/57) and33.33%(19/57)(P=0.211), the median levels of CK19mRNA-positiveCTC expressed as MCF-7cell equivalents/2μg RNA before and after surgery were0.21(0-15.16) and0.43(0-9)(P=0.123) and17patients (29.8%) had increased micrometastaticrisk related to surgery; In the endoscopic-group, the positive rate of CTC before and aftersurgery were24.53%(13/53) and28.3%(15/53)(P=0.659), the median levels of CK19mRNA-positive CTC expressed as MCF-7cell equivalents/2μg RNA before and after surgerywere0.27(0-26.49) and0.36(0-10.56)(P=0.717), respectively, and7patients (13.2%) hadincreased micrometastatic risk related to surgery.The results showed a higher clinical but notstatistical elevation in postoperative CTC detection rate and median levels in the open-groupcompared with the endoscopic-group.An increased micrometastatic risk caused by operationwas observed in the open-group as compared to the endoscopic approach (OR=2.79,95%CI1.05-7.42), and the difference of micrometastatic risk related to surgery between these twogroups correlated with the status of hormone receptors, not the status of menopause, lymphnode, tumor stage or HER-2.Part II. Predictive and prognostic value of circulating tumor cells for assessingresponse to breast cancer related adjuvant therapies: a meta-analysisMethods: All eligible studies assessing the predictive and prognostic value of CTC forevaluating tumor response to breast cancer related adjuvant therapies were identified bysearch of medical databases including PubMed, Web of Science, EMBASE, and ChineseBiomedical Literature database and China Academic Literature Full-text Database for theperiod up to April2012, and the reference lists of identified studies, conference proceedingsfrom San Antonio Breast Cancer Symposium, annual meetings of American Society ofClinical Oncology and American Association for Cancer Research from2000to2011werereviewed as a augmented searching. The quality of all included studies were assessed and thedata were extracted. A meta-analysis was performed with RevMan5.0software, and then theGRADE System was used to evaluate the level of evidence. Results: Among the24studies involving1551cases included, there were984cases of18studies involved in the analysis of total response rate (TRR) and537cases of10studies inclinical benefit response (CBR) correlated with the detection of CTC prior to adjuvant therapy,795cases of13studies involved in the analysis of TRR and462cases of7studies in CBRrelated to the detection of CTC during/at the end of adjuvant therapy.The results of thismeta-analysis showed a higher TRR in the group of patients with CTC-negative result thanCTC-positive both prior to treatment (RR=0.75,95%CI0.63-0.89,P=0.001) and during/at theend of therapy (RR=0.31,95%CI0.22-0.45,P<0.00001), there was also a higher CBR in thegroup of patients with CTC-negative result than CTC-positive both prior to treatment(RR=0.73,95%CI0.59-0.92,P<0.00001) and during/at the end of therapy (RR=0.53,95%CI0.42-0.67,P<0.00001), which indicated a better TRR and CBR could be obtained in patientswith a negative result of CTC detection before and after therapy than positive ones.Accordingto GRADE system, the levels of evidence in the relationship between TRR and CTC detectionresult before and during/at the end of therapy were all Grade B, which were Grade D and Cfor the evidence in the relationship between CBR and CTC detection result before andduring/at the end of therapy, respectively. suggesting a more predictive and prognostic valueof CTC detection result for assessing response to breast cancer related adjuvant therapies.Conclusions1. CTC tends to be detected in patients with operative breast cancer after surgery, andthere is an increased micrometastatic risk on surgery in the open-group as compared to theendoscopic breast surgery.2. CTC might have a clinically valuable predictive and prognostic power in patients withbreast cancer to evaluate tumor response to adjuvant therapies, and the presence of CTC priorto therapy or not might provide more effective reference information.