Predictors of Persistent Micrometastatic Disease after Neoadjuvant Chemotherapy.
Authors: Gainer S. , Lodhi A. , Krishnamurthy S. , Jackson S. , Hall C. , Andreopoulou E. , Singh B. , Bedrosian I. , Meric-Bernstam F. , Kuerer H. , Hunt K. , Cristofanilli M. , Lucci A. 
Published: December 2010

Introduction: Patients who receive neoadjuvant chemotherapy (NAC) for breast cancer typically do not receive further cytotoxic chemotherapy after surgery. We hypothesized that some patients would have micrometastatic disease in the bone marrow (disseminated tumor cells, DTCs) or peripheral blood (circulating tumor cells, CTCs) after NAC. This study documented rates and factors predicting DTCs and CTCs after NAC.Methods: We prospectively evaluated patients undergoing surgery for stage I-III breast cancer. All patients had blood and bone marrow samples taken after completing systemic NAC. CTCs (per 7.5ml blood) were detected using the CellSearchTM system (Veridex). CTCs were defined as nucleated cells lacking CD45 but expressing cytokeratins (CK) 8, 18, or 19. DTCs were assessed using anti-CK antibody cocktail (AE1/AE3, CAM5.2, MNF116, CK8 and 18) following cytospin. The presence of ≥1 CK positive cells and ≥1 epithelial cells meeting morphologic criteria for malignancy was considered a positive result for DTCs and CTCs, respectively. Clinicopathologic factors correlated with DTCs and CTCs and response after NAC included: Her2/neu, estrogen receptor (ER), progesterone receptor (PR) and COX2 status as well as tumor size and grade. Complete pathologic response (pCR) was defined as lack of any residual invasive disease in primary tumor and regional lymph nodes after NAC. Statistical analyses used chi-square and Fischer's exact test.Results: Results were available for 53 patients who had bone marrow and blood collected after NAC. Median follow-up was 26 months. Mean age was 52 years. NAC included anthracyclines and taxanes +/- trastuzumab. Forty percent of patients had either DTCs or CTCs after NAC. Six patients had DTCs amongst 11 patients (55%) who received trastuzumab as compared to those who did not 6/33 (18%), P=0.019. DTCs and CTCs were found in 10/43 patients (23%) and 11/43 patients (27%), respectively. Factors predicting the presence of DTCs after NAC were Her2/neu positivity (P=0.001) and COX2 positivity determined in the primary tumor at diagnosis (P=0.04). No statistically significant correlations were found between CTCs after NAC and primary tumor characteristics. Thirty percent of patients with evidence of DTCs and 10% with CTCs had a pCR. Among the 7 patients with pCR after NAC, 2 (28%) had DTCs and 2 (28%) had CTCs. Factors predicting pCR following NAC were Her2/neu positivity (P=0.0003) and ER negativity (P=0.044). In our analysis, the best predictor of the presence of DTCs and the most likely reason for pCR following NAC was Her2/neu positivity.Conclusions: A significant number of patients have persistent DTCs and/or CTCs after NAC. Interestingly, HER2 positive patients were more likely to have pCR but were also more likely to show persistence of DTCs following NAC. Follow-up is needed to determine if these patients comprise groups at higher risk for recurrence, and therefore benefit from additional chemotherapy or targeted therapies.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3020.