Neoadjuvant endocrine therapy has been reported to decrease tumor size, which leads to increased breast conservation rates. To improve the clinical response, metronomic chemotherapy with endocrine therapy is a promising strategy. A multicenter phase II single-arm neoadjuvant trial with letrozole and cyclophosphamide was conducted. Eligibility criteria included postmenopausal status, T2-4 N0-1, and estrogen receptor-positive breast carcinoma. Letrozole (2.5 mg) plus cyclophosphamide (50 mg) was given orally once a day for 24 weeks. The primary endpoint was the clinical response rate (CRR). To investigate anti-angiogenic effects, circulating endothelial cells (CECs) were quantified using the CellSearch system. From October 2007 to March 2010, 41 patients were enrolled. The CRR was 67.5% (52.0-80.0%), which was above the prespecified threshold (65%). The conversion rate from total mastectomy to breast-conserving surgery was 64% (18/28). Grade 3 or greater nonhematological toxicity was not reported. Clinical response was associated with improved disease-free survival (DFS) (P = 0.020). The increase in CEC counts at 8 weeks was observed in nonresponders (P = 0.004) but not in responders. Patients with higher CEC counts at baseline or post-treatment showed worse DFS than those with lower counts (P < 0.001 at baseline and = 0.014 post-treatment). Multivariate analysis showed that post-treatment CEC counts but not pretreatment counts were independently correlated with DFS (P = 0.046). In conclusion, neoadjuvant letrozole plus cyclophosphamide showed a good clinical response for postmenopausal patients with estrogen receptor-positive breast cancer. CEC quantification is a promising tool for treatment monitoring and prognostic stratification for metronomic therapy following validation of our results in larger studies.
Clinical trial registration number: UMIN000001331 Phase II study of neoadjuvant letrozole combined with low-dose metronomic cyclophosphamide for postmenopausal women with endocrine-responsive breast cancer (JBCRG-07).
Keywords: Breast cancer; chemo-endocrine therapy; circulating endothelial cell; metronomic therapy; neoadjuvant.
© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.