Abstract P1-11-07: Results of a Phase II Study of Neoadjuvant Platinum/Taxane Based Chemotherapy and Erlotinib for Triple Negative Breast Cancer
Authors: Sharma P , Khan QJ , Kimler BF , Klemp JR , Connor CJ , McGinness MK , Mammen JMW , Tawfik OW , Fan F , Fabian CJ. 
Published: April 2011

Abstract
Introduction: Patients with triple negative breast cancer (TNBC) have a worse prognosis compared to other breast cancer subtypes, primarily due to lack of targeted treatment options. EGFR1 (epidermal growth factor receptor) is often over-expressed in TNBC and could be a promising therapeutic target. Clinical studies have shown platinums and taxanes to be effective in TNBC and in vitro data has demonstrated synergy between carboplatin, docetaxel and an EGFR inhibitor in TNBC cell lines. Aim: To evaluate the efficacy of platinum/taxane based chemotherapy in combination with a small molecule EGFR inhibitor, Erlotinib, in patients with TNBC.
Methods: Patients with stage II/III TNBC were eligible for this phase II trial. All patients received 6 cycles of chemotherapy (Carboplatin AUC 6, Docetaxel 75mg/m2 every 21 d). In addition patients were equally randomized between two erlotinib arms. Patients in arm A received Erlotinib (150 mg PO d 3 - 14 every 21 d) during all 6 cycles of chemotherapy & patients in arm B received erlotinib only during the last 4 cycles of chemotherapy. This randomization was intended to reduce bias in the evaluation of the effect of erlotinib on biomarkers in a core biopsy of the tumor performed after the second cycle of chemotherapy. All but one patient underwent comprehensive BRCA analysis (Myriad Genetic Laboratories). Following neo-adjuvant therapy, all patients underwent breast surgery. The primary end point was pathological complete response (pCR: no evidence of invasive tumor in the breast & axilla). Minimal Residual Disease [MRD= Residual Cancer Burden (RCB) groups 0+1] status was also evaluated.
Results: 30 eligible patients with TNBC were enrolled between 8/2007 and 6/2010. This analysis includes 28 patients since 2 patients are still on study treatment. Median age: 51yrs (range 31-68), 21%: African American, 54%: postmenopausal. Median tumor size was 3.3 cm & 39% had LN+ disease. Fifteen patients were assigned to each arm of erlotinib. Five of 28 patients (17%) carried a BRCA mutation (two BRCA1deleterious, two BRCA2 deleterious, one BRCA1 uncertain). The overall pCR and MRD (RCB 0+1) rates were 39% & 50% respectively. On univariate analysis, tumor size, LN status, menopausal status, age and number of erlotinib cycles did not correlate with pCR. However, BRCA mutation status strongly correlated with pCR, with a pCR rate of 100% in BRCA mutation carriers compared to 27% in those without BRCA mutation (p=0.006). Baseline EGFR and/or p53 expression of ≥10% was associated with a lower pCR rate in BRCA non-carriers (pCR: 12% vs. 66%, p = 0.025). Common Erlotinib related AEs were: rash (G3/4:7%) & diarrhea (G3/4:30%) with 32% of subjects requiring erlotinib dose reduction/discontinuation due to AEs. Conclusions: Pathological complete response rates of TNBC to a combination of platinum/taxane chemotherapy & an oral EGFR inhibitor are encouraging and should be explored further. The response to this regimen was significantly influenced by BRCA mutation status, indicating a need to stratify patients by their BRCA status in future TNBC trials. Tissue biomarker analysis of downstream targets of EGFR inhibition should be informative regarding the exact role of erlotinib in this patient population.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-07.