Background: Monoclonal antibodies (mAb), such as trastuzumab are a valuable addition to breast cancer therapy. Data obtained from neoadjuvant settings revealed that antibody-dependent cell-mediated cytotoxicity (ADCC) is a major mechanism of action for the mAb trastuzumab. Conflicting results still call into question whether disease progression, prolonged treatment or concomitant chemotherapy influences ADCC and related immunological phenomena.Methods: We analyzed the activity of ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) of peripheral blood mononuclear cells (PBMCs) from human epidermal growth factor receptor 2 (HER2/neu) positive breast cancer patients receiving trastuzumab therapy either in an adjuvant (n = 13) or metastatic (n = 15) setting as well as from trastuzumab treatment-naive (t-naive) HER2/neu negative patients (n = 15). PBMCs from healthy volunteers (n = 24) were used as controls. ADCC and ADCP activity was correlated with the expression of antibody binding Fc-gamma receptor (FcγR)I (CD64), FcγRII (CD32) and FcγRIII (CD16) on CD14+ (monocytes) and CD56+ (NK) cells, as well as the expression of CD107a+ (LAMP-1) on CD56+ cells and the total amount of CD4+CD25+FOXP3+ (T_reg) cells. In metastatic patients, markers were correlated with progression-free survival (PFS).Results: ADCC activity was significantly down regulated in metastatic, adjuvant and t-naive patient cohorts as compared to healthy controls. Reduced ADCC activity was inversely correlated with the expression of CD107a on CD56+ cells in adjuvant patients. ADCC and ADCP activity of the patient cohorts were similar, regardless of treatment duration or additional chemotherapy. PFS in metastatic patients inversely correlated with the number of peripheral T_regcells.Conclusion: The reduction of ADCC in patients as compared to healthy controls calls for adjuvant strategies, such as immune-enhancing agents, to improve the activity of trastuzumab. However, efficacy of trastuzumab-specific ADCC and ADCP appears not to be affected by treatment duration, disease progression or concomitant chemotherapy. This finding supports the application of trastuzumab at any stage of the disease.

Purpose: Preoperative (neoadjuvant) chemotherapy for operable breast cancer downstages tumors initially not suitable for breast-conserving surgery. A pathologic complete response (pCR) to neoadjuvant chemotherapy may be a surrogate for longer overall survival, but this beneficial effect remains to be established. This phase III trial evaluated whether doubling the number of cycles of neoadjuvant treatment increased the pCR rate. Patients and Methods: Patients with biopsy-proven breast cancer (T1-4a-c, N±, M0; stage I to III) were eligible and randomly assigned to either three or six cycles of epirubicin 75 mg/m² and docetaxel 75 mg/m² on day 1 and granulocyte colony-stimulating factor on days 3 through 10 (ED+G), every 21 days. The primary end point was the pCR rate of the breast tumor. Secondary end points were pathologic nodal status after surgery and the rate of breast-conserving surgery. Results: A total of 292 patients were accrued, and 288 patients were assessable for efficacy and safety. Groups were well balanced for known prognostic factors. Six cycles of ED+G, compared with three cycles, resulted in a significantly higher pCR rate (18.6% v 7.7%, respectively; P = .0045), a higher percentage of patients with negative axillary status (56.6% v 42.8%, respectively; P = .02), and a trend towards more breast-conserving surgery (75.9% v 66.9%, respectively; P = .10). Rates of adverse events were similar, and no patients died on treatment. Conclusion: Doubling the number of neoadjuvant ED+G cycles from three to six results in higher rates of pCR and negative axillary nodal status with no excess of adverse effects. Thus, six cycles of ED+G should be the standard neoadjuvant treatment for operable breast cancer if this combination is chosen.

This randomized phase III trial compared pathologic complete response (pCR) rates of early breast cancer (EBC) following neoadjuvant epirubicin–docetaxel (ED) ± capecitabine (C), and evaluated the addition of trastuzumab in HER2-positive tumors. Patients with invasive breast cancer (except T4d) were randomly assigned to receive six 3-weekly cycles of ED (both 75 mg/m²) ± C (1000 mg/m², twice daily, days 1–14). Patients with HER2-positive disease were further randomized to receive trastuzumab (8 mg/kg, then 6 mg/kg every 3 weeks) or not. Primary end point: pCR rate at the time of surgery. Five hundred thirty-six patients were randomized to ED (n = 266) or EDC (n = 270); 93 patients were further randomized to trastuzumab (n = 44) or not (n = 49). pCR rate was significantly increased with EDC (23.0% versus 15.4% ED, P = 0.027), and nonsignificantly further increased with trastuzumab (38.6% EDC versus 26.5% ED, P = 0.212). Rates of axillary node involvement at surgery and breast conservation were improved with EDC versus ED, but not significantly; the addition of trastuzumab had no further impact. Hormone receptor status, tumor size, grade, and C (all P ≤ 0.035) were independent prognostic factors for pCR. Trastuzumab added to ED ± C significantly increased the number of serious adverse events (35 versus 18; P = 0.020), mainly due to infusion-related reactions. These findings show that the integration of C into a neoadjuvant taxane-/anthracycline-based regimen is a feasible, safe, and effective treatment option, with incorporation of trastuzumab in HER2-positive disease. NCT00309556, www.clinicaltrials.gov.

Trastuzumab-based therapy after diagnosis of brain metastases (BM) may improve survival due to prolonged systemic disease control. We investigated whether lapatinib may yield additional survival benefit. Eighty patients with BM from HER2-positive breast cancer were identified. Karnofsky Performance Score (KPS) of at least 70 was required. We included a control group of 37 patients treated before 2003, when continuation of trastuzumab after diagnosis of BM was not yet recommended. Remainders received either trastuzumab or lapatinib and trastuzumab (either concomitantly or sequentially) with or without chemotherapy. Median overall survival (OS) in patients receiving trastuzumab after diagnosis of BM was 13 months; corresponding numbers were 9 months in patients treated with chemotherapy, and 3 months with radiotherapy alone. Median OS was not reached in the lapatinib group. Addition of lapatinib prolonged OS over trastuzumab alone (P=0.002). After correction for potential confounders, lapatinib therapy remained an independent positive predictor for survival (HR 0.279; P=0.012). This retrospective single-centre study suggests that the introduction of lapatinib improved survival in patients with BM from HER2-positive breast cancer. Patients with KPS 70 may benefit when treated with lapatinib in addition to trastuzumab after completion of local therapy.

Purpose: This phase II study determined the efficacy of lacnotuzumab added to gemcitabine plus carboplatin (gem-carbo) in patients with advanced triple-negative breast cancer (TNBC). Experimental Design: Female patients with advanced TNBC, with high levels of tumor-associated macrophages, and not amenable to curative treatment by surgery or radiotherapy, were enrolled. Lacnotuzumab was dosed at 10 mg/kg every 3 weeks (Q3W), {plus minus} a dose on Cycle 1, Day 8. Gem and carbo were given at 1000 mg/m² and area under curve 2 dose in mg, respectively, Q3W. Treatment continued until unacceptable toxicity, disease progression, or discontinuation by physician/patient. Results: Patients received lacnotuzumab+gem-carbo (n=34) or gem-carbo (n=15). Enrollment was halted due to recruitment challenges owing to rapid evolution of the therapeutic landscape; formal hypothesis testing of the primary endpoint, was therefore not performed. Median progression-free survival was 5.6 months (90% CI: 4.47, 8.64) in the lacnotuzumab+gem-carbo arm and 5.5 months (90% CI: 3.45, 7.46) in the gem-carbo arm. Hematologic adverse events were common in both treatment arms; however, patients treated with lacnotuzumab experienced more frequent aspartate aminotransferase, alanine aminotransferase, and creatine kinase elevations. Pharmacokinetic results showed that free lacnotuzumab at 10 mg/kg exhibited a typical IgG pharmacokinetic profile and target engagement of circulating CSF-1 ligand. Conclusions: Despite successful target engagement and anticipated pharmacokinetic profile, lacnotuzumab+gem-carbo showed comparable antitumor activity to gem-carbo alone, with slightly poorer tolerability. However, the data presented in this manuscript would be informative for future studies testing agents targeting the CSF-1-CSF-1R pathway in TNBC.