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Background: In recent years, preoperative volume reduction of locally advanced breast cancers, resulting in higher rates of breast-conserving surgery (BCS), has become increasingly important also in postmenopausal women. Clinical interest has come to center on the third-generation nonsteroidal aromatase inhibitors (AIs), including letrozole, for such neoadjuvant endocrine treatment. This usually lasts 3-4 months and has been extended to up to 12 months, but optimal treatment duration has not been fully established., Methods: This study was designed as a multicenter, open-label, single-arm, exploratory phase IIb/III clinical trial of letrozole 2.5 mg, one tablet daily, for 4-8 months. The primary objective was to investigate the effect of neoadjuvant treatment duration on tumor regression and BCS eligibility to identify optimal treatment duration. Tumor regression (by clinical examination, mammography, and ultrasound), shift towards BCS eligibility, and safety assessments were the main outcome measures. Standard parametric and nonparametric descriptive statistics were performed., Results: Letrozole treatment was received by 32 of the enrolled 33 postmenopausal women (median (range): 67.0 (56-85) years) with unilateral, initially BCS-ineligible primary breast cancer (clinical stage > or = T2, N0, M0). Letrozole treatment duration in the modified intent-to-treat (ITT; required 4 months' letrozole treatment) analysis population (29 patients) was 4 months in 14 patients and > 4 months in 15 patients. The respective per-protocol (PP) subgroup sizes were 14 and 11. The majority of partial or complete responses were observed at 4 months, though some beneficial responses occurred during prolonged letrozole treatment. Compared with baseline, median tumor size in the ITT population was reduced by 62.5% at Month 4 and by 70.0% at final study visit (Individual End). Similarly, in the PP population, respective reductions were 64.0% and 67.0%. Whereas initially all patients were mastectomy candidates, letrozole treatment enabled BCS (lumpectomy) in 22 ITT (75.9%) and 18 PP (72.0%) patients., Conclusion: Over half of patients become BCS-eligible within 4 months of preoperative letrozole treatment. While prolonged treatment for up to 8 months can result in further tumor volume reduction in some patients, there is no clear optimum for treatment duration. Letrozole has a favorable overall safety and tolerability profile., Trial Registration: ClinicalTrials.gov identifier NCT00535418.

Background: The overexpression of syndecan-1 in breast carcinomas correlates with poorer prognosis and an aggressive phenotype. The effect of syndecan-1 expression on tumor response to neoadjuvant chemotherapy was determined in locally advanced breast cancer., Patients and Methods: Semi-quantitative syndecan-1 immunohistochemistry was performed in pre-chemotherapy breast cancer biopsies of 37 patients undergoing high-dose neoadjuvant treatment with cyclophosphamide and epirubicin., Results: 43.2% of breast carcinomas stained positive for syndecan-1. Syndecan-1 expression was more frequent in ductal invasive carcinomas than in other histological types (p=0.062). The pathological response to chemotherapy was decreased in syndecan-1-positive patients: 37.5% of syndecan-1-positive vs. 19% of syndecan-1-negative patients attained pathologically "no change". No syndecan-1-positive patient showed complete remission. Also, a correlation between syndecan-1 immunostaining intensity and response to chemotherapy was observed. Of the responding tumors, none showed strong syndecan-1 expression (Score 3+), whereas 20% of the non-responding tumors were strongly syndecan-1-positive., Conclusion: Syndecan-1-expressing breast carcinomas show a trend towards a decreased response to chemotherapy.

Objective: The status of the axillary lymph nodes is one of the most important prognostic factors in patients with breast cancer. A panel of molecular markers of tumor aggressiveness in addition to conventional clinical and histopathologic features were analyzed in an attempt to identify a subgroup of patients with a low risk of axillary lymph node metastases., Material and Methods: Data from 358 patients with T1 breast cancer who underwent level I/II axillary lymph node dissection (ALND) were investigated. Hormone receptor status, Ki-67, S-phase fraction, DNA ploidy, HER-2/neu, p53, epidermal growth factor receptor, urokinase type plasminogen activator, plasminogen activator inhibitor-1, bone marrow micrometastases as well as patient age, menopausal status, tumor site, tumor size, histologic type, tumor grade, carcinoma in situ, multifocality, and lymph vascular invasion (LVI) were studied to predict axillary lymph node status., Results: In a multivariate logistic regression analysis LVI (present v.s. not present), Ki-67 (> or = 18% v.s. < 18%), tumor size (1.1-2 cm v.s. < or = 1 cm), and histologic grade (G3 v.s. G1/2) were identified as independent predictive factors of axillary lymph node metastases. Approximately 13% of patients (n = 47) with well or moderately differentiated tumors less than or equal to 1 cm, no lymph vascular invasion, and a low Ki-67 staining were identified as having a low risk of axillary lymph node metastases of 4.3%. However, 20 patients with all four unfavorable predictive factors had a 75% incidence of axillary lymph node involvement., Conclusion: Primary tumor characteristics can be used to identify a subgroup of patients with a low risk of axillary lymph node metastases in T1 breast cancer. Preoperative risk assessment might be used to omit routine ALND in those patients at low risk of axillary lymph node metastases.

Timing of systemic treatment in primary operable breast cancer is subject to extensive investigation, suggesting that pathologic complete remission (pCR) might improve survival in this setting. The German Adjuvant Breast Cancer Group previously demonstrated the feasibility of a dose-dense biweekly schedule of 4 cycles doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 (ddAT) +/- tamoxifen in the neoadjuvant setting to yield a pCR of 9.7% (Gepardo trial). Patients assigned to ddAT received prophylactic granulocyte colony-stimulating factor support (5 micro g/kg days 5-10). The current study (GeparDUO) was designed to assess whether the pCR rate, including no viable invasive and preinvasive tumor cells, achieved with ddAT was equivalent to sequential administration of doxorubicin/cyclophosphamide followed by docetaxel (AC-DOC) over 24 weeks in primary operable breast cancer. From June 1999 to September 2001, 913 patients were enrolled in this trial. In total, 395 patients randomized before August 1, 2000, were included in the second interim analysis. Safety data were available from 369 patients (ddAT, n = 191; AC-DOC, n = 178) demonstrating that toxicity of both regimens was tolerable. Grade 3/4 neutropenia occurred in 39.8% of patients receiving ddAT and in 69.3% of patients treated with AC-DOC. Efficacy data were available in 378 patients. A pCR occurred in 14.8% of the primary breast tumors. According to the recommendations of the data monitoring committee, recruitment to the study was halted as of September 2001 (n = 913/1000) due to the significant difference in pCR rates observed between the treatment arms. Surgery was documented in 380 patients. Breast conservation was possible in 288 cases (75.8%). The application of both schedules is safe and feasible in an outpatient setting. Although, results obtained from this interim analysis are encouraging, caution is recommended until the results obtained show statistical difference in pCR.