Günther Raab

Introduction: To investigate the predictive value of clinical and biological markers for a pathological complete remission after a preoperative dose-dense regimen of doxorubicin and docetaxel, with or without tamoxifen, in primary operable breast cancer. Methods: Patients with a histologically confirmed diagnosis of previously untreated, operable, and measurable primary breast cancer (tumour (T), nodes (N) and metastases (M) score: T2-3(≥ 3 cm) N0-2 M0) were treated in a prospectively randomised trial with four cycles of dose-dense (bi-weekly) doxorubicin and docetaxel (ddAT) chemotherapy, with or without tamoxifen, prior to surgery. Clinical and pathological parameters (menopausal status, clinical tumour size and nodal status, grade, and clinical response after two cycles) and a panel of biomarkers (oestrogen and progesterone receptors, Ki-67, human epidermal growth factor receptor 2 (HER2), p53, bcl-2, all detected by immunohistochemistry) were correlated with the detection of a pathological complete response (pCR). Results: A pCR was observed in 9.7% in 248 patients randomised in the study and in 8.6% in the subset of 196 patients with available tumour tissue. Clinically negative axillary lymph nodes, poor tumour differentiation, negative oestrogen receptor status, negative progesterone receptor status, and loss of bcl-2 were significantly predictive for a pCR in a univariate logistic regression model, whereas in a multivariate analysis only the clinical nodal status and hormonal receptor status provided significantly independent information. Backward stepwise logistic regression revealed a response after two cycles, with hormone receptor status and lymph-node status as significant predictors. Patients with a low percentage of cells stained positive for Ki-67 showed a better response when treated with tamoxifen, whereas patients with a high percentage of Ki-67 positive cells did not have an additional benefit when treated with tamoxifen. Tumours overexpressing HER2 showed a similar response to that in HER2-negative patients when treated without tamoxifen, but when HER2-positive tumours were treated with tamoxifen, no pCR was observed. Conclusion: Reliable prediction of a pathological complete response after preoperative chemotherapy is not possible with clinical and biological factors routinely determined before start of treatment. The response after two cycles of chemotherapy is a strong but dependent predictor. The only independent factor in this subset of patients was bcl-2. Trial registration number: NCT00543829

Neoadjuvant chemotherapy can increase the rate of breast-conserving surgery in patients with operable breast cancer. However, uncertainty remains regarding surgical procedures and predictors for successful breast-conserving surgery. This study was an analysis of surgical data of a representative data subset of 607 patients enrolled in the GEPARDUO study. This prospective, multicenter, phase III study randomly assigned patients with operable breast cancer (≥ 2 cm) to neoadjuvant 8-week dose-dense doxorubicin plus docetaxel or a 24-week schedule of doxorubicin plus cyclophosphamide followed by docetaxel (AC-DOC). Breast conservation was attempted in 493 (81.2%) patients, but 43 patients eventually required mastectomy, thus resulting in a breast-conserving surgery rate of 74.1%. Breast-conserving re-excision was performed in 61 patients (12.4%). Factors associated with a significantly higher breast-conserving surgery rate were a prechemotherapy tumor size ≤ 40 mm, nonlobular histological characteristics, treatment with AC-DOC, clinical response, postchemotherapy tumor size ≤ 20 mm, and treatment in a larger center (>10 enrolled patients). Nonlobular histological characteristics and intraoperative frozen-section analysis for margin evaluation were associated with significantly lower reoperation rates (P = .015). Breast conservation after neoadjuvant chemotherapy is feasible in most patients with operable breast cancer. For surgical planning, tumor characteristics and response to neoadjuvant chemotherapy should be taken into account. Improved breast-imaging modalities are necessary to improve detection of residual disease after neoadjuvant chemotherapy, especially when breast cancer is of lobular invasive histology. Margin assessment by intraoperative frozen-section analysis is helpful to avoid reoperation. To achieve an optimal result, an interdisciplinary surgical approach is important.