Abstract
IntroductionTo 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.MethodsPatients 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).ResultsA 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.ConclusionReliable 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 numberNCT00543829
Highlights
Preoperative chemotherapy in primary operable breast cancer has been shown to produce an outcome equivalent to that of postoperative chemotherapy [1,2]
This has led to the hypothesis that the response of the primary tumour in the breast parallels the response of distant micrometastases, and that it can be used as a surrogate parameter for clinical outcome
A total of 250 patients were recruited into the trial between April 1998 and June 1999 by 56 participating centres all over Germany
Summary
Preoperative (neo-adjuvant) chemotherapy in primary operable breast cancer has been shown to produce an outcome equivalent to that of postoperative (adjuvant) chemotherapy [1,2]. Randomised preoperative trials have, in contrast to trials in metastatic disease, the advantage of offering a relatively homogeneous population of patients without previous treatment; the therapeutic effect can be evaluated more precisely and at an early stage due to the pathological examination that takes place at the time of surgery. This setting can be described as an in vivo chemosensitivity test. 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
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