Randomised phase III trial of FEC120 vs EC-docetaxel in patients with high-risk node-positive primary breast cancer: final survival analysis of the ADEBAR study.

BACKGROUND: Taxane-containing adjuvant chemotherapy has been established as standard treatment in node-positive breast cancer. This study compared efficacy and tolerability of epirubicin (E)/cyclophosphamide (C) followed by docetaxel (Doc) with a dose-dense 5-fluorouracil (F)+E+ C regimen. METHODS: The ADEBAR study was a randomised phase III trial for women with primary invasive breast cancer and ⩾4 metastatic axillary lymph nodes (n=1364). Treatment consisted of four 21-day cycles of E plus C, followed by four 21-day cycles of Doc (EC-Doc), or six 28-day cycles of E plus F plus C (FEC120). RESULTS: Disease-free survival (DFS) was similar in the two treatment arms as shown by multivariate Cox regression adjusted for other prognostic factors (EC-Doc vs FEC120, hazard ratio (HR): 1.087; 95% confidence interval (CI): 0.878-1.346, P=0.444). In addition, there was no significant difference in overall survival (OS) between the two groups (HR: 0.974; 95% CI: 0.750-1.264, P=0.841). Haematologic toxicity was more common in FEC120 recipients; non-haematologic toxicities occurred more frequently in the EC-Doc arm. The serious adverse event rate was significantly higher in the FEC120 group (29.7% vs 22.5%). CONCLUSIONS: EC-Doc provides a feasible and effective alternative therapy option to FEC120 with a different safety profile in this high-risk breast cancer cohort.

Disseminated and circulating tumor cells in bone marrow and blood of breast cancer patients: properties, enrichment, and potential targets.

INTRODUCTION: From the early days of pathology back in the nineteenth century until now, there has been an ongoing search for the missing link between solid tumors such as breast cancer and distant metastases, which sometimes occur many years after removal of the primary tumor. The "seed and soil" theory hypothesizes the early dissemination of occult tumor cells into blood or bone marrow, which can persist in a dormant state for a long time and then become precursors of metastases in distant organs which offer appropriate conditions. METHOD: Advances in immunocytochemical methods have enabled the enrichment and visualization of those disseminated tumor cells in bone marrow (DTC-BM) or circulating tumor cells (CTC) in blood. Many studies could demonstrate prognostic significance of the detection of DTC-BM or CTC in different stages of breast cancer. CONCLUSION: Further characterization of those cells by immunocytochemical stainings, fluorescence in situ hybridizations, or PCR-based molecular methods will help to understand the biology of tumor cell dissemination and metastasis formation, as well as to define potential drug targets.

Hormone Therapy and its Effect on the Prognosis in Breast Cancer Patients.

Introduction: Use of hormone therapy (HT) has declined dramatically in recent years. Some studies have reported that HT use before a diagnosis of breast cancer (BC) may be a prognostic factor in postmenopausal patients. This study aimed to examine the prognostic relevance of HT use before BC diagnosis. Methods: Four BC cohort studies in Germany were pooled, and 4492 postmenopausal patients with HT use data were identified. Patient data and tumor characteristics were compared between users and nonusers, along with overall survival (OS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS). Cox proportional hazards models were stratified by study center and adjusted for age at diagnosis, tumor stage, grading, nodal status, and hormone receptors. Results: Women with HT use before the diagnosis of BC were more likely to have a lower tumor stage, to be estrogen receptor-negative, and to have a lower grading. With regard to prognosis there were effects seen for OS, DMFS and LRFS, specifically in the subgroup of women with a positive hormone receptor. In these subgroups, BC patients had a better prognosis with previous HT use. Conclusions: HT use before a diagnosis of BC is associated with a more favorable prognosis in women with a positive hormone receptor status. It may be recommended that the prognostic factor HT should be documented and analyzed as a confounder for prognosis in studies of postmenopausal hormone-responsive breast cancers.

Adjuvant therapeutic decisions in elderly breast cancer patients: the role of chemotherapy in a retrospective analysis.

PURPOSE: Decisions on the type of adjuvant treatment in older breast cancer patients are challenging. Side effects of chemotherapy have to be weighed against life expectancy, comorbidities, functional status, and frailty on the basis of studies usually excluding patients over 69 years. To aid this decision, we analyzed a database of 6000 unselected patients and of those evaluated elderly primary breast cancer patients with hormone receptor-negative tumors from 1963 until 2003 in respect of survival data depending on adjuvant treatment. METHODS: A total of 131 elderly (i.e., >65 years) patients were observed retrospectively for a median of 72 months. Patients received breast-conserving therapy or mastectomy and adjuvant radiotherapy, chemotherapy, and endocrine therapy. Data were collected from a hospital-intern database. RESULTS: Median age at diagnosis was 72 years. Mostly, tumors were small (81 % T1, 17 % T2) but of unfavorable grading (40 % G2, 35 % G3). Lymph nodes were positive in 42 %. Mastectomy was performed in 65 %. While 42 % of patients received radiotherapy, only 10 % were treated with chemotherapy. Patients with G2 and G3 tumors (p = 0.027), younger women (p = 0.012), and patients with positive lymph node status (p < 0.0001) more likely received chemotherapy. Recurrence-free survival was longer in patients without chemotherapy (37 vs. 29 months, p = 0.234). Overall survival was non-significantly shorter in patients who received chemotherapy (59 vs. 81 months, p = 0.131). CONCLUSIONS: In this analysis, adjuvant chemotherapy was not associated with improved survival, presumably caused by an a priori poor prognosis of these patients. For an aging society more data are urgently needed to help selecting and personalizing adjuvant treatment within subgroups of breast cancer in older women.

Evaluation of two different analytical methods for circulating tumor cell detection in peripheral blood of patients with primary breast cancer.

BACKGROUND: Evidence is accumulating that circulating tumor cells (CTC) out of peripheral blood can serve as prognostic marker not only in metastatic but also in early breast cancer (BC). Various methods are available to detect CTC. Comparisons between the different techniques, however, are rare. MATERIAL AND METHODS: We evaluate two different methods for CTC enrichment and detection in primary BC patients: the FDA-approved CellSearch System (CSS; Veridex, Warren, USA) and a manual immunocytochemistry (MICC). The cut-off value for positivity was ≥1 CTC. RESULTS: The two different nonoverlapping patient cohorts evaluated with one or the other method were well balanced regarding common clinical parameters. Before adjuvant CHT 21.1% (416 out of 1972) and 20.6% (247 out of 1198) of the patients were CTC-positive, while after CHT 22.5% (359 out of 1598) and 16.6% (177 out of 1066) of the patients were CTC-positive using CSS or MICC, respectively. CTC positivity rate before CHT was thus similar and not significantly different (P = 0.749), while CTC positivity rate immediately after CHT was significantly lower using MICC compared to CSS (P < 0.001). CONCLUSION: Using CSS or MICC for CTC detection, we found comparable prevalence of CTC before but not after adjuvant CHT.

Prognostic relevance of disseminated tumor cells in the bone marrow of patients with primary breast cancer--results of a standardized follow-up.

BACKGROUND: The prognostic significance of disseminated tumor cells from bone marrow (BM-DTCs) of breast cancer patients has been demonstrated previously. In this study, data of a standardized long term follow-up of 829 patients with examination of BM-DTCs at primary diagnosis are presented. PATIENTS AND METHODS: BM aspiration and immunocytochemical examination of DTCs was performed according to a standardized protocol. Follow-up data of all patients were adjusted with the cancer registries of southern Bavaria. RESULTS: A total of 268 patients (32%) had BM-DTCs with a median of 2 (1-1223)/2 x 106 cells. Positive BM findings correlated with tumor size (p=0.032), but not with other histopathological parameters. After a median follow-up of 73 months, BM-DTCs were highly relevant for the development of distant metastases (p=0.006) and, beneath standard histological parameters, reduced overall survival (p=0.038). CONCLUSION: These results confirm the prognostic relevance of the detection of BM-DTCs. Newer methods, such as detection of circulating tumor cells in blood, will have to demonstrate comparable prognostic information in the future.

Managing hyperemesis gravidarum: a multimodal challenge.

Up to 90% of pregnant women experience nausea and vomiting. When prolonged or severe, this is known as hyperemesis gravidarum (HG), which can, in individual cases, be life threatening. In this article the aetiology, diagnosis and treatment strategies will be presented based on a selective literature review. Treatment strategies range from outpatient dietary advice and antiemetic drugs to hospitalization and intravenous (IV) fluid replacement in persistent or severe cases. Alternative methods, such as acupuncture, are not yet evidence based but sometimes have a therapeutic effect.In most cases, the condition is self limiting and subsides by around 20 weeks gestation. More severe forms require medical intervention once other organic causes of nausea and vomiting have been excluded. In addition, a psychosomatic approach is often helpful.In view of its potential complexity, general practitioners and obstetricians should be well informed about HG and therapy should be multimodal.

Topoisomerase IIalpha expression rather than gene amplification predicts responsiveness of adjuvant anthracycline-based chemotherapy in women with primary breast cancer.

INTRODUCTION: Adjuvant anthracycline-based chemotherapy (AbCTX) is a standard treatment for patients with primary breast cancer. Its main target is topoisomerase IIalpha (TopIIa), a nuclear protein which is important for DNA replication and mitosis. We propose that the overexpression of the TopIIa protein or amplification of the TopIIa gene may be useful in predicting increased responsiveness towards AbCTX. METHODS: Tumor tissues of 118 patients who received adjuvant AbCTX were examined by immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) for TopIIa and HER2. For IHC, the primary antibodies 485 (Dako) and NCL-TOPOIIA (Novocastra) were used. FISH analysis was performed with the SPEC HER2/CEP 17 Dual Color Probe (Zytovision) and LSI TOP 2A Spectrum Orange/CEP 17 Spectrum Green probe (Abbott). TopIIa IHC was evaluated by the immunoreactive score (IRS). FISH amplification was stated at an HER2-TopIIa/CEP 17 ratio > or = 2, deletion of TopIIa at a ratio <0.8. RESULTS: The median age of the patient population was 50 years (range 23-77), 76 (64%) had tumors >2 cm in size, 98 (85%) were nodal positive, and 72 (66%) estrogen-receptor positive. Chemotherapy regimes consisted of epirubicin-cyclophosphamide (EC 40 pts), EC-CMF (18 pts), FAC/FEC (33 pts), anthracycline-taxane combinations (23 pts) and others (4 pts). After IHC, it was found that 19% of the tumors were positive for HER2 (3+) and the median IRS for TopIIa staining was 2 (49% positive); 28 (24%) tumors showed HER2 amplification, therefrom 20/22 (91%) within the HER2 3+ group. TopIIa gene was amplified in 17 cases (16%) and deletion was seen in 6 (5%) tumors. Of all cases with HER2 gene amplification, 14 (50%) cases of TopIIa co-amplification and one case of deletion were seen. Looking at histological parameters, TopIIa IHC correlated with nodal status (P = 0.018) and high grading (G3) (P = 0.047). After a median follow-up of 42 months (range 1-242), a significant prognostic factor for local recurrence was HER2 positivity (IHC P = 0.013 and FISH P = 0.023). Thirty-two patients developed metastasis (27%), which was correlated with HER2 FISH positivity (P = 0.024) and, as a trend, Top IIa IHC negativity (P = 0.094); 25 (21%) patients died from the disease. Negative prognostic parameters were the lack of estrogen-receptor expression (P = 0.008), lymphangiosis (P = 0.02), and TopIIa IHC negativity (P = 0.03). CONCLUSION: In this cohort of patients, HER2 positivity indicated higher rates of local and distant recurrence. In contrast, TopIIa IHC positivity predicted lower risk of metastases and death, thus being a positive-predictive factor for the responsiveness to AbCTX. TopIIa gene amplification did not add predictive information. Therefore, we conclude that TopIIa protein expression might rather be the target of anthracyclines independent from gene copy number.