Thorsten Kühn

Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial

BACKGROUND We compared the efficacy and safety of the addition of lapatinib versus trastuzumab to anthracycline-taxane-based neoadjuvant chemotherapy. METHODS In the GeparQuinto randomised phase 3 trial, patients with untreated HER2-positive operable or locally advanced breast cancer were enrolled between Nov 7, 2007, and July 9, 2010. Patients were eligible if their tumours were classified as cT3/4a-d, or hormone receptor (HR)-negative, HR-positive with clinically node-positive and cT2 disease (cT2 cN+), or HR-positive and pathologically node-positive in the sentinel lymph node for those with cT1 disease (cT1 pN(SLN+)). Patients were randomly assigned in a 1:1 ratio to receive neoadjuvant treatment with four cycles of EC (epirubicin [90 mg/m(2) intravenously] plus cyclophosphamide [600 mg/m(2) intravenously], every 3 weeks), and four cycles of docetaxel (100 mg/m(2) intravenously every 3 weeks) with either trastuzumab (6 mg/kg intravenously, with a starting loading dose of 8 mg/kg, for eight cycles, every 3 weeks) or lapatinib (1000-1250 mg per day orally) throughout all cycles before surgery. Randomisation was done by dynamic allocation with the minimisation method of Pocock and patients were stratified by participating site, HR status, and extent of disease (cT1-3 cN0-2 vs T4 or N3). The primary endpoint was pathological complete response (defined as ypT0 and ypN0) and was analysed in all patients who received at least one cycle of EC. Participants and investigators were not masked to treatment assignment. Pathologists in centres assessing surgery outcomes were masked to group assignment. This trial is registered with ClinicalTrials.gov, number NCT00567554. FINDINGS Of 620 eligible patients, 309 were randomly assigned to chemotherapy with trastuzumab (ECH-TH group) and 311 to chemotherapy with lapatinib (ECL-TL group). Two patients in the ECH-TH group and three patients in the ECL-TL group did not start treatment because of withdrawal of consent or immediate surgery. 93 (30·3%) of 307 patients in the ECH-TH group and 70 (22·7%) of 308 patients in the ECL-TL group had a pathological complete response (odds ratio [OR] 0·68 [95%CI 0·47-0·97]; p=0·04). Chemotherapy with trastuzumab was associated with more oedema (119 [39·1%] vs 88 [28·7%]) and dyspnoea (90 [29·6%] vs 66 [21·4%]), and ECL-TL with more diarrhoea (231 [75·0%] vs 144 [47·4%]) and skin rash (169 [54·9%] vs 97 [31·9%]). 43 (14·0%) patients discontinued in the ECH-TH group and 102 (33·1%) in the ECL-TL group. 70 serious adverse events were reported in the ECH-TH group and 87 in the ECL-TL group. INTERPRETATION This direct comparison of trastuzumab and lapatinib showed that pathological complete response rate with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab. Unless long-term outcome data show different results, lapatinib should not be used outside of clinical trials as single anti-HER2-treatment in combination with neoadjuvant chemotherapy. FUNDING GlaxoSmithKline, Roche, and Sanofi-Aventis.

Pathologic Complete Response After Neoadjuvant Chemotherapy Plus Trastuzumab Predicts Favorable Survival in Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer: Results From the TECHNO Trial of the AGO and GBG Study Groups

PURPOSE To evaluate efficacy and safety of epirubicin and cyclophosphamide followed by paclitaxel and trastuzumab as neoadjuvant treatment in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. PATIENTS AND METHODS Patients with centrally confirmed HER2-overexpressing breast cancer (≥ 2 cm or inflammatory) received four 3-week cycles epirubicin and cyclophosphamide (90/600 mg/m(2)) followed by four 3-week cycles paclitaxel (175 mg/m(2)) and trastuzumab (6 mg/kg) before surgery. Trastuzumab was continued after surgery to complete 1 year of treatment. Primary end point was pathologic complete response (pCR) defined as no residual invasive tumor in breast and lymphatic tissue. RESULTS Thirty-nine percent of 217 enrolled patients achieved a pCR. Breast conservation was possible in 64% of patients. Three-year disease-free survival (DFS) was 88% in patients with pCR compared to 73% in patients without pCR (P = .01). Three-year overall survival (OS) was 96% in patients with pCR compared to 86% in patients without pCR (P = .025). pCR was the only significant prognostic factor for DFS (hazard ratio [HR] 2.5; 95% CI, 1.2 to 5.1; P = .013) and OS (HR, 4.9; 95% CI, 1.4 to 17.4; P = .012) in multivariable analysis. Cardiac toxicity was reported in eight patients (3.7%) of whom six presented with an asymptomatic left ventricular ejection fraction decrease and two with symptomatic chronic heart failure. CONCLUSION Neoadjuvant combination of trastuzumab and chemotherapy resulted in a high pCR rate in HER2-overexpressing primary breast cancer. Patients with a pCR after neoadjuvant anti-HER2 therapy in combination with chemotherapy followed by maintenance trastuzumab have an improved long-term outcome. Patients without a pCR had an increased risk for relapse and death.

Fluorine-18 2-deoxy-2-fluoro-D-glucose PET in the preoperative staging of breast cancer: comparison with the standard staging procedures.

The present study compared the diagnostic accuracy of fluorine-18 2-deoxy-2-fluoro-D-glucose positron emission tomography (FDG-PET) with conventional staging techniques. The differentiation between malignant and benign lesions and the detection of multifocal disease, axillary and internal lymph node involvement, and distant metastases were evaluated. One hundred and seventeen female patients were prospectively examined using FDG-PET and conventional staging methods such as chest X-ray, ultrasonography of the breast and liver, mammography and bone scintigraphy. All patients were examined on a modern full-ring PET scanner. Histopathological analysis of resected specimens was employed as the reference method. The readers of FDG-PET were blinded to the results of the other imaging methods and to the site of the breast tumour. The sensitivity and specificity of FDG-PET in detecting malignant breast lesions were 93% and 75% respectively. FDG-PET was twofold more sensitive (sensitivity 63%, specificity 95%) in detecting multifocal lesions than the combination of mammography and ultrasonography (sensitivity 32%, specificity 93%). Sensitivity and specificity of FDG-PET in detecting axillary lymph node metastases were 79% and 92% (41% and 96% for clinical evaluation). FDG-PET correctly indicated distant metastases in seven patients. False-positive or false-negative findings were not encountered with FDG-PET. Chest X-ray was false-negative in three of five patients with lung metastases. Bone scintigraphy was false-positive in four patients. Three patients were upstaged since FDG-PET detected distant metastases missed with the standard staging procedure. It is concluded that, compared with the imaging methods currently employed for initial staging, FDG-PET is as accurate in interpreting the primary tumour and more accurate in screening for lymph node metastases and distant metastases. Due to a false-negative rate of 20% in detecting axillary lymph node metastases, FDG-PET cannot replace histological evaluation of axillary status.

Early Detection and Accurate Description of Extent of Metastatic Bone Disease in Breast Cancer With Fluoride Ion and Positron Emission Tomography

PURPOSE Previous studies have shown that bone metastases are revealed by magnetic resonance imaging (MRI) or bone marrow scintigraphy several months before they are visible by conventional bone scintigraphy (BS). We present a new approach for detecting bone metastases in patients with breast cancer. We compared findings obtained with fluoride ion (F-18) and positron emission tomography (PET) with those obtained with conventional BS. PATIENTS AND METHODS Thirty-four breast cancer patients were prospectively examined using F-18-PET and conventional BS. F-18-PET and BS were performed within 3 weeks of each other. Metastatic bone disease was previously known to be present in six patients and was suspected (bone pain or increasing levels of tumor markers, Ca(2+), alkaline phosphatase) in 28 patients. Both imaging modalities were compared by patient-by-patient analysis and lesion-by-lesion analysis, using a five-point scale for receiver operating characteristic (ROC) curve analysis. A panel of reference methods was used, including MRI (28 patients), planar x-ray (17 patients), and spiral computed tomography (four patients). RESULTS With F-18-PET, 64 bone metastases were detected in 17 patients. Only 29 metastases were detected in 11 patients with BS. As a result of F-18-PET imaging, clinical management was changed in four patients (11.7%). For F-18-PET, the area under the ROC curve was 0.99 on a lesion basis (for BS, it was 0.74; P <.05) and 1.00 on a patient basis (for BS, it was 0.82; P <.05). CONCLUSION F-18-PET demonstrates a very early bone reaction when small bone marrow metastases are present, allowing accurate detection of breast cancer bone metastases. This accurate detection has a significant effect on clinical management, compared with the effect on management brought about by detection with conventional BS.

FDG uptake in breast cancer: correlation with biological and clinical prognostic parameters

Abstract. The aim of this study was to evaluate the possible correlation between preoperative FDG-PET results in human breast cancer and the prognostic markers Ki-67, c-erb B2, p53, oestrogen/progesterone receptor status, axillary lymph node status, tumour size and tumour grading. Seventy-five female patients with breast cancer were included in this prospective study. Patient selection was independent of tumour size and the suspected clinical stage of disease. A high-resolution full-ring scanner (Siemens ECAT HR+) was used for PET imaging. The FDG uptake of breast tumours was calculated as the tumour to background ratio (TBR). In resected cancer tissue specimens, the proliferative fraction was evaluated by Ki-67 immunostaining. Additionally, immunostaining of the prognostic markers c-erb B2, p53, and progesterone and oestrogen receptors was performed. Haematoxylin and eosin-stained sections were used for tumour grading. Correlations between FDG uptake and prognostic markers were assumed to be significant at P<0.05 using the Mann-Whitney U test. In ductal breast cancer, mean TBR was 17.3 (median 7.7, range 1.6–122.7), while in lobular cancer it was 6.5 (median 3.7, range 1.4–22.7). Mean proliferative fraction (% Ki-67 positive tumour cells) was 15%±13.8% (median 10%, range 0%–60%). Twenty-three carcinomas showed <5% Ki-67 positive tumour cells. Statistical analysis indicated a positive correlation between FDG uptake and proliferative index in ductal breast cancer (P<0.0001, r=0.63). By contrast, there was no correlation between FDG uptake and c-erb B2 (P=0.79), p53 (P=0.92), tumour grading (P=0.09), oestrogen receptor status (P=0.41), progesterone receptor status (P=0.34), axillary lymph node status (P=0.90) and tumour size (P=0.3). It is concluded that FDG uptake is significantly higher in ductal breast cancer than in lobular cancer (P<0.05). FDG uptake correlates with proliferative activity assessed by Ki-67 immunostaining (P<0.05). A significant correlation with the other prognostic markers, however, could not be demonstrated.

Stufe-3-Leitlinie Brustkrebs-Früherkennung in Deutschland 2008

ZusammenfassungDie aktualisierte Stufe-3-Leitlinie Brustkrebs-Früherkennung in Deutschland 2008 vermittelt den wissenschaftlichen Kenntnisstand in evidenz- und konsensbasierter Form und ist unter Beteiligung der Deutschen Gesellschaft für Chirurgie e.V, der Deutschen Gesellschaft der Plastischen, Rekonstruktiven und Ästhetischen Chirurgen e.V. und 29 weiterer Fachgesellschaften, Berufsverbänden und nichtärztlichen Organisationen erstellt. Ziel der Stufe-3-Leitlinie ist es, Ärzte sowie gesunde und betroffene Frauen durch evidenzbasierte und formal konsentierte Empfehlungen bei anstehenden medizinischen Entscheidungen im Rahmen der Diagnosekette zur Früherkennung von Brustkrebs zu unterstützen. Die Leitlinie umfasst neben den Empfehlungen zur Diagnosekette die Beschreibung zur Ausgestaltung der Qualitätssicherung von Struktur-, Prozess- und Ergebnisqualität (Outcomes) sowie deren Evaluation durch einen Qualitätsindikatorensatz.Die aktualisierte Stufe-3-Leitlinie 2008 löst die 2003 erstellte Leitlinie ab.Die Leitlinienempfehlungen werden dargestellt. Die Details sind der Publikation in Geburtsh Frauenh 2008; 68: 251–26 zu entnehmen. Die Langfassung der Leitlinie ist als Buch im W. Zuckschwerdt Verlag GmbH/München erschienen und ist, wie der Methodenreport und der Evidenzreport auch, über die Internetseite www.awmf-leitlinien.de (Reg.: Nr. 077/001) frei zugänglich.AbstractThe updated 2008 German Guideline for Early Detection of Breast Cancer provides evidence-based and consensus-based recommendations of the knowledge gained by the German Society for Surgery and the German Society of Plastic, Aesthetic, and Reconstructive Surgeons together with 29 professional societies, associations, and nonmedical organizations. The guideline is meant to assist physicians, healthy women, and patients in medical decisions with recommendations regarding the diagnostic chain in early detection of breast cancer. In addition to these recommendations, the guideline also includes descriptions of quality assurance for resources, procedures, outcomes, and evaluation using a set of quality indicators. It updates the previous version from 2003. The guideline’s recommendations are presented. They are described in detail in the full publication (in German) Geburtsh Frauenh 2008; 68:251–261. The long version of the Guideline, methods report, and evidence report are available on the internet at www.awmf-leitlinien.de (reg. no. 077/001) with free access.The updated 2008 German Guideline for Early Detection of Breast Cancer provides evidence-based and consensus-based recommendations of the knowledge gained by the German Society for Surgery and the German Society of Plastic, Aesthetic, and Reconstructive Surgeons together with 29 professional societies, associations, and nonmedical organizations. The guideline is meant to assist physicians, healthy women, and patients in medical decisions with recommendations regarding the diagnostic chain in early detection of breast cancer. In addition to these recommendations, the guideline also includes descriptions of quality assurance for resources, procedures, outcomes, and evaluation using a set of quality indicators. It updates the previous version from 2003. The guidelines recommendations are presented. They are described in detail in the full publication (in German) Geburtsh Frauenh 2008; 68:251-261. The long version of the Guideline, methods report, and evidence report are available on the internet at www.awmf-leitlinien.de (reg. no. 077/001) with free access.

2008 update of the guideline: early detection of breast cancer in Germany

IntroductionThe goal of the 2008 updated guideline: early detection of breast cancer in Germany is to support physicians as well as healthy and affected women in the decision-making process involved in the diagnostic chain for the early detection of breast cancer by providing them with evidence- and consensus-based recommendations. The updated guideline replaces the guideline issued in 2003.Materials and methodsThe guideline forms the basis for developing an effective and efficient national early breast cancer detection program that meets the standards set by the Council of Europe and WHO for cancer control programs. The guideline presents the current, evidence- and consensus-based state of scientific knowledge in a multidisciplinary approach for the entire diagnostic chain, consisting of history taking and risk consultation, information on health behavior, clinical breast examination, diagnostic imaging, image-guided percutaneous tissue-acquisition techniques, open surgical excisional biopsy and pathomorphological tissue evaluation. The guideline recommends a set of quality indicators to assure resource availability, performance quality and outcomes enhancing total quality management for early breast cancer diagnosis.Conclusion Currently, early detection of breast cancer offers the most promising possibility to optimize the diagnosis and treatment of breast cancer and, as a result, reduce breast cancer mortality and improve health related quality of life in women.

Impact of the axillary nodal status on sentinel node mapping in breast cancer and its relevance for technical proceeding

AbstractObjective. The aim of this study is to analyze whether the axillary status influences the lymphatic mapping procedure in malignant breast disease and whether clinically relevant consequences for the technique of Sentinel Node (SN) biopsy may be drawn from this information. Materials and methods. SN biopsy was performed in 150 consecutive patients using a combination of the radioguided and the blue-dye technique. Axillary status was compared with the number of detected nodes. In cases of numerous nodes with tracer uptake, the radioactivity of each radiolabeled node was measured separately in a dose calibrator. We analyzed whether an increased tracer uptake could possibly indicate a ‘true’ or ‘dominant’ SN. Blue dye uptake was registered and compared with radioactivity. The findings were related to the histologic results. Results. In patients with a positive axillary status, significantly more radiolabeled nodes were detected than in node negative patients (median 3 vs. 2; p<0.001). In 54/86 patients with numerous SNs a ‘dominant’ node with at least twice the radioactivity than other marked nodes could be identified (62.8%). From 26 cases with axillary involvement, 20 patients (76.9%) were identified by the ‘dominant’ and the remaining six women (23.1%) by others than the seemingly leading SN. Conclusion. Axillary lymph node involvement influences the drainage pattern in breast cancer. Patients with numerous SNs have an increased risk of axillary involvement. A high tracer uptake does not permit the identification of a ‘true’ SN. A lack of surgical accuracy may lead to pitfalls if the axilla is not screened carefully for all radioactive nodes.

Axilloscopy and endoscopic sentinel node detection in breast cancer patients

AbstractBackground: Sentinel node biopsy is a promising technique that allows the axillary status of breast cancer patients to be predicted with high accuracy. Reducing false negative results remains a major challenge for the improvement of this procedure. Furthermore, new techniques are required to achieve axillary clearing with less morbidity in cases of unsuccessful mapping or multicentric carcinoma. We analyzed whether axilloscopy and endoscopic sentinel node biopsy is a feasible procedure for visualization of the axillary space and resection of the sentinel node using endoscopic techniques. Methods: Following blue dye-guided lymphography and liposuction of the axillary fat, endoscopic axillary sentinel node biopsy was performed in 35 breast cancer patients. We then assessed the exposure of anatomical landmarks, the detection rate of the sentinel node, the false negative rate, and the accuracy of consecutive axillary clearing. Results: In almost every case, an excellent anatomical orientation was achieved. The detection rate for the sentinel node was 83.3%. In one case, the sentinel node did not reflect the status of the residual axilla. A mean number of 17.1 lymph nodes was harvested at consecutive axillary clearing. Conclusions: Axilloscopy and endoscopic sentinel node biopsy, following liposuction of the axillary fat, is a feasible procedure that allows identification and minimally invasive resection of the sentinel node with high accuracy. The endoscopic approach might help to minimize the pitfalls of sentinel node biopsy by visualizing the axillary space. In future, it may become a technique that enables minimally invasive axillary clearing when complete lymphadenectomy is required.

Sentinel Node Biopsy and Axillary Dissection in Breast Cancer: The Evidence and Its Limits

BACKGROUND Increasing evidence suggests that surgical removal of the axillary lymph nodes (axillary dissection, ALD) in early breast cancer yields no advantage in terms of either overall or disease-free survival, even in women with involvement of sentinel nodes. The optimal role of sentinel node biopsy (SNB) in neo-adjuvant therapy is currently under discussion. METHOD This review is based on a selective search in the Medline, EMBASE, Cochrane Library, and G.I.N. (Guidelines International Network) databases for relevant articles on the role of axillary dissection in node-positive breast cancer and the role of SNB in neo-adjuvant chemotherapy. RESULTS Although no single study provides adequate evidence, the available literature increasingly casts doubt on the putative therapeutic benefit of ALD as part of a multimodal treatment strategy for breast cancer. It is currently unclear what group of patients, if any, might benefit from ALD. Nor is any definitive judgment possible, from the available evidence, regarding the optimal role of SNB in neo-adjuvant therapy. The most recent evidence indicates that SNB after neo-adjuvant chemotherapy in ycN0 patients who had suspect lymph nodes before systemic treatment has a low rate of sensitivity. CONCLUSION Current evidence indicates that the radicality of lymph node surgery in the treatment of breast cancer can be reduced, even if the node status is positive.