Christoph Tausch

Endocrine therapy plus zoledronic acid in premenopausal breast cancer.

BACKGROUND Ovarian suppression plus tamoxifen is a standard adjuvant treatment in premenopausal women with endocrine-responsive breast cancer. Aromatase inhibitors are superior to tamoxifen in postmenopausal patients, and preclinical data suggest that zoledronic acid has antitumor properties. METHODS We examined the effect of adding zoledronic acid to a combination of either goserelin and tamoxifen or goserelin and anastrozole in premenopausal women with endocrine-responsive early breast cancer. We randomly assigned 1803 patients to receive goserelin (3.6 mg given subcutaneously every 28 days) plus tamoxifen (20 mg per day given orally) or anastrozole (1 mg per day given orally) with or without zoledronic acid (4 mg given intravenously every 6 months) for 3 years. The primary end point was disease-free survival; recurrence-free survival and overall survival were secondary end points. RESULTS After a median follow-up of 47.8 months, 137 events had occurred, with disease-free survival rates of 92.8% in the tamoxifen group, 92.0% in the anastrozole group, 90.8% in the group that received endocrine therapy alone, and 94.0% in the group that received endocrine therapy with zoledronic acid. There was no significant difference in disease-free survival between the anastrozole and tamoxifen groups (hazard ratio for disease progression in the anastrozole group, 1.10; 95% confidence interval [CI], 0.78 to 1.53; P=0.59). The addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy without zoledronic acid, resulted in an absolute reduction of 3.2 percentage points and a relative reduction of 36% in the risk of disease progression (hazard ratio, 0.64; 95% CI, 0.46 to 0.91; P=0.01); the addition of zoledronic acid did not significantly reduce the risk of death (hazard ratio, 0.60; 95% CI, 0.32 to 1.11; P=0.11). Adverse events were consistent with known drug-safety profiles. CONCLUSIONS The addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival in premenopausal patients with estrogen-responsive early breast cancer. (ClinicalTrials.gov number, NCT00295646.)

Pathologic Complete Response With Six Compared With Three Cycles of Neoadjuvant Epirubicin Plus Docetaxel and Granulocyte Colony-Stimulating Factor in Operable Breast Cancer: Results of ABCSG-14

PURPOSE Preoperative (neoadjuvant) chemotherapy for operable breast cancer downstages tumors initially not suitable for breast-conserving surgery. A pathologic complete response (pCR) to neoadjuvant chemotherapy may be a surrogate for longer overall survival, but this beneficial effect remains to be established. This phase III trial evaluated whether doubling the number of cycles of neoadjuvant treatment increased the pCR rate. PATIENTS AND METHODS Patients with biopsy-proven breast cancer (T1-4a-c, N+/-, M0; stage I to III) were eligible and randomly assigned to either three or six cycles of epirubicin 75 mg/m2 and docetaxel 75 mg/m2 on day 1 and granulocyte colony-stimulating factor on days 3 through 10 (ED+G), every 21 days. The primary end point was the pCR rate of the breast tumor. Secondary end points were pathologic nodal status after surgery and the rate of breast-conserving surgery. RESULTS A total of 292 patients were accrued, and 288 patients were assessable for efficacy and safety. Groups were well balanced for known prognostic factors. Six cycles of ED+G, compared with three cycles, resulted in a significantly higher pCR rate (18.6% v 7.7%, respectively; P = .0045), a higher percentage of patients with negative axillary status (56.6% v 42.8%, respectively; P = .02), and a trend towards more breast-conserving surgery (75.9% v 66.9%, respectively; P = .10). Rates of adverse events were similar, and no patients died on treatment. CONCLUSION Doubling the number of neoadjuvant ED+G cycles from three to six results in higher rates of pCR and negative axillary nodal status with no excess of adverse effects. Thus, six cycles of ED+G should be the standard neoadjuvant treatment for operable breast cancer if this combination is chosen.

Tamoxifen and Anastrozole As a Sequencing Strategy: A Randomized Controlled Trial in Postmenopausal Patients With Endocrine-Responsive Early Breast Cancer From the Austrian Breast and Colorectal Cancer Study Group

PURPOSE Anastrozole (ANA) alone delivers significant disease-free survival benefits over tamoxifen (TAM) monotherapy in postmenopausal women with early estrogen receptor-positive breast cancer. The ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) study is a large phase III clinical trial addressing the sequence strategy containing ANA in comparison with 5 years of TAM in a low- to intermediate-risk group of postmenopausal patients. PATIENTS AND METHODS Endocrine receptor-positive patients with G1 or G2 tumors were eligible. After surgery, patients were randomly assigned to 5 years of TAM or 2 years of TAM followed by 3 years of ANA. Adjuvant chemotherapy and G3 and T4 tumors were exclusion criteria. Intention-to-treat and censored analyses of on-treatment recurrence-free survival (RFS) were performed, and exploratory survival end points and toxicity were investigated. RESULTS Information from 3,714 patients, including 17,563 woman-years, with a median of 60 months of follow-up was available for this analysis. Median age was 63.8 years, 75% were node negative, and 75% had T1 tumors. Sequencing of ANA after identical 2-year treatment with TAM in both arms did not result in a statistically significant improvement of RFS (hazard ratio [HR], 0.80; 95% CI, 0.63 to 1.01; P = .06). Exploratory analyses of distant relapse-free survival indicated a 22% improvement (HR, 0.78; 95% CI, 0.60 to 1.00). On-treatment adverse events and serious adverse events were consistent with known toxicity profiles of ANA and TAM treatment. CONCLUSION Despite a low overall rate of recurrence in a population with breast cancer at limited risk of relapse, the a priori sequence strategy of 2 years of TAM followed by 3 years of ANA led to small outcome and toxicity benefits.

Sentinel Lymph Node Biopsy After Preoperative Chemotherapy for Breast Cancer: Findings from the Austrian Sentinel Node Study Group

BackgroundSentinel lymph node biopsy (SLNB) has become an accurate alternative to axillary lymph node dissection for early breast cancer. However, data are still insufficient as regards the combination of SLNB with preoperative chemotherapy (PC).MethodsThe Austrian Sentinel Node Study Group investigated 167 patients who underwent SLNB and axillary lymph node dissection after 3 to 6 courses of PC. SLNB was limited to patients with a clinically negative axilla after PC. Blue dye was used in 29 cases (17%), and tracers were used in 20 (12%). A combination of the two methods was applied in most patients (n = 120; 72%).ResultsAt least 1 sentinel lymph node (SLN) was identified in 144 patients (identification rate, 85%): in 86% by blue dye alone, in 65% by tracers alone, and in 88% by a combination of methods. The SLN was positive in 70 women (42%) and was the only positive node with otherwise negative axillary nodes in 39 patients (23%). In 6 cases, the SLN was diagnosed as negative although tumor infiltration was detected in an upper node of the axillary basin (false-negative rate, 8%; 6 of 76 patients; sensitivity, 92%). At least 62 patients (37%) were free of tumor cells in the SLN and in the axillary nodes.ConclusionThe results of SLNB after PC are comparable to the results of SLNB without PC. Further investigation in a prospective setting is warranted to confirm these promising results.

Randomized trial of tamoxifen versus tamoxifen plus aminoglutethimide as adjuvant treatment in postmenopausal breast cancer patients with hormone receptor-positive disease: Austrian breast and colorectal cancer study group trial 6.

PURPOSE To determine whether the addition of aminoglutethimide to tamoxifen is able to improve the outcome in postmenopausal patients with hormone receptor-positive, early-stage breast cancer. PATIENTS AND METHODS A total of 2,021 postmenopausal women were randomly assigned to receive either tamoxifen for 5 years alone or tamoxifen in combination with aminoglutethimide (500 mg/d) for the first 2 years of treatment. Tamoxifen was administered at 40 mg/d for the first 2 years and at 20 mg/d for 3 years. RESULTS All randomized and eligible patients were included in the analysis according to the intention-to-treat principle. After a median follow-up of 5.3 years, the 5-year disease-free survival in the aminoglutethimide plus tamoxifen group was 83.6% versus 83.7% in the monotherapy group (P =.89). The corresponding data for overall survival at 5 years were 91.4% and 91.2%, respectively (P =.74). More patients failed to complete combination treatment (13.7%) because of side effects as compared to tamoxifen alone (5.2%; P =.0001). CONCLUSION Aminoglutethimide given for 2 years in addition to tamoxifen for 5 years does not improve the prognosis of postmenopausal patients with receptor-positive, lymph node-negative or lymph node-positive breast cancer.

Sentinel node mapping performed before preoperative chemotherapy may avoid axillary dissection in breast cancer patients with negative or micrometastatic sentinel nodes.

BACKGROUND Sentinel node (SN) biopsy after preoperative chemotherapy (PC) in breast cancer patients is associated with a lower identification rate (IR) and an increased false-negative rate (FNR) compared with SN biopsy in untreated patients. Our aims were to examine the feasibility of SN mapping before PC and the possibility to assess the lymph node status after chemotherapy through a follow-up lymphatic mapping. METHODS SN biopsy was performed in 45 clinically node-negative breast cancer patients before PC. A follow-up lymphatic mapping was done after completion of chemotherapy and irrespective of the lymph node status was followed by axillary lymph node dissection (ALND). RESULTS SN mapping before chemotherapy identified a mean of 2.3 SNs in all patients (IR 100%). Nineteen patients revealed a negative SN; 26 patients had a positive SN (micrometastasis found in 6/26 patients). After PC follow-up lymphatic mapping was successful in 29 of 45 patients (IR 64%). IR for follow-up mapping was 80% for patients with a negative or micrometastatic SN before chemotherapy compared with 45% for patients with macrometastatic SNs (P = .027, Fisher exact test). None of the patients with a negative or micrometastatic SN before chemotherapy revealed positive lymph nodes after PC (P = .031, McNemar test) and the FNR for follow-up lymphatic mapping in these patients was 0%. Contrary to that, 15 of 20 patients with a macrometastasis before PC had positive nodes after chemotherapy, and the FNR of follow-up mapping in these patients was 50%. CONCLUSIONS Patients with a negative SN before PC may forego complete ALND after PC, whereas this may not be valid for patients with macrometastatic SNs. Follow-up lymphatic mapping in patients with positive nodal status before chemotherapy is associated with a low IR and a high FNR.

Significant Increase in Breast Conservation in 16 Years of Trials Conducted by the Austrian Breast & Colorectal Cancer Study Group

ObjectiveTo confirm evidence that breast-conserving treatment (BCT) does not impair the prognosis in breast cancer patients as compared to mastectomy and to argue that it be regarded as the treatment of choice in stage I and II disease. Summary Background DataScientifically, survival rates in breast cancer have been shown to be stage-dependent, but independent of the extent of surgical breast tissue removal, as long as the resection margins are free of tumor infiltration. MethodsBetween 1984 and 1997, six different trials conducted by the Austrian Breast & Colorectal Cancer Study Group accrued a total of 4,259 women with hormone-responsive disease. The authors selected and compared three patient groups (n = 3,316) according to pathologic stage, age, and the surgical procedure applied. ResultsOver this interval, the BCT rate in the premenopausal node-positive subgroup experienced a highly significant increase from 27.2% to 73.2% overall. In the group of postmenopausal node-negative patients, the BCT rate grew significantly by 37.3% to 77.3% in total. With an overall BCT rate growing from 22.5% to 56.8% in postmenopausal node-positive women, those presenting with T1 tumors saw a significant increase from 35.1% to 65.9%. Mortality and local recurrence rates proved stable or even decreased considerably over time and in all subgroups. ConclusionsThe presented outcome of BCT rates, significantly improved over this 16-year period and in no way counterbalanced by higher local recurrence or death rates, reflects an excellent example of surgical quality control. BCT can safely be regarded as the standard of therapy for T1 and increasingly for T2 disease. Especially in multi-institutional adjuvant breast cancer trials, the highest priority should be given to breast-conserving procedures.

Intramammarian flap reconstruction (IFR) technique in breast conserving surgery

As large segmentectomies often lead to asymmetries and indentations in the breast, numerous oncoplastic reconstruction methods have been published over the past years. Many of these involve additional skin incisions, resulting in more and larger scars.This article presents a method, which uses the same incision as for the segmentectomy and does not lead to additional scars. First, the breast gland body is being detached from the pectoralis major muscle; then the largest part of the remaining gland body is being cut horizontally parallel to the thoracic wall, exactly in the middle between the skin and the pectoralis major muscle. The pectoral part of the gland body can then be placed into the tumor bed without tension as a f;ap with a length of approximately 7-14 cm and a width of approximately 4-10 cm. In 2007, the first author performed a total of 134 breast conserving surgeries (9 benign and 125 malignant diagnoses) which have been prospectively documented. The intramammarian f;ap reconstruction technique was applied 87 times (65% of all cases), with three cases of postoperative infection and two cases needing surgical evacuation of a hematoma. In 131 cases the cosmetic results were considered favorable or moderate. The results in the 4 remaining patients were cosmetically unsatisfactory; 3 were treated with and 1 without the intramammarian flap reconstruction.In most cases the technique leads to a quick and acceptable filling of the defect and avoids nipple deviation even after a large segmentectomy, so that the breast shape can be preserved and the original breast size is being only marginally reduced. A short video demonstrates the technique on youtube and yahoo (search terms: oncoplastic, ifr).

Mapping lymph nodes in cancer management - role of (99m)Tc-tilmanocept injection.

Two decades ago, lymphatic mapping of sentinel lymph nodes (SLN) was introduced into surgical cancer management and was termed sentinel node navigated surgery. Although this technique is now routinely performed in the management of breast cancer and malignant melanoma, it is still under investigation for use in other cancers. The radioisotope technetium (99mTc) and vital blue dyes are among the most widely used enhancers for SLN mapping, although near-infrared fluorescence imaging of indocyanine green is also becoming more commonly used. 99mTc-tilmanocept is a new synthetic radioisotope with a relatively small molecular size that was specifically developed for lymphatic mapping. Because of its small size, 99mTc-tilmanocept quickly migrates from its site of injection and rapidly accumulates in the SLN. The mannose moieties of 99mTc-tilmanosept facilitate its binding to mannose receptors (CD206) expressed in reticuloendothelial cells of the SLN. This binding prevents transit to second-echelon lymph nodes. In Phase III trials of breast cancer and malignant melanoma, and Phase II trials of other malignancies, 99mTc-tilmanocept had superior identification rates and sensitivity compared with blue dye. Trials comparing 99mTc-tilmanocept with other 99mTc-based agents are required before it can be routinely used in clinical settings.

First international consensus conference on standardization of oncoplastic breast conserving surgery

PurposeTo obtain consensus recommendations for the standardization of oncoplastic breast conserving surgery (OPS) from an international panel of experts in breast surgery including delegates from the German, Austrian and Swiss societies of senology.MethodsA total of 52 questions were addressed by electronic voting. The panel’s recommendations were put into context with current evidence and the report was circled in an iterative open email process until consensus was obtained.ResultsThe panelists considered OPS safe and effective for improving aesthetic outcomes and broadening the indication for breast conserving surgery (BCS) towards larger tumors. A slim majority believed that OPS reduces the rate of positive margins; however, there was consensus that OPS is associated with an increased risk of complications compared to conventional BCS. The panel strongly endorsed patient-reported outcomes measurement, and recommended selected scales of the Breast-Q™-Breast Conserving Therapy Module for that purpose. The Clough bi-level classification was recommended for standard use in clinical practice for indicating, planning and performing OPS, and the Hoffmann classification for surgical reports and billing purposes. Mastopexy and reduction mammoplasty were the only two recognized OPS procedure categories supported by a majority of the panel. Finally, the experts unanimously supported the statement that every OPS procedure should be tailored to each individual patient.ConclusionsWhen implemented into clinical practice, the panel recommendations may improve safety and effectiveness of OPS. The attendees agreed that there is a need for prospective multicenter studies to optimize patient selection and for standardized criteria to qualify and accredit OPS training centers.