Publications 2005 – 2011

Sentinel Node Biopsy After Primary Chemotherapy in Breast Cancer: A Note of Caution from Results of ABCSG-14

Christoph Tausch, MD, Gunther G. Steger, MD, Anton Haid, MD, Raimund Jakesz, MD, Michael A. Fridrik, MD, Roland Reitsamer, MD, Sabine Pöstlberger, MD, Alois Lang, MD, Michael Gnant, MD, and Richard Greil, MD.

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Abstract

Over the past years, experience has been increasing with lymphatic mapping and sentinel node biopsy (SNB) after preoperative chemotherapy for breast cancer, with a wide range of results reported in the literature and final conclusions on the diagnostic value and clinical consequences of this sequential approach still missing. Between 1999 and 2002, the Austrian Breast and Colorectal Cancer Study Group (ABCSG) conducted a prospective randomized multicenter trial comparing three versus six preoperative cycles of epirubicin ⁄ docetaxel + granulocyte colony-stimulating factor for operable breast cancer. Of the 292 patients recruited to the trial overall, 111 were enrolled in a prospective subprotocol for performing LM and SNB in addition to obligatory axillary lymph node dissection (ALND) after PC. SNB after PC identified at least one sentinel node in 100 of 111 patients (identification rate 90%). In six cases, a false-negative SN was identified, resulting in a false-negative rate of 13% (6 of 47). We only found little correlation between patients and tumor characteristics and the identification rate or false-negative rate. Lymphatic mapping and SNB after primary chemotherapy failed to predict histologic infiltration of the sentinel node with sufficient sensitivity. The routine use of SNB after primary chemotherapy should therefore be discouraged.

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Clin Cancer Res; 17(18); 6012–20.2011AACR.

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Impact of Body Mass Index on the Efficacy of Endocrine Therapy in Premenopausal Patients With Breast Cancer: An Analysis of the Prospective ABCSG-12 Trial

Georg Pfeiler, Robert Königsberg, Christian Fesl, Brigitte Mlineritsch, Herbert Stoeger, Christian F. Singer, Sabine Pöstlberger, Guenther G. Steger, Michael Seifert, Peter Dubsky, Susanne Taucher, Hellmut Samonigg, Vesna Bjelic-Radisic, Richard Greil, Christian Marth, and Michael Gnant.

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Abstract

Purpose Aromatase inhibitors are effective as endocrine treatment for patients with hormone receptor– positive breast cancer. According to the hypothesis that overweight patients have higher levels of aromatase enzyme availability, we investigated the influence of body mass index (BMI) on the efficacy of adjuvant endocrine therapy in premenopausal patients in a retrospective analysis of the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 12 trial.

Patients and Methods ABCSG-12 examined the efficacy of ovarian suppression using goserelin (3.6 mg subcutaneously every 28 days) in combination with anastrozole or tamoxifen with or without zoledronic acid (4 mg intravenously every 6 months) in premenopausal women with endocrine-responsive breast cancer. BMI was calculated using the prospectively collected data on patients’ height and weight at study entry. BMI categories have been differentiated according to the WHO definition.

Results Overweight patients treated with anastrozole had a 60% increase in the risk of disease recurrence (hazard ratio [HR], 1.60; 95% CI, 1.06 to 2.41; P  .02) and more than a doubling in the risk of death (HR, 2.14; 95% CI, 1.17 to 3.92; P  .01) compared with normal weight patients treated with anastrozole. In the overweight group, patients treated with anastrozole had a nearly 50% increase in the risk of disease recurrence (HR, 1.49; 95% CI, 0.93 to 2.38; P  .08) and a three-fold increase in the risk of death (HR, 3.03; 95% CI, 1.35 to 6.82; P.004) compared with patients treated with tamoxifen.

Conclusion BMI significantly impacts on the efficacy of anastrozole plus goserelin in premenopausal patients with breast cancer, probably through influencing aromatase availability and/or ovarian suppression by goserelin.

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J Clin Oncol 29:2653-2659. © 2011 by American Society of Clinical Oncology

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Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial

Michael Gnant, Brigitte Mlineritsch, Herbert Stoeger, Gero Luschin-Ebengreuth, Dietmar Heck, Christian Menzel, Raimund Jakesz, Michael Seifert, Michael Hubalek, Gunda Pristauz, Thomas Bauernhofer, Holger Eidtmann, Wolfgang Eiermann, Guenther Steger, Werner Kwasny, Peter Dubsky, Gerhard Hochreiner, Ernst-Pius Forsthuber, Christian Fesl, Richard Greil, on behalf of the Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria

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Summary

Background Analysis of the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) at 48 months’ follow-up showed that addition of zoledronic acid to adjuvant endocrine therapy signifi cantly improved disease-free survival. We have now assessed long-term clinical effi cacy including disease-free survival and disease outcomes in patients receiving anastrozole or tamoxifen with or without zoledronic acid.

Methods ABSCG-12 is a randomised, controlled, open-label, two-by-two factorial, multicentre trial in 1803 pre menopausal women with endocrine-receptor-positive early-stage (stage I–II) breast cancer receiving goserelin (3·6 mg every 28 days), comparing the effi cacy and safety of anastrozole (1 mg per day) or tamoxifen (20 mg per day) with or without zoledronic acid (4 mg every 6 months) for 3 years. Randomisation (1:1:1:1 ratio) was computerised and based on the Pocock and Simon minimisation method to balance the four treatment arms across eight prognostic variables (age, neoadjuvant chemotherapy, pathological tumour stage; lymph-node involvement, type of surgery or locoregional therapy, complete axillary dissection, intraoperative radiation therapy, and geographical region). Treatment allocation was not masked. The primary endpoint was disease-free survival (defi ned as disease recurrence or death) and analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00295646; follow-up is ongoing.

Findings At a median follow-up of 62 months (range 0–114·4 months), more than 2 years after treatment completion, 186 disease-free survival events had been reported (53 events in 450 patients on tamoxifen alone, 57 in 453 patients on anastrozole alone, 36 in 450 patients on tamoxifen plus zoledronic acid, and 40 in 450 patients on anastrozole plus zoledronic acid). Zoledronic acid reduced risk of disease-free survival events overall (HR 0·68, 95% CI 0·51–0·91; p=0·009), although the diff erence was not signifi cant in the tamoxifen (HR 0·67, 95% CI 0·44–1·03; p=0·067) and anastrozole arms (HR 0·68, 95% CI 0·45–1·02; p=0·061) assessed separately. Zoledronic acid did not signifi cantly aff ect risk of death (30 deaths with zoledronic acid vs 43 deaths without; HR 0·67, 95% CI 0·41–1·07; p=0·09). There was no diff erence in disease-free survival between patients on tamoxifen alone versus anastrozole alone (HR 1·08, 95% CI 0·81–1·44; p=0·591), but overall survival was worse with anastrozole than with tamoxifen (46 vs 27 deaths; HR 1·75, 95% CI 1·08–2·83; p=0·02). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. Bone pain was reported in 601 patients (33%; 349 patients on zoledronic acid vs 252 not on the drug), fatigue in 361 (20%; 192 vs 169), headache in 280 (16%; 147 vs 133), and arthralgia in 266 (15%; 145 vs 121).

Interpretation Addition of zoledronic acid improved disease-free survival in the patients taking anastrozole or tamoxifen. There was no diff erence in disease-free survival between patients receiving anastrozole and tamoxifen overall, but those on anastrozole alone had inferior overall survival. These data show persistent benefi ts with zoledronic acid and support its addition to adjuvant endocrine therapy in premenopausal patients with early-stage breast cancer.

Funding AstraZeneca; Novartis.

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Lancet Oncol 2011; 12: 631–41

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A New Molecular Predictor of Distant Recurrence in ER-Positive, HER2-Negative Breast Cancer Adds Independent Information to Conventional Clinical Risk Factors

Martin Filipits, Margaretha Rudas, Raimund Jakesz, Peter Dubsky, Florian Fitzal, Christian F. Singer, Otto Dietze, Richard Greil, Andrea Jelen, Paul Sevelda, Christa Freibauer, Volkmar Müller, Fritz Jänicke, Marcus Schmidt, Heinz Kölbl, Achim Rody, Manfred Kaufmann, Werner Schroth, Hiltrud Brauch, Matthias Schwab, Peter Fritz, Karsten E. Weber, Inke S. Feder, Guido Hennig, Ralf Kronenwett, Mathias Gehrmann, and Michael Gnant, for the EP Investigators.

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Abstract

Purpose: According to current guidelines, molecular tests predicting the outcome of breast cancer patients can be used to assist in making treatment decisions after consideration of conventional markers. We developed and validated a gene expression signature predicting the likelihood of distant recurrence in patients with estrogen receptor (ER)–positive, HER2-negative breast cancer treated with adjuvant endocrine therapy.

Experimental Design: RNA levels assessed by quantitative reverse transcriptase PCR in formalinfixed, paraffin-embedded tumor tissue were used to calculate a risk score (Endopredict, EP) consisting of eight cancer-related and three reference genes. EP was combined with nodal status and tumor size into a comprehensive risk score, EPclin. Both prespecified risk scores including cutoff values to determine a risk group for each patient (low and high) were validated independently in patients from two large randomized phase III trials [Austrian Breast and Colorectal Cancer Study Group (ABCSG)-6: n ¼ 378, ABCSG-8: n ¼ 1,324].

Results: In both validation cohorts, continuous EP was an independent predictor of distant recurrence in multivariate analysis (ABCSG-6: P ¼ 0.010, ABCSG-8: P < 0.001). Combining Adjuvant!Online, quantitative ER, Ki67, and treatment with EP yielded a prognostic power significantly superior to the clinicopathologic factors alone [c-indices: 0.764 vs. 0.750, P ¼ 0.024 (ABCSG-6) and 0.726 vs. 0.701, P ¼ 0.003 (ABCSG-8)]. EPclin had c-indices of 0.788 and 0.732 and resulted in 10-year distant recurrence rates of 4% and 4% in EPclin low-risk and 28% and 22% in EPclin high-risk patients in ABCSG-6 (P < 0.001) and ABCSG-8 (P < 0.001), respectively.

Conclusions: Themultigene EP risk score provided additional prognostic information to the risk of distant recurrence of breast cancer patients, independent from clinicopathologic parameters. The EPclin score outperformed all conventional clinicopathologic risk factors.

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Clin Cancer Res; 17(18); 6012–20.2011AACR.

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A prospective randomised trial to study the role of levamisole and interferon alfa in an adjuvant therapy with 5-FU for stage III colon cancer (Study 90)

W Schippinger, M Jagoditsch, C Sorré, M Gnant, G Steger, H Hausmaninger, B Mlineritsch, R Schaberl-Moser, HJ Mischinger, F Hofbauer, P Holzberger, M Mittlböck and R Jakesz for the Austrian Breast and Colorectal Cancer Study Group

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Abstract

The purpose of this trial was to examine the efficacy of the addition of levamisole (LEV) or interferon alfa (IFN) to an adjuvant chemotherapy with 5-fluorouracil (5-FU) in patients with stage III colon cancer. According to a 2 × 2 factorial study design, 598 patients were randomly assigned to one of four adjuvant treatment arms. Patients in arm one received 5-FU weekly for 1 year, patients in arm two 5-FU plus LEV, in arm three 5-FU plus IFN and patients in arm four 5-FU, LEV and IFN. The relative risk of relapse and the relative risk of death were significantly higher for patients treated with LEV compared with those without LEV treatment (HR 1.452, 95% CI 1.135–1.856, P=0.0028; HR 1.506, 95% CI 1.150–1.973, P=0.0027, respectively). No significant impact on survival was observed for therapy with IFN in the univariate analysis. The addition of LEV to adjuvant 5-FU significantly worsened the prognosis of patients with stage III colon cancer. Interferon alfa had no significant influence on survival when combined with adjuvant 5-FU, but increased the toxicity of therapy substantially.

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British Journal of Cancer (2005) 92, 1655 – 1662

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Zoledronic Acid Prevents Cancer Treatment?Induced Bone Loss in Premenopausal Women Receiving Adjuvant Endocrine Therapy for Hormone-Responsive Breast Cancer: A Report From the Austrian Breast and Colorectal Cancer Study Group

Michael F. X. Gnant, Brigitte Mlineritsch, Gero Luschin-Ebengreuth, Stephan Grampp, Helmut Kaessmann, Marianne Schmid, Christian Menzel, Jutta Claudia Piswanger-Soelkner, Arik Galid, Martina Mittlboeck, Hubert Hausmaninger, and Raimund Jakesz

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Abstract

Purpose Adjuvant therapy for breast cancer can be associated with decreased bone mineral density (BMD) that may lead to skeletal morbidity. This study examined whether zoledronic acid can prevent bone loss associated with adjuvant endocrine therapy in premenopausal patients.

Patients and Methods This study is a randomized, open-label, phase III, four-arm trial comparing tamoxifen (20 mg/d orally) and goserelin (3.6 mg every 28 days subcutaneously) ± zoledronic acid (4 mg intravenously every 6 months) versus anastrozole (1 mg/d orally) and goserelin ± zoledronic acid for 3 years in premenopausal women with hormone-responsive breast cancer. In a BMD subprotocol at three trial centers, patients underwent serial BMD measurements at 0, 6, 12, 24, and 36 months.

Results Four hundred one patients were included in the BMD subprotocol. Endocrine treatment without zoledronic acid led to significant (P < .001) overall bone loss after 3 years of treatment (BMD, –14.4% after 36 months; mean T score reduction, –1.4). Overall bone loss was significantly more severe in patients receiving anastrozole/goserelin (BMD, –17.3%; mean T score reduction, –2.6) compared with patients receiving tamoxifen/goserelin (BMD, –11.6%; mean T score reduction, –1.1). In contrast, BMD remained stable in zoledronic acid–treated patients (P < .0001 compared with endocrine therapy alone). No interactions with age or other risk factors were noted.

Conclusion Endocrine therapy caused significant bone loss that increased with treatment duration in premenopausal women with breast cancer. Zoledronic acid 4 mg every 6 months effectively inhibited bone loss. Regular BMD measurements and initiation of concomitant bisphosphonate therapy on evidence of bone loss should be considered for patients undergoing endocrine therapy.

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J Clin Oncol 25:820-828, 2007

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Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years? adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial

Raimund Jakesz, Walter Jonat, Michael Gnant, Martina Mittlboeck, Richard Greil, Christoph Tausch, Joern Hilfrich, Werner Kwasny, Christian Menzel, Hellmut Samonigg, Michael Seifert, Guenther Gademann, Manfred Kaufmann, on behalf of the ABCSG and the GABG.

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Abstract

BACKGROUND: Tamoxifen has been the standard adjuvant treatment for postmenopausal women with hormone-responsive early breast cancer for more than 20 years. However, the third-generation aromatase inhibitor anastrozole has proven efficacy and tolerability benefits compared with tamoxifen when used as initial adjuvant therapy. We investigate whether women who have received a period of adjuvant tamoxifen would benefit from being switched to anastrozole.

METHODS: We present a combined analysis of data from two prospective, multicentre, randomised, open-label trials with nearly identical inclusion criteria. Postmenopausal women with hormone-sensitive early breast cancer who had completed 2 years’ adjuvant oral tamoxifen (20 or 30 mg daily) were randomised to receive 1 mg oral anastrozole (n=1618) or 20 or 30 mg tamoxifen (n=1606) daily for the remainder of their adjuvant therapy. The primary endpoint was event-free survival, with an event defined as local or distant metastasis, or contralateral breast cancer. Analysis was by intention to treat.

FINDINGS: 3224 patients were included in analyses. At a median follow-up of 28 months, we noted a 40% decrease in the risk for an event in the anastrozole group as compared with the tamoxifen group (67 events with anastrozole vs 110 with tamoxifen, hazard ratio 0.60, 95% CI 0.44-0.81, p=0.0009). Both study treatments were well tolerated. There were significantly more fractures (p=0.015) and significantly fewer thromboses (p=0.034) in patients treated with anastrozole than in those on tamoxifen.

INTERPRETATION: These data lend support to a switch from tamoxifen to anastrozole in patients who have completed 2 years’ adjuvant tamoxifen.

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Lancet 2005; 366: 455–62

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Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta-analysis

Walter Jonat, Michael Gnant, Francesco Boccardo, Manfred Kaufmann, Alessandra Rubagotti, Ivan Zuna, Mike Greenwood, Raimund Jakesz

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Abstract

Background: For more than 20 years, tamoxifen has been the mainstay of adjuvant endocrine therapy for women with hormone-sensitive early-stage breast cancer. However, not only does tamoxifen have potential side-effects such as an increased risk of endometrial cancer and thromboembolic events, but patients can also develop resistance to the drug. We aimed to investigate whether switching treatment of postmenopausal women with such breast cancer to anastrozole after 2—3 years of tamoxifen would be more effective than continuing on tamoxifen for a total of 5 years.

Methods: We did a meta-analysis of three clinical trials—the Austrian Breast and Colorectal Cancer Study Group (ABCSG 8), Arimidex-Nolvadex (ARNO 95), and the Italian Tamoxifen Anastrozole (ITA) studies—in which postmenopausal women with histologically confirmed, hormone-sensitive early-stage breast cancer were randomised to 1 mg/day anastrozole (n=2009) after 2—3 years of tamoxifen treatment or to continued 20 or 30 mg/day tamoxifen (n=1997). We analysed the data with a stratified Cox proportional hazards model with the covariates of age, tumour size, nodal status, grade, surgery, and chemotherapy.

Findings: Patients who switched to anastrozole had fewer disease recurrences (92 vs 159) and deaths (66 vs 90) than did those who remained on tamoxifen, resulting in significant improvements in disease-free survival (hazard ratiro 0·59 [95% CI 0·48—0·74]; p<0·0001), event-free survival (0·55 [0·42—0·71]; p<0·0001), distant recurrence-free survival (0·61 [0·45—0·83]; p=0·002), and overall survival (0·71 [0·52—0·98]; p=0·04).

Interpretation: Our results show that the clinical benefits in terms of event-free survival seen in individual trials for those patients who switched to anastrozole translate into a benefit in overall survival. These findings confirm that clinicians should consider switching postmenopausal women who have taken adjuvant tamoxifen for 2—3 years to anastrozole.

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Lancet Oncol 2006; 7: 991–96

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Extended Adjuvant Therapy With Anastrozole Among Postmenopausal Breast Cancer Patients: Results From the Randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a

Raimund Jakesz, Richard Greil, Michael Gnant, Marianne Schmid, Werner Kwasny, Ernst Kubista, Brigitte Mlineritsch, Christoph Tausch, Michael Stierer, Friedrich Hofbauer, Karl Renner, Christian Dadak, Ernst Rücklinger, Hellmut Samonigg, on behalf of the Austrian Breast and Colorectal Cancer Study Group

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Abstract

Background Clinical trial data have shown that among breast cancer patients who were disease free after 5 years of adjuvant treatment with tamoxifen, further extended treatment with the nonsteroidal aromatase inhibitor letrozole reduces breast cancer recurrence. We examined the efficacy and tolerability of extended adjuvant therapy with another aromatase inhibitor, anastrozole, for 3 years among women who had completed 5 years of adjuvant therapy.

Methods Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 6a is an extension of ABCSG Trial 6, in which hormone receptor–positive postmenopausal patients received 5 years of adjuvant tamoxifen, with or without the aromatase inhibitor aminoglutethimide, for the first 2 years of therapy. For ABCSG Trial 6a, patients who were disease free at the end of Trial 6 were randomly assigned to receive either 3 years of anastrozole or no further treatment. Efficacy data were analyzed with the use of a Cox proportional hazards regression model with two-sided P values and Kaplan–Meier curves, and tolerability data were estimated using logistic regression analysis with odds ratios and 95% confidence intervals (CIs).

Results ABCSG Trial 6a included 856 patients. At a median follow-up of 62.3 months, women who received anastrozole (n = 387) had a statistically significantly reduced risk of recurrence (locoregional recurrence, contralateral breast cancer, or distant metastasis) compared with women who received no further treatment (n = 469; hazard ratio = 0.62; 95% CI = 0.40 to 0.96, P = .031). Anastrozole was well tolerated, and no unexpected adverse events were reported.

Conclusions These data confirm the benefit of extending adjuvant tamoxifen therapy beyond 5 years with anastrozole compared with no further treatment. Further research is required to define the optimum length of extended adjuvant therapy and to investigate the possibility of tailoring this period to suit different disease types.

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J Natl Cancer Inst 2007;99: 1845 – 53

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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

Günther G. Steger, Arik Galid, Michael Gnant, Brigitte Mlineritsch, Alois Lang, Christoph Tausch, Margaretha Rudas, Richard Greil, Catharina Wenzel, Christian F. Singer, Anton Haid, Sabine Pöstlberger, Hellmut Samonigg, Gero Luschin-Ebengreuth, Werner Kwasny, Eduard Klug, Ernst Kubista, Christian Menzel, and Raimund Jakesz

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Abstract

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.

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J Clin Oncol 25:2012-2018, 2007

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Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy

Michael Gnant, Brigitte Mlineritsch, Gero Luschin-Ebengreuth, Franz Kainberger, Helmut Kässmann, Jutta Claudia Piswanger-Sölkner,Michael Seifert, Ferdinand Ploner, Christian Menzel, Peter Dubsky, Florian Fitzal, Vesna Bjelic-Radisic, Günther Steger, Richard Greil, Christian Marth, Ernst Kubista, Hellmut Samonigg, Peter Wohlmuth, Martina Mittlböck, Raimund Jakesz, on behalf of the Austrian Breast and Colorectal Cancer Study Group

Lancet Oncol 2008; 9: 840–49

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Cyclin D1 Expression in Breast Cancer Patients Receiving Adjuvant Tamoxifen-Based Therapy

Margaretha Rudas, Martina Lehnert, Anh Huynh, Raimund Jakesz, Christian Singer,Sigurd Lax, Walter Schippinger, Otto Dietze, Richard Greil, Wolfgang Stiglbauer, Werner Kwasny, Renate Grill, Michael Stierer, Michael F. X. Gnant and Martin Filipits for the Austrian Breast and Colorectal Cancer Study Group

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Abstract

PURPOSE: The objective of our study was to determine the clinical relevance of cyclin D1 expression in hormone receptor-positive breast cancer patients who were treated with tamoxifen-based therapy.

EXPERIMENTAL DESIGN: We assessed expression of cyclin D1 in surgical specimens of breast carcinoma by means of immunohistochemistry. Patients had been enrolled in either Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 05 or ABCSG Trial 06 and received tamoxifen as part of their adjuvant treatment. Overall survival and relapse-free survival were analyzed with Cox models adjusted for clinical and pathologic factors.

RESULTS: Cyclin D1 was expressed in 140 of 253 (55%) tumors of ABCSG Trial 05 and in 569 of 948 (60%) tumors of ABCSG Trial 06. Expression of cyclin D1 was associated with poor outcome in both cohorts. Overall survival was significantly shorter in patients with cyclin D1-positive tumors compared with patients with cyclin D1-negative tumors [adjusted hazard ratio (HR) for death (ABCSG Trial 05), 2.47; 95% confidence interval (95% CI), 1.08-5.63; P = 0.03; adjusted HR for death (ABCSG Trial 06), 1.78; 95% CI, 1.36-2.34; P < 0.0001]. Relapse-free survival was also shorter in patients with cyclin D1-positive tumors than in patients with cyclin D1-negative tumors [adjusted HR for relapse (ABCSG Trial 05), 2.73; 95% CI, 1.50-4.96; P = 0.001; adjusted HR for relapse (ABCSG Trial 06), 1.52; 95% CI, 1.14-2.04; P = 0.005].

CONCLUSION: Cyclin D1 expression is an independent poor prognostic factor in women with early-stage, hormone receptor-positive breast cancer who received adjuvant tamoxifen-based therapy.

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Clin Cancer Res 2008;14(6) March 15, 2008

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Exemestane as primary systemic treatment for hormone receptor positive post-menopausal breast cancer patients: a phase II trial of the Austrian Breast and Colorectal Cancer Study Group (ABCSG-17)

Brigitte Mlineritsch, Christoph Tausch, Christian Singer, Gero Luschin-Ebengreuth, Raimund Jakesz, Ferdinand Ploner, Michael Stierer, Elisabeth Melbinger, Christian Menzel, Andrea Urbania, Michael Fridrik, Günther Steger, Peter Wohlmuth, Michael Gnant, Richard Greil, on behalf of the Austrian Breast and Colorectal Cancer Study Group

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Abstract

Background A multicenter phase II study was conducted to analyze the clinical activity of the steroidal aromatase inhibitor exemestane in the neoadjuvant treatment of post-menopausal women with strongly ER- and/or PgR- positive operable breast cancer.

Patients and methods: From September 2000 to December 2003, 80 women were recruited for treatment with exemestane 25 mg once daily for 4 months. The primary end-point was the clinical response rate according the WHO criteria; the secondary end-points included toxicity and the number of patients who qualified for breast conserving surgery at the end of treatment, comparability of evaluation methods for response, potential alterations of hormone receptor and Her2/neu status during treatment.

Results: On an intention to evaluate analysis, according to the prespecified criteria the overall clinical objective response rate was 34%, the pCR rate was 3% and the rate of breast conserving surgery was 76%. When sonographic and mammographic longitudinal measurements were included in patients with missing palpation data, response rates were 38% and 41%, respectively. The tumor response was independent of the Her2/neu status which remained unchanged during treatment. In contrast, while the ER expression remained unaltered, downregulation of the PgR was observed. The treatment was well tolerated with no grade 3 and 4 toxicities except gastrointestinal (one grade 3 case) and hot flushes (two grade 3 cases).

Conclusion: This study shows that exemestane is effective and safe as a preoperative therapy in post-menopausal patients with strongly hormone receptor-positive breast cancer.

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Breast Cancer Res Treat DOI 10.1007/s 10549-007-9843-x

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A prospective randomised phase III trial of adjuvant chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer

W Schippinger, H Samonigg, R Schaberl-Moser, R Greil, R Thödtmann, J Tschmelitsch, M Jagoditsch, GG Steger, R Jakesz, F Herbst, F Hofbauer, H Rab, P Wohlmuth, M Gnant and J Thaler for the Austrian Breast and Colorectal Cancer Study Group

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Abstract

The purpose of this trial was to investigate the efficacy of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) in stage II colon cancer. Patients with stage II colon cancer were randomised to either adjuvant chemotherapy with 5-FU/LV (100 mg m(-2) LV+450 mg m(-2) 5-FU weekly, weeks 1-6, in 8 weeks cycles x 7) or surveillance only. Five hundred patients were evaluable for analyses. After a median follow-up of 95.6 months, 55 of 252 patients (21.8%) have died in the 5-FU/LV arm and 58 of 248 patients (23.4%) in the surveillance arm. There was no statistically significant difference in overall survival (OS) between the two treatment arms (hazard ratios, HR 0.88, 95% CI 0.61-1.27, P=0.49). The relative risk for tumour relapse was higher for patients on the surveillance arm than for those on the 5-FU/LV arm; however, this difference was not statistically significant (HR 0.69, 95% CI 0.45-1.06, P=0.09). Consequently, disease-free survival (DFS) was not significantly different between the two trial arms. In conclusion, results of this trial demonstrate a trend to a lower risk for relapse in patients treated with adjuvant 5-FU/LV for stage II colon cancer. However, in this study with limited power to detect small differences between the study arms, adjuvant chemotherapy failed to significantly improve DFS and OS.

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British Journal of Cancer (2007) 97, 1021 – 1027

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Lumpectomy plus Tamoxifen or Anastrozole with or without Whole Breast Irradiation in Women with Favorable Early Breast Cancer

Richard Pötter, Michael Gnant, Werner Kwasny, Christoph Tausch, Leonore Handl-Zeller, Brigitte Pakisch, Susanne Taucher, Josef Hammer, Geor Luschin-Ebengreuth, Marianne Schmid, Felix Sedlmayer, Michael Stierer, Georg Reiner, Karin Kapp, Friedrich Hofbauer, Andrea Rottenfusser, Sabine Pöstlberger, Karin Haider, Wolfgang Draxler, Raimund Jakesz, on behalf of the Austrian Breast & Colorectal Cancer Study Group

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Abstract

Purpose: In women with favorable early breast cancer treated by lumpectomy plus tamoxifen or anastrazole, it remains unclear whether whole breast radiotherapy is beneficial.

Methods and Material: Between January 1996 and June 2004, the Austrian Breast and Colorectal Cancer Study Group (ABCSG) randomly assigned 869 women to receive breast radiotherapy ± boost (n = 414) or not (n = 417) after breast-conserving surgery (ABCSG Study 8A). Favorable early breast cancer was specified as tumor size

Results: The mean age was 66 years. Overall, there were 21 local relapses, with 2 relapses in the radiotherapy group (5-y rate 0.4%) vs. 19 in the no-radiotherapy group (5.1%), respectively (p = 0.0001, hazard ratio 10.2). Overall relapses occurred in 30 patients, with 7 events in the radiotherapy group (5-y rate 2.1%) vs. 23 events in the no-radiotherapy group (6.1%) (p = 0.002, hazard ratio 3.5). No significant differences were found for distant metastases and overall survival.

Conclusion: Breast radiotherapy ± boost in women with favorable early breast cancer after lumpectomy combined with tamoxifen/anastrazole leads to a significant reduction in local and overall relapse.

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Int. J. Radiation Oncology Biol. Phys., Vol. 68, No. 2, pp. 334–340, 2007

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The potential risk of neoadjuvant chemotherapy in breast cancer patients?results from a prospective randomized trial of the Austrian Breast and Colorectal Cancer Study Group (ABCSG-07)

Susanne Taucher, Günther G. Steger, Raimund Jakesz, Christoph Tausch, Viktor Wette, Walter Schippinger, Werner Kwasny, Georg Reiner, Richard Greil, Peter Dubsky, Sabine Pöstlberger, Jörg Tschmelitsch, Hellmut Samonigg, Michael Gnant

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Abstract

PURPOSE: To evaluate the impact that pre- and postoperatively administered chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF) and postoperative chemotherapy vs. postoperative chemotherapy alone have on long-term prognosis.

PATIENTS AND METHODS: The ABCSG conducted a nationwide randomized phase III trial in high-risk endocrine non-responsive breast cancer patients comparing pre- and postoperative chemotherapy containing CMF as preoperative treatment vs. postoperative chemotherapy alone between 1991 and 1999. From 1996 the ABCSG-07 protocol was amended to also allow randomization of high-risk endocrine-responsive patients. Of 423 eligible patients with high-risk primary breast cancer, 203 patients were randomly assigned to preoperatively receive three cycles of CMF (cyclophosphamide, methotrexate, fluorouracil; 600/40/600 mg/m(2)) intravenously on day 1 and 8, while 195 patients received postoperative chemotherapy alone. In both groups, three cycles of CMF were given initially, and another three cycles of CMF were administered in node-negative patients, whereas node-positive patients received three cycles of EC (epirubicin, cyclophosphamide; 70/600 mg/m(2)).

RESULTS: Overall response rate to preoperative chemotherapy with three cycles of CMF was 56.2%; complete pathological response was achieved in 12 patients (5.9%). Recurrence-free survival was significantly better in patients receiving chemotherapy postoperatively (HR 0.7, 0.515-0.955; P = 0.024). No survival difference was observed between the two therapy groups (HR 0.800, 0.563-1.136; P = 0.213).

DISCUSSION: Preoperative chemotherapy with CMF has to be considered as insufficient in high-risk breast cancer patients. Delayed surgery and anthracycline-based chemotherapy result in shorter recurrence-free survival but not overall survival.

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Breast Cancer Res Treat – accepted in November 2007

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Invasive ductal carcinoma and invasive lobular carcinoma of breast differ in response following neoadjuvant therapy with epidoxorubicin and docetaxel + G-CSF

Catharina Wenzel, Rupert Bartsch, Dagmar Hussian, Ursula Pluschnig, Gabriela Altorjai, Christoph C. Zielinski, Alois Lang, Anton Haid, Raimund Jakesz, Michael Gnant, Guenther G. Steger

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Abstract

PURPOSE: Preoperative chemotherapy in patients with primary breast cancer treated with anthracyclines and taxanes results in high response rates, allowing breast conserving surgery (BCS) in patients primarily not suitable for this procedure. Pathological responses are important prognostic parameters for progression free and overall survival. We questioned the impact of histologic type invasive ductal carcinoma (IDC) versus invasive lobular carcinoma (ILC) on response to primary chemotherapy.

PATIENTS AND METHODS: 161 patients with breast cancer received preoperative chemotherapy consisted of epidoxorubicin 75 mg/m(2) and docetaxel 75 mg/m(2) administered in combination with granulocyte-colony stimulating factor (G-CSF) on days 3-10 (ED + G). Pathological complete response (pCR), biological markers and type of surgery as well as progression free and overall survival were compared between IDC and ILC.

RESULTS: Out of 161 patients, 124 patients presented with IDC and 37 with ILC. Patients with ILC were less likely to have a pCR (3% vs. 20%, P < 0.009) and breast conserving surgeries (51% vs. 79%, P < 0.001). Patients with ILC tended to have oestrogen receptor positive tumors (86% vs. 52%, P < 0.0001), HER 2 negative tumors (69% vs. 84%), and lower nuclear grade (nuclear grade 3, 16% vs. 46%, P < 0.001). Patients with ILC tended to have longer time to progression (TTP) (42 months vs. 26 months) and overall survival (69 months vs. 65 months).

CONCLUSIONS: Our results indicate that patients with ILC achieved a lower pCR rate and ineligibility for BCS to preoperative chemotherapy, but this did not result in a survival disadvantage. Because of these results new strategies to achieve a pCR are warranted.

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Breast Cancer Res Treat (2007) 104:109-114

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Anemia Is a Significant Prognostic Factor in Local Relapse-Free Survival of Premenopausal Primary Breast Cancer Patients Receiving Adjuvant Cyclophosphamide/Methotrexate/5-Fluorouracil Chemotherapy

Peter Dubsky, Paul Sevelda, Raimund Jakesz, Hubert Hausmaninger, Hellmut Samonigg, Michael Seifert, Ursula Denison, Brigitte Mlineritsch, Günther Steger, Werner Kwasny, Herbert Stöger, Rupert Bartsch, Michael Stierer, Susanne Taucher, Michael Fridrik, Walter Schippinger, Richard Greil, Richard Pötter, Michael Gnant

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Abstract

PURPOSE: To determine the effects of anemia on local relapse-free, relapse-free, and overall survival (LRFS, RFS, and OS, respectively) in premenopausal, primary breast cancer patients receiving adjuvant polychemotherapy, and to determine which conventional prognostic factors affected these outcomes.

EXPERIMENTAL DESIGN: Four hundred twenty-four premenopausal patients with early-stage primary breast cancer and hormone receptor-expressing tumors were treated with i.v. cyclophosphamide/methotrexate/5-fluorouracil (CMF) polychemotherapy as part of an adjuvant phase III trial (Austrian Breast and Colorectal Cancer Study Group Trial 5). The influence of anemia (hemoglobin

RESULTS: Of 424 patients, 77 (18.2%) developed anemia on CMF chemotherapy. After a median follow-up time of 5 years, 8.9% of nonanemic patients had local relapse compared with 19.6% of anemic patients (P=0.0006). Although mastectomy was associated with anemia (26% versus 13.7% in breast conserving surgery; P=0.002), multivariate analysis did not show mastectomy per se to be a significant risk factor for LRFS. Age, lymph node status, and hemoglobin had an independent significant influence on LRFS (P<0.005). Anemic patients had a relative risk of 2.96 (95% confidence interval, 1.41-6.23) for developing local relapse in comparison with nonanemic patients.

CONCLUSION: Premenopausal breast cancer patients who developed anemia during the CMF regimen had significantly worse LRFS. In Austrian Breast and Colorectal Cancer Study Group Trial 5, anemia may have contributed to an almost doubled incidence of local recurrence in the chemotherapy arm. Molecular targets associated with tumor hypoxia and distinct from erythropoiesis should receive further attention in experimental and clinical settings.

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Clin Cancer Res 2008;14(7) April 1, 2008

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Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer

Michael Gnant, M.D., Brigitte Mlineritsch, M.D., Walter Schippinger, M.D., Gero Luschin-Ebengreuth, M.D., Sabine Pöstlberger, M.D., Christian Menzel, M.D., Raimund Jakesz, M.D., Michael Seifert, M.D., Michael Hubalek, M.D., Vesna Bjelic-Radisic, M.D., Hellmut Samonigg, M.D., Christoph Tausch, M.D., Holger Eidtmann, M.D., Günther Steger, M.D., Werner Kwasny, M.D., Peter Dubsky, M.D., Michael Fridrik, M.D., Florian Fitzal, M.D., Michael Stierer, M.D., Ernst Rücklinger, Ph.D., and Richard Greil, M.D., for the ABCSG-12 Trial Investigators

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Abstract

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.)

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N Engl J Med 2009;360:679-91

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Maintaining Bone Density in Patients Undergoing Treatment for Breast Cancer: Is There an Adjuvant Benefit?

Michael Gnant, Peter Dubsky, Florian Fitzal, Peter Blaha, Sebastian Schoppmann, Günther Steger, Christian Marth, Hellmut Samonigg, Katharina Hüttner, Hannes Fohler, Ernst Rücklinger, Raimund Jakesz, Richard Greil, on behalf of the Austrian Breast and Colorectal Cancer Study Group

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Abstract

Women undergoing treatment for breast cancer often experience a marked decrease in bone mineral density. This decrease is observed with chemotherapy as well as endocrine therapy and is more pronounced and rapid than normal postmenopausal bone loss. Pharmacologic intervention is, therefore, necessary in many cases to preserve bone health and prevent fractures.

Many small studies have demonstrated that cancer therapy-induced bone loss (CTIBL) is effectively prevented by bone-targeted therapies, such as bisphosphonates and other inhibitors of bone resorption. Recently, several trials have confirmed the efficacy of bisphosphonates in the prevention of CTIBL in both premenopausal and postmenopausal women with early-stage breast cancer. In addition, concomitant treatment with zoledronic acid 4 mg every 6 months and standard adjuvant endocrine therapy has been reported to significantly improve disease-free survival and decrease disease recurrence in bone as well as other sites compared with standard therapy alone. Zoledronic acid treatment has also decreased residual tumor volume in the neoadjuvant setting.

Furthermore, long-term follow-up of a single study in patients with bone marrow micrometastases from breast cancer revealed overall survival benefits for patients receiving clodronate 1600 mg/day compared with placebo; however, combined results from several trials of clodronate are inconclusive. Overall, a large body of evidence is accumulating to support the potential adjuvant benefits of bisphosphonates in the treatment of early-stage breast cancer.

Results from ongoing studies are expected to further elucidate the benefits of bisphosphonates in maintaining bone health and improving clinical outcomes in patients with breast cancer.

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Clinical Breast Cancer, Vol. 9, Suppl. 1, S18-S27, 2009

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Can oral bisphosphonates really reduce the risk of breast cancer in healthy women?

Von Univ.-Prof. Dr. Michael Gnant, publiziert im Journal of Clinical Oncology.

Journal of Clinical Oncology

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Clinical role of multidrug resistance protein 1 expression in chemotherapy resistance in early-stage breast cancer: the Austrian Breast and Colorectal Cancer Study Group

Filipits M, Pohl G, Rudas M, Dietze O, Lax S, Grill R, Pirker R, Zielinski C, Hausmaninger H, Kubista E, Samonigg H, Jakesz R

Journal of Clinical Oncology 2005, 23:1161-1168

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