Publications 2011

62-Month follow-up of ABCSG-12: Adjuvant endocrine therapy, alone or in combination with zoledronic acid, in premenopausal patients with endocrine-responsive early breast cancer

Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Poestlberger S, Steger G, Jakesz R, Singer C, Eidtmann H, Greil R

Bone 48 (2011) S13–S21.

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Preoperative oxaliplatin, capecitabine, and external beam radiotherapy in patients with newly diagnosed, primary operable, cT3NxM0, low rectal cancer a phase II study

Öfner D, DeVries AF, Schaberl-Moser R, Greil R, Rabl H, Tschmelitsch J, Zitt M, Kapp KS, Fastner G, Keil F, Eisterer W, Jäger R, Offner F, Gnant M, Thaler J

Strahlentherapie und Onkologie 2011 Feb;187(2):100-7. Epub 2011 Jan 21.

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Adjuvant bisphosphonates – an option with low estrogen?

Gnant M

Nature Reviews Clin. Oncol. 8, 698-699 (2011).

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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.

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.

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.

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.

Clin Cancer Res; 17(18); 6012–20. 2011AACR.

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