Publications 2015

TP53 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients

Kandioler D, Mittlböck M, Kappel S, Puhalla H, Herbst F, Langner C, Wolf B, Tschmelitsch J, Schippinger W, Steger G, Hofbauer F, Samonigg H, Gnant M, Teleky B, Kührer I
On behalf of the p53 Research Group and the Austrian Breast and Colorectal Study Group (ABCSG)

EBioMedicine. 2015 Jun 8;2(8):823-8. eCollection 2015 Aug.

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The genomic expression test EndoPredict is a prognostic tool for identifying risk of local recurrence in postmenopausal endocrine receptor-positive, her2neu-negative breast cancer patients randomised within the prospective ABCSG 8 trial

Fitzal F, Filipits M, Rudas M, Greil R, Dietze O, Samonigg H, Lax S, Herz W, Dubsky P, Bartsch R, Kronenwett R and Gnant M

British Journal of Cancer (2015) 112, 1405–1410.

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Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial

John F Forbes, Ivana Sestak, Anthony Howell, Bernardo Bonanni, Nigel Bundred, Christelle Levy, Gunter von Minckwitz, Wolfgang Eiermann, Patrick Neven, Michael Stierer, Chris Holcombe, Robert E Coleman, Louise Jones, Ian Ellis, Jack Cuzick, on behalf of the IBIS-II investigators

The Lancet. Epub 2015 Dec 11.

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Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials

Dowsett M, Forbes F, Bradley R, Ingle J, Aihara T, Bliss J, Boccardo F, Coates A, Coombes RC, Cuzick J, Dubsky P, Gnant M, Kaufmann M, Kilburn L, Perrone F, Rea D, Thürlimann B, van de Velde C, Pan H, Peto R, Davies C, Gray R

The Lancet, 2015 Oct 3;386(10001):1341-1352. Epub 2015 Jul 23.

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Final 10-year results of the Breast International Group 2–98 phase III trial and the role of Ki67 in predicting benefit of adjuvant docetaxel in patients with oestrogen receptor positive breast cancer

Sonnenblick A, Francis P A, Azim Jr. H A, de Azambuja E, Nordenskjöld B, Gutiérez J, Quinaux E, Mastropasqua M G, Ameye L, Anderson M, Lluch A, Gnant M, Goldhirsch A, Di Leo A, Barnadas A, Cortes-Funes H, Piccart M, Crown J

European Journal of Cancer, 2015 Aug;51(12):1481-1489. Epub 2015 Jun 11.

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Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

Coleman R, Powles T, Paterson A, Gnant M, Anderson S, Diel I, Gralow J, von Minckwitz G, Moebus V, Bergh J, Pritchard KI, Bliss J, Cameron D, Evans V, Pan H, Peto R, Bradley R, Gray R

The Lancet, 2015 Oct 3;386(10001):1353–1361. Epub 2015 Jul 23.

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Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial

Gnant M, Pfeiler G, Dubsky P, Hubalek M, Greil R, Jakesz R, Wette V, Balic M, Haslbauer F, Melbinger E, Bjelic-Radisic V, Artner-Matuschek S, Fitzal F, Marth C, Sevelda P, Mlineritsch B, Steger G, Manfreda D, Exner R, Egle D, Bergh J, Kainberger F, Talbot S, Warner D, Fesl C, Singer C, on behalf of the Austrian Breast and Colorectal Cancer Study Group

The Lancet, 2015 Aug 1;386(9992):433-443. Epub 2015 Jun 1.

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Summary

Background:
Adjuvant endocrine therapy compromises bone health in patients with breast cancer, causing osteopenia, osteoporosis, and fractures. Antiresorptive treatments such as bisphosphonates prevent and counteract these side-effects. In this trial, we aimed to investigate the effects of the anti-RANK ligand antibody denosumab in postmenopausal, aromatase inhibitor-treated patients with early-stage hormone receptor-positive breast cancer.

Methods
In this prospective, double-blind, placebo-controlled, phase 3 trial, postmenopausal patients with early hormone receptor-positive breast cancer receiving treatment with aromatase inhibitors were randomly assigned in a 1:1 ratio to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months in 58 trial centres in Austria and Sweden. Patients were assigned by an interactive voice response system. The randomisation schedule used randomly permuted block design with block sizes 2 and 4, stratified by type of hospital regarding Hologic device for DXA scans, previous aromatase inhibitor use, and baseline bone mineral density. Patients, treating physicians, investigators, data managers, and all study personnel were masked to treatment allocation. The primary endpoint was time from randomisation to first clinical fracture, analysed by intention to treat. As an additional sensitivity analysis, we also analysed the primary endpoint on the per-protocol population. Patients were treated until the prespecified number of 247 first clinical fractures was reached. This trial is ongoing (patients are in follow-up) and is registered with the European Clinical Trials Database, number 2005-005275-15, and with ClinicalTrials.gov, number NCT00556374.

Findings
Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled into the trial, of whom 3420 were randomly assigned to receive denosumab 60 mg (n=1711) or placebo (n=1709) subcutaneously every 6 months. Compared with the placebo group, patients in the denosumab group had a significantly delayed time to first clinical fracture (hazard ratio [HR] 0·50 [95% CI 0·39–0·65], p<0·0001). The overall lower number of fractures in the denosumab group (92) than in the placebo group (176) was similar in all patient subgroups, including in patients with a bone mineral density T-score of –1 or higher at baseline (n=1872, HR 0·44 [95% CI 0·31–0·64], p<0·0001) and in those with a bone mineral density T-score of less than –1 already at baseline (n=1548, HR 0·57 [95% CI 0·40–0·82], p=0·002). The patient incidence of adverse events in the safety analysis set (all patients who received at least one dose of study drug) did not differ between the denosumab group (1366 events, 80%) and the placebo group (1334 events, 79%), nor did the numbers of serious adverse events (521 vs 511 [30% in each group]). The main adverse events were arthralgia and other aromatase-inhibitor related symptoms; no additional toxicity from the study drug was reported. Despite proactive adjudication of every potential osteonecrosis of the jaw by an international expert panel, no cases of osteonecrosis of the jaw were reported. 93 patients (3% of the full analysis set) died during the study, of which one death (in the denosumab group) was thought to be related to the study drug.

Interpretation
Adjuvant denosumab 60 mg twice per year reduces the risk of clinical fractures in postmenopausal women with breast cancer receiving aromatase inhibitors, and can be administered without added toxicity. Since a main side-effect of adjuvant breast cancer treatment can be substantially reduced by the addition of denosumab, this treatment should be considered for clinical practice.

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Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cance Study Group Trial 12

Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Knauer M, Moik M, Jakesz R, Seifert M, Taucher S, Bjelic-Radisic V, Balic M, Eidtmann H, Eiermann W, Steger G, Kwasny W, Dubsky P, Selim U, Fitzal F, Hochreiner G, Wette V, Sevelda P, Ploner F, Bartsch R, Fesl C, Greil R

Annals of Oncology 2015;26:313-320. Epub 2014 Nov 17.

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Abstract

Background:
Zoledronic acid (ZOL) plus adjuvant endocrine therapy significantly improved disease-free survival (DFS) at 48- and 62-month follow-up in the ABCSG-12 trial. We present efficacy results of a final additional analysis after 94.4 months.

Patients and methods:
Patients were premenopausal women who had undergone primary surgery for stage I/II estrogen-receptor-positive and/or progesterone-receptor-positive breast cancer with <10 positive lymph nodes, and were scheduled for standard goserelin therapy. All 1803 patients received goserelin (3.6 mg every 28 days) and were randomized to tamoxifen (20 mg/days) or anastrozole (1 mg/days), both with or without ZOL (4 mg every 6 months) for 3 years. The primary end point was DFS; recurrence-free survival and overall survival (OS) were secondary end points.

Results:
After 94.4-month median follow-up (range, 0–114 months), relative risks of disease progression [hazard ratio (HR) = 0.77; 95% confidence interval (CI) 0.60–0.99; P = 0.042] and of death (HR = 0.66; 95% CI 0.43–1.02; P = 0.064) are still reduced by ZOL although no longer significant at the predefined significance level. Overall, 251 DFS events and 86 deaths were reported. Absolute risk reductions with ZOL were 3.4% for DFS and 2.2% for OS. There was no DFS difference between tamoxifen alone versus anastrozole alone, but there was a pronounced higher risk of death for
anastrozole-treated patients (HR = 1.63; 95% CI 1.05–1.45; P = 0.030). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw.

Conclusion:
These final results from ABCSG 12 suggest that twice-yearly ZOL enhances the efficacy of adjuvant endocrine treatment, and this benefit is maintained long-term.

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Identifying clinically relevant prognostic subgroups of postmenopausal women with node-positive hormone receptor-positive early-stage breast cancer treated with endocrine therapy: a combined analysis of ABCSG-8 and ATAC using the PAM50 risk of recurrence score and intrinsic subtype

Gnant M, Sestak I, Filipits M, Dowsett M, Balic M, Lopez-Knowles E, Greil R, Dubsky P, Stoeger H, Rudas M, Jakesz R, Ferree S, Cowens JW, Nielsen T, Schaper C, Fesl C, Cuzick J

Annals of Oncology 00:1-7, 2015. Epub 2015 May 1.

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Abstract

Background:
In the adjuvant treatment of hormone receptor-positive (HR+) breast cancer, variables like tumour size, grade and nodal status have great impact on therapy decisions. As most node-positive patients with HR+ breast cancer currently receive adjuvant chemotherapy improved methods for characterization of individuals’ metastasis risk are needed to reduce overtreatment.

Patients and methods:
Tissue specimens from node-positive patients of the ABCSG-8 and ATAC trials who received adjuvant tamoxifen and/or anastrozole were included in this study. Analysing RNA from paraffin blocks using the PAM50 test, the primary objective was to evaluate the prognostic information of the risk of recurrence (ROR) score added to combined clinical standard variables in patients with one positive node (1N+) and in patients with two or three positive nodes (2–3N+), using log-likelihood ratio tests.

Results:
At a median follow-up of 9.6 years, distant metastases occurred in 97 (18%) of 543 node-positive patients. In a multivariate analysis, the PAM50-derived ROR score provided reliable prognostic information in addition to and beyond established clinical factors for 1N+ (P < 0.0001) and 2–3N+ patients (P = 0.0002). Ten-year distant recurrence risk was significantly increased in the high-risk compared with the low-risk group derived from ROR score for 1N+ [25.5%, 95% confidence interval (CI) 17.5% to 36.1%versus 6.6%, 95% CI 3.3% to 12.8%] and compared with the combined low/intermediate risk group for 2–3N+ patients (33.7%, 95% CI 25.5% to 43.8% versus 12.5%, 95% CI 6.6% to 22.8%). Additionally, the luminal A intrinsic subtype (IS) exhibited significantly lower risk of distant recurrence compared with the luminal B subtype in 1N+ and 2–3N+ patients.

Conclusion:
PAM50 ROR score and IS can identify node-positive patient subgroups with limited risk of metastasis after endocrine therapy, for whom adjuvant chemotherapy can be spared. The PAM50 test is a valuable tool in determining treatment of node-positive early-stage breast cancer patients.

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Prediction of Late Distant Recurrence After 5 Years of Endocrine Treatment: A Combined Analysis of Patients From the Austrian Breast and Colorectal Cancer Study Group 8 and Arimidex, Tamoxifen Alone or in Combination Randomized Trials Using the PAM50 Risk of Recurrence Score

Ivana Sestak, Jack Cuzick, Mitch Dowsett, Elena Lopez-Knowles, Martin Filipits, Peter Dubsky, John Wayne Cowens, Sean Ferree, Carl Schaper, Christian Fesl, and Michael Gnant

J Clin Oncol 2015 March 10;33(8):916-922. Epub 2014 Oct 20.

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Abstract

Purpose
We have previously shown that the PAM50-based risk of recurrence (ROR) score is significantly correlated with distant recurrence in both the translational research cohort within the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial (TransATAC) and Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG 8) randomized trials. Here, we focus on the ROR score for predicting distant recurrence after 5 years of follow-up in a combined analysis of these two randomized trials.

Methods
Long-term follow-up data and tissue samples were obtained from 2,137 postmenopausal women with hormone receptor–positive early-stage breast cancer from the ABCSG 8 and TransATAC trials. We used Cox proportional hazard regression models to determine the prognostic value of ROR for distant recurrence beyond 5 years in the combined data set.

Results
A total of 2,137 women who did not have a recurrence 5 years after diagnosis were included in the combined analyses. The Clinical Treatment Score (CTS) was the strongest prognostic factor 5 years after diagnosis (univariable: likelihood ratio [LR] 2  94.12, bivariable: LR 2  61.43). The ROR score was significantly prognostic by itself in years 5 to 10. In the node-negative/human epidermal growth factor receptor 2–negative subgroup, more prognostic value for late distant recurrence was added by the ROR score compared with the CTS.

Conclusion
The ROR score added clinically meaningful prognostic information to the CTS in all patients and all subgroups in the late follow-up period. These results suggest that the ROR score may be helpful for separating patients into risk groups who could be spared or potentially benefit from extended hormonal therapy beyond 5 years of treatment.

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