Publikationen 2012

CYP2D6 Metabolism and Patient Outcome in the Austrian Breast and Colorectal Cancer Study Group Trial (ABCSG) 8

Matthew P. Goetz, Vera J. Suman, Tanya L. Hoskin, Michael Gnant, Martin Filipits, Stephanie L. Safgren, Mary Kuffel, Raimund Jakesz, Margaretha Rudas, Richard Greil, Otto Dietze, Alois Lang, Felix Offner, Carol A. Reynolds, Richard M. Weinshilboum, Matthew M. Ames and James N. Ingle

Clin Cancer Res 2013;19:500-507. Published OnlineFirst December 4, 2012.

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Abstract

Purpose:
Controversy exists about CYP2D6 genotype and tamoxifen efficacy.

Experimental Design:
A matched case–control study was conducted using the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG8) that randomized postmenopausal women with estrogen receptor (ER)-positive breast cancer to tamoxifen for 5 years (arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (arm B). Cases had disease recurrence, contralateral breast cancer, second non–breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/ radiation, and tumor–node—metastasis (TNM) stage. Genotyping was conducted for alleles associated with no (PM; 3, 4, 6), reduced (IM; 10, and 41), and extensive (EM: absence of these alleles) CYP2D6 metabolism.

Results:
The common CYP2D64 allele was in Hardy–Weinberg equilibrium. In arm A during the first 5 years of therapy, women with two poor alleles [PM/PM: OR, 2.45; 95% confidence interval (CI), 1.05–5.73, P¼0.04] and women with one poor allele (PM/IM or PM/EM: OR, 1.67;95% CI, 0.95–2.93; P¼0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3 to 5 when patients remained on tamoxifen (arm A) or switched to anastrozole (arm B), PM/PM tended toward a higher likelihood of a disease event relative to EM/EM (OR, 2.40; 95% CI, 0.86–6.66; P ¼ 0.09) among women on arm A but not among women on arm B (OR, 0.28; 95% CI, 0.03–2.30).

Conclusion:
In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration and not after switching to anastrozole.

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Ovarian function suppression and fulvestrant as endocrine therapy in premenopausal women with metastatic breast cancer

Bartsch R, Bago-Horvath Z, Berghoff A, DeVries C, Pluschnig U, Dubsky P, Rudas M, Mader RM, Rottenfusser A, Fitzal F, Gnant M, Zielinski C, Steger G

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Abstract 

Background
Endocrine therapy is the preferred treatment for hormone-receptor (HR) positive metastatic breast cancer. In premenopausal patients, ovarian function suppression with goserelin in combination with anastrozole yielded promising results in phase II studies. Fulvestrant, a pure antioestrogen, yields high rates of disease stabilisation in postmenopausal women. Therefore, we investigated the feasibility and safety of fulvestrant plus goserelin in premenopausal women with HR-positive metastatic breast cancer.

Methods
Premenopausal patients with metastatic breast cancer eligible for endocrine treatment received fulvestrant 250 mg and goserelin 3.6 mg every four weeks as first- to fourth-line therapy. Clinical benefit rate (CBR; response rate plus disease stabilisation 6 months) was defined as the primary study end-point. Time to progression (TTP) and overall survival (OS) were estimated using the Kaplan–Meier product limit method.

Findings
Twenty-six patients received treatment as scheduled. 81% were pre-treated with tamoxifen and 69% had received prior aromatase inhibitors in combination with goserelin. The majority of patients (69%) presented with visceral metastases.

Complete response was observed in a single patient, partial response in three and disease stabilisation 6 months in eleven patients, resulting in a CBR of 58%. Median TTP was 6 months (95% confidence interval (CI), 2.4–9.6) and OS 32 months (95% CI, 14.28–49.72), respectively.

Interpretation
Results suggest that the combination of fulvestrant and goserelin offers promising activity in premenopausal patients and further investigation is warranted.

Eur J Cancer. 2012 Mar 27.


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

Peter C. Dubsky, Raimund Jakesz, Brigitte Mlineritsch, Sabine Pöstlberger, Hellmut Samonigg, Werner Kwasny, Christoph Tausch, Herbert Stöger, Karin Haider, Florian Fitzal, Christian F. Singer, Michael Stierer, Paul Sevelda, Gero Luschin-Ebengreuth, Susanne Taucher, Margaretha Rudas, Rupert Bartsch, Günther G. Steger, Richard Greil, Lidija Filipcic, and Michael Gnant

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Abstract

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 lowto 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.

J Clin Oncol 30. © 2012
DOI: 10.1200/JCO.2011.36.8993

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EndoPredict improves the prognostic classification derived from common clinical guidelines in ER-positive, HER2-negative early breast cancer

P. Dubsky, M. Filipits, R. Jakesz, M. Rudas, C. F. Singer, R. Greil, O. Dietze, I. Luisser, E. Klug, R. Sedivy, M. Bachner, D. Mayr, M. Schmidt, M. C. Gehrmann, C. Petry, K. E. Weber, R. Kronenwett, J. C. Brase & M. Gnant on behalf of the Austrian Breast and Colorectal Cancer Study Group (ABCSG

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Abstract

Background:
In early estrogen receptor (ER)-positive/HER2-negative breast cancer, the decision to administer chemotherapy is largely based on prognostic criteria. The combined molecular/clinical EndoPredict test (EPclin) has been validated to accurately assess prognosis in this population. In this study, the clinical relevance of EPclin in relation to well-established clinical guidelines is assessed.

Patients and methods:
We assigned risk groups to 1702 ER-positive/HER2-negative postmenopausal women from two large phase III trials treated only with endocrine therapy. Prognosis was assigned according to National Comprehensive Cancer Center Network-, German S3-, St Gallen guidelines and the EPclin. Prognostic groups were compared using the Kaplan–Meier survival analysis.

Results:
After 10 years, absolute risk reductions (ARR) between the high- and low-risk groups ranged from 6.9% to 11.2% if assigned according to guidelines. It was at 18.7% for EPclin. EPclin reassigned 58%–61% of women classified as high-/intermediate-risk (according to clinical guidelines) to low risk. Women reclassified to low risk showed a 5% rate of distant metastasis at 10 years.

Conclusion:
The EPclin score is able to predict favorable prognosis in a majority of patients that clinical guidelines would assign to intermediate or high risk. EPclin may reduce the indications for chemotherapy in ER-positive postmenopausal women with a limited number of clinical risk factors.

Key words:
adjuvant treatment, breast cancer, endocrine therapy, EndoPredict gene, expression

Annals of Oncology 0: 1–8, 2012
doi:10.1093/annonc/mds334

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Dual inhibition of HER2 in breast cancer treatment

Michael Gnant, Guenther G Steger

www.thelancet.com. Published online January 17, 2012 DOI:10.1016/S0140-6736(12)60068-3

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Prognostic Value of Number of Removed Lymph Nodes, Number of Involved Lymph Nodes, and Lymph Node Ratio in 7502 Breast Cancer Patients Enrolled onto Trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG)

Christoph Tausch, MD, Susanne Taucher, MD, Peter Dubsky, MD, Michael Seifert, MD, Roland Reitsamer, MD, Werner Kwasny, MD, Raimund Jakesz, MD, Florian Fitzal, MD, Lidija Filipcic, MSc, Michael Fridrik, MD, Richard Greil, MD, and Michael Gnant, MD, FACS.

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Abstract

Purpose. The number of removed axillary lymph nodes and the ratio of involved to removed lymph nodes are described as independent prognostic factors beside the absolute number of involved lymph nodes in breast cancer patients. The correlation between these factors and prognosis were investigated in trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG).

Methods. This retrospective analysis is based on the data of 7052 patients with endocrine-responsive breast cancer who were randomized in four trials of the ABCSG in the years 1990–2006 and underwent axillary lymph node dissection. The prognostic value of number of removed nodes (NRN), number of involved nodes (NIN), and ratio of involved to removed nodes (lymph node ratio, LNR) concerning recurrence- free survival and overall survival was analyzed.

Results. A total of 2718 patients had node-positive disease. No correlation was found between NRN and prognosis. Increasing NIN and LNR were significantly associated with worse recurrence-free survival and overall survival in univariate and multivariate analyses (P.001). Only in the subgroup of patients with one to three positive lymph nodes and treated with mastectomy (n = 728) was LNR an additional prognostic factor in univariate and multivariate analyses.

Conclusions. For breast cancer patients stringently medicated in the framework of prospective adjuvant clinical trials and requiring a mandatory minimum of removed nodes, NRN does not influence prognosis, and LNR is not superior to NIN as prognostic factor. In patients with one to three positive lymph nodes and mastectomy, LNR could play a role as an additional prognostic factor.

Ann Surg Oncol (2012) 19:1808–1817

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Neoadjuvant Chemotherapy Increases the Rate of Breast Conservation in Lobular-Type Breast Cancer Patients

Florian Fitzal, MD, Martina Mittlboeck, PhD, Guenther Steger, MD, Rupert Bartsch, MD, Margaretha Rudas,MD, Peter Dubsky, MD, Otto Riedl, MD, Raimund Jakesz, MD, and Michael Gnant, MD

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Abstract

Introduction. Our study aims to determine whether patients with lobular-type breast cancer have significantly improved rates of breast conservation (BCT) after neoadjuvant chemotherapy (nCT).

Methods. Patients who received nCT and surgery within three prospective trials between 1995 and 2007 at the Medical University of Vienna were retrospectively analyzed.

Results. 325 patients had median follow-up of 53 months; 21% had lobular cancer, and 70% of these women were initially scheduled for mastectomy (MX). Twenty-one finally received BCT, yielding a MX–BCT turnover rate of 45%. Of patients primarily scheduled for BCT, 20% had to finally undergo MX in lobular cancer. The 256 patients with ductal-type breast cancer finally had a MX–BCT turnover rate of 52% (p = 0.561 versus lobular) and a BCT–MX turnover rate of 15% (p = 0.933 versus lobular). Secondary MX after initial BCT was necessary in 2% (ductal) and 10% (lobular, p = 0.110). There was no difference in local recurrence in lobular- as compared with ductal-type breast cancer patients after BCT (2.7% versus 10%, p = 0.135), nor was a difference seen in lobular breast cancer patients when comparing BCT with MX (2.7% versus 3.4%, p = 0.795). Tumor type was not an independent predictor for either BCT or local recurrence.

Conclusion. We do not suggest excluding patients with lobular-type breast cancer who are primarily scheduled for MX from nCT, since BCT rates may still increase by 45% without influencing the oncologic outcome.

Ann Surg Oncol (2012) 19:519–526

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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

Peter C. Dubsky, Raimund Jakesz, Brigitte Mlineritsch, Sabine Pöstlberger, Hellmut Samonigg, Werner Kwasny, Christoph Tausch, Herbert Stöger, Karin Haider, Florian Fitzal, Christian F. Singer, Michael Stierer, Paul Sevelda, Gero Luschin-Ebengreuth, Susanne Taucher, Margaretha Rudas, Rupert Bartsch, Günther G. Steger, Richard Greil, Lidija Filipcic, and Michael Gnant.

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Abstract

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 lowto 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.

Published online before print January 23, 2012, doi: 10.1200/JCO.2011.36.8993
JCO March 1, 2012 vol. 30 no. 7 722-728

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