Top

Published in:

01-07-2011 | Clinical Trial

Topoisomerase II alpha protein and responsiveness of breast cancer to adjuvant chemotherapy with CEF compared to CMF in the NCIC CTG randomized MA.5 adjuvant trial

Authors: F. P. O’Malley, S. Chia, D. Tu, L. E. Shepherd, M. N. Levine, D. Huntsman, V. H. Bramwell, I. L. Andrulis, K. I. Pritchard

Published in: Breast Cancer Research and Treatment | Issue 2/2011

Abstract

Overexpression of topoisomerase II protein (topo 2α) is postulated to be more closely associated with responsiveness to anthracycline-containing chemotherapy than human epidermal growth factor receptor type 2 (HER2) gene amplification or alterations in the topoisomerase II alpha gene (TOP2A). The authors used tissue microarrays from 477 of 710 premenopausal women with node-positive breast cancer randomized to CEF or CMF adjuvant chemotherapy in the NCIC Clinical Trials Group Mammary 5 (MA.5) trial. No significant interaction was found between treatment and continuous topo 2α level in either relapse-free (RFS) or overall survival (OS). In 136 patients (28.5%) whose tumors showed topo 2α overexpression by immunohistochemistry based on a cut-off of 13%, CEF was superior to CMF for RFS (adjusted HR 0.45; 95% CI 0.25–0.82; P = 0.009) and OS (adjusted HR 0.50; 95% CI 0.26–0.96; P = 0.04). When tumors lacked topo 2α overexpression, CEF was not superior for RFS (adjusted HR 0.88; 95% CI 0.64–1.22; P = 0.46) or OS (adjusted HR 0.95; 95% CI 0.66–1.38; P = 0.80). Interaction between topo 2α and treatment was borderline significant for RFS (P = 0.04) and OS (P = 0.05) and not substantially more significant than between TOP2A gene alteration (P _interaction = 0.09 for RFS and 0.02 for OS) or HER2 overexpression (P _interaction = 0.002 for RFS and 0.009 for OS). Topo 2α protein overexpression based on the cut-off identified in this study, TOP2A gene alterations and HER2 protein overexpression were each associated with responsiveness to anthracycline-containing chemotherapy. The topo 2α protein analysis was exploratory and will require further validation.

Pritchard KI, Shepherd LE, O’Malley FP et al (2006) HER2 and responsiveness of breast cancer to adjuvant chemotherapy. New Eng J Med 354:2103–2111PubMedCrossRef

Gennari A, Sormani M, Puntoni M, Bruzzi P (2006) A pooled analysis on the interaction between Her-2 expression and responsiveness of breast cancer to adjvuant chemotherapy [abstract]. Breast Can Res Treat 100:S19

Dhesy-Thind B, Pritchard KI, Messersmith H, O’Malley F, Elavathil L, Trudeau M (2007) Her-2/neu in systemic therapy for women with breast cancer: a systemic review. Br Can Res Treat 109:209–229 OnlineCrossRef

De Laurentiis M, Arpino G, Massarelli E et al (2005) A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clin Cancer Res 11:4741–4748PubMedCrossRef

O’Malley F, Chia S, Tu D et al (2009) Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Nat Cancer Inst 101:644–650PubMedCrossRef

Knoop AS, Knudsen H, Balslev E et al (2005) Retrospective analysis of Topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish breast cancer cooperative group. J Clin Oncol 23:7483–7490PubMedCrossRef

Tanner M, Isola J, Wiklund T et al (2006) Topoisomerase II alpha gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian breast cancer trial 9401. J Clin Oncol 24:2428–2436PubMedCrossRef

Mueller RE, Parkes RK, Andrulis I, O’Malley FP (2004) Amplification of the TOP2A gene does not predict high levels of Topoisomerase II alpha protein in human breast tumor samples. Genes Chromosom Cancer 39:288–297PubMedCrossRef

Mo YY, Beck WT (1997) Heterogeneous expression of DNA topoisomerase II alpha isoforms in tumor cell lines. Oncol Res 9:193–204PubMed

10.

Tandon AK, Clark GM, Chamness GC et al (1989) Her-2/neu oncogene protein and prognosis in breast cancer. J Clin Oncol 7:1120–1128PubMed

11.

Di Leo A, Larsimont D, Gabcberg D et al (2001) HER-2 and topoisomerase II alpha as predictive markers in a population of node-positive breast cancer patients randomly treated with adjuvant CMF or epirubicin plus cyclophosphamide. Annals of Oncol 12:1081–1089CrossRef

12.

Durbecq V, Paesmans M, Cardoso F et al (2004) Topoisomerase-II alpha expression as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel. Mol Cancer Ther 3:1207–1214PubMed

13.

Levine MN, Bramwell VH, Pritchard KI et al (1998) A randomized trial of cyclophosphamide, epirubicin, fluorouracil chemotherapy compared with cyclophosphamide, methrotrexate, fluorouracil in premenopausal women with node positive breast cancer. J Clin Oncol 16:2651–2658PubMed

14.

Levine MN, Pritchard KI, Bramwell VH, Shepherd L, Tu D, Paul N (2005) A randomized trial comparing CEF to CMF in premenopausal women with node positive breast cancer: update of NCIC CTG MA.5. J Clin Oncol 23:5166–5170PubMedCrossRef

15.

Lazar AA, Cole BF, Bonetti M, Gelber RD (2010) Evaluation of treatment-effect heterogeneity using biomarkers measured on a continuous scale: subpopulation treatment effect pattern plot. J Clin Oncol 28:4539–4544PubMedCrossRef

16.

Brase JC, Schmidt M, Fischbach T et al (2010) Erb B2 and TOP2A in breast cancer: a comprehensive analysis of gene amplification, RNA levels and protein expression and their influence on prognosis and prediction. Clin Cancer Res 16:2391–2401PubMedCrossRef

17.

Campiglio M, Somenzi G, Olgiati C et al (2003) Role of proliferation in HER2 status predicted response to doxorubicin. Int J Cancer 105:568–573PubMedCrossRef

18.

Slamon D, Eiermann W, Robert N et al (2007) BCIRG 006: 2nd Interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC/ET) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC/ETH) with docetaxel carboplatin and trastuzumab (TCH) in Her-2/neu positive early breast cancer patients [abstract]. Breast Cancer Res Treat 106:S147

19.

Schindlbeck C, Mayr D, Olivier C et al (2010) Topoisomerase II alpha expression rather than gene amplification predicts responsiveness of adjuvant anthracycline-based chemotherapy in women with primary breast cancer. J Cancer Res Clin Oncol. doi:10.1007/s00432-990-0748-4 PubMed

20.

Schindlebeck C, Janni W, Shabani N et al (2005) Isolated tumor cells in the bone marrow (ITC-BM) of breast cancer patients before and after anthracline based therapy: influenced by the HER2 and topoisomerase II alpha status of the primary tumor? J Cancer Res Clin Oncol 131:539–546CrossRef

21.

Fritz P, Cabrera CM, Dippon J et al (2005) c-erbB2 and topoisomerase II alpha protein expression independently predict poor survival in primary human breast cancer: a retrospective study. Br Cancer Res 7:R374–R384. doi:10.1185/.bcr1012 CrossRef

22.

Minisini AM, Di Lorefto C, Mansutti M et al (2005) Topoisomerase II alpha and APE/ref-1 are associated with pathologic response to primary anthracycline-based chemotherapy for breast cancer. Cancer Lett 224:133–139PubMedCrossRef

23.

Arpino G, Ciocca DR, Weiss H et al (2005) Predictive value of apoptosis, proliferation, HER-2, and topoisomerase II alpha for anthracycline chemotherapy in locally advanced breast cancer. Br Cancer Res Treat 92:69–75CrossRef

24.

Zhu L, Ya-fen L, Chen WG et al (2008) HER2 and topoisomerase II alpha: possible predictors of response to neoadjuvant chemotherapy for breast cancer patients. Chinese Med J 121:1965–1968

25.

Martin-Richard M, Munoz M, Albanell J, Colomo L et al (2004) Serial topoisomerase II expression in primary breast cancer and response to neoadjuvant anthracycline-based chemotherapy. Oncology 66:388–394PubMedCrossRef

26.

MacGrogan G, Rudolph P, de Mascarel I et al (2003) DNA topoisomerase II alpha expression and the response to primary chemotherapy in breast cancer. Br J Cancer 89:666–671PubMedCrossRef

27.

Dubecq V, Desmedt C, Paesmans M, Cardoso F et al (2004) Correlation between topoisomerase II alpha gene amplification and protein expression in HER2 amplified breast cancer. Int J Oncol 25:1473–1479

28.

Cardoso F, Durbecq V, Larsimont D, Paesmans M et al (2004) Correlation between complete response to anthracycline-based chemotherapy and topoisomerase II alpha gene amplification and protein overexpression in locally advanced/metastatic breast cancer. Int J Oncol 24:201–209PubMed

29.

Press MF, Sauter G, Buyse M et al (2010) Alteration of topoisomerase II-Alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy. JCO. doi:10.1200/JCO.2009.27.5644 published online

30.

Bartlett JMS, Munro A, Cameron DA, Thomas J, Prescott R, Twelves C (2008) Type I receptor tyrosine kinase profiles identify patients with enhanced benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial. J Clin Oncol 26:5027–5035PubMedCrossRef

31.

Di Leo A, Gancberg D, Larsimont D, Tanner M, Jarvinen TA, Rouas G (2002) HER-2 amplification and topoisomerase II alpha gene aberrations as predictive markers in node positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil. Clin Cancer Res 8:1107–1116PubMed

32.

Poole CJ, Earl H, Hiller L et al (2006) Epirubicin and cyclophosphamide, methotrexate, and fluourouracil as adjuvant therapy for early breast cancer. New Engl J Med 355:1851–1862PubMedCrossRef

33.

Di Leo A, Desmedt C, Bartlett JMS et al (2010) Final results of a meta-analysis testing HER2 and topoisomerase II genes as predictors of incremental benefit from anthracyclines in breast cancer. J Clin Oncol 28:72S Abstract 519

Title: Topoisomerase II alpha protein and responsiveness of breast cancer to adjuvant chemotherapy with CEF compared to CMF in the NCIC CTG randomized MA.5 adjuvant trial
Authors: F. P. O’Malley
S. Chia
D. Tu
L. E. Shepherd
M. N. Levine
D. Huntsman
V. H. Bramwell
I. L. Andrulis
K. I. Pritchard
Publication date: 01-07-2011
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2011
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-011-1511-5

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2011

Functional polymorphisms in CD166/ALCAM gene associated with increased risk for breast cancer in a Chinese population

Breast cancer scalp metastasis as first metastatic site after scalp cooling: Two cases of occurrence after 7- and 9-year follow-up

Tumor necrosis factor-α 308 G/A polymorphism in breast cancer risk

G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer

Endothelial nitric oxide synthase (eNOS) G894T polymorphism is not associated with breast cancer risk: new evidence

Oral fluoropyrimidine may augment the efficacy of aromatase inhibitor via the down-regulation of estrogen receptor in estrogen-responsive breast cancer xenografts

Keynote webinar | Spotlight on antibody–drug conjugates in cancer