Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cellular Oncology
Published in: Cellular Oncology 2/2014

01-04-2014 | Original Paper

Prognostic and predictive value of copy number alterations in invasive breast cancer as determined by multiplex ligation-dependent probe amplification

Authors: Sanaz Tabarestani, Sayyed Mohammad Hossein Ghaderian, Hamid Rezvani, Reza Mirfakhraie, Abdolali Ebrahimi, Hamid Attarian, Jahangir Rafat, Mojtaba Ghadyani, Hossein Afshin Alavi, Naser Kamalian, Afshin Rakhsha, Eznollah Azargashb

Published in: Cellular Oncology | Issue 2/2014

Login to get access

Abstract

Background

Breast cancer is a leading cause of morbidity and mortality in women worldwide. About 70 % of breast cancers are estrogen receptor (ER) positive. Blocking estrogen action by tamoxifen has been the treatment of choice in ER positive breast cancers for more than 30 years. In the past, several studies have revealed associations between gene copy number alterations and responsiveness to tamoxifen therapy, but so far no single gene copy number alteration could completely explain the response variation observed between individual breast cancer patients. Here, we set out to perform a simultaneous analysis of copy number alterations of several genes involved in the prognosis and response to therapy by multiplex ligation-dependent probe amplification (MLPA).

Methods

A case–control study was designed encompassing 170 non-metastatic ER positive breast cancer patients (case group = 85, control group = 85). All patients in the control group had received standard adjuvant tamoxifen treatment for 5 years without any evidence of recurrence. Patients in the case group had experienced early recurrences while receiving tamoxifen treatment. 76 % of the patients of the case group and 73 % of the patients of the control group had received anthracycline-based adjuvant chemotherapy. Gene copy number alterations detected by MLPA in both groups were compared.

Results

Amplification of CCND1 (OR = 3.13; 95 % CI = 1.35 to 7.26; p = 0.006) and TOP2A (OR = 3.05; 95 % CI = 1.13 to 8.24; p = 0.022) were significantly more prevalent in the case group, compared to the control group. In a multivariate analysis CCND1 (p = 0.01) and TOP2A (p = 0.041) amplifications remained significant predictors of recurrence.

Conclusions

Our results indicate that CCND1 amplification may serve as a useful biomarker for hormone responsiveness, and that TOP2A amplification may serve as a useful prognostic biomarker.
Appendix
Available only for authorised users
Literature
1.
M.H. Forouzanfar, K.J. Foreman, A.M. Delossantos, R. Lozano, A.D. Lopez, C.J. Murray et al., Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. Lancet 378, 1461–1484 (2011)PubMedCrossRef
2.
J.M. Harvey, G.M. Clark, C.K. Osborne, D.C. Allred, Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J. Clin. Oncol. 17, 1474–1481 (1999)PubMed
3.
E.V. Jensen, V.C. Jordan, The estrogen receptor: a model for molecular medicine. Clin. Cancer Res. 9, 1980–1989 (2003)PubMed
4.
Early Breast Cancer Trialists’ Collaborative Group, C. Davies, J. Godwin, R. Gray, M. Clarke, D. Cutter et al., Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 378, 771–784 (2011)PubMedCrossRef
5.
Early Breast Cancer Trialists’ Collaborative Group, Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365, 1687–1717 (2005)CrossRef
6.
A. Ring, M. Dowsett, Mechanisms of tamoxifen resistance. Endocr. Relat. Cancer 11, 643–658 (2004)PubMedCrossRef
7.
M.D. Pegram, G. Pauletti, D.J. Slamon, HER-2/neu as a predictive marker of response to breast cancer therapy. Breast Cancer Res. Treat. 52, 65–77 (1998)PubMedCrossRef
8.
J.S. Ross, J.A. Fletcher, The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Oncologist 3, 237–252 (1998)PubMed
9.
F. Holst, C.B. Moelans, M. Filipits, C.F. Singer, R. Simon, P.J. van Diest, On the evidence for ESR1 amplification in breast cancer. Nat. Rev. Cancer 12, 149 (2012)PubMedCrossRef
10.
K. Park, S. Han, E. Shin, H.J. Kim, J.Y. Kim, EGFR gene and protein expression in breast cancers. Eur. J. Surg. Oncol. 33, 956–960 (2007)PubMedCrossRef
11.
S.L. Deming, S.J. Nass, R.B. Dickson, B.J. Trock, C-myc amplification in breast cancer: a meta-analysis of its occurrence and prognostic relevance. Br. J. Cancer 83, 1688–1695 (2000)PubMedCentralPubMedCrossRef
12.
K. Al-Kuraya, P. Schraml, J. Torhorst, C. Tapia, B. Zaharieva, H. Novotny et al., Prognostic relevance of gene amplifications and coamplifications in breast cancer. Cancer Res. 64, 8534–8540 (2004)PubMedCrossRef
13.
K. Holm, J. Staaf, G. Jonsson, J. Vallon-Christersson, H. Gunnarsson, A. Arason et al., Characterisation of amplification patterns and target genes at chromosome 11q13 in CCND1-amplified sporadic and familial breast tumours. Breast Cancer Res. Treat. 133, 583–594 (2012)PubMedCrossRef
14.
K.V. Nielsen, B. Ejlertsen, S. Moller, J.T. Jorgensen, A. Knoop, H. Knudsen et al., The value of TOP2A gene copy number variation as a biomarker in breast cancer: update of DBCG trial 89D. Acta Oncol. 47, 725–734 (2008)PubMedCrossRef
15.
N. Turner, A. Pearson, R. Sharpe, M. Lambros, F. Geyer, M.A. Lopez-Garcia et al., FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 70, 2085–2094 (2010)PubMedCentralPubMedCrossRef
16.
I.J. Chalmers, M. Aubele, E. Hartmann, E. Braungart, M. Werner, H. Hofler et al., Mapping the chromosome 16 cadherin gene cluster to a minimal deleted region in ductal breast cancer. Cancer Genet. Cytogenet. 126, 39–44 (2001)PubMedCrossRef
17.
K. Lundgren, K. Holm, B. Nordenskjold, A. Borg, G. Landberg, Gene products of chromosome 11q and their association with CCND1 gene amplification and tamoxifen resistance in premenopausal breast cancer. Breast Cancer Res. 10, R81 (2008)PubMedCentralPubMedCrossRef
18.
K. Jirstrom, M. Stendahl, L. Ryden, A. Kronblad, P.O. Bendahl, O. Stal et al., Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification. Cancer Res. 65, 8009–8016 (2005)PubMed
19.
K. Lundgren, M. Brown, S. Pineda, J. Cuzick, J. Salter, L. Zabaglo et al., Effects of cyclin D1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study. Breast Cancer Res. 14, R57 (2012)PubMedCentralPubMedCrossRef
20.
E.M. Berns, J.A. Foekens, I.L. van Staveren, W.L. van Putten, H.Y. de Koning, H. Portengen et al., Oncogene amplification and prognosis in breast cancer: relationship with systemic treatment. Gene 159, 11–18 (1995)PubMedCrossRef
21.
J.P. Schouten, C.J. McElgunn, R. Waaijer, D. Zwijnenburg, F. Diepvens, G. Pals, Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 30, e57 (2002)PubMedCentralPubMedCrossRef
22.
C.B. Moelans, R.A. de Weger, M.T. van Blokland, C. Ezendam, S. Elshof, M.G. Tilanus et al., HER-2/neu amplification testing in breast cancer by multiplex ligation-dependent probe amplification in comparison with immunohistochemistry and in situ hybridization. Cell. Oncol. 31, 1–10 (2009)PubMed
23.
C.B. Moelans, R.A. de Weger, H.N. Monsuur, R. Vijzelaar, P.J. van Diest, Molecular profiling of invasive breast cancer by multiplex ligation-dependent probe amplification-based copy number analysis of tumor suppressor and oncogenes. Mod. Pathol. 23, 1029–1039 (2010)PubMedCrossRef
24.
G. Farshid, G. Cheetham, R. Davies, S. Moore, Z. Rudzki, Validation of the multiplex ligation-dependent probe amplification (MLPA) technique for the determination of HER2 gene amplification in breast cancer. Diagn. Mol. Pathol. 20, 11–17 (2011)PubMedCrossRef
25.
D.J. Bunyan, D.M. Eccles, J. Sillibourne, E. Wilkins, N.S. Thomas, J. Shea-Simonds et al., Dosage analysis of cancer predisposition genes by multiplex ligation-dependent probe amplification. Br. J. Cancer 91, 1155–1159 (2004)PubMedCentralPubMedCrossRef
26.
O. Krijgsman, D. Israeli, H.F. van Essen, P.P. Eijk, M.L. Berens, C.H. Mellink et al., Detection limits of DNA copy number alterations in heterogeneous cell populations. Cell. Oncol. 36, 27–36 (2013)CrossRef
27.
E. Wiechec, J. Overgaard, E. Kjeldsen, L.L. Hansen, Chromosome 1q25.3 copy number alterations in primary breast cancers detected by multiplex ligation-dependent probe amplification and allelic imbalance assays and its comparison with fluorescent in situ hybridization assays. Cell. Oncol. 36, 113–120 (2013)CrossRef
28.
S. Elsheikh, A.R. Green, M.A. Aleskandarany, M. Grainge, C.E. Paish, M.B. Lambros et al., CCND1 amplification and cyclin D1 expression in breast cancer and their relation with proteomic subgroups and patient outcome. Breast Cancer Res. Treat. 109, 325–335 (2008)PubMedCrossRef
29.
R. Hui, J.R. Ball, R.D. Macmillan, F.S. Kenny, O.W. Prall, D.H. Campbell et al., EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival. Oncogene 17, 1053–1059 (1998)PubMedCrossRef
30.
J. Bostner, M. Ahnstrom Waltersson, T. Fornander, L. Skoog, B. Nordenskjold, O. Stal, Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer. Oncogene 26, 6997–7005 (2007)PubMedCrossRef
31.
M.J. Duffy, M. Mullooly, N. O’Donovan, S. Sukor, J. Crown, A. Pierce et al., The ADAMs family of proteases: new biomarkers and therapeutic targets for cancer? Clin. Proteomics 8, 9 (2011)PubMedCentralPubMedCrossRef
32.
K. Chin, S. DeVries, J. Fridlyand, P.T. Spellman, R. Roydasgupta, W.L. Kuo et al., Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer cell 10, 529–541 (2006)PubMedCrossRef
33.
N. Nishikawa, M. Toyota, H. Suzuki, T. Honma, T. Fujikane, T. Ohmura et al., Gene amplification and overexpression of PRDM14 in breast cancers. Cancer Res. 67, 9649–9657 (2007)PubMedCrossRef
34.
G. Hu, R.A. Chong, Q. Yang, Y. Wei, M.A. Blanco, F. Li et al., MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer cell 15, 9–20 (2009)PubMedCentralPubMedCrossRef
35.
I. Bieche, M. Olivi, C. Nogues, M. Vidaud, R. Lidereau, Prognostic value of CCND1 gene status in sporadic breast tumours, as determined by real-time quantitative PCR assays. Br. J. Cancer 86, 580–586 (2002)PubMedCentralPubMedCrossRef
36.
C.M. Schlotter, U. Vogt, U. Bosse, B. Mersch, K. Wassmann, C-myc, not HER-2/neu, can predict recurrence and mortality of patients with node-negative breast cancer. Breast Cancer Res. 5, R30–R36 (2003)PubMedCentralPubMedCrossRef
37.
J.M. Bartlett, A.F. Munro, J.A. Dunn, C. McConkey, S. Jordan, C.J. Twelves et al., Predictive markers of anthracycline benefit: a prospectively planned analysis of the UK National Epirubicin Adjuvant Trial (NEAT/BR9601). Lancet Oncol. 11, 266–274 (2010)PubMedCrossRef
38.
M. Cuny, A. Kramar, F. Courjal, V. Johannsdottir, B. Iacopetta, H. Fontaine et al., Relating genotype and phenotype in breast cancer: an analysis of the prognostic significance of amplification at eight different genes or loci and of p53 mutations. Cancer Res. 60, 1077–1083 (2000)PubMed
39.
X. Cui, R. Schiff, G. Arpino, C.K. Osborne, A.V. Lee, Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy. J. Clin. Oncol. 23, 7721–7735 (2005)PubMedCrossRef
40.
X. Cui, P. Zhang, W. Deng, S. Oesterreich, Y. Lu, G.B. Mills, A.V. Lee, Insulin-like growth factor-I inhibits progesterone receptor expression in breast cancer cells via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway: progesterone receptor as a potential indicator of growth factor activity in breast cancer. Mol. Endocrinol. 17, 575–588 (2003)PubMedCrossRef
41.
V.J. Bardou, G. Arpino, R.M. Elledge, C.K. Osborne, G.M. Clark, Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J. Clin. Oncol. 21, 1973–1979 (2003)PubMedCrossRef
42.
R.M. Elledge, S. Green, R. Pugh, D.C. Allred, G.M. Clark, J. Hill et al., Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: a Southwest Oncology Group Study. Int. J. Cancer 89, 111–117 (2000)PubMedCrossRef
43.
E.A. Musgrove, C.E. Caldon, J. Barraclough, A. Stone, R.L. Sutherland, Cyclin D as a therapeutic target in cancer. Nat. Rev. Cancer 11, 558–572 (2011)PubMedCrossRef
44.
A.J. Butt, C.M. McNeil, E.A. Musgrove, R.L. Sutherland, Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E. Endocr. Relat. Cancer 12(Suppl 1), S47–S59 (2005)PubMedCrossRef
45.
A. Arnold, A. Papanikolaou, Cyclin D1 in breast cancer pathogenesis. J. Clin. Oncol. 23, 4215–4224 (2005)PubMedCrossRef
46.
R.M. Zwijsen, R.S. Buckle, E.M. Hijmans, C.J. Loomans, R. Bernards, Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1. Genes Dev. 12, 3488–3498 (1998)PubMedCentralPubMedCrossRef
47.
R.M. Zwijsen, E. Wientjens, R. Klompmaker, J. van der Sman, R. Bernards, R.J. Michalides, CDK-independent activation of estrogen receptor by cyclin D1. Cell 88, 405–415 (1997)PubMedCrossRef
48.
P.G. Roy, N. Pratt, C.A. Purdie, L. Baker, A. Ashfield, P. Quinlan et al., High CCND1 amplification identifies a group of poor prognosis women with estrogen receptor positive breast cancer. Int. J. Cancer 127, 355–360 (2010)PubMed
49.
S.P. Linke, T.M. Bremer, C.D. Herold, G. Sauter, C. Diamond, A multimarker model to predict outcome in tamoxifen-treated breast cancer patients. Clin. Cancer Res. 12, 1175–1183 (2006)PubMedCrossRef
50.
E.A. Musgrove, R.L. Sutherland, Biological determinants of endocrine resistance in breast cancer. Nat. Rev. Cancer 9, 631–643 (2009)PubMedCrossRef
51.
O. Stal, A. Borg, M. Ferno, A.C. Kallstrom, P. Malmstrom, B. Nordenskjold et al., ErbB2 status and the benefit from two or five years of adjuvant tamoxifen in postmenopausal early stage breast cancer. Ann. Oncol. 11, 1545–1550 (2000)PubMedCrossRef
52.
M. Ferrero-Pous, K. Hacene, C. Bouchet, V. Le Doussal, M. Tubiana-Hulin, F. Spyratos, Relationship between c-erbB-2 and other tumor characteristics in breast cancer prognosis. Clin. Cancer Res. 6, 4745–4754 (2000)PubMed
53.
A.S. Knoop, S.M. Bentzen, M.M. Nielsen, B.B. Rasmussen, C. Rose, Value of epidermal growth factor receptor, HER2, p53, and steroid receptors in predicting the efficacy of tamoxifen in high-risk postmenopausal breast cancer patients. J. Clin. Oncol. 19, 3376–3384 (2001)PubMed
54.
D.A. Berry, H.B. Muss, A.D. Thor, L. Dressler, E.T. Liu, G. Broadwater et al., HER-2/neu and p53 expression versus tamoxifen resistance in estrogen receptor-positive, node-positive breast cancer. J. Clin. Oncol. 18, 3471–3479 (2000)PubMed
55.
B. Ejlertsen, J. Aldridge, K.V. Nielsen, M.M. Regan, K.L. Henriksen, A.E. Lykkesfeldt et al., Prognostic and predictive role of ESR1 status for postmenopausal patients with endocrine-responsive early breast cancer in the Danish cohort of the BIG 1-98 trial. Ann. Oncol. 23, 1138–1144 (2012)PubMedCentralPubMedCrossRef
56.
K.V. Nielsen, B. Ejlertsen, S. Muller, S. Moller, B.B. Rasmussen, E. Balslev et al., Amplification of ESR1 may predict resistance to adjuvant tamoxifen in postmenopausal patients with hormone receptor positive breast cancer. Breast Cancer Res. Treat. 127, 345–355 (2011)PubMedCrossRef
57.
F. Holst, P.R. Stahl, C. Ruiz, O. Hellwinkel, Z. Jehan, M. Wendland et al., Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer. Nat. Genet. 39, 655–660 (2007)PubMedCrossRef
58.
A. Ooi, M. Inokuchi, S. Harada, J. Inazawa, R. Tajiri, S.S. Kitamura et al., Gene amplification of ESR1 in breast cancers–fact or fiction? A fluorescence in situ hybridization and multiplex ligation-dependent probe amplification study. J. Pathol. 227, 8–16 (2012)PubMedCrossRef
59.
C.B. Moelans, H.N. Monsuur, J.H. de Pinth, R.D. Radersma, R.A. de Weger, P.J. van Diest, ESR1 amplification is rare in breast cancer and is associated with high grade and high proliferation: a multiplex ligation-dependent probe amplification study. Cell. Oncol. 34, 489–494 (2011)CrossRef
60.
C.B. Moelans, R.A. de Weger, M.T. van Blokland, E. van der Wall, P.J. van Diest, Simultaneous detection of TOP2A and HER2 gene amplification by multiplex ligation-dependent probe amplification in breast cancer. Mod. Pathol. 23, 62–70 (2010)PubMedCrossRef
61.
A.S. Knoop, H. Knudsen, E. Balslev, B.B. Rasmussen, J. Overgaard, K.V. Nielsen et al., 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, 7483–7490 (2005)PubMedCrossRef
62.
E. Arriola, S.M. Rodriguez-Pinilla, M.B. Lambros, R.L. Jones, M. James, K. Savage et al., Topoisomerase II alpha amplification may predict benefit from adjuvant anthracyclines in HER2 positive early breast cancer. Breast Cancer Res. Treat. 106, 181–189 (2007)PubMedCrossRef
63.
M.F. Press, G. Sauter, M. Buyse, L. Bernstein, W. Eiermann, T. Pienkowski et al., Alteration of topoisomerase II-alpha gene in human breast cancer and its association with responsiveness to anthracycline- based chemotherapy [Abstract]. In: Proceedings of 2007 Asco Annual Meeting; J. Clin. Oncol. 25, 524 (2007)
Metadata
Title
Prognostic and predictive value of copy number alterations in invasive breast cancer as determined by multiplex ligation-dependent probe amplification
Authors
Sanaz Tabarestani
Sayyed Mohammad Hossein Ghaderian
Hamid Rezvani
Reza Mirfakhraie
Abdolali Ebrahimi
Hamid Attarian
Jahangir Rafat
Mojtaba Ghadyani
Hossein Afshin Alavi
Naser Kamalian
Afshin Rakhsha
Eznollah Azargashb
Publication date
01-04-2014
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 2/2014
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-013-0165-1

Other articles of this Issue 2/2014

Cellular Oncology 2/2014 Go to the issue

Original Paper

Analysis of gene copy number alterations by multiplex ligation-dependent probe amplification in columnar cell lesions of the breast

Review

The chemosensitivity of testicular germ cell tumors

Original Paper

Transcription of the vascular endothelial growth factor receptor-3 (VEGFR3) gene is regulated by the zinc finger proteins Sp1 and Sp3 and is under epigenetic control

ReviewPaper

Genetic alterations in chondrosarcomas – keys to targeted therapies?

Original Paper

Combined arsenic trioxide-cisplatin treatment enhances apoptosis in oral squamous cell carcinoma cells
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
Image Credits