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The Genomic Heritage of Lymph Node Metastases: Implications for Clinical Management of Patients with Breast Cancer

  • Breast Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Metastatic breast cancer is an aggressive disease associated with recurrence and decreased survival. To improve outcomes and develop more effective treatment strategies for patients with breast cancer, it is important to understand the molecular mechanisms underlying metastasis.

Methods

We used allelic imbalance (AI) to determine the molecular heritage of primary breast tumors and corresponding metastases to the axillary lymph nodes. Paraffin-embedded samples from primary breast tumors and matched metastases (n = 146) were collected from 26 patients with node-positive breast cancer involving multiple axillary nodes. Hierarchical clustering was used to assess overall differences in the patterns of AI, and phylogenetic analysis inferred the molecular heritage of axillary lymph node metastases.

Results

Overall frequencies of AI were significantly higher (P < 0.01) in primary breast tumors (23%) than in lymph node metastases (15%), and there was a high degree of discordance in patterns of AI between primary breast carcinomas and the metastases. Metastatic tumors in the axillary nodes showed different patterns of chromosomal changes, suggesting that multiple molecular mechanisms may govern the process of metastasis in individual patients. Some metastases progressed with few genomic alterations, while others harbored many chromosomal alterations present in the primary tumor.

Conclusions

The extent of genomic heterogeneity in axillary lymph node metastases differs markedly among individual patients. Genomic diversity may be associated with response to adjuvant therapy, recurrence, and survival, and thus may be important in improving clinical management of breast cancer patients.

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References

  1. Eifel P, Axelson JA, Costa J, et al. National Institutes of Health consensus development conference statement: adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst 2001;93:979–89

    Article  PubMed  CAS  Google Scholar 

  2. Ries LAG, Melbert D, Krapcho M, et al. (eds). (2007) SEER Cancer Statistics Review, 1975–2004. National Cancer Institute, Bethesda, MD. Available: http://www.seer.cancer.gov/csr/1975_2004

  3. Weigelt B, Peterse JL, van’t Veer LJ. Breast cancer metastasis: markers and models. Nat Rev Cancer 2005;5:591–602

    Article  PubMed  CAS  Google Scholar 

  4. Fidler IJ, Kripke ML. Metastasis results from preexisting variant cells within a malignant tumor. Science 1977;197:893–5

    Article  PubMed  CAS  Google Scholar 

  5. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759–67

    Article  PubMed  CAS  Google Scholar 

  6. Bernards R, Weinberg RA. Metastasis genes: a progression puzzle. Nature 2002;418:823

    Article  PubMed  CAS  Google Scholar 

  7. Schmidt-Kittler O, Ragg T, Daskalakis A, et al. From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci U S A 2003;100:7737–42

    Article  PubMed  CAS  Google Scholar 

  8. Goldhirsch A, Glick JH, Gelber RD, et al. Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 2005;16:1569–83

    Article  PubMed  CAS  Google Scholar 

  9. Greene FL, Page DL, Fleming ID, et al. (eds). AJCC Cancer Staging Manual, Sixth Edition. Springer-Verlag, New York, 2002

  10. Ellsworth DL, Shriver CD, Ellsworth RE, et al. Laser capture microdissection of paraffin-embedded tissues. BioTechniques 2003;34:42–6

    PubMed  CAS  Google Scholar 

  11. Bertheau P, Plassa LF, Lerebours F, et al. Allelic loss detection in inflammatory breast cancer: improvement with laser microdissection. Lab Invest 2001;81:1397–402

    PubMed  CAS  Google Scholar 

  12. Ellsworth RE, Ellsworth DL, Lubert SM, et al. High-throughput loss of heterozygosity mapping in 26 commonly deleted regions in breast cancer. Cancer Epidemiol Biomark Prev 2003;12:915–9

    CAS  Google Scholar 

  13. Medintz IL, Lee C-CR, Wong WW, et al. Loss of heterozygosity assay for molecular detection of cancer using energy-transfer primers and capillary array electrophoresis. Genome Res 2000;10:1211–8

    Article  PubMed  CAS  Google Scholar 

  14. Ellsworth RE, Ellsworth DL, Neatrour DM, et al. Allelic imbalance in primary breast carcinomas and metastatic tumors of the axillary lymph nodes. Mol Cancer Res 2005;3:71–7

    Article  PubMed  CAS  Google Scholar 

  15. Sneath PHA, Sokal RR. Numerical taxonomy. W.H. Freeman, San Francisco, 1973

  16. Felsenstein J. PHYLIP: phylogeny inference package (version 3.63). Cladistics 1989; 5:164–6. Available: http://www.evolution.genetics.washington.edu/phylip.html

  17. Camin JH, Sokal RR. A method for deducing branching sequences in phylogeny. Evolution 1965;19:311–26

    Article  Google Scholar 

  18. Kluge AG, Farris JS. Quantitative phyletics and the evolution of Anurans. Syst Zool 1969;18:1–32

    Article  Google Scholar 

  19. Felsenstein J. Confidence limits on phylogenies: an approach using the bootstrap. Evolution 1985;39:783–91

    Article  Google Scholar 

  20. Gray JW. Evidence emerges for early metastasis and parallel evolution of primary and metastatic tumors. Cancer Cell 2003;4:4–6

    Article  PubMed  CAS  Google Scholar 

  21. Nishizaki T, DeVries S, Chew K, et al. Genetic alterations in primary breast cancers and their metastases: direct comparison using modified comparative genomic hybridization. Genes Chromosomes Cancer 1997;19:267–72

    Article  PubMed  CAS  Google Scholar 

  22. Hampl M, Hampl JA, Reiss G, et al. Loss of heterozygosity accumulation in primary breast carcinomas and additionally in corresponding distant metastases is associated with poor outcome. Clin Cancer Res 1999;5:1417–25

    PubMed  CAS  Google Scholar 

  23. Kuukasjärvi T, Karhu R, Tanner M, et al. Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer. Cancer Res 1997;57:1597–604

    PubMed  Google Scholar 

  24. van’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002;415:530–6

    Article  CAS  Google Scholar 

  25. Lähdesmäki H, Hao X, Sun B, et al. Distinguishing key biological pathways between primary breast cancers and their lymph node metastases by gene function-based clustering analysis. Int J Oncol 2004;24:1589–96

    PubMed  Google Scholar 

  26. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003;100:3983–8

    Article  PubMed  CAS  Google Scholar 

  27. Holmgren L, O’Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1995;1:149–53

    Article  PubMed  CAS  Google Scholar 

  28. Klein CA, Hölzel D. Systemic cancer progression and tumor dormancy: mathematical models meet single cell genomics. Cell Cycle 2006;5:1788–98

    PubMed  CAS  Google Scholar 

  29. Demicheli R, Miceli R, Moliterni A, et al. Breast cancer recurrence dynamics following adjuvant CMF is consistent with tumor dormancy and mastectomy-driven acceleration of the metastatic process. Ann Oncol 2005;16:1449–57

    Article  PubMed  CAS  Google Scholar 

  30. Luzzi KJ, MacDonald IC, Schmidt EE, et al. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 1998;153:865–73

    PubMed  CAS  Google Scholar 

  31. Guba M, Cernaianu G, Koehl G, et al. A primary tumor promotes dormancy of solitary tumor cells before inhibiting angiogenesis. Cancer Res 2001;61:5575–9

    PubMed  CAS  Google Scholar 

  32. Fisher B, Gunduz N, Coyle J, et al. Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Cancer Res 1989;49:1996–2001

    PubMed  CAS  Google Scholar 

  33. Benson JR, della Rovere GQ. Axilla Management Consensus Group. Management of the axilla in women with breast cancer. Lancet Oncol 2007;8:331–48

    Article  PubMed  Google Scholar 

  34. Giuliano AE, Dale PS, Turner RR, et al. Improved axillary staging of breast cancer with sentinel lymphadenectomy. Ann Surg 1995;222:394–401

    Article  PubMed  CAS  Google Scholar 

  35. Stockler M, Wilcken NRC, Ghersi D, et al. Systematic reviews of chemotherapy and endocrine therapy in metastatic breast cancer. Cancer Treat Rev 2000;26:151–68

    Article  PubMed  CAS  Google Scholar 

  36. Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 1997;337:956–62

    Article  PubMed  CAS  Google Scholar 

  37. Overgaard M, Jensen M-B, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999;353:1641–8

    Article  PubMed  CAS  Google Scholar 

  38. Cavalli LR, Urban CA, Dai D, et al. Genetic and epigenetic alterations in sentinel lymph nodes metastatic lesions compared to their corresponding primary breast tumors. Cancer Genet Cytogenet 2003;146:33–40

    Article  PubMed  CAS  Google Scholar 

  39. Goodison S, Viars C, Urquidi V. Molecular cytogenetic analysis of a human breast metastasis model: identification of phenotype-specific chromosomal rearrangements. Cancer Genet Cytogenet 2005;156:37–48

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Presented in part at the Society of Surgical Oncology’s 61st Annual Cancer Symposium, March 13–16, 2008, in Chicago, IL. This work was performed under the auspices of the Clinical Breast Care Project, a joint effort of many investigators and staff members whose contributions are gratefully acknowledged. We especially thank the program participants. Supported by the United States Department of Defense (Military Molecular Medicine Initiative MDA W81XWH-05-2-0075). The opinion and assertions contained herein are the private views of the authors and are not to be construed as official or as representing the views of the Department of the Army or the Department of Defense.

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Authors and Affiliations

  1. Clinical Breast Care Project, Windber Research Institute, 620 Seventh Street, Windber, PA, 15963, USA

    Tyson E. Becker MD, Rachel E. Ellsworth PhD, Brenda Deyarmin HT(ASCP), Heather L. Patney BS, Rick M. Jordan MS & Darrell L. Ellsworth PhD

  2. Henry M. Jackson Foundation for the Advancement of Military Medicine, 1401 Rockville Pike, Suite 600, Rockville, MD, 20852, USA

    Rachel E. Ellsworth PhD

  3. Clinical Breast Care Project, Walter Reed Army Medical Center, 6900 Georgia Avenue, NW, Washington, DC, 20307, USA

    Jeffrey A. Hooke MD & Craig D. Shriver MD

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  1. Tyson E. Becker MD
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  2. Rachel E. Ellsworth PhD
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Correspondence to Darrell L. Ellsworth PhD.

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Becker, T.E., Ellsworth, R.E., Deyarmin, B. et al. The Genomic Heritage of Lymph Node Metastases: Implications for Clinical Management of Patients with Breast Cancer. Ann Surg Oncol 15, 1056–1063 (2008). https://doi.org/10.1245/s10434-008-9815-3

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  • DOI: https://doi.org/10.1245/s10434-008-9815-3

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