Skip to main content

Advertisement

SpringerLink
Log in

HER2 discordance between primary breast cancer and its paired metastasis: tumor biology or test artefact? Insights through meta-analysis

  • Review
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The proto-oncogene, HER2, has prognostic and predictive relevance in invasive breast cancer (IBC). HER2 testing of primary IBC guides treatment selection and is assumed to reflect HER2 status of associated metastases, although HER2 discordance between IBC and metastasis has been reported. Systematic review and meta-analysis of HER2 status in IBC and its paired loco-regional or distant metastasis were done. Quality appraisal considered whether (within-subject) testing conditions were maintained for paired primary and metastasis. Random effects logistic regression models were used to estimate pooled within-subject HER2 discordant proportions and to examine study-level covariates, including tumor-related and testing-related variables, potentially associated with HER2 discordance differences across (between) studies. Modelled paired HER2 data for primary and metastatic cancer (2520 subjects, 26 studies) showed a pooled HER2 discordance of 5.5% (3.6–8.5%). Sensitivity analysis, excluding the only study not maintaining same conditions for paired testing, gave a pooled estimate of 5.2% (3.5–7.8%). Pooled discordant proportion was not associated with differences between studies in test type, test scoring or interpretation criteria, subjects’ median age, study time-frame, or HER2 positivity in primary cancer (all P > 0.05). However, type of metastasis was significantly associated with estimated HER2 discordance (P = 0.0017): studies of primary tumor paired with distant metastases had higher discordance [11.5% (6.9–18.6%)] than studies of primary paired with lymph node metastases only [4.1% (2.4–7.2%)], or those paired with nodal or various metastases [3.3% (2.0–5.6%)]; P < 0.01. HER2 discordant proportion was higher where paired metastases were metachronous relative to synchronous to primary IBC (P = 0.0024). Sensitivity analysis provided weak evidence (P = 0.074) that discordance in the direction of change from HER2-negative primary cancer to HER2-positive paired metastasis was more likely than the reverse. Study-level meta-analysis suggests factors associated with the type of metastasis as underlying mechanisms for observed HER2 discordance between primary IBC and paired metastasis. Test-related factors did not account for differences across studies in the HER2 discordant proportion.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Wolff AC, Hammond ME, Schwartz JN et al (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118–145

    Article  PubMed  CAS  Google Scholar 

  2. Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792

    Article  PubMed  CAS  Google Scholar 

  3. Bang YJ, Van CE, Feyereislova A et al (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376:687–697

    Article  PubMed  CAS  Google Scholar 

  4. Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN (2009) The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 14:320–368

    Article  PubMed  CAS  Google Scholar 

  5. Romond EH, Perez EA, Bryant J et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684

    Article  PubMed  CAS  Google Scholar 

  6. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672

    Article  PubMed  CAS  Google Scholar 

  7. Vogel CL, Cobleigh MA, Tripathy D et al (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719–726

    Article  PubMed  CAS  Google Scholar 

  8. Pegram MD, Lipton A, Hayes DF et al (1998) Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 16:2659–2671

    PubMed  CAS  Google Scholar 

  9. Pegram MD, Pienkowski T, Northfelt DW et al (2004) Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J Natl Cancer Inst 96:759–769

    Article  PubMed  CAS  Google Scholar 

  10. Hurley J, Doliny P, Reis I et al (2006) Docetaxel, cisplatin, and trastuzumab as primary systemic therapy for human epidermal growth factor receptor 2-positive locally advanced breast cancer. J Clin Oncol 24:1831–1838

    Article  PubMed  CAS  Google Scholar 

  11. Johnston S, Pippen J Jr, Pivot X et al (2009) Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 27:5538–5546

    Article  PubMed  CAS  Google Scholar 

  12. Harris L, Fritsche H, Mennel R et al (2007) American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25:5287–5312

    Article  PubMed  CAS  Google Scholar 

  13. Dowsett M, Hanby AM, Laing R, Walker R, National HER (2007) HER2 testing in the UK: consensus from a national consultation. J Clin Pathol 60:685–689

    Article  PubMed  Google Scholar 

  14. Carlson RW, Allred DC, Anderson BO et al (2009) Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Cancer Netw 7:122–192

    CAS  Google Scholar 

  15. Tanner M, Jarvinen P, Isola J (2001) Amplification of HER-2/neu and topoisomerase IIalpha in primary and metastatic breast cancer. Cancer Res 61:5345–5348

    PubMed  CAS  Google Scholar 

  16. Cardoso F, Di Leo A, Larsimont D et al (2001) Evaluation of HER2, p53, bcl-2, topoisomerase II-alpha, heat shock proteins 27 and 70 in primary breast cancer and metastatic ipsilateral axillary lymph nodes. Ann Oncol 12:615–620

    Article  PubMed  CAS  Google Scholar 

  17. Lower EE, Glass E, Blau R, Harman S (2009) HER-2/neu expression in primary and metastatic breast cancer. Breast Cancer Res Treat 113:301–306

    Article  PubMed  CAS  Google Scholar 

  18. Pusztai L, Viale G, Kelly C, Hudis C (2010) Estrogen and HER-2 receptor discordance between primary breast cancer and metastasis. Oncologist 15:1164–1168

    Article  PubMed  Google Scholar 

  19. Amir E, Clemons M (2009) Should a biopsy be recommended to confirm metastatic disease in women with breast cancer? Lancet Oncol 10:933–935

    Article  PubMed  Google Scholar 

  20. Aoyama K, Kamio T, Nishikawa T, Kameoka S (2010) A comparison of HER2/neu gene amplification and its protein overexpression between primary breast cancer and metastatic lymph nodes. Jpn J Clin Oncol 40:613–619

    Article  PubMed  Google Scholar 

  21. Shimizu C, Fukutomi T, Tsuda H et al (2000) c-erbB-2 protein overexpression and p53 immunoreaction in primary and recurrent breast cancer tissues. J Surg Oncol 73:17–20

    Article  PubMed  CAS  Google Scholar 

  22. Masood S, Bui MM (2000) Assessment of Her-2/neu overexpression in primary breast cancers and their metastatic lesions: an immunohistochemical study. Ann Clin Lab Sci 30:259–265

    PubMed  CAS  Google Scholar 

  23. Gancberg D, Di Leo A, Cardoso F et al (2002) Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites. Ann Oncol 13:1036–1043

    Article  PubMed  CAS  Google Scholar 

  24. Tsutsui S, Ohno S, Murakami S, Kataoka A, Kinoshita J, Hachitanda Y (2002) EGFR, c-erbB2 and p53 protein in the primary lesions and paired metastatic regional lymph nodes in breast cancer. Eur J Surg Oncol 28:383–387

    PubMed  CAS  Google Scholar 

  25. Vincent-Salomon A, Jouve M, Genin P et al (2002) HER2 status in patients with breast carcinoma is not modified selectively by preoperative chemotherapy and is stable during the metastatic process. Cancer 94:2169–2173

    Article  PubMed  CAS  Google Scholar 

  26. Sekido Y, Umemura S, Takekoshi S et al (2003) Heterogeneous gene alterations in primary breast cancer contribute to discordance between primary and asynchronous metastatic/recurrent sites: HER2 gene amplification and p53 mutation. Int J Oncol 22:1225–1232

    PubMed  CAS  Google Scholar 

  27. Edgerton SM, Moore D, Merkel D, Thor AD (2003) erbB-2 (HER-2) and breast cancer progression. Appl Immunohistochem Mol Morphol 11:214–221

    PubMed  CAS  Google Scholar 

  28. Regitnig P, Schippinger W, Lindbauer M, Samonigg H, Lax SF (2004) Change of HER-2/neu status in a subset of distant metastases from breast carcinomas. J Pathol 203:918–926

    Article  PubMed  CAS  Google Scholar 

  29. Carlsson J, Nordgren H, Sjöström J et al (2004) HER2 expression in breast cancer primary tumours and corresponding metastases. Original data and literature review. Br J Cancer 90:2344–2348

    PubMed  CAS  Google Scholar 

  30. Zidan J, Dashkovsky I, Stayerman C, Basher W, Cozacov C, Hadary A (2005) Comparison of HER-2 overexpression in primary breast cancer and metastatic sites and its effect on biological targeting therapy of metastatic disease. Br J Cancer 93:552–556

    Article  PubMed  CAS  Google Scholar 

  31. Azam M, Qureshi A, Mansoor S (2009) Comparison of estrogen receptors, progesterone receptors and HER-2/neu expression between primary and metastatic breast carcinoma. J Pak Med Assoc 59:736–740

    PubMed  Google Scholar 

  32. Aitken SJ, Thomas JS, Langdon SP, Harrison DJ, Faratian D (2010) Quantitative analysis of changes in ER, PR and HER2 expression in primary breast cancer and paired nodal metastases. Ann Oncol 21:1254–1261

    Article  PubMed  CAS  Google Scholar 

  33. Santiago MP, Vazquez-Boquete A, Fernandez B et al (2009) Whether to determine HER2 status for breast cancer in the primary tumour or in the metastasis. Histol Histopathol 24:675–682

    PubMed  CAS  Google Scholar 

  34. Idirisinghe PK, Thike AA, Cheok PY et al (2010) Hormone receptor and c-ERBB2 status in distant metastatic and locally recurrent breast cancer. Pathologic correlations and clinical significance. Am J Clin Pathol 133:416–429

    Article  PubMed  Google Scholar 

  35. Simon R, Nocito A, Hubscher T et al (2001) Patterns of her-2/neu amplification and overexpression in primary and metastatic breast cancer. J Natl Cancer Inst 93:1141–1146

    Article  PubMed  CAS  Google Scholar 

  36. Guarneri V, Giovannelli S, Ficarra G et al (2008) Comparison of HER-2 and hormone receptor expression in primary breast cancers and asynchronous paired metastases: impact on patient management. Oncologist 13:838–844

    Article  PubMed  CAS  Google Scholar 

  37. Santinelli A, Pisa E, Stramazzotti D, Fabris G (2008) HER-2 status discrepancy between primary breast cancer and metastatic sites. Impact on target therapy. Int J Cancer 122:999–1004

    Article  PubMed  CAS  Google Scholar 

  38. Gong Y, Booser DJ, Sneige N (2005) Comparison of HER-2 status determined by fluorescence in situ hybridization in primary and metastatic breast carcinoma. Cancer 103:1763–1769

    Article  PubMed  CAS  Google Scholar 

  39. Tapia C, Savic S, Wagner U et al (2007) HER2 gene status in primary breast cancers and matched distant metastases. Breast Cancer Res 9:R31

    Article  PubMed  Google Scholar 

  40. Cho EY, Han JJ, Choi YL, Kim KM, Oh YL (2008) Comparison of Her-2, EGFR and cyclin D1 in primary breast cancer and paired metastatic lymph nodes: an immunohistochemical and chromogenic in situ hybridization study. J Korean Med Sci 23:1053–1061

    Article  PubMed  Google Scholar 

  41. Simmons C, Miller N, Geddie W et al (2009) Does confirmatory tumor biopsy alter the management of breast cancer patients with distant metastases? Ann Oncol 20:1499–1504

    Article  PubMed  CAS  Google Scholar 

  42. Xu R, Perle MA, Inghirami G, Chan W, Delgado Y, Feiner H (2002) Amplification of Her-2/neu gene in Her-2/neu-overexpressing and -nonexpressing breast carcinomas and their synchronous benign, premalignant, and metastatic lesions detected by FISH in archival material. Mod Pathol 15:116–124

    Article  PubMed  Google Scholar 

  43. Lear-Kaul KC, Yoon HR, Kleinschmidt-DeMasters BK, McGavran L, Singh M (2003) Her-2/neu status in breast cancer metastases to the central nervous system. Arch Pathol Lab Med 127:1451–1457

    PubMed  CAS  Google Scholar 

  44. Niehans GA, Singleton TP, Dykoski D, Kiang DT (1993) Stability of HER-2/neu expression over time and at multiple metastatic sites. J Natl Cancer Inst 85:1230–1235

    Article  PubMed  CAS  Google Scholar 

  45. Krogerus LA, Leivonen M (2001) HER-2/neu oncogene expression in advanced breast cancer. Cancer Detect Prev 25:1–7

    PubMed  CAS  Google Scholar 

  46. D’Andrea MR, Limiti MR, Bari M et al (2007) Correlation between genetic and biological aspects in primary non-metastatic breast cancers and corresponding synchronous axillary lymph node metastasis. Breast Cancer Res Treat 101:279–284

    Article  PubMed  Google Scholar 

  47. Bozzetti C, Personeni N, Nizzoli R et al (2003) HER-2/neu amplification by fluorescence in situ hybridization in cytologic samples from distant metastatic sites of breast carcinoma. Cancer 99:310–315

    Article  PubMed  CAS  Google Scholar 

  48. Broom RJ, Tang PA, Simmons C et al (2009) Changes in estrogen receptor, progesterone receptor and Her-2/neu status with time: discordance rates between primary and metastatic breast cancer. Anticancer Res 29:1557–1562

    PubMed  Google Scholar 

  49. Meng S, Tripathy D, Shete S et al (2004) HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci USA 101:9393–9398

    Article  PubMed  CAS  Google Scholar 

  50. Strien L, Leidenius M, von Smitten K, Heikkila P (2010) Concordance between HER-2 and steroid hormone receptor expression between primary breast cancer, sentinel node metastases, and isolated tumor cells. Pathol Res Pract 206:253–258

    Article  PubMed  Google Scholar 

  51. McShane LM, Altman DG, Sauerbrei W et al (2005) Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 97:1180–1184

    Article  PubMed  CAS  Google Scholar 

  52. Pepe MS, Feng Z, Janes H, Bossuyt PM, Potter JD (2008) Pivotal evaluation of the accuracy of a biomarker used for classification or prediction: standards for study design. J Natl Cancer Inst 100:1432–1438

    Article  PubMed  CAS  Google Scholar 

  53. Press MF, Finn RS, Cameron D et al (2008) HER-2 gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer. Clin Cancer Res 14:7861–7870

    Article  PubMed  CAS  Google Scholar 

  54. Bilous M, Dowsett M, Hanna W et al (2003) Current perspectives on HER2 testing: a review of national testing guidelines. Mod Pathol 16:173–182

    Article  PubMed  Google Scholar 

  55. Dowsett M, Bartlett J, Ellis IO et al (2003) Correlation between immunohistochemistry (HercepTest) and fluorescence in situ hybridization (FISH) for HER-2 in 426 breast carcinomas from 37 centres. J Pathol 199:418–423

    Article  PubMed  CAS  Google Scholar 

  56. Bilous M, Morey A, Armes J, Cummings M, Francis G (2006) Chromogenic in situ hybridisation testing for HER2 gene amplification in breast cancer produces highly reproducible results concordant with fluorescence in situ hybridisation and immunohistochemistry. Pathology 38:120–124

    Article  PubMed  CAS  Google Scholar 

  57. van de Vijver V, Bilous M, Hanna W et al (2007) Chromogenic in situ hybridisation for the assessment of HER2 status in breast cancer: an international validation ring study. Breast Cancer Res 9:R68

    Article  PubMed  Google Scholar 

  58. National Collaborating Centre for Cancer (developed for National Institute for Health and Clinical Excellence (NICE) clinical guideline 81). Advanced breast cancer: diagnosis and treatment 2009. Website: www.nice.org.uk/nicemedia/live/11778/43305/43305.pdf

  59. Sjöström J, Collan J, von Boguslawski K et al (2002) C-erbB-2 expression does not predict response to docetaxel or sequential methotrexate and 5-fluorouracil in advanced breast cancer. Eur J Cancer 38:535–542

    Article  PubMed  Google Scholar 

  60. Piccart MJ, Di Leo A, Beauduin M et al (2001) Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol 19:3103–3110

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was partly funded by Australia’s National Health and Medical Research Council (NHMRC) program grant 633003 to the Screening and Test Evaluation Program. RLB is a Cancer Institute New South Wales Fellow.

Conflict of interest

The authors Houssami, Macaskil, Balleine, Pegram have no conflict of interest to declare, and the author Bilous is a member of Roche HER2 testing Advisory Board.

Author information

Authors and Affiliations

  1. Screening and Test Evaluation Program (STEP), School of Public Health (A27), Sydney Medical School, University of Sydney, Sydney, 2006, Australia

    Nehmat Houssami & Petra Macaskill

  2. Translational Oncology, Westmead Hospital, Westmead Institute for Cancer Research, Westmead Millennium Institute, Sydney Medical School, University of Sydney, Sydney, Australia

    Rosemary L. Balleine

  3. Healthscope Pathology, Sydney, Australia

    Michael Bilous

  4. Miller School of Medicine, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA

    Mark D. Pegram

Authors
  1. Nehmat Houssami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Petra Macaskill
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rosemary L. Balleine
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Bilous
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mark D. Pegram
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nehmat Houssami.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 108 kb)

 

 

Appendix 1
figure a

Flow diagram summarising the literature search strategy. Flow diagram adapted from PRISMA recommendations (accessed January 2011 via www.prisma-satement.org)

Full size image

Rights and permissions

Reprints and permissions

About this article

Cite this article

Houssami, N., Macaskill, P., Balleine, R.L. et al. HER2 discordance between primary breast cancer and its paired metastasis: tumor biology or test artefact? Insights through meta-analysis. Breast Cancer Res Treat 129, 659–674 (2011). https://doi.org/10.1007/s10549-011-1632-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1632-x

Keywords

Search

Navigation