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.
Similar content being viewed by others
References
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
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
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
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
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
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
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
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
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
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
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
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
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
Carlson RW, Allred DC, Anderson BO et al (2009) Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Cancer Netw 7:122–192
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
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
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
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
Amir E, Clemons M (2009) Should a biopsy be recommended to confirm metastatic disease in women with breast cancer? Lancet Oncol 10:933–935
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
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
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
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
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
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
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
Edgerton SM, Moore D, Merkel D, Thor AD (2003) erbB-2 (HER-2) and breast cancer progression. Appl Immunohistochem Mol Morphol 11:214–221
Regitnig P, Schip**er 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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Krogerus LA, Leivonen M (2001) HER-2/neu oncogene expression in advanced breast cancer. Cancer Detect Prev 25:1–7
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
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
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
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
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
McShane LM, Altman DG, Sauerbrei W et al (2005) Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 97:1180–1184
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
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
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
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
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
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
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
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
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
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
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-011-1632-x