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Activating human epidermal growth factor receptor 2 (HER2) gene mutation in bone metastases from breast cancer

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Abstract

In addition to amplification, point mutations of the human epidermal growth factor receptor 2 (HER2) gene (ERBB2) have been shown to activate the corresponding signaling pathway in breast cancer. The prevalence of ERBB2/HER2 mutation in bone metastasis of breast cancer and the associated phenotype are not known. In this study, bone metastases from breast cancer patients (n = 231) were analyzed for ERBB2/HER2 mutation. In 7 patients (3%; median age 70 years, range 50–83 years), gain-of-function mutations of ERBB2/HER2 were detected. The most frequent mutation was p.L755S (71%). In 29% of mutated cases, p.V777L was found. Lobular breast cancer was present in 71% of mutated cases (n = 5) and in 49% of all samples (n = 231; p = 0.275). Mutation frequency was 4.4% in the lobular subgroup and 17.4% in the pleomorphic subtype of lobular cancer (n = 23), respectively. All but one mutated lobular cancers were of the pleomorphic subtype (p = 0.006). Mutated cancers belonged either to the luminal (n = 4) or to the triple-negative types (n = 3). With regard to protein expression and gene amplification, HER2 was negative in all mutated cases. Among the 14% of metastatic luminal cancers with estrogen receptor gene (ESR1) mutation, conveying resistance against aromatase inhibitors, no concomitant ERBB2/HER2 mutation occurred. We conclude that activating HER2 mutation is present in about 3% of bone metastases from breast cancers, with significantly higher rates in the pleomorphic subtype of lobular cancer. Since mutated cases appear to be HER2-negative by conventional testing, the opportunity for specific anti-HER2 therapy may be missed.

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References

  1. Krop I, Ismaila N, Andre F, Bast RC, Barlow W, Collyar DE, Hammond ME, Kuderer NM, Liu MC, Mennel RG, Van Poznak C, Wolff AC, Stearns V (2017) Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. J Clin Oncol 35:2838–2847. https://doi.org/10.1200/JCO.2017.74.0472

    Article  PubMed  Google Scholar 

  2. Choritz H, Büsche G, Kreipe H, Study Group HER2 Monitor (2011) Quality assessment of HER2 testing by monitoring of positivity rates. Virchows Arch 459:283–289. https://doi.org/10.1007/s00428-011-1132-8

    Article  PubMed Central  PubMed  Google Scholar 

  3. Greulich H, Kaplan B, Mertins P, Chen TH, Tanaka KE, Yun CH, Zhang X, Lee SH, Cho J, Ambrogio L, Liao R, Imielinski M, Banerji S, Berger AH, Lawrence MS, Zhang J, Pho NH, Walker SR, Winckler W, Getz G, Frank D, Hahn WC, Eck MJ, Mani DR, Jaffe JD, Carr SA, Wong KK, Meyerson M (2012) Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc Natl Acad Sci U S A 109:14476–14481. https://doi.org/10.1073/pnas.1203201109

    Article  PubMed Central  PubMed  Google Scholar 

  4. Petrelli F, Tomasello G, Barni S, Lonati V, Passalacqua R, Ghidini M (2017) Clinical and pathological characterization of HER2 mutations in human breast cancer: a systematic review of the literature. Breast Cancer Res Treat 166:339–349. https://doi.org/10.1007/s10549-017-4419-x

    Article  CAS  PubMed  Google Scholar 

  5. Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, Monsey J, Goel N, Aronson AB, Li S, Ma CX, Ding L, Mardis ER, Ellis MJ (2013) Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 3:224–237. https://doi.org/10.1158/2159-8290.CD-12-0349

    Article  CAS  PubMed  Google Scholar 

  6. Desmedt C, Zoppoli G, Gundem G, Pruneri G, Larsimont D, Fornili M, Fumagalli D, Brown D, Rothé F, Vincent D, Kheddoumi N, Rouas G, Majjaj S, Brohée S, Van Loo P, Maisonneuve P, Salgado R, Van Brussel T, Lambrechts D, Bose R, Metzger O, Galant C, Bertucci F, Piccart-Gebhart M, Viale G, Biganzoli E, Campbell PJ, Sotiriou C (2016) Genomic characterization of primary invasive lobular breast cancer. J Clin Oncol 34:1872–1881. https://doi.org/10.1200/JCO.2015.64.0334

    Article  CAS  PubMed  Google Scholar 

  7. Fang Y, Jiang Y, Wang X, Yang X, Gao Y, Wang J (2014) Somatic mutations of the HER2 in metastatic breast cancer. Tumour Biol 35:11851–11854. https://doi.org/10.1007/s13277-014-2414-y

    Article  CAS  PubMed  Google Scholar 

  8. Lien HC, Chen YL, Juang YL, Jeng YM (2015) Frequent alterations of HER2 through mutation, amplification, or overexpression in pleomorphic lobular carcinoma of the breast. Breast Cancer Res Treat 150:447–455. https://doi.org/10.1007/s10549-015-3336-0

    Article  CAS  PubMed  Google Scholar 

  9. Ross JS, Gay LM, Wang K, Ali SM, Chumsri S, Elvin JA, Bose R, Vergilio JA, Suh J, Yelensky R, Lipson D, Chmielecki J, Waintraub S, Leyland-Jones B, Miller VA, Stephens PJ (2016) Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: an emerging opportunity for anti-HER2 targeted therapies. Cancer 122:2654–2662. https://doi.org/10.1002/cncr.30102

    Article  CAS  PubMed  Google Scholar 

  10. Si P, Chen T, Fang B, Yao J, Liu G, Chen H, Zhai B, Li W (2017) HER2 exon 27 mutations predict worse survival of breast cancer patients, especially in HER2-negative patients. Cancer Med 6:2832–2839. https://doi.org/10.1002/cam4.1236

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Yardley DA (2016) Pharmacologic management of bone-related complications and bone metastases in postmenopausal women with hormone receptor-positive breast cancer. Breast Cancer (Dove Med Press) 8:73–82. https://doi.org/10.2147/BCTT.S97963

    Article  CAS  Google Scholar 

  12. Gaedcke J, Traub F, Milde S, Wilkens L, Stan A, Ostertag H, Christgen M, von Wasielewski R, Kreipe HH (2007) Predominance of the basal type and HER-2/neu type in brain metastasis from breast cancer. Mod Pathol 20:864–870

    Article  CAS  PubMed  Google Scholar 

  13. Priedigkeit N, Hartmaier RJ, Chen Y, Vareslija D, Basudan A, Watters RJ, Thomas R, Leone JP, Lucas PC, Bhargava R, Hamilton RL, Chmielecki J, Puhalla SL, Davidson NE, Oesterreich S, Brufsky AM, Young L, Lee AV (2017) Intrinsic subtype switching and acquired ERBB2/HER2 amplifications and mutations in breast cancer brain metastases. JAMA Oncol 3:666–671. https://doi.org/10.1001/jamaoncol.2016.5630

    Article  PubMed Central  PubMed  Google Scholar 

  14. Bartels S, Lehmann U (2015) Analysis of mutational hotspots in routinely processed bone marrow trephines by Pyrosequencing®. Methods Mol Biol 1315:103–114. https://doi.org/10.1007/978-1-4939-2715-9_8

    Article  PubMed  Google Scholar 

  15. Bartels S, Christgen M, Luft A, Persing S, Jödecke K, Lehmann U, Kreipe H (2018) Estrogen receptor (ESR1) mutation in bone metastases from breast cancer. Mod Pathol 31:56–61. https://doi.org/10.1038/modpathol.2017.95

    Article  CAS  PubMed  Google Scholar 

  16. Gluz O, Nitz UA, Christgen M, Grischke EM, Augustin D, Kuemmel S, Braun M, Potenberg J, Kohls A, Krauss K, Stefek A, Schumacher C, Forstbauer H, Reimer T, Fischer H, Liedtke C, Wuerstlein R, Schumacher J, Kates R, Kreipe H, Harbeck N, West-German Study Group (WSG)-ADAPT Investigators (2016) West German Study Group Phase III PlanB Trial: first prospective outcome data for the 21-gene recurrence score assay and concordance of prognostic markers by central and local pathology assessment. J Clin Oncol 34:2341–2349. https://doi.org/10.1093/annonc/mdx494

    Article  PubMed  Google Scholar 

  17. Bartels S, Schipper E, Hasemeier B, Kreipe H, Lehmann U (2016) Routine clinical mutation profiling using next generation sequencing and a customized gene panel improves diagnostic precision in myeloid neoplasms. Oncotarget 7:30084–30093. https://doi.org/10.18632/oncotarget.8310

    Article  PubMed Central  PubMed  Google Scholar 

  18. Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70. https://doi.org/10.1038/nature11412

    Article  CAS  Google Scholar 

  19. Hanker AB, Brewer MR, Sheehan JH, Koch JP, Sliwoski GR, Nagy R, Lanman R, Berger MF, Hyman DM, Solit DB, He J, Miller V, Cutler RE Jr, Lalani AS, Cross D, Lovly CM, Meiler J, Arteaga CL (2017) An acquired HER2 T798I gatekeeper mutation induces resistance to neratinib in a patient with HER2 mutant-driven breast cancer. Cancer Discov 7:575–585. https://doi.org/10.1158/2159-8290.CD-16-1431

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Jain S, Fisher C, Smith P, Millis RR, Rubens RD (1993) Patterns of metastatic breast cancer in relation to histological type. Eur J Cancer 29A:2155–2157

    Article  CAS  PubMed  Google Scholar 

  21. Borst MJ, Ingold JA (1993) Metastatic patterns of invasive lobular versus invasive ductal carcinoma of the breast. Surgery 114:637–641

    CAS  PubMed  Google Scholar 

  22. Ross JS, Wang K, Sheehan CE, Boguniewicz AB, Otto G, Downing SR, Sun J, He J, Curran JA, Ali S, Yelensky R, Lipson D, Palmer G, Miller VA, Stephens PJ (2013) Relapsed classic E-cadherin (CDH1)-mutated invasive lobular breast cancer shows a high frequency of HER2 (ERBB2) gene mutations. Clin Cancer Res 19:2668–2676. https://doi.org/10.1158/1078-0432.CCR-13-0295

    Article  CAS  PubMed  Google Scholar 

  23. Deniziaut G, Tille JC, Bidard FC, Vacher S, Schnitzler A, Chemlali W, Trémoulet L, Fuhrmann L, Cottu P, Rouzier R, Bièche I, Vincent-Salomon A (2016) ERBB2 mutations associated with solid variant of high-grade invasive lobular breast carcinomas. Oncotarget 7:73337–73346. https://doi.org/10.18632/oncotarget.11819

    Article  PubMed Central  PubMed  Google Scholar 

  24. Chmielecki J, Ross JS, Wang K, Frampton GM, Palmer GA, Ali SM, Palma N, Morosini D, Miller VA, Yelensky R, Lipson D, Stephens PJ (2015) Oncogenic alterations in ERBB2/HER2 represent potential therapeutic targets across tumors from diverse anatomic sites of origin. Oncologist 20:7–12. https://doi.org/10.1634/theoncologist.2014-0234

    Article  CAS  PubMed  Google Scholar 

  25. Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, Juric D, Quinn DI, Moreno V, Doger B, Mayer IA, Boni V, Calvo E, Loi S, Lockhart AC, Erinjeri JP, Scaltriti M, Ulaner GA, Patel J, Tang J, Beer H, Selcuklu SD, Hanrahan AJ, Bouvier N, Melcer M, Murali R, Schram AM, Smyth LM, Jhaveri K, Li BT, Drilon A, Harding JJ, Iyer G, Taylor BS, Berger MF, Cutler RE Jr, Xu F, Butturini A, Eli LD, Mann G, Farrell C, Lalani AS, Bryce RP, Arteaga CL, Meric-Bernstam F, Baselga J, Solit DB (2018) HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature 554:189–194. https://doi.org/10.1038/nature25475

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Ali SM, Alpaugh RK, Downing SR, Stephens PJ, Yu JQ, Wu H, Buell JK, Miller VA, Lipson D, Palmer GA, Ross JS, Cristofanilli M (2015) Response of an ERBB2-mutated inflammatory breast carcinoma to human epidermal growth factor receptor 2–targeted therapy. J Clin Oncol 32:e86–e96. https://doi.org/10.1200/JCO.2013.49.0599

    Article  Google Scholar 

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Contributions

MC, SB, UL, and HK conceived and designed the study and wrote, edited, and reviewed the manuscript. MC, SB, AL, SP, DH, and HK researched and analyzed data and wrote, edited, and reviewed the manuscript. All authors gave final approval for publication. HK takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.

Funding

The study was supported by a grant from the Deutsche Krebshilfe to HK (Grant Number 1097154).

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Correspondence to Hans Kreipe.

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Christgen, M., Bartels, S., Luft, A. et al. Activating human epidermal growth factor receptor 2 (HER2) gene mutation in bone metastases from breast cancer. Virchows Arch 473, 577–582 (2018). https://doi.org/10.1007/s00428-018-2414-1

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