Activating human epidermal growth factor receptor 2 (HER2) gene mutation in bone metastases from breast cancer
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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.
KeywordsBreast cancer Bone metastasis HER2 Mutation
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.
The study was supported by a grant from the Deutsche Krebshilfe to HK (Grant Number 1097154).
Compliance with ethical standards
The authors adhere to institutional ethical standards.
Conflict of interest
The authors declare that they have no conflict of interest.
- 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 CrossRefPubMedCentralPubMedGoogle 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 CrossRefPubMedCentralPubMedGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefGoogle 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 CrossRefPubMedCentralPubMedGoogle 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 CrossRefGoogle 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 CrossRefPubMedCentralPubMedGoogle 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 CrossRefPubMedCentralPubMedGoogle Scholar
- 21.Borst MJ, Ingold JA (1993) Metastatic patterns of invasive lobular versus invasive ductal carcinoma of the breast. Surgery 114:637–641Google 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 CrossRefGoogle 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 CrossRefPubMedCentralPubMedGoogle 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 CrossRefPubMedCentralPubMedGoogle 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 CrossRefPubMedCentralPubMedGoogle 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 CrossRefGoogle Scholar