Frequent alterations of HER2 through mutation, amplification, or overexpression in pleomorphic lobular carcinoma of the breast
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Mutations in HER2 gene have been identified in a small subset of breast cancer cases. Identification of HER2 mutation has therapeutic implications for breast cancer, but whether a subgroup of breast cancer with a higher frequency of HER2 mutation exists, remains unknown. We analyzed HER2 mutation and pathologic factors on 73 formalin-fixed, paraffin-embedded samples, including 21 pleomorphic invasive lobular carcinoma (p-ILC) cases, 3 pleomorphic lobular carcinoma in situ (p-LCIS) cases, and 49 classic invasive lobular carcinoma (c-ILC) cases. Mutations were identified through direct sequencing. HER2 overexpression and amplification were determined through immunohistochemistry and fluorescent in situ hybridization. Six mutations were identified, including five in the 24 p-ILC or p-LCIS (p-ILC/p-LCIS) cases (20.8 %) and one in the 49 c-ILC cases (2.0 %), and the difference in frequency was significant (p = 0.013). Eight of the 24 (33.3 %) p-ILC/p-LCIS cases exhibited HER2 amplification or overexpression (amplification/overexpression), which was significantly higher than in the c-ILC cases (1/49, 2 %). Mutation and amplification/overexpression were mutually exclusive. HER2 mutations were identified more frequently in the p-ILC/p-LCIS cases with extensive apocrine change (p = 0.018). Combined HER2 alterations through mutation or amplification/overexpression were more frequently identified in p-ILC/p-LCIS cases without estrogen receptor expression. The high frequency (54.1 %, 13/24) of combined HER2 alterations in the p-ILC/p-LCIS cases suggests a crucial role of HER2 in the pathogenesis of p-ILC/p-LCIS. Because of the reported responsiveness of HER2 mutation to anti-HER2 therapy, p-ILC patients without HER2 amplification/overexpression should receive HER2 mutation analysis to identify this therapeutically relevant target.
KeywordsBreast cancer Lobular carcinoma Pleomorphic lobular carcinoma HER2 mutation
This study was supported by National Taiwan University Hospital and National Science Council Grant NSC 102-2320-B-002-009 and 103-2320-B-002-030-MY2. The authors thank the second core laboratory of National Taiwan University Hospital for the technical support.
Conflict of interest
The authors declare that they have no conflicts of interest and no financial relationship with the organization that sponsored the research.
- 6.Orvieto E, Maiorano E, Bottiglieri L, Maisonneuve P, Rotmensz N, Galimberti V, Luini A, Brenelli F, Gatti G, Viale G (2008) Clinicopathologic characteristics of invasive lobular carcinoma of the breast: results of an analysis of 530 cases from a single institution. Cancer 113(7):1511–1520CrossRefPubMedGoogle Scholar
- 10.Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB Jr, Fisher ER, Wickerham DL, Wolmark N, DeCillis A, Hoehn JL, Lees AW, Dimitrov NV (1997) Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 15(7):2483–2493PubMedGoogle Scholar
- 15.Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A, Delaney A, Gelmon K, Guliany R, Senz J, Steidl C, Holt RA, Jones S, Sun M, Leung G, Moore R, Severson T, Taylor GA, Teschendorff AE, Tse K, Turashvili G, Varhol R, Warren RL, Watson P, Zhao Y, Caldas C, Huntsman D, Hirst M, Marra MA, Aparicio S (2009) Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461(7265):809–813CrossRefPubMedGoogle Scholar
- 16.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(10):2668–2676CrossRefPubMedGoogle Scholar
- 19.Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31(31):3997–4013CrossRefPubMedGoogle Scholar
- 21.Ali SM, Alpaugh RK, Downing SR, Stephens PJ, Yu JQ, Wu H, Buell JK, Miller VA, Lipson D, Palmer GA, Ross JS, Cristofanilli M (2013) Response of an ERBB2-mutated inflammatory breast carcinoma to human epidermal growth factor receptor 2-targeted therapy. J Clin Oncol 32(25):e88–e91CrossRefGoogle Scholar
- 23.Fujiwara M, Horiguchi M, Mori S, Yokoyama K, Horiguchi H, Fukazawa M, Fujiwara H, Yano Y, Satoh H, Kamma H (2005) Histiocytoid breast carcinoma: solid variant of invasive lobular carcinoma with decreased expression of both E-cadherin and CD44 epithelial variant. Pathol Int 55(6):353–359CrossRefPubMedGoogle Scholar
- 27.Farmer P, Bonnefoi H, Becette V, Tubiana-Hulin M, Fumoleau P, Larsimont D, Macgrogan G, Bergh J, Cameron D, Goldstein D, Duss S, Nicoulaz AL, Brisken C, Fiche M, Delorenzi M, Iggo R (2005) Identification of molecular apocrine breast tumours by microarray analysis. Oncogene 24(29):4660–4671CrossRefPubMedGoogle Scholar
- 28.Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752CrossRefPubMedGoogle Scholar
- 29.Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lonning PE, Brown PO, Borresen-Dale AL, Botstein D (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100(14):8418–8423CrossRefPubMedCentralPubMedGoogle Scholar
- 30.Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350(21):2129–2139CrossRefPubMedGoogle Scholar
- 31.Ross JS, Wang K, Gay LM, Al-Rohil RN, Nazeer T, Sheehan CE, Jennings TA, Otto GA, Donahue A, He J, Palmer G, Ali S, Nahas M, Young G, Labrecque E, Frampton G, Erlich R, Curran JA, Brennan K, Downing SR, Yelensky R, Lipson D, Hawryluk M, Miller VA, Stephens PJ (2014) A high frequency of activating extracellular domain ERBB2 (HER2) mutation in micropapillary urothelial carcinoma. Clin Cancer Res 20(1):68–75CrossRefPubMedGoogle Scholar
- 32.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 USA 109(36):14476–14481CrossRefPubMedCentralPubMedGoogle Scholar
- 34.Minami Y, Shimamura T, Shah K, LaFramboise T, Glatt KA, Liniker E, Borgman CL, Haringsma HJ, Feng W, Weir BA, Lowell AM, Lee JC, Wolf J, Shapiro GI, Wong KK, Meyerson M, Thomas RK (2007) The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272. Oncogene 26(34):5023–5027CrossRefPubMedGoogle Scholar
- 35.Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, Stevens C, O’Meara S, Smith R, Parker A, Barthorpe A, Blow M, Brackenbury L, Butler A, Clarke O, Cole J, Dicks E, Dike A, Drozd A, Edwards K, Forbes S, Foster R, Gray K, Greenman C, Halliday K, Hills K, Kosmidou V, Lugg R, Menzies A, Perry J, Petty R, Raine K, Ratford L, Shepherd R, Small A, Stephens Y, Tofts C, Varian J, West S, Widaa S, Yates A, Brasseur F, Cooper CS, Flanagan AM, Knowles M, Leung SY, Louis DN, Looijenga LH, Malkowicz B, Pierotti MA, Teh B, Chenevix-Trench G, Weber BL, Yuen ST, Harris G, Goldstraw P, Nicholson AG, Futreal PA, Wooster R, Stratton MR (2004) Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431(7008):525–526CrossRefPubMedGoogle Scholar