Immunohistochemical Expression of “c-MET” in Breast Carcinomas
DOI:
https://doi.org/10.3889/oamjms.2020.5070Keywords:
c-MET, Immunohistochemistry, Breast cancer, Clinicopathological variablesAbstract
BACKGROUND: Targeted therapies achieved great success in managing breast cancer, however, triple negative breast cancers (TNBCs) lack the expression of traditional therapeutic targets, and other subtypes develop resistance to current therapies. The c-MET receptor emerged as a potential target with well documented pro-proliferative pro-motility downstream signals and wide network of crosstalk with other effectors. Some reports describe a preferential expression of c-MET in TNBCs and promising results in early anti-c-MET clinical trials. However, the main cause of failure of these trials was attributed to patient selection.
AIM: The objectives of the study were to assessment of c-MET in subtypes of breast cancer and its association with other clinicopathological variables that may predict its expression and possibly establish other rationales to refine patient selection for clinical trials.
MATERIALS AND METHODS: Retrospective immunohistochemical study assessing c-MET (clone SP44) in 55 cases of breast carcinoma. The expression of c-MET> 5% was considered positive.
RESULTS: c-MET was detected in 42% of cases. A statistically significant association of c-MET with extremes of age, advanced prognostic stage, carcinoma with medullary features, and high tumor infiltrating lymphocytes (TILs) was observed for the first time in our study. Grade III, hormone receptor negativity and TNBCs were also significantly associated with c-MET. Only negative progesterone receptor (PR) and high TILs were independently associated with c-MET in a multivariate analysis (p < 0.05). No significant association between c-MET and multifocality, size, node status, anatomic stage, lymphovascular or perineural invasion, and Ki-67 expression.
CONCLUSION: PR negativity and high TILs might be useful c-MET predictors and selection tools for clinical trials but further studies are needed to validate the unprecedented findings which may not only aid in patient selection but may also inspire new paradigms in future studies.
Downloads
Metrics
Plum Analytics Artifact Widget Block
References
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. https://doi.org/10.3322/caac.21492 PMid:30207593
Higgins MJ, Baselga J. Targeted therapies for breast cancer. J Clin Invest. 2011;121(10):3797-803. https://doi.org/10.1172/jci57152 PMid:21965336
Ren X, Yuan L, Shen S, Wu H, Lu J, Liang Z. C-met and ERβ _expression differences in basal-like and non-basal-like triple-negative breast cancer. Tumor Biol. 2016;37(8):11385-95. https://doi.org/10.1007/s13277-016-5010-5 PMid:26968553
Organ SL, Tsao MS. An overview of the c-MET signaling pathway. Ther Adv Med Oncol. 2011;3(1):S7-19. https://doi.org/10.1177/1758834011422556 PMid:22128289
Lindemann K, Resau J, Nährig J, Kort E, Leeser B, Annecke K, et al. Differential expression of c-Met, its ligand HGF/SF and HER2/neu in DCIS and adjacent normal breast tissue. Histopathology. 2007;51(1):54-62. https://doi.org/10.1111/j.1365-2559.2007.02732.x PMid:17593080
Tang C, Cortez MA, Hong D, Welsh JW. Targeting the c-met kinase. In: Targeted Therapy in Translational Cancer Research. Hoboken, NJ, USA: John Wiley & Sons, Inc.; 2015. p. 341-6. https://doi.org/10.1002/9781118468678.ch34
Yam C, Mani SA, Moulder SL. Targeting the molecular subtypes of triple negative breast cancer: Understanding the diversity to progress the field. Oncologist. 2017;22(9):1086-93. https://doi.org/10.1634/theoncologist.2017-0095 PMid:28559413
Wang M, Liang L, Lei X, Multani A, Meric-Bernstam F, Tripathy D, et al. Evaluation of c-MET aberration by immunohistochemistry and fluorescence in situ hybridization (FISH) in triple negative breast cancers. Ann Diagn Pathol. 2018;35:69-76. https://doi.org/10.1016/j.anndiagpath.2018.04.004
Rayson D, Lupichuk S, Potvin K, Dent S, Shenkier T, Dhesy-Thind S, et al. Canadian cancer trials group IND197: A phase II study of foretinib in patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-negative recurrent or metastatic breast cancer. Breast Cancer Res Treat. 2016;157(1):109-16. https://doi.org/10.1007/s10549-016-3812-1 PMid:27116183
Puccini A, Marín-Ramos NI, Bergamo F, Schirripa M, Lonardi S, Lenz HJ, et al. Safety and tolerability of c-MET inhibitors in cancer. Drug Saf. 2019;42(2):211-33. https://doi.org/10.1007/s40264-018-0780-x PMid:30649748
Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ. WHO Classification of Tumors of the Breast. 4th ed. Lyon: IARC; 2012.
Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: Experience from a large study with long-term follow-up. Histopathology. 1991;19(5):403-10. https://doi.org/10.1046/j.1365-2559.2002.14691.x PMid:1757079
Nakopoulou L, Gakiopoulou H, Keramopoulos A, Giannopoulou I, Athanassiadou P, Mavrommatis J, et al. C-met tyrosine kinase receptor expression is associated with abnormal beta-catenin expression and favourable prognostic factors in invasive breast carcinoma. Histopathology. 2000;36(4):313-25. https://doi.org/10.1046/j.1365-2559.2000.00847.x PMid:10759945
Dunn M, Morgan MB, Beer TW. Perineural invasion: Identification, significance, and a standardized definition. Dermatol Surg. 2009;35(2):214-21. https://doi.org/10.1111/j.1524-4725.2008.34412.x PMid:19215258
Hoda SA, Hoda RS, Merlin S, Shamonki J, Rivera M. Issues relating to lymphovascular invasion in breast carcinoma. Adv Anat Pathol. 2006;13(6):308-15. https://doi.org/10.1097/01.pap.0000213048.69564.26
Gujam FJ, Going JJ, Edwards J, Mohammed ZM, McMillan DC. The role of lymphatic and blood vessel invasion in predicting survival and methods of detection in patients with primary operable breast cancer. Crit Rev Oncol Hematol. 2014;89(2):231-41. https://doi.org/10.1016/j.critrevonc.2013.08.014 PMid:24075309
Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: Recommendations by an international TILs working group 2014. Ann Oncol. 2015;26(2):259-71. https://doi.org/10.1093/annonc/mdu450 PMid:25214542
Polónia A, Pinto R, Cameselle-Teijeiro JF, Schmitt FC, Paredes J. Prognostic value of stromal tumour infiltrating lymphocytes and programmed cell death-ligand 1 expression in breast cancer. J Clin Pathol. 2017;70(10):860-7. https://doi.org/10.1136/jclinpath-2016-203990 PMid:28373294
Tomioka N, Azuma M, Ikarashi M, Yamamoto M, Sato M, Watanabe K, et al. The therapeutic candidate for immune checkpoint inhibitors elucidated by the status of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression in triple negative breast cancer (TNBC). Breast Cancer 2018;25(1):34-42. https://doi.org/10.1007/s12282-017-0781-0 PMid:28488168
Hortobagyi GN, Connolly JL, D’Orsi CJ, Edge SB, Mittendorf EA, Rugo HS, et al. Breast. In: Edge SB, Greene FL, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, et al, editors. American Joint Committee on Cancer Cancer Staging Manual. 8th ed. New York: Springer-Verlag; 2017. p. 570-610. https://doi. org/10.1007/978-3-319-40618-3_2
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American society of clinical oncology/college of American pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med. 2010;134(7):e48-72. https://doi.org/10.1016/j.ypat.2010.11.008 PMid:20586616
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al, American Society of Clinical Oncology; College of American Pathologists. 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. Arch Pathol Lab Med. 2014;138(2):241-56. https://doi.org/10.5858/arpa.2013-0953-sa PMid:24099077
Bustreo S, Osella-Abate S, Cassoni P, Donadio M, Airoldi M, Pedani F, et al. Optimal Ki67 cut-off for luminal breast cancer prognostic evaluation: A large case series study with a long-term follow-up. Breast Cancer Res Treat. 2016;157(2):363-71. https://doi.org/10.1007/s10549-016-3817-9 PMid:27155668
Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thürlimann B, et al. Personalizing the treatment of women with early breast cancer: Highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2013. Ann Oncol. 2013;24(9):2206-23. https://doi.org/10.1016/j.breast.2003.09.007 PMid:23917950
Curigliano G, Burstein HJ, Winer EP, Gnant M, Dubsky P, Loibl S, et al. De-escalating and escalating treatments for early-stage breast cancer: The St. Gallen international expert consensus conference on the primary therapy of early breast cancer 2017. Ann Oncol. 2017;28(8):1700-12. https://doi.org/10.1093/annonc/mdz235 PMid:28838210
Lee WY, Chen HH, Chow NH, Su WC, Lin PW, Guo HR. Prognostic significance of co-expression of RON and MET receptors in node-negative breast cancer patients. Clin Cancer Res. 2005;11(6):2222-8. https://doi.org/10.1158/1078-0432.ccr-04-1761 PMid:15788670
Koh YW, Lee HJ, Ahn JH, Lee JW, Gong G. MET expression is associated with disease-specific survival in breast cancer patients in the neoadjuvant setting. Pathol Res Pract. 2014;210(8):494-500. https://doi.org/10.1016/j.prp.2014.04.002 PMid:24814255
Kim YJ, Choi JS, Seo J, Song JY, Lee SE, Kwon MJ, et al. MET is a potential target for use in combination therapy with EGFR inhibition in triple-negative/basal-like breast cancer. Int J Cancer. 2014;134(10):2424-36. https://doi.org/10.1002/ijc.28566 PMid:24615768
Kang JY, Dolled-Filhart M, Ocal IT, Singh B, Lin CY, Dickson RB, et al. Tissue microarray analysis of hepatocyte growth factor/ met pathway components reveals a role for met, matriptase, and hepatocyte growth factor activator inhibitor 1 in the progression of node-negative breast cancer. Cancer Res. 2003;63(5):1101- 5. https://doi.org/10.1002/cncr.11335 PMid:12615728
Garcia S, Dales JP, Charafe-Jauffret E, Carpentier-Meunier S, Andrac-Meyer L, Jacquemier J, et al. Overexpression of c-met and of the transducers PI3K, FAK and JAK in breast carcinomas correlates with shorter survival and neoangiogenesis. Int J Oncol. 2007;31(1):49-58. https://doi.org/10.3892/ijo.31.1.49 PMid:17549404
Chollet-Hinton L, Anders CK, Tse CK, Bell MB, Yang YC, Carey LA, et al. Breast cancer biologic and etiologic heterogeneity by young age and menopausal status in the Carolina breast cancer study: A case-control study. Breast Cancer Res. 2016;18(1):79. https://doi.org/10.1186/s13058-016-0736-y PMid:27492244
Ho-Yen CM, Green AR, Rakha EA, Brentnall AR, Ellis IO, Kermorgant S, et al. C-met in invasive breast cancer. Cancer. 2014;120(2):163-71. https://doi.org/10.1002/cncr.28386
Lengyel E, Prechtel D, Resau JH, Gauger K, Welk A, Lindemann K, et al. C-met overexpression in node-positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu. Int J Cancer. 2005;113(4):678-82. https://doi.org/10.1002/ijc.20598 PMid:15455388
Zagouri F, Bago-Horvath Z, Rössler F, Brandstetter A, Bartsch R, Papadimitriou CA, et al. High MET expression is an adverse prognostic factor in patients with triple-negative breast cancer. Br J Cancer. 2013;108(5):1100-5. https://doi.org/10.1038/bjc.2013.31 PMid:23422757
Jia L, Yang X, Tian W, Gou S, Huang W, Zhao W. Increased expression of c-met is associated with chemotherapy-resistant breast cancer and poor clinical outcome. Med Sci Monit. 2018;24:8239. https://doi.org/10.12659/msm.913514 PMid:30444219
Kong DS, Song SY, Kim DH, Joo KM, Yoo JS, Koh JS, et al. Prognostic significance of c-met expressionin glioblastomas. Cancer. 2009;115(1):140-8. https://doi.org/10.1002/cncr.23972 PMid:18973197
Papotti M, Olivero M, Volante M, Negro F, Prat M, Comoglio PM, et al. Expression of hepatocyte growth factor (HGF) and its receptor (MET) in medullary carcinoma of the thyroid. Endocr Pathol. 2000;11(1):19-30. https://doi.org/10.1385/ep:11:1:19 PMid:12114654
Sweeney P, El-Naggar AK, Lin SH, Pisters LL. Biological significance of c-met over expression in papillary renal cell carcinoma. J Urol. 2002;168(1):51-5. https://doi.org/10.1016/s0022-5347(05)64830-6
Wang SX, Lei L, Guo HH, Shrager J, Kunder CA, Neal JW. Synchronous primary lung adenocarcinomas harboring distinct MET Exon 14 splice site mutations. Lung Cancer. 2018;122:187- 91. https://doi.org/10.1016/j.lungcan.2018.06.019
Ho-Yen CM, Jones JL, Kermorgant S. The clinical and functional significance of c-Met in breast cancer: A review. Breast Cancer Res. 2015;17(1):52. https://doi.org/10.1186/s13058-015-0547-6 PMid:25887320
Zhao X, Qu J, Hui Y, Zhang H, Sun Y, Liu X, et al. Clinicopathological and prognostic significance of c-met overexpression in breast cancer. Oncotarget. 2017;8(34):56758. https://doi.org/10.18632/oncotarget.18142 PMid:28915628
Constantinou C, Papadopoulos S, Karyda E, Alexopoulos A, Agnanti N, Batistatou A, et al. Expression and clinical significance of claudin-7, PDL-1, PTEN, c-Kit, c-Met, c-Myc, ALK, CK5/6, CK17, p53, EGFR, Ki67, p63 in triple-negative breast cancer-a single centre prospective observational study. In Vivo. 2018;32(2):303-11.35. https://doi.org/10.21873/invivo.11238 PMid:29475913
Komarowska I, Coe D, Wang G, Haas R, Mauro C, Kishore M, et al. Hepatocyte growth factor receptor c-met instructs T cell cardiotropism and promotes T cell migration to the heart via autocrine chemokine release. Immunity. 2015;42(6):1087-99. https://doi.org/10.1016/j.immuni.2015.05.014 PMid:26070483
Li H, Li CW, Li X, Ding Q, Guo L, Liu S, et al. MET inhibitors promote liver tumor evasion of the immune response by stabilizing PDL1. Gastroenterology. 2019;156(6):1849-61. https://doi.org/10.1053/j.gastro.2019.01.252 PMid:30711629
Gayyed MF, Abd El-Maqsoud NM, El-Hameed El-Heeny AA, Mohammed MF. c-MET expression in colorectal adenomas and primary carcinomas with its corresponding metastases. J Gastrointest Oncol. 2015;6(6):618-27. PMid:26697193
Cruz J, Reis-Filho JS, Silva P, Lopes JM. Expression of c-met tyrosine kinase receptor is biologically and prognostically relevant for primary cutaneous malignant melanomas. Oncology. 2003;65(1):72-82. https://doi.org/10.1159/000071207 PMid:12837985
Carracedo A, Egervari K, Salido M, Rojo F, Corominas JM, Arumi M, et al. FISH and immunohistochemical status of the hepatocyte growth factor receptor (c-Met) in 184 invasive breast tumors. Breast Cancer Res. 2009;11(2):R402. https://doi.org/10.1186/bcr2239 PMid:19439036
Gajdos C, Tartter PI, Bleiweiss IJ, Bodian C, Brower ST. Stage 0 to stage III breast cancer in young women. J Am Coll Surgeons. 2000;190(5):523-9. https://doi.org/10.1016/ s1072-7515(00)00257-x PMid:10801018832
Downloads
Published
How to Cite
License
Copyright (c) 2020 Nehal Ali Yehia Elleithy, Gina Assaad Nakhla, Samar A. Elsheikh, Mona Salah Eldin Abdelmagid (Author)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
http://creativecommons.org/licenses/by-nc/4.0
