Attempt towards a novel classification of triple-negative breast cancer using immunohistochemical markers

Liu,Yan‑Xi; Wang,Ke‑Ren; Xing,Hua; Zhai,Xu‑Jie; Wang,Li‑Ping; Wang,Wan

doi:10.3892/ol.2016.4778

Attempt towards a novel classification of triple-negative breast cancer using immunohistochemical markers

Authors:
- Yan‑Xi Liu
- Ke‑Ren Wang
- Hua Xing
- Xu‑Jie Zhai
- Li‑Ping Wang
- Wan Wang
View Affiliations

Affiliations: Department of Breast Surgery, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China, Department of Pathology, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
Published online on: June 23, 2016 https://doi.org/10.3892/ol.2016.4778
Pages: 1240-1256
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Significant efforts have been made to gain a better understanding of the heterogeneity of triple-negative breast cancers from the histological to the molecular and genomic levels. In this study, we attempted to bring forward gene expression subtypes of triple-negative breast cancer (TBNC) to the clinic, by translating gene stratification to clinically accessible immunohistochemical (IHC) classification. Using IHC analysis, we categorized 154 TBNC cases into three main subclasses. Differences in the frequencies of basic characteristics and clinicopathological parameters between the subtypes were examined using Chi‑square tests. We defined three main groups among the 154 triple‑negative cases. The basal‑like (BL) group expressed cytokeratin (CK) 5/6 and/or CK14 (83 cases), the AR+ group demonstrated positivity for androgen receptor (18 cases), and the final group exhibited a CD44+CD24‑/low phenotype (39 cases). There were three overlapping cases between the BL subgroup and the CD44+CD24‑/low phenotype subgroup, and 11 unclassified cases. In this new IHC classification, three subcategories exhibited a statistical difference with regard to age, tumor size, histological grade, tumor necrosis, Ki67 labeling index, relapse‑free survival, breast cancer‑specific survival and response to chemotherapy. According to our definition, the BL group and CD44+CD24‑/low phenotype could be observed in tumors that were not triple‑negative, and BL tumors that were triple‑negative demonstrated almost undistinguishable clinicopathological characteristics compared with BL tumors that were not triple‑negative. The same observation was made with CD44+CD24‑/low tumors that were triple‑negative vs. CD44+CD24‑/low tumors that were not. The AR+ group demonstrated undistinguishable clinicopathological characteristics compared with the luminal subtype. We successfully distinguished three subtypes exhibiting diverse clinicopathological and prognostic characteristics with the minimum use of IHC markers.

View Figures

View References

1	Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, Perou CM and Nielsen TO: Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res. 14:1368–1376. 2008. View Article : Google Scholar : PubMed/NCBI
2	Aguiar FN, Mendes HN, Cirqueira CS, Bacchi CE and Carvalho FM: Basal cytokeratin as a potential marker of low risk of invasion in ductal carcinoma in situ. Clinics (Sao Paulo). 68:638–643. 2013. View Article : Google Scholar : PubMed/NCBI
3	Fadare O, Wang SA and Hileeto D: The expression of cytokeratin 5/6 in invasive lobular carcinoma of the breast: evidence of a basal-like subset? Hum Pathol. 39:331–336. 2008. View Article : Google Scholar : PubMed/NCBI
4	Lee HJ, Seo AN, Kim EJ, Jang MH, Kim YJ, Kim JH, Kim SW, Ryu HS, Park IA, Im SA, et al: Prognostic and predictive values of EGFR overexpression and EGFR copy number alteration in HER2-positive breast cancer. Br J Cancer. 112:103–111. 2015. View Article : Google Scholar : PubMed/NCBI
5	Park HS, Jang MH, Kim EJ, Kim HJ, Lee HJ, Kim YJ, Kim JH, Kang E, Kim SW, Kim IA and Park SY: High EGFR gene copy number predicts poor outcome in triple-negative breast cancer. Mod Pathol. 27:1212–1222. 2014. View Article : Google Scholar : PubMed/NCBI
6	Rakha EA, El-Sayed ME, Green AR, Lee AH, Robertson JF and Ellis IO: Prognostic markers in triple-negative breast cancer. Cancer. 109:25–32. 2007. View Article : Google Scholar : PubMed/NCBI
7	Sood N and Nigam JS: Correlation of CK5 and EGFR with clinicopathological profile of triple-negative breast cancer. Patholog Res Int. 2014:1418642014.PubMed/NCBI
8	Niemeier LA, Dabbs DJ, Beriwal S, Striebel JM and Bhargava R: Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod Pathol. 23:205–212. 2010. View Article : Google Scholar : PubMed/NCBI
9	Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, He X and Perou CM: Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 12:R682010. View Article : Google Scholar : PubMed/NCBI
10	Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y and Pietenpol JA: Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 121:2750–2767. 2011. View Article : Google Scholar : PubMed/NCBI
11	Turner NC and Reis-Filho JS: Tackling the diversity of triple-negative breast cancer. Clin Cancer Res. 19:6380–6388. 2013. View Article : Google Scholar : PubMed/NCBI
12	Lehmann BD and Pietenpol JA: Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes. J Pathol. 232:142–150. 2014. View Article : Google Scholar : PubMed/NCBI
13	Prat A, Adamo B, Cheang MC, Anders CK, Carey LA and Perou CM: Molecular characterization of basal-like and non-basal-like triple-negative breast cancer. Oncologist. 18:123–133. 2013. View Article : Google Scholar : PubMed/NCBI
14	Abramson VG, Lehmann BD, Ballinger TJ and Pietenpol JA: Subtyping of triple-negative breast cancer: implications for therapy. Cancer. 121:8–16. 2015. View Article : Google Scholar : PubMed/NCBI
15	Schmadeka R, Harmon BE and Singh M: Triple-negative breast carcinoma: current and emerging concepts. Am J Clin Pathol. 141:462–477. 2014. View Article : Google Scholar : PubMed/NCBI
16	Choo JR and Nielsen TO: Biomarkers for basal-like breast cancer. Cancers (Basel). 2:1040–1065. 2010. View Article : Google Scholar : PubMed/NCBI
17	Ricardo S, Vieira AF, Gerhard R, Leitão D, Pinto R, Cameselle-Teijeiro JF, Milanezi F, Schmitt F and Paredes J: Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype. J Clin Pathol. 64:937–946. 2011. View Article : Google Scholar : PubMed/NCBI
18	Mylona E, Giannopoulou I, Fasomytakis E, Nomikos A, Magkou C, Bakarakos P and Nakopoulou L: The clinicopathologic and prognostic significance of CD44⁺/CD24^(−/low) and CD44⁻/CD24⁺ tumor cells in invasive breast carcinomas. Hum Pathol. 39:1096–1102. 2008. View Article : Google Scholar : PubMed/NCBI
19	Mayer IA, Abramson VG, Lehmann BD and Pietenpol JA: New strategies for triple-negative breast cancer - deciphering the heterogeneity. Clin Cancer Res. 20:782–790. 2014. View Article : Google Scholar : PubMed/NCBI
20	Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, Clark L, Bayani N, Coppe JP, Tong F, et al: A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 10:515–527. 2006. View Article : Google Scholar : PubMed/NCBI
21	Kao J, Salari K, Bocanegra M, Choi YL, Girard L, Gandhi J, Kwei KA, Hernandez-Boussard T, Wang P, Gazdar AF, et al: Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery. PLoS One. 4:e61462009. View Article : Google Scholar : PubMed/NCBI
22	Liu T, Zhang X, Shang M, Zhang Y, Xia B, Niu M, Liu Y and Pang D: Dysregulated expression of Slug, vimentin and E-cadherin correlates with poor clinical outcome in patients with basal-like breast cancer. J Surg Oncol. 107:188–194. 2013. View Article : Google Scholar : PubMed/NCBI
23	Lee J, Hahm ER, Marcus AI and Singh SV: Withaferin A inhibits experimental epithelial-mesenchymal transition in MCF-10A cells and suppresses vimentin protein level in vivo in breast tumors. Mol Carcinog. 54:417–429. 2015. View Article : Google Scholar : PubMed/NCBI
24	Rito M, Schmitt F, Pinto AE and André S: Fibromatosis-like metaplastic carcinoma of the breast has a claudin-low immunohistochemical phenotype. Virchows Arch. 465:185–191. 2014. View Article : Google Scholar : PubMed/NCBI
25	Zhang Y, Toy KA and Kleer CG: Metaplastic breast carcinomas are enriched in markers of tumor-initiating cells and epithelial to mesenchymal transition. Mod Pathol. 25:178–184. 2012.PubMed/NCBI
26	Giatromanolaki A, Sivridis E, Fiska A and Koukourakis MI: The CD44+/CD24- phenotype relates to ‘triple-negative’ state and unfavorable prognosis in breast cancer patients. Med Oncol. 28:745–752. 2011. View Article : Google Scholar : PubMed/NCBI
27	Honeth G, Bendahl PO, Ringner M, Ringnér M, Saal LH, Gruvberger-Saal SK, Lövgren K, Grabau D, Fernö M, Borg A and Hegardt C: The CD44+/CD24-phenotype is enriched in basal-like breast tumors. Breast Cancer Res. 10:R532008. View Article : Google Scholar : PubMed/NCBI
28	Hammond ME, Hayes DF, Wolff AC, Mangu PB and Temin S: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Oncol Pract. 6:195–197. 2010. View Article : Google Scholar : PubMed/NCBI
29	Barry WT, Kernagis DN, Dressman HK, Griffis RJ, Hunter JD, Olson JA, Marks JR, Ginsburg GS, Marcom PK, Nevins JR, et al: Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome. J Clin Oncol. 28:2198–2206. 2010. View Article : Google Scholar : PubMed/NCBI
30	Prat A, Parker JS, Fan C and Perou CM: PAM50 assay and the three-gene model for identifying the major and clinically relevant molecular subtypes of breast cancer. Breast Cancer Res Treat. 135:301–306. 2012. View Article : Google Scholar : PubMed/NCBI
31	Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, et al: Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 10:5367–5374. 2004. View Article : Google Scholar : PubMed/NCBI
32	Badve S, Dabbs DJ, Schnitt SJ, Baehner FL, Decker T, Eusebi V, Fox SB, Ichihara S, Jacquemier J, Lakhani SR, et al: Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists. Mod Pathol. 24:157–167. 2011. View Article : Google Scholar : PubMed/NCBI
33	Choi YL, Oh E, Park S, Kim Y, Park YH, Song K, Cho EY, Hong YC, Choi JS, Lee JE, et al: Triple-negative, basal-like and quintuple-negative breast cancers: better prediction model for survival. BMC Cancer. 10:5072010. View Article : Google Scholar : PubMed/NCBI
34	Won JR, Gao D, Chow C, Cheng J, Lau SY, Ellis MJ, Perou CM, Bernard PS and Nielsen TO: A survey of immunohistochemical biomarkers for basal-like breast cancer against a gene expression profile gold standard. Mod Pathol. 26:1438–1450. 2013. View Article : Google Scholar : PubMed/NCBI
35	Safarpour D, Pakneshan S and Tavassoli FA: Androgen receptor (AR) expression in 400 breast carcinomas: is routine AR assessment justified? Am J Cancer Res. 4:353–368. 2014.PubMed/NCBI
36	McNamara KM, Yoda T, Miki Y, Chanplakorn N, Wongwaisayawan S, Incharoen P, Kongdan Y, Wang L, Takagi K, Mayu T, et al: Androgenic pathway in triple negative invasive ductal tumors: its correlation with tumor cell proliferation. Cancer Sci. 104:639–646. 2013. View Article : Google Scholar : PubMed/NCBI
37	Tsutsumi Y: Apocrine carcinoma as triple-negative breast cancer: novel definition of apocrine-type carcinoma as estrogen/progesterone receptor-negative and androgen receptor-positive invasive ductal carcinoma. Jpn J Clin Oncol. 42:375–386. 2012. View Article : Google Scholar : PubMed/NCBI
38	Thike AA, Yong-Zheng Chong L, Cheok PY, Li HH, Wai-Cheong Yip G, Huat Bay B, Tse GM, Iqbal J and Tan PH: Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer. Mod Pathol. 27:352–360. 2014.PubMed/NCBI
39	Tsang JY, Ni YB, Chan SK, Shao MM, Law BK, Tan PH and Tse GM: Androgen receptor expression shows distinctive significance in ER positive and negative breast cancers. Ann Surg Oncol. 21:2218–2228. 2014. View Article : Google Scholar : PubMed/NCBI
40	Pistelli M, Caramanti M, Biscotti T, Santinelli A, Pagliacci A, De Lisa M, Ballatore Z, Ridolfi F, Maccaroni E, Bracci R, et al: Androgen receptor expression in early triple-negative breast cancer: clinical significance and prognostic associations. Cancers (Basel). 6:1351–1362. 2014. View Article : Google Scholar : PubMed/NCBI
41	McNamara KM, Yoda T, Takagi K, Miki Y, Suzuki T and Sasano H: Androgen receptor in triple negative breast cancer. J Steroid Biochem Mol Biol. 133:66–76. 2013. View Article : Google Scholar : PubMed/NCBI
42	Gasparini P, Fassan M, Cascione L, Guler G, Balci S, Irkkan C, Paisie C, Lovat F, Morrison C, Zhang J, et al: Androgen receptor status is a prognostic marker in non-basal triple negative breast cancers and determines novel therapeutic options. PLoS One. 9:e885252014. View Article : Google Scholar : PubMed/NCBI
43	Loibl S, Müller BM, von Minckwitz G, Schwabe M, Roller M, Darb-Esfahani S, Ataseven B, du Bois A, Fissler-Eckhoff A, Gerber B, et al: Androgen receptor expression in primary breast cancer and its predictive and prognostic value in patients treated with neoadjuvant chemotherapy. Breast Cancer Res Treat. 130:477–487. 2011. View Article : Google Scholar : PubMed/NCBI
44	Micello D, Marando A, Sahnane N, Riva C, Capella C and Sessa F: Androgen receptor is frequently expressed in HER2-positive, ER/PR-negative breast cancers. Virchows Arch. 457:467–476. 2010. View Article : Google Scholar : PubMed/NCBI
45	Ogawa Y, Hai E, Matsumoto K, Ikeda K, Tokunaga S, Nagahara H, Sakurai K, Inoue T and Nishiguchi Y: Androgen receptor expression in breast cancer: relationship with clinicopathological factors and biomarkers. Int J Clin Oncol. 13:431–435. 2008. View Article : Google Scholar : PubMed/NCBI
46	Witzel I, Graeser M, Karn T, Schmidt M, Wirtz R, Schütze D, Rausch A, Jänicke F, Milde-Langosch K and Müller V: Androgen receptor expression is a predictive marker in chemotherapy-treated patients with endocrine receptor-positive primary breast cancers. J Cancer Res Clin Oncol. 139:809–816. 2013. View Article : Google Scholar : PubMed/NCBI
47	Tang D, Xu S, Zhang Q and Zhao W: The expression and clinical significance of the androgen receptor and E-cadherin in triple-negative breast cancer. Med Oncol. 29:526–533. 2012. View Article : Google Scholar : PubMed/NCBI
48	Hu R, Dawood S, Holmes MD, Collins LC, Schnitt SJ, Cole K, Marotti JD, Hankinson SE, Colditz GA and Tamimi RM: Androgen receptor expression and breast cancer survival in postmenopausal women. Clin Cancer Res. 17:1867–1874. 2011. View Article : Google Scholar : PubMed/NCBI
49	Lu S, Singh K, Mangray S, Tavares R, Noble L, Resnick MB and Yakirevich E: Claudin expression in high-grade invasive ductal carcinoma of the breast: correlation with the molecular subtype. Mod Pathol. 26:485–495. 2013. View Article : Google Scholar : PubMed/NCBI
50	Gerhard R, Ricardo S, Albergaria A, Gomes M, Silva AR, Logullo ÂF, Cameselle-Teijeiro JF, Paredes J and Schmitt F: Immunohistochemical features of claudin-low intrinsic subtype in metaplastic breast carcinomas. Breast. 21:354–360. 2012. View Article : Google Scholar : PubMed/NCBI
51	Sabatier R, Guille A, Adelaide J, Chaffanet M, Viens P, Birnbaum D, Bertucci F and Finetti P: Claudin-low breast cancers: clinical, pathological, molecular and prognostic characterization. Mol Cancer. 13:2282014. View Article : Google Scholar : PubMed/NCBI
52	Masuda H, Baggerly KA, Wang Y, Zhang Y, Gonzalez-Angulo AM, Meric-Bernstam F, Valero V, Lehmann BD, Pietenpol JA, Hortobagyi GN, et al: Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes. Clin Cancer Res. 19:5533–5540. 2013. View Article : Google Scholar : PubMed/NCBI