Biomarkers for Inflammatory Breast Cancer: Diagnostic and Therapeutic Utility

CONCLUSION

Despite the multimodal treatment, patients with IBC still have particularly poor prognosis and high risk of early recurrence. Their survival rate remains significantly worse compared to patients with nonIBC.

An improved biological understanding of IBC suggesting the possibility of more personalized effective targeted therapies with the improvement of the clinical outcomes in these patients. The contribution of tumor microenvironment with the abundance of cytokines and chemokines to the disease is fundamental. Thus, cytokine blockade and immunotherapy may play a crucial role in the treatment of IBC in the future.

Acknowledgments

We would like to acknowledge Denisa Manasova for her excellent technical help. We are grateful to all patients for their participation in the study.

Funding

This research was funded by the Slovak Research and Development Agency (APVV), grant number APVV-16-0010.

Disclosure

The authors declare no conflict of interest.


Barbora Dobiasova, Michal Mego

2nd Department of Oncology, Comenius University, Faculty of Medicine, National Cancer Institute, Bratislava, Slovak Republic

Correspondence: Michal Mego
2 nd Department of Oncology, Comenius University, Faculty of Medicine, National Cancer Institute, Klenova 1, Bratislava 833 10, Slovak Republic
Tel +421-2-59378366
Fax +421-2-54774943
Email [email protected]


References

1. Hance KW, Anderson WF, Devesa SS, et al. Trends in inflammatory breast carcinoma incidence and survival: the surveillance, epidemiology, and end results program at the National Cancer Institute. J Natl Cancer Inst. 2005;97:966–975. doi:10.1093/jnci/dji172

2. Dawood S, Lei X, Dent R, et al. Survival of women with inflammatory breast cancer: a large population-based study. Ann Oncol. 2014;25:1143–1151. doi:10.1093/annonc/mdu121

3. Boussen H, Bouzaiene H, Ben Hassouna J, et al. Inflammatory breast cancer in Tunisia: epidemiological and clinical trends. Cancer. 2010;116(S11):2730–2735. doi:10.1002/cncr.25175

4. Lyman GH, Giuliano AE, Somerfield MR, et al. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol. 2005;23:7703. doi:10.1200/JCO.2005.08.001

5. Dawood S, Merajver SD, Viens P, et al. International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment. Ann Oncol. 2011;22:515. doi:10.1093/annonc/mdq345

6. McCarthy NJ, Yang X, Linnoila IR, et al. Microvessel density, expression of estrogen receptor alpha, MIB-1, p53, and c-erbB-2 in inflammatory breast cancer. Clin Cancer Res. 2002;8:3857.

7. Lim B, Woodward WA, Wang X, et al. Inflammatory breast cancer biology: the tumour microenvironment is key. Nat Rev Cancer. 2018;18:485–499. doi:10.1038/s41568-018-0010-y

8. Robbins GF, Shah J, Rosen P, et al. Inflammatory carcinoma of the breast. Surg Clin North Am. 1974;54:801. doi:10.1016/S0039-6109(16)40383-X

9. Bonnier P, Charpin C, Lejeune C, et al. Inflammatory carcinomas of the breast: a clinical, pathological, or a clinical and pathological definition? Int J Cancer. 1995;62:382–385. doi:10.1002/ijc.2910620404

10. Manfrin E, Remo A, Pancione M, et al. Comparison between invasive breast cancer with extensive peritumoral vascular invasion and inflammatory breast carcinoma: a clinicopathologic study of 161 cases. Am J Pathol. 2014;142:299–306.

11. Charpin C, Bonnier P, Khouzami A, et al. Inflammatory breast carcinoma: an immunohistochemical study using monoclonal anti- pHER-2/neu, pS2, cathepsin, ER and PR. Anticancer Res. 1992;12:591–597.

12. Xiao Y, Ye Y, Zou X, et al. The lymphovascular embolus of inflammatory breast cancer exhibits a Notch 3 addiction. Oncogene. 2011;30(3):287–300. doi:10.1038/onc.2010.405

13. Ye Y, Gao J-X, Tian H, et al. Early to intermediate steps of tumor embolic formation involve specific proteolytic processing of E- cadherin regulated by Rab7. Mol Cancer Res. 2012;10:713–726. doi:10.1158/1541-7786.MCR-12-0009

14. Charafe-Jauffret E, Ginestier C, Iovino F, et al. Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin Cancer Res. 2010;16:45–55. doi:10.1158/1078-0432.CCR-09-1630

15. Silvera D, Schneider RJ. Inflammatory breast cancer cells are constitutively adapted to hypoxia. Cell Cycle. 2009;8:3091–3096. doi:10.4161/cc.8.19.9637

16. Grosse-Wilde A, Fouquier d’Hérouël A, McIntosh E, et al. Stemness of the hybrid epithelial/mesenchymal state in breast cancer and its association with poor survival. PLoS One. 2015;10:e0126522. doi:10.1371/journal.pone.0126522

17. Jolly MK, Boareto M, Debeb BG, et al. Inflammatory breast cancer: a model for investigating cluster-based dissemination. NPJ Breast Cancer. 2017;3(1):21. doi:10.1038/s41523-017-0023-9

18. Masuda H, Brewer TM, Liu DD, et al. Long- term treatment efficacy in primary inflammatory breast cancer by hormonal receptor- and HER2-defined subtypes. Ann Oncol. 2014;25:384–391. doi:10.1093/annonc/mdt525

19. Kertmen N, Babacan T, Keskin O, et al. Molecular subtypes in patients with inflammatory breast cancer; a single center experience. J BUON. 2015;20:35–39.

20. Parton M, Dowsett M, Ashley S, et al. High incidence of HER-2 positivity in inflammatory breast cancer. Breast. 2004;13(2):97–103. doi:10.1016/j.breast.2003.08.004

21. Ross JS, Ali SM, Wang K, et al. Comprehensive genomic profiling of inflammatory breast cancer cases reveals a high frequency of clinically relevant genomic alterations. Breast Cancer Res Treat. 2015;154(1):152–162. doi:10.1007/s10549-015-3592-z

22. Matsuda N, Lim B, Wang Y, et al. Identification of frequent somatic mutations in inflammatory breast cancer. Breast Cancer Res Treat. 2017;163(2):263–272. doi:10.1007/s10549-017-4165-0

23. Rana HQ, Sacca R, Drogan C, et al. Prevalence of Germline Variants in Inflammatory Breast Cancer. Cancer. 2019;125(13):2194–2202.

24. Moll UM, Riou G, Levine AJ. Two distinct mechanisms alter p53 in breast cancer: mutation and nuclear exclusion. Proc Natl Acad Sci U S A. 1992;89:7262. doi:10.1073/pnas.89.15.7262

25. Riou G, Lê MG, Travagli JP, et al. Poor prognosis of p53 gene mutation and nuclear overexpression of p53 protein in inflammatory breast carcinoma. J Natl Cancer Inst. 1993;85(21):1765. doi:10.1093/jnci/85.21.1765

26. Qi Y, Wang X, Kong X, et al. Expression signatures and roles of microRNAs in inflammatory breast cancer. Cancer Cell Int. 2019;19:23. doi:10.1186/s12935-018-0709-6

27. Ding Q, Wang Y, Zuo Z, et al. Decreased expression of microRNA-26b in locally advanced and inflammatory breast cancer. Hum Pathol. 2018;77:121–129. doi:10.1016/j.humpath.2018.04.002

28. Huo L, Wang Y, Gong Y, et al. MicroRNA expression profiling identifies decreased expression of miR-205 in inflammatory breast cancer. Mod Pathol. 2016;29(4):330–346. doi:10.1038/modpathol.2016.38

29. Kleer CG, Zhang Y, Pan Q, et al. WISP3 is a novel tumor suppressor gene of inflammatory breast cancer. Oncogene. 2002;21:3172–3180. doi:10.1038/sj.onc.1205462

30. Haga RB, Ridley AJ. Rho GTPases: regulation and roles in cancer cell biology. Small GTPases. 2016;7:207–221. doi:10.1080/21541248.2016.1232583

31. Van Golen KL, Wu ZF, Qiao XT, et al. RhoC GTPase overexpression modulates induction of angiogenic factors in breast cells. Neoplasia. 2000;2:418–425. doi:10.1038/sj.neo.7900115

32. Wu M, Wu ZF, Kumar-Sinha C, et al. RhoC induces differential expression of genes involved in invasion and metastasis in MCF10A breast cells. Breast Cancer Res Treat. 2004;84:3–12. doi:10.1023/B:BREA.0000018426.76893.21

33. Van Golen KL, Wu ZF, Qiao XT, et al. RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype. Cancer Res. 2000;60:5832–5838.

34. Joglekar M, Elbazanti WO, Weitzman MD, Lehman HL, van Golen KL. Caveolin-1 mediates inflammatory breast cancer cell invasion via the Akt1 pathway and RhoC GTPase. J Cell Biochem. 2015;116:923–933. doi:10.1002/jcb.25025

35. Van Laere SJ, Ueno NT, Finetti P, et al. Uncovering the molecular secrets of inflammatory breast cancer biology: an integrated analysis of three distinct Affymetrix gene expression datasets. Clin Cancer Res. 2013;19:4685–4696. doi:10.1158/1078-0432.CCR-12-2549

36. Manai M, Thomassin-Piana J, Gamoudi A, et al. MARCKS protein overexpression in inflammatory breast cancer. Oncotarget. 2017;8(4):6246–6257. doi:10.18632/oncotarget.14057

37. Boersma BJ, Reimers M, Yi M, et al. A stromal gene signature associated with inflammatory breast cancer. Int J Cancer. 2008;122(6):1324–1332. doi:10.1002/ijc.23237

38. Rosen PP. Rosen’s Breast Pathology. Philadelphia: Lippincott-Raven; 1996.

39. Levine PH, Portera CC, Hoffman HJ, et al. Evaluation of lymphangiogenic factors, vascular endothelial growth factor D and E- cadherin in distinguishing inflammatory from locally advanced breast cancer. Clin Breast Cancer. 2012;12:232–239. doi:10.1016/j.clbc.2012.04.005

40. Skobe M, Hawighorst T, Jackson DG, et al. Induction of tumor lymphangiogenesis by VEGFC promotes breast cancer metastasis. Nat Med. 2001;7:192. doi:10.1038/84643

41. Stacker SA, Caesar C, Baldwin ME, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med. 2001;7:186. doi:10.1038/84635

42. Kurebayashi J, Otsuki T, Kunisue H, et al. Expression of vascular endothelial growth factor (VEGF) family members in breast cancer. Jpn J Cancer Res. 1999;90:977. doi:10.1111/j.1349-7006.1999.tb00844.x

43. Pierga JY, Petit T, Delozier T, et al. Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for primary inflammatory HER2-positive breast cancer (BEVERLY-2): an open- label, single- arm phase 2 study. Lancet Oncol. 2012;13:375–384. doi:10.1016/S1470-2045(12)70049-9

44. Cabioglu N, Gong Y, Islam R, et al. Expression of growth factor and chemokine receptors: new insights in the biology of inflammatory breast cancer. Ann Oncol. 2007;18(6):1021–1029. doi:10.1093/annonc/mdm060

45. Nemunaitis JJ, Small KA, Kirschmeier P, et al. A first-in-human, Phase 1, dose-escalation study of dinaciclib, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies. J Transl Med. 2013;11:259. doi:10.1186/1479-5876-11-259

46. Mitri Z, Karakas C, Wei C, et al. A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer. Invest New Drugs. 2015;33:890–894. doi:10.1007/s10637-015-0244-4

47. Mita MM, Joy AA, Mita A, et al. Randomized Phase II trial of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus capecitabine in patients with advanced breast cancer. Clin Breast Cancer. 2014;14:169–176. doi:10.1016/j.clbc.2013.10.016

48. Alexander A, Karakas C, Chen X, et al. Cyclin E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer. Oncotarget. 2017;8(9):14897–14911. doi:10.18632/oncotarget.14689

49. Debeb BG, Gong Y, Atkinson RL, et al. EZH2 expression correlates with locoregional recurrence after radiation in inflammatory breast cancer. J Exp Clin Cancer Res. 2014;33(1):58. doi:10.1186/s13046-014-0058-9

50. Shostak K, Chariot A. NF-kappaB, stem cells and breast cancer: the links get stronger. Breast Cancer Res. 2011;13:214. doi:10.1186/bcr2886

51. Xia Y, Shen S, Verma IM. NF-kappaB, an active player in human cancers. Cancer Immunol Res. 2014;2:823–830. doi:10.1158/2326-6066.CIR-14-0112

52. Wang W, Kryczek I, Dostál L, et al. Effector T cells abrogate stroma- mediated chemoresistance in ovarian cancer. Cell. 2016;165:1092–1105. doi:10.1016/j.cell.2016.04.009

53. Jhaveri K, Teplinsky E, Silvera D, et al. Hyperactivated mTOR and JAK2/STAT3 pathways: molecular drivers and potential therapeutic targets of inflammatory and invasive Ductal breast cancers after neoadjuvant chemotherapy. Clin Breast Cancer. 2016;16(2):113–122. doi:10.1016/j.clbc.2015.11.006

54. Aaronson DS, Horvath CM. A road map for those who don’t know JAK- STAT. Science. 2002;296:1653–1655. doi:10.1126/science.1071545

55. Bieche I, Lerebours F, Tozlu S, et al. Molecular profiling of inflammatory breast cancer: identification of a poor- prognosis gene expression signature. Clin Cancer Res. 2004;10:6789–6795. doi:10.1158/1078-0432.CCR-04-0306

56. US National Library of Medicine. ClinicalTrials.gov; 2017. Available from: https://www.clinicaltrials.gov/ct2/show/NCT02041429. Accessed October 7, 2020.

57. Drygin D, Ho CB, Omori M, et al. Protein kinase CK2 modulates IL-6 expression in inflammatory breast cancer. Biochem Biophys Res Commun. 2011;415:163–167. doi:10.1016/j.bbrc.2011.10.046

58. Wolfe AR, Trenton NJ, Debeb BG, et al. Mesenchymal stem cells and macrophages interact through IL-6 to promote inflammatory breast cancer in pre- clinical models. Oncotarget. 2016;7:82482–82492. doi:10.18632/oncotarget.12694

59. Hamm CA, Moran D, Rao K, et al. Genomic and immunological tumor profiling identifies targetable pathways and extensive CD8+/PDL1 +immune infiltration in inflammatory breast cancer tumors. Mol Cancer Ther. 2016;15(7):1746–1756. doi:10.1158/1535-7163.MCT-15-0353

60. Andre F, O’Regan R, Ozguroglu M, et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled Phase 3 trial. Lancet Oncol. 2014;15:580–591. doi:10.1016/S1470-2045(14)70138-X

61. Ristimaki A, Sivula A, Lundin J, et al. Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res. 2002;62:632–635.

62. Wang X, Reyes ME, Zhang D, et al. EGFR signaling promotes inflammation and cancer stem- like activity in inflammatory breast cancer. Oncotarget. 2017;8:67904–67917. doi:10.18632/oncotarget.18958

63. Reddy JP, Atkinson RL, Larson R, et al. Mammary stem cell and macrophage markers are enriched in normal tissue adjacent to inflammatory breast cancer. Breast Cancer Res Treat. 2018;171(2):283–293. doi:10.1007/s10549-018-4835-6

64. Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124:263–266. doi:10.1016/j.cell.2006.01.007

65. Morrow RJ, Etemadi N, Yeo B, et al. Challenging a misnomer? The role of inflammatory pathways in inflammatory breast cancer. Mediators Inflamm. 2017;2017:4754827. 33. doi:10.1155/2017/4754827

66. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–1437. doi:10.1038/nm.3394

67. Rahal OM, Wolfe AR, Mandal PK, et al. Blocking Interleukin (IL)4- and IL13-mediated phosphorylation of STAT6 (Tyr641) decreases M2 polarization of macrophages and protects against macrophage-mediated radioresistance of inflammatory breast cancer. Int J Radiat Oncol Biol Phys. 2018;100(4):1034–1043. doi:10.1016/j.ijrobp.2017.11.043

68. Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother. 2007;56:739–745. doi:10.1007/s00262-006-0272-1

69. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563–567. doi:10.1038/nature14011

70. Bertucci F, Finetti P, Birnbaum D, et al. The PD1/PDL1 axis, a promising therapeutic target in aggressive breast cancers. Oncoimmunology. 2015;5:e1085148.

71. Bertucci F, Finetti P, Colpaert C, et al. PDL1 expression in inflammatory breast cancer is frequent and predicts for the pathological response to chemotherapy. Oncotarget. 2015;6:13506–13519. doi:10.18632/oncotarget.3642

72. Peng W, Liu C, Xu C, et al. PD-1 blockade enhances T-cell migration to tumors by elevating IFN-gamma inducible chemokines. Cancer Res. 2012;72:5209–5218. doi:10.1158/0008-5472.CAN-12-1187

73. He J, Huo L, Ma J, et al. Expression of programmed death ligand 1 (PD-L1) in posttreatment primary inflammatory breast cancers and clinical implications. Am J Clin Pathol. 2018;149(3):253–261. doi:10.1093/ajcp/aqx162

74. Arias-Pulido H, Cimino-Mathews A, Chaher N, et al. The combined presence of CD20 + B cells and PD-L1 + tumor-infiltrating lymphocytes in inflammatory breast cancer is prognostic of improved patient outcome. Breast Cancer Res Treat. 2018;171(2):273–282. doi:10.1007/s10549-018-4834-7

75. Mego M, Gao H, Cohen EN, et al. Circulating tumor cells (CTCs) are associated with abnormalities in peripheral blood dendritic cells in patients with inflammatory breast cancer. Oncotarget. 2016;8:35656–35658. doi:10.18632/oncotarget.10290

76. Fei M, Bhatia S, Oriss TB, et al. TNF- alpha from inflammatory dendritic cells (DCs) regulates lung IL-17A/IL-5 levels and neutrophilia versus eosinophilia during persistent fungal infection. Proc Natl Acad Sci USA. 2011;108:5360–5365. doi:10.1073/pnas.1015476108

77. Hilkens CM, Kalinski P, de Boer M, et al. Human dendritic cells require exogenous interleukin-12-inducing factors to direct the development of naive T- helper cells toward the Th1 phenotype. Blood. 1997;90:1920–1926. doi:10.1182/blood.V90.5.1920

78. Janni WJ, Rack B, Terstappen LW, et al. Pooled analysis of the prognostic relevance of circulating tumor cells in primary breast cancer. Clin Cancer Res. 2016;22:2583–2593. doi:10.1158/1078-0432.CCR-15-1603

79. Pierga JY, Bidard FC, Autret A, et al. Circulating tumour cells and pathological complete response: independent prognostic factors in inflammatory breast cancer in a pooled analysis of two multicentre phase II trials (BEVERLY-1 and −2) of neoadjuvant chemotherapy combined with bevacizumab. Ann Oncol. 2017;28(1):103–109. doi:10.1093/annonc/mdw535

80. Mego M, Giordano A, De Giorgi U, et al. Circulating tumor cells in newly diagnosed inflammatory breast cancer. Breast Cancer Res. 2015;17(1):2. doi:10.1186/s13058-014-0507-6

81. Mego M, Gao H, Cohen EN, et al. Circulating tumor cells (CTC) are associated with defects in adaptive immunity in patients with inflammatory breast cancer. J Cancer. 2016;7(9):1095–1104. doi:10.7150/jca.13098

82. Tabouret E, Bertucci F, Pierga JY, et al. MMP2 and MMP9 serum levels are associated with favorable outcome in patients with inflammatory breast cancer treated with bevacizumab-based neoadjuvant chemotherapy in the BEVERLY-2 study. Oncotarget. 2016;7(14):18531–18540. doi:10.18632/oncotarget.7612

83. Mohamed MM, El-Ghonaimy EA, Nouh MA, et al. Cytokines secreted by macrophages isolated from tumor microenvironment of inflammatory breast cancer patients possess chemotactic properties. Int J Biochem Cell Biol. 2014;46:138–147. doi:10.1016/j.biocel.2013.11.015

Source: Breast Cancer: Targets and Therapy.
Originally published October 14, 2020.

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