Prognostic Value of Lymphocyte Vascular Density and E-Cadherin in Inflammatory Breast Cancer

Paul H. Levine^1*, Heather J. Hoffman¹, Audra MacNeil¹, Salman Hashmi¹, Sherry X. Yang², Stephen Hewitt³, Kenneth L. van Golen⁴, Sandra M. Swain⁵

¹Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, The George Washington University, Washington DC, USA.
²National Clinical Target Validation Laboratory, Division of Cancer Treatment & Diagnosis, National Cancer Institute, Bethesda, USA.
³Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, USA.
⁴Department of Biological Sciences, Center for Translational Cancer Research, The University of Delaware, Newark, USA.
⁵Washington Cancer Institute, MedStar Washington Hospital Center, Washington DC, USA.

DOI: 10.4236/jct.2014.514139                

Abstract

Background: We recently evaluated four laboratory assays, vascular endothelial growth factor D (VEGF-D), E-cadherin, lymphatic vessel density (LVD) measured by podoplanin, and intra-lymphatic tumor emboli (ILTE), which showed notable differences between inflammatory breast cancer (IBC) and non-inflammatory locally advanced breast cancer (LABC). In this study we investigated the potential of the three most quantitatively measured markers, E-cadherin, LVD and VEGF-D, to predict survival in the IBC patients. Materials and Methods: This study involved the 100 cases identified in the Inflammatory Breast Cancer Registry (IBCR) whose tumors were previously evaluated for the four assays noted above. Living patients were recontacted and survival data were available for up to 17 years. Overall survival (OS) was analyzed through the Kaplan-Meier method stratified by E-cadherin, LVD, VEGF-D, and response to chemotherapy. The differences in OS curves were compared using the log-rank test. Results: The median OS for patients with high LVD was 6.63 years (95% CI: 4.06 to 10.14), compared to median at 10 years not reached in those with low LVD (p = 0.03). There was a trend towards a longer median OS in patients with high E-cadherin (10.14, 95% CI: 6.63 to 11.67), compared with those with low E-cadherin (6.26, 95% CI: 3.42 to undeterminable). VEGF-D levels showed no correlation with survival. Conclusion: Low LVD significantly predicts better survival. High E-cadherin expression, as with non-IBC breast cancer and several other malignancies, tends to be associated with a better prognosis.

Keywords

IBC, Prognostic Markers, E-Cadherin, Lymphocyte Vascular Density

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Hance, K.W., Anderson, W.F., Devesa, S.S., Young, H.A. and Levine, P.H. (2005) Trends in Inflammatory Breast Carcinoma Incidence and Survival: The Surveillance, Epidemiology, and End Results Program at the National Cancer Institute. Journal of the National Cancer Institute, 97, 966-975. http://dx.doi.org/10.1093/jnci/dji172
[2]	Hoffman, H.J., Khan, A., Ajmera, K.M., Zolfaghari, L., Schenfeld, J.R. and Levine, P.H. (2014) Initial Response to Chemotherapy, Not Delay in Diagnosis, Predicts Overall Survival in Inflammatory Breast Cancer Cases. American Journal of Clinical Oncology, 37, 315-321. http://dx.doi.org/10.1097/COC.0b013e318271b34b
[3]	Levine, P.H., Portera, C.C., Hoffman, H.J., Yang, S.X., Takikita, M., Duong, Q.N., Hewitt, S.M. and Swain, S.M. (2012) Evaluation of Lymphangiogenic Factors, Vascular Endothelial Growth Factor D and E-Cadherin in Distinguishing Inflammatory from Locally Advanced Breast Cancer. Clinical Breast Cancer, 12, 232-239. http://dx.doi.org/10.1016/j.clbc.2012.04.005
[4]	Levine, P.H., Zolfaghari, L., Young, H., Hafi, M., Cannon, T., Ganesan, C., Veneroso, C., Brem, R. and Sherman, M. (2010) What Is Inflammatory Breast Cancer? Revisiting the Case Definition. Cancers, 2, 143-152. http://dx.doi.org/10.3390/cancers2010143
[5]	Van der Auwera, I., Van Laere, S.J., Van den Eynden, G.G., Benoy, I., van Dam, P., Colpaert, C.G., Fox, S.B., Turley, H., Harris, A.L., Van Marck, E.A., Vermeulen, P.B. and Dirix, L.Y. (2004) Increased Angiogenesis and Lymphangiogenesis in Inflammatory versus Noninflammatory Breast Cancer by Real-Time Reverse Transcriptase-PCR Gene Expression Quantification. Clinical Cancer Research, 10, 7965-7971. http://dx.doi.org/10.1158/1078-0432.CCR-04-0063
[6]	Van der Auwera, I., Van den Eynden, G.G., Colpaert, C.G., Van Laere, S.J., van Dam, P., Van Marck, E.A., Dirix, L.Y. and Vermeulen, P.B. (2005) Tumor Lymphangiogenesis in Inflammatory Breast Carcinoma: A Histomorphometric Study. Clinical Cancer Research, 11, 7637-7642. http://dx.doi.org/10.1158/1078-0432.CCR-05-1142
[7]	Tan, A.R., Yang, X., Hewitt, S.M., Berman, A., Lepper, E.R., Sparreboom, A., Parr, A.L., Figg, W.D., Chow, C., Steinberg, S.M., Bacharach, S.L., Whatley, M., et al. (2004) Evaluation of Biologic End Points and Pharmacokinetics in Patients with Metastatic Breast Cancer after Treatment with Erlotinib, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor. Journal of Clinical Oncology, 22, 3080-3090. http://dx.doi.org/10.1200/JCO.2004.08.189
[8]	Kleer, C.G., van Golen, K.L. and Merajver, S.D. (2000) Molecular Biology of Breast Cancer Metastasis. Inflammatory Breast Cancer: Clinical Syndrome and Molecular Determinants. Breast Cancer Research, 2, 423-429. http://dx.doi.org/10.1186/bcr89
[9]	Woodward, W.A. and Cristofanilli, M. (2009) Inflammatory Breast Cancer. Seminars in Radiation Oncology, 19, 256-265. http://dx.doi.org/10.1016/j.semradonc.2009.05.008
[10]	Cristofanilli, M., Valero, V., Buzdar, A.U., Kau, S.W., Broglio, K.R., Gonzalez-Angulo, A.M., et al. (2007) Inflammatory Breast Cancer (IBC) and Patterns of Recurrence: Understanding the Biology of a Unique Disease. Cancer, 110, 1436-1444. http://dx.doi.org/10.1002/cncr.22927
[11]	Jaiyesimi, I.A., Buzdar, A.U. and Hortobagyi, G. (1992) Inflammatory Breast Cancer: A Review. Journal of Clinical Oncology, 10, 1014-1024.
[12]	Joglekar, M. and van Golen, K.L. (2012) Molecules That Drive the Invasion and Metastasis of Inflammatory Breast Cancer. In: Ueno, N.T. and Cristofanilli, M., Eds., Inflammatory Breast Cancer: An Update, Springer, New York, 161-184. http://dx.doi.org/10.1007/978-94-007-3907-9_15
[13]	Ye, Y., Tellez, J.D., Durazo, M., Belcher, M., Yearsley, K. and Barsky, S.H. (2010) E-Cadherin Accumulation within the Lymphovascular Embolus of Inflammatory Breast Cancer Is Due to Altered Trafficking. Anticancer Research, 30, 3903-3910.
[14]	Kleer, C.G., van Golen, K.L., Braun, T. and Merajver, S.D. (2001) Persistent E-Cadherin Expression in Inflammatory Breast Cancer. Modern Pathology, 14, 458-464. http://dx.doi.org/10.1038/modpathol.3880334
[15]	Tomlinson, J.S., Alpaugh, M.L. and Barsky, S.H. (2001) An Intact Overexpressed E-Cadherin/Alpha, Beta-Catenin Axis Characterizes the Lymphovascular Emboli of Inflammatory Breast Carcinoma. Cancer Research, 61, 5231-5241.
[16]	Alpaugh, M.L., Tomlinson, J.S., Shao, Z.M. and Barsky, S.H. (1999) A Novel Human Xenograft Model of Inflammatory Breast Cancer. Cancer Research, 59, 5079-5084.
[17]	Pignatelli, M., Ansari, T.W., Gunter, P., Liu, D., Hirano, S., Takeichi, M., et al. (1994) Loss of Membranous E-Cadherin Expression in Pancreatic Cancer: Correlation with Lymph Node Metastasis, High Grade, and Advanced Stage. The Journal of Pathology, 174, 243-248. http://dx.doi.org/10.1002/path.1711740403
[18]	Perl, A.K., Wilgenbus, P., Dahl, U., Semb, H. and Christofori, G. (1998) A Causal Role for E-Cadherin in the Transition from Adenoma to Carcinoma. Nature, 392, 190-193. http://dx.doi.org/10.1038/32433
[19]	Christofori, G. and Semb, H. (1999) The Role of the Cell-Adhesion Molecule E-Cadherin as a Tumour-Suppressor Gene. Trends in Biochemical Sciences, 24, 73-76. http://dx.doi.org/10.1016/S0968-0004(98)01343-7
[20]	Alpaugh, M.L., Tomlinson, J.S., Kasraeian, S. and Barsky, S.H. (2002) Cooperative Role of E-Cadherin and Sialyl-Lewis X/A-Deficient MUC1 in the Passive Dissemination of Tumor Emboli in Inflammatory Breast Carcinoma. Oncogene, 21, 3631-3643. http://dx.doi.org/10.1038/sj.onc.1205389
[21]	Price, J.E., Carr, D. and Tarin, D. (1984) Spontaneous and Induced Metastasis of Naturally Occurring Tumors in Mice: Analysis of Cell Shedding into the Blood. Journal of the National Cancer Institute, 73, 1319-1326.
[22]	McMaster, P.D. (1947) The Relative Pressures with Cutaneous Lymphatic Capillaries and the Tissues. Journal of Experimental Medicine, 86, 293-308. http://dx.doi.org/10.1084/jem.86.4.293
[23]	Daroczy, J. (1988) The Dermal Lympahtic Capillaries. Springer, New York. http://dx.doi.org/10.1007/978-3-642-73480-9
[24]	Gray, H. (2000) The Lymphatic System. In: Lewis, W.H., Ed., Anatomy of the Human Body, 20th Edition, Bartleby, New York.
[25]	Lehman, H.L., Dashner, E.J., Lucey, M., Vermeulen, P., Dirix, L., Van Laere, S. and van Golen, K.L. (2013) Modeling and Characterization of Inflammatory Breast Cancer Emboli Grown in Vitro. International Journal of Cancer, 132, 2283-2294. http://dx.doi.org/10.1002/ijc.27928
[26]	Dong, H.M., Liu, G., Hou, Y.F., Wu, J., Lu, J.S., Luo, J.M., et al. (2007) Dominant-Negative E-Cadherin Inhibits the Invasiveness of Inflammatory Breast Cancer Cells in Vitro. Journal of Cancer Research and Clinical Oncology, 133, 83-92. http://dx.doi.org/10.1007/s00432-006-0140-6
[27]	Alpaugh, M.L., Tomlinson, J.S., Ye, Y. and Barsky, S.H. (2002) Relationship of Sialyl-Lewis (X/A) Underexpression and E-Cadherin Overexpression in the Lymphovascular Embolus of Inflammatory Breast Carcinoma. The American Journal of Pathology, 161, 619-628. http://dx.doi.org/10.1016/S0002-9440(10)64217-4
[28]	Popov, Z., Gil-Diez de Medina, S., Lefrere-Belda, M.A., Hoznek, A., Bastuji-Garin, S., Abbou, C.C., et al. (2000) Low E-Cadherin Expression in Bladder Cancer at the Transcriptional and Protein Level Provides Prognostic Information. British Journal of Cancer, 83, 209-214.
[29]	Mell, L.K., Meyer, J.J., Tretiakova, M., Khramtsov, A., Gong, C., Yamada, S.D., et al. (2004) Prognostic Significance of E-Cadherin Protein Expression in Pathological Stage I-III Endometrial Cancer. Clinical Cancer Research, 10, 5546-5553. http://dx.doi.org/10.1158/1078-0432.CCR-0943-03
[30]	Safford, S.D., Freemerman, A.J., Langdon, S., Bentley, R., Goyeau, D., Grundy, P.E., et al. (2005) Decreased E-Cadherin Expression Correlates with Higher Stage of Wilms’ Tumors. Journal of Pediatric Surgery, 40, 341-348. http://dx.doi.org/10.1016/j.jpedsurg.2004.10.030
[31]	Chunthapong, J., Seftor, E.A., Khalkhali-Ellis, Z., Seftor, R.E., Amir, S., Lubaroff, D.M., et al. (2004) Dual Roles of E-Cadherin in Prostate Cancer Invasion. Journal of Cellular Biochemistry, 91, 649-661. http://dx.doi.org/10.1002/jcb.20032
[32]	Auersperg, N., Pan, J., Grove, B.D., Peterson, T., Fisher, J., Maines-Bandiera, S., Somasiri, A. and Roskelley, C.D. (1999) E-Cadherin Induces Mesenchymal-to-Epithelial Transition in Human Ovarian Surface Epithelium. Proceedings of the National Academy of Sciences of the United States of America, 96, 6249-6254. http://dx.doi.org/10.1073/pnas.96.11.6249
[33]	Haupt, H.M., Hood, A.F. and Cohen, M.H. (1984) Inflammatory Melanoma. Journal of the American Academy of Dermatology, 10, 52-55. http://dx.doi.org/10.1016/S0190-9622(84)80042-0
[34]	Schoppmann, S.F., Bayer, G., Aumary, K., Taucher, S., Geleff, S., Rudas, K., Kubista, E., Hausmaninger, H., Samonigg, H., Gnant, M., Jakesz, R. and Horvat, R., Austrian Breast and Colorectal Cancer Study Group (2004) Prognostic Value of Lymphangiogenesis and Lymphovascular Invasion in Invasive Breast Cancer. Annals of Surgery, 240, 306-312. http://dx.doi.org/10.1097/01.sla.0000133355.48672.22
[35]	Nakumara, Y., Yasuoka, H., Tsujimoto, M., Imabun, S., Nakahara, M., Nakao, K., Nakamura, M., Mori, I. and Kakudo, K. (2005) Lymph Vessel Density Correlates with Nodal Status, VEGF-C Expression and Prognosis in Breast Cancer. Breast Cancer Research and Treatment, 91, 125-132. http://dx.doi.org/10.1007/s10549-004-5783-x
[36]	Mohammed, R.A., Ellis, I.O., Eisheikh, S., Paish, E.C. and Martin, S.G. (2009) Lymphatic and Angiogenic Characteristics in Breast Cancer: Morphometric Analysis and Prognostic Implications. Breast Cancer Research and Treatment, 113, 261-273. http://dx.doi.org/10.1007/s10549-008-9936-1
[37]	Mohamed, M.M. (2012) Monocytes Conditioned Media Stimulate Fibronectin Expression and Spreading of Inflammatory Breast Cancer Cells in Three-Dimensional Culture: A Mechanism Mediated by IL-8 Signaling Pathway. Cell Communication and Signaling, 10, 3. http://dx.doi.org/10.1186/1478-811X-10-3
[38]	van Golen, K.L. and Cristofanilli, M. (2013) The Third International Inflammatory Breast Cancer Conference. Breast Cancer Research, 15, 318.