Evaluation of Prognostic Factors in Triple Negative Breast Cancer Patients with Emphasis on Angiogenesis


Affiliations

  • Banaras Hindu University, Department of General Surgery, Institute of Medical Sciences, Varanasi, U.P., 221005, India

Abstract

Developing new therapeutic methods and exploring other possible future strategies in Triple Negative Breast Cancer (TNBC) is an area of interest. Angiogenesis is one such sought for area that can even serve as a targeted therapy in this subset of breast cancer. The objective of the study was to evaluate the prognostic factors in TNBC patients with emphasis on angiogenesis. Prospectively 120 patients with histologically confirmed breast cancer from June 2015 to July 2019 were included. The Colour Doppler evaluation of breast lump and axilla in terms of RI, PI and Vmax was done. Patients were categorized as having ‘high’ or ‘low’ RI, PI and Vmax on the basis of their mean value. Immunohistochemistry (IHC) was performed on viable tumour blocks obtained from mastectomy specimen using CD31 vascular endothelial staining. The idea was to obtain Microvascular Density (MVD) by counting all immunostained vessels at magnification of 400x. The association between TNBC and non TNBC with well-known Doppler parameters, tumour size, clinical lymph node status, number of positive lymph nodes, tumour grade, stage of disease and hormonal receptor status was investigated. Also the association between high and low MVD with these prognostic parameters were evaluated. A total of 120 patients were included in the study with the mean age of 42.43±7.73 years (range 30-65 years). The mean RI, PI and Vmax were 0.92±0.26, 2.19±1.84 and 16.52±10.70 respectively. The comparison between TNBC and non-TNBC with prognostic parameters showed significant association with age of patients, duration of disease, use of oral contraceptive pills (>1 year), tumour size, histological grade, RI and MVD (p=0.041, p=0.011, p=0.002, p=0.029, p=0.026, p=0.014 and p=0.007 respectively). The MVD value >13.17 (high) was found in 45 (37.5%) patients while 75 (62.5%) patients had low MVD value (<13.17). The high MVD (>16.52) was significantly associated with tumour size (p<0.001), axillary lymph node (p=0.022), clinical stage (p=0.015), histological grade (p<0.001), RI (p<0.001), ER status (p<0.001) and HER2 over expression (p=0005). TNBC is a subset of breast cancer showing aggressive biological behaviour as seen by presence of poor prognostic marker and increased vascularity.

Keywords

Colour Doppler, CD31, Micro-vessel Density, Triple Negative Breast Cancer

Subject Discipline

General Surgery

Full Text:

References

Rakha EA Chan S. Overview Metastatic Triple-negative Breast Cancer. Clin Oncol 2011; 23: 587–600. https://doi.org/10.1016/j.clon.2011.03.013

Haffty BG, Yang Q, Reiss M, et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 2006; 24: 5652–5657. https://doi.org/10.1200/JCO.2006.06.5664

Rakha EA, Sayed ME Green RA et al. Prognostic Markers in Triple-Negative Breast Cancer. Cancer 2007; 109: 25–32. https://doi.org/10.1002/cncr.22381

Bauer KR, Brown M, Cress RD et al. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer 2007; 109: 1721–1728. https://doi.org/10.1002/cncr.22618

Rhee J, Han SW. The clinicopathologic characteristics and prognostic significance of triple-negativity in node-negative breast cancer. BMC Cancer. 2008; 8: 307–312. https://doi.org/10.1186/1471-2407-8-307

Carey LA, Perou CM, Livasy CA et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006; 295: 2492–2502. https://doi.org/10.1001/jama.295.21.2492

Cleator S, Heller W. Coombes RC. Triple-negative breast cancer: therapeutic options. Lancet Oncol 2007; 8: 235– 244. https://doi.org/10.1016/S1470-2045(07)70074-8

Pal SK, Mortimer J. Triple-negative breast cancer: novel therapies and new directions. Maturitas. 2009; 20: 63(4): 269–274. https://doi.org/10.1016/j.maturitas.2009.06.010

Mohammed RAA, Ellis IO Mahmmod AM et al. Lymphatic and blood vessels in basal and triple-negative breast cancers: characteristics and prognostic significance. Modern Pathology 2011; 24: 774–785. https://doi.org/10.1038/modpathol.2011.4

Rayson D, Vantyghem SA, Chambers AF. Angiogenesis as a target for breast cancer therapy. J Mammary Gland Biol Neoplasia 1999; 4(4): 415–423. https://doi.org/10.1023/A:1018774618873

Browder T, Butterfield CE, Kraling BM et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug resistant cancer. Cancer Res 2000; 60(7): 1878–1886.

Kumar A, Singh S, Pradhan S, Shukla RC, et al. Doppler ultrasound scoring to predict chemotherapeutic response in advanced breast cancer. World Journal of Surgical Oncology 2007; 5: 99–110. https://doi.org/10.1186/14777819-5-99

Kumar A, Srivastava V, Singh S, et al. Colour Doppler ultrasonography for treatment response prediction and evaluation in breast cancer. Future Oncol 2010; 6(8):1265– 1278. https://doi.org/10.2217/fon.10.93

Chao TC, Lo YF, Chen SC, et al. Colour Doppler ultrasound in benign and malignant breast tumours. Br

Cancer Res Treat 1999; 57: 193–199. https://doi.org/10.1023/A:1006277617884

Weidner N, Semple JP, Welch WR, Folkman J. Tumour angiogenesis and metastasis – correlation in invasive breast carcinoma. N Engl J Med 1991; 324: 1–8. https://doi.org/10.1056/NEJM199101033240101

Kim MJ, Ro JY, Ahn SH, et al. Clinicopathological significance of the basal-like subtype of breast cancer: a comparison with hormone receptor and HER-2/neu-overexpressing phenotypes. Hum Pathol. 2006; 37: 1217–1226. https://doi.org/10.1016/j.humpath.2006.04.015

Patil VW, Singhai R, Patil AV et al. Triple-negative (ER, PgR, HER-2/neu) breast cancer in Indian women 2011; 3: 9–19. https://doi.org/10.2147/BCTT.S17094

Ghosh J, Gupta S, Desai S et al. Estrogen, progesterone and HER2 receptor expression in breast tumours of patients, and their usage of HER2-targeted therapy, in a tertiary care centre in India. Indian journal of cancer 2011; 48: 391–396. https://doi.org/10.4103/0019-509X.92245

Tan GH, Taib NA, Choo WY et al. Clinical Characteristics of Triple negative Breast Cancer: Experience in an Asian Developing Country. Asian Pacific J Cancer Pre 2009; 10: 395–398.

Dent R, Trudeau M, Pritchard KI et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007; 13: 4429–4434. https://doi.org/10.1158/1078-0432.CCR-06-3045

Collett K, Stefansonn IM, Eide J et al. A basal epithelial phenotype is more frequent in interval breast cancers compared with screen detected tumours. Cancer Epidemiol Biomarkers Prev 2005; 14: 1108–1112. https://doi.org/10.1158/1055-9965.EPI-04-0394

Millikan RC, Newman B, Tse CK et al. Epidemiology of basal-like breast cancer. Breast Cancer Res Treat 2008; 109: 23–39. https://doi.org/10.1007/s10549-007-9790-6

Phipps A, Malone K, Porter P et al. Reproductive and hormonal risk factors for postmenopausal luminal, Her-2overexpressing, and triple-negative breast cancer. Cancer 2008; 113: 1521–1526. https://doi.org/10.1002/cncr.23786

Yang X, Sherman M, Rimm D et al. Differences in risk factors for breast cancer molecular subtypes in a populationbased study. Cancer Epidemiol Biomarkers Prev 2007; 16: 439–443. https://doi.org/10.1158/1055-9965.EPI-060806

White E, Malone KE, Weiss NS et al. Breast cancer among young United States women in relation to oral contraceptive use. J Natl Cancer Inst 1994; 86: 505–514. https://doi.org/10.1093/jnci/86.7.505

Marchbanks PA, McDonald JA, Wilson HG et al. Oral contraceptives and the risk of breast cancer. N Engl J Med 2002; 346: 2025–2032. https://doi.org/10.1056/NEJMoa013202

Kahlenborn C, Modugno F, Potter DM et al. Oral contraceptive use as a risk factor for premenopausal breast cancer: a metaanalysis. Mayo Clin Proc 2006; 81: 1290–302. https://doi.org/10.4065/81.10.1290

Rookus MA, van Leeuwen FE. Oral contraceptives and risk of breast cancer in women aged 20-54 years. Netherlands Oral Contraceptives and Breast Cancer Study Group. Lancet 1994; 344: 844–851. https://doi.org/10.1016/S01406736(94)92826-6

Rosenberg L, Palmer JR, Rao RS et al. Case-control study of oral contraceptive use and risk of breast cancer. Am J Epidemiol 1996; 143: 25–37. https://doi.org/10.1093/ oxfordjournals.aje.a008654

Dolle JM, Daling JR, White E et al. Risk Factors for TripleNegative Breast Cancer in Women Under the Age of 45 Years. Cancer Epidemiol Biomarkers Prev 2009; 18: 1157– 1166. https://doi.org/10.1158/1055-9965.EPI-08-1005

Donegan WL. Prognostic factors, stage and receptor status in breast cancer. Cancer 1992; 70(6 Suppl): 1755–1764. https://doi.org/10.1002/1097-0142(19920915)70:4+<1755::AIDCNCR2820701617> 3.0.CO;2-G

Fisher ER, Anderson S, Tan-Chiu E et al. Fifteen-year prognostic discriminants for invasive breast carcinoma: National Surgical Adjuvant Breast and Bowel Project Protocol-06. Cancer 2001; 91: 1679–687. https://doi.org/10.1002/10970142(20010415)91:8+<1679::AID-CNCR1183>3.0.CO;2-8

Rakha EA, Reis-Filho JS, Ellis IO. Basal-like breast cancer: a critical review. J Clin Oncol 2008; 26: 2568–2581. https://doi.org/10.1200/JCO.2007.13.1748

Crabb SJ, Cheang MC, Leung S et al. Basal breast cancer molecular subtype predicts for lower incidence of axillary lymph node metastases in primary breast cancer. Clin Breast Cancer. 2008; 8:249–256. https://doi.org/10.3816/ CBC.2008.n.028

Tan DS, Marchió C, Jones RL, et al. Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients. Breast Cancer Res Treat. 2008; 111: 27–44. https://doi.org/10.1007/s10549007-9756-8

Thike AA, Cheok PY, Jara-Lazaro AR et al. Triple-negative breast cancer: clinicopathological characteristics and relationship with basal-like breast cancer. Mod Pathol 2010; 23: 123–133. https://doi.org/10.1038/modpathol.2009.145

Choi HY, Kim HY, Baek SY et al. Significance of resistive index in colour Doppler ultrasonogram: differentiation between benign and malignant breast masses. Clin Imaging 2000; 23: 284–288. https://doi.org/10.1016/S08997071(99)00152-7

Zhu Q, You S, Jiang Y et al. Detecting angiogenesis in breast tumourssss: comparison of colour Doppler flow imaging with ultrasound-guided diffuse optical tomography. Ultrasound in Med. & Biol 2011; 37: 862–869. https://doi.org/10.1016/j.ultrasmedbio.2011.03.010

Kook SH, Park HW, Lee YR, et al. Evaluation of solid breast lesions with power Doppler sonography. J Clin Ultrasound 1999; 27: 231–237. https://doi.org/10.1002/(SICI)10970096(199906)27:5<231::AID-JCU2>3.0.CO;2-P

Peters Engl C, Medl M, Leodolter S. The use of colour coded and spectral Doppler ultrasound in the differentiation of benign and malignant breast lesions. Br J Cancer 1995; 71: 137–139. https://doi.org/10.1038/bjc.1995.28

Wang Y, Dan HJ, Fan JH, et al. Evaluation of the correlation between colourpower doppler flow imaging and vascular endothelial growth factor in breast cancer. The journal of international medical research 2010; 38: 1077–1083. https://doi.org/10.1177/147323001003800335

Shin HJ, Kim HH, Huh MO, Kim MJ, Yi A, Kim H, t al. Correlation between mammographic and sonographic findings and prognostic factors in patients with node-negative invasive cancer. Br J Radiol 2011; 84: 19–30. https://doi.org/10.1259/bjr/92960562

Kojima Y, Tsunoda H. Mammography and ultrasound features of triple-negative breast cancer. Breast Cancer 2011; 18(3):146–151. `

Lacroix MB, Grogan GM, Debled M et al. Radiological features of triple-negative breast Cancers. Diagnostic and Interventional Imaging 2012; 93: 183–190. https://doi.org/10.1016/j.diii.2012.01.006

Nathanson SD. Insights into the mechanisms of lymph node metastasis. Cancer 2003; 98: 413–423. https://doi.org/10.1002/cncr.11464

Choi WW, Lewis MM, Lawson D et al. Angiogenic and lymphangiogenic microvessel density in breast carcinoma: correlation with clinico-pathologic parameters and VEGFfamily gene expression. Mod Pathol 2005; 18: 143–152. https://doi.org/10.1038/modpathol.3800253

Gasparini G, Weidner N, Bevilacqua P, Maluta S, Dalla Palma P, Caffo O, Barbareschi M, Boracchi P, Marubini E, Pozza F. Tumour microvessel density, p53 expression, tumour size, and peritumoural lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma. J Clin Oncol 1994; 12: 454–66. https://doi.org/10.1200/JCO.1994.12.3.454

Valkovic T, Dobrila F, Melato M, Sasso F, Rizzardi C, Jonjic N. Correlation between vascular endothelial growth factor, angiogenesis, and tumour-associated macrophages in invasive ductal breast carcinoma. Virchows Arch 2002;440: 583–8. https://doi.org/10.1007/s004280100458

Şener E, Şipal S, Gündoğdu C. Comparison of Microvessel Density with Prognostic Factors in Invasive Ductal Carcinomas of the Breast. Comparison of Microvessel Density with Prognostic Factors in Invasive Ductal Carcinomas of the Breast. Turk Patoloji Derg 2016; 32(3): 164–170. https://doi.org/10.5146/tjpath.2016.01366

Bharti JN, Rani P, Kamal V, Agarwal PN. Angiogenesis in breast cancer and its correlation with estrogen, progesterone receptors and other prognostic factors. J Clin Diagn Res 2015; 9: 5–7. https://doi.org/10.7860/ JCDR/2015/10591.5447

Biesaga B, Niemiec J, Ziobro M. Microvessel density and status of p53 protein as potential prognostic factors for adjuvant anthracycline chemotherapy in retrospective analysis of early breast cancer patients group. Pathol Oncol Res 2012; 18: 949–60. https://doi.org/10.1007/s12253-0129525-9

Tsutsui S, Kume M, Era S. Prognostic value of microvessel density in invasive ductal carcinoma of the breast. Breast Cancer 2003; 10: 312–9. https://doi.org/10.1007/ BF02967651

Horak ER, Leek R, Klenk N, LeJeune S, Smith K, Stuart N, Greenall M, Stepniewska K, Harris AL. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet 1992; 340: 1120–4. https://doi.org/10.1016/0140-6736(92)93150-L

Wang G, Liang Y, Zhang H, Wang L, XU J. Microvessel density recognized by Endoglin as prognostic markers in breast carcinoma. Journal of Materials and Applications 2014; 3: 41–6.

Kato T, Kimura T, Ishii N, Fujii A, Yamamoto K, Kameoka S, Nishikawa T, Kasajima T. The methodology of quantitation of microvessel density and prognostic value of neovascularization associated with long-term survival in Japanese patients with breast cancer. Breast Cancer Res Treat 1999; 53: 19–31. https://doi.org/10.1023/A:1006193024382

Erdem O, Dursun A, Coskun U, Gunel N. The prognostic value of p53 and c-erbB-2 expression, proliferative activity and angiogenesis in node-negative breast carcinoma. Tumouri 2005; 91: 46–52. https://doi.org/10.1177/030089160509100109

Ludovini V, Sidoni A, Pistola L, Bellezza G, De Angelis V, Gori S, Mosconi AM, Bisagni G, Cherubini R, Bian AR, Rodino C, Sabbatini R, Mazzocchi B, Bucciarelli E, Tonato M, Colozza M. Evaluation of the prognostic role of vascular endothelial growth factor and microvessel density in stages I and II breast cancer patients. Breast Cancer Res Treat 2003; 81: 159–68. https://doi.org/10.1023/A:1025755717912

Vogl G, Bartel H, Dietze O, Hauser-Kronberger C. HER2 is unlikely to be involved in directly regulating angiogenesis in human breast cancer. Appl Immunohistochem Mol Morphol 2006; 14: 138–45. https://doi.org/10.1097/01.pai.0000168591.58721.a6

Martin L, Green B, Renshaw C, Lowe D, Rudland P, Leinster SJ, Winstanley J. Examining the technique of angiogenesis assessment in invasive breast cancer. Br J Cancer 1997; 76: 1046–54. https://doi.org/10.1038/bjc.1997.506

da Silva BB, Lopes-Costa PV, dos Santos AR, de SousaJunior EC, Alencar AP, Pires CG, Rosal MA. Comparison of three vascular endothelial markers in the evaluation of microvessel density in breast cancer. Eur J Gynaecol Oncol 2009; 30: 285–8.

Kanjanapanjapol S, Wongwaisayawan S, Phuwapraisirisan S, Wilasrusmee C. Prognostic significance of microvessel density in breast cancer of Thai women. J Med Assoc Thai 2007; 90: 282–90.

Obermair A, Kurz C, Czerwenka K, Thoma M, Kaider A, Wagner T, Gitsch G, Sevelda P. Microvessel density and vessel invasion in lymph-node-negative breast cancer: Effect on recurrence-free survival. Int J Cancer 1995; 62: 126–31. https://doi.org/10.1002/ijc.2910620203

Axelsson K, Ljung BM, Moore DH 2nd, Thor AD, Chew KL, Edgerton SM, Smith HS, Mayall BH. Tumour angiogenesis as a prognostic assay for invasive ductal breast carcinoma. J Natl Cancer Inst 1995; 87: 997–1008. https://doi.org/10.1093/jnci/87.13.997

Medri L, Nanni O, Volpi A, Scarpi E, Dubini A, Riccobon A, Becciolini A, Bianchi S, Amadori D. Tumour microvessel density and prognosis in node-negative breast cancer. Int J Cancer 2000; 89: 74–80. https://doi.org/10.1002/(SICI)1097-0215(20000120)89:1<74::AIDIJC12> 3.0.CO;2-L

Bosari S, Lee AK, DeLellis RA, Wiley BD, Heatley GJ, Silverman ML. Microvessel quantitation and prognosis in invasive breast carcinoma. Hum Pathol 1992; 23: 755–761. https://doi.org/10.1016/0046-8177(92)90344-3

Fridman V, Humblet C, Bonjean K, Boniver J. Assessment of tumour angiogenesis in invasive breast carcinomas: Absence of correlation with prognosis and pathological factors. Virchows Arch 2000; 437: 611–7. https://doi.org/10.1007/s004280000292

de Jong JS, van Diest PJ, Baak JP. Hot spot microvessel density and the mitotic activity index are strong additional prognostic indicators in invasive breast cancer. Histopathology 2000; 36: 306–12. https://doi.org/10.1046/ j.1365-2559.2000.00850.x

Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumourigenesis. Cell 1996; 86: 353–64. https://doi.org/10.1016/ S0092-8674(00)80108-7

Heimann R, Ferguson D, Powers C, Recant WM, Weichselbaum RR, Hellman S. Angiogenesis as a predictor of long-term survival for patients with node-negative breast cancer. J Natl Cancer Inst 1996; 88: 1764–9. https://doi.org/10.1093/jnci/88.23.1764


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