Top

Published in:

Open Access 01-10-2012 | Research

Microvessel Density and Status of p53 Protein as Potential Prognostic Factors for Adjuvant Anthracycline Chemotherapy in Retrospective Analysis of Early Breast Cancer Patients Group

Authors: Beata Biesaga, Joanna Niemiec, Marek Ziobro

Published in: Pathology & Oncology Research | Issue 4/2012

Abstract

A considerable subgroup of patients with early breast cancer does not address benefits of anthracycline based chemotherapy. The aim of this retrospective study was to investigate the effect of microvessel density (MVD) and status of p53 protein on 5-year disease free survival (DFS) in the group of breast cancer patients treated with anthracyclines in adjuvant setting. Correlations between MVD, p53 status and other clinicopathological parameters were also assessed. MVD and p53 status were analyzed immunohistochemically in the group of 172 women with breast cancer in clinical stage T1-2, N1-N2, M0. There were 123 tumors (71.5 %) with lower MVD (≤214.8 microvesells/mm²) and 49 (28.5 %) with higher MVD (>214.8 microvesells/mm²). The proportion of higher MVD tumors significantly increased in N2 (P = 0.000) and in estrogen (P = 0.046) or progesterone receptors (P = 0.029) negative tumors. p53 positivity was indicated in 50 cancers (29.1 %) and was significantly associated with higher grade (P = 0.000), steroid receptors negativity (P = 0.000), cytokeratin5/6 positivity (P = 0.026), topoisomerase IIα overexpression (P = 0.005) and higher proliferation rate (P = 0.001). In univariate analysis, higher MVD (P = 0.016) and p53 negativity (P = 0.023) were significantly related with longer DFS (median follow-up 36 months). In multivariate Cox regression analysis MVD was independently associated with DFS. These data suggest that higher MVD is favourable prognostic factors for early advanced breast cancer patients after adjuvant anthracycline based chemotherapy.

Early Breast Cancer Trialists' Collaborative Group (EBCTCG) (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365(9472):1687–717CrossRef

Andre F, Pusztai L (2006) Heterogeneity of breast cancer among patients and implications for patient selection for adjuvant chemotherapy. Pharm Res 23(9):1951–8PubMedCrossRef

Biesaga B, Niemiec J, Ziobro M, Wysocka J, Kruczak A (2011) Prognostic potential of topoisomerase IIα and HER2 in a retrospective analysis of early advanced breast cancer patients treated with adjuvant anthracycline chemotherapy. Breast 20(4):338–350PubMedCrossRef

Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis correlation with invasive breast carcinoma. N Engl J Med 324:1–8PubMedCrossRef

Gasparini G, Weidner N, Bevilacqua P, Maluta S, Dalla Palma P, Caffo O, Barbareschi M, Boracchi P, Marubini E, Pozza F (1994) Tumor microvessel density, expression, tumor size, and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma. J Clin Oncol 12(3):454–66PubMed

Heimann R, Ferguson D, Powers C, Recant WM, Weichselbaum RR, Hellman S (1996) Angiogenesis as a predictor of long-term survival for patients with node-negative breast cancer. J Natl Cancer Inst 88(23):1764–69PubMedCrossRef

Uzzan B, Nicolas P, Cucherat M, Perret GY (2004) Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis. Cancer Res 64(9):2941–55PubMedCrossRef

Nieto Y, Woods J, Nawaz F, Baron A, Jones RB, Shpall EJ, Nawaz S (2007) Prognostic analysis of tumor angiogenesis, determined by microvessel density and expression of vascular endothelial growth factor, in high-risk primary breast cancer patients treated with high-dose chemotherapy. Br J Cancer 97(3):391–7PubMedCrossRef

Tas F, Yavuz E, Aydiner A, Saip P, Disci R, Iplikci A (2000) Angiogenesis and p53 protein expression in breast cancer: prognostic roles and interrelationships. Am J Clin Oncol 23(6):546–53PubMed

10.

Viens P, Jacquemier J, Bardou VJ et al (1999) Association of angiogenesis and poor prognosis in node-positive patients receiving anthracycline-based adjuvant chemotherapy. Breast Cancer Res Treat 54(3):205–12PubMedCrossRef

11.

Gluz O, Wild P, Liedtke C, Kates R et al (2011) Tumor angiogenesis as prognostic and predictive marker for chemotherapy dose-intensification efficacy in high-risk breast cancer patients within the WSG AM-01 trial. Breast Cancer Res Treat 126(3):643–51PubMedCrossRef

12.

Kanjanapanjapol S, Wongwaisayawan S, Phuwapraisirisan S, Wilasrusmee C (2007) Prognostic significance of microvessel density in breast cancer of Thai women. J Med Assoc Thai 90(2):282–90PubMed

13.

Hansen S, Sørensen FB, Vach W, Grabau DA, Bak M, Rose C (2004) Microvessel density compared with the Chalkley count in a prognostic study of angiogenesis in breast cancer patients. Histopathology 44(5):428–36PubMedCrossRef

14.

Ludovini V, Sidoni A, Pistola L et al (2003) 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 81(2):159–68PubMedCrossRef

15.

Guidi AJ, Berry DA, Broadwater G, Helmchen B, Bleiweiss IJ, Budman DR, Henderson IC, Norton L, Hayes DF (2002) Association of angiogenesis and disease outcome in node-positive breast cancer patients treated with adjuvant cyclophosphamide, doxorubicin, and fluorouracil: a Cancer and Leukemia Group B correlative science study from protocols 8541/8869. J Clin Oncol 20(3):732–42PubMedCrossRef

16.

Ioachim E, Charchanti A, Charalabopoulos K, Tsanou H, Briasoulis E, Karavasilis V, Pavlidis N, Agnantis NJ (2002) The prognostic evaluation of tumor angiogenesis in invasive breast carcinoma. Electronic Journal of Pathology and Histology 8.1 021–02

17.

Protopapa E, Delides GS, Révész L (1993) Vascular density and the response of breast carcinomas to mastectomy and adjuvant chemotherapy. Eur J Cancer 29A(10):1391–3PubMedCrossRef

18.

Gunel N, Akcali Z, Coskun U, Akyol G, Yamac D, Yenidünya S (2002) Prognostic importance of tumor angiogenesis in breast carcinoma with adjuvant chemotherapy. Pathol Res Pract 198(1):7–12PubMedCrossRef

19.

Fedier A, Moawad A, Haller U, Fink D (2003) p53-deficient cells display increased sensitivity to anthracyclines after loss of the catalytic subunit of the DNA-dependent protein kinase. Int J Oncol 23(5):1431–7PubMed

20.

Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE, Housman DE, Jacks T (1994) p53 status and the efficacy of cancer therapy in vivo. Science 266(5186):807–10PubMedCrossRef

21.

Malamou-Mitsi V, Gogas H, Dafni U et al (2006) Evaluation of the prognostic and predictive value of p53 and Bcl-2 in breast cancer patients participating in a randomized study with dose-dense sequential adjuvant chemotherapy. Ann Oncol 17(10):1504–11PubMedCrossRef

22.

Faneyte IF, Peterse JL, Van Tinteren H et al (2004) Predicting early failure after adjuvant chemotherapy in high-risk breast cancer patients with extensive lymph node involvement. Clin Cancer Res 10(13):4457–63PubMedCrossRef

23.

Mottolese M, Benevolo M, Del Monte G, Buglioni S, Papaldo P, Nisticò C, Di Filippo F, Vasselli S, Vici P, Botti C (2000) Role of P53 and BCL-2 in high-risk breast cancer patients treated with adjuvant anthracycline-based chemotherapy. J Cancer Res Clin Oncol 126(12):722–29PubMedCrossRef

24.

Thor AD, Berry DA, Budman DR et al (1998) erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 90(18):1346–60PubMedCrossRef

25.

Chrisanthar R, Knappskog S, Løkkevik E et al (2011) Predictive and prognostic impact of TP53 mutations and MDM2 promoter genotype in primary breast cancer patients treated with epirubicin or paclitaxel. PLoS One 6(4):e19249PubMedCrossRef

26.

Geisler S, Lønning PE, Aas T, Johnsen H, Fluge O, Haugen DF, Lillehaug JR, Akslen LA, Børresen-Dale AL (2001) Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer. Cancer Res 61(6):2505–12PubMed

27.

Niskanen E, Blomqvist C, Franssila K, Hietanen P, Wasenius VM (1997) Predictive value of c-erbB-2, p53, cathepsin-D and histology of the primary tumor in metastatic breast cancer. Br J Cancer 76(7):917–22PubMedCrossRef

28.

Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Statl Association 53:457–81CrossRef

29.

Chien AJ, Moasser MM (2008) Cellular mechanisms of resistance to anthracyclines and taxanes in cancer: intrinsic and acquired. Semin Oncol 35(2 Suppl 2):S1–S14PubMedCrossRef

30.

Khromova NV, Kopnin PB, Stepanova EV, Agapova LS, Kopnin BP (2009) p53 hot-spot mutants increase tumor vascularization via ROS-mediated activation of the HIF1/VEGF-A pathway. Cancer Lett 276(2):143–51PubMedCrossRef

31.

Ushio-Fukai M (2006) Redox signaling in angiogenesis: Role of NADPH oxidase. Cardiovascular Res 71:226–35CrossRef

32.

Rykala J, Przybylowska K, Majsterek I, Pasz-Walczak G, Sygut A, Dziki A, Kruk-Jeromin J (2011) Angiogenesis markers quantification in breast cancer and their correlation with clinicopathological prognostic variables. Pathol Oncol Res 17(4):809–17PubMedCrossRef

33.

Martin L, Green B, Renshaw C, Lowe D, Rudland P, Leinster SJ, Winstanley J (1997) Examining the technique of angiogenesis assessment in invasive breast cancer. Br J Cancer 76(8):1046–54PubMedCrossRef

34.

Dittmer D, Pati S, Zambetti G, Chu S, Teresky AK, Moore M, Finlay C, Levine AJ (1993) Gain of function mutations in p53. Nat Genet 4(1):42–6PubMedCrossRef

35.

Chrisanthar R, Knappskog S, Lokkevik E et al (2008) CHEK2 mutations affecting kinase activity together with mutations in TP53 indicate a functional pathway associated with resistance to epirubicin in primary breast cancer. PLoS ONE 3(8):e3062PubMedCrossRef

36.

Bug M, Dobbelstein M (2011) Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms. Oncogene 30(33):3612–24PubMedCrossRef

Title: Microvessel Density and Status of p53 Protein as Potential Prognostic Factors for Adjuvant Anthracycline Chemotherapy in Retrospective Analysis of Early Breast Cancer Patients Group
Authors: Beata Biesaga
Joanna Niemiec
Marek Ziobro
Publication date: 01-10-2012
Publisher: Springer Netherlands
Published in: Pathology & Oncology Research / Issue 4/2012
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI: https://doi.org/10.1007/s12253-012-9525-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2012

Oncolytic Viruses in the Treatment of Cancer: A Review of Current Strategies

RUNX3 Downregulation in Human Lung Adenocarcinoma is Independent of p53, EGFR or KRAS Status

Expression of High Mobility GroupA2 is Associated with Poor Survival in Hepatocellular Carcinoma

Primary Esophageal Small Cell Carcinoma with Brain Metastasis and with CD56, KIT, and PDGFRA Expressions

Menthol Inhibits the Proliferation and Motility of Prostate Cancer DU145 Cells

The Clinical Significance of Serum Soluble Fas and p53 Protein in Breast Cancer Patients: Comparison with Serum CA 15-3

Keynote webinar | Spotlight on antibody–drug conjugates in cancer