Nodal staging in breast cancer is a key predictor of prognosis. This paper presents the results of potential clinicopathological predictors of axillary lymph node involvement and develops an efficient prediction model to assist in predicting axillary lymph node metastases. Seventy patients with primary early breast cancer who underwent axillary dissection were evaluated. Univariate and multivariate logistic regression were performed to evaluate the association between clinicopathological factors and lymph node metastatic status. A logistic regression predictive model was built from 50 randomly selected patients; the model was also applied to the remaining 20 patients to assess its validity. Univariate analysis showed a significant relationship between lymph node involvement and absence of nm-23 (p = 0.010) and Kiss-1 (p = 0.001) expression. Absence of Kiss-1 remained significantly associated with positive axillary node status in the multivariate analysis (p = 0.018). Seven clinicopathological factors were involved in the multivariate logistic regression model: menopausal status, tumor size, ER, PR, HER2, nm-23 and Kiss-1. The model was accurate and discriminating, with an area under the receiver operating characteristic curve of 0.702 when applied to the validation group. Moreover, there is a need discover more specific candidate proteins and molecular biology tools to select more variables which should improve predictive accuracy.
References
[1]
Soerjomataram, I.; Louwman, M.W.; Ribot, J.G.; Roukema, J.A.; Coebergh, J.W. An overview of prognostic factors for long-term survivors of breast cancer. Breast Cancer Res. Treat. 2008, 107, 309–330.
[2]
Velanovich, V.; Szymanski, W. Quality of life of breast cancer patients with lymphedema. Am. J. Surg. 1999, 177, 184–187.
[3]
Maunsell, E.; Brisson, J.; Deschenes, L. Arm problems and psychological distress after surgery for breast cancer. Can. J. Surg. 1993, 36, 315–320.
[4]
Gipponi, M.; Bassetti, C.; Canavese, G.; Catturich, A.; Di Somma, C.; Vecchio, C.; Nicolò, G.; Schenone, F.; Tomei, D.; Cafiero, F. Sentinel lymph node as a new marker for therapeutic planning in breast cancer patients. J. Surg. Oncol. 2004, 85, 102–111.
[5]
Gipponi, M.; Bassetti, C.; Canavese, G.; Catturich, A.; di Somma, C.; Vecchio, C.; Nicolò, G.; Schenone, F.; Tomei, D.; Cafiero, F. Morbidity of sentinel lymph node biopsy (SLN) alone versus SLN and completion axillary lymph node dissection after breast cancer surgery. Ann. Surg. 2007, 245, 452–461.
[6]
Gipponi, M.; Bassetti, C.; Canavese, G.; Catturich, A.; di Somma, C.; Vecchio, C.; Nicolò, G.; Schenone, F.; Tomei, D.; Cafiero, F. Lymphedema after sentinel lymphadenectomy for breast carcinoma. Cancer 2001, 92, 748–752.
[7]
R?nk?, R.; von Smitten, K.; Tasmuth, T.; Leidenius, M. One-year morbidity after sentinel node biopsy and breast surgery. Breast 2005, 14, 28–36.
[8]
Barone, J.E.; Tucker, J.B.; Perez, J.M.; Odom, S.R.; Ghevariya, V. Evidence-based medicine applied to sentinel lymph node biopsy in patients with breast cancer. Am. Surg. 2005, 71, 66–70.
[9]
Veronesi, U. The sentinel node and breast cancer. Br. J. Surg. 1999, 86, 1–2.
[10]
Kamath, V.J.; Giuliano, R.; Dauway, E.L.; Cantor, A.; Berman, C.; Ku, N.N.; Cox, C.E.; Reintgen, D.S. Characteristics of the sentinel lymph node in breast cancer predict further involvement of higher-echelon nodes in the axilla: A study to evaluate the need for complete axillary lymph node dissection. Arch. Surg. 2001, 136, 688–692.
[11]
Rahusen, F.D.; Torrenga, H.; van Diest, P.J.; Pijpers, R.; van der Wall, E.; Licht, J.; Meijer, S. Predictive factors for metastatic involvement of nonsentinel nodes in patients with breast cancer. Arch. Surg. 2001, 136, 1059–1063.
[12]
Giuliano, A.E.; Hunt, K.K.; Ballman, K.V.; Beitsch, P.D.; Whitworth, P.W.; Blumencranz, P.W.; Leitch, A.M.; Saha, S.; McCall, L.M.; Morrow, M. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: A randomized clinical trial. J. Am. Med. Assoc. 2011, 305, 569–575.
[13]
Cady, B. Case against axillary lymphadenectomy for most patients with infiltrating breast cancer. J. Surg. Oncol. 1997, 66, 7–10.
[14]
Van Zee, K.J.; Manasseh, D.M.; Bevilacqua, J.L.; Boolbol, S.K.; Fey, J.V.; Tan, L.K.; Borgen, P.I.; Cody, H.S.; Kattan, M.W. A nomogram for predicting the likelihood of additional nodal metastasis in breast cancer patients with a positive sentinel node biopsy. Ann. Surg. Oncol. 2003, 10, 1140–1151.
[15]
Barranger, E.; Coutant, C.; Flahault, A.; Delpech, Y.; Darai, E.; Uzan, S. An axilla scoring system to predict non-sentinel lymph node status in breast cancer patients with sentinel lymph node involvement. Breast Cancer Res. Treat. 2005, 91, 113–119.
[16]
Pal, A.; Provenzano, E.; Duffy, S.W.; Pinder, S.E.; Purushotham, A.D. A model for predicting non-sentinel lymph node metastatic disease when the sentinel lymph node is positive. Br. J. Surg. 2008, 95, 302–309.
[17]
Katz, A.; Smith, B.L.; Golshan, M.; Niemierko, A.; Kobayashi, W.; Raad, R.A.; Kelada, A.; Rizk, L.; Wong, J.S.; Bellon, J.R.; et al. Nomogram for the prediction of having four or more involved nodes for sentinel lymph node-positive breast cancer. J. Clin. Oncol. 2008, 26, 2093–2098.
[18]
Gur, A.S.; Unal, B.; Ozbek, U.; Ozmen, V.; Aydogan, F.; Gokgoz, S.; Gulluoglu, B.M.; Aksaz, E.; Ozbas, S.; Baskan, S.; et al. Validation of breast cancer nomograms for predicting the non-sentinel lymph node metastases after a positive sentinel lymph node biopsy in a multi-center study. Eur. J. Surg. Oncol. 2010, 36, 30–35.
[19]
Bevilacqua, J.L.; Kattan, M.W.; Fey, J.V.; Cody, H.S.; Borgen, P.I.; van Zee, K.J. Doctor, what are my chances of having a positive sentinel node? A validated nomogram for risk estimation. J. Clin. Oncol. 2007, 25, 3670–3679.
[20]
Harvey, J.M.; Clark, G.M.; Osborne, C.K.; Allred, D.C. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J. Clin. Oncol. 1999, 17, 1474–1481.
[21]
Mickey, R.M.; Greenland, S. The impact of confounder selection criteria on effect estimation. Am. J. Epidemiol. 1989, 129, 129–137.
[22]
Mansel, R.E.; Fallowfield, L.; Kissin, M.; Goyal, A.; Newcombe, R.G.; Dixon, J.M.; Yiangou, C.; Horgan, K.; Bundred, N.; Monypenny, I.; et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: The ALMANAC trial. J. Natl. Cancer Inst. 2006, 98, 599–609.
[23]
Langer, I.; Guller, U.; Berclaz, G.; Koechli, O.R.; Schaer, G.; Fehr, M.K.; Hess, T.; Oertli, D.; Bronz, L.; Schnarwyler, B.; et al. Morbidity of sentinel lymph node biopsy (SLN) alone versus SLN and completion axillary lymph node dissection after breast cancer surgery: A prospective Swiss multicenter study on 659 patients. Ann. Surg. 2007, 245, 452–461.
[24]
Krag, D.N.; Julian, T.B.; Harlow, S.P.; Weaver, D.L.; Ashikaga, T.; Bryant, J.; Single, R.M.; Wolmark, N. NSABP-32: Phase III, randomized trial comparing axillary resection with sentinel lymph node dissection: A description of the trial. Ann. Surg. Oncol. 2004, 11, 208S–210S.
[25]
Chagpar, A.B.; Martin, R.C.; Scoggins, C.R.; Carlson, D.J.; Laidley, A.L.; El-Eid, S.E.; McGlothin, T.Q.; Noyes, R.D.; Ley, P.B.; Tuttle, T.M.; et al. Factors predicting failure to identify a sentinel lymph node in breast cancer. Surgery 2005, 138, 56–63.
[26]
Martel, P.; Capdet, J.; Méry, E.; Zerdoud, S.; Ferron, G.; Rafii, A.; Roché, H.; Querleu, D. Critical study of our initial experience of 993 sentinel node biopsies for breast surgery. 2008, 95, 763–772.
[27]
Ramjeesingh, R.; Quan, M.L.; Gardner, S.; Holloway, C.M. Prediction of involvement of sentinel and nonsentinel lymph nodes in a Canadian population with breast cancer. Can. J. Surg. 2009, 52, 23–30.
[28]
Steeg, P.S.; Bevilacqua, G.; Kopper, L.; Thorgeirsson, U.P.; Talmadge, J.E.; Liotta, L.A.; Sobel, M.E. Evidence for a novel gene associated with low tumour metastatic potential. J. Natl. Cancer Inst. 1988, 80, 200–204.
[29]
Chen, S.L.; Wu, Y.S.; Shieh, H.Y.; Yen, C.C.; Shen, J.J.; Lin, K.H. p35 is a regulator of the metastasis suppressor gene nm23-H. Mol. Carcinog. 2003, 36, 204–214.
[30]
Martinez, J.A.; Prevot, S.; Nordlinger, B.; Nguyen, T.M.; Lacarriere, Y.; Munier, A.; Lascu, I.; Vaillant, J.C.; Capeau, J.; Lacombe, M.L. Overexpression of nm23-H1 and nm23-H2 genes in colorectal carcinomas and loss of nm23-H1 expression in advanced tumor stages. Gut 1995, 37, 712–720.
[31]
Mao, H.; Liu, H.; Fu, X.; Fang, Z.; Abrams, J.; Worsham, M.J. Loss of nm23 expression predicts distal metastasis and poorer survival for breast cancer. Int. J. Oncol. 2001, 18, 387–391.
[32]
Hirayama, R.; Sawai, S.; Takagi, Y.; Mishima, Y.; Kimura, N.; Shimada, N.; Esaki, Y.; Kurashima, C.; Utsuyama, M.; Hirokawa, K. Positive relationship between expression of anti-metastatic factor (nm23 gene product or nucleoside diphosphate kinase) and good prognosis in human breast cancer. J. Natl. Cancer Inst. 1991, 83, 1249–1250.
[33]
Tokunaga, Y.; Urano, T.; Furukawea, K.; Kondo, H.; Kanematsu, T.; Shiku, H. Reduced expression of nm23/NDP kinase-h1, but not nm23/NDP kinase-h2, is concordant with the frequency of lymph-node metastasis of human breast cancer. 1993, 55, 66–71.
[34]
Lee, J.H.; Miele, M.E.; Hicks, D.J.; Phillips, K.K.; Trent, J.M.; Weissman, B.E.; Welch, D.R. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J. Natl. Cancer Inst. 1996, 88, 1731–1737.
[35]
Lee, J.H.; Welch, D.R. Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res. 1997, 57, 2384–2387.
[36]
Mitchell, D.C.; Abdelrahim, M.; Weng, J.; Stafford, L.J.; Safe, S.; Bar-Eli, M.; Liu, M. Regulation of KiSS-1 metastasis suppressor gene expression in breast cancer cells by direct interaction of transcription factors activator protein-2alpha and specificity protein-1. J. Biol. Chem. 2006, 281, 51–58.
[37]
Kostadima, L.; Pentheroudakis, G.; Pavlidis, N. The missing kiss of life: Transcriptional activity of the metastasis suppressor gene KiSS1 in early breast cancer. Anticancer Res. 2007, 27, 2499–2504.
[38]
Wada, N.; Imoto, S.; Yamauchi, C.; Hasebe, T.; Ochiai, A. Predictors of tumor involvement in remaining axillary lymph nodes of breast cancer patients with positive sentinel lymph node. Eur. J. Surg. Oncol. 2006, 32, 29–33.
[39]
Cutuli, B.; Velten, M.; Martin, C. Assessment of axillary lymph node involvement in small breast cancer: Analysis of 893 cases. 2001, 2, 59–65.
[40]
Chu, K.U.; Turner, R.R.; Hansen, N.M.; Brennan, M.B.; Bilchik, A.; Giuliano, A.E. Do all patients with sentinel node metastasis from breast carcinoma need complete axillary node dissection? Ann. Surg. 1999, 229, 536–541.
[41]
Henderson, I.C.; Patek, A.J. The relationship between prognostic and predictive factors in the management of breast cancer. Breast Cancer Res. Treat. 1998, 52, 261–288.
[42]
Nouh, M.A.; Ismail, H.; El-Din, N.H.; El-Bolkainy, M.N. Lymph node metastasis in breast carcinoma: Clinicopathological correlations in 3747 patients. J. Egypt. Natl. Cancer Inst. 2004, 16, 50–56.
[43]
Cetinta?, S.K.; Kurt, M.; Ozkan, L.; Engin, K.; G?kg?z, S.; Ta?delen, I. Factors influencing axillary node metastasis in breast cancer. Tumori 2006, 92, 416–422.
[44]
Anderson, W.F.; Katki, H.A.; Rosenberg, P.S. Incidence of breast cancer in the United States: Current and future trends. J. Natl. Cancer Inst. 2011, 103, 1397–402.
[45]
Ravdin, P.M.; de Laurentiis, M.; Vendely, T.; Clark, G.M. Prediction of axillary lympth node status in breast cancer patients by use of prognostic indicators. J. Natl. Cancer Inst. 1994, 86, 1171–1175.
[46]
Gann, P.H.; Colilla, S.A.; Gapstur, S.M.; Winchester, D.J.; Winchester, D.P. Factors associated with axillary lymph node metastasis from breast carcinoma: Descriptive and predictive analyses. Cancer 1999, 86, 1511–1519.
[47]
Viale, G.; Zurrida, S.; Maiorano, E.; Mazzarol, G.; Pruneri, G.; Paganelli, G.; Maisonneuve, P.; Veronesi, U. Predicting the status of axillary sentinel lymph nodes in 4351 patients with invasive breast carcinoma treated in a single institution. Cancer 2005, 103, 492–500.
[48]
Kastner, P.; Krust, A.; Turcotte, B.; Stropp, U.; Tora, L.; Gronemeyer, H.; Chambon, P. Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J. 1990, 9, 1603–1614.
[49]
Hopp, T.A.; Weiss, H.L.; Hilsenbeck, S.G.; Cui, Y.; Allred, D.C.; Horwitz, K.B.; Fuqua, S.A. Breast cancer patients with progesterone receptor PR-A-rich tumors have poorer disease-free survival rates. Clin. Cancer Res. 2004, 10, 2751–2760.