Clinical Cancer Research, Vol 1, Issue 2 189-198, Copyright © 1995 by American Association for Cancer Research

ARTICLES

Expression of bcl-2 protein predicts efficacy of adjuvant treatments in operable node-positive breast cancer

G Gasparini, M Barbareschi, C Doglioni, PD Palma, FA Mauri, P Boracchi, P Bevilacqua, O Caffo, L Morelli and P Verderio
St. Bortolo Medical Center, Vicenza, Italy.

The proto-oncogene bcl-2 encodes a protein that inhibits apoptosis, a common mechanism of cell death caused by hormone and chemotherapy. We have analyzed bcl-2 protein expression by immuno-cytochemistry in primary node-positive breast cancers in two groups of patients (for a total of 180 cases). One group received adjuvant hormone therapy, the other chemotherapy (cyclophosphamide, methotrexate, and fluorouracil), and both groups were followed for a median time of 63 months. We compared our findings with conventional clinicopathological indicators [menopausal status, number of axillary nodes, histological grade, tumor size and type, estrogen receptor (ER), and progesterone receptor] and with p53 protein expression. bcl-2 protein was present in 65% of the carcinomas (117/180) and it was significantly associated with ER and progesterone receptor and inversely associated with p53 in both the groups of patients treated with adjuvant chemotherapy and tamoxifen. In patients treated either with adjuvant chemotherapy or tamoxifen, relapse-free survival at 5 years was significantly better among patients with bcl-2-positive tumors than in those with bcl-2 negative ones (P = 0.05 and 0.02, respectively). As far as overall survival is concerned, patients with bcl-2-positive tumors had a significantly better outcome in the group treated with adjuvant chemotherapy (P = 0.03). Multivariate analyses were performed for the two treatment groups. In the group treated with tamoxifen, lack of expression of ER and of bcl-2 was the only significant and independent predictor for poor relapse-free survival (P < 0.01). A number of nodes above 3 was the only significant and independent predictor for poor overall survival (P < 0.01). In the cyclophosphamide-methotrexate-fluorouracil-treated group, bcl-2 absence was significant for poor overall survival (P = 0.02) as well as a number of nodes above 3 (P = 0.04) and a tumor size above 2 cm (P = 0.05). For poor relapse-free survival only a number of nodes above 3 (P < 0.01) and progesterone negativity (P = 0.02) were significant and independent predictors of a higher probability of relapse. Thus, in contrast to in vitro data on drug resistance, bcl-2 expression was associated with better outcomes in patients treated with hormone and chemotherapy. Overall, these results suggest that expression of bcl-2 protein and the number of metastatic lymph nodes are independent features predictive of clinical outcome in patients with node-positive breast cancer, irrespective of the type of adjuvant treatment. The determination of bcl-2 protein may prove to be a useful tool to distinguish patients for whom conventional forms of adjuvant therapy are beneficial from those with bcl-2 negative and ER-negative tumors for whom novel therapeutic strategies are needed.

This article has been cited by other articles:

				E. A. Rakha, M. E. El-Sayed, A. R. Green, E. C. Paish, D. G. Powe, J. Gee, R. I. Nicholson, A. H.S. Lee, J. F.R. Robertson, and I. O. Ellis Biologic and Clinical Characteristics of Breast Cancer With Single Hormone Receptor Positive Phenotype J. Clin. Oncol., October 20, 2007; 25(30): 4772 - 4778. [Abstract] [Full Text] [PDF]

				D Trere, L Montanaro, C Ceccarelli, S Barbieri, G Cavrini, D Santini, M Taffurelli, and M Derenzini Prognostic relevance of a novel semiquantitative classification of Bcl2 immunohistochemical expression in human infiltrating ductal carcinomas of the breast Ann. Onc., June 1, 2007; 18(6): 1004 - 1014. [Abstract] [Full Text] [PDF]

				N. Boku, A. Ohtsu, S. Yoshida, K. Shirao, Y. Shimada, I. Hyodo, H. Saito, Y. Miyata, and Gastrointestinal Oncology Study Group of Japan Cli Significance of Biological Markers for Predicting Prognosis and Selecting Chemotherapy Regimens of Advanced Gastric Cancer Patients between Continuous Infusion of 5-FU and a Combination of 5-FU and Cisplatin Jpn. J. Clin. Oncol., May 23, 2007; (2007) hym015v1. [Abstract] [Full Text] [PDF]

				V Malamou-Mitsi, H Gogas, U Dafni, A Bourli, T Fillipidis, M Sotiropoulou, D Vlachodimitropoulos, S Papadopoulos, O Tzaida, G Kafiri, et al. 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. Onc., October 1, 2006; 17(10): 1504 - 1511. [Abstract] [Full Text] [PDF]

				S. P. Linke, T. M. Bremer, C. D. Herold, G. Sauter, and C. Diamond A Multimarker Model to Predict Outcome in Tamoxifen-Treated Breast Cancer Patients Clin. Cancer Res., February 15, 2006; 12(4): 1175 - 1183. [Abstract] [Full Text] [PDF]

				M. Hensel, A. Schneeweiss, H.-P. Sinn, G. Egerer, M. Kornacker, E. Solomayer, R. Haas, G. Bastert, and A. D. Ho Stem Cell Dose and Tumorbiologic Parameters as Prognostic Markers for Patients with Metastatic Breast Cancer Undergoing High-Dose Chemotherapy with Autologous Blood Stem Cell Support Stem Cells, January 1, 2002; 20(1): 32 - 40. [Abstract] [Full Text] [PDF]

				S. H. Meterissian, M. Kontogiannea, M. Al-Sowaidi, A. Linjawi, F. Halwani, B. Jamison, and M. Edwardes Bcl-2 Is a Useful Prognostic Marker in Dukes' B Colon Cancer Ann. Surg. Oncol., July 1, 2001; 8(6): 533 - 537. [Abstract] [Full Text] [PDF]

				E. Hanna, D. C. Shrieve, V. Ratanatharathorn, X. Xia, R. Breau, J. Suen, and S. Li A Novel Alternative Approach for Prediction of Radiation Response of Squamous Cell Carcinoma of Head and Neck Cancer Res., March 1, 2001; 61(6): 2376 - 2380. [Abstract] [Full Text]

				R. Clarke, F. Leonessa, J. N. Welch, and T. C. Skaar Cellular and Molecular Pharmacology of Antiestrogen Action and Resistance Pharmacol. Rev., March 1, 2001; 53(1): 25 - 72. [Abstract] [Full Text] [PDF]

				A. Bottini, A. Berruti, A. Bersiga, M. P. Brizzi, A. Brunelli, G. Gorzegno, B. DiMarco, S. Aguggini, G. Bolsi, F. Cirillo, et al. p53 but not bcl-2 Immunostaining Is Predictive of Poor Clinical Complete Response to Primary Chemotherapy in Breast Cancer Patients Clin. Cancer Res., July 1, 2000; 6(7): 2751 - 2758. [Abstract] [Full Text]

				J. Chang, T. J. Powles, D. C. Allred, S. E. Ashley, G. M. Clark, A. Makris, L. Assersohn, R. K. Gregory, C. K. Osborne, and M. Dowsett Biologic Markers as Predictors of Clinical Outcome From Systemic Therapy for Primary Operable Breast Cancer J. Clin. Oncol., October 1, 1999; 17(10): 3058 - 3063. [Abstract] [Full Text] [PDF]

				M. Baekelandt, G. B. Kristensen, J. M. Nesland, C. G. Trope, and R. Holm Clinical Significance of Apoptosis-Related Factors p53, Mdm2, and Bcl-2 in Advanced Ovarian Cancer J. Clin. Oncol., July 1, 1999; 17(7): 2061 - 2061. [Abstract] [Full Text] [PDF]