EXPRESSION OF P53, GLUTATHIONE-S-TRANSFERASE-PI, AND BCL-2 PROTEINS AND BENEFIT FROM ADJUVANT RADIOTHERAPY IN BREAST-CANCER

Background: In clinical breast cancer research, the utility of certain biomarkers as predictors of response to surgery, chemotherapy, or hor monal therapy has been studied intensively. Much less research has bee n done on the relevance of biologic predictors of response to radiothe rapy, which represents an effective local-regional treatment for breas t cancer. Purpose: The utility of biomarkers involved in DNA damage re pair (p53 protein), control of programmed cell death (p53 and Bcl-2 pr oteins), and cellular detoxification (glutathione S-transferase-pi [GS T-pi] enzyme) in predicting local breast cancer recurrence was analyze d retrospectively in two cohorts of breast cancer patients. These pati ents had had no detectable metastases in the axillary lymph nodes (i.e ., node-negative) or in distant sites and had had similar distribution s of clinicopathologic and biologic prognostic features. They had been treated by conservative surgery alone (139 case patients) or by conse rvative surgery folIowed by adjuvant radiotherapy (496 case patients) during the period from 1984 through 1990. Methods: The expression of t he p53, GST-pi, and Bcl-2 proteins in the specimens of primary breast tumor obtained from these patients was determined by use of immunohist ochemistry; cell proliferation activity and levels of steroid receptor s were determined by use of a [H-3]thymidine-labeling index assay and the dextran-coated charcoal technique, respectively. The median time o f follow-up of patients was 6 years. In the analyses of patient outcom es, only local failures that presented as first events were considered . Results: After surgery alone, the risk of local recurrence at 6 year s was higher for patients with tumors exhibiting elevated levels of p5 3 and GST-pi protein expression than for patients with low levels (haz ard ratio [HR] = 3.1, 95% confidence interval [CI] = 1.3-7.7, two-side d P = .012; HR = 2.7, 95% CI = 1.1-6.4, two-sided P = .026, respective ly). Weak or no observable expression of Bcl-2 protein was only sugges tive of a higher frequency of local failures. Adjustment for patient a ge, tumor size, cell proliferation, and estrogen receptor status did n ot change these findings. Conversely, in the series of patients given conservative surgery followed by radiotherapy, there was no difference in local tumor recurrence between patients with tumors expressing or not expressing each of the three markers. Conclusions: Our study provi des indirect evidence of a benefit from radiation therapy in preventin g local breast cancer relapse, particularly among node-negative patien ts with tumors that express elevated levels of the p53 or GST-pi prote ins or that express little or no Bcl-2 protein.