Immune regulation and potential responsiveness to breast cancer
In contrast to shed markers that correlate with tumour mass, such as CA15.3 for cancer of the breast, any tumour-related immune response will be subject to complex regulation. Autoantibody responses to p53 will require appropriate primary immunization. Initial low-dose antigen exposure may induce immune tolerance and lack of response. Higher antigen doses may activate either antibody-mediated immunity, or cellular immunity.
In breast cancer patients, the present results suggest that, once an active humoral response against p53 is established, this response remains active. This persistent humoral reaction may be driven by persistent antigenic stimulation by p53 protein derived from overexpression of p53 at distant metastatic sites. Alternatively, irradiated normal tissue may be a source of continued antigenic stimulation, because a long-term side effect of radiation therapy is an increased expression of p53 in normal breast tissue, which persists for several years [12]. Since the great majority of our total patient cohort had received radiotherapy, humoral immunity to p53 associated with primary disease might persist, even in those patients who enter remission, due to tumour-independent antigenic stimulation.
Loss of p53 function is known to correlate with loss of efficacy of cancer therapy in vivo [13,14]. This raised the possibility that autoantibodies to p53 that develop during follow up might indicate those patients whose tumor has become resistant to therapy. However, the present results show that if no immunity has been generated at the time of primary diagnosis, then later immunity is unlikely to occur. This corresponds to the finding that expression of p53 antigen in biopsies of locally advanced breast cancer did not correlate with drug resistance [15,16]. Overall, our observations show that screening for p53 autoantibody status is not informative on residual tumour activity, nor on therapeutic responsiveness. We conclude that the potential value of p53 autoantibody screening in patients with breast cancer is limited to the prognostic information obtained at diagnosis.
Table 1  Incidence of autoantibodies to p53 compared with disease status at last clinic attendance  Pearson χ2: P = 0.606. *Information on disease status at last sample time was available for 960 out of 1006 patients
Table 2  Incidence of autoantibodies to p53 compared with menopausal status at diagnosis  Pearson χ2: P = 0.788.
Table 3  Anti-p53 negative patients do not become positive with recurrent disease  Sixty patients who were negative for p53 autoantibodies had also had a plasma sample taken within 30 days of their primary diagnosis of breast cancer. To determine whether antibody status at diagnosis might have been predictive of later disease behaviour (ie independent of the current negative status), we compared two patient subgroups: patients with current nonactive disease and patients with current active disease. With one exception, all patients were antibody negative within 30 days of initial diagnosis. This showed that recurrent disease is highly unlikely to induce a humoral anti-p53 response in those patients who were initially antibody negative.