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    Awarded Grants
    Earlier Detection of Primary and Recurrent Breast Cancer Using Autoantibodies

    Scientific Abstract:
    Earlier detection of primary and recurrent breast cancer using autoantibodies. Background: This project expands our work in this area in order to provide evidence for the clinical usefulness of anti-tumour autoantibody (a-t AAb) detection in the early detection of either primary or recurrent breast cancer. Current tumour markers (TMs) are not ideal, they are a measure of tumour bulk rather than tumour presence and may be elevated in some benign conditions. Over recent years, the presence of autoantibodies (AAbs) to tumour-associated antigens in the circulation of individuals diagnosed with carcinoma has been reported. The documented presence of these individual AAbs ranges from 10% - 45 % dependent upon the cancer type, the detection modality and the specificity reported: these fall far short of an acceptable level for clinical utility. Studies undertaken in our laboratory using serum samples taken at the time of clinical diagnosis from a cohort of 200 patients with newly diagnosed primary breast cancer, have demonstrated an incidence rate of 82% (at 100% specificity) for a panel of 4 a-t AAbs ( MUC1, p53, c-myc & HER2). Furthermore, analysis of serum taken from 333 individuals with no clinical evidence of breast cancer, but with a family history of the disease who underwent annual mammography, has demonstrated an incident rate for a-t AAbs of 60% at 95% specificity (50% at 100% specificity ) in those individuals who went on to develop breast cancer. The lead-time for AAb detection over mammographic detection in these cases ranged from 6 to 27 months. Recent work in our own laboratory has also indicated the existence of AAbs to other tumour associated molecules. Objective/Hypothesis: This study is based on the hypothesis that AAbs provide an in-vivo amplification of the earliest cancer signal and that to detect multiple a-t AAbs will provide an earlier detection of both primary and recurrent breast cancer than is currently possible. Serum samples held in our serum bank and taken as part of two prospective clinical studies (of early diagnosis of primary disease and recurrent cancer respectively) will be analysed for the presence of AAbs to MUC1, p53, HER2, c-myc, MUC16 and constructs of BRCA1 and BRCA2 and the data used to elucidate their clinical utility for early detection of primary and recurrent breast cancer. Specific Aims: 1) Evaluation of incidence of AAb detection (to MUC1, p53, HER2 and c-myc) in serial samples taken prior to the onset of clinically defined primary breast cancer. 2) Determine lead-time over mammography given by serologic detection of disease onset using these assays. 3) Develop assays for the detection of AAbs to MUC16, and constructs of BRCA1 and BRCA2. 4) Determine the additive value generated by the addition of these further assays to the original panel with regard to incidence and lead-time. 5) Evaluate the clinical utility of AAb assays for the earlier detection of recurrent disease during treatment and follow-up as compared to current tumour marker utility. Study Design: Serum samples are held in our serum bank which have been taken with informed consent as part of two prospective clinical studies - i) of 500 individuals with a family history of breast cancer who have had annual mammographic screening, and ii) of 280 primary breast cancer patients who have had regular blood samples taken over the last 5 years during their follow-up for the detection of recurrent breast cancer. ELISA’s for the detection of AAbs to MUC1, p53, HER2 and c-myc are already available in our laboratory allowing rapid generation of data. MUC16 will be purified from natural sources, whilst constructs of BRCA1 and BRCA2 will be generated recombinantly using a double-tagged system for ease of purification and assay design. Our experience designing ELISA’s for the detection of AAbs will allow for rapid work-up of assays using these molecules. Serum samples already analysed for aims 1, 2 and 5 will then be re-analysed using these further assays and the data pooled. To allow comparison between AAbs and TMs, all serum samples will also be assayed for the TMs MUC1 (CA15.3), HER2 and MUC16 (CA125). Potential Outcomes and Benefits of the research: The successful conclusion of this project will provide information regarding the clinical utility of serologic AAb assays for breast cancer screening and early detection (of both primary and recurrent disease), providing the information necessary to support the development of multi-centre trials using AAbs for these indications. If these confirm our pilot results then AAbs will allow earlier detection of breast cancer leading to more women being cured.

    Lay Abstract:
    Earlier detection of primary and recurrent breast cancer using autoantibodies. Considerable evidence has accumulated over recent years to indicate that the presence of a tumour can lead to the generation of an immune response. In other words, individuals with a developing tumour may potentially have autoantibodies to that tumour present in their circulation. These autoantibodies are likely to recognise any one of a variety of abnormal markers associated with a tumour, but not their normal counterpart. In general, the smaller a tumour the lower the amount of abnormal marker present. This means that currently, abnormal marker detection itself is not sensitive enough for the early detection of small tumours. However, in a similar manner to vaccination generally, only a very small amount of tumour associated abnormal marker needs to be present in order to generate a detectable level of autoantibodies, and therefore such autoantibodies may be detectable when the tumour itself is extremely small and clinically undetectable. Our previous work has followed the generation of anti-tumour antibodies in individuals with breast cancer. In common with other researchers, we have found that the detection of these autoantibodies individually is too low to provide useful clinical data. However, we have also found that by combining the results of individual assays, the detection rate in women with early breast cancer with no clinical sign of spreading, increases dramatically to a level which makes these tests viable for screening. Indeed, our pilot data has shown that autoantibodies can be detected in a significant percentage of women even before a breast cancer can currently be detected by mammography. This project is designed to enable us to expand our work in this area in order to provide evidence for the usefulness of anti-tumour autoantibodies in the earlier detection in of breast cancer which we believe will lead to more women being cured of this disease.