European Society of Mastology Abstracts 323

With a median follow-up of 16 months (range 3-22 months) no late side effects have been reported. In particular no measurable arm-swelling or bra&al plexus impairments has been observed.

We conclude that our technique is easy and safe. As regards the role of axillary irradiation in early breast lesions treated with conservative surgery without axillary dissection, the long-terms results of this trial must be awaited.

BIOLOGY

Genetic predisposition to breast cancer

BAJ Ponder CRC Human Cancer Genetics Group, Addenbrooke’s Hospital, Cambridge, UK

Three strongly predisposing genes for breast cancer have been identified to date: BRCAl, BRCA2 and ~53. BRCAl and 2 are together responsible for about half of multiple case breast cancer families (more, if the family has ovarian cancer as well), but a minority of families in which only 2 cases (sister-sister/mother-daughter pairs) are affected. Both BRCAl and 2 prob- ably act as tumour suppressor genes. The precise function of each gene is still unknown, although recent data suggest that BRCAl may have a role in the processes of DNA recombination and repair. Surprisingly, somatic mutations of BRCAl and 2 are rarely found in sporadic breast cancers. The explanation for this is still unclear.

A number of multiple-case breast cancer families appear to have neither BRCAl or 2 mutation, suggesting that at least one further highly pre- disposing gene (‘BRCA3’) should exist. There may also be common genes which are less strongly predisposing but which, because they are common, account for a substantial fraction of all breast cancer incidence. These genes are currently being sought in case-control comparisons.

Genetic predisposition to breast cancer: the ethical dilemma

M Baum University College London Medical School, London, UK Many women with an extensive family history of breast cancer suspect they may have a genetic predisposition to the disease because of all the recent publicity surrounding the discovery of the first two breast cancer genes. They present themselves at a clinic and may be invited to take part in linkage analysis. Furthermore they may be offered genetic testing to determine whether or not they have inherited one of the BRCA genes. These are well women who come to us in all innocence, assuming that our tests are precise and that having been diagnosed as a gene carrier that there are useful interventions that can reduce the risk of developing breast cancer. Unfortunately even if they test negative this does not exclude the possibility of having inherited a third gene which is yet unidentified. Furthermore if they test positive there is no proven intervention that can reduce their risk of developing breast cancer and even prophylactic bilat- eral mastectomy has been associated with the appearance of the disease. Again if they test negative this does not exclude the possibility that their sisters or cousins may have inherited the disease and the family dynamics can be disrupted. What we witness therefore is that biotechnology has raced ahead faster than the clinicians are able to cope with and it is indeed a false promise to offer women genetic testing when there is no useful intervention in place. The only justification for genetic testing is for the women to recognise that they are volunteers in an ongoing research progranune that is unlikely to be of benefit to them but may be of benefit to their daughters.

This has to be made explicit in ongoing research programmes such as the trials of screening and randomised controlled trials of chemoprevention.

Recent issues in breast cancer chemoprevention A Decensi, B Bonanni, LL Manetti, A Guerrieri Gonzaga, G Farante, R Travaglini, V Sacchini, A Costa FIRC Chemoprevention Unit, European Institute of Oncology, Milan, Italy

The importance of the precursor or latent stage of cancer, i.e., the carcino- genesis process, is now well established and finds its biological basis both at the molecular and morphological levels. Chemoprevention aims either to block or reverse further progression during the precursor phase, much the same as a timely treatment of precursor conditions associated with atherosclerosis, e.g., hypertension and high cholesterol levels, has reduced incidence and mortality from end-stage cardiovascular events.

Breast cancer is the most frequent tumor in the female and attempts to prevent this disease by chemical agents have received increased attention. Four different levels of chemoprevention may be recognized. The first level is primary chemoprevention, and involves healthy participants at high risk for the development of malignancy for life-style (e.g., smokers), or because they have received known carcinogens (e.g., asbestosis). At this level, trials are difficult to perform since cancer incidence is the primary endpoint, so thousands of participants and years of observation are required as well as a high compliance rate and a positive beneficial/adverse effect balance. A second level involves individuals who are at genetically pre- disposed risk for cancer (e.g., BRCA-1 mutation carriers). The third level involves subjects with preinvasive lesions, e.g., breast atypical hyperplasia or carcinoma in situ. The aim of the studies, at this level, is to determine whether the agent can induce regression of the precancerous lesion or pre- vent the development of invasive cancer. These studies are performed on a smaller number of patients and may provide important information on the activity of the selected agents. The fourth level is performed in patients previously diagnosed with a malignant tumonr, whether or not they have received previous chemotherapy and/or radiotherapy. This is the case for tumours of the upper aerodigestive or urothelial tract, which are frequent- ly multifocal, a phenomenon that is summarized in the concept of “field- cancerisation”. Similarly, patients diagnosed with a primary breast cancer are at higher risk of developing a contralateral tumour. Women with intra- epithelial or early invasive breast cancer have an extremely good prog- nosis, but they are at high risk of developing a second primary tumour in the opposite breast.6 This population may thus represent a suitable cohort for assessment of the efficacy of new chemopreventive agents in trials. Unpublished data from the 4-HPR trial of breast cancer indicate that contralateral breast cancer in premenopausal women with early breast can- cer has an average incidence rate of approximately 800/100,000 per year, that is approximately 5-6 times higher the age standardized incidence rate of Northern Italy. The rate of homolateral cancer (which includes local recurrence and true homolateral primary tumour) is even higher, ranging from 2-3 times that of contralateral cancer depending on time from the initial diagnosis. Although inferences from these studies may not be applicable to the general population, the constant and predictable risk and the increasing incidence of contralateral breast cancer provides an impor- tant setting for chemoprevention trials of high risk women and offers clues to the process of breast carcinogenesis. In addition, compliance may be higher since these patients are already under medical follow-up.

Given the high costs which are inherent to chemopreventive clinical trials (i.e. the need for a huge number of subjects and years of follow up), and, more recently, the risk of unexpected detrimental effects, much emphasis has recently been put on the search of intermediate, surrogate endpoints. Surrogate endpoints are biological markers or events that may be assessed or observed prior to the clinical appearance of the disease, and that bear some