Causes of breast cancer

Breast cancer is the commonest cancer in the UK and the commonest cause of female cancer deaths (30% of the total) in this country for the last fifty years. Whether there has been an overall increase in incidence over this period or whether there has been better reporting of cases (augmented by the increased and earlier pick-up due to the screeening programme) over his period is not clear.

 

The marked downward trend in mortality over the last twenty years is due to the improved treatment strategies and to the screening programme which brings cases earlier top medical attention.

 

Whilst regular mammographic screening and better therapies account for improved survival statistics, the quest is on to improve our knowledge of the causes of this disease such that prevention becomes the byword. Epidemiological studies have identified risk factors that relate to breast cancer incidence, many relating to a patient's reproductive history: early menarche, late first pregnancy, low parity and late menopause - implying a long and uninterrupted exposure to oestrogens - all increasing the risk of breast cancer in an individual woman.For example,women who pass through the menopause (which is accompanied by an enormous decrease in the circulating oestrogen levels in the blood) before the age of 45 years are half as likely as women who undergo the menopause after the age of 55 years to develop breast cancer. For example, the risk of a woman,who has given birth her first child before the age of 20 years,of developing breast cancer is one third that of a woman who gives birth to her first child after te age of 34 years, although, curiously, the relationship to parity seems independent of the age at first birth relationship. Thus, there is now very good epidemiological evidence for the involvement of female sex hormones in the incidence of breast cancer. Breast cancer risk appears to be related to a prolonged cumulative exposure of the milk duct epithelium cells (from which breast cancer arises)to unopposed oestrogens. Some studies have directly correlatedthe incidence of breast cancer with the level of circulating oestrogen in the blood.

 

Where there is a strong family history in first degree relatives, there are now available tests for the oncogenes that have been found to predispose to this disease. The common ones to be responsible such familial breast cancer are the BRCA-1/ BRCA-2 and the p53 genes and the routine testing for these genes in families with such strong incidences is something for which clinical geneticist counselling is now available.

 

Amongst patients with a strong family history of breast cancer, there have been several studies looking at the chances of a specific gene being at fault: The Breast Cancer Linkage Consortium recently published a study of 237 families with at least four cases of breast cancer within the family. They found that 52% of families were harbouring the BRCA 1 gene, 32% the BRCA 2 gene and 16% were due to some other genetic predisposition. Almost all families with breast and ovarian cancer represented within the family were associated with one of the BRCA genes (81% BRCA 1 and 14% BRCA 2 and only 5% unidentified). In families with one or more cases of male breast cancer (usually only 1% of the overall cases of breast cancer) there was a greater than 75% chance of the predisposing gene being BRCA 2 gene, which also seemed to be more likely to cause very large penetrance of the risk (i.e to be associated with 6 or more family members to be affected).

 

There are dilemmas for patients who undergo such testing: On the one hand the patient will know, if she tests positive, that she falls into a category of patient who is at very high risk of developing a breast cancer or ovarian cancer, or, if she has already had one breast cancer, that she is at an 85% risk of developing another, and the whole issue of bilateral prophylactic/insurance mastectomies (or even prophylactic removal ovaries) then comes into discussion.

 

Next, patients have to consider the issues of having subsequent life insurance premiums loaded against them or mortgages etc – because for sure they will be required to disclose these results in the application forms in the future.

 

Lastly, they have to consider that all these points will apply to their children. The medical discovery of genetic predisposition genes (oncogenes) and the knowledge by patients of their possession within their genetic code and the whole question of testing is a highly controversial and important one in breast cancer, and many other cancers at present.

 

Statistical models based on the above data have been researched to estimate a patient's chance of having the BRCA 1 or 2 mutation based on their family and personal medical histories. Computer modelling estimates probabilities of breast cancer risk and one of these is now available via the internet: www.isds.duke.edu/~gp/brcapro.html. Whilst all such modelling contains flaws (biases due to selection ) they give an overall band of risk category for patients which can then be furhter discussed with clinical geneticists if appropriate.