Royal Society of Edinburgh An Epidemiological Perspective on the Causes and Prevention of Breast Cancer Professor Valerie Beral, Head

of Cancer Epidemiology Unit, University of Oxford 15 June 2010 Report by Matthew Shelley
Professor Valerie Beral, Head of the Cancer Epidemiology Unit, at Oxford University, argued that there is compelling evidence for a close link between breast cancer rates, number of children and breast-feeding. She believes that in the past there has been an over-emphasis on the importance of a womans age when she has a first child. In fact, she claimed, something happens to women in the later stages of pregnancy which has a protective effect. She called for this to be studied with the aim of producing a breast cancer vaccine. Professor Beral was welcomed by RSE President Lord Wilson of Tillyorn and the event was supported by the Cruden Foundation and Scottish Cancer Foundation. Women in the West have a 6.3% chance of developing breast cancer by the age of 70, compared to 1% in areas of rural Asia and Africa. Understanding why, could provide the key for a successful approach to prevention. Breast cancer has been known for a long time; surviving evidence shows that it was present in Ancient Egypt. In 1743 Ramazzini described it as an occupational disease of nuns. Professor Beral said this observation was given strength by Rigoni-Stern in 1842, who reported that it caused 2.7% of deaths among nuns in Verona compared to 0.4% for other women seven times higher, and a similar magnitude to the differences between developed and developing societies today. A League of Nations study in 1925 showed that single women in England and Wales had higher rates of breast cancer than those who were married. In 1926 Lane-Claypons epidemiological study demonstrated that married women with an average 5.3 children were less likely to have breast cancer than those with fewer (3.5). She also found that rates were higher among those who did not breast-feed. For centuries it was thought that women got breast cancer because they didnt use their breasts for their natural purpose, breast-feeding and actually thats right and that is the reason why there was the difference in rates between nuns and other women, and between developing countries and the West, said Professor Beral. The Professor argued that our understanding of the causes of breast cancer took a wrong turn in 1970 following a large scale study by MacMahon et al. This claimed that births after the first, even at an early age, give little or no protection against breast cancer. The idea that age at first birth is the key to breast cancer rates became the dominant theory. However, Professor Beral pointed out that Western and rural Asian and African women all tend to have their first child at around 25, yet there is a six- to seven-fold difference in rates. She added that if the average age of first childbirth was 19 there would only be a slight reduction in the occurrence of breast cancer. If its just age at first birth then why do we have this big gap between developing and developed countries? More recently questions have been raised about whether the difference in rates may be due to environmental, lifestyle, chemical or genetic factors. In 1991 The Collaborative Group on

Hormonal Factors in Breast Cancer was set up and has looked at the effects of the pill and hormone replacement therapy (HRT). The Professor said the group found that when people are on the pill they have an increased risk of breast cancer and when they stop taking the pill the risk goes away. The findings were similar for HRT, with the breast cancer risk rising while they were on it then reducing between two and five years afterwards. This, said the Professor, seems strange to many people as they do not tend to think of cancer-causing factors being reversible. But the fall in breast cancer rates after women stop using HRT has now been observed in around a dozen countries, including Scotland. Turning to childbearing, Professor Beral asserted that age at first birth does matter but is not the only factor. You can also look at how many children someone has had and you can see that the more they have had, the more the risk goes down, and down, and down. It takes around a decade for the protective effect of childbirth to show; indeed breast cancer risks increase immediately after a birth. One reason the Professor became interested in the pill and breast cancer was that she hoped that the oral contraceptive provided protection but it doesnt. Also, the natural protection is not simply related to pregnancy, as it does not occur in women who have been induced or had spontaneous abortions. But the final factor in childbearing, which does have an effect, is breast-feeding; the more time spent breast-feeding the higher the protection. Pulling all the evidence together, it is possible to estimate what the impact on breast cancer rates would be if Western women had more children and breast-fed for longer. A shift to five or six children, rather than two or three, and to breast-feeding for two years would more than halve the levels in developed countries. Im not saying thats what women should do; Im saying it does account for a very large part of the high rates of breast cancer in the West. When nutritional factors, including alcohol consumption and post-menopausal obesity, are taken into account, Western rates would drop to around 1.8%, closer to those of rural Asia and Africa. The Professor added that genetic predisposition does make a difference, but only for individuals (and not as much as many imagine) and is not significant between populations. A woman in the West with the lowest genetic predisposition to breast cancer is still at greater risk than a typical woman in the developing world. Ethnicity is not an important factor as black and white Americans have similar breast cancer rates, while rural Africans do not. Similarly the incidence used to be low in Japan, but has accelerated as social changes take place. Rapid increases in breast cancer numbers are currently being reported in China. Current trends suggest that the number of new cases a year worldwide will double from two million in 2000 to four million by 2040. The question is what we are going to do about it. Its not going to go away; its going to get worse, said Professor Beral. Returning to having very high numbers of children is not an option, nor is concentrating simply on cures, thus a preventative approach is essential. Of the 50,000 annual cases in the UK around a fifth could be avoided if all women stopped drinking, using HRT and avoided obesity still leaving the bulk of the problem untouched. Emphasising that that she was now straying into an area of speculation, the Professor said: Shouldnt we be thinking of some kind of intervention that mimics the positive effects of childbearing? We know that something happens in the later stages of pregnancy that gives life-long protection against breast cancer, and it appears to be linked to hormonal changes. What is needed, she argued, is a concerted drive to identify the source of this protection so it can be used to create a hormonal vaccine. We know where we should be looking but we are just not doing it, she concluded.

Questions: Asked if differences in diagnosis between developed and developing countries could have an effect on her statistics the Professor said that diagnosis is relatively simple and that the evidence is from reliable sources. Oncologist Professor Ian Kunkler asked what explained the rapid rise of breast cancer rates in China where a single child policy applies in rural and urban areas. Professor Beral said we are still waiting to see how things develop in China. Lord Wilson (a noted Sinologist) added that the reality is that the policy is applied less rigorously in rural areas. Asked if there was a difference between HRT delivered orally or by a patch, she said there is not. The main difference is that the greatest risk is when progesterone is present. Obstetrician and gynaecologist Professor Hilary Critchley asked why the breast cancer rate map of Western Europe showed lower rates in Spain than elsewhere, including neighbouring Portugal. Professor Beral replied that while she did not know enough about Spain to provide a full answer, the rates there are rapidly catching up with elsewhere. Questioned on the confidence intervals on a slide addressing the relationship between the pill and breast cancer rates, the Professor said the figures were from a small study in 1996, but added that more recent and larger studies had confirmed the findings. As correlation and cause are not the same thing, the Professor was asked how she could be sure of her conclusions on the reasons for differences in breast cancer rates. She replied that the evidence comes from a wide variety of data sets and, taken together, they are unlikely to be wrong. Professor Annie Anderson from the University of Dundee asked what is known about the impact of exposure to alcohol at an early age. Professor Beral answered that the exact effect is unclear but it is known to have an impact. On the subject of whether there is an interaction between genetic predisposition to breast cancer and lifestyle issues such as drink or obesity, Professor Beral said this does not appear to be the case, adding that you cant change your genes but you can change your lifestyle.

The evening ended with a vote of thanks.

Opinions expressed here do not necessarily represent the views of the RSE, nor of its Fellows The Royal Society of Edinburgh, Scotlands National Academy, is Scottish Charity No. SC000470