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Phyto-oestrogens and breast cancer
CORRESPONDENCE
transit and lowered oestrogen reabsorption. We are not aware of any such data and there is some evidence to the contrary, a history of stressful life events being associated with an increase in breast-cancer risk.1 Women with newly diagnosed breast cancer will be very anxious. While this may be a factor in reducing phytooestrogen excretion, as suggested, we did measure total urinary nitrogen excretion, as an index of overall intake/absorption of nutrients, and there was little difference between cases and controls. There is no ideal moment to undertake a case-control study of nutrition and cancer and we felt that the best time was before any treatment had started. If Heaton and Lewis believe that habitual slow intestinal transit is a risk factor for breast cancer they should do the study. However, it is always going to be difficult to separate the effect of phyto-oestrogens from transit because lignans are in the outer fibre coat of cereals2 and high fibre intake is also associated with more rapid intestinal transit. Punam Mangtani and Isabel dos Santos Silva discuss issues in relation to timing and possible biases in our study. The many studies of dietary records in relation to breast cancer all suffer from the fact that dietary recall is inaccurate. We did collect dietary questionnaires but did not use them in the analysis. We measured excretion, a much more reliable index of consumption and metabolism of phyto-oestrogens. This measures intake and metabolism at only one point in time and may not reflect intake in earlier years, so our study needs to be followed by a large prospective cohort study. If one of the cohort studies done elsewhere collected and stored urine samples, it might not require the usual long interval before results are available. Mangtani and dos Santos Silva also argue that the controls might have been influenced by publicity and so they consumed a diet containing more phyto-oestrogens. However, our controls did not know they were taking part in a study of breast cancer and phyto-oestrogens; they were invited to take part in a study of diet and health. Furthermore, in 1993 and 1994 soy and linseed breads were not available and phyto-oestrogens were not widely known. Publicity will, however, make similar studies more difficult in the future. Rafael Marques de Souza argues that family history should have been taken into account. In fact, there was no increase in the number of controls
THE LANCET • Vol 351 • January 10, 1998
with a first-degree family history of breast cancer (7·7%); as expected, there was a higher proportion in the cases (11·3%). We did not control for family history in the final model because preliminary analyses had shown this factor to have a nonsignificant effect on risk. If the cases had changed to a diet rich in phytooestrogens once the diagnosis was made, that would have brought urinary excretion of phyto-oestrogens closer to that of the controls. Furthermore, at the time of the study there was little information readily available to the public on phyto-oestrogens and breast cancer. Part of the reason this time period (ie, immediately after diagnosis) was chosen was so that the women would not have time to do any personal research into diet and breast cancer. Charles Humfrey makes the point that a 3-day urine tells us only about phyto-oestrogen consumption and metabolism at that time and not when the cancer was developing, many years earlier. The pooled 72 h urine gives an index of phyto-oestrogen consumption and metabolism over 4–5 days not 24–48 h, as Humfrey says. Nevertheless he is basically correct. A study such as ours proves nothing but it does provide one more piece in the jigsaw of the aetiology of breast cancer. It is probably more useful than the case-control studies on soy consumption and breast cancer because we measured excretion, a more accurate index of consumption and metabolism than dietary recall, and because it is the first such study in a western population, where breast cancer is such a major problem. Jan Tesarik and Carmen Mendoza make the point that there are several possible mechanisms by which phytooestrogens might reduce breast cancer risk other than by interactions with the nuclear oestrogen receptor. There are more than 150 publications of the inhibitory effect of genistein on tyrosine specific protein kinases and topoisomerases, a topic excellently reviewed by the “father” of the modern phyto-oestrogen hypothesis, Herman Adlercreutz.3 David Ingram Suite 44, Mount Vernon Medical Center, 146 Mounts Bay Road, Perth, WA 6000, Australia 1
2
3
Ginsberg A, Price SD, Ingram DM, Nottage E. Life events and the risk of breast cancer: a case-control study. Eur J Cancer 1996; 32A: 2049–52. Nilsson M, Aman P. Hankonen H, et al. Contents of nutrients and lignans in roller milled fractions of rye. J Sci Food Agr 1997; 73: 143–48. Adlercreutz H, Mazur W. Phyto-oestrogens and western diseases. Ann Med 1997; 29: 95–120.
SIR—Just 1 month after your Sept 6 editorial, 1 “Meta-analysis under scrutiny”, you published David Ingram and colleagues’ case-control study of phyto-oestrogens and breast cancer (Oct 4, p 990),2 which refers to “the hypothesis that a diet rich in fats predisposes a woman to breast cancer . . . does not support this hypothesis.”. The World Cancer Research Fund and the American Institute for Cancer Research published an overall review entitled “Food, nutrition and the prevention of cancer; a global perspective”, on Sept 30, 1997, 3 which states that “total fat, saturated fat/animal fat, and meat increase the risk of cancer of the breast”, and that “diets high (sic) in red meat, total fat, and animal/saturated fat possibly increase the risk”. Whom does the non-specialist reader believe? A E Bender 2 Willow Vale, Fetcham, Leatherhead, Surrey KT22 9TE, UK 1 2
3
Editorial. Meta-analysis under scrutiny. Lancet 1997; 350: 675. Ingram D, Sanders K, Kolybaba M, Lopez D. Case-control study of phytooestrogens and breast cancer. Lancet 1997; 350: 990–94. World Cancer Research Fund/American Institute for Cancer Research. Food, nutrition, and prevention of cancer: a global perspective. Washington DC: American Institute for Cancer Research, 1977.
Percutaneous absorption of sunscreens SIR—Hayden and colleagues (Sept 20, p 863) 1 raise the issue of percutaneous absorption of sunscreens. Cosmetic manufacturers increasingly promote their products as containing sunscreens with sun protection factors of 15 or more. Since these creams are used throughout the year, particularly on the face, and since percutaneous absorption through facial skin is 2–13 times that through the forearm2,3,4 (on which Hayden’s study is based) a significant amount may be absorbed over time. However, the systemic effects of any drug depend on plasma concentration. Although we have information on urinary excretion, we know little about plasma concentration (which depends on the drug’s pharmacokinetics), the accumulation of oxybenzone (absorption in excess of metabolism and excretion), and its long-term biological effects. Clearly, more research is needed because sunscreens
139
transit and lowered oestrogen reabsorption. We are not aware of any such data and there is some evidence to the contrary, a history of stressful life events being associated with an increase in breast-cancer risk.1 Women with newly diagnosed breast cancer will be very anxious. While this may be a factor in reducing phytooestrogen excretion, as suggested, we did measure total urinary nitrogen excretion, as an index of overall intake/absorption of nutrients, and there was little difference between cases and controls. There is no ideal moment to undertake a case-control study of nutrition and cancer and we felt that the best time was before any treatment had started. If Heaton and Lewis believe that habitual slow intestinal transit is a risk factor for breast cancer they should do the study. However, it is always going to be difficult to separate the effect of phyto-oestrogens from transit because lignans are in the outer fibre coat of cereals2 and high fibre intake is also associated with more rapid intestinal transit. Punam Mangtani and Isabel dos Santos Silva discuss issues in relation to timing and possible biases in our study. The many studies of dietary records in relation to breast cancer all suffer from the fact that dietary recall is inaccurate. We did collect dietary questionnaires but did not use them in the analysis. We measured excretion, a much more reliable index of consumption and metabolism of phyto-oestrogens. This measures intake and metabolism at only one point in time and may not reflect intake in earlier years, so our study needs to be followed by a large prospective cohort study. If one of the cohort studies done elsewhere collected and stored urine samples, it might not require the usual long interval before results are available. Mangtani and dos Santos Silva also argue that the controls might have been influenced by publicity and so they consumed a diet containing more phyto-oestrogens. However, our controls did not know they were taking part in a study of breast cancer and phyto-oestrogens; they were invited to take part in a study of diet and health. Furthermore, in 1993 and 1994 soy and linseed breads were not available and phyto-oestrogens were not widely known. Publicity will, however, make similar studies more difficult in the future. Rafael Marques de Souza argues that family history should have been taken into account. In fact, there was no increase in the number of controls
THE LANCET • Vol 351 • January 10, 1998
with a first-degree family history of breast cancer (7·7%); as expected, there was a higher proportion in the cases (11·3%). We did not control for family history in the final model because preliminary analyses had shown this factor to have a nonsignificant effect on risk. If the cases had changed to a diet rich in phytooestrogens once the diagnosis was made, that would have brought urinary excretion of phyto-oestrogens closer to that of the controls. Furthermore, at the time of the study there was little information readily available to the public on phyto-oestrogens and breast cancer. Part of the reason this time period (ie, immediately after diagnosis) was chosen was so that the women would not have time to do any personal research into diet and breast cancer. Charles Humfrey makes the point that a 3-day urine tells us only about phyto-oestrogen consumption and metabolism at that time and not when the cancer was developing, many years earlier. The pooled 72 h urine gives an index of phyto-oestrogen consumption and metabolism over 4–5 days not 24–48 h, as Humfrey says. Nevertheless he is basically correct. A study such as ours proves nothing but it does provide one more piece in the jigsaw of the aetiology of breast cancer. It is probably more useful than the case-control studies on soy consumption and breast cancer because we measured excretion, a more accurate index of consumption and metabolism than dietary recall, and because it is the first such study in a western population, where breast cancer is such a major problem. Jan Tesarik and Carmen Mendoza make the point that there are several possible mechanisms by which phytooestrogens might reduce breast cancer risk other than by interactions with the nuclear oestrogen receptor. There are more than 150 publications of the inhibitory effect of genistein on tyrosine specific protein kinases and topoisomerases, a topic excellently reviewed by the “father” of the modern phyto-oestrogen hypothesis, Herman Adlercreutz.3 David Ingram Suite 44, Mount Vernon Medical Center, 146 Mounts Bay Road, Perth, WA 6000, Australia 1
2
3
Ginsberg A, Price SD, Ingram DM, Nottage E. Life events and the risk of breast cancer: a case-control study. Eur J Cancer 1996; 32A: 2049–52. Nilsson M, Aman P. Hankonen H, et al. Contents of nutrients and lignans in roller milled fractions of rye. J Sci Food Agr 1997; 73: 143–48. Adlercreutz H, Mazur W. Phyto-oestrogens and western diseases. Ann Med 1997; 29: 95–120.
SIR—Just 1 month after your Sept 6 editorial, 1 “Meta-analysis under scrutiny”, you published David Ingram and colleagues’ case-control study of phyto-oestrogens and breast cancer (Oct 4, p 990),2 which refers to “the hypothesis that a diet rich in fats predisposes a woman to breast cancer . . . does not support this hypothesis.”. The World Cancer Research Fund and the American Institute for Cancer Research published an overall review entitled “Food, nutrition and the prevention of cancer; a global perspective”, on Sept 30, 1997, 3 which states that “total fat, saturated fat/animal fat, and meat increase the risk of cancer of the breast”, and that “diets high (sic) in red meat, total fat, and animal/saturated fat possibly increase the risk”. Whom does the non-specialist reader believe? A E Bender 2 Willow Vale, Fetcham, Leatherhead, Surrey KT22 9TE, UK 1 2
3
Editorial. Meta-analysis under scrutiny. Lancet 1997; 350: 675. Ingram D, Sanders K, Kolybaba M, Lopez D. Case-control study of phytooestrogens and breast cancer. Lancet 1997; 350: 990–94. World Cancer Research Fund/American Institute for Cancer Research. Food, nutrition, and prevention of cancer: a global perspective. Washington DC: American Institute for Cancer Research, 1977.
Percutaneous absorption of sunscreens SIR—Hayden and colleagues (Sept 20, p 863) 1 raise the issue of percutaneous absorption of sunscreens. Cosmetic manufacturers increasingly promote their products as containing sunscreens with sun protection factors of 15 or more. Since these creams are used throughout the year, particularly on the face, and since percutaneous absorption through facial skin is 2–13 times that through the forearm2,3,4 (on which Hayden’s study is based) a significant amount may be absorbed over time. However, the systemic effects of any drug depend on plasma concentration. Although we have information on urinary excretion, we know little about plasma concentration (which depends on the drug’s pharmacokinetics), the accumulation of oxybenzone (absorption in excess of metabolism and excretion), and its long-term biological effects. Clearly, more research is needed because sunscreens
139