Breast Cancer — Early Life Matters
http://www.100md.com
《新英格兰医药杂志》
Despite improved treatment, mortality rates from breast cancer remain high, partly because of the increasing incidence of the disease. Understanding the causes of breast cancer could ultimately lead to its prevention. Many observations point to early life as a susceptible period in mammary carcinogenesis. Early menarche, late first delivery, and ionizing radiation during early life are documented risk factors. High stature, which to a certain extent is determined by childhood nutrition, has consistently been associated with an increase in the risk of breast cancer.1
Studies in animals also indicate that the mammary gland is most vulnerable to carcinogenic influences before a woman's first delivery, when many of the cells in the breast differentiate to assume their intended function.2 Since some differentiation is likely to occur during the development of the mammary glands and sexual maturation, the period between conception and mammary-gland development may be one of particular sensitivity. Among survivors of atomic bomb explosions, the excess relative risk of breast cancer was greatest among girls who were exposed before 10 years of age.3
In their study of growth patterns in a Danish population, reported in this issue of the Journal, Ahlgren and colleagues4 found that high birth weight, rapid growth around the time of mammary-gland development, high stature, and low body-mass index during adolescence were independent risk factors for breast cancer later in life. Interestingly, the investigators found that after they had accounted for the growth pattern during childhood and adolescence, the age at menarche was not related to the risk of breast cancer. The strengths of this study are its considerable size and the unbiased source of the data on early life, which were abstracted from school health records. The findings of Ahlgren et al. add to a substantial literature indicating that there is a positive association between birth weight and the risk of breast cancer,5 primarily before menopause, and that childhood adiposity is inversely associated with the risk of breast cancer.
An association between the risk of breast cancer and the rate of growth during adolescence has been suggested previously, but these new data are the most convincing. An important new finding from the current study is that rapid growth between 8 and 14 years of age carries an additional risk of breast cancer independent of a woman's final height. Although information on risk factors during adult life was not available in this study, others have found that the body-mass index during early adulthood is inversely related to the risk of breast cancer but that weight gain during adulthood and higher body mass after menopause are associated with an increased risk of breast cancer among postmenopausal women.6 Thus, a key question that was not addressed by this study is the independent contribution of the body-mass index in childhood and early adulthood to the risk of breast cancer.
How does this observation from Denmark relate to trends occurring elsewhere? Among the most dramatic and well-documented changes are those in Japan, where a large increase in height has been observed over the past five decades, presumably primarily because of a change in diet. This increase in height has been followed by a steady increase in the rate of breast cancer (Figure 1). Generally, the world population has become taller over time, especially during the past century. At least part of the increasing incidence of breast cancer may be attributable to this growth.
Figure 1. Relation between Height at 12 Years of Age among Japanese Girls and the Incidence of Breast Cancer 30 Years Later among Japanese Women 40 to 44 Years of Age.
Data are from Takahashi7 and the Research Group for Population-Based Cancer Registration in Japan.8
Currently available data paint a complex picture of the lifetime body build associated with the lowest risk of breast cancer: one would want to be born light, to grow slowly but steadily into a chubby, short child, and to maintain one's fat mass until one reached menopause, at which point, one would want to shed the excess pounds immediately in order to keep the risk of breast cancer low. However, we should not necessarily interpret these associations as directly causal. Low birth weight and short stature could be related to genetically determined low levels of insulin-like growth factor 1 or other growth factors that affect breast cells later during adulthood; if so, modifying birth weight, which may just be an early marker of hormonal effects, might not change the risk of breast cancer. One must also bear in mind that higher birth weight, higher stature, and lower body-mass index during adolescence are related to lower risks of cardiovascular disease and diabetes.9 Thus, modifying these factors in an effort to reduce the risk of breast cancer, even if they were causal, might not be desirable for overall health. A rapid rate of growth during early adolescence, however, may be of particular interest as a potentially modifiable risk factor, since it does not, as yet, seem advantageous for other health outcomes.
We still face the challenge of discovering the biologic pathways underlying the observed associations. Growth factors are likely to play a role, because they affect susceptible mammary tissue. When the mammary gland matures, it undergoes rapid cell division, increasing the opportunities for mutations to occur — opportunities that may be further increased by an accelerated rate of growth. The identification of biologic mechanisms that could translate into practical preventive strategies is even more important. One factor that has been related to the rate of growth in children is animal protein. Milk has been hypothesized to be a factor in the rapid changes in growth among Japanese girls, in part because of its protein content, but also because of its high content of many anabolic hormones. Recent findings have confirmed that milk consumption does increase the circulating levels of insulin-like growth factor 1 and is associated with higher stature.10 Understanding how these and other factors are related to childhood growth and to the risk of breast cancer will not be an easy task, but it is one that deserves serious attention.
Source Information
From the Obstetrics and Gynecology Epidemiology Center (K.B.M.) and the Channing Laboratory (K.B.M., W.C.W.), Brigham and Women's Hospital, Harvard Medical School; and the Departments of Epidemiology (K.B.M., W.C.W.) and Nutrition (W.C.W.), Harvard School of Public Health — all in Boston.
References
van den Brandt PA, Spiegelman D, Yaun SS, et al. Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am J Epidemiol 2000;152:514-527.
Russo J, Tay LK, Russo IH. Differentiation of the mammary gland and susceptibility to carcinogenesis. Breast Cancer Res Treat 1982;2:5-73.
Land CE. Studies of cancer and radiation dose among atomic bomb survivors: the example of breast cancer. JAMA 1995;274:402-407.
Ahlgren M, Melbye M, Wohlfahrt J, S?rensen TIA. Growth patterns and the risk of breast cancer in women. N Engl J Med 2004;351:1619-1626.
McCormack VA, dos Santos Silva I, De Stavola BL, Mohsen R, Leon DA, Lithell HO. Fetal growth and subsequent risk of breast cancer: results from long term follow up of Swedish cohort. BMJ 2003;326:248-248.
Huang Z, Hankinson SE, Colditz GA, et al. Dual effects of weight and weight gain on breast cancer risk. JAMA 1997;278:1407-1411.
Takahashi E. Growth and environmental factors in Japan. Hum Biol 1966;38:112-130.
The Research Group for Population-based Cancer Registration in Japan. Cancer incidence and incidence rates in Japan in 1999: estimates based on data from 11 population-based cancer registries. Jpn J Clin Oncol 2004;34:352-356.
Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS. Fetal nutrition and cardiovascular disease in adult life. Lancet 1993;341:938-941.
Hoppe C, Udam TR, Lauritzen L, Molgaard C, Juul A, Michaelsen KF. Animal protein intake, serum insulin-like growth factor I, and growth in healthy 2.5-y-old Danish children. Am J Clin Nutr 2004;80:447-452.(Karin B. Michels, Sc.D., )
Studies in animals also indicate that the mammary gland is most vulnerable to carcinogenic influences before a woman's first delivery, when many of the cells in the breast differentiate to assume their intended function.2 Since some differentiation is likely to occur during the development of the mammary glands and sexual maturation, the period between conception and mammary-gland development may be one of particular sensitivity. Among survivors of atomic bomb explosions, the excess relative risk of breast cancer was greatest among girls who were exposed before 10 years of age.3
In their study of growth patterns in a Danish population, reported in this issue of the Journal, Ahlgren and colleagues4 found that high birth weight, rapid growth around the time of mammary-gland development, high stature, and low body-mass index during adolescence were independent risk factors for breast cancer later in life. Interestingly, the investigators found that after they had accounted for the growth pattern during childhood and adolescence, the age at menarche was not related to the risk of breast cancer. The strengths of this study are its considerable size and the unbiased source of the data on early life, which were abstracted from school health records. The findings of Ahlgren et al. add to a substantial literature indicating that there is a positive association between birth weight and the risk of breast cancer,5 primarily before menopause, and that childhood adiposity is inversely associated with the risk of breast cancer.
An association between the risk of breast cancer and the rate of growth during adolescence has been suggested previously, but these new data are the most convincing. An important new finding from the current study is that rapid growth between 8 and 14 years of age carries an additional risk of breast cancer independent of a woman's final height. Although information on risk factors during adult life was not available in this study, others have found that the body-mass index during early adulthood is inversely related to the risk of breast cancer but that weight gain during adulthood and higher body mass after menopause are associated with an increased risk of breast cancer among postmenopausal women.6 Thus, a key question that was not addressed by this study is the independent contribution of the body-mass index in childhood and early adulthood to the risk of breast cancer.
How does this observation from Denmark relate to trends occurring elsewhere? Among the most dramatic and well-documented changes are those in Japan, where a large increase in height has been observed over the past five decades, presumably primarily because of a change in diet. This increase in height has been followed by a steady increase in the rate of breast cancer (Figure 1). Generally, the world population has become taller over time, especially during the past century. At least part of the increasing incidence of breast cancer may be attributable to this growth.
Figure 1. Relation between Height at 12 Years of Age among Japanese Girls and the Incidence of Breast Cancer 30 Years Later among Japanese Women 40 to 44 Years of Age.
Data are from Takahashi7 and the Research Group for Population-Based Cancer Registration in Japan.8
Currently available data paint a complex picture of the lifetime body build associated with the lowest risk of breast cancer: one would want to be born light, to grow slowly but steadily into a chubby, short child, and to maintain one's fat mass until one reached menopause, at which point, one would want to shed the excess pounds immediately in order to keep the risk of breast cancer low. However, we should not necessarily interpret these associations as directly causal. Low birth weight and short stature could be related to genetically determined low levels of insulin-like growth factor 1 or other growth factors that affect breast cells later during adulthood; if so, modifying birth weight, which may just be an early marker of hormonal effects, might not change the risk of breast cancer. One must also bear in mind that higher birth weight, higher stature, and lower body-mass index during adolescence are related to lower risks of cardiovascular disease and diabetes.9 Thus, modifying these factors in an effort to reduce the risk of breast cancer, even if they were causal, might not be desirable for overall health. A rapid rate of growth during early adolescence, however, may be of particular interest as a potentially modifiable risk factor, since it does not, as yet, seem advantageous for other health outcomes.
We still face the challenge of discovering the biologic pathways underlying the observed associations. Growth factors are likely to play a role, because they affect susceptible mammary tissue. When the mammary gland matures, it undergoes rapid cell division, increasing the opportunities for mutations to occur — opportunities that may be further increased by an accelerated rate of growth. The identification of biologic mechanisms that could translate into practical preventive strategies is even more important. One factor that has been related to the rate of growth in children is animal protein. Milk has been hypothesized to be a factor in the rapid changes in growth among Japanese girls, in part because of its protein content, but also because of its high content of many anabolic hormones. Recent findings have confirmed that milk consumption does increase the circulating levels of insulin-like growth factor 1 and is associated with higher stature.10 Understanding how these and other factors are related to childhood growth and to the risk of breast cancer will not be an easy task, but it is one that deserves serious attention.
Source Information
From the Obstetrics and Gynecology Epidemiology Center (K.B.M.) and the Channing Laboratory (K.B.M., W.C.W.), Brigham and Women's Hospital, Harvard Medical School; and the Departments of Epidemiology (K.B.M., W.C.W.) and Nutrition (W.C.W.), Harvard School of Public Health — all in Boston.
References
van den Brandt PA, Spiegelman D, Yaun SS, et al. Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am J Epidemiol 2000;152:514-527.
Russo J, Tay LK, Russo IH. Differentiation of the mammary gland and susceptibility to carcinogenesis. Breast Cancer Res Treat 1982;2:5-73.
Land CE. Studies of cancer and radiation dose among atomic bomb survivors: the example of breast cancer. JAMA 1995;274:402-407.
Ahlgren M, Melbye M, Wohlfahrt J, S?rensen TIA. Growth patterns and the risk of breast cancer in women. N Engl J Med 2004;351:1619-1626.
McCormack VA, dos Santos Silva I, De Stavola BL, Mohsen R, Leon DA, Lithell HO. Fetal growth and subsequent risk of breast cancer: results from long term follow up of Swedish cohort. BMJ 2003;326:248-248.
Huang Z, Hankinson SE, Colditz GA, et al. Dual effects of weight and weight gain on breast cancer risk. JAMA 1997;278:1407-1411.
Takahashi E. Growth and environmental factors in Japan. Hum Biol 1966;38:112-130.
The Research Group for Population-based Cancer Registration in Japan. Cancer incidence and incidence rates in Japan in 1999: estimates based on data from 11 population-based cancer registries. Jpn J Clin Oncol 2004;34:352-356.
Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS. Fetal nutrition and cardiovascular disease in adult life. Lancet 1993;341:938-941.
Hoppe C, Udam TR, Lauritzen L, Molgaard C, Juul A, Michaelsen KF. Animal protein intake, serum insulin-like growth factor I, and growth in healthy 2.5-y-old Danish children. Am J Clin Nutr 2004;80:447-452.(Karin B. Michels, Sc.D., )