Breast cancer is the malignant tumor with the highest incidence in women, accounting for 22% of female malignant tumors in 2000, and the mortality rate is second only to lung cancer, accounting for 15% of female malignant tumors. According to statistics, there are 1 million breast cancer patients worldwide each year, including 200,000 in the United States (27% of female malignancies); and 320,000 in Europe (31% of female malignancies). For example, the standardized incidence rate in Shanghai was 17.7 per 100,000 in 1972, ranking second among female malignancies, and rose to first in 1990, and reached 36 per 100,000 in 2000. This is not unrelated to the gradual westernization of the economy and lifestyle of the people in the above mentioned regions, and therefore the global gap in breast cancer incidence rates is gradually narrowing. The incidence of breast cancer in the United States has continued to increase over the past two decades, yet the mortality rate has declined at an annual rate of 2.3%, largely due to early detection of breast cancer and improvements in comprehensive treatment methods.
Breast cancer is a complex disease whose onset and progression is associated with multiple risk factors. The main risk factors for the development of breast cancer are: those who have had breast cancer before or have a history of benign breast disease; those who have a family history of breast cancer; women with first pregnancy older than 30 years old and those who have not given birth; women who eat too much animal fat and are overweight or gain weight after menopause; women who have menarche before the age of 12 or menopause after the age of 55; and those who apply estrogen replacement therapy to control menopausal symptoms.
I. Epidemiology of breast cancer
1. Age
In the United States, the incidence of breast cancer in women under 25 years of age is very low, with the number of new cases less than 10/100,000, but the incidence rate has increased to 100 times by the age of 45. This result strongly suggests that hormone levels in women may play an important role in the etiology of breast cancer, because the incidence of non-hormone-dependent tumors does not increase dramatically during the peak reproductive years. The incidence of postmenopausal breast cancer varies markedly across four continents, with the risk of incidence persisting until age 75 years in the United States and Sweden, and decreasing significantly after age 45 years in Latin America. On the contrary, in Japan, there is a plateau in the incidence rate after 45 years of age and then a slow decline.
2. Global geographic distribution of breast cancer incidence
There are significant differences in the incidence of breast cancer among women around the world: North America and Northern Europe are the most prevalent regions, followed by Eastern and Southern Europe and South America, and Asia has the lowest incidence rate, even after menopause. The overall incidence of breast cancer in the United States is 91.4 per 100,000, while the highest incidence rate is as high as 91.6 per 105 in the Netherlands, but the age-stratified incidence rate for white women in California and Hawaii in the United States is 100 per 105 or more. The significant world regional differences in breast cancer incidence are mainly due to the genetic and/or lifestyle habits of the population, including exposure factors such as diet and environment.
Interestingly, the incidence of breast cancer is mildly higher among urban women and women of better socioeconomic status than among rural women and women of poorer socioeconomic status.
3. Epidemiological studies of immigrants
Immigrant epidemiology can provide us with information about racial and geographic differences in the occurrence of breast cancer. The incidence of breast cancer among Asian, Hispanic, and Indian immigrants in the United States is significantly lower than that of whites (non-Hispanic), and between 1973 and 1986, the incidence of breast cancer among U.S.-born Chinese and Japanese was nearly 25% lower than that of U.S.-born whites. However, it has been found that there are significant differences in the incidence of breast cancer among people of the same race depending on their geographic location. For example, the annual incidence rate for Chinese women living in the United States is twice as high compared to Chinese women living in mainland China, Singapore, and Hong Kong. In contrast, after Japanese immigrants to Hawaii or California, the incidence of breast cancer among the first generation of immigrants is greatly increased compared to native Japanese, while the second generation of immigrants approaches the incidence level of white Americans. Therefore, geographical differences in breast cancer incidence are not exclusively related to genetic susceptibility, but are also influenced by environmental and sociocultural factors.
Risk factors associated with breast cancer
1. Reproductive factors
The breast gland matures during adolescence due to the action of ovarian hormones, and the breast cells undergo physiological proliferation due to the cyclical changes of hormone levels in the body every month and the increase of hormone levels in the body during pregnancy. This form of cell proliferation and division ends at the time of menopause. The occurrence of breast cancer is closely related to many of the reproductive factors mentioned above.
1) Age at menarche: Women with a young age at menarche (<12 years = increased chance of breast cancer and is associated with both pre- and post-menopausal breast cancer. In the US experience, a 1-year delay in age at menarche reduces the risk of breast cancer by 20%. Some authors have reported that women of childbearing age with a young age of menarche have higher hormone levels and shorter menstrual cycles and are therefore more exposed to the endogenous hormonal environment, which may be the main reason for the vulnerability of this group of women to breast cancer.
2) Age of menopause: Early studies on the relationship between age of menopause and breast cancer focused on women who underwent artificial menopause (surgical or radiological ovarian debulking) at a young age, and a cohort study in the United States found that the risk of breast cancer for those who underwent artificial menopause before age 45 was 1/2 that of those who underwent natural menopause after age 55. The risk of breast cancer increases by 3% for each year of delayed menopause. Whether it is early menarche or late menopause, women’s menstrual history is actually lengthened.
3) Menstrual cycle: The length of menstrual cycle is now more consistently considered as one of the risk factors for breast cancer. Studies have found that women with short menstrual cycles between the ages of 20 and 39 have a greater risk of developing breast cancer. This may be due to the relatively long luteal phase in those with short menstrual cycles, where both estrogen and progesterone are at high levels. Longer menstrual cycles, whether regular or not, reduce the risk of breast cancer.
4) Age at first full-term pregnancy: A large number of epidemiological surveys have found that the risk of breast cancer increases in women who have not given birth to a child compared to women who have given birth to a child. In contrast, the younger a woman’s first normal gestation age is, the lower her lifetime risk of breast cancer, but these differences in risk are mainly seen in women diagnosed with breast cancer after the age of 40, not in younger breast cancer patients. Because the first full-term pregnancy leads to a series of changes in the breast epithelium, and mature epithelial cells are more resistant to mutations, the earlier the age of the first full-term pregnancy, the less likely it is that the breast tissue will be affected by internal and external environmental factors that can lead to mutations. However, the decrease in breast cancer risk after pregnancy compared to infertile women is not immediate but takes 10 to 15 years to become clear. In fact, the risk of breast cancer increases within 10 years after the first normal childbirth because the proliferation of breast cells during pregnancy may promote the proliferation of cells that have already undergone mutations, leading to an increased risk of breast cancer within the next 10 years.
5) Number of births: Studies have found that women with a high number of births are less likely to develop breast cancer. In addition, recent studies have shown that the shorter the interval between full-term pregnancies, the lower the lifetime risk of breast cancer.
6) Breastfeeding history: As early as 1926, there was a hypothesis that women who did not breastfeed were more likely to get breast cancer. This hypothesis is in line with the physiology of the breast and breast carcinogenesis, and can explain the regional differences in breast cancer incidence, because it is known that breastfeeding is less prevalent and shorter in people in areas with high incidence of breast cancer than in those with low incidence. More than half of the 30 studies have shown that prolonged breastfeeding reduces the risk of breast cancer in a statistically significant way.
2. Sex hormones
The age distribution curve of breast cancer is suddenly flattened during menopause when the level of sex hormones in the body decreases; the risk factors of reproduction-related breast cancer are mostly related to the level of sex hormones in the body; and animal tests have confirmed the view that sex hormones can promote the occurrence of breast cancer. Thus, there are indications that sex hormones play an important role in the development of breast cancer.
Endogenous and exogenous estrogens: There is now a consensus on the relationship between total estrogen levels and breast cancer in postmenopausal women. Studies have found that postmenopausal women with breast cancer have an average of 15% to 24% higher total estrogen levels than healthy women. And prospective studies suggest a significant positive correlation between plasma estrogen levels and breast cancer risk in postmenopausal women who have not used hormone replacement therapy. Fewer studies have been conducted in premenopausal women because total estrogen levels in this group are not easily sampled due to the influence of the menstrual cycle, but there is now at least one large prospective study that confirms the correlation between endogenous estrogen and the risk of breast cancer in premenopausal women. Women undergo estrogen replacement therapy after menopause for a variety of reasons, and many studies have found that supplementation with exogenous estrogens increases the chance of developing breast cancer, yet the risk is much less than that of developing endometrial cancer. Androgens: Androgens increase the risk of breast cancer both directly through a pro-proliferative effect on breast cancer cells and indirectly through conversion to estrogen before acting. Most studies do confirm a positive correlation between androgen levels and breast cancer risk in postmenopausal women, however, further studies are needed in premenopausal women.
Prolactin: In 2003, a large prospective case-control study confirmed that prolactin is also a risk factor for breast cancer, but the risk is not very high. That is, premenopausal women with elevated serum prolactin levels (9.7-37.4 ng/ml) have a 2-fold increased risk of breast cancer.
Other hormones: insulin-like growth factor (IGF-1), serum insulin-like growth factor and its major binding protein IGFBP-3 levels have been targeted in several epidemiological studies and shown to have a positive correlation with breast cancer development. Estriol and progesterone, on the other hand, are considered by most scholars to have a protective effect. However, the link between each hormone in the mechanism of breast cancer development is not fully understood as of now.
3. Nutritional diet
1) Fat and high-calorie diet: As early as 1979, Gray et al. reported that the mortality rate of breast cancer in various countries was positively correlated with the average fat consumption in each country. Many case-control studies have since concluded that excessive intake of fat and processed meat can increase the risk of cancer. It is the wide variation in dietary structure and habits among women of various ethnic groups in different regions of the world that leads to different types and levels of nutritional and energy intake, resulting in significant differences in the incidence of breast cancer among countries.
2) Alcohol: Longnecker et al. and Howe reported that women who drank alcohol more than 3 times a day had a 50% to 70% increased risk of breast cancer. It was also reported that estrogen levels increased in those who drank alcohol twice a day.
3) Fiber: Fiber has an inhibitory effect on the occurrence of both breast and colorectal cancers. Studies have found that women who eat less vegetables and fruits have a mildly increased risk of breast cancer, and Howe et al. reported that increasing the intake of dietary fiber to 20g per day will reduce the risk of breast cancer by 15%, and the results are statistically significant.
4) Micronutrients: Experimental studies have found that vitamin A-like substances have a protective effect on breast cells. However, so far there is no sufficient evidence that foods rich in Vit A have the effect of reducing the risk of breast cancer. However, it is reported abroad that soy protein and its important component Soilbin have a significant role in inhibiting the occurrence of breast cancer, and further prospective studies are still underway.
4.Obesity and physical exercise
A large number of studies in the United States and Europe have confirmed that postmenopausal women with obesity and weight gain have an increased risk of breast cancer, especially for extremely obese women who do not use hormone replacement therapy have a more significant risk of breast cancer. For every 5 kg increase in body weight from the lowest adult weight, the risk of breast cancer increases by 8%. In addition, a high-calorie diet during adolescence leads to accelerated growth and early menstruation, which leads to weight gain in middle age and ultimately increases the risk of breast cancer. The mechanism is due to higher levels of endogenous estrogen in postmenopausal obese women, as adipose tissue is an important source of estrogen. Conversely, obesity in premenopausal women decreases the risk of breast cancer in the premenopausal period, but the mechanism is not yet clear.
Recent studies have shown that physical activity between the ages of 12 and 24 years can reduce breast cancer incidence by 20%, with a 3% reduction in breast cancer incidence for each additional hour/week of physical activity during adolescence. In addition, Bernstern et al. in 1994 estimated that an average of 4 hours of physical activity per week in women of childbearing age reduced the risk by 60% compared to women who did not exercise. The mechanism by which physical activity can reduce the incidence of breast cancer is due to its delaying the age of menarche and adjusting the levels of biologically active hormones.
5. Family history of breast cancer
In 1974, Anderson et al. noted that American women with first-degree relatives who had breast cancer were 2 to 3 times more likely to develop breast cancer than those without a family history, and the relative risk was up to 9 times higher if the first-degree relatives had bilateral breast cancer before menopause. 2001 meta-analysis of 52 independent epidemiological studies showed that 12% of of women with breast cancer had a family member with breast cancer. In a family with 2 related members having breast cancer, it can be called familial breast cancer.
6. History of benign breast disease
Pathological epidemiology is a discipline that studies the relationship between the natural history of malignancy and epidemiology, the relationship between different pre-cancerous lesions and cancer, and the relationship between different tissue types and risk level. Pathological epidemiological studies have found that the risk of breast cancer is associated with certain benign breast diseases, with severe epithelial atypical hyperplasia increasing the risk of breast cancer by 4-5 times, and up to 9 times if there is also a family history of breast cancer. Some reports show that the relative risk decreases if breast cancer does not occur within 10 years after diagnosis of atypical hyperplasia. This shows that even in high-risk histological types, the risk decreases with time. Lobular carcinoma in situ (LCIS) should be considered a high risk factor for breast cancer as a precancerous lesion, and mastectomy in such patients is a preventive rather than curative measure. The incidence of breast cancer in women diagnosed with LCIS increases by approximately 1% per year, with a relative risk of 6.9 to 12.0.
6. Other factors
1) Density of glands in mammograms
Gland density in mammograms is another recognized risk factor for pre- and postmenopausal women. Two independent studies (the Breast Cancer Detection Showcase Program and the Canadian National Breast Screening Study) have confirmed that women with more than 75% increased gland density on mammograms have approximately a 5-fold increased risk of breast cancer than women with less than 5% increased gland density on mammograms, and that pre and postmenopausal nulliparous women and thinner women generally have higher gland density and therefore may have an increased risk of cancer. There is a synergistic effect of childlessness and high gland density, with a 7-fold increased risk of breast cancer in women who have both of these factors. The gland density in breast slices of women on hormone replacement therapy is more than twice that of women on non-hormone replacement therapy.
2) Ionizing Radiation
High doses of ionizing radiation increase the risk of breast cancer, and the risk is dose-dependent and decreases with increasing radiation exposure. The incidence of breast cancer among the survivors of the atomic bombings in Nagasaki and Hiroshima tends to increase; the incidence of breast cancer in women treated with radiation for postpartum mastitis and in infant girls treated with radiation for enlarged thymus also increases. The younger the age of exposure to radiation, the greater the risk. Therefore, it has been suggested that mammography screening may increase the risk of breast cancer. However, the benefits of mammography outweigh the risks because the radiation dose is extremely low and the early detection of breast cancer reduces mortality.
3) Drugs
While chemotherapeutic drugs treat tumors, they also have carcinogenic effects of their own. Among them, alkylating agents can induce the development of many solid tumors, including breast cancer. Williams et al. suggested that long-term use of reserpine may increase the incidence of breast cancer, but short-term use may decrease its incidence. The relationship between reserpine and breast cancer needs further study at present. Other drugs, such as non-steroidal anti-inflammatory drugs (NSAIDS) like aspirin, have been shown to have an inhibitory effect on colorectal carcinogenesis, and some authors have found that they have the same effect of reducing the risk of breast cancer.
There has been widespread concern about whether oral contraceptives increase the risk of breast cancer because they contain sex hormones associated with breast cancer and because previous studies have found a slightly higher prevalence of breast cancer in women who are taking and have recently taken oral contraceptives. However, at least 50 prospective studies to date have provided good evidence that oral contraceptives do not increase the risk of breast cancer in women, even in those who have been taking them for more than 10 years.
4) Chemopreventive agents
Among chemopreventive agents, TAM is the only one approved by the FDA as a preventive agent for women at high risk for breast cancer, including women over 35 years of age with a 5-year probability of developing breast cancer suggested by the Gail model of greater than 1.66%, premenopausal women with BRCA1/BRCA2 mutations or a history of ductal or lobular atypical hyperplasia. Recently, clinical trials have also investigated other selective estrogen receptor modulators, of which anastrozole-aromatase inhibitor may become another chemical inhibitor, and the IBIS-II trial is comparing its effects with TAM.
5) Occupation and height
A total of 115 studies on the relationship between women’s occupations and breast cancer between 1971 and 1994 showed an increased risk of breast cancer in women in occupations such as cosmetology and drug manufacturing. Height is an independent risk factor for breast cancer in postmenopausal women (relative risk 1.07 to 1.10/ 5 cm increase in height), while for premenopausal women height has no significant relationship with breast cancer risk.
6) Other systemic diseases and breast cancer
Some diseases increase the risk of breast cancer, the most representative one is type II diabetes. A case-control study showed that insulin resistance and hyperinsulinemia had a significantly higher incidence of breast cancer and was a risk factor independent of body weight and fat distribution. Since insulin is one of the growth factors of human breast cancer cells, hyperinsulinemia in type II diabetes may directly contribute to the development of breast cancer. In addition, insulin levels in the body are negatively correlated with sex hormone binding globulin levels, so high insulin levels can lead to both high estrogen and androgen levels. The relationship between thyroid disorders and breast cancer has also been reported, but opinions are still not consistent.
Other diseases reduce the risk of breast cancer, for example, studies have found a lower incidence of breast cancer in women with eclampsia, pre-eclampsia or gestational hypertension syndrome than in the normal population.
III. Molecular epidemiology of breast cancer
The high-extrinsic breast cancer predisposition genes BRCA-1, BRCA-2, p53, ATM, PTEN, NBS1 or LKB1 are all independent risk factors for hereditary breast cancer, but only 5-10% of breast cancers are caused by mutations in these genes. Most breast cancers are due to low ectopic breast cancer predisposition genes and risk factors such as endogenous and lifestyle patterns. Hereditary breast cancers commonly occur in young women, multicentrically or bilaterally, whereas non-hereditary breast cancers are often unilateral and develop at an older age. For example, the incidence of breast cancer is high in young women with Li-Fraumeni syndrome (a rare genetic syndrome predisposing to intracranial and adrenocortical tumors in childhood), in which mutations in the oncogene P53 have been found.BRCA1, which has recently been isolated from chromosome 17q21, has been shown to be present in 45% of hereditary breast cancers and 80% of The BRCA1 gene has been shown to be mutated in 45% of hereditary breast cancers and 80% of patients with breast cancer with ovarian cancer. Foulkes et al. demonstrated that BRCA1 mutations are associated with younger onset, poor grading, estrogen receptor negativity, and P53 overexpression. The clinical significance of BRCA-2 mutations is similar to that of BRCA-1, but the correlation with ovarian carcinogenesis is not significant.
Prevention strategies for women at high risk of breast cancer
Can breast cancer be prevented in women with high risk factors for breast cancer? The answer is yes. The chance of developing breast cancer in women with bilateral mastectomy is almost zero. But this preventive measure is clearly too harsh and unnecessary for women at low to moderate risk of developing breast cancer. For most women, close surveillance for early detection of breast cancer is a good strategy, i.e. monthly breast self-examinations, clinical checkups every 4-6 months and mammography every 1 to 2 years from age 40. There are of course more aggressive, yet non-disfiguring, preventive measures that can be taken, such as taking triamcinolone and participating in other ongoing chemoprevention trials. It has been shown that taking 10mg of triamcinolone twice daily for 5 years can reduce the incidence of breast cancer by nearly half. Other chemopreventive drugs are also being studied. The cause of breast cancer is not yet fully understood, but epidemiological studies have found that it is associated with dietary and environmental factors, so the risk of breast cancer can be reduced through proper control of caloric intake in the diet, increased exercise, and improved lifestyle habits.