Breast cancer is the most frequently diagnosed cancer in women worldwide. Approximately 1 in 8 women have a lifetime risk of developing breast cancer. There were over 2 million new cases of breast cancer in 2018. The top countries with the highest rates of breast cancer in 2018 were Belgium, Luxembourg, Netherlands and metropolitan France. Belgium topped the list with an age-standardized rate of 113.2 cases per 100,000. The U.S.A ranked at 22, with 84.9 new cases per 100,000.
It is estimated that 268,600 new cases of invasive breast cancer will be diagnosed in the USA in 2019, together with 62,930 new cases of non-invasive (in situ) breast cancer in women. Although the rate of breast cancer is high in developed countries, almost half of the breast cancer cases and more than half of breast cancer mortality occur in developing countries.
Stages of Breast Cancer
In the USA, the American Joint Committee on Cancer (AJCC) describes the stages of breast cancer using the TNM system where:
“T” depicts the size and extent of the primary or main tumor; “N” refers to the number of lymph nodes with cancer; and “M” describes whether the cancer has metastasized to other parts of the body.
In 2018, the AJCC provided additional guidelines to help identify the staging of breast cancer. The committee added tumor grade, estrogen and progesterone receptor status, HER2 (human epidermal growth factor receptor 2) gene status, and Oncotype DX test results to the existing TNM system. The additional characteristics added complexity, but improved accuracy in the determination of the stage of the cancer. The Oncotype DX test can determine systemic recurrence risk based on the tumor genomic character. Using gene expression analysis in calculating risks greatly aids decision making in the use of systemic therapies such as chemotherapy.
Survival Rates & Risk Factors for Breast Cancer
The 5-year relative survival rate is over 80% in North America, but below 40% in African countries. Lack of early detection programs, inadequate diagnosis and treatment facilities may account for the major reason for low survival rates in less developed countries. Breast cancer typically lack symptoms when the tumor is small, and could be easily treated. The most common physical sign is a painless lump. Less common symptoms include breast pain or heaviness; changes in skin texture characterized by swelling, thickening or inflammation; as well as nipple abnormalities that include discharge which may be bloody.
Ethnicity has often been cited as one of the major risk factors in the development of breast cancer. White women are more likely to develop breast cancer than African American, Hispanic, and Asian women. However, African American women have been observed to develop more aggressive and advanced-stage breast cancer that is often diagnosed at a young age. In addition, African American women also have a higher mortality rate.
Age-specific Female Breast Cancer Incidence Rates by Race/Ethnicity, 2010-2014, USA
Rates are per 100,000 and age adjusted to the 2000 US standard population. [Sources: Incidence: North American Association of Central Cancer Registries (NAACCR), 2017. Mortality: National Center for Health Statistics, Centers for Disease Control and Prevention, 2017. American Cancer Society, Inc., Surveillance Research, 2017]
A comparison of mortality rates between 2012 to 2016 showed a 41% higher death rate in African American women than Whites, despite having a lower incidence rate. Between 2008 – 2014, the relative 5-year survival rate for breast cancer incidence was 81% for African American women and 91% for Whites.
[Source: Clement G. Yedjou, Paul B. Tchounwou, Marinelle Payton, Lucio Miele, Duber D. Fonseca, Leroy Lowe, and Richard A. Alo. Assessing the Racial and Ethnic Disparities in Breast Cancer Mortality in the United States Int J Environ Res Public Health. 2017 May; 14(5): 486. doi: 10.3390/ijerph1405048 PMCID: PMC5451937]
Age is also an important consideration when assessing risk in the development of breast cancer. In the United States, breast cancer is the second leading cause of cancer-related deaths in women aged 40-55. The median age of diagnosis for African American women is 58 years, compared with 62 years for White women. Before the age of 30, the risk of an individual developing breast cancer is 1 in 1900. The risk rises to 1 in 15 when the individual reaches the age of 70.
[Source: National Cancer Institute-Surveillance, Epidemiology & End Results Program: https://seer.cancer.gov/statfacts/html/breast.html]
Obesity is often cited as one of the risk factors in the development of breast cancer. Females with a body mass index (BMI) of over 25 have higher risks of developing breast cancer compared to women with a healthy weight. This risk increases after menopause due to the influence of additional estrogen produced by adipose tissues. In addition, increased breast density, abdominal fat, especially excess visceral fat all contribute to elevated cancer risks as adipose tissue is now understood to be almost the exclusive source of estrogen in postmenopause women.
Pregnancy is also a risk factor in the consideration of breast cancer development. A study published in 2018 using a cohort of 2.3 million Danish women showed that pregnancy at an early age (before 30) offered significant long-term protection against breast cancer. In addition, only pregnancies longer than 34 weeks was associated with reduced breast cancer risk, regardless of whether the pregnancy ended in stillbirth or live birth. The authors believed that early-age full-term pregnancies induced changes in gene expression, epigenetic structures and epithelial stem cell composition in the mammary glands.
However, a study published in 2019 that analyzed individual-level data from 15 prospective cohort studies involving 9.6 million person-years of follow-ups discovered that women who have given birth to offspring had increased risk for developing breast cancer. The risk peaked at about 5 years after birth and began to decline after 34 years. This association changed from positive to negative at about 24 years after birth for women, and only in estrogen-receptor positive breast cancer. Pregnancy offered no protective benefits seen in estrogen receptor-negative breast cancer, regardless of breastfeeding patterns.
The Role of Estrogen in Breast Cancer Development
There is evidence that shows current and recent users of menopausal hormone therapy (MHT) are at an increased risk of breast cancer. The rate of breast cancer increased steadily from 1980 to the year 2000, then dropped by more than 50% during the following decade. This large reduction is believed to be the result of an influential study published by the Women’s Health Initiative in 2002. The study effectively delineated the association between the use of Menopausal Hormone Therapy (MHT) and the risk of breast cancer.
Estimated Number of MHT Users in Western Countries in the 50 years since 1970 versus the Rate of Distribution of Diagnosis of Breast Cancer
[Source: Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence – The Lancet Collaborative Group on Hormonal Factors in Breast Cancer http://dx.doi.org/10.1016/S0140-6736(19)31709-X]
Estrogen production in women has been linked to increased risk of breast cancer. Early menarche, late menopause, obesity and use of menopausal hormone therapy, and plasma estradiol (E2) levels have all been shown to increase breast cancer risks. The proposed mechanisms by which estrogen modulate cancer risks include the stimulation of breast cancer cell proliferation and mutation by estrogen receptors, and the DNA mutations caused by metabolites produced during estradiol metabolism.
The conversion of estradiol to genotoxic metabolites in breast tissue initiates the formation of estrogen-DNA adducts, producing reactive oxygen species (ROS) that can cause genomic instability and stimulate the progression of mammary carcinogenicity. DNA adduct is a piece of DNA that is bound to a chemical. This process could be the start of a cancerous cell because the binding of the chemical to the DNA can damage its structure, resulting in abnormal replication. Without proper DNA repair, the formation of DNA adduct will lead to tumorigenesis.
Major risk factors such as obesity, age, pregnancy, and the use of menopausal hormone therapy all point to the association between estrogen metabolism and the risk of breast cancer development. However, the ethnic disparity in incidence and mortality rates between White, Black, Hispanic and Asian/Pacific Islander females has yet to be clearly elucidated.
Female Breast Cancer Incidence (2010-2014) and Mortality (2011-2015) Rates by Race/Ethnicity in USA
[Statistics based on data from Contract Health Service Delivery Area (CHSDA) counties. Note: Rates are age adjusted to the 2000 US standard population. Sources: Incidence – NAACCR, 2017. Mortality – National Center for Health Statistics, Centers for Disease Control and Prevention, 2017. ©2017, American Cancer Society, Inc., Surveillance Research]
Estrogen is now linked causally to increased risks of breast cancer. Competing hypothesis for how the metabolism of estrogens affect risk exists. Most scientific evidence indicates that total estrogen levels that include all 15 estrogens and estrogen metabolites can strongly affect breast cancer risk. A specific metabolic pathway that involves the 2-hydroxylation of estrogen metabolites has actually been found to confer a protective advantage because it is able to accelerate the clearance of estrogen metabolites, reducing breast cancer risks.
It has been recognized since the mid-1960’s that the incidence of breast cancer in the United States exceeded that observed in China. There is a sixfold difference in breast cancer incidence between Asia and the West, while breast cancer risks are at least three times higher in the United States than in China. Similar trends are observed in Hong Kong, Singapore, as well as Japan.
Yet a disturbing trend of increased breast cancer incidence has been observed in China. One recent study estimated that of the 130 million Chinese women aged between 35-49 years in 2001, some 2.5 million of those women would develop breast cancer over the next 20 years. The authors believed that recent abrupt changes in lifestyle in China may be the cause for the increase.
The reason for the hypothesis was based upon the fact that during the mid-1980’s, Chinese women who migrated to the United States developed breast cancer at a rate doubling those found in the two largest cities of Shanghai and Tianjin in China. In addition, breast cancer incidence rates for Chinese American born in the United States actually approached levels found in White women. In the meantime, a sampling of a small number of third generation Chinese Americans indicated breast cancer incidence surpassed those of White females in the USA.
Since the late 1960’s, estrogen metabolism was thought to be the underlying cause for the global ethnic disparity in breast cancer rates. Postmenopausal Asian women were found to have comparatively lower estrogen concentrations, particularly in women who lived in China.
When scientists compared total estrogen and estrogen metabolite concentrations in White females located in three different areas in the USA and Chinese women who lived in the United States against Chinese women who lived in Shanghai, they found that median concentration of total estrogen/estrogen metabolites of women who lived in Shanghai was lower by 2.5 to SIX times than the other four groups of Chinese and White females living in the United States.
Total Estrogens & Estrogen Metabolites (pmol/mg creatinine) in Postmenopausal Chinese, Asian & White Women in Shanghai & United States
[Source: Steven C. Moore, Charles E. Matthews, Xiao Ou Shu, Kai Yu, Mitchell H. Gail et al. Endogenous Estrogens, Estrogen Metabolites, and Breast Cancer Risk in Postmenopausal Chinese Women,JNCI J Natl Cancer Inst (2016) 108(10): djw103, doi: 10.1093/jnci/djw103]
Estrogen metabolism is probably the most important factor that influences the risk of breast cancer development, as all the other risk factors such as early menarche, late menopause, pregnancy, obesity and use of menopausal hormone therapy are all deeply tied to estrogen metabolism. Ultimately, environmental exposures and lifestyle choices may play equal if not more important roles in determining how estrogen may be metabolized, contributing to either elevated or reduced risks in breast cancer progression.