Science Series #16: Factors that contribute to the development of breast cancer

Understanding breast cancer

The main cause of cancer-related deaths in women globally is breast cancer (BC). It ranks as the second-leading cause of cancer-related death in women in industrialized countries and the primary cause in poor countries. BC occurs when cells begin to proliferate uncontrollably in certain parts of the breast. The affected area where the cancer begins will define the patient’s type of BC.

A breast is made up of three main parts: lobules, ducts, and connective tissue. It is crucial to realize that the majority of breast lumps are benign and not cancerous. Breast tumors that are not cancerous are abnormal growths that do not spread to the exterior of the breast. The majority of BC occurs in women over 50, which is a frequently cited argument against screening women between the ages of 40 and 49. Less than 5% of BC cases are diagnosed in people under the age of 40, with 17% of diagnoses happening in women under the age of 50.

Source: Centers for Disease Control and Prevention; American Cancer Society and Screening for breast cancer in 2018—what should we be doing today?

Types of breast cancer

BC can be divided into two categories: inherited and acquired.

The acquired type is the more common of the two mutations. Several factors, such as lifestyle-related risk factors, diet, and frequency of exercise, can contribute to the development of acquired BC.

In addition, hormones also seem to play a role in many cases of acquired BC. In particular, two types of acquired BC are regulated by hormones: HER2-positive and hormone-receptor-positive.

HER2-positive: Up to 20% of BC depends on the proliferation of the human epidermal growth factor receptor 2 (HER2) gene. This type of cancer has many copies of the HER2 gene or high levels of HER2 receptors. A HER2-positive cancer cell can grow very quickly. Cancer with very low levels of HER2 proteins or genes is called “HER2-negative”.

Hormone-receptor-positive: This subtype of cancer expresses the estrogen hormone and/or progesterone receptors. Estrogen and/or progesterone receptors are present in about 60% to 75% of breast tumors. Cancer cells that have estrogen receptors are called “ER-positive,” while the type of cancer that has progesterone receptors is called “PR-positive.” Conversely, the term “hormone receptor-negative” refers to a malignancy that lacks both ER and PR.

Hormone receptor-positive cancer can occur at any age. However, people who have gone through menopause have an increased chance of developing this type of BC.

On the other hand, the inherited type of BC often occurs due to mutations in the BRCA1 and BRCA2 genes that are responsible for the suppression of abnormally developing cells. Young women, especially young black women, are more susceptible to this type of BC.

The most common type of BC found in people with a BRCA1 gene mutation is Triple-Negative BC (TNBC), which may spread faster than other types of BC. A breast tumor is considered “triple-negative” if it does not express ER, PR, or HER2. An estimated 15% of invasive breast tumors are triple-negative. Mutations in the BRCA gene should be checked in all triple-negative patients.

BC can begin proliferating in different parts of the breast, such as in the lobules, ducts, nipples, fat and connective tissues, blood vessels, and lymph nodes. The types of BC, depending on the affected tissue, can be classified as follows.

• Infiltrating ductal carcinoma: This type of cancer starts in the duct and spreads to surrounding breast tissue, making up about 80% of all cases.

• Ductal carcinoma in situ: This is considered precancerous since it does not spread to other tissues and is easily treatable.

• Infiltrating lobular carcinoma: This type of carcinoma starts in the lobules, spreads to other surrounding tissues and accounts for 10-15% of BC.

• Lobular carcinoma in situ: A precancerous condition of lobular carcinoma.

• Inflammatory BC: Rare and aggressive, this type of cancer resembles an infection. People with inflammatory BC usually notice redness, swelling, pitting, and dimpling of their breast skin. It is caused by obstructive cancer cells in the skin’s lymph vessels.

• Paget’s disease of the breast: The symptoms of this type of cancer are visible on the skin of the nipple and areola.

The most reliable way to treat BC is to run early screening tests and identify early symptoms. Common symptoms of BC include:

• A lump under the arm or in the breast.

• Swelling or thickening of a breast region.

• Breast skin irritation or dimples.

• Redness or flaky skin in the breast or nipple area.

• Nipples pulling in or nipple region discomfort.

• Bleeding from the breasts, in addition to breast milk.

• Any modification to the breast’s size or form.

• Pain in any region of the breast.

Source:  American Society of Clinical Oncology; Cleveland Clinic and Centers for Disease Control and Prevention.

Screening of BC

A screening test is a method for diagnosing cancer before symptoms appear. Early screening dramatically increases the chances of treating BC. Some of the most important elements in determining a woman’s prognosis for BC include the size of the tumor and the extent to which it has spread.

Regular mammograms, which are low-dose X-rays of the breast, can help find BC at an early stage when treatment is most likely to be successful. A mammogram can often detect breast changes that could be cancer years before physical symptoms develop. This reduces the need for aggressive treatments like surgery to remove the entire breast (mastectomy) and chemotherapy, making it more likely to be cured.

Mammography screening for women in their 40s is recommended by the majority of national screening guidelines, including the American College of Surgeons, the American Preventive Services Task Force, and the Canadian Task Force on Preventive Health Care. Women between the ages of 45 and 54 should have annual screening, while those over the age of 55 should switch to biennial screening.

The ideal recommended screening interval for premenopausal women is annual due to the greater BC growth rate in this group. Although biennial screening is more incrementally beneficial than annual screening in postmenopausal women, most programs advocate biennial screening for this age group to reach the highest level of cost-effectiveness.

Sometimes, BC screening can lead to false-positive or false-negative results. A recall for extra testing following abnormal mammography is considered a false positive if further analysis shows that the initial test was not cancer. False positives are common, and the majority of cases will be resolved with additional image testing, while some will require detailed tissue diagnosis. The use of postmenopausal hormone therapy, greater mammography density, first mammography, longer intervals between screenings, a lack of prior mammograms for comparison, and variations in the work and training of interpretive radiologists are just a few of the factors that contribute to the variability in recall rates.

On the other hand, false-negative results can be obtained in 20% of BCs, as the sensitivity of mammography as a whole is 80%. Mammography screening sometimes skips BCs that are more prone to false negative results, particularly lobular carcinomas.

Patients with thick breast tissue which hides BC, are also more prone to experience false negative results. However, digital mammography screening has an advantage over film screening, primarily for women with thick breast sensitivity, as it produces higher image quality.

Additionally, digital breast tomosynthesis (DBT), a pseudo “three-dimensional” mammography technique in which multiple low-dose mammography images of the compressed breast are acquired from multiple angles and are then reconstructed into overlapping thin slices that can be displayed either individually or in a cine loop, represents another significant technological advance in recent years. DBT is being utilized more frequently as an additional screening method for the detection of BC.

Source: Screening for breast cancer in 2018—what should we be doing today?

Risk factors

Women at high risk of developing BC, depending on certain factors, should have an MRI and mammogram every year, usually starting at age 30. This includes women who:

• Have a lifetime risk of BC between 20% and 25% or higher, according to risk assessment tools based primarily on family history

• Have a known BRCA1 or BRCA2 gene mutation (based on genetic testing)

• Have a first-degree relative (parent, sibling, or child) with a BRCA1 or BRCA2 mutation and have not been genetically tested themselves

• Have had chest radiotherapy when they were between the ages of 10 and 30

• Have Li-Fraumeni syndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, or have a first-degree relative with one of these syndromes

Research is still being conducted to determine how specific aspects of a person’s lifestyle, habits, and surroundings may increase their chance of developing BC. Numerous studies are investigating how nutrition, weight gain or loss, and physical exercise affect the risk of developing BC.

In the United States, the average woman’s BC risk is about 13%, meaning about one in eight women will be diagnosed with invasive BC in their lifetime. A man’s risk is much lower, but about 1 in 833 men will get BC in their lifetime.

In particular, acquired genetic mutations put patients in a high-risk position, and 90% of BC is acquired, while 10% comes from BRCA1 and BRCA2 gene mutations. Therefore, it is important to run more frequent screenings and provide treatments such as prophylactic mastectomies, prophylactic ovary removals, and hormonal therapy medicine.

Statistically, women who are Asian, Hispanic, or Native American are the least likely to develop BC, while non-Hispanic white women and non-Hispanic black women have a higher chance of developing BC. The lifetime risk of BC is 14% for non-Hispanic white women, 12% for non-Hispanic black, Asian, and Pacific Islander women, 11% for Hispanic women, and 10% for non-Hispanic American Indian women and Alaska Native women.

Additionally, the frequency of TNBC is higher among Black women, African American women, and Hispanic women than women of other ethnicities. The reason for this is unclear, but lifestyle may have an impact. Compared to White women, black and African American women may be more likely to have preventive variables that may not be as strongly associated with the risk of TNBC as they are with the risk of ER-positive malignancies.

Additionally, black women and Hispanic women tend to have a lower rate of breastfeeding and carry excess weight in the abdominal area. They are also more likely to have more children, have their first childbirth at an early age, and be overweight before menopause, which may increase their chances of developing TNBC. Other factors that contribute to the development of BC include smoking, alcohol use, radiation exposure, and hormone replacement therapy, etc.

Breastfeeding and BC

The protective effect of breastfeeding reduces the risk of BC in places where prolonged breastfeeding is customary. This effect is less evident in the West, where breastfeeding rates have declined.

According to a series of studies presented in “Epidemiology and the causes of BC”, the frequency and length of breastfeeding varied widely between study sites in terms of lactation, but after controlling for pertinent factors, there were no discernible differences between cases and comparison patients in terms of (i) the proportion of women who had children but never breastfed, (ii) the proportion of children who were not breastfed, or (iii) the overall length of lactation for each woman.

These findings were generally backed up by several other studies conducted in industrialized nations, but with one modification: breastfeeding appears to be associated with a little reduction in BC risk among young women, who are frequently referred to as premenopausal.

The relationship between these factors was first discovered in 1985 before being expanded on by others. The notion that breastfeeding cannot account for the link between childbearing and BC risk is unaffected by the fact that pre-menopausal women make up only around 20% of BC cases in Western nations.

Ovaries and BC

MacMahon, B. (2006) also noted that the BC risk was 50% lower for all women whose menopause was surgically induced compared to those whose menopause happened naturally. Women who underwent surgery before the age of 35 had a lower risk of developing BC than those whose menopause happened naturally.

Ionizing Radiation and BC

Ionizing radiation has the ability to convert mammary tissue into cancer. Factors such as having multiple fluoroscopies or radiotherapy for ankylosing spondylitis or the enlargement of the thymus gland, as well as being a survivor of the atomic bombings, a painter of radium watch faces, or an X-ray technician have all been linked to an increased risk of BC. It is important to mention that among the survivors of the Japanese atomic bombs, the risk of BC was higher among those exposed during childhood and was not elevated among adults.

Alcohol and BC

A study found that women who consumed alcohol four or more times per day on average had a 50% increased chance of developing BC than those who did not. The specific type of alcoholic beverages they ingested did not appear to significantly affect their risk levels.

Early Life and BC

Linking data from birth certificates and school health exams, the Danish Cancer Registry allowed researchers to find nearly 3,000 occurrences of BC in a large cohort of girls born in Copenhagen. Their weights at birth, heights at ages 8 and 14, growth rates around puberty, and body mass indexes at age 14 were all connected to their risks of BC.

This, along with links to body size and childhood growth, directs suspicion toward etiologic factors associated with growth in early childhood as well as in intra-uterine life. Earlier authors had reported the association with birth weight, and this association, though initially thought to be unlikely, is now well established.

The impact of early childbirth and the variation in the age association of the disease globally, however, leaves no doubt that some factor or factors operating during and possibly after reproductive life also have roles to play.

Source: Susan G. Komen and Epidemiology and the causes of BC.

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