Risk Factors For Development Of Breast Cancer

Breast Cancer Surveillance Consortium Risk Calculator

The Breast Cancer Surveillance Consortium Risk Calculator was developed and validated in 1.1 million women undergoing mammography across the United States, of whom 18,000 were diagnosed with invasive breast cancer. The BCSC Risk Calculator has been externally validated in the Mayo Mammography Health Study. In 2015, the BCSC risk calculator was updated to include benign breast disease diagnoses and to estimate both 5-year and 10-year breast cancer risk.

Why Does Breast Density Matter

Dense breasts make it harder for radiologists to detect breast cancers when they read a mammogram. Cancers typically show up as small white spots or masses on a mammogram. Dense breast tissue also appears white on a mammogram. Small areas of cancer can hide behind the dense tissue, and its challenging to tell the difference between normal, healthy tissue and abnormal growths. The organization DenseBreast-info.org compares it to trying to see a snowman in a blizzard. Fatty breast tissue appears dark on a mammogram, so areas of concern that show up white are much easier to see.

Mammograms can miss about half of cancers in women with dense breasts. 3 4In addition, women with dense breasts are more likely to be diagnosed with breast cancer within the year after receiving a normal mammogram result, usually based on symptoms such as a lump or other breast changes.

Apart from hiding cancers on mammograms, dense breast tissue itself is associated with a higher risk of breast cancer. Doctors arent sure exactly why. Cancers develop in glandular tissue: the more glandular tissue there is, the greater the risk. Fibrous tissue may also produce growth factors that cause glandular tissue cells to divide and reproduce more than cells in fatty tissue do. Every time a cell divides, there is an opportunity for a mistake in the DNA to occur in the new cells and multiple mistakes can eventually result in cancer.

Risks For Breast Cancer

A risk factor is something that increases the risk of developing cancer. It could be a behaviour, substance or condition. Most cancers are the result of many risk factors. But sometimes breast cancer develops in women who dont have any of the risk factors described below.

Most breast cancers occur in women. The main reason women develop breast cancer is because their breast cells are exposed to the female hormones estrogen and progesterone. These hormones, especially estrogen, are linked with breast cancer and encourage the growth of some breast cancers.

Breast cancer is more common in high-income, developed countries such as Canada, the United States and some European countries. The risk of developing breast cancer increases with age. Breast cancer mostly occurs in women between 50 and 69 years of age.

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Her2 Signaling And Her2

Human epidermal growth factor receptors 1 to 4 constitute a family of tyrosine kinase receptors expressed in normal tissues and in many types of cancer.102, 103, 104, 105, 106 Human epidermal growth factor receptor-2 is a member of the EGFRs.104, 106 Like the others, HER2 is a receptor tyrosine kinase that consists of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain.105, 107 The constitutively active form makes HER2 the preferred component to form dimers with other molecules and grants HER2 the capability of affecting many cellular functions through various pathways.108, 109 Ligand binding and subsequent dimerization stimulate phosphorylation of tyrosine residues in the intracellular domain of HER2, leading to the activation of multiple downstream signaling pathways such as the mitogen-activated protein kinase and the phosphatidylinositol 4,5-bisphosphate 3-kinase pathways.110, 111, 112 These signaling pathways are heavily associated with breast tumorigenesis .105, 106, 107, 113

HER2 signaling pathway. HER2 as well as the other members of the EGFR family are receptor tyrosine kinases which are located on the cell membrane and responds to a wide variety of ligands. Phosphorylation of the tyrosine kinase domain in the cytoplasm initiates downstream oncogenic signaling pathways such as PI3K/AKT pathway and Ras/MAPK pathway.

What Do Scientists Actually Know About The Cause Of Breast Cancer

Cancer grows when a cells DNA is damaged, but why or how that DNA becomes damaged is still unknown. It could be genetic or environmental, or in most cases, a combination of the two. But most patients will never know exactly what caused their cancer. However, there are certain established risk factors that are associated with breast cancer.

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Your Personal History Of Breast Cancer

If youve been diagnosed with breast cancer in the past, you are more likely to develop a new cancer in the other breast or in another part of the same breast. This is not considered a recurrence but a new breast cancer.

What to do: Follow your cancer teams instructions on monitoring to stay on top of this risk. Ask your doctor whether you should see a genetic counselor.

If You Have Had Breast Cancer Before

Your risk of developing invasive breast cancer is increased if you have had breast cancer or ductal carcinoma in situ before.

In this case, you will have regular follow-up appointments. Any changes in the same breast or the other breast can be checked quickly.

Having certain breast conditions can also increase the risk of developing breast cancer:

• Lobular carcinoma in situ

  LCIS is also called lobular neoplasia. This is when there are abnormal cell changes in the lining of the lobules.

• Atypical ductal hyperplasia

  This is when there are slightly abnormal-looking cells in the milk ducts in a small area of the breast.

Women with these non-cancerous conditions are usually monitored regularly, so any changes can be found early.

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How Is Breast Density Measured

When you have a mammogram, a radiologist reads the results using the Breast Imaging Reporting and Data System, or BI-RADS, published by the American College of Radiology. This is a standard system for reporting whats seen on the imaging.

BI-RADS uses an assessment scale from 1 through 6 to indicate whether there were no unusual findings or, if something was found, whether it was more likely benign or malignant . The report will also give a recommendation for routine screening or indicate what follow-up tests may be needed. An assessment of 0 means that additional imaging is first needed in order to characterize a potential finding.

In the BI-RADS report, the radiologist also includes a score for breast density on a scale from A through D:

A) Mostly fatty: The breasts are made up of mostly fatty tissue and contain very little fibrous and glandular tissue. About 10% of women have fatty breasts.

B) Scattered fibroglandular densities: The breasts are mostly fatty tissue, but there are a few areas of fibrous and glandular tissue visible on the mammogram. About 40% of women have scattered density.

C) Heterogeneously dense: A mammogram shows many areas of fibrous and glandular tissue. About 40% of women get this result.

D) Extremely dense: The breasts have large amounts of fibrous and glandular tissue. About 10% of women fall into this category. 1

A: Mostly fatty

Image copyright: DenseBreast-info.org and Dr. Wendie Berg

Menstrual And Obstetric History

Factors that increase the number of menstrual cycles also increase the risk of breast cancer, probably due to increased endogenous estrogen exposure. Such factors include the following:

• Menarche when younger than 13 years
• First full pregnancy when older than 30 years
• Not breastfeeding
• Menopause when older than 50 years

Conversely, late menarche, anovulation, and early menopause are protective, owing to their effect on lowering endogenous estrogen levels or shortening the duration of estrogenic exposure.

Other factors affecting the risk of breast cancer include the following:

• Tobacco exposure
• Diethylstilbestrol exposure in utero
• Alcohol consumption
• Exposure to dichlorodiphenyldichloroethylene , a metabolite of the insecticide dichlorodiphenyltrichloroethane
• Socioeconomic class
• Hair product use

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Environmental And Lifestyle Risk Factors

Major Signaling Pathways In Breast Cancer Development And Progression

There are remarkable parallels between normal development and cancer progression at the molecular level.52, 53 Normal human development is tightly controlled by complex signaling pathways, which allow cells to communicate with each other and their surrounding environment.72, 73 Not surprisingly, many of these same signaling pathways are dysregulated or hijacked by cancer cells and CSCs.74 In essence, cancer is driven by genetic and epigenetic alterations that allow cells to escape the mechanisms that normally control their proliferation, survival and migration.74 Many of these alterations map to signaling pathways that govern cell proliferation and division, cell death, cell differentiation and fate, and cell motility.74 Thus, activating mutations of proto-oncogenes can cause hyperactivation of these signaling pathways, whereas inactivation of tumor suppressors eliminates critical negative regulators of signaling.74 Here, we will focus on the predominant signaling pathways that regulate normal mammary gland development and breast cancer stem cell functions, namely estrogen receptor signaling, HER2 signaling and canonical Wnt signaling.

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Family History And Inherited Genes

Some people have a higher risk of developing breast cancer than the general population because other members of their family have had particular cancers. This is called a family history of cancer.

Having a mother, sister or daughter diagnosed with breast cancer increases the risk of breast cancer. This risk is higher when more close relatives have breast cancer, or if a relative developed breast cancer under the age of 50. But most women who have a close relative with breast cancer will never develop it.

Some people have an increased risk of breast cancer because they have an inherited gene fault. We know about several gene faults that can increase breast cancer risk and there are tests for some of them. Having one of these faulty genes means that you are more likely to get breast cancer than someone who doesnt. But it is not a certainty.

Two of these faulty genes are known as BRCA1 and BRCA2. These are not common. Only about 2 out of every hundred of breast cancers are related to a change in the BRCA1 or BRCA2 genes.

Ionising radiation includes tests such as x-rays and CT scans and treatment such as radiotherapy.

Molecular Basis Of Triple

Triple-negative breast cancer is broadly defined as tumors that lack expression of the estrogen receptor , progesterone receptor , and HER2.285, 286, 287 TNBC accounts for approximately 20% of breast cancers and is more commonly diagnosed in women younger than 40 years, as well as in African-American women.288 Genetically, < 20% of patients with TNBC harbor a breast cancer gene mutation, particularly in BRCA1.289 Pathologically, TNBC is usually high grade and commonly infiltrating ductal carcinoma exhibiting geographic necrosis.290 TNBC Patients usually have a poorer outcome compared with those with other breast cancer subtypes owing to an inherently aggressive clinical behavior and a lack of effective targeted therapies.286, 291 The diagnosis of TNBC relies on the accurate determination of ER and PR protein levels by immunohistochemistry and of HER2 by IHC and/or fluorescence in situ hybridization .286, 287 Such accurate assessment is crucial to avoid false diagnosis of ER-negative and/or HER2-negative disease in patients that would be benefited from endocrine therapy and/or HER2-targeted drugs.285, 286 TNBC clinical phenotype usually consists of the basal-like molecular subtype, although TNBC and basal-like breast cancers are not synonymous and yet there is substantial heterogeneity within TNBCs.

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Mammary Gland Development And Mammary Stem Cells

Human mammary gland development is a progressive process that is initiated during embryonic life.52, 53 The mammary gland consists of a highly branched network of epithelial tubes, embedded within a complex stroma .53 The mammary epithelium originates during embryonic development from an epidermal placode.53 Regulated by epithelialmesenchymal interactions, the placodes descend into the underlying mesenchyme and produce the rudimentary ductal structure of the gland present at birth.52, 53 At birth, the breast rudiment is formed by 1012 primitive ductal elements located beneath the nippleareola complex.52 The breast undergoes dramatic changes in size, shape, and function in association with puberty, pregnancy, and lactation, in response to steroid hormone and growth factor receptor signaling.53 One unique feature of the breast is that mammary epithelium is highly responsive to local and systemic signals and displays significant morphologic changes of the ductal tree during puberty and pregnancy.54

Anatomical and histologic origins of breast cancer. Most breast cancers arise from the lobules or the ducts of the breast. In some cases, the tumor infiltrates the skin or components of the chest wall such as the pectoralis muscles. The tumor cells also are capable of converting the microenvironment into a tumor-friendly state to promote their growth and expansion.

How Has The Risk Of Being Diagnosed With Breast Cancer Changed In Recent Years

For a woman born in the 1970s in the United States, the lifetime risk of being diagnosed with breast cancer, based on breast cancer statistics from that time, was just under 10% .

The last five annual SEER Cancer Statistics Review reports show the following estimates of lifetime risk of breast cancer, all very close to a lifetime risk of 1 in 8:

• 12.83%, based on statistics for 2014 through 2016
• 12.44%, based on statistics for 2013 through 2015
• 12.41%, based on statistics for 2012 through 2014
• 12.43%, based on statistics for 2011 through 2013
• 12.32%, based on statistics for 2010 through 2012

SEER statisticians expect some variability from year to year. Slight changes may be explained by a variety of factors, including minor changes in risk factor levels in the population, slight changes in breast cancer screening rates, or just random variability inherent in the data.

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• Reviewed:December 16, 2020

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Certain Precancerous Breast Conditions

Women diagnosed with certain benign breast conditions may have an increased risk of breast cancer. These changes are often discovered only after you have a breast biopsy for another reason, but they can double your risk of developing breast cancer. Discuss treatment and monitoring options with your doctor.

Being Overweight Or Obese

Women who are overweight after their menopause have a higher risk of breast cancer than women who are not overweight. Men also have an increased risk of breast cancer if they are overweight or obese. For both men and women, the risk increases as more weight is gained.

Body mass index is a measure that uses your height and weight to work out whether you are a healthy weight. For most adults, an ideal is between 18.5 to 24.9. Being overweight means having a BMI of between 25 and 30. Obesity means being very overweight with a BMI of 30 or higher.

Try to keep a healthy weight by being physically active and eating a healthy, balanced diet.

Drinking alcohol increases the risk of breast cancer in women. The risk increases with each extra unit of alcohol per day. The number of units in a drink depends on the size of the drink, and the volume of alcohol.

The latest UK government guidelines advise drinking no more than 14 units of alcohol a week.

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How Common Is Breast Cancer

The American Cancer Society estimates that a womans chance of developing breast cancer during her lifetime is about 13 percent. That translates to a 1 in 8 chance of developing breast cancer. At the same time, it means there is a 7 in 8 chance that you wont develop breast cancer.

In terms of cancers that affect women, 1 in 3 are breast cancer. The ACS reports that the incidence of a woman developing breast cancer has risen by 0.5 percent per year in recent years.

Less Common Types Of Breast Cancer

While IDC and ILC account for approximately 9095% of all breast cancer cases, several rare types of breast cancers can observed in a clinical setting.4, 8, 9, 22, 23, 24

Inflammatory breast cancers : IBC is an uncommon type of invasive breast cancer that comprise 1%5% of all breast cancers.4, 8, 9, 22, 23, 24 IBC differs from other types of breast cancers in its symptoms, prognosis and treatment. Typical IBC symptoms include inflammation-like breast swelling, purple or red color of the skin, and pitting or thickening of the skin of the breast, all of which are likely caused by cancer cells blocking lymph vessels in the skin. IBC often does not present with a breast lump and may not be identifiable on mammograms. IBC tends to occur in younger women, and is more common in African-American women as well as in women who are overweight or obese. Furthermore, IBC tends to be more aggressive, growing and spreading much more quickly than the common types of breast cancers. IBC is always first diagnosed at a locally advanced stage where the breast cancer cells have grown into the skin. In about one-third cases, IBCs are already metastasized to distant sites of the body at diagnosis, which makes it more difficulty to treat successfully.4, 8, 9, 22, 23, 24

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