Risk Factors for Breast Cancer

Not all women have the same risk of developing breast cancer during their lifetime. Studies have shown that certain factors, called risk factors, increase the likelihood that a woman will develop breast cancer.

Many risk factors associated with breast cancer cannot be changed, but some can be modified. The presence of breast cancer risk factors does not mean that cancer is inevitable; many women with risk factors never develop breast cancer.

Risk factors, instead, help to identify women who may benefit most from screening or other preventive measures.

Risk Factors:

  1. Age- The risk of breast cancer increases with older age.

The multifactorial process of transformation from normal cells to cancer includes the accumulation of DNA damage and mutations over time coupled with disruptions of the DNA repair and cell growth regulation system.

  1. Gender- Breast cancer is 100 times more common in women than men.

Most women have fully formed breasts by age 14; While it is uncommon for male breasts to fully form- most of it is fat, not formed glands.

A woman’s breast cells are very responsive to estrogen and other hormones which is not seen in men; Most men also have very low levels of estrogen.

  1. Race- In the United States Breast Cancer is more common in Whites than in Blacks.

Although Cancer doesn’t discriminate as we humans do, much of these ethnic differences are related to lifestyle (BMI, reproductive patterns) and access to health care.

  1. Postmenopausal Weight Gain- A higher Body Mass Index (BMI) and/or perimenopausal(around time of menopause) weight gain is assosciated with a higher risk of breast cancer. 

Estrogen precursors are converted into estrogen in adipose(fat) tissue which is responsible for the increased risk of Ca Breast. In premenopausal(before menopause has set in) age group risk of breast cancer decreases with increasing BMI probably due to a protective effect of increasing weight which is a predictor of anovulatory cycles and lower levels of progesterone and estrogen.

  1. Tall stature- Increased height is associated with a higher risk of breast cancer in both premenopausal and postmenopausal women.

An individual’s stature is influenced by her genes as well as nutritional status during their growth and development. In high income countries, children tend to be taller and obesity rates also tend to be higher. The age at which girls see their first period has dropped. These changes are directly or indirectly related to nutrition and altered hormone levels.

  1. Oestrogen levels- High oestrogen levels are associated with an increased risk of breast cancer in both premenopausal and postmenopausal women.* 

To put this into perspective, a moderate intake of alcohol (one unit a day) which increases risk by 7%, has been proposed to have this effect through increased concentrations of circulating oestrogens.

  1. Benign breast disease- Among benign breast disease, the proliferative ones(associated with atypia) are associated with ca breast.
    Examples include atypical ductal hyperplasia, atypical lobular hyperplasia and intraductal papilloma.
  1. Dense breast tissue- Dense breasts are characterised by radiodense glandular dense tissue(composed of milk glands, milk ducts and supportive tissue) greater than 75% of the breast.

They have 4-5 times higher risk of breast cancer compared with women of similar age and no dense breast tissue. 

Breast density is mostly an inherited trait, although exogenous hormones can affect density, as in Hormone Replacement Therapy.

  1. Bone mineral density- Bone contains Estrogen Receptors: Estrogen acts on these receptors and increases bone density. 

Bone Mineral density can hence be used as a surrogate marker for long term exposure to endogenous and exogenous estrogen. Women with higher bone density have a higher risk for breast cancer.

Other hormonal factors

  1. Androgens- Androgens have a dual effect: Proliferative effects on breast tissue by acting on oestrogen receptors and anti-proliferative effect by acting on androgen receptors.

    Elevated androgens(mainly testosterone) have been associated with an increased risk of Ca Breast.

An elevated level of intratumoural androgen precursors and estrogen producing enzymes result in increased local synthesis of estradiol which stimulates growth of the tumour by acting on the estrogen receptors.

  1. Insulin pathway and related hormones- Although Diabetes is not associated with Ca breast, Insulin like growth factors(IGF-1) have been associated with increased risk of premenopausal and postmenopausal risk factors.
  1. Menopausal hormone therapy- Menopausal Hormone Replacement Therapy(HRT)  is associated with an increased risk of Breast Cancer.

    Long term hormonal therapy has been associated with the highest risk, short term (HRT) < 3 years does not significantly increase the risk of breast cancer.

Reproductive Factors

  1. Early menarche or later menopause- Early menarche is associated with a higher risk of breast cancer.

    Women with higher age of menarche- 15 years or above were less likely to develop ER/PR** Positive  breast cancer compared with women who experienced menarche before the age of 13.
  1. Nulliparity and Multiparity: Nulliparous women are at  an increased risk of breast cancer compared with parous women.

Parity confers a protective effect after delivery.

Being nulliparous and overweight may have a synergistic effect on breast cancer for women >70 years of age.

  1. Increasing age at first pregnancy– Women who became pregnant later in life have an increased risk of breast cancer. 

This risk is the same for a nulliparous woman and a woman with first full term birth at 35 years.

Factors based on History of breast cancer

  1. A personal history of breast cancer or ductal carcinoma in situ or invasive breast cancer increases the risk of developing breast cancer in the contralateral breast.
  1. Family history of breast cancer– The risk of developing breast cancer is associated with the number of first degree relatives(parents, siblings, child) with and without cancer and the age at diagnosis. 

The risk increased two fold if the woman had one first degree relative with ca breast and three fold if the women had two first degree relatives with ca breast.

The age at diagnosis of the affected relative also influences the risk of breast cancer. There is a threefold increase in the risk of developing breast cancer if the first degree relatives were diagnosed with Ca breast before the age of thirty, and 1.5 fold increase in risk if the age at diagnosis was above 60.

  1. Genetic mutations– Specific genetic mutations that contribute to breast cancer are rare. 5-6 % are directly attributable to breast cancer susceptibility genes such as BRCA 1, BRCA 2, p53, PTEN, CDH1, STK11 and the mismatch repair genes.

Lifestyle factors

  1. Alcohol- Alcohol consumption increases the risk of breast cancer. 

Alcohol increases estrogens and other hormones responsible for hormone receptor positive breast cancer. It also causes DNA damage.

  1. Smoking– Multiple studies suggest that there is a double the risk of breast cancer in smokers. Increased risks were mostly seen in women who had early initiation, longer duration and many pack years(number of cigarettes smoked over the years). Similar results were seen for passive smoking.
  1. Night shift work– Night shift work is recognized by the international agency for research on cancer and WHO as a probable carcinogen. The association maybe related to an increased risk of nocturnal light exposure, which results in the suppression of melatonin production. Low levels of 6-sulfatoxymelatonin are associated with an increased risk of breast cancer.
  1. Ionizing radiation– Ionizing radiation to the chest wall is associated with an increased risk of breast cancer. The most vulnerable are children in age group between 10-14 years, however even after 45 years of age there is still an increased risk.

Protective factors that may reduce breast cancer risk

  1. Breastfeeding– It has been estimated that for every 12 months of breastfeeding there has been a 4.3 % reduction in the relative risk of breast cancer. This association was stronger for hormone receptor negative breast cancer.
  1. Physical activity– Regular physical exercise provides modest protection against breast cancer. Particularly in postmenopausal women. Increased physical activity may reduce breast cancer risk by reducing serum insulin, estrogens and insulin growth factor levels.

The suggested exercise time is a walk of 10 or more hours per week which has shown benefits.

Inconclusive Factors

  1. Mediterranean diet– A Mediterranean diet containing plant foods, fish and olive oil may decrease the risk of developing breast cancer.
  1. Fruits and vegetables– studies have shown that a high circulating level of alpha, beta and total carotenes found typically in fruits and vegetables may reduce the risk of breast cancer.
  1. Fat intake– A metaanalysis  of epidemiologic studies found highest levels of total fat intake had 13% higher risk of breast cancer.

The current guidelines to lower total fat consumption and recommendation to consumption of unsaturated fats such as MUFAs and w-3 fatty acids(fish oils, canola and flax seed oil) and also reduction of SFAs (meat and dairy products) intake to avoid heart disease is also useful for breast cancer risk.

Environmental factors

  1. Geographic factors– Breast cancer rates are highest in North America, Australia/New Zealand, and in western and northern Europe and lowest in Asia and Sub Saharan Africa.

    These international changes are likely due to changes in lifestyle (eg. Body weight, reproductive habits such as fewer pregnancies, late age at first birth, early age at menarche and/or lactation).
  1. Exposure to diagnostic radiation– whether there is a risk of developing breast cancer in women exposed to diagnostic radiation(mammography, ct scan) in women without a genetic predisposition is not exactly known. But in those with BRCA1 mutation there is an increased risk of breast cancer.

Medications

  1. Calcium/Vitamin D– A review of 9 prospective studies have shown that post menopausal breast cancer risk was decreased by 12% for every 5 ng/ml increase in 25(OH)D levels between 27 and <35 ng/mL.

Moderate morning Sun Exposure, and a diet rich in calcium hence have shown protective effects on the risks for breast cancer.

  1. Antioxidants- There is no evidence for an effect of intake of vitamin A, E, C or beta carotene on breast cancer risk.

Factors that do not influence breast cancer risk

  1. Abortion– Studies have not shown an association between breast cancer and abortion.
  1. Chemicals– Organochlorine pesticides such as DDT are weakly estrogenic and highly lipophilic and persist in the body for many years after exposure. These chemicals have not shown an increased risk of breast cancer.
  1. Tubal ligation– studies have shown no association between breast cancer and tubal ligation.
  1. Caffeine– Studies have failed to show an association between breast cancer and caffeine intake.
  1. Cosmetic implants and hair dyes have not shown an increase in risk of breast cancer.

_______________________

* In an analysis from 7 studies, including 767 premenopausal women with breast cancer and 1699 matched controls, concentrations of estradiol, calculated free estradiol, estrone, androstenedione, dehydroepiandrosterone sulphate, and testosterone had increased breast cancer risk. Every twofold increase in estradiol concentration was associated with an odds ratio (OR) for breast cancer of 1.19 (95% CI 1.06-1.35). Concentrations of luteal-phase progesterone and calculated free testosterone were not significantly associated with such risk.

** ER/PR: Estrogen Receptor/Progestrogen Receptor- These are biochemical receptors present on tumor cells sensitive to hormones.

1 thought on “Risk Factors for Breast Cancer”

Leave a Reply