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Breast cancer
Causes and risk factors

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1. Family history

The degree of relativity

• The relative risk of patients with an affected first-degree relative (mother, daughter, or sister) is 1.7 times higher when compared to controls without affected family members.

• Having two first-degree relatives affected (female or male) increases relative risk by more than 4-6 times when compared to patients without this risk factor.

Age of affected relative at time of diagnosis

• A patient with a mother diagnosed when younger than 60 years is at 2 times increased risk.

• Premenopausal onset of the disease in a first-degree relative is associated with a 3 times increase in breast cancer risk.

Bilateral breast cancer in a relative

• Bilateral cancer in a first-degree relative may increase risk by more than 6 times.

• The relative risk for a woman whose first-degree relative developed bilateral breast cancer prior to menopause is nearly 9 times.

2. Menstrual and reproductive factors

• Early menarche (before the age of 12) has been associated with a two-fold increase in risk.
• Late menopause (after the age of 55) also have a two-fold increase in the risk of developing breast cancer.
• A first full term pregnancy after the age of 30 is associated with a two-fold increase in risk when compared to those with an early first full term pregnancy.

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3. Contraceptive pills and Hormone replacement therapy

Epidemiologic data provide strong evidence for an association between plasma estrogens and breast cancer risk.

Oral contraceptive pills

• In 1996 a large meta-analysis showed that a history of recent oral contraceptive use, rather than the duration of use, was a predictor of breast cancer risk.

• This data was based on older high-dose and moderate-dose oral contraceptive pills and not the recently used low-dose pills.

Hormone replacement therapy

In regard to hormone replacement therapy (HRT) or postmenopausal hormone use, results from the Women’s Health Initiative (WHI) showed that the overall risks of a combined estrogen and progestin outweigh the benefits.

• In the arm taking estrogen plus progestin there was a 26% increase in risk of invasive breast cancer, compared with the arm taking a placebo. In addition, in women taking these hormones, there were increased risks of heart disease, stroke, and blood clots.

• In the estrogen-alone arm there was no increase in breast cancer risk reported. The  trial also concluded that estrogen alone does not appear to increase or decrease a woman’s risk of heart disease, although it does appear to increase her risk of stroke and decrease her risk of hip fracture.

4. Genetic factors

Genetic risk factors account for less than 10% of breast cancers.

Autosomal dominant inheritance is seen in:

• Li-Fraumeni syndrome

• Muir-Torre syndrome

• Cowden disease

• Peutz-Jeghers syndrome

• BRCA1 and BRCA2 mutations

BRCA1, although rare, accounts for 45% of high-risk familial inheritances of breast cancer. The risk of developing invasive carcinoma is close to 50% when younger than 50 years and exceeds 80% prior to 65 years.

Autosomal recessive inheritance is seen in:

• Ataxia-telangiectasia

5. Proliferative breast diseases

This category comprises the following conditions moderate or florid epithelial hyperplasia, with or without atypica, sclerosing adenosis, and small duct papillomas.

Other benign conditions (mild ductal hyperplasia, adenosis, cystic changes, apocrine metaplasia) are not associated with increased risk.

Histological variants

• Epithelial hyperplasia: Involves proliferation of epithelial layers usually three or more layers in thickness.

• Sclerosing adenosis: Involves increased numbers of benign ducts distorted by sclerosis.

• Papillomas: Papillomas are composed of bland epithelial cells with a well defined fibrovascular core, a basal myoepithelial layer, and intact basement membrane.

• Atypical ductal hyperplasia: Is associated with proliferation of ductal epithelial cells sharing some but not all the features of ductal carcinoma in situ (DCIS).

• Atypical lobular hyperplasia: Is the proliferation of lobular cells sharing features of lobular carcinoma in situ (LCIS) but filling or distending less than 50% of the acini within the lobule.

Risk associated with each type

• Moderate or florid ductal hyperplasia and sclerosing adenosis, papillomas (proliferative breast disease without atypia) pose only a slightly increased risk of breast cancer (1.5-2.0 times).

• Benign proliferative changes with atypical hyperplasia, such as atypical ductal or lobular hyperplasia. These may increase relative risk by 4 times. Patients who have a family history of breast cancer along with a personal history of atypical epithelial hyperplasia have an 8-fold increase in breast cancer risk when compared with patients with a positive family history alone and an 11-fold increase in breast cancer risk when compared with patients who do not have atypical hyperplasia and have a negative family history.

• Noninvasive carcinoma (ductal carcinoma in situ or lobular carcinoma in situ) on previous biopsy: Lobular carcinoma in situ, markedly increases risk (8-11 times).

• Personal history of breast cancer: This also is a recognized risk factor. This factor depends on patient age at time of diagnosis. Risk is increased for younger women. The risk is about 1% per year from the time of diagnosis of an initial sporadic breast cancer. The risk for development of a second primary breast cancer is significantly higher for women with hereditary breast cancer, approximately 5% per year (50%-60% lifetime risk). Also in cases with history of endometrial, ovarian, or colon cancer.

6. Radiation exposure

• Atomic bomb survivors: An increased rate of breast cancer has been observed in survivors of the atomic bomb explosions in Japan, with a peak latency period of 15-20 years.

• Radiation therapy: Patients with Hodgkin’s disease who are treated with mantle irradiation, particularly women who are younger than age 20 at the time of radiation therapy were found to have an increased incidence of breast cancer.

7. High-fat diet

Diets that are high in fat have been associated with an increased risk for breast cancer. It has been suggested that differences in dietary fat content may account for the variations in breast cancer incidence observed among different countries.

8. Obesity

Alterations in endogenous estrogen levels secondary to obesity may enhance breast cancer risk (aromatization of testosterone to estradiol occurs in the adipose tissue).

9. Alcohol

Moderate alcohol intake (two or more drinks per day) appears to modestly increase breast cancer risk.

10. Socioeconomic status

The incidence of breast cancer is greater in women of higher socioeconomic background. This relationship is most likely related to lifestyle differences, such as age at first birth.

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