Risk Factors for Developing Breast Carcinoma

Risk Factors for Developing Breast Carcinoma

The most important risk factors for young women developing breast cancer are family history and ethnicity. The cancers are frequently poorly differentiated, highly proliferative, and ER negative.

Risk factors for older women are typically associated with estrogen exposure, hormone replacement therapy, and screening. Most common are well- to moderately differentiated ER-positive image cancers.



  • Breast cancer is most common non-skin malignancy among women and is 2nd most common cause of cancer death

  • All women are considered to be at risk, but level of risk varies in population

  • Lifetime risk of developing invasive breast cancer ranges from 3% (for women without risk factors) to > 80% (for women with highly penetrant germline mutations)

    • Average lifetime risk of developing breast cancer is 1 in 8 women (approximately 12%)

  • Measuring degree of risk aids in

    • Individual choices about risk reduction (e.g., chemoprevention or prophylactic surgery)

    • Optimal screening strategy

    • Decisions about testing for single gene mutations

    • Stratification of patients for enrollment in trials

    • Providing important clues into cause and biology of breast cancer

  • Risk factors for developing different molecular types of breast cancer vary and are not yet well understood

  • Majority of risk factors cannot be modified (e.g., age, gender, ethnicity, family history) or would be very difficult to modify (e.g., age at 1st pregnancy, age at menopause)

Breast Cancer Risk Assessment Tools

  • Gail and Claus models are among most widely known examples of breast cancer risk assessment tools

    • Useful to quantify magnitude of risk for individual patients

      • Not applicable for women who have been diagnosed with DCIS or LCIS

      • Different models are used for predicting risk for women with BRCA1 or BRCA2 mutations

      • Do not take into account increased risk due to chest wall radiation

  • Gail model (http://www.cancer.gov/bcrisktool/) provides risk estimate for the next 5 years and for lifetime

    • Incorporates patient age (must be 35 or older), ethnicity, age at menarche, age at 1st live birth, number of 1st-degree relatives with invasive breast cancer, number of prior breast biopsies, and diagnosis of atypical hyperplasia

    • Women with risk of ≥ 1.66% in next 5 years are eligible for chemoprevention with hormonal agents

  • Claus model uses information about family history

    • Incorporates patient age, 1st- and 2nd-degree relatives with breast cancer, age of onset in relatives, family history of ovarian cancer

  • These models perform better for predicting ER-positive cancer than ER-negative cancer



  • Women are at much higher risk than men

    • Only 1 of every 100 breast cancers occur in males

    • Most likely due to larger pool of potential cancer precursor cells and estrogenic effects in women


  • Age-specific incidence rates for breast cancer increase dramatically after age 40

    • Increase with age is primarily for ER-positive cancers

  • Peak incidence for breast cancer among women occurs between 75-79 years

    • Median age at diagnosis in USA: 61 years

  • Lifetime probability of being diagnosed with breast cancer diminishes as increased age ranges are achieved

    • Age 30, lifetime risk of breast cancer: 12.5%

    • Age 50, lifetime risk of breast cancer: 11.1%

    • Age 70, lifetime risk of breast cancer: 6.6%

Estrogen Exposure

  • Exposure to higher levels of estrogen increases lifetime risk of developing breast cancer

  • Factors that reduce risk of breast cancer

    • Late menarche, early natural menopause, or oophorectomy

    • Prolonged breastfeeding (4.3% reduction in risk for each year of breastfeeding)

    • Use of estrogen antagonists such as tamoxifen

    • Low endogenous estradiol levels

    • Obesity in premenopausal women

  • Factors that increase risk of breast cancer

    • Early menarche and late menopause (early age at menarche [relative risk (RR) = 1.3], late menopause [RR=1.5])

    • Nulliparity

    • Obesity in postmenopausal women (elevated estradiol levels compared with women of normal weight)

      • Adult weight gain and abdominal fatness

      • Excess body fat may influence steroid hormone levels and inflammatory responses

    • Hormone replacement therapy (HRT)

      • After publication of the Women’s Health Initiative trial in 2002, number of women using HRT decreased

      • Incidence of invasive breast carcinoma and DCIS dropped 10-15% in women over age 50 but not in younger age groups

      • Decrease occurred for ER-positive cancers

      • It is not known if HRT causes cancer, increases rate of growth of existing cancers, stimulates angiogenesis, &/or has effects on breast cancer detection

  • How estrogen exposure increases breast cancer risk is unknown

    • Estrogen increases mitotic rate of breast cells

      • Increased mitogenic stimulus may increase the risk of mutation

      • Estrogen mitogenic drive may act as cancer promoter and contribute to disease progression

    • Estrogen can act as carcinogen when converted to mutagenic metabolites


  • Pregnancy both increases and decreases risk of breast cancer

    • Transiently increases risk of breast cancer; over many years, risk declines and eventually becomes lower than for nulliparous women (cross-over effect)

  • For young women (< 20 years), protective effect predominates, and lifetime risk of ER-positive breast cancer is reduced by 1/2

    • Terminal differentiation of epithelial cells may occur, thus reducing potential pool of cancer precursors

      • Additional pregnancies further reduce risk (˜ 7% per pregnancy)

    • Pregnancy permanently changes gene expression profiles of breast tissue

  • For older women (> 35 years), increased risk predominates and extends for longer period of time

  • Cancers diagnosed during pregnancy or in postpartum period usually present at higher stages and have poor prognosis

    • In only 1 of 3,000-10,000 pregnancies is breast cancer diagnosed during or within 1 year

  • Many proposed mechanisms for the increase in risk

    • High hormonal levels could stimulate proliferation of precursor lesions, increasing risk of cancer

    • High hormonal levels may stimulate preexisting cancers to proliferate

      • However, many pregnancy-associated carcinomas are ER and PR negative

    • Stroma may become more permissive to allow lobular expansion and branching during pregnancy, which could facilitate progression from carcinoma in situ to invasive carcinoma

    • Stroma during post-pregnancy involution is similar to that of wound-healing and could promote cancer growth and metastasis

Mammographic Density

  • Mammographic appearance depends on tissue composition of breast

    • Stromal tissue and glandular epithelium attenuate x-rays more than fat and increase mammographic density

  • Mammographic density is strong risk factor for breast cancer

    • 4-5x greater risk in women with density in > 75% of the breast

  • Density of breast tissue is influenced by age, parity, body mass index, and menopause

    • Twin studies suggest that % mammographic density, at a given age, is heritable

      • Hereditary factors may explain up to 63% of variance in breast density

    • Investigation of gene associated with breast density is an active area of research

      • Gene profile associated with density may help identify potential targets for breast cancer prevention

Family History

Jul 6, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Risk Factors for Developing Breast Carcinoma

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