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Health Care Provider: Risk Models for Breast Cancer, a Primer

Several breast cancer risk assessment tools have been developed that combine known major risk factors. Risk models either predict risk of pathogenic mutation in BRCA1 or BRCA2, risk of developing invasive breast cancer, or both. Risk models can be useful in stratifying patients into risk categories to facilitate personalized screening and surveillance plans for clinical management of the patient.

Featured in the Table are details and live links to several commonly utilized breast cancer risk assessment models: Gail, Tyrer-Cuzick (IBIS), Penn II, and a link to a paper on the Claus model .

PLEASE NOTE, NO CURRENT RISK MODELS INCLUDE BREAST DENSITY IN RISK CALCULATIONS.

How are the models used?

  1. To Identify Women Who May Benefit from Risk-Reducing Medications
    • The Gail model is used to determine risk for purposes of advising on use of medications to reduce risk. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) P1 study, women at increased risk for breast cancer were defined as follows: 1) age 35 to 59 years with at least a 1.66% five-year risk for developing breast cancer by the Gail model; or 2) personal history of lobular carcinoma in situ (LCIS); or 3) over age 60 years of age. 13388 such women were randomized to receive tamoxifen or placebo daily for five years. Tamoxifen reduced the risk of invasive breast cancer by 49% and reduced the risk of noninvasive cancer by 50%. The reduced risk of breast cancer was only seen for estrogen-receptor expressing tumors. There was a 2.5-fold increase in risk of endometrial cancer in women taking tamoxifen and a decrease in hip and spine fracture risk. Blood clots casuing stroke and deep vein thrombosis are increased in women taking tamoxifen.
  2. To Identify Women Who May Carry a Pathogenic Mutation in BRCA1 or BRCA2.
    • The Tyrer-Cuzick (IBIS), Penn II, BOADICEA, and BRCAPRO are among the models that predict risk of pathogenic mutation. Women with risk of mutation estimated to be more than 10% are usually recommended for genetic testing, though there has been the recent suggestion to perform genetic testing much more broadly as many women who have pathogenic mutations do not have a suggestive family history.
  3. To Identify Women Who Meet Criteria for High-Risk Screening MRI
    • Current American Cancer Society guidelines recommend annual screening MRI beginning by age 25 to 30 in women who have a lifetime risk (LTR) of breast cancer of 20 to 25% or more. Any of the models used to predict risk of a pathogenic mutation, or the Claus model, but NOT the Gail model, can be used to estimate lifetime risk for purposes of screening MRI guidelines. Annual screening MRI is also recommended in women who are known to carry pathogenic mutations in BRCA1 or BRCA2 (unless the woman has had bilateral mastectomy), and in women who are first-degree relatives of known mutation carriers but who are themselves untested. Women who are known to carry or are first-degree untested relatives of individuals with less common disease-causing mutations (such as those associated with Li-Fraumeni, Bannayan-Riley-Ruvalcaba, or Cowden's syndrome) are also recommended for annual screening MRI. Finally, women with prior chest radiation therapy (such as for Hodgkin's disease) between ages 10 and 30, and at least 8 years earlier, are at high risk for developing breast cancer, similar to BRCA1 or -2 carriers, and are also recommended for annual screening MRI.

Diagnostic considerations in the use of risk models:

  • Not all known risk factors are included in models (e.g. personal history of breast cancer or breast density)
  • Estimated absolute risk can vary dramatically between models
  • As a woman gets older, her 5 and 10year risk of developing breast cancer increase but her lifetime risk decreases
  • Risks change every year (as age is an important risk factor) and additional family members may have been diagnosed with breast or ovarian cancer in the interim
  • Limitations:
    • Adoption (or otherwise unknown family history)
    • Small family size
    • All models underestimate rates of breast cancer at the population level
    • All models are inaccurate at the individual level
  • Indications for genetic testing
    • Model estimates pathogenic mutation risk at >10%
    • Male breast cancer: 6% have pathogenic mutation in BRCA2
    • Personal history of breast cancer and young age at dx (< age 45); diagnosis < 50 and close blood relative dx at any age (or vice versa); triple negative breast cancer diagnosed < age 60
    • Personal history of ovarian cancer
  • Risk Reduction: Consider tamoxifen, bilateral prophylactic mastectomy, risk reducing salpingo-oophorectomy if > 10 year life expectancy
  • Increased surveillance: Supplemental MR screening beginning by age 25 in high-risk women (lifetime risk, LTR, estimated at > 20-25% by models that predict mutation carrier status), continue to age 70 (unless bilateral mastectomy) if > 10-year life expectancy and continues to meet risk guidelines and can tolerate MRI (no kidney failure, pacemaker, some other metallic implants, severe claustrophobia). Supplemental ultrasound screening in women at high risk who cannot tolerate MR, and consider in women with dense breasts, esp. if other risk factors (personal history of breast cancer, atypical, intermediate family history).

Risk models under development:

There are two risk models under development include breast density in risk calculations. However, please note, risk models which include breast density in risk calculations need further validation at this time. CONTENT PENDING

Claus EB, Risch N, Thompson WD. Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer 1994; 73:643-651

Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90:1371-1388

http://www.ncbi.nlm.nih.gov/pubmed/19569248 and http://www.ncbi.nlm.nih.gov/pubmed/16288118

Gabai-Kapara E, Lahad A, Kaufman B, et al. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proceedings of the National Academy of Sciences of the United States of America 2014; 111:14205-14210

Saslow D, Boetes C, Burke W, et al. American cancer society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007; 57:75-89

Moskowitz CS, Chou JF, Wolden SL, et al. Breast cancer after chest radiation therapy for childhood cancer. J Clin Oncol 2014; 32:2217-2223