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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.

How are the models used?X

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[i] 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. 13,388 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 causing stroke and deep vein thrombosis are increased in women taking tamoxifen [ii].

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[iii] 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[iv] 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 syndrome) are also recommended for annual screening MRI. Finally, women with prior chest radiation therapy (such as for Hodgkin disease) between ages 10 and 30, and at least 8 years earlier, are at high risk for developing breast cancer[v], similar to BRCA1 or -2 carriers, and are also recommended for annual screening MRI.

[i] 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

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

[iii] 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

[iv] 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

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

Risk model explanations X

Table 1 features 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 describing the Claus model[vi]. None of these models include breast density in risk calculations.

There are risk models that do include breast density in risk calculations.

  • Breast Cancer Surveillance Consortium (BCSC) model[vii] was developed and validated in a large, ethnically diverse, prospective cohort of women undergoing screening mammography. It includes the risk factors with the greatest population attributable risks for breast cancer including age, breast density, family history, history of a breast biopsy, and a polygenic risk score (PRS) based on common genetic variations[viii]. The updated model is the only breast cancer risk assessment model that uses BI-RADS breast density and the only model to include the full range of breast biopsy results including hyperplasia, atypical hyperplasia and lobular carcinoma in situ.[ix],[x] A link to the BCSC model is also included in Table 1.
  • Planned update to Tyrer-Cuzick Model will include density - The latest version (v8) of the Tyrer-Cuzick (IBIS) model, based on input from Dr. Jennifer Harvey at the University of Virginia and Dr. Martin Yaffe at University of Toronto, which includes breast density, is now available in a beta testing version: http://www.ems-trials.org/riskevaluator (Windows/PC only, click on “Pre–Release v8 for Testing”). In this model, breast density is one of the top five factors determining breast cancer risk.

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

vii Tice JA, Cummings SR, Smith-Bindman R, et al: Using clinical factors and mammographic breast density to estimate breast cancer risk: development and validation of a new predictive model. Ann Intern Med 148:337-47, 2008

viii Vachon CM, Pankratz VS, Scott CG, et al: The contributions of breast density and common genetic variation to breast cancer risk. JNCI In press, 2014

ix Tice JA, O'Meara ES, Weaver DL, et al: Benign breast disease, mammographic breast density, and the risk of breast cancer. J Natl Cancer Inst 105:1043-9, 2013

x Tice J, Miglioretti DL, Li C, et al: Breast density and benign breast disease: Risk assessment to identify women at high risk of breast cancer. J Clin Oncol, In submission, 2015

Diagnostic considerations X

Risk Models and Diagnostic Considerations:

  • Risk models may not include known risk factors (e.g. personal history of breast cancer, detailed family history or breast density)
  • Estimated absolute risk can vary substantially between models
  • Age: As a woman gets older, her 5- and 10-year risk of developing breast cancer increases but her lifetime risk decreases
  • Known risks can change every year (particularly as age is a risk factor). Family history may also change as family members may have been diagnosed with breast or ovarian cancer in the interim

    Risk Model Limitations:

    • Adoption (or otherwise unknown family history)
    • Small family size
    • All models underestimate rates of breast cancer. At best they predict about 67% of women who will develop cancer at the population level.
    • All models are low in accuracy at the individual level ("discrimination")

    Risk Model Indications for Genetic Testing Include:*

    • If model estimates pathogenic mutation risk at >10%
    • Male breast cancer or family history of male breast cancer: 6% have pathogenic mutation in BRCA2
    • Personal history of breast cancer and <= age 50 at dx; diagnosis at any age and <= 50 and close blood relative dx <= age 50; triple negative breast cancer diagnosed <= age 60
    • Personal history of ovarian cancer

      *http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf accessed on April 17, 2015

    Risk-Reducing Interventions:

    • Consider tamoxifen or raloxifene in post-menopausal women with at least one of the following:
      • At least 1.67% 5-year risk by Gail model
      • Personal history of lobular carcinoma in situ
      • Age at least 60 years
    • For women with disease-causing BRCA mutation(s), consider bilateral prophylactic mastectomy, risk-reducing salpingo-oophorectomy if at least 10-year life expectancy

    Risk Model Indications for Increased Surveillance:

    • Supplemental MR screening beginning by age 25 in “high-risk” women
      • Lifetime risk (LTR) estimated at 20-25% or more by models that predict mutation carrier status
      • Disease-causing BRCA or p53 or PTEN mutation(s) or first-degree untested relative of disease-causing mutation carrier but untested
      • Prior chest radiation therapy (e.g. for Hodgkin’s disease) before age 30 and at least 8 years earlier
    • Continue annual MRI screening (and mammography) to age 70 (unless bilateral mastectomy) if at least 10-year life expectancy, patient continues to meet high-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, especially if other risk factors (personal history of breast cancer, prior atypical biopsy, intermediate family history).

Risk Models TableX

Gail Personal risk 5-year and lifetime risk (LTR) of developing breast cancer Current age, age at menarche, age at first live birth childbirth, number of first-degree relatives (mother, sisters, daughters) with breast cancer, prior benign biopsies, prior atypical biopsy and race/ethnicity.
DOES NOT INCLUDE: Age of diagnosis of relatives; not to be used to assess “high-risk” criteria for MRI screening
Web:http://www.cancer.gov/bcrisktool/ When considering tamoxifen or other risk-reducing medications (>1.7% 5-year risk); NOT to be used for risk assessment for purposes of screening MRI nor for genetic testing
Tyrer-Cuzick (IBIS) Personal risk and risk of mutation carrier 5-year, 10-year and LTR of developing breast cancer Current age, age at menarche, height, weight, parity, age of first childbirth, age at menopause, HRT use, prior breast biopsy, ovarian cancer, age of dx of breast/ovarian cancer in mother/sister/daughter and if bilateral maternal and paternal grandmothers and aunts; and Ashkenazi descent Web: http://www.ems-trials.org/riskevaluator/

Version (v8), which includes breast density, is now available as a testing version (Windows/PC only). Use current link and click on “Pre–Release v8 for Testing".
Risk assessment for genetic testing (10% risk for pathogenic mutations is commonly used) or MRI screening (20% lifetime risk threshold)
Penn II Personal risk and risk of mutation carrier LTR risk of developing breast cancer Ashkenazi descent, # of women in family dx with both breast and ovarian cancer, # of women in family dx’ed with ovarian or fallopian cancer in absence of breast cancer (BC), # of BC cases in family diagnosed < age 50, age of youngest BC case in family; # of people in family with: presence of mother-daughter dx, w/ bilateral BC, male BC dx, presence of pancreatic cancer or prostate cancer Web: http://www.afcri.upenn.edu/itacc/penn2/ Risk assessment for genetic testing (10% risk for pathogenic mutations is commonly used) or MRI screening (20% lifetime risk threshold)
Claus Personal risk LTR of developing breast cancer Occurrence(s) of breast cancer in specific female relative(s) Web: http://www.ncbi.nlm.nih.gov/pubmed/8299086 MRI screening (20% lifetime risk threshold)
Breast Cancer Surveillance Consortium (BCSC) Personal risk 5-year and 10-year risk of developing invasive breast cancer Current age, race/ethnicity, BI-RADS breast density, first-degree relative, prior breast biopsy. Web: https://tools.bcsc-scc.org/BC5yearRisk/calculator.htm
App: https://itunes.apple.com/us/app/bcsc-risk-calculator/id919034661?ls=1&mt=8
Risk assessment for use of medications for prevention (tamoxifen, raloxifene, aromatase inhibitors)