1. Breast Cancer Risk and Risk Assessment Models
Jessica Ray, MS, CGC
Cancer Genetic Counselor
Ambry Genetic Laboratories
¡Vida! Educational Series - Promoting Good Health

2. Learning Objectives
Identify Personal and Family Characteristics that may indicate an inherited increased risk for cancer
Understand the role of genetic counseling in assessing patients with possible hereditary cancer syndromes
Understand characteristics, advantages, limitations, and differences of the Gail and BRCAPRO risk-assessment tools used by clinicians to help establish cancer risk

4. Who Is at “High Risk”? Atypia 5-year Gail risk >1.7%
2 or more 2nd-degree premenopausal affected relatives
Combined estrogen-progesterone hormone therapy for more than 10 years
Mammographically dense breasts
Obesity
Factors that put women at “high risk” for BC include atypia, a 5-year Gail risk >1.7%, having 2 or more second-degree premenopausal affected relatives, taking combined estrogen-progesterone hormone therapy for longer than 10 years,1 having mammographically dense breasts,2 and postmenopausal obesity.3 Quantitative risk-assessment estimates the probability that a woman will develop BC within a defined period. Therefore, risk may become more concrete and comprehensible to the patient.1
Hollingsworth AB et al. Am J Surg. 2004;187:
Kerlikowske K et al. J Natl Cancer Inst. 2005;97:
Davison D. Lifestyle Factors and Breast Cancer Risk. In: Vogel VG, Bevers T, eds. Handbook of Breast Cancer Risk-Assessment. Sudbury, MA: Jones and Bartlett Publishers; 2003:10-19.

5. Who Is at “Very High Risk”?
Personal history of BC <50
BRCA1 or BRCA2 mutation carrier
2 or more 1st-degree relatives with BC
Lobular carcinoma in situ (LCIS)
Atypia and a 1st-degree relative with BC
The Breast Cancer Risk Assessment Working Group established a BC risk assessment schema for identifying and facilitating clinical management of women at risk for developing BC.1 Factors that put women at “very high risk” include a personal history of BC, such as ductal or lobular carcinoma in situ; being a BRCA1 or BRCA2 mutation carrier; having 2 or more first-degree relatives with BC; and having atypia and a first-degree relative with BC.1
Hollingsworth AB et al. Am J Surg. 2004;187:

6. What is Genetic Counseling?
Genetic Counseling is a communication process that deals with both the medical and psychological issues associated with the occurrence of a genetic disorder in a family
Cancer genetic counseling focuses on hereditary cancer syndromes
This process involves one or more trained professionals to help the individual or family

7. Reasons for Seeking Genetics Consultation
To learn about
Personal risk for cancer
Children’s risk for cancer
Family’s risk for cancer
Risks for developing cancer if you have a “cancer gene”
Recommendations for screening, surveillance, and/or treatment
Educational information
To obtain genetic DNA testing
J Med Genet 2000; 37:

10. Key Flags that Warrant Genetic Counseling
Significant family medical history-breast, ovarian, prostate, colon, uterine, melanoma, pancreatic, or other cancers
Cancer occurs in every generation
Early age of onset (< 50 years)
Male breast cancer
Bilateral cancer, or multiple primary cancers in one individual
Known family genetic mutation
Ethnicity – Ashkenazi Jewish ancestry

11. Sporadic, Familial or Hereditary?
5-10% cancers have a hereditary component
Over 200 hereditary cancer syndromes described
Hereditary cancer tends to occur at younger ages than sporadic cancer, often bilateral, multifocal
Lifetime risks of cancer exceed cancer risks due to noninherited factors (early menarche, nulliparity, late age of menopause, HRT, etc)
Majority show an autosomal dominant inheritance pattern (few are recessive)

14. Average Age of Diagnosis Hereditary Sporadic
Breast 62
Ovarian 60
Prostate 71
Breast 41
Ovarian
Prostate 63

20. Gail Model
National Cancer Institute
The Gail model can be accessed on line through the National Cancer Institute’s Web site at:

24. Gail Model: Advantages
Identifies women who could benefit from preventive interventions; may assist in making clinical decisions (Determination of eligibility for tamoxifen for breast cancer risk reduction…Gail score>1.7)
Incorporates risk factors other than family history (eg, reproductive variables, atypical hyperplasia, history of breast biopsies)
Calculation of breast cancer risk in absence of family history in women
Shows that BC risk increases with age and, therefore, may prompt discussion about the importance of BC screening
Used to counsel and educate women, especially those who overestimate their BC risk
The Gail model is accessible via the Internet.1 Questionnaires can be printed and given to patients to complete. A member of the healthcare team enters patient data, and the software calculates the patient’s risk.1
The Gail Model takes into account a woman’s medical and family history. It also incorporates a woman’s reproductive history (ie, her age when she had children, the number of children she had) and whether she has had a breast biopsy.2 Furthermore, the Gail model can help women who overestimate their risk of BC.3
Euhus DM et al. Breast J. 2002;8:23-27.
Domchek SM et al. J Clin Oncol. 2003;21:
Gail MH et al. J Natl Cancer Inst. 2001;93:

25. Gail Model: Limitations
Not validated for black, Hispanic, and other ethnic groups
Only solicits family history involving first-degree relatives
May underestimate risk when family history is on father’s side
Does not take into account age at which relatives developed BC
Effect of number of breast biopsies (without atypical hyperplasia) may cause inflated risk estimates
May underestimate risk for women with demonstrated mutations of the BRCA1 or BRCA2 genes
The Gail model has several limitations. It underestimates risk by neglecting family history of bilateral BC, BC in second-degree relatives diagnosed before the age of 50, the age at which relatives developed BC, and personal history of lobular carcinoma in situ.1 Because the Gail model only includes family history involving first-degree relatives, it underestimates BC risk when family history is on the father’s side.2
The Gail model does not directly calculate the risk of having an adverse genotype, so the risk of BC is underestimated for women with demonstrated mutations of the BRCA1 or BRCA2 genes.3 Finally, the Gail model offers limited validated data for African-American, Hispanic, and other ethnic groups.3
Euhus DM et al. Breast J. 2002;8:23-27.
Domchek SM et al. J Clin Oncol. 2003;21:
Gail MH et al. J Natl Cancer Inst. 2001;93:

27. BRCAPRO - Advantages
Incorporates both affected and unaffected family members in estimation of carrier probability
incorporates maternal and paternal breast and ovarian cancer history
age at cancer diagnosis, current ages, ages relatives became deceased considered
Ashkenazi Jewish ethnicity taken into consideration
Oophorectomy status and breast cancer receptor status considered

28. BRCAPRO - Limitations
Dependent on published estimates of prevalence and penetrance of BRCA1 and BRCA2
Does not consider more distant family history past 1st and 2nd degree relatives
Does not consider other potential susceptibility genes with features similar to BRCA1 and BRCA2

29. When Do You Offer Testing?
American Society of Clinical Oncology recommends genetic testing :
The individual has a personal or family history of features suggestive of a genetic cancer susceptibility condition
The test can be adequately interpreted
The results will aid in diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer
ASCO recommendations:
Genetic testing only be done in the setting of pre-and post-test counseling,
Should discuss possible risks and benefits of cancer early detection and prevention modalities

30. Implications/Important Points
What do we offer individuals at high risk for hereditary cancers who test negative for a genetic mutation?
Negative genetic test result does not mean No Increased Risk!!
AZCC High Risk Clinic for individuals at greater risk of developing cancer
Must continue studies to find other genes responsible for hereditary cancers
Must develop more advanced, individualized risk assessment tools