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

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

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;187:349-362. Kerlikowske K et al. J Natl Cancer Inst. 2005;97:368-374. 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.

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;187:349-362.

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

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; 37:866-874

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

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)

Average Age of Diagnosis Hereditary Sporadic Breast 62 Ovarian 60 Prostate 71 Breast 41 Ovarian 40-50 Prostate 63

Gail Model National Cancer Institute http://www.cancer.gov/bcrisktool/Default.aspx The Gail model can be accessed on line through the National Cancer Institute’s Web site at: http://bcra.nci.nih.gov/brc/questions.htm.

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;21:593-601. Gail MH et al. J Natl Cancer Inst. 2001;93:334-335.

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;21:593-601. Gail MH et al. J Natl Cancer Inst. 2001;93:334-335.

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

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

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

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