Clinical Pearls and Tools for Optimizing Breast Cancer Risk Assessment Anna Maria Storniolo, MD Professor of Clinical Medicine Division of Hematology/Oncology Director, Catherine Peachey Breast Cancer Prevention Program Indiana University School of Medicine Indianapolis, Indiana

Value of Risk Assessment Improves overall quality of care Encourages BC awareness Enhances physician-patient relationship Improves trust Dispels misperceptions Allays unwarranted fears Provides basis for discussion of risk management Risk assessment for breast cancer (BC) is a valuable clinical tool for OB/GYNs and primary care physicians (PCPs) because it can be used to open a dialogue with patients, allay fears, and provide patients with the knowledge they need to discuss risk-management options.

Estimating BC Risk: Gail Model1 Features Provides 5-year and lifetime risk estimates based on Age Race Age at first live birth or nulliparity Number of first-degree relatives with a history of BC Age at menarche # of previous breast biopsies Atypical hyperplasia The Gail model was developed by the National Cancer Institute as a clinical tool for estimating the risk of BC.1 A modified version of the Gail model, developed during the Breast Cancer Prevention Trial, provides women with their 5-year and lifetime BC risk estimates.1 The computer program of the Gail model calculates a risk estimate from an individual’s risk factors, including age, race, age at first birth or nulliparity, number of first-degree relatives with a history of BC, age at menarche, number of previous breast biopsies, and presence of atypical hyperplasia.1 Coyne RL et al. Counseling About Risk Management. In: Vogel VG, Bevers T, eds. Handbook of Breast Cancer Risk-Assessment. Sudbury, MA: Jones and Bartlett Publishers; 2003:126-145. 1. Coyne RL, Bevers T. In: Vogel VG, Bevers T, eds. Handbook of Breast Cancer Risk-Assessment. Sudbury, MA: Jones and Bartlett Publishers; 2003:126-145.

Gail Model: Advantages An appropriate risk assessment tool for most women attending specialized clinics1 Identifies women who could benefit from preventive interventions; may assist in making clinical decisions2 Incorporates risk factors other than family history (eg, reproductive variables, atypical hyperplasia, history of breast biopsies)3 Shows that BC risk increases with age and, therefore, may prompt discussion about the importance of BC screening4 Used to counsel and educate women, especially those who overestimate their BC risk2 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. 1. Euhus DM et al. Breast J. 2002;8:23-27. 2. Gail MH, Costantino JP. J Natl Cancer Inst. 2001;93:334-335 (editorial). 3. Domchek SM et al. J Clin Oncol. 2003;21:593-601. 4. National Cancer Institute. Breast Cancer Risk Factors. Available at: http://bcra.nci.nih.gov/brc/learnmore.htm. Accessed September 28, 2005.

Gail Model: Limitations Modest discriminatory accuracy for individual women1 Not validated for black, Hispanic, and other ethnic groups1 May underestimate risk for women with demonstrated mutations of the BRCA1 or BRCA2 genes1 Only solicits family history involving first-degree relatives2,3 May underestimate risk when family history is on father’s side3 Does not take into account age at which relatives developed BC4 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. 1. Gail M, Costantino JP. J Natl Cancer Inst. 2001;93:334-335 (editorial). 2. Coyne RL, Bevers T. In: Vogel VG, Bevers T, eds. Handbook of Breast Cancer Risk-Assessment. Sudbury, MA: Jones and Bartlett Publishers; 2003:126-145. 3. Domchek SM et al. J Clin Oncol. 2003;21:593-601. 4. Euhus DM et al. Breast J. 2002;8:23-27.

Gail Model National Cancer Institute http://bcra.nci.nih.gov/brc/questions.htm 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. National Cancer Institute. Breast Cancer Risk Assessment Tool. Available at: http://bcra.nci.nih.gov/brc/questions.htm. Accessed September 28, 2005.

Other Risk-Assessment Models Claus1 Cuzick2 BRCAPRO3 Improvements in screening for early detection of BC have led to other risk-assessment models, including the Claus,1 Cuzick,2 and BRCAPRO models.3 The Claus model provides BC risk estimates in 10-year increments and lifetime risks for women with a family history of BC, including first- and second-degree relatives with BC and their age at onset of BC.1 The Cuzick model provides a personalized risk estimate by combining personal risk factors with a detailed genetic analysis.2 The BRCAPRO model calculates the probability of a BRCA1 or a BRCA2 mutation in a family and takes into account the individual’s personal cancer history, their first- and second-degree relatives’ medical history, the ages of cancer onset, Ashkenazi Jewish heritage, and whether BC has occurred in any men in the family.3 Claus EB et al. Cancer. 1994;73:643-651. Tyrer J et al. Stat Med. 2004;23:1111-1130. Euhus DM et al. J Natl Cancer Inst. 2002;94:844-851. 1. Claus EB et al. Cancer. 1994;73:643-651. 2. Tyrer J et al. Stat Med. 2004;23:1111-1130. 3. Euhus DM et al. J Natl Cancer Inst. 2002;94:844-851.

Who Is at “Very High Risk”? Personal history of BC1 BRCA1 or BRCA2 mutation carrier1 2 or more 1st-degree relatives with BC2 Lobular carcinoma in situ (LCIS)1 Atypia and a 1st-degree relative with BC1 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. 1. Hollingsworth AB et al. Am J Surg. 2004;187:349-362. 2. Carpenter CL et al. Int J Cancer. 2003;106:96-102.

Who Is at “High Risk”? Atypia1 5-year Gail risk >1.7%1 2 or more 2nd-degree premenopausal affected relatives1 Combined estrogen-progesterone hormone therapy for more than 10 years1 Mammographically dense breasts2 Obesity3 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. 1. Hollingsworth AB et al. Am J Surg. 2004;187:349-362. 2. Kerlikowske K et al. J Natl Cancer Inst. 2005; 97:368-374. 3. Davison D. In: Vogel VG, Bevers T. Handbook of Breast Cancer Risk-Assessment. Sudbury, MA: Jones and Bartlett Publishers; 2003:10-19.

Risk Counseling in the Primary Care Setting1 Inform patients about personalized risk information for BC Support and reinforce positive health behaviors (eg, healthier eating, exercise, quitting smoking) Educate and correct misperceptions about actual risk when the patient is overestimating or underestimating it Talk to anxious patients about “coping behaviors” (eg, meditation, self-talk, keeping a journal) Reduce time spent waiting for BC-related test results and improve communication about the tests Encourage patients to call their OB/GYNs/PCPs to explain test results Risk counseling for BC in the primary care setting can provide information for patients at risk as well as support and reinforce positive health behaviors, such as healthier eating, exercise, and smoking cessation.1 Another benefit of risk counseling is that physicians can educate and correct misperceptions, for example, when a patient is overestimating or underestimating risk.1 Discussing coping behaviors, including positive self-talk and keeping a journal, may help patients work through the anxiety and fear of being diagnosed with BC.1 Reducing the amount of time that patients wait for test results can also alleviate anxiety.1 Stollings SR. Psychological Management of Women at Increased Risk. In: Vogel VG, Bevers T, eds. Handbook of Breast Cancer Risk-Assessment. Sudbury, MA: Jones and Bartlett Publishers; 2003:170-179. 1. Stollings SR. In: Vogel VG, Bevers T, eds. Handbook of Breast Cancer Risk-Assessment. Sudbury, MA: Jones and Bartlett Publishers; 2003:170-179.

Reasons Requiring Referral for Imaging/Cytology Intensive surveillance for women at very high risk1 Follow-up for prior BC or benign lesions2 Abnormalities on screening mammograms2 Reassurance (eg, family history, anxiety about BC)2 Deciding when to refer a patient for imaging or cytology depends on her risk of BC. Possible reasons for referring a patient for breast imaging include follow-up for prior BC or benign lesions, abnormalities on screening mammograms, or reassurance in the case of family history or patient anxiety.1 Techniques for imaging the breast include mammograms, magnetic resonance imaging, and ultrasound.2 Merck Medicus. Ultrasound Improves Accuracy of Breast Cancer Diagnosis. Available at: http://merck.micromedix.com/index.asp?page=newsarchive&news_id=5138&news=md. Accessed January 18, 2006. Agnese DM. Surg Technol Int. 2005;14:51-56. 1. Gilbert FJ. Cancer Imaging. 2005;5:32-38. 2. Merck Medicus. Ultrasound Improves Accuracy of Breast Cancer Diagnosis. Available at: http://merck.micromedex.com/index.asp?page=newsarchive& news_id=5138&news=md. Accessed September 28, 2005.

Reasons Requiring Referral for Genetic Testing1 Diagnosis of BC before age 50 Diagnosis of two unique BCs Diagnosis of BC and another primary cancer, especially ovarian cancer Family history of BC, especially when occurring at a young age Male relative with BC Diagnosis of BC and Ashkenazi Jewish ancestry In most cases of BC, the cause is unknown.1 One in 10 cases of BC may involve an inherited risk.1 Reasons requiring referral for genetic testing should be considered if a person has at least 1 of the following risk factors1: a diagnosis of BC before the age of 50, a diagnosis of 2 separate BCs, a diagnosis of BC and another cancer (such as pancreatic, colon, thyroid, stomach, melanoma, or especially, ovarian), or a family member with a history of BC. Other genetic risk factors for a woman include a male relative with BC or a diagnosis of BC and Ashkenazi Jewish ancestry.1 Cedars-Sinai. Common Reasons for Referral. Available at: http://www.csmc.edu/pf_1014.html. Accessed November 2, 2005. 1. Cedars-Sinai. Common Reasons for Referral. Available at: http://www.csmc.edu/1014.html. Accessed September 28, 2005.

Screening for BC1 Mammography American Cancer Society (ACS) recommends yearly mammograms starting at age 40 and continuing for as long as a woman is in good health Clinical Breast Examination (CBE) ACS recommends CBE be part of a periodic health examination, about every 3 years for women in their 20s and 30s and every year for women 40 and older Breast Self-Examination (BSE) BSE is an option for women starting in their 20s The American Cancer Society (ACS) recommends that women aged 40 and older should have a screening mammogram every year.1 The ACS also recommends that women in their 20s and 30s should have a clinical breast examination (CBE) as part of their regular health examination every 3 years and every year after age 40.1 A CBE can be an opportunity for a woman and her healthcare provider to discuss changes in her breasts, early detection testing, and factors in her history that might make her more likely to develop BC.2 American Cancer Society. ACS Cancer Detection Guidelines. Available at: http://www.cancer.org/docroot/PED_2_3X_ACS_Cancer_Detection_Guidelines_36.asp. Accessed September 28, 2005. American Cancer Society. Detailed Guide: Breast Cancer. Can Breast Cancer Be Found Early? Available at: http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_Can_breast_cancer_be_found_early_5.asp?sitearea=. Accessed January 12, 2006. 1. American Cancer Society. ACS Cancer Detection Guidelines. Available at: http://www.cancer.org/docroot/PED/ content/PED_2_3X_ACS_Cancer_Detection_Guidelines_36.asp. Accessed September 28, 2005.

BC Screening Mammography screening in women aged 50 to 69 years demonstrated reduction of 20% to 35% in mortality from BC1 In 2002, ~40% of US women ≥40 years reported NOT having a mammography in the last year2 During the past few years, scientific controversy about the benefits of screening mammography has increased.1 Patients should be informed of the risks and benefits of any medical intervention. A possible risk may include false-positive mammographies.1 In support of mammography screening, a statistically significant reduction of 20% to 35% in BC mortality rate was demonstrated in women aged 50 to 69 years.1 Among women aged 40 years and older, 30% to 48% of all deaths from BC could have been prevented with timely mammograms.2 In 2002, 40% of United States women aged 40 years and older reported not having had a mammogram within the last year.2 By initiating evidence-based guidelines for BC screening, morbidity and mortality rates may be reduced.2 Fletcher SW et al. N Engl J Med. 2003;348:1672-1680. Smith RA et al. CA Cancer J Clin. 2004;54:41-52. 1. Fletcher SW, Elmore JG. N Engl J Med. 2003;348:1672-1680. 2. Smith RA et al. CA Cancer J Clin. 2004;54:41-52.

Advice to All Women Comply with mammography guidelines1 Maintain a healthy weight2 Get regular exercise2 Don’t rely on diet to reduce risk2 Consider other reasonable lifestyle modifications that may reduce risk Reduce alcohol intake2 Avoid smoking2 The guidelines provided by the ACS for early detection of BC provide women with opportunities for early diagnosis and successful treatment of BC.1 Therefore, women should comply with mammography guidelines: Women aged 40 or older should have a mammogram every year.1 Some BC risks cannot be avoided, such as age and genetic makeup, but other risks are within a woman’s control. Women may minimize BC risk and improve their overall health by maintaining a healthy weight, avoiding smoking, reducing alcohol intake, and exercising regularly.2 American Cancer Society. Detailed Guide: Breast Cancer. Can Breast Cancer Be Found Early? Available at: http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_Can_breast_cancer_be_found_early_5.asp?sitear ea=. Accessed January 12, 2006. Vogel VG. CA Cancer J Clin. 2000;50:156-170. 1. American Cancer Society. Can Breast Cancer Be Found Early? Available at: http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_Can_breast_cancer_be_found_early_5.asp. Accessed September 28, 2005. 2. Vogel VG. CA Cancer J Clin. 2000;50:156-170.

Key Take-Away Messages Screening for BC is an important part of risk assessment The OB/GYN/PCP’s understanding of risk factors and use of risk assessment tools are necessary for BC disease-state awareness The Gail risk-assessment model, though it has its limitations, is useful Risk assessment for BC adds value to the OB/GYN/PCP practice, notably improving the overall quality of women’s healthcare Screening for BC is an important component of early detection and risk assessment. The OB/GYN’s and PCP’s understanding of risk factors and use of clinical risk-assessment tools are necessary for early detection and successful treatment of BC. A woman’s OB/GYN and PCP are appropriately situated to provide information on BC risk and risk-management strategies, thereby improving the quality of her healthcare.