1. Identify women at increased risk for breast cancer.

2. Determine the appropriate surveillance and risk-reducing strategies for breast cancer.

3. Provide appropriate follow-up care for women with a history of breast cancer.

4. Identify and treat complications of therapy for breast cancer.

5. Educate patients about direct-to-consumer marketing of genetic testing.

Breast Cancer Prevention: A Role for Drug Therapy
Leo B. Twiggs, MD, Professor and Chair, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Miami Miller School of Medicine, and Chief of Service, Jackson Memorial Hospital, Miami

Risk factors: no family history in 80% of women diagnosed; 5% to 10% of breast cancer related to genetic abnormalities; sex and age most common risk factors; women >50 yr of age account for 78% of all newly diagnosed breast cancer; younger women more concerned, but older women more at risk; atypical hyperplasia associated with 4-fold increased risk in 15-yr period; lobular neoplasia defines spectrum of histologic changes; breast density noted on mammography increases risk 4 to 6 times; number of first-degree relatives with breast cancer important risk factor; family history more heavily weighted risk factor for younger women; risk >4 times greater with BRCA1 and BRCA2 gene mutations; 4 times greater with history of abnormal biopsy; 5 times greater when breasts dense; greater exposure to endogenous estrogen (eg, early menarche, late menopause) increases risk; Women’s Health Initiative (WHI)—showed postmenopausal obesity increased risk by 50% (likely because of estrone and estradiol concentration); estrogen associated with trend toward decreased risk for breast cancer; estrogen and medroxyprogesterone increased incidence of invasive breast cancer by 26% (excess of 8 cases per 10,000 women-years of follow-up)

Risk assessment: take accurate history; use validated tools to assess patient’s risk; informed decision-making requires open dialogue; results interpreted in context of patient’s overall health; informed patient likely more compliant with screening; communication about personal risk increases screening test compliance, enhances patient-physician relationship, dispels misperceptions, and lessens fears; low to average risk—risk factors confer ≤1.5-fold relative risk of developing breast cancer; elevated or high risk—Gail model 5-yr risk score, 1.66%; very high risk—history of atypical hyperplasia and family history that includes one affected first-degree relative; BRCA1 or BRCA2 gene mutation carriers; genetic counselor important for women at very high risk

Gail model risk assessment tool: good for predicting absolute risk of developing breast cancer for women as a group; however, not useful for individual risk prediction; factors in current model include age, personal history, family history, and ethnicity; risk expressed as percentage; incorporates risk factors other than family history; not appropriate for women with history of breast cancer or atypical hyperplasia; not validated in some ethnic groups; used to determine eligibility for chemoprevention with tamoxifen; number of breast biopsies without atypical hyperplasia may cause inflated risk estimates; does not incorporate age of onset of breast cancer in relatives, or all known risk factors for breast cancer (eg, breast density, body mass index); underestimates risk from heredity (ie, maternal and paternal family history of breast or ovarian cancer)

Risk-reducing strategies: primary preventive strategies—lifestyle modification; chemoprevention; risk-reducing surgery; secondary preventive strategies—combination of clinical breast examinations and breast imaging modalities to detect disease at earlier stage; modifiable lifestyle risk factors—alcohol consumption and dietary fat intake; multiple cohort studies reported consumption of ≥1 alcoholic drinks per day increases risk by ≈26%; no prospective trials showing whether omission of alcohol reduces risk; low-fat diet in postmenopausal women did not result in statistically significant reduction in risk

American Cancer Society guidelines for surveillance: clinical breast examination as part of periodic health examination for women in their 20s and 30s, continuing annually beginning at 40 yr of age; annual mammography beginning at 40 yr of age; awareness of new breast symptoms and prompt reporting of changes to physician providing primary care; women at high or very high risk—clinical breast examination performed every 6 to 12 mo and annual mammography; mammography should begin 5 to 10 yr earlier than age of youngest affected relative, or at 40 yr of age (whichever earlier); magnetic resonance imaging (MRI)—associated with high sensitivity for detecting invasive breast cancer; no data on frequency; studies show specificity ranges from 37% to 97%; screening MRI recommended for women with strong family history of breast and ovarian cancer, BRCA gene mutation carriers, women with history of chest irradiation between the ages of 10 and 30 yr, and women with lifetime risk >20% to 25% as defined by Gail model, dependent on family history; controversial risk groups—women with personal history of invasive or in situ breast cancer, atypical hyperplasia, and extremely dense breasts on mammography; reasons why women discontinue mammography—lack of recommendation; access problems (eg, inadequate insurance, cost barriers); perception that mammography does not provide sufficient benefit; possibility of false-positive result leading to possible surgery and biopsy; unsubstantiated fear of irradiation to breast; no fear of breast cancer

Risk-reducing surgery: risk-reducing mastectomy reasonable and effective option in very high-risk women; data show prophylactic mastectomy reduced incidence by 90%; prophylactic oophorectomy decreases ovarian cancer by 90% and breast cancer by 50% if performed at <40 yr of age; prophylactic oophorectomy more often choice than prophylactic mastectomy because it is not associated with alteration in body image and self-esteem

Risk-reducing chemoprevention: tamoxifen—first-generation selective estrogen receptor modulator (SERM); 10-yr use approved for breast cancer risk reduction; reduction in contralateral breast cancer shown with adjunctive tamoxifen; data support decrease in risk of developing breast cancer with tamoxifen use, but do not show decreased mortality; adverse effects include hot flushes, vaginal discharge, endometrial cancer, stroke, and life-threatening thromboembolic disease; less pronounced in premenopausal women and women with medical comorbities; raloxifene (Evista)— second-generation SERM; less effect on endometrium; increases bone mineral density in postmenopausal women; data show incidence of estrogen-receptor positive invasive breast cancer reduced by 66% (profile similar to tamoxifen); increased risk for thromboembolic disease; does not result in increased risk for endometrial cancer; data show no significant reduction in cardiovascular disease among women with multiple cardiac risk factors; raloxifene vs tamoxifen— data showed raloxifene as effective as tamoxifen in reducing risk for invasive breast cancer; more vasomotor symptoms, leg cramps, and gynecologic problems, but better sexual function reported in tamoxifen arm; more dyspareunia, weight gain, and musculoskeletal problems in raloxifene arm; raloxifene alternative to tamoxifen in women willing to accept potential adverse effects; not recommended for premenopausal women; occurrence of noninvasive breast cancer lower with tamoxifen (reason unclear); fewer thromboembolic events, fewer cataracts, and fewer cases of uterine hyperplasia among women taking raloxifene; women with 5-yr projected breast cancer risk score of 1.66% should be offered tamoxifen 20 mg daily for 5 yr to reduce risk; greatest clinical benefit with fewest adverse effects associated with tamoxifen use in younger women; failure to discuss risk-prevention strategies puts clinician at medicolegal risk; Evista indicated for treatment and prevention of osteoporosis and for reduction in risk for invasive breast cancer in postmenopausal women; aromatase inhibitors—shown to reduce contralateral breast cancer; ongoing worldwide studies; counsel or refer high-risk patient for chemoprevention; document discussion about risk prevention; important to define role in patient’s breast care and cancer surveillance

Follow-up Care of the Breast Cancer Survivor
Deborah J. Rhodes, MD, Assistant Professor, Department of Medicine, Mayo Clinic Scottsdale, Scottsdale, AZ

General considerations: 182,000 new cases of breast cancer annually; >2.5 million survivors; 90% of women survive ≥5 yr from diagnosis; survivors monitored by >1 medical professional, resulting in redundancy of effort; data show generalist-directed care associated with greater cost-effectiveness, greater patient satisfaction, and no difference in time to detection of breast cancer recurrence

Types of recurrence: locoregional—recurrence in breast, chest wall or scar, or regional recurrence in lymph nodes or soft tissue of axilla; accounts for ≈25% of all recurrences; occurs in 6% of survivors; distant metastasis—evidence of tumor anywhere in body; 75% of all recurrences; bone most common site for metastasis, followed by lung, disseminated liver, and brain; majority of recurrences seen ≤5 yr after diagnosis; recurrences possible after 20 yr; tumor size and lymph node involvement most important predictors of recurrence

Minimal vs intensive surveillance: minimal surveillance—physical examination and annual mammography; intensive surveillance—chest x-ray, bone scan, liver ultrasonography (US), and blood tests (eg, tumor markers); 70% of survivors wanted frequent evaluation and testing, even when asymptomatic; assumption that tests detect recurrence early— majority of recurrences detected by patient; 15% detected by physician at time of routine health care appointment; 14% detected by tests; assumption that early detection of metastasis matters—data show no significant differences in overall survival between groups receiving either minimal or intensive surveillance; no impact on survival with early detection of metastasis; treatment only prolongs survival; educating patient may lessen fear and anxiety; early detection of locoregional recurrence—important; ipsilateral breast recurrence after lumpectomy occurs in ≈1% of lumpectomy patients per year; few have distant disease at time of local recurrence; >50% remain free from disease after salvage mastectomy; most patients have distant disease; theoretically curable if no distant disease; early detection important for primary breast cancer and locoregional recurrence; cost associated with intensive surveillance—frequent visits and waiting for test results causes anxiety; tests imperfect; almost 5000 additional dollars/patient per year, compared to minimal surveillance; almost $12 billion; data found patient education resulted in acceptance of minimal surveillance

Guidelines for breast cancer surveillance: history and physical examination—every 3 to 6 mo for first 3 yr, then every 6 to 12 mo for years 4 and 5, annually thereafter; breast self-examination—monthly; mammography—first posttreatment mammogram 1 yr after initial diagnosis, then annually, provided no changes; what to look for—changes in breast (eg, lumps, nipple discharge, skin changes); chest wall nodules (eg, sores, skin changes); axillary lymph node examination important and should be performed with patient standing; look for early signs of lymphedema; persistent cough or other chest symptoms; abdominal pain, musculoskeletal pain; weight loss and nausea, vertigo, or headache; regular pelvic examination recommended; counsel patient about symptoms of recurrence; not recommended—routine blood tests, imaging studies, or tumor markers; history of breast cancer in patient or any first- or second-degree relative merits testing; annual MRI recommended for—carrier of BRCA gene mutation; first-degree relative of BRCA gene mutation carrier (untested); patient suspected of being carrier of BRCA gene mutation; patient receiving chest wall irradiation; patient with high lifetime risk; data insufficient for women with history of breast cancer; additional tests for high-risk patients— annual CA-125 blood test, annual pelvic US and breast MRI if BRCA-positive; imaging in addition to mammography may be warranted in those with extremely dense breast tissue

Complications associated with treatment: surgery and irradiation—pain or numbness in breast, chest wall, or axilla most common; lymphedema; restricted arm motion and weakness, and reoperation after breast reconstruction (refer patient to rehabilitation center); lymphedema—present in ≈10% of women having sentinel node biopsy; risk directly related to extent of axillary surgery; irradiation of left breast associated with 30% higher risk for premature coronary artery disease; chemotherapy and hormonal therapy—tamoxifen doubles risk for uterine cancer; yearly pelvic examination recommended; patient should be instructed to report vaginal bleeding; routine endometrial US and/or biopsy not indicated (majority of patients present with vaginal spotting); increases risk for deep venous thrombosis, pulmonary embolism, and stroke; higher incidence of cataracts; hot flushes most common complaint; hot flushes increased in women who had hot flushes before taking tamoxifen; may diminish after several months; vaginal discharge; metabolism of tamoxifen—poor metabolism to endoxifen may explain some patients’ lack of response to tamoxifen; drugs that inhibit metabolism include fluoxetine, paroxetine and many other common antidepressants, analgesics, antiemetics, cardiac drugs, and H2 blockers; treatment of hot flushes—venlafaxine (Effexor) good option; estrogen therapy—data show risk for recurrence associated with use of hormone therapy in survivors; consider only if patient’s symptoms severe and all nonhormonal treatments have failed; consider woman’s risk for recurrence; patient needs to weigh quality-of-life issues against possible increased risk for recurrence

The Pros and Cons of Genomic Testing in Primary Care
Katherine S. Hunt, MS, CGC, Assistant Professor of Medicine, Mayo Clinic Scottsdale

Human genome: 30,000 genes; different species have different genomes; ≈3.1 billion base pairs in each cell; genomic testing involves thousands to millions of base pairs being simultaneously analyzed for susceptibility to any given disease; genomics is study of function of genes as they communicate to one another and communication of environment to these genes

Genomic inheritance pattern: multifactorial inheritance—gene-environment and gene-to-gene interactions; majority of common diseases inherited in multifactorial manner (90% of all cancers); variation in human genome—unrelated individuals share in common 99.9% of DNA sequence; 0.1% difference equates to differences at millions of bases; variants (at single base pair) called single-nucleotide polymorphisms (SNPs); HapMap project—international project designed to map haplotypes (25,000 base pairs grouped and tagged) and correlate with disease susceptibility; SNPs and haplotypes key to association studies necessary to identify genes involved in complex common diseases

Genomic testing: practical genomic testing—cytochrome P450 (CYP450 ), factor V Leiden, oncotype DX and UGT1A1 gene testing, BRCA1 and BRCA2, hereditary melanoma, and hereditary colorectal cancer; research-based genomic testing (eg, Alzheimer’s disease); pros of practical genomic testing—scientifically validated data; personalization of health care; health care team involvement in discussing results and monitoring patients; patient management improved because of testing; cons—long-term follow-up necessary to track outcomes; more gene-to-gene interactions yet to be discovered, making current story incomplete; environmental interactions not fully understood; direct-to-consumer marketing of genetic testing—laboratories unregulated; data not validated; consumer potentially harmed by incomplete or uninterpretable information; misunderstanding of test results; companies privately owned, for-profit enterprises (conflict of interest); increased awareness of genetic testing has helped to lessen public’s fears about implications of genetic testing; more research needed before personal genomics reaches mainstream medicine; genomic testing proven effective for patient care; certain to reshape delivery of health care; regulation of laboratories needed to ensure scientific validity