Menopause: The Journal of The North American Menopause Society Epidemiology, genetics, and risk evaluation of postmenopausal women at risk of breast cancer Menopause: The Journal of The North American Menopause Society Vol. 15, No. 4, pp. 782/789 Jul-Aug, 2008

Classic Breast Cancer Risk Factors All women are at risk of breast cancer, and the single most important risk factor is age.

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Sclerosing adenosis increases the risk of breast cancer by approximately 70%.

5% to 10% of proliferative lesions show cellular atypia, which increases the risk of breast cancer fivefold. Nearly 40% of women with a family history of breast cancer and atypical hyperplasia subsequently develop breast cancer.

LCIS (lobular carcinoma in situ) has generally been considered a risk indicator, conferring an increased rate of development of invasive carcinoma of approximately 1% to 2% per year, with a lifetime risk of 30% to 40%.

FAMILY HISTORY OF BREAST CANCER AND BRCA1 AND BRCA2 MUTATIONS Genetic factors contribute to approximately 5% of all breast cancers, but to 25% of cases diagnosed before 30 years of age. Having more relatives with breast cancer before age 50 increases the cumulative lifetime risk of developing the disease to almost 50% The risk of breast cancer associated with either a BRCA1 or BRCA2 mutation is more than 200 times greater in individuals younger than age 40 but drops to 15-fold in the seventh decade of life. High-grade DCIS is more common in BRCA1 mutation carriers than in patients without a mutation

MAMMOGRAPHIC DENSITY AND CIRCULATING ENDOGENOUS HORMONE LEVELS Levels of both circulating sex steroids and mammographic density are significantly and independently associated with breast cancer risk. High mammographic density on a first examination is associated with a high rate of breast cancer that remains high even if breast density decreases in subsequent mammographic examinations. Increased risk with elevated total estradiol, free estradiol, non-SHBG-bound estradiol (which comprises free and albumin-bound estradiol), estrone, estrone sulfate, androstenedione, DHEA, DHEA-S, and testosterone.

IMPACT OF DIET, EXERCISE, AND ENVIRONMENTAL FACTORS Excess weight and weight gain in adult life are related to higher risk of postmenopausal breast cancer. Weight loss after menopause is associated with substantially reduced risk. Physical activity and the prevention of weight gain can improve survival after a breast cancer diagnosis. The only well-established individual diet-related risk factor for breast cancer other than obesity is alcohol consumption. Populations with high fat intakes generally have higher rates of breast cancer, but studies of individual women have not confirmed an association of high-fat diets with breast cancer risk. Folic acid: dual effect? Phytoestrogen: inconsistent.

QUANTITATIVE RISK ASSESSMENT AND THE GAIL MODEL The average age at diagnosis of breast cancer among women in North America is 60 years, and the risk of developing breast cancer among these women is 1.67% in the 5 years between ages 60 and 65. Women whose 5-year risk of developing invasive breast cancer is greater than 1.67% are considered to be at increased risk. FDA used this risk level to define high-risk subjects who might consider the use of selective estrogen receptor modulators (tamoxifene or raloxifene) for reduction of breast cancer risk.