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Assessing Women's Potential Risk of Developing Breast Cancer

Assessing Women's Potential Risk of Developing Breast Cancer

Available data show that women tend to overestimate their risk of developing breast cancer. Available models allow for the rapid identification of women who are at increased risk for breast cancer, along with a quantitative estimate of their probability of developing breast cancer over a period of years or by a certain age. Important risk factors include age; family history of breast cancer in first-degree (mother, sister, or daughter) or second-degree (aunt or grandmother) relatives; history of biopsy for benign breast disease, with or without atypical hyperplasia; nulliparity or first live birth after age 30; and menarche before age 12. Risk should be quantified routinely when women seek advice about breast cancer risk-management strategies. Counseling, with appropriate referrals when required, should always accompany specific recommendations for managing risk. Additional predictive models are needed for nonwhite women and for women not being screened regularly with mammography.

Introduction

Available data show that women are anxious about their risk of developing breast cancer and that they tend to overestimate this risk. A large literature on the epidemiology of breast cancer has led to the development of validated, quantitative risk-assessment models. These models allow for the rapid identification of women who are at increased risk for breast cancer, along with an estimation of their probability of developing breast cancer over a period of years or by a certain age. Expressing the risk of developing breast cancer in quantitative terms facilitates the education of individual patients about their risk. It also permits the rational design of prospective interventional and management strategies and the selection of eligible participants for clinical prevention trials.

This article will describe currently available models for quantitative assessment of breast cancer risk and strategies for managing women shown to be at increased risk for this cancer. First, however, key terms will be defined and established risk factors reviewed.

Definitions

We evaluate risk of breast cancer both to identify women who require special management and to increase our understanding of the biologic processes that lead to this cancer. "Risk" is a relative term derived by comparing the incidence of a disease in a group having a particular risk factor or trait with the incidence of the same disease in a comparison group of individuals who do not carry the risk factor but who are otherwise the same.[1]

Odds Ratio and Relative Risk

Risk calculations derived from retrospective data are expressed as an odds ratio, or the ratio of the odds of having the disease in those with a trait of interest compared with those without the trait. Odds and probabilities are related mathematically in such a way that if either is known, the other can be calculated. In a prospective study, the risk of disease is expressed as the ratio of the incidence of the disease in those with a particular trait divided by its incidence in those without the trait. This ratio is known as the relative risk. A relative risk (or an odds ratio) of 1.5 means that a person with a given trait or characteristic is 1.5 times more likely to develop the disease than is someone without the trait. A trait associated with a relative risk of this magnitude can also be described as conferring a 50% increase in risk.

Attributable Risk

The presence of a risk factor does not guarantee the development of a disease, just as the absence of a risk factor does not afford absolute protection against the disease. The relationship between a risk factor and the proportion of cases of a disease that it may cause is known as the attributable risk. Determination of attributable risk requires that we know the prevalence of a particular risk factor in the population and the relative risk associated with that risk factor.[1] This so-called population attributable risk (PAR) is calculated according to the following formula: PAR = [prevalence ´ relative risk] ¸ {[(prevalence ´ relative risk) - 1] + 1}. For example, a risk factor that is present in 20% of the population and that has an associated relative risk of 1.5 has an attributable risk of 0.09, or 9%; in other words, the presence of this risk factor explains 9% of the incidence of the disease in the population.

Common breast cancer risk factors and their associated relative risks, population prevalence, and attributable risks are presented in Table 1. Few breast cancer risk factors have a population prevalence more than 10% to 15%, although some (eg, mutated genes, cellular atypia) are associated with very large relative risks, making them important to consider in the clinical management of breast cancer risk. Traits associated with large relative risks are rare; common risk factors are associated with relative risks less than 2.0 so that the attributable risk for any particular risk factor is small, as shown in Table 1.

In addition, because many women possess multiple risk factors for breast cancer and because of the epidemiologic confounding that may occur in evaluating both relative and attributable risks, it may not be possible to add up the known attributable risks to obtain a summary attributable risk. If the risk factors were independent and there were no interactions among them affecting the respective levels of risk associated with the individuals factors, the summary attributable risk would be as expressed according to the following formula: summary attributable risk = 1 - [Pi - (1 - PARi)], where P denotes the product of all individual risk terms; i, each specific risk factor included (ie, eight risk factors in Table 1); and PAR, population attributable risk.

Attributable risk does not establish causality, and it is clear that nearly half the attributable risk for breast cancer remains unexplained.[2] Nevertheless, it is instructive to examine briefly what is known about established risk factors for breast cancer.

Established Risk Factors

Age

All women are at risk for breast cancer, and the most important single risk factor is age. The risk of breast cancer increases throughout a woman's lifetime, and the annual incidence of breast cancer in US women 80 to 85 years old is 15 times higher than that in women 30 to 35 years old.[3] We do not yet know whether these observed differences are explained by the accumulation of a number of events that occur throughout a woman's lifetime or by a single event triggered with greater frequency in older than in younger women.

Race and ethnicity modify the effect of age on breast cancer risk. For example, African-American women under age 50 have a higher age-specific incidence of breast cancer than their white American counterparts, but older African-Americans have a lower age-specific incidence than older white Americans.[3] As yet, there is no adequate explanation for these differences. Furthermore, breast cancer incidence among Hispanic women living in North America is only 40% to 50% as great as that among non-Hispanic white women. Asian women born in Asia have an extremely low lifetime risk of breast cancer, but their daughters born in North America have the same lifetime risk of breast cancer as American white women.[4] No explanation, including dietary factors, yet accounts for these observed differences.

Gynecologic Events

Many breast cancer risk factors relate to gynecologic or endocrinologic events in a woman's life.[5-9] Both age at menarche and age at menopause are related to a woman's chance of developing breast cancer (Table 1). These data indicate that one way of expressing the risk of breast cancer in relation to gynecologic events is simply to count the number of ovulatory menstrual cycles that a woman experiences in her lifetime. Early menarche and late menopause lead to an increased total lifetime number of menstrual cycles and a corresponding 30% to 50% increase in breast cancer risk. Conversely, late menarche and early menopause lead to a reduction in breast cancer risk of similar magnitude. Consistent with this observation is the fact that oophorectomy before a woman reaches menopause (especially before age 40) lowers her risk of breast cancer by approximately two-thirds.[6]

Pregnancy at a young age, especially before age 20, markedly reduces the incidence of subsequent breast cancer.[6] Conversely, both nulliparity and age over 30 years at first live birth are associated with nearly a doubling of the risk of subsequent breast cancer.[10] Pregnancies not ending in the birth of a viable fetus do not reduce the risk of breast cancer.[10] For obvious technical, practical, and ethical reasons, there are no data from women that provide a histologic explanation for the protection from breast cancer afforded by an early pregnancy.

Benign Breast Disease

Symptomatic changes in the breast are observed quite commonly in clinical practice. Some studies show a correlation between risk factors for breast cancer and those for benign breast disease,[11] while other studies do not.[12] The latter studies raise the possibility that benign breast disease is not a precursor to breast cancer. Also, few benign lesions show amplification of the HER-2/neu oncogene or mutation of the p53 tumor-suppressor gene.[13]

Although there is some correlation between the presence of nodularity on physical examination and the appearance of the mammogram, benign breast disease is not more common in women with other risk factors for breast cancer, such as a family history of the disease. The signs and symptoms of benign breast disease often resolve without treatment and usually do not require breast biopsy for definitive diagnosis; fewer than 20% of women in North America have undergone a biopsy for benign breast disease by age 50.[14] Benign breast disease that results in biopsy does increase the subsequent risk of developing breast cancer, however.[15]

Proliferative vs Nonproliferative Disease--Among women undergoing biopsy for benign breast disease, the risk of subsequent breast cancer is not uniform. The most informative classification scheme is based on histopathology: It divides benign disease into proliferative and nonproliferative categories.[16] Proliferative disease includes lobular and ductal hyperplasia of the usual type; florid ductal or lobular hyperplasia; apocrine metaplasia, sclerosing adenosis, intraductal papilloma, and radial scar; and lobular or ductal hyperplasia with atypia. Nonproliferative lesions that do not increase risk include normal cysts, duct ectasia, mild hyperplasia, and fibroadenoma that has not been biopsied.

Proliferative disease accounts for between one fourth and one third of all biopsies for benign disease, and 5% to 10% of the proliferative lesions show cellular atypia, the histologic change associated with the highest risk.[16-20] The atypical features are similar to some found in carcinoma in situ. Greater use of mammographic screening has led to increased identification of women with proliferative breast lesions.[21] Although early classification schemes for benign disease did not include sclerosing adenosis among the lesions that increase risk, recent data indicate that sclerosing adenosis increases the risk of breast cancer by approximately 70%, which justifies its inclusion among proliferative disease without atypia.[22]

A family history of breast cancer in a first-degree relative (mother, sister, or daughter) has an additive effect with proliferative changes or atypia on the subsequent risk of breast cancer.[16,19,20] Although fewer than 5% of women whose biopsy shows no proliferative changes develop breast cancer over the ensuing 25 years, nearly 40% of women with a family history of breast cancer and atypical hyperplasia subsequently develop breast cancer. Biopsy before the age of 50 to 55 years may be associated with a fivefold to sixfold increase in the risk of breast cancer, whereas biopsy at an older age is associated with only half this risk.[15]

Family History of Breast Cancer

Genetic factors contribute to approximately 5% of all breast cancers but to 25% of cases diagnosed before 30 years of age.[23] Early-onset breast cancer is that which occurs before age 50, at which point there is a flattening in the rate of increase in the age-specific incidence rates. Risk can be quantified rapidly and simply by assessing the number and degree of a woman's relatives affected with breast cancer and their ages at diagnosis (Table 2). Women without a diagnosis of breast cancer who have increased pretest probabilities of carrying a BRCA1 mutation can be identified on the basis of the number of relatives diagnosed with breast cancer and their ages at diagnosis.[23-27] Having more relatives diagnosed with breast cancer before age 50 increases the cumulative lifetime risk of developing the disease to near 50%, indicating the autosomal-dominant behavior of some syndromes of genetically predisposed breast cancer.

BRCA1 Mutation--Mutation of one gene, BRCA1, appears to account for 45% of families with a significantly high incidence of breast cancer and at least 80% of families with an increased incidence of both early-onset breast cancer and ovarian cancer.[28,29] BRCA1 is located on chromosome 17q and appears to encode a tumor-suppressor protein that acts as a negative regulator of tumor growth.[30-32]

The presence of a mutated BRCA1 gene with a resultant truncated protein has important clinical consequences, as shown in Table 3. The relative risk of breast cancer associated with a BRCA1 mutation is more than 200 in individuals under age 40 but drops to 15 in the seventh decade of life.[33] Penetrance of the phenotype in carriers of mutated genes is estimated to be 87% for breast cancer and 44% for ovarian cancer by age 70. There is also evidence of allelic heterogeneity, with 29% of BRCA1 mutations conferring a high risk of ovarian cancer and 71% conferring a moderate risk. If these observations hold true, the average lifetime risk of ovarian cancer in BRCA1 mutation carriers is approximately 40%.

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