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Assessing Women's Potential Risk of Developing Breast Cancer

Assessing Women's Potential Risk of Developing Breast Cancer

ABSTRACT: 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. [ONCOLOGY 10(10):1451-1463, 1996]

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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