Genetic epidemiology of breast cancer

279

Genetic Epidemiology of Breast Cancer W. Douglas Thompson, Ph.D.

It has been recognized for some time that a family history of breast cancer is associated rather strongly with a woman’s own risk of developing the disease. Recent segregation analyses of population-based data on familial patterns provide evidence for a rare autosomal dominant allele that increases a carrier’s susceptibility to breast cancer. The estimated proportion of breast cancer patients who carry this allele declines sharply with age at diagnosis. Empirical estimates of the risk associated with particular patterns of family history of breast cancer indicate the following: (1) having any first-degree relative with breast cancer increases a woman’s risk of breast cancer 1.5-3-fold, depending on age, (2) having multiple first degree relatives affected is associated with particularly elevated risks, (3) having a second-degree relative affected increases the risk by approximately 50%, (4) affected family members on the maternal side and the paternal side contribute similarly to the risk, (5) a family history of breast cancer is associated with bilateral disease, and (6) breast cancer in males is associated with breast cancer in female relatives in much the same way as is breast cancer in women.

Ovarian cancer clearly has been shown to be associated with breast cancer in families, and genetic linkage has provided strong evidence for a breast-ovarian cancer gene located somewhere on chromosome 17q. At the population level, having a first degree relative with ovarian cancer may be at least as predictive of a woman’s risk for developing breast cancer as is having a second-degree relative with breast cancer. Considerably weaker evidence points to a possible familial relationship between breast and endometrial cancer and between breast cancer in women and prostatic cancer in males.

The clinical applications of the genetic epidemiology of breast cancer are complicated by uncertainty as to the efficacy of mammographic screening in women under the age of 50. For the vast majority of women with a positive family history, the epidemiologic evidence does provide the basis for offering considerable reassurance in that

Presented at the National Conference on Breast Cancer, Boston, Massachusetts, August 26-28, 1993.

From the Department of Applied Medical Sciences, School of Applied Science, University of Southern Maine, Portland, Maine.

Address for reprints: W. Douglas Thompson, Ph.D., Department of Applied Medical Sciences, School of Applied Science, University of Southern Maine, 96 Falmouth Street, Portland, ME 04103.

Accepted for publication January 31, 1994.

risks are not extremely high. For that rather small subgroup at exceptionally high risk, realistic estimates of the magnitude of absolute risk over the next 10-20 years may be more informative and less alarming than lifetime probabilities. Cancer 1994; 74979-87.

Key words: breast neoplasms, genetics, ovarian neoplasms, prostatic neoplasms, endometrial neoplasms.

Breast cancer is by far the most frequently diagnosed type of malignant neoplasm among women, and it claims tens of thousands of lives annually in the United States. Despite extensive investigation into the etiology of breast cancer over the past several decades, the risk factors that have been identified to date account for only a minority of the disease in the population. Breast cancer in a first degree relative generally has been found to increase the risk of breast cancer two- to threefold.’ Having multiple affected first degree relatives may increase the risk sub~tant ia l ly .~ ,~

Awareness of family history as a risk factor leads to considerable concern on the part of many women who have affected family members, and some even seek prophylactic mastectomy. Clinicians also recognize the importance of family history as an indicator of risk and often query their female patients about the occurrence of breast cancer in family members. The use to which such information most appropriately should be put, however, is generally unclear.

This paper is not intended as an exhaustive review of the literature on the genetic epidemiology of breast cancer. Instead, its purpose is to present and synthesize some of the more recent data available on the subject and to evaluate those data from the perspective of public health and clinical decision making for individual patients.

Familial Aggregation of Breast Cancer

A number of case-control epidemiologic studies have examined the degree of familial aggregation of breast cancer. A large population-based study of this type is the Cancer and Steroid Hormone Study.4 In this study,

280 CANCER Supplement July 2, 2994, Volume 74, No. 1

Table 1. Numbers and Odds Ratios for Reported History of Breast Cancer in the Female Relatives of Breast Cancer Patients and Control Subjects, Age 20-44, Cancer and Steroid Hormone Study*

Occurrence of breast cancer in female relatives (N = 2080) (N = 2058) Odds ratio (95% CI)

No. of patients No. of control subjects

No first- or second-degree reported to

First-degree have been affected

Mother affected Sister affected Mother or sister with onset < 45 yr 2 or more affected

Second-degree

1459 1665 1.00 (referent)

191 57 93 19

70 21 30

1

3.11 (2.33-4.17) 3.10 (1 32-5.30) 3.54 (2.29-5.49)

21.68 (3.09-94.74)

Maternal grandmother or aunt affected 235 187 1.43 (1.16-1.77) Paternal grandmother or aunt affected 178 129 1.57 (1.23-2.01) 2 or more affected 66 34 2.22 (1.43-3.44)

CI: confidence interval. Excluded are 13 patients and 11 control subjects who did not provide information on the number of sisters they had had. The only second-degree relatives for

whom information was collected were grandmothers and aunts. Categories for first-degree relatives included women regardless of whether second-degree relatives were also affected; categories for second-degree relatives were restricted to women with no first-degree relative affected.

detailed family histories were collected from approximately 4500 newly diagnosed breast cancer patients between the ages of 20 and 54 and from a comparable number of age-matched control women from the general population. The initial findings were reported in 1 985,5 and extensive genetic and epidemiologic analyses have been conducted using these Here, I present some previously unpublished empirical estimates of the magnitude of the odds ratio (relative risk) for various patterns of family history of breast cancer among breast cancer cases versus controls in the Cancer and Steroid Hormone Study.

Table 1 gives data for breast cancer patients diagnosed between the ages of 20 and 44 and control women in the same age group. Table 2 presents corre-

sponding data for women between the ages of 45 and 54. From Table 1, it can be seen that for women under the age of 45, the risk of developing breast cancer is increased approximately threefold if a mother or sister has been diagnosed with the disease (odds ratios, 3.1 1 and 3.10, respectively; 95% confidence intervals, 2.33- 4.17 and 1.82-5.30, respectively). Diagnosis of breast cancer before age 45 in either a mother or sister increases the risk somewhat more (odds ratio, 3.54; 95% confidence interval, 2.29-5.49). The risk is elevated particularly in women who report that two or more of their first-degree female relatives have had breast cancer (odds ratio, 21.68; 95% confidence interval, 3.09- 94.74). Having an affected second-degree relative but not an affected first-degree relative increases the risk by

Table 2. Numbers and Odds Ratios for Reported History of Breast Cancer in the Female Relatives of Breast Cancer Patients and Control Subjects, Ages 45-54, Cancer and Steroid Hormone Study*

Occurrence of breast cancer in female relatives

No. of patients (N = 2614) (N = 2604) Odds ratio (95% CI)

No. of control subjects

No first- or second-degree reported to

First-degree have been affected

Mother affected Sister affected Mother or sister with onset < 45 yr 2 or more affected

Maternal grandmother or aunt affected Paternal grandmother or aunt affected 2 or more affected

Second-degree

1865

220 125 97 30

257 188

69

2100

132 64 39 5

186 134 35

1.00 (referent)

1.88 (1.49-2.36) 2.20 (1.60-3.07) 2.80 (1.92-4.08) 6.76 (2.49-19.84)

1.56 (1.27-1.9 1) 1.58 (1.25-2.00) 2.22 (1.44-3.42)

CI: confidence interval. * Excluded are 23 patients and 15 control subjects who did not provide information on the number of sisters they had had. The only second-degree relatives for whom information was collected were grandmothers and aunts. Categories for first-degree relatives included women regardless of whether second-degree relatives were also affected; cateeories for second-deeree relatives were restricted to women with no first-deeree relative affected.

Genetic Epidemiology of Breast Cancer/Thompson 281

approximately 50%, and the increase is of similar magnitude, regardless of whether the relative is on the maternal or paternal side of the family.

For women between the ages of 45 and 54, Table 2 indicates an overall pattern similar to that observed for women between the ages of 20 and 44, except that the magnitude of the increase in risk associated with having an affected first-degree relative is somewhat smaller.

Other epidemiologic studies generally have found similar magnitudes of risk associated with family history of breast c a n ~ e r . ~ , ~ , ' ~ - ' ~ Women with an affected first-degree relative are estimated to have a 1.5-3.0-fold increase in risk, with early age at onset in relatives often associated with a greater increase than late age at onset. An important qualification on the interpretation of many of these estimates, however, is the retrospective nature of the information collected in case-control investigations. Because of their own recent diagnosis of breast cancer, case patients may be more knowledge- able than controls about cancer in their family members, and as a consequence, the relative risks reported in some studies may be inflated. Results presented in a recent report from the Nurses' Health Study" are not subject to this sort of distortion, because the information on family history was collected prospectively, before the diagnosis of breast cancer in cohort members. In that study, a maternal history of breast cancer again was found to increase a woman's risk of breast cancer, with the magnitude of the increase related to age at diagnosis of the mother's cancer. For women whose mother developed breast cancer before age 40, the mul- tivariate relative risk was 2.00 (95% confidence interval, 1.49-2.70), and for women whose mother developed the disease a t age 70 or later, the value was 1.46 (95% confidence interval, 1.01-2.11). Women with one or more affected sisters were found to be more than twice as likely as women with no affected sister to develop breast cancer. These estimates of relative risk, although of smaller magnitude than some of those obtained from case-control studies, indicate that the results from retrospective investigations of the familial aggregation of breast cancer are generally valid. Prospective data from a cohort of women in Iowa yielded a relative risk of 1.53 for any affected first-degree relative, but that study was restricted to women who were older than age 54 at the beginning of the follow-up period."

Application of segregation analysis to population- based data on breast cancer in families indicates a pattern consistent with inheritance of a rare autosomal dominant allele.' The estimated proportion of breast cancer patients who carry this allele declines sharply with increasing age a t diagnosis.

Results from several studies indicate that having a relative with bilateral breast cancer may put a woman

at a particularly high risk of developing breast cancer, 14~17-25 although other studies do not.3,5,26,27 Retro- spective collection of family history data may be particularly problematic when the women providing the history are asked to differentiate between unilateral and bilateral disease. Recently, prospective population- based interview data addressing this issue have been published.2' Selected results are summarized in Table 3. For that study, the breast cancer cases from the Cancer and Steroid Hormone Study, who were diagnosed with breast cancer between 1980 and 1982 and interviewed about their family history shortly thereafter, were fol- lowed through 1986 via the Surveillance, Epidemiology and End Results Program of the National Cancer Insti- tute to monitor the occurrence of a second primary breast cancer in the contralateral breast. As the results in the table indicate, women who have had a first primary breast cancer are more likely to develop a contralateral second primary breast cancer if they have a family history of breast cancer than if they do not. In addi- tion, the magnitude of the rate ratio (relative risk) is greater if a first-degree relative was diagnosed with breast cancer before age 45 than if she was diagnosed with breast cancer at a later age.

Several of the pedigrees reported in the literature as illustrative of families with an extremely high rate of occurrence of breast cancer have been remarkable in that they include instances of male breast cancer, which in the general population is extremely rare. Therefore, it would seem that the presence of male breast cancer in a family may be a particularly powerful indicator that female family members are at high risk for developing breast cancer. A recent population-based study, however, indicates that the familial association between male and female breast cancer is not strikingly stronger than the corresponding association for female breast cancer within families.29 Table 4 presents selected results from that study. Having a mother affected with breast cancer is found to increase the risk of male breast cancer 2.33-fold, and having an affected sister is found to increase the risk 2.23-fold. These estimates are close to the corresponding figures of 1.97 and 2.25 obtained from a metaanalysis of five studies of female breast cancer. The table also indicates that male breast cancer may be related particularly strongly to early-onset breast cancer in female first-degree relatives, but the confidence interval around the estimate of 10.47 is wide. The finding of a 4.08-fold increase in risk associated with having an affected second-degree female relative makes little genetic or epidemiologic sense in the context of the estimates for first-degree relatives; it may reflect insta- bility due to small numbers or systematic bias due to case-control differences in the knowledge that men

282 CANCER Supplement ju ly I , 1994, Volume 74, No. 1

Table 3. Numbers and Rate Ratios for Reported History of Breast Cancer in Female Relatives as It Relates to the Incidence of Second Primary Breast Cancer, Cancer and Steroid Hormone Study

Occurrence of breast cancer in female relatives

No. with No. at second primary Adjusted rate risk breast cancer ratio (95% CI)

No first- or second-degree reported

First-degree to have been affected

Any affected Onset < 46 yr

any affected Second-degree but not first-degree,

3268

524 176

732

86

26 12

24

1.00 (referent)

1.91 (1.22-2.99) 2.73 (1.48-5.03)

1.32 (0.84-2.08)

C1: confidence interval.

may have of the history of breast cancer in their second- degree relatives.

Association of Breast Cancer with Family History of Other Types of Cancer

It has been hypothesized that breast and ovarian cancer share a common genetic etiology. Strong evidence for this hypothesis is provided by recent linkage analyses of 214 pedigree^,^' which suggest that one or more genes located on chromosome 17q account for the majority of cancer in those families manifesting early-onset breast cancer and ovarian cancer. Other studes have attempted to evaluate the genetic relationship between breast and ovarian cancer in the general population rather than in selected families. One population-based case-control study of women newly diagnosed with ovarian cancer found that the case subjects were 50% more likely than control subjects to report having a first- degree relative affected with breast cancer.31 A similar magnitude of association between the two cancers in families was reported by Cramer et aL3’ For the breast cancer patients in the Cancer and Steroid Hormone Study, the reported frequency of ovarian cancer in fam-

ily members also was found to be greater than the corresponding frequency for control subjects (odds ratio, 1.50 for cases and controls between the ages of 20 and 44; odds ratio, 1.88 for cases and controls between the ages of 45 and 54).9 Less direct evidence for a genetic relationship between breast and ovarian cancer is provided by studies of multiple primary cancers in the same individual. These studies have found the incidence of breast cancer to be elevated by 10-40% after a first primary cancer of the ovary, and the incidence of ovarian cancer to be elevated by 30-70% after a first primary breast ~ a n c e r . ~ ~ - ~ ~

These same studies of multiple primary cancers also suggest that there may be a genetic relationship between cancers of the breast and endometrium, because the incidence of breast cancer after a first diagnosis of endometrial cancer is increased by 20-30%, and because the incidence of endometrial cancer after a first diagnosis of breast cancer is increased by approximately 4 0 Y 0 . ~ ~ - ~ ~ On the other hand, evidence from case-control studies of family history have provided relatively little evidence for an association, although a nonsignificant odds ratio of 1.5 was reported in one and a nonsignificant odds ratio of 1.29 was reported for

Table 4. Numbers and Odds Ratios for Reported History of Breast Cancer in the Female Relatives of Male Breast Cancer Patients and Control Subjects

Occurrence of breast cancer in No. of No. of control Adjusted odds female relatives patients subjects ratio (95% CI)

No first- or second-degree reported

First-degree

to have been affected 174 163 1 .OO (referent)

Mother affected 15 9 2.33 (0.98-5.54) Sister affected 22 17 2.23 (1.10-4.50) Any affected 53 37 2.29 (1.30-4.04) Onset < 45 yr NR NR 10.47 (2.31-47.38)

Second-degree any affected 21 11 4.08 (1.79-9.32)

CI. confidence interval: NR: not reoorted.

Genetic Epidemiology of Breast Cancer/Thompson 283

women between the ages of 20 and 44 in the Cancer and Steroid Hormone Study.' The strongest evidence to date for a familial association between breast cancer and endometrial cancer comes from the prospective evaluation of second primary breast cancer in the Can- cer and Steroid Hormone Study.28 Based on family histories collected shortly after the diagnosis of first primary breast cancer, a family history of endometrial cancer was associated significantly with the subsequent development of a second primary breast cancer (rate ratio, 2.13 for one or more affected first-degree relatives; 95% confidence interval, 1.04-4.35).

Two recent studies also have suggested that the incidence of breast cancer in women may be associated with a history of prostate cancer in male relatives. An- derson and Badzioch3' found that, within a group of families ascertained through an index patient with male breast cancer, the occurrence of breast cancer in women was 3.7-fold higher if there was a history of prostate cancer within the family. A recent record linkage study in Iceland yielded a relative risk of 1.4 for the familial association of prostate cancer and female breast can- ~ e r . ~ ~ Further studies are needed to elucidate the nature and magnitude of the familial association between these two cancers.

Population-wide Perspective on Familial Risks

There clearly is a familial component to breast cancer that is likely to represent genetic transmission and that accounts for some proportion of the incidence of the disease in the population. The precise magnitude of that proportion, and therefore the importance of genetic transmission in the etiology of breast cancer at the population level, has not yet been established. Therefore, to put the genetic epidemiology of breast cancer into clearer public health perspective, I have conducted some multivariable analyses of familial risks in the Can- cer and Steroid Hormone Study4 and have attempted to quantify the implications of these risks at the population level.

The first step in this process is the fitting of logistic regression models4' to the family histories of the breast cancer cases and controls to estimate the multiplicative factor by which each component of family history contributes to the incidence of breast cancer. The models provide for the possibility that the contribution of each component may differ in magnitude for women between the ages of 20 and 44 for those between the ages of 45 and 54. Results are given in Table 5. Because nei- ther a family history of endometrial cancer nor the dis- tinction between unilateral and bilateral breast cancer in family members was found to be associated with the incidence of breast cancer, these factors are not in-

Table 5. Computation of a Woman's Relative Risk for Breast Cancer Development Based on Data from the Cancer and Steroid Hormone Study+

History of cancer in female relatives

Multiplicative factor for increased risk

Breast cancer in one or more first- degree relatives

Breast cancer with onset younger than age 45 in one or more first. degree relatives

Breast cancer in two or more first- degree relatives

Breast cancer in one or more second-degree relatives

Breast cancer in two or more second-degree relatives

2.22 or 1.47t

1.38

3.83

1.36

1.49 Ovarian cancer in one or more first-

degree relatives 1.59 The baseline group was women with no breast cancer in first- or second-de-

gree relatives and no ovarian cancer in first-degree relatives. Estimates were based on logistic regression analysis. t The value of 2.22 was used for women age 20-44 yr, and the value of 1.47 was used for women age 45-54 vr.

cluded in the table. The only component of family history found to differ significantly with age in terms of its impact on the incidence of breast cancer is having one or more first-degree relatives affected with breast cancer. The odds ratio (i.e., relative risk or multiplicative factor for the increase in risk) for this component is estimated to be 2.22 for women between the ages of 20 and 44 and 1.47 for women between the ages of 45 and 54. Having a second-degree relative with ovarian cancer was not found to be associated significantly with breast cancer in this study.

Using the estimates in Table 5, one can calculate the risk of developing breast cancer for a woman having a particular pattern of family history relative to that for a woman with no breast cancer in first- and second-degree relatives and no ovarian cancer in first-degree relatives. Because the control subjects in the Cancer and Steroid Hormone Study were selected randomly from defined geographic areas, they provide useful information on the frequency with which various patterns of family history occur in the general population. Tables 6 and 7 give, separately for the two age groups, the relative risk for each distinct pattern of family history that occurred at least once in the control group. The relative risks are obtained by multiplying together the bracketed factors for each component of family history that ap- plies to a particular woman. Thus, in Table 6 the value of 4.51 is calculated by multiplying 2.22 X 1.36 X 1.49 to obtain the relative risk for developing breast cancer among women who are between the ages of 20 and 44 and who have one first-degree relative affected with breast cancer (age at onset of 45 or older), two or more

284 CANCER Supplement July 1,1994, Volume 74, No. 3

Table 6. Relative Risk of Breast Cancer According to History of Cancer of the Breast and Ovary in Female Relatives Age 20-44

Family history of breast cancer

First-degree

Onset < 45 yr cancer in first-degree Relative in population Second-degree Family history of ovarian Representation

I+ (2.22). 11.38) 2'13.831 1+[1.36] 2'11.49) relative [1.59] risk (per 1000)

1 .oo 803 X 1.36 128

X 1.59 6 X X 2.03 17 X X 2.17 2

X 2.22 20 X X 3.03 8 X X 3.06 1 1 X X X 4.16 2 X X X 4.51 1 X X X X 6.21 1 X X X X 6.62 < l X X X X 15.96 < I

Total 1.17 1000

Numbers in brackets are the multiplicative factors for increase in risk as listed in Table 5.

Table 7. Relative Risk of Breast Cancer According to History of Cancer of the Breast and Ovary in Female Relatives Age 45-54

Family history of breast cancer

First -degree Second -degree Family history of ovarian Representation

I + Onset <45 yr 2+ I+ 2+ cancer in first-degree relative Relative in population (1.47]* (1.381 (3.831 (2.361 (1.491 (1.591 risk (per 1000)

X

X

X

X

X

X

X

X

X

X

X

X

X X

X

X

X X

X

X

X

X

X X

Total

X

X

X

X

1 .oo 1.36 1.47 1.59 2.00 2.02 2.03 2.16 2.34 2.76 2.99 3.22 4.11 5.64 7.76

16.81 1.15

797 105 4 6

8 12 1 1 13

< 1 < I

2 2

< I I 1 1

< l 1000

Numbers in brackets are the multiolicative factors for increase in risk as listed in Table 5.

second-degree relatives with breast cancer, and no first- degree relative with ovarian cancer. This risk is ex- pressed relative to the risk for women between the ages

of 20 and 44 who have no first- or second-degree relative with breast cancer and no first-degree relative with ovarian cancer. The final column in Tables 6 and 7 is

Genetic Epidemiology of Breast Cancer/ Thompson 285

calculated from the control group and indicates the estimated number of women per 1000 in the general population that has the particular pattern of family history.

The estimates given in Tables 6 and 7 indicate that, although certain patterns of family history are associated with substantial elevations in the risk of breast cancer, these high risk patterns occur only infrequently in the general population. Even among those women who do have some history of breast cancer in first- or second- degree relatives and/or some history of ovarian cancer in first-degree relatives, the majority have a level of risk that is less than 50% higher than that for women without a family history. The last figure given in the final column of each table is an estimate of the magnitude of the incidence for the population as a whole divided by the incidence in the subgroup that has no history of breast cancer in either first- or second-degree relatives and has no history of ovarian cancer in first-degree relatives. It is obtained by taking a weighted average of the relative risks listed in that table, with the weights being the proportion of the population having the particular pattern of family history. This estimate can be used to calculate the approximate percentage of all breast cancer in the population that is attributable to family history. For women between the ages of 20 and 44, this percentage is (1.17-1.00)/1.17, 14.5%, and for women between the ages of 45 and 54, it is (1.15-1.00)/1.15,

These percentages are considerably larger than the recently published and widely cited figure of 2.5% based on prospective data from the Nurses’ Health Study.I5 That figure, however, was obtained from erro- neous calculations, and the appropriate figure is 6.0% (GA Colditz, M.B.B.S. personal communication, 1993). A major basis for the discrepancy between the estimates from the Cancer and Steroid Hormone Study and the estimate of 6.0% from the Nurses’ Health Study is that the latter value is based only on first-degree relatives. It is evident from Tables 6 and 7, however, that although the relative risk is greater when a first-degree relative is affected with breast cancer than when only a second- degree relative is affected, more women in the population have an affected second-degree relative than have an affected first-degree relative. Consequently, failure to consider the contribution of affected second-degree relatives can lead to substantial underestimation of the total contribution of family history to the incidence of breast cancer in the population as a whole. When information on only first-degree family members is consid- ered in the Cancer and Steroid Hormone Study, the estimated percentage is, in fact, close to the figure of 6.0% from the Nurses’ Health Study (7.1% for women between the ages of 20 and 44; 5.3% for women between

13.0 yo.

the ages of 45 and 54). Data from the prospective study by Sellers et a1.16 yield an estimate of 6.1%.

It also should be noted that rather little of the breast cancer occurring in the population is attributable to ovarian cancer in first-degree relatives, because only a small proportion of women in the population have that risk factor. For those women who do, in fact, have such a history, however, it seems to be at least as strong a predictor of breast cancer as is having a second-degree relative affected with breast cancer.

If further studies support the reported familial association between prostate cancer in males (which is a common cancer) and breast cancer in females, then con- sideration of a family history of prostate cancer may yield estimates appreciably higher than 13.0-14.5?40 for the total percentage of breast cancer that is explicable in terms of family history of cancer. Additionally, some women in the Cancer and Steroid Hormone Study ap- parently underreported breast cancer in second-degree relative^,^ so that the true proportion of women with an affected second-degree relative is probably greater than that indicated in Tables 6 and 7. The true contribution of breast cancer in second-degree relatives to the incidence of breast cancer in the population therefore is probably greater than what I have estimated, unless the extent of underreporting of breast cancer in second-degree relatives differs for case and control subjects, and the estimates of relative risk used for the calculations thereby have been inflated.

Unfortunately, the Cancer and Steroid Hormone Study4 included only case and control subjects under the age of 55. It would be important to conduct comparable multivariable analyses in datasets that include older women.

Clinical Implications

Current knowledge concerning the genetic epidemiology of breast cancer indicates that, for a sizable minority of the breast cancers that occur in the population, some sort of genetically transmitted susceptibility contributes to their etiology. At the same time, a positive history of breast cancer or certain other malignant neoplasms in family members should not lead to especially great worry on the part of most women and their health care providers. For the majority of women with a family history of breast cancer in first- or second-degree relatives, the elevation in risk is less than 50% higher than the risk for women without a family history. All women, irrespective of their family history, are at a high enough risk for developing breast cancer that screening via mammography and physical examination of the breast should be conducted at appropriate intervals.

The small subgroup of women who are, in fact, at

286 CANCER Supplement July 1, 2994, Volume 74, No. 1

exceptionally high risk for developing breast cancer due to a particularly intense family history pose undeniable dilemmas to the clinician. Although one strategy would be to institute screening for breast cancer at a relatively young age among women at highest risk, the efficacy of mammographic screening in women under the age of 50 has not been established. Prophylactic mastectomy is an extreme measure that conceivably might be con- sidered in situations of incapacitating anxiety about the development of breast cancer, but even in such situations it is not clear that surgery is the most appropriate means for addressing that anxiety. For those women at highest risk, the perceptions of the absolute magnitude of risk may in fact be exaggerated by both the women themselves and their health care providers. The most frequently cited risks for breast cancer are lifetime risks. If the probability of developing breast cancer for women in the general population is approximately lo%, and if a woman is known on the basis of her family history to have an expected incidence that is several times greater than that of other women, then it may well seem that it is nearly inevitable that the woman will develop the disease. Because the incidence of breast cancer increases with age and because there are differ- ential social and personal impacts of developing a life- threatening disease during later life as opposed to during midlife, lifetime risks may not be the most appropriate means for assessing risk and choosing among al- ternative interventions. Projecting risks over a period of 10-20 years may be more appropriate in many clinical settings.

Once specific genes regulating susceptibility to breast cancer are identified and cloned, the clinical is- sues relating to risk of breast cancer will change dramat- i ~ a l l y . ~ ' , ~ ~ In the years ahead, both genetics and epidemiology, and particularly the interface between the two, undoubtedly will play an increasingly important role in the field of breast cancer.

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Genetic epidemiology of breast cancer