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Relative risk of breast cancer varies with time since diagnosis of atypical hyperplasia
Current Topics Relative Risk of Breast Cancer Varies With Time Since Diagnosis of Atypical Hyperplasia WILLIAM D. DUPONT, PHD,AND DAVID L. PAGE, MD We recently reported’ the utility of histopathologic patterns in breast biopsies as predictors of future breast cancer risk. The acceptance of an intermediate category between carcinomas in situ and the most common patterns of hyperplasia was supported by the fact that this intermediate category, atypical hyperplasia (AH), was predictive of a relative risk of later carcinoma development intermediate between that of common hyperplasia and microscopic examples of carcinoma in situ. The present discussion is the result of subsequent practical considerations concerning the translation of those relative risk figures into clinical recommendations (refer to Term Definitions). Ideally, clinical recommendations would involve absolute risk figures for individual patients, or at least for subsets of women defined by age and family history, the most potent of non-anatomic risk factor determinants currently known. Unfortunately, while it is possible to investigate absolute cancer risk in large subgroups of study subjects, the limitations of study size rarely permit estimates of absolute cancer
risk for subgroups of patients defined by all the relevant variables that may affect the risk of subsequent morbidity. Instead, study results are usually expressed in terms of relative risks because these statistics can meaningfully summarize the experience of women with widely differing absolute risk figures by adjusting for age, length of follow-up, and other variables that have a profound effect on cancer risk. This has permitted our presentation of the cancer risk for AH to be summarized by a single number from the experience of women with this lesion who differed widely with respect to other risk factors. Thus, relative risk provides a measure of the meaningfulness of a factor studied within diverse patient populations as opposed to providing prognostic information about an individual patient. We have found that women with AH on biopsy have approximately a fivefold increase in breast cancer risk over that of women of similar ages from the general population.* It is important to bear in mind, however, that the clinical implications of this result for a patient in her 30s are quite different from those of a 60-year-old woman, since the breast cancer risk in the general population increases rapidly with age. Thus, a newly diagnosed 40-year-old woman with AH will have approximately a 9% chance of developing breast cancer in the next 20 years, while the 20-year risk for a 60-year-old woman with atypia is approximately 25%.3 Our objective in deriving the relative risk of AH is to measure the increase in breast cancer risk that can be attributed to AH. Unfortunately, the numerator and denominator populations of relative risk may vary with respect to factors other than AH that affect cancer risk. When these factors are known, we can eliminate their effects on our relative risk estimates by calculating an adjusted relative risk. This statistic estimates the relative risk value that we would have obtained had our numerator and denominator populations been identical with respect to those factors that have been adjusted for. The practical or clinical meaning of the term relative risk is widely misunderstood, particularly when it is applied to patients who have a substantial risk of developing the disease of interest during the remainder of their lives. This uncertainty is due to incorrect inferences about relative risks in combination with lifetime risks and may be best expressed by the frequently posed following questions: We know that one in ten women will develop invasive breast cancer (IBC) during their lives4 and
The incidence of breast cancer in a population is the number of newly diagnosed cases of breast cancer in this population over a year divided by the population size. The relative risk of breast cancer for women with atypical hyperplasia (AH) is the incidence of breast cancer among women with a history of AH divided by the breast cancer incidence in women in some reference population. This reference population may be defined in any sensible way, eg, women from the general population, study subjects without a history of AH, or study subjects without a history of proliferative disease (with or without atypia). The magnitude of the relative risk is critically dependent on the breast cancer incidence in both the numerator and denominator subgroups. A woman’s absolute risk of breast cancer is her probability of developing breast cancer during some specified time period, eg, the next 10 or 20 years.
Received from the Departments of Preventive Medicine and Pathology, Vanderbilt University School of Medicine, Nashville, TN. Supported by the National Cancer Institute (contract NOlCB-74098 and arants no. ROl-CA-31698. ROl CA-40517. and ROlCA-46492). ” Key words: atypical hyperplasia, breast cancer risk, timedependent cancer risk, hazard regression models. Address correspondence and reprint requests to William D. DuPont, PhD, Department of Preventive Medicine, Vanderbilt School of Medicine, Nashville, TN 37232-2637. 0 1989 by W.B. Saunders Company. 0046-8177/89/2008-0001$5.00/O
723
HUMAN PATHOLOGY
Volume 20, No. 8 (August 1989)
under the assumption that each patient’s relative risk remains constant over time. It is possible, however, for the relative risk of an individual patient to vary either as a function of age or time since initial diagnosis. An example of such a change can be found in our own studies of benign breast disease. We previously reported that women who have undergone breast biopsy revealing AH have 5.3 times the breast cancer risk of biopsied women who lacked proliferative disease, and that the corresponding relative risk for women with proliferative disease without atypia (PDWA) is 1.9.2 These results were obtained using a proportional hazards regression model that assumes that relative risk remains constant over time. Figure 1, however, shows an alternative analysis of these same data. The risk estimates presented in this illustration were derived from a hazard regression model that used time-dependent covariates.* Figure 1 shows that the breast cancer risk associated with both AH and PDWA is greatest in the first 10 years after the benign breast biopsy. Women with PDWA who remain free of breast cancer for 10 years are at no greater risk of breast cancer than women of similar age who do not have such a history. The relative risk of breast cancer in women with AH is halved if they remain free of breast cancer for 10 years following the initial biopsy. This supports the hypothesis that the AHs are not obligate precursor lesions for breast cancer, and that these lesions may either progress to cancer, remain unchanged, or possibly regress over a substantial period of time. The absolute risk for all the women in this study group2 seems to be approximately evenly distributed over the 17-year period of follow-up (Fig 2). The knowledge that invasive carcinomas were fairly evenly distributed over this period of time combined with the knowledge that approximately half of the invasive carcinomas had occurred by year 10 would have led us to predict the finding just described. Thus, an approximately constant cancer incidence over a 17-year age span, together with an increasing
that the relative risk of developing IBC among women with microscopic ductal carcinoma in situ (MDCIS) is ten times that of women in the general reference population. 5 Does this mean that a young woman with MDCIS is certain to develop IBC during her lifetime (ie, (l/10) X 10 = l)? If, in fact, this is not the case and there is a good chance that this woman will not develop IBC, then what is meant when it is stated that she has a tenfold increase in breast cancer risk over women of similar age from the general population? These questions can be answered by considering a specific example: the age-specific incidence of breast cancer for American women aged between 30 and 60 years is 27.5 and 292 cases per annum per 100,000 women, respectively.6 Suppose that Sally Smith is diagnosed at age 30 with MDCIS. When we say that she has a relative risk of ten for developing IBC, we mean that her chances of developing this cancer during her 30th year are 275/100,000, ten times that of a typical 30-year-old woman. If her relative risk remains constant for the next 30 years, and if she remains free of breast cancer until her 59th birthday, then her chances of developing breast cancer in her 60th year are 2,920/100,000, ten times that of a typical 60-year-old. Her probability of developing IBC between ages 30 and 100 years equals the sum of the probabilities of her first developing IBC at the age of 30,31,32. . . 100. Each of these probabilities is the product of two terms: her probability of disease-free survival until the start of the year of interest, and her probability of developing cancer during that year (given that she is alive and cancer-free at the start of that year). For example, given that Sally Smith is now 30 years of age, her probability of first developing breast cancer in her 60th year equals her probability of disease-free survival until age 59 times her probability of developing breast cancer in her 60th year, given that she will be alive and disease-free at her 59th birthday. Symbolically, if Si denotes the probability that she survives until her (i-1)st birthday without developing IBC, and Bi denotes her probability of developing IBC during her i-th year, given disease-free survival until the start of that year, then her lifetime probability of developing IBC will be the sum of the SiBi terms for each year of her possible remaining life (C SiBi). The effect of the Si terms will be to ensure that this sum is always less than one. Even if the Bi terms are all ten times the corresponding age-specific breast cancer probabilities from the general population, and even though the lifetime risk in the general population is one in ten, the lifetime risk for Sally Smith, Z SiBi, will not come close to 100%. In fact, one can estimate that the lifetime risk for IBC in a 30year-old with a relative risk of ten is approximately 64s.’ (The task of following a sufficiently large cohort of women to determine such a life-time risk directly would be extremely formidable.) There is another complexity concerning clinical implications of relative risks. Most relative risk estimates from longitudinal studies have been derived
1
PROLIFERATIVE
DISEASE WITHOUT
NO PROLIFERATIVE
L
AMP,*
DISEASE
1.0
Relative
Risk of Breast
Cancer
FIWRE 1. Relative risk (RR) of breast cancer in women with proliferative disease. Risks of patients with and without atypia are contrasted with risks of biopsied women who did not have proliferalive disease. Breast cancer relative risks decrease substantially in women who remaln free of breast cancer for 10 years following their proliferative disease biopsy. The thin vertical bars enclose the 95% confidence intervals for each of the displayed RR figures.
724
BREAST CANCER RISK AND ATYTXN
Atypical
Hypsrplasla
plus
Family
History
r-
‘re---‘---‘-‘---
i
I
rr’
Prolifarotlve
0
5
10
15 YEARS
SINCE
20 BENIGN
hyperplasla
dlteme without ______________
\ ____,--
______/.--
;
Atypical +---_
25
30
atypio
35
BIOPSY
HYPERPIASLA (Dupont & Page)
The clinical significance of this time-dependent analysis is that follow-up of women with AH must be most vigilant during the first 10 years following diagnosis and that women who have remained free of breast cancer for 10 or more years after a diagnosis of AH can be reassured with the knowledge that their breast cancer risk is now closer to that of the general population than it was at the time the AH was first diagnosed, although the absolute risk per year has remained about the same. Women with the more common and non-atypical hyperplasias who remain free of cancer for 10 years following this diagnosis can be reassured with the knowledge that their breast cancer risk is no different from that of women of similar age from the general population.
FIGURE 2. Proportion of patients who have developed IBC as a function of time since their benign breast biopsy. (Data from Dupont and Page.?
REFERENCES
age-specific incidence in the general population (the denominator of the relative risk statistic) implies that a woman’s relative risk of breast cancer must decrease with increasing time since biopsy. Whether relative risk will continue to drop with further follow-up is, of course, yet to be determined. This time-dependent analysis does suggest that the constancy of relative risk figures through an entire lifetime should not be presumed when making clinical decisions. We have previously discussed the advisability of confining predictive statements to the length of time covered by the specific studies that form the basis of these predictions.g This stance was predicated on the knowledge of increasing competing causes of death with advancing age. 3 We now add further credibility to that stance by noting that, while yearly incidence of invasive cancer following diagnosis of AH is fairly stable, relative risk decreases.
1. Page DL: Cancer risk assessment in benign breast biopsies. HUM PATHOL 17:871-874, 1986 2. DuPont WD, Page DL: Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 312: 146151, 1985 3. DuPont WD: Converting relative risks to absolute risks: A graphical approach. Stat Med 1989 (in press) 4. Seidman H, Mushinski MH, &lb SK, et al: Probabilities of eventually developing or dying of cancer-United States, 1985. CA 35:36-56, 1985 5. Page DL, DuPont WD, Rogers LW, et al: lntraductal carcinoma of the breast: Follow-up after biopsy only. Cancer 49:751758, 1982 6. SEER: 1987 Annual Cancer Statistics Review Including Cancer Trends 1950-1985. Washington, DC. National Cancer Institute, 1988 7. Chiang CL: Introduction to Stochastic Processes in Biostatistics. New York, Wiley, 1980 8. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, Wiley, 1980 9. Page DL, DuPont WD: Histopathologic risk factors for breast cancer in women with benign breast disease. Semin Surg Oncol 4:213-217, 1988 “.
risk for subgroups of patients defined by all the relevant variables that may affect the risk of subsequent morbidity. Instead, study results are usually expressed in terms of relative risks because these statistics can meaningfully summarize the experience of women with widely differing absolute risk figures by adjusting for age, length of follow-up, and other variables that have a profound effect on cancer risk. This has permitted our presentation of the cancer risk for AH to be summarized by a single number from the experience of women with this lesion who differed widely with respect to other risk factors. Thus, relative risk provides a measure of the meaningfulness of a factor studied within diverse patient populations as opposed to providing prognostic information about an individual patient. We have found that women with AH on biopsy have approximately a fivefold increase in breast cancer risk over that of women of similar ages from the general population.* It is important to bear in mind, however, that the clinical implications of this result for a patient in her 30s are quite different from those of a 60-year-old woman, since the breast cancer risk in the general population increases rapidly with age. Thus, a newly diagnosed 40-year-old woman with AH will have approximately a 9% chance of developing breast cancer in the next 20 years, while the 20-year risk for a 60-year-old woman with atypia is approximately 25%.3 Our objective in deriving the relative risk of AH is to measure the increase in breast cancer risk that can be attributed to AH. Unfortunately, the numerator and denominator populations of relative risk may vary with respect to factors other than AH that affect cancer risk. When these factors are known, we can eliminate their effects on our relative risk estimates by calculating an adjusted relative risk. This statistic estimates the relative risk value that we would have obtained had our numerator and denominator populations been identical with respect to those factors that have been adjusted for. The practical or clinical meaning of the term relative risk is widely misunderstood, particularly when it is applied to patients who have a substantial risk of developing the disease of interest during the remainder of their lives. This uncertainty is due to incorrect inferences about relative risks in combination with lifetime risks and may be best expressed by the frequently posed following questions: We know that one in ten women will develop invasive breast cancer (IBC) during their lives4 and
The incidence of breast cancer in a population is the number of newly diagnosed cases of breast cancer in this population over a year divided by the population size. The relative risk of breast cancer for women with atypical hyperplasia (AH) is the incidence of breast cancer among women with a history of AH divided by the breast cancer incidence in women in some reference population. This reference population may be defined in any sensible way, eg, women from the general population, study subjects without a history of AH, or study subjects without a history of proliferative disease (with or without atypia). The magnitude of the relative risk is critically dependent on the breast cancer incidence in both the numerator and denominator subgroups. A woman’s absolute risk of breast cancer is her probability of developing breast cancer during some specified time period, eg, the next 10 or 20 years.
Received from the Departments of Preventive Medicine and Pathology, Vanderbilt University School of Medicine, Nashville, TN. Supported by the National Cancer Institute (contract NOlCB-74098 and arants no. ROl-CA-31698. ROl CA-40517. and ROlCA-46492). ” Key words: atypical hyperplasia, breast cancer risk, timedependent cancer risk, hazard regression models. Address correspondence and reprint requests to William D. DuPont, PhD, Department of Preventive Medicine, Vanderbilt School of Medicine, Nashville, TN 37232-2637. 0 1989 by W.B. Saunders Company. 0046-8177/89/2008-0001$5.00/O
723
HUMAN PATHOLOGY
Volume 20, No. 8 (August 1989)
under the assumption that each patient’s relative risk remains constant over time. It is possible, however, for the relative risk of an individual patient to vary either as a function of age or time since initial diagnosis. An example of such a change can be found in our own studies of benign breast disease. We previously reported that women who have undergone breast biopsy revealing AH have 5.3 times the breast cancer risk of biopsied women who lacked proliferative disease, and that the corresponding relative risk for women with proliferative disease without atypia (PDWA) is 1.9.2 These results were obtained using a proportional hazards regression model that assumes that relative risk remains constant over time. Figure 1, however, shows an alternative analysis of these same data. The risk estimates presented in this illustration were derived from a hazard regression model that used time-dependent covariates.* Figure 1 shows that the breast cancer risk associated with both AH and PDWA is greatest in the first 10 years after the benign breast biopsy. Women with PDWA who remain free of breast cancer for 10 years are at no greater risk of breast cancer than women of similar age who do not have such a history. The relative risk of breast cancer in women with AH is halved if they remain free of breast cancer for 10 years following the initial biopsy. This supports the hypothesis that the AHs are not obligate precursor lesions for breast cancer, and that these lesions may either progress to cancer, remain unchanged, or possibly regress over a substantial period of time. The absolute risk for all the women in this study group2 seems to be approximately evenly distributed over the 17-year period of follow-up (Fig 2). The knowledge that invasive carcinomas were fairly evenly distributed over this period of time combined with the knowledge that approximately half of the invasive carcinomas had occurred by year 10 would have led us to predict the finding just described. Thus, an approximately constant cancer incidence over a 17-year age span, together with an increasing
that the relative risk of developing IBC among women with microscopic ductal carcinoma in situ (MDCIS) is ten times that of women in the general reference population. 5 Does this mean that a young woman with MDCIS is certain to develop IBC during her lifetime (ie, (l/10) X 10 = l)? If, in fact, this is not the case and there is a good chance that this woman will not develop IBC, then what is meant when it is stated that she has a tenfold increase in breast cancer risk over women of similar age from the general population? These questions can be answered by considering a specific example: the age-specific incidence of breast cancer for American women aged between 30 and 60 years is 27.5 and 292 cases per annum per 100,000 women, respectively.6 Suppose that Sally Smith is diagnosed at age 30 with MDCIS. When we say that she has a relative risk of ten for developing IBC, we mean that her chances of developing this cancer during her 30th year are 275/100,000, ten times that of a typical 30-year-old woman. If her relative risk remains constant for the next 30 years, and if she remains free of breast cancer until her 59th birthday, then her chances of developing breast cancer in her 60th year are 2,920/100,000, ten times that of a typical 60-year-old. Her probability of developing IBC between ages 30 and 100 years equals the sum of the probabilities of her first developing IBC at the age of 30,31,32. . . 100. Each of these probabilities is the product of two terms: her probability of disease-free survival until the start of the year of interest, and her probability of developing cancer during that year (given that she is alive and cancer-free at the start of that year). For example, given that Sally Smith is now 30 years of age, her probability of first developing breast cancer in her 60th year equals her probability of disease-free survival until age 59 times her probability of developing breast cancer in her 60th year, given that she will be alive and disease-free at her 59th birthday. Symbolically, if Si denotes the probability that she survives until her (i-1)st birthday without developing IBC, and Bi denotes her probability of developing IBC during her i-th year, given disease-free survival until the start of that year, then her lifetime probability of developing IBC will be the sum of the SiBi terms for each year of her possible remaining life (C SiBi). The effect of the Si terms will be to ensure that this sum is always less than one. Even if the Bi terms are all ten times the corresponding age-specific breast cancer probabilities from the general population, and even though the lifetime risk in the general population is one in ten, the lifetime risk for Sally Smith, Z SiBi, will not come close to 100%. In fact, one can estimate that the lifetime risk for IBC in a 30year-old with a relative risk of ten is approximately 64s.’ (The task of following a sufficiently large cohort of women to determine such a life-time risk directly would be extremely formidable.) There is another complexity concerning clinical implications of relative risks. Most relative risk estimates from longitudinal studies have been derived
1
PROLIFERATIVE
DISEASE WITHOUT
NO PROLIFERATIVE
L
AMP,*
DISEASE
1.0
Relative
Risk of Breast
Cancer
FIWRE 1. Relative risk (RR) of breast cancer in women with proliferative disease. Risks of patients with and without atypia are contrasted with risks of biopsied women who did not have proliferalive disease. Breast cancer relative risks decrease substantially in women who remaln free of breast cancer for 10 years following their proliferative disease biopsy. The thin vertical bars enclose the 95% confidence intervals for each of the displayed RR figures.
724
BREAST CANCER RISK AND ATYTXN
Atypical
Hypsrplasla
plus
Family
History
r-
‘re---‘---‘-‘---
i
I
rr’
Prolifarotlve
0
5
10
15 YEARS
SINCE
20 BENIGN
hyperplasla
dlteme without ______________
\ ____,--
______/.--
;
Atypical +---_
25
30
atypio
35
BIOPSY
HYPERPIASLA (Dupont & Page)
The clinical significance of this time-dependent analysis is that follow-up of women with AH must be most vigilant during the first 10 years following diagnosis and that women who have remained free of breast cancer for 10 or more years after a diagnosis of AH can be reassured with the knowledge that their breast cancer risk is now closer to that of the general population than it was at the time the AH was first diagnosed, although the absolute risk per year has remained about the same. Women with the more common and non-atypical hyperplasias who remain free of cancer for 10 years following this diagnosis can be reassured with the knowledge that their breast cancer risk is no different from that of women of similar age from the general population.
FIGURE 2. Proportion of patients who have developed IBC as a function of time since their benign breast biopsy. (Data from Dupont and Page.?
REFERENCES
age-specific incidence in the general population (the denominator of the relative risk statistic) implies that a woman’s relative risk of breast cancer must decrease with increasing time since biopsy. Whether relative risk will continue to drop with further follow-up is, of course, yet to be determined. This time-dependent analysis does suggest that the constancy of relative risk figures through an entire lifetime should not be presumed when making clinical decisions. We have previously discussed the advisability of confining predictive statements to the length of time covered by the specific studies that form the basis of these predictions.g This stance was predicated on the knowledge of increasing competing causes of death with advancing age. 3 We now add further credibility to that stance by noting that, while yearly incidence of invasive cancer following diagnosis of AH is fairly stable, relative risk decreases.
1. Page DL: Cancer risk assessment in benign breast biopsies. HUM PATHOL 17:871-874, 1986 2. DuPont WD, Page DL: Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 312: 146151, 1985 3. DuPont WD: Converting relative risks to absolute risks: A graphical approach. Stat Med 1989 (in press) 4. Seidman H, Mushinski MH, &lb SK, et al: Probabilities of eventually developing or dying of cancer-United States, 1985. CA 35:36-56, 1985 5. Page DL, DuPont WD, Rogers LW, et al: lntraductal carcinoma of the breast: Follow-up after biopsy only. Cancer 49:751758, 1982 6. SEER: 1987 Annual Cancer Statistics Review Including Cancer Trends 1950-1985. Washington, DC. National Cancer Institute, 1988 7. Chiang CL: Introduction to Stochastic Processes in Biostatistics. New York, Wiley, 1980 8. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, Wiley, 1980 9. Page DL, DuPont WD: Histopathologic risk factors for breast cancer in women with benign breast disease. Semin Surg Oncol 4:213-217, 1988 “.