PREVENTIVE
MEDICINE
8, 573-579
(1979)
GUEST
Screening
EDITORIAL
for Breast NATHANIEL
Cancer
Today’
I. BERLIN
Cancer Center, Northwestern University, 303 East Chicago Avenue, Chicago, Illinois 60611
The care of the woman with breast cancer continues to be controversial. In the past, the controversy centered around simple vs radical mastectomy. But more recently, other controversies have arisen: the role of adjuvant radiation therapy, the role of adjuvant drug therapy, multicentricity, and linked to multicentricity, the role of lumpectomy, what is atypical hyperplasia and carcinoma in situ and, most recently, the subject of screening for breast cancer has received wide attention from the press and the profession. In the midst of these controversies, we should ask first, “What do we have to offer women today,” not “What we hope to have tomorrow?” For prevention we know that women who have a baby before the age of 20 have a significant reduction in the incidence of breast cancer as do the women who have a surgical menopause before the age of 35 (5). We have no other means of reducing the incidence of breast cancer. For treatment, at the time the woman first comes to medical attention we offer a surgical procedure, of varying extent, and in some instances, radiation therapy. We do this with the hope that there are no distant metastases, but we must recognize that today many of these women have metastases at the time diagnosis is made, which in some, about lo%, are clinically evident, in the remainder they are there but not diagnosable by current methods. For the women with known distant metastases, we offer some prolongation of life by endocrine manipulation for some and by drug therapy for some. The prolongation is usually not very long. We offer the women with metastatic disease, few, if any, cures. What remains today is to make it possible for the diagnosis to be made before metastases have occurred. This requires screening of asymptomatic women. We must acknowledge that a palpable cancer is not an “early” cancer. The principal issues in breast cancer screening today are: (a) to screen or not to screen women under the age of 50, (b) how often to screen, (c) what is the cost and what is the benefit, (d) what is the hazard of mammography, and (e) what is the significance of atypical hyperplasia and carcinoma in situ. This last question can be rephrased, “Will these lesions progress to become invasive and metastasize?“, and if so, how often. What follows is an attempt to answer these questions-where possible. 1 This
work
was supported
in part by grant
CA15145
from
the National
Cancer
Institute.
573 0091-7435/79/050573-07$02.00/O Copyright All rights
0 1979 by Academic Press. Inc. of reproduction in any form reserved
574
NATHANIEL
I.
BERLIN
The first and only controlled and randomized clinical trial of screening began in the early 1960s and was supported by the National Cancer Institute. Sixty thousand women who were enrolled in the prepaid Health Insurance Plan (HIP) were divided into two groups (9). Thirty thousand women were invited by letter to come into a HIP medical facility, have a physical examination by a physician and a mammographic examination, and to have three additional annual examinations. Twenty thousand women responded by coming in for the first examination. All the women in the study group were invited to come back for three additional annual examinations. There was a dropoff for each reexamination, such that a little less than half of the 30,000 women in the study group actually completed the four planned screening examinations. All 60,000 women were followed. There was approximately a 30% reduction in the mortality due to breast cancer in the 30,000 women in the study group, as compared with the 30,000 women in the control group. When further analyzed, there was no reduction in mortality in the women under the age of 49, as compared with women over age 50, that is, the beneficial effects were confined to the women over 50. Of considerable significance but rarely mentioned is that we do not know what would have been found if all 30,000 women in the study group had the four planned examinations, but it is conceivable and entirely likely that the mortality reduction would have been even greater. In 1971, as the HIP data began to become known, the American Cancer Society’s Task Force on Breast Cancer Control made a recommendation that Demonstration Projects be created to promote the use of mammography and physical examination. The National Cancer Institute joined with the American Cancer Society and as a result 27 Breast Cancer Detection Demonstration Projects were created. This effort has come under considerable criticism. The criticisms were, that the benefit was small, the radiation hazard large, and the cost great. Some of the facts and some of the confusion can be summarized. The first is: The HIP study did show that screening by physical examination and mammography would reduce breast cancer mortality. The confusion is that this reduction was confined to women over the age of 50. The next fact is that the HIP study tested compliance with the program; that is, whether women would come in for four annual screening examinations. The confusion is that only 20,000 actually had one examination and only 15,000 completed the examination program. Next the HIP study tested mammography and it tested physical examination. The confusion is that it is not possible to distinguish well, how much of the benefit that was observed could be attributed to mammography, although this is estimated to be one-third. The next fact is that radiation is carcinogenic (1, 6, lo), but the confusion is that in two of the three groups of women studied, there was no evidence that above age 35 that there were radiation-induced cancers. The exception usually quoted is the women treated by radiation therapy for postpartum mastitis (10). Closer inspection of all the data shows that there is almost no data on the risk in women over 40. The last fact and one of the most important is that there are groups of women who are at high risk for developing breast cancer, but the confusion is that one cannot identify a low-low risk group, that is, one cannot say to any woman above the age of 40, that your probability for getting breast cancer is so low that you may dismiss it.
GUEST
575
EDITORIAL
What is the radiation hazard? There is agreement among the radiobiologists the hazard can be expressed in the following way:
that
One tad of X-radiation to the breast in a million women could produce 6 breast cancers per year more than would occur naturally. These would begin to occur about 10 years after the radiation and would continue throughout the woman’s lifetime (12). This means that if 1 million 40-year-old women received 1 rad of radiation to their breasts that there would be produced approximately 120 breast cancers more than the 70,000 that would occur naturally.
In the women who had multiple fluoroscopies during the course of treatment for pulmonary tuberculosis there were no excess breast cancers at the lowest dose level and hence, at this dose, X-radiation could not be shown to be carcinogenic (1). In the same study, and in the women exposed to radiation at Hiroshima and Nagasaki, there were no excess cancers in the women over 35 at age of exposure (6). Hence, the effect of radiation on the breast is age dependent with the greatest effect in the women between 15 and 20. It was not age dependent in the women treated with much larger doses of radiation for postpartum mastitis. An important element to be considered is the relationship of size of the primary tumor to prognosis. This has been shown (see Fig. 1) by Duncan and Kerret al. (3) in three groups of women with breast cancer followed for 20 years, those with l-, 2-, or 3-cm size primary tumors. The women with the l-cm tumors have a much better probability of surviving than the women with a 2- or 3-cm tumor. Figure 2 shows the percentage of women with axillary node metastases as a function of the size of the primary (11). Clearly, as the size of the primary increases, the probability of nodal metastases increase. Next it should be pointed out that 75% of the women with axillary node metastases will demonstrate clinically evident distant metastases within 10 years, while 75% of the women with “clean” axillary nodes will not have a recurrence within 10 years, that is 25% will have a recurrence (3). Clearly, prognosis is very significantly influenced by the presence or absence of axillary node metastases, and the presence or absence of axillary node metastases is dependent upon the size of the primary.
oT02 . 4. 6. 8. IO.
I2
14
. 18. 20.
lb
Years
FIG. 1. Age-corrected survival rates for women treated for breast cancers up to 3.0 cm in diameter. Reprinted, by permission, from Ref. (2).
NATHANIEL
576 70%
I. BERLIN
r -66.1%
60%
l 49.1%
40% -
l 40.8%
30% -
~29.2%
(1.0-1.9
(3.0-3.9
(2.0-2.9
(10.0 cm+t) cm)
cm)
l 57.9%.~4.0-4.9
50%-
l 70.82 (5.0-9.9
cm)
cm)
cm)
cm) 20% - -20.2% (.S-.9 .l7.2% (CO.5 cm) 10% . h 1.0
2.0
3.0
4.0
Brhst
Cancer
s.o’/ Site
9.9
1C-t
in Cm's
FIG. 2. SEER Breast Cancer Data 1975: Invasive tumor vs lymph node involvement in 6,528 cases that had resected primary and regional nodes with available nodal information. The size of the breast cancer is measured in centimeters. Reprinted, by permission, from Ref. (11).
These data can be interpreted as indicating that one of the goals of breast cancer screening should be to make the diagnosis when the tumor is small, less than 1 cm, when there will be fewer women with axillary node metastases. For if all women were diagnosed with a cancer 1 cm or less and with negative axillary nodes, the mortality from breast cancer would be very much lower than it is today. In the HIP study the women who were detected by mammography alone had a 14% mortality at 8 years after diagnosis, compared with a 32% mortality in the women who were diagnosed by physical examination alone and a 41% mortality in women who were detected by both physical examination and mammography. Thus the women detected by mammography alone had a much better prognosis. Probably the most significant data to compare in the HIP study with the current Breast Cancer Detection Demonstration Projects is in Table 1 (7). This shows that in the age group 40-49 in the HIP study, only 19% of the women were detected by mammography alone, while in the current Breast Cancer Detection Projects it is 41%. In the other age groups, the detection rates for mammography alone are comparable. It should also be pointed out, that for all age groups there is a higher TABLE DETECTION
Age
Modality Mammography only Physical exam only Both
HIP 19% 61 19
Mammography
38
positive
40-49 BCCDP 44% 9 47 91
1
MODALITIES
HIP 41% 40 18 60
50-59 BCDDP 48% 8 42 92
60 HIP 31% 39 31
BCDDP 38% 5 55
61
95
577
GUEST EDITORIAL
detection rate by mammography in the current projects and that it is considerably higher than in the HIP study and particularly so in the 40-49 age group. Clearly mammography today is much more effective in finding breast cancer in the younger women. It should be pointed out that there are some instances (about 10%) where mammography was negative, but physical examination was positive. A negative mammogram, with a positive physical examination, does not mean that a biopsy should not be done-a biopsy should be done. Today, there is not a very large difference in the younger women as compared with the older women in terms of the detection by mammography or by physical examination. This is a major change, and can be used to explain the difference in the HIP study between 40- to 49-year-old and 50 and greater age groups. In the HIP study the detection rate by mammography in the younger women was so low-that but few “early” cancers were detected, and hence the mortality rate could not have been expected to be reduced. There have been several approaches to estimating the benefit hazard ratio (7,8). For a given benefit the ratio is clearly dependent and linearly dependent on the hazard. If the hazard chosen is radiation-induced breast cancer, then as the radiation dose is reduced, the benefit-hazard ratio is increased. It is entirely likely that the radiation dose has been reduced so much that the hazard has become so low that the question will become, what is the benefit? Other hazards have been mentioned, these include the morbidity and psychologic trauma of a breast biopsy. We are perhaps entering into a new era in the interpretation of breast biopsies particularly those that are “minimal” breast cancers. The term “minimal” as used in this context are those cancers that are (a) carcinoma in situ or (b) invasive cancers less than 1 cm in diameter. There are those who hold that this may not be a good descriptor-since it groups together tumors that are histologically malignant by the criteria of invasion with those that are not invasive and which may not become invasive. The biopsy slides from 66 women were reviewed by a group of four distinguished pathologists selected for their skill in the diagnosis of breast cancer (7). These biopsies were obtained in the Breast Cancer Detection Demonstration projects of the ACS and NC1 and represent a subset of 506 “minimal” cancers reviewed by an expert committee. Each pathologist saw the slides, made a diagnosis, then they sat around the table and derived a consensus diagnosis. There were three diagnoses: benign, in situ carcinoma, and infiltrating cancer. TABLE PATHOLOGY
2 REVIEW”
Range of individual pathologists agreement (with consensus diagnosis) Consensus diagnosis
Benign
Carcinoma in-SitU
Infiltrating carcinoma
Benign In situ carcinoma Infiltrating cancer
74.2 -98.5% 4.1-10.4 1.0%
1.5-21.2% 88. I-93.3% l.O-9.6%
1.5-4.6% 1.5-3.4% 90.4 -99.9
a See Ref. (7).
578
NATHANIEL
I.
BERLIN
Table 2 shows the results. If the agreement between the pathologists were perfect, each of the underlined data should show 100%. The fact that it does not indicates that there is variation among the pathologists, even among pathologists selected for their skill in the diagnosis of breast cancer, but it should be pointed out these specimens represent a small subset derived from approximately 1,800 specimens and by the nature of the criterion used -the most difficult to interpret. While there was not uniformity in interpretation there was agreement in most instances. Those who are familiar with the history of carcinoma in situ of the cervix, will see again a familiar story, but this time, the answer can not be as simple. A minor surgical procedure is often sufficient treatment for carcinoma in situ of the cervix, but removal of the breast is not a minor procedure, not from the standpoint of the psychologic trauma. Today the major questions are, should women under 50 be screened by physical examination and mammography and how frequently should women of any age be screened. The answers I would choose to give to these questions are: If screening requires that there have been demonstrated a mortality reduction in a randomized trial, then the answer is No. If finding cancer at an “earlier” stage (that is, smaller tumors) is a criterion, then the answer is Yes. If the improvement in mammography in women under 50 is sufficient to predict that the HIP study would have shown a reduction in mortality in this group, the answer is Yes. If the radiation dose is now sufficiently low, that the hazard becomes very small compared with the benefit, then the answer is Yes. But there is no question that women over 50 should be screened. The benefit has been proved, and this should not be lost from sight in the discussion about the women under 50. Regular breast self examination can be helpful. Greenwald and his colleagues (4) have estimated that this form of examination can reduce significantly the mortality from breast cancer, but it should be recalled that today only about one-half of the cancers that could be detected were detected by physical examination in the current screening projects and hence while regular breast selfexamination or regular examination by a physician is better than none at all, the yield is less than with mammography and hence it is an examination that is not necessarily the best possible today. How frequently should women be screened by physical examination and mammography? We really do not know. There have been no studies carried out to determine this, although some who have examined this question propose that it should be about once a year, but I would venture to predict that as data becomes available from groups that will have screened women annually, that the detection rate will become lower and lower, reaching a low level after five to seven screenings. I know of only one such study, that of Dr. Agnes Stark of England. Eighty-five percent of the cancers that were detected in 9 years of annual screening were in fact found in the first five annual screenings (A. Stark, personal communication). As physicians, our obligation is to determine if the mortality from breast cancer can be reduced by screening and how much the mortality can be reduced. We are obliged to determine the hazards and we are obliged to determine the cost in dollars. We as physicians have another obligation to make certain that if a woman
GUEST
EDITORIAL
579
is examined, the radiation dose be held to a minimum. I would not hesitate to set the standard at the lowest radiation dose now technically possible. Our second obligation is to communicate this information to society. I think it is then the obligation of society to determine what they want and it is society’s obligation to determine how it will be paid for, particularly, if it is expensive. I do not think we as physicians should draw conclusions for society that it is too costly, or that it might be impractical. We spend a lot of money for a lot of things which may not be either necessary or practical. Society should judge how much it wants to spend for its health. REFERENCES 1. Boice, J. D., and Monson, R. R. Breast cancer in women after repeated fluoroscopic examination of the chest. J. Nat. Cancer Inst. 59, 823-832 (1977). 2. Duncan, W., and Kerr, G. R. The curability of breast cancer. Bit. Med. J. 2, 781-783 (1976). 3. Fisher, B., Slack, N., Katrych, D., and Wolmark, N. Ten year follow-up results ofpatients with carcinoma of the breast in a co-operative clinical trial evaluating surgical adjuvant chemotherapy. Sup. Gynecol. Obstet. 140, 528-534 (1975). 4. Greenwald, P., Nasca, P. C., Lawrence, C. E., Horton, J., McGarrah, R. P., Gabriele, T., and Carlton, K. Estimated effect of breast self examination on breast cancer mortality. New Engl. J. Med. 299, 271-273 (1978). 5. MacMahon, B., Cole, P., and Brown, J. Etiology of human breast cancer: A review. J. Nat. Cancer Inst. 50, 21-42 (1973). 6. McGregor, D. H., Land, C. E., Choi, K., Tokuoka, S., Liu, P. I., Wakabayashi, T., and Beebe, G. W. Breast cancer incidence among atomic bomb survivors, Hiroshima and Nagasaki, 1950-1%9. J. Nat. Cancer Inst. 59, 7991811 (1977). 7. Report of the Working Group to Review the NCI/ACS Breast Cancer Demonstration Detection Projects. J. Nat. Cancer Inst. 62, 639-710 (1979). 8. Seidman, H. Screening for breast cancer in younger women: Life expectancy gains and losses. CA 27,66-87 (1977). 9. Shapiro, S. Evidence on screening for breast cancer from a randomized trial. Cancer 39, 2772-2782 (1977). 10. Shore, R. E., Hempehnann, L. H., Kowaluk, E., Mansur, P. S., Pastemack, B. S., Albert, R. E., and Haughie, G. E. Breast neoplasms in women treated with x-rays for acute postpartum mastitis. J. Nat. Cancer Inst. 59, 813-822 (1977). 11. Smart, C. R., Myers, M. H., and Gloeckler, L. A. Implications from Seer data on breast cancer management. Cancer 41, 787-789 (1978). 12. “The Effects on Populations of Exposure to Low Levels of Ionizing Radiation.” Report of the Advisory Committee on the Biological Effects of Ionizing Radiation. National Academy of Science, November 1972 (also known as BEIR Report).
MEDICINE
8, 573-579
(1979)
GUEST
Screening
EDITORIAL
for Breast NATHANIEL
Cancer
Today’
I. BERLIN
Cancer Center, Northwestern University, 303 East Chicago Avenue, Chicago, Illinois 60611
The care of the woman with breast cancer continues to be controversial. In the past, the controversy centered around simple vs radical mastectomy. But more recently, other controversies have arisen: the role of adjuvant radiation therapy, the role of adjuvant drug therapy, multicentricity, and linked to multicentricity, the role of lumpectomy, what is atypical hyperplasia and carcinoma in situ and, most recently, the subject of screening for breast cancer has received wide attention from the press and the profession. In the midst of these controversies, we should ask first, “What do we have to offer women today,” not “What we hope to have tomorrow?” For prevention we know that women who have a baby before the age of 20 have a significant reduction in the incidence of breast cancer as do the women who have a surgical menopause before the age of 35 (5). We have no other means of reducing the incidence of breast cancer. For treatment, at the time the woman first comes to medical attention we offer a surgical procedure, of varying extent, and in some instances, radiation therapy. We do this with the hope that there are no distant metastases, but we must recognize that today many of these women have metastases at the time diagnosis is made, which in some, about lo%, are clinically evident, in the remainder they are there but not diagnosable by current methods. For the women with known distant metastases, we offer some prolongation of life by endocrine manipulation for some and by drug therapy for some. The prolongation is usually not very long. We offer the women with metastatic disease, few, if any, cures. What remains today is to make it possible for the diagnosis to be made before metastases have occurred. This requires screening of asymptomatic women. We must acknowledge that a palpable cancer is not an “early” cancer. The principal issues in breast cancer screening today are: (a) to screen or not to screen women under the age of 50, (b) how often to screen, (c) what is the cost and what is the benefit, (d) what is the hazard of mammography, and (e) what is the significance of atypical hyperplasia and carcinoma in situ. This last question can be rephrased, “Will these lesions progress to become invasive and metastasize?“, and if so, how often. What follows is an attempt to answer these questions-where possible. 1 This
work
was supported
in part by grant
CA15145
from
the National
Cancer
Institute.
573 0091-7435/79/050573-07$02.00/O Copyright All rights
0 1979 by Academic Press. Inc. of reproduction in any form reserved
574
NATHANIEL
I.
BERLIN
The first and only controlled and randomized clinical trial of screening began in the early 1960s and was supported by the National Cancer Institute. Sixty thousand women who were enrolled in the prepaid Health Insurance Plan (HIP) were divided into two groups (9). Thirty thousand women were invited by letter to come into a HIP medical facility, have a physical examination by a physician and a mammographic examination, and to have three additional annual examinations. Twenty thousand women responded by coming in for the first examination. All the women in the study group were invited to come back for three additional annual examinations. There was a dropoff for each reexamination, such that a little less than half of the 30,000 women in the study group actually completed the four planned screening examinations. All 60,000 women were followed. There was approximately a 30% reduction in the mortality due to breast cancer in the 30,000 women in the study group, as compared with the 30,000 women in the control group. When further analyzed, there was no reduction in mortality in the women under the age of 49, as compared with women over age 50, that is, the beneficial effects were confined to the women over 50. Of considerable significance but rarely mentioned is that we do not know what would have been found if all 30,000 women in the study group had the four planned examinations, but it is conceivable and entirely likely that the mortality reduction would have been even greater. In 1971, as the HIP data began to become known, the American Cancer Society’s Task Force on Breast Cancer Control made a recommendation that Demonstration Projects be created to promote the use of mammography and physical examination. The National Cancer Institute joined with the American Cancer Society and as a result 27 Breast Cancer Detection Demonstration Projects were created. This effort has come under considerable criticism. The criticisms were, that the benefit was small, the radiation hazard large, and the cost great. Some of the facts and some of the confusion can be summarized. The first is: The HIP study did show that screening by physical examination and mammography would reduce breast cancer mortality. The confusion is that this reduction was confined to women over the age of 50. The next fact is that the HIP study tested compliance with the program; that is, whether women would come in for four annual screening examinations. The confusion is that only 20,000 actually had one examination and only 15,000 completed the examination program. Next the HIP study tested mammography and it tested physical examination. The confusion is that it is not possible to distinguish well, how much of the benefit that was observed could be attributed to mammography, although this is estimated to be one-third. The next fact is that radiation is carcinogenic (1, 6, lo), but the confusion is that in two of the three groups of women studied, there was no evidence that above age 35 that there were radiation-induced cancers. The exception usually quoted is the women treated by radiation therapy for postpartum mastitis (10). Closer inspection of all the data shows that there is almost no data on the risk in women over 40. The last fact and one of the most important is that there are groups of women who are at high risk for developing breast cancer, but the confusion is that one cannot identify a low-low risk group, that is, one cannot say to any woman above the age of 40, that your probability for getting breast cancer is so low that you may dismiss it.
GUEST
575
EDITORIAL
What is the radiation hazard? There is agreement among the radiobiologists the hazard can be expressed in the following way:
that
One tad of X-radiation to the breast in a million women could produce 6 breast cancers per year more than would occur naturally. These would begin to occur about 10 years after the radiation and would continue throughout the woman’s lifetime (12). This means that if 1 million 40-year-old women received 1 rad of radiation to their breasts that there would be produced approximately 120 breast cancers more than the 70,000 that would occur naturally.
In the women who had multiple fluoroscopies during the course of treatment for pulmonary tuberculosis there were no excess breast cancers at the lowest dose level and hence, at this dose, X-radiation could not be shown to be carcinogenic (1). In the same study, and in the women exposed to radiation at Hiroshima and Nagasaki, there were no excess cancers in the women over 35 at age of exposure (6). Hence, the effect of radiation on the breast is age dependent with the greatest effect in the women between 15 and 20. It was not age dependent in the women treated with much larger doses of radiation for postpartum mastitis. An important element to be considered is the relationship of size of the primary tumor to prognosis. This has been shown (see Fig. 1) by Duncan and Kerret al. (3) in three groups of women with breast cancer followed for 20 years, those with l-, 2-, or 3-cm size primary tumors. The women with the l-cm tumors have a much better probability of surviving than the women with a 2- or 3-cm tumor. Figure 2 shows the percentage of women with axillary node metastases as a function of the size of the primary (11). Clearly, as the size of the primary increases, the probability of nodal metastases increase. Next it should be pointed out that 75% of the women with axillary node metastases will demonstrate clinically evident distant metastases within 10 years, while 75% of the women with “clean” axillary nodes will not have a recurrence within 10 years, that is 25% will have a recurrence (3). Clearly, prognosis is very significantly influenced by the presence or absence of axillary node metastases, and the presence or absence of axillary node metastases is dependent upon the size of the primary.
oT02 . 4. 6. 8. IO.
I2
14
. 18. 20.
lb
Years
FIG. 1. Age-corrected survival rates for women treated for breast cancers up to 3.0 cm in diameter. Reprinted, by permission, from Ref. (2).
NATHANIEL
576 70%
I. BERLIN
r -66.1%
60%
l 49.1%
40% -
l 40.8%
30% -
~29.2%
(1.0-1.9
(3.0-3.9
(2.0-2.9
(10.0 cm+t) cm)
cm)
l 57.9%.~4.0-4.9
50%-
l 70.82 (5.0-9.9
cm)
cm)
cm)
cm) 20% - -20.2% (.S-.9 .l7.2% (CO.5 cm) 10% . h 1.0
2.0
3.0
4.0
Brhst
Cancer
s.o’/ Site
9.9
1C-t
in Cm's
FIG. 2. SEER Breast Cancer Data 1975: Invasive tumor vs lymph node involvement in 6,528 cases that had resected primary and regional nodes with available nodal information. The size of the breast cancer is measured in centimeters. Reprinted, by permission, from Ref. (11).
These data can be interpreted as indicating that one of the goals of breast cancer screening should be to make the diagnosis when the tumor is small, less than 1 cm, when there will be fewer women with axillary node metastases. For if all women were diagnosed with a cancer 1 cm or less and with negative axillary nodes, the mortality from breast cancer would be very much lower than it is today. In the HIP study the women who were detected by mammography alone had a 14% mortality at 8 years after diagnosis, compared with a 32% mortality in the women who were diagnosed by physical examination alone and a 41% mortality in women who were detected by both physical examination and mammography. Thus the women detected by mammography alone had a much better prognosis. Probably the most significant data to compare in the HIP study with the current Breast Cancer Detection Demonstration Projects is in Table 1 (7). This shows that in the age group 40-49 in the HIP study, only 19% of the women were detected by mammography alone, while in the current Breast Cancer Detection Projects it is 41%. In the other age groups, the detection rates for mammography alone are comparable. It should also be pointed out, that for all age groups there is a higher TABLE DETECTION
Age
Modality Mammography only Physical exam only Both
HIP 19% 61 19
Mammography
38
positive
40-49 BCCDP 44% 9 47 91
1
MODALITIES
HIP 41% 40 18 60
50-59 BCDDP 48% 8 42 92
60 HIP 31% 39 31
BCDDP 38% 5 55
61
95
577
GUEST EDITORIAL
detection rate by mammography in the current projects and that it is considerably higher than in the HIP study and particularly so in the 40-49 age group. Clearly mammography today is much more effective in finding breast cancer in the younger women. It should be pointed out that there are some instances (about 10%) where mammography was negative, but physical examination was positive. A negative mammogram, with a positive physical examination, does not mean that a biopsy should not be done-a biopsy should be done. Today, there is not a very large difference in the younger women as compared with the older women in terms of the detection by mammography or by physical examination. This is a major change, and can be used to explain the difference in the HIP study between 40- to 49-year-old and 50 and greater age groups. In the HIP study the detection rate by mammography in the younger women was so low-that but few “early” cancers were detected, and hence the mortality rate could not have been expected to be reduced. There have been several approaches to estimating the benefit hazard ratio (7,8). For a given benefit the ratio is clearly dependent and linearly dependent on the hazard. If the hazard chosen is radiation-induced breast cancer, then as the radiation dose is reduced, the benefit-hazard ratio is increased. It is entirely likely that the radiation dose has been reduced so much that the hazard has become so low that the question will become, what is the benefit? Other hazards have been mentioned, these include the morbidity and psychologic trauma of a breast biopsy. We are perhaps entering into a new era in the interpretation of breast biopsies particularly those that are “minimal” breast cancers. The term “minimal” as used in this context are those cancers that are (a) carcinoma in situ or (b) invasive cancers less than 1 cm in diameter. There are those who hold that this may not be a good descriptor-since it groups together tumors that are histologically malignant by the criteria of invasion with those that are not invasive and which may not become invasive. The biopsy slides from 66 women were reviewed by a group of four distinguished pathologists selected for their skill in the diagnosis of breast cancer (7). These biopsies were obtained in the Breast Cancer Detection Demonstration projects of the ACS and NC1 and represent a subset of 506 “minimal” cancers reviewed by an expert committee. Each pathologist saw the slides, made a diagnosis, then they sat around the table and derived a consensus diagnosis. There were three diagnoses: benign, in situ carcinoma, and infiltrating cancer. TABLE PATHOLOGY
2 REVIEW”
Range of individual pathologists agreement (with consensus diagnosis) Consensus diagnosis
Benign
Carcinoma in-SitU
Infiltrating carcinoma
Benign In situ carcinoma Infiltrating cancer
74.2 -98.5% 4.1-10.4 1.0%
1.5-21.2% 88. I-93.3% l.O-9.6%
1.5-4.6% 1.5-3.4% 90.4 -99.9
a See Ref. (7).
578
NATHANIEL
I.
BERLIN
Table 2 shows the results. If the agreement between the pathologists were perfect, each of the underlined data should show 100%. The fact that it does not indicates that there is variation among the pathologists, even among pathologists selected for their skill in the diagnosis of breast cancer, but it should be pointed out these specimens represent a small subset derived from approximately 1,800 specimens and by the nature of the criterion used -the most difficult to interpret. While there was not uniformity in interpretation there was agreement in most instances. Those who are familiar with the history of carcinoma in situ of the cervix, will see again a familiar story, but this time, the answer can not be as simple. A minor surgical procedure is often sufficient treatment for carcinoma in situ of the cervix, but removal of the breast is not a minor procedure, not from the standpoint of the psychologic trauma. Today the major questions are, should women under 50 be screened by physical examination and mammography and how frequently should women of any age be screened. The answers I would choose to give to these questions are: If screening requires that there have been demonstrated a mortality reduction in a randomized trial, then the answer is No. If finding cancer at an “earlier” stage (that is, smaller tumors) is a criterion, then the answer is Yes. If the improvement in mammography in women under 50 is sufficient to predict that the HIP study would have shown a reduction in mortality in this group, the answer is Yes. If the radiation dose is now sufficiently low, that the hazard becomes very small compared with the benefit, then the answer is Yes. But there is no question that women over 50 should be screened. The benefit has been proved, and this should not be lost from sight in the discussion about the women under 50. Regular breast self examination can be helpful. Greenwald and his colleagues (4) have estimated that this form of examination can reduce significantly the mortality from breast cancer, but it should be recalled that today only about one-half of the cancers that could be detected were detected by physical examination in the current screening projects and hence while regular breast selfexamination or regular examination by a physician is better than none at all, the yield is less than with mammography and hence it is an examination that is not necessarily the best possible today. How frequently should women be screened by physical examination and mammography? We really do not know. There have been no studies carried out to determine this, although some who have examined this question propose that it should be about once a year, but I would venture to predict that as data becomes available from groups that will have screened women annually, that the detection rate will become lower and lower, reaching a low level after five to seven screenings. I know of only one such study, that of Dr. Agnes Stark of England. Eighty-five percent of the cancers that were detected in 9 years of annual screening were in fact found in the first five annual screenings (A. Stark, personal communication). As physicians, our obligation is to determine if the mortality from breast cancer can be reduced by screening and how much the mortality can be reduced. We are obliged to determine the hazards and we are obliged to determine the cost in dollars. We as physicians have another obligation to make certain that if a woman
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is examined, the radiation dose be held to a minimum. I would not hesitate to set the standard at the lowest radiation dose now technically possible. Our second obligation is to communicate this information to society. I think it is then the obligation of society to determine what they want and it is society’s obligation to determine how it will be paid for, particularly, if it is expensive. I do not think we as physicians should draw conclusions for society that it is too costly, or that it might be impractical. We spend a lot of money for a lot of things which may not be either necessary or practical. Society should judge how much it wants to spend for its health. REFERENCES 1. Boice, J. D., and Monson, R. R. Breast cancer in women after repeated fluoroscopic examination of the chest. J. Nat. Cancer Inst. 59, 823-832 (1977). 2. Duncan, W., and Kerr, G. R. The curability of breast cancer. Bit. Med. J. 2, 781-783 (1976). 3. Fisher, B., Slack, N., Katrych, D., and Wolmark, N. Ten year follow-up results ofpatients with carcinoma of the breast in a co-operative clinical trial evaluating surgical adjuvant chemotherapy. Sup. Gynecol. Obstet. 140, 528-534 (1975). 4. Greenwald, P., Nasca, P. C., Lawrence, C. E., Horton, J., McGarrah, R. P., Gabriele, T., and Carlton, K. Estimated effect of breast self examination on breast cancer mortality. New Engl. J. Med. 299, 271-273 (1978). 5. MacMahon, B., Cole, P., and Brown, J. Etiology of human breast cancer: A review. J. Nat. Cancer Inst. 50, 21-42 (1973). 6. McGregor, D. H., Land, C. E., Choi, K., Tokuoka, S., Liu, P. I., Wakabayashi, T., and Beebe, G. W. Breast cancer incidence among atomic bomb survivors, Hiroshima and Nagasaki, 1950-1%9. J. Nat. Cancer Inst. 59, 7991811 (1977). 7. Report of the Working Group to Review the NCI/ACS Breast Cancer Demonstration Detection Projects. J. Nat. Cancer Inst. 62, 639-710 (1979). 8. Seidman, H. Screening for breast cancer in younger women: Life expectancy gains and losses. CA 27,66-87 (1977). 9. Shapiro, S. Evidence on screening for breast cancer from a randomized trial. Cancer 39, 2772-2782 (1977). 10. Shore, R. E., Hempehnann, L. H., Kowaluk, E., Mansur, P. S., Pastemack, B. S., Albert, R. E., and Haughie, G. E. Breast neoplasms in women treated with x-rays for acute postpartum mastitis. J. Nat. Cancer Inst. 59, 813-822 (1977). 11. Smart, C. R., Myers, M. H., and Gloeckler, L. A. Implications from Seer data on breast cancer management. Cancer 41, 787-789 (1978). 12. “The Effects on Populations of Exposure to Low Levels of Ionizing Radiation.” Report of the Advisory Committee on the Biological Effects of Ionizing Radiation. National Academy of Science, November 1972 (also known as BEIR Report).
