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Clinical breast examination, breast self-examination: What is the evidence for utility in screening for breast cancer?
Clinical Breast Examination, Breast Self-Examination: What Is the Evidence for Utility in Screening for Breast Cancer? Mary E. Costanza, MD D e p a r t m e n t of Medicine University of M a s s a c h u s e t t s Medical School Worcester, M a s s a c h u s e t t s
linical breast examination (CBE) and breast self-examination (BSE) are two of the three traditional time-honored methods of early breast cancer detection. Although the National Cancer Institute ~ and the American Cancer Society2 continue to recommend both CBE and BSE, other groups do not recommend BSE.3 It should be understood that the type of evidence supporting the utility of these two methods of detection are different and of unequal scientific merit compared with that supporting the efficacy of mammography. Because mammography is playing such an increasing role in breast cancer screening, it is timely to reconsider the role and merit of CBE and BSE. Evidence for the utility of a screening method should be reviewed on a scientific basis. This would include two key conditions: 1) the screening test must actually be able to detect cancers earlier, and 2) there must be evidence that treatment at that earlier stage of disease will result in a better outcome. These requirements are similar to those now used by the National Cancer Institute in reviewing their cancer screening guidelines (Barnett Kramer, MD, personal communication). Measures of improved outcome vary. The strongest evidence would be a decrease in cause-specific mortality. Weaker evidence would be a reduction in the incidence of later-stage cancer. Weakest of all would be a shift to a lower stage. The gold standard for evidence of utility would be several randomized, well-designed, well-controlled studies using cause-specific mortality as an end point in the screened versus the unscreened population. 4 Not many screening tests have met these strict requirements. Almost all of those are studies of breast cancer screening by mammography or by mammography and CBE against control. More common are case-control studies. These provide less direct evidence for utility because they only suggest mortality reduction and because bias cannot be controlled, s'6 Other common screening studies often use downshifts in stage or increase in survival or decrease in size or the number of positive lymph nodes as the end point to prove "effectiveness" of the proposed screening modality. Such studies may
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Table 1.
Study
STUDIES OF M A M M O G R A P H Y
Age (Years)
Screening Interval (Months)
Randomized controlled trials HIP 7 40-64 12 T w o - c o u n t y s 40-74 24-33 Malmo 9 45-69 18-24 Edinburgh 1° 45-64 12-24 Stockholm 11 40-64 24 Canadian 12 40-49 12 50-59 12 N o n r a n d o m i z e d controlled trials UK 13 45-64 24 12 Nijmegen TM 35-65 24 DOM 15 50-64 12-24 Florence t6 40-70 30
Decrease in Mortality
Modality M 2 + CBE M1
29% 31% 4% 17% 29% NA NA
M2
M 2 + CBE M1 M 2 + CBE M 2 + CBE
M CBE M1
Significance + +
NA NA
20% 49% 70% 47%
M2
M2
+
+ +
M ~, one-view m a m m o g r a m ; M 2, two-view m a m m o g r a m ; CBE, clinical breast examination; NA, not available.
be helpful in first noting a potentially effective screening test, but such studies cannot establish the utility of the screening test because of the absence of suitable controls. 4 Although there is an "intuitive" sense that downshifts in stage, smaller tumors, and less involved l y m p h nodes must be associated with a decrease in cause-specific mortality, it is not necessarily so. Relying on the related increase in survival as evidence of efficacy is likely to be treacherous because this increase may be accounted for by lead time bias. Put a n o t h e r way, finding a smaller breast cancer m a y not be associated with decreased mortality from breast cancer. Therefore, tests that are evaluated principally by their ability to detect smaller tumors at a less advanced stage m a y not alter the natural history of breast cancer.
E V I D E N C E REVIEWED Mammography (With or Without Clinical Breast Exam) A brief review of the published evidence concerning the efficacy of mamm o g r a p h y screening is informative. There is consistent evidence from controlled trials that breast cancer mortality is reduced by the use of m a m m o g raphy, with or w i t h o u t CBE (see Table 1). There are five r a n d o m i z e d controlled m a m m o g r a p h y trials, all with positive results (a decrease in mortality). 7-12 In two, the decrease in mortality reaches statistical significance. 7.s There are four n o n r a n d o m i z e d or case-controlled studies also consistently showing a decrease in breast cancer mortality. 13-16 Three of these reach statistical significance. There are several i m p o r t a n t issues involved regarding the efficacy of m a m m o g r a p h y in reducing mortality from breast cancer. These include the age at which m a m m o g r a p h y begins to confer a reduction in mortality, the intervals at which it should be performed, the n u m b e r of views of the breast to be taken, and w h e t h e r adding CBE to m a m m o g r a p h y improves the mortality reduction. Regarding the appropriate n u m b e r of views (one or two) or
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the appropriate interval (12-33 months), no clear answers can be given. There does not seem to be any consistent relationship between these variables and the size of mortality reduction. The age at which mammography begins to be useful is also unclear. The trials include a range of ages from 35-74, without stratifying for age. Accordingly, retrospective analyses of women below and above the age of 50 are less compelling. Nonetheless, in all but the Health Insurance Plan of New York (HIP) study, no decrease in breast cancer mortality with mammography was seen in women under the age of 50. The HIP study 17 has been analyzed differently by different authors, and the under age 50 benefit is a matter of controversy. The one trial of women randomized on the basis of age under 50 is the as yet unpublished Canadian trial. ~2 It is widely rumored to be a negative study, that is, there is no difference in breast cancer mortality whether women under age 50 receive annual mammography and CBE or receive only an initial baseline CBE. Clinical Breast Examination
With the exception of the Canadian study, 12 there are no randomized studies looking at CBE and its impact on the reduction of breast cancer mortality. The previously mentioned studies do not study the effects of CBE alone. The contribution of CBE to the reduction in mortality from breast cancer can therefore be only indirectly inferred. A recent review of CBETM notes that observational studies have associated CBE with downshift in stage, fewer positive axillary lymph nodes, and better survival.19,2° A review 7 of the HIP study notes that CBE alone detected a large percentage of breast cancers and suggests that CBE may have contributed up to two-thirds of the mortality reduction seen in that study. This large effect may be due to the poor technical quality of mammography available in the 1960s as compared with modern equipment. By the time of the Breast Cancer Detection Demonstration Project study 21 (which was done in the 1970s), only 9% of breast cancers were found by CBE alone. With the advent and increasing use of better mammography, the role of CBE may, in principle, be limited. Most radiologists now estimate that only 10% or less of breast cancers that are missed by mammography can be detected by CBE. The role of CBE appears to be complementary to mammography. However, the critical question is, even though CBE may be able to detect 10% of breast cancers missed by mammography screening, what is the evidence that the detection of these cancers leads to a decrease in mortality from the disease? The answer is that there is no direct evidence. Regarding indirect evidence, it seems that, if properly done, CBE can detect smaller tumors at earlier stages; evidence of this is available from various historical control studies. The next step is intuitive: a leap from a downward shift in stage to a decrease in death from breast cancer. This is a logically dangerous step. Is there any evidence that smaller size actually is associated with a true decrease in breast cancer mortality? Breast Self-Examination
Breast self-examination has not been the subject of prospective randomized trials until quite recently. 18'22'23 All past studies have been observational in nature. A fairly consistent finding has been the association of regular BSE with downshift in stage, size, number of positive axillary lymph nodes, 24-32 and, more recently, with an increase in survival. 33'34 However, there have been studies that failed to show any benefits. 3s-37 Breast self-examination has not been incorporated with mammography in any prospective randomized trials with breast cancer mortality as an end point, as has been the case with CBE. However, there are two new studies in progress that will illuminate 222
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this point. The Russian trial 38'39 is addressing the impact of BSE versus control. Currently there are no mortality data available but there does appear to be a downshift in stage and axillary node positivity. The other trial still in analysis is the Nottingham trial, 4° which has s h o w n no difference in breast cancer mortality w h e t h e r or not BSE was performed. Both of these were prospective randomized control trials, with strong scientific end points. Both will clearly add to our u n d e r s t a n d i n g of BSE.
POTENTIAL FOR DECREASING BREAST CANCER MORTALITY The potential for CBE and BSE to decrease breast cancer mortality must rest on a sound biologic base. Survival curves for the different stages and sizes of tumor show parallel curves. These parallel shapes show a shift "forward," that is, an increased survival time from diagnosis rather than increased cure. 41 This survival increase could simply be accounted for by lead-time bias. A recent analysis 42 of the data from the Swedish study suggests clinical evidence for a change in the slope of the survival curves with a breaking point at sizes smaller than 1 cm. This evidence, although indirect, suggests that finding tumors smaller than 1 cm m a y be associated with an increased cure rather than merely an increase in the survival time from diagnosis. Is there any evidence from a biologic basis that cure can be increased by finding tumors smaller than 1 cm? Tumors usually thought of as at the limit of clinical palpation (whether CBE or BSE) are approximately 1 cm. Such a size contains approximately 1 billion cancer cells. To get to this size, it took perhaps 30 doublings of tumor cells and perhaps as long as 6-8 years from the development of the first breast cancer cell. Hence, w h e n we detect a 1-cm tumor, we are not really detecting "early disease" in the life of the tumor. By the time the tumor is 1 cm the chances are considerable that it has developed metastatic capabilities and invaded lymphatics and blood vessel spaces within the breast primary itself. 43 Once the tumor has metastasized, even subclinically, chances for cure are significantly decreased. Finding a 3-cm tumor, for example (the average size found in BSE), means most likely finding a tumor that is associated with positive axillary lymph nodes and that already has established considerable micrometastases. The possibility that CBE or BSE could decrease breast cancer mortality would be greater if either examination could regularly discover lesions < 1 cm. The key to mortality from breast cancer rests with the acquired ability of breast cancer cells to metastasize and grow independently in other organs of the body. This ability is d e p e n d e n t on the acquisition of multiple biochemical and biologic characteristics or activities, such as the ability to secrete cathepsins, collagenases, autocrine motility factors, and tumor angiogenesis factor, to name but a few. 44"4sSuch capability or acquisition of characteristics appears to be time dependent; that is, it is not present in the cancer cells from the beginning. The successful expression of metastatic potential most likely requires the evolution of specific and successful tumor cell subpopulations. 46 It is unlikely that this h a p p e n s in the early "life" of the transformed cell (ie, within the first 20 doublings). It is more likely to begin between 20-30 doublings, and most likely to have h a p p e n e d by the time 30 doublings OCCUr. 43 In this sense, size could be surrogate for the likelihood of metastases occurring. Because we know that w o m e n can be cured of their breast cancer and that cure is more likely w h e n the cancer is small, it is an intuitive leap of faith to believe that there must be a continuous inverse relationship between tumor size and chance for a cure (or decrease in breast cancer mortality). Survival curves are quite parallel if d r a w n by size of the primary tumor at diagnosis, for tumors
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< 2 cm, 2-2.9 cm, 3-3.9 cm, 4-4.9 cm, or ~ 5 c m . 14 This suggests that the increase in survival is most likely related to lead-time bias. It is only in looking at tumors < 1 cm that the survival curve takes on a n e w shape. 42 One must be careful here in hypothesizing about "typical" breast cancers. We k n o w that there are large breast cancers that never seem to metastasize (although this is the exception rather than the rule), and we also k n o w that there are very small cancers that do metastasize (again the exception and not the rule). Breast cancers are h e t e r o g e n e o u s in their behavior. With this caveat, a 1-cm t u m o r is m u c h less likely to have showers of micrometastases than would a 3- or 4-cm tumor. In this sense, small size, particularly < 1 cm, could rationally be considered a proxy for the probability of associated mortality reduction.
WHAT TO DO? Although it is clear that m a m m o g r a p h y will decrease breast cancer mortality in w o m e n over 50, it is not at all clear that it has any beneficial effect for w o m e n y o u n g e r than 50. So, although we m a y feel comfortable doing regular m a m m o g r a p h y on w o m e n over 50 and ignoring the issue of exactly h o w useful c o m p l e m e n t a r y CBE is for the 10% of cases w h e r e m a m m o g r a p h y does not pick up a lesion, w h a t are we to do about the w o m e n y o u n g e r than 50? Even if the Canadian study does show that annual m a m m o g r a p h y and annual CBE is no better at reducing mortality than a single initial baseline CBE, it seems unlikely that investigators in this country will willingly give u p the use of routine m a m m o g r a p h y screening. But indeed, what good evidence is there that regularly applied m a m m o g r a p h y and CBE are useful in this y o u n g e r population? This year in the United States more than 50,000 w o m e n y o u n g e r than 50 will develop breast cancer. Approximately 16,000 w o m e n in this age g r o u p will die from breast cancer. 47 Saying that we do not have strong e n o u g h evidence to continue to do regular m a m m o g r a p h y , CBE, or BSE does not seem appropriate given the m a g n i t u d e of such disease. On the other hand, in the face of such n u m b e r s it seems inappropriate not to continue to study this question. Certainly there will be sufficient n u m b e r s of cases to a n s w e r any question we might w a n t to ask! In m a n y ways, the simplest solution would be to initiate prospective r a n d o m i z e d control trials in this country to answer issues regarding the relative roles of m a m m o g r a p h y , CBE, and BSE. But there are several i m p o r t a n t problems about developing such a study: first is the willingness of w o m e n or their physicians to be enrolled in a controlled or u n s c r e e n e d arm, or an arm that does not contain m a m m o g r a p h y . Second is the difficulty of ensuring that the screening modalities are technically optimal. A poor m a m m o g r a m , for example, will not detect early breast cancer and neither will i m p r o p e r l y or poorly performed CBE or BSE. We might wait for the current CBE and BSE r a n d o m i z e d studies to be matured or to be made public. Even then, we may not have our answer. If, for example, m a m m o g r a p h y is not state-of-theart as some allege of the Canadian study, or if BSE is not first rate, as might be true of the Russian or UK studies, t h e n a negative result m a y be interpreted to mean that the test has not been given a fair chance to prove its potential. Let us be clear that if we do u n d e r t a k e new studies, we must test stateof-the-art m a m m o g r a p h y and state-of-the-art breast examinations. Such technically optimal modalities are not universally available. 48-sl Currently, only a third of m a m m o g r a p h y facilities in the United States are accredited by the American College of Radiology (ACR). Although this is a laudable step, the standard applied by the ACR is not m e a n t to be a maximal one. Facilities 224
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could certainly do better t h a n m e r e l y m e e t the ACR accreditation standards. Clinical breast e x a m i n a t i o n as p e r f o r m e d b y physicians w h o h a v e no special training takes less t h a n 2 minutes, s2`s3 Surely, this is not an optimal exam. Breast self-examination that detects a typically sized 3-cm t u m o r is clearly not optimal BSE. If w e are to u n d e r t a k e further study, w e m u s t be sure that screening modalities u s e d are state-of-the-art (M. E. C o s t a n z a et al, u n p u b lished data, 1992).
CONCLUSION Barring further studies, w h a t are w e left with? There is no strong direct evidence that m a m m o g r a p h y reduces mortality from breast cancer in w o m e n y o u n g e r t h a n 50; no strong evidence that CBE reduces mortality from breast cancer in w o m e n of a n y age; a n d no strong evidence that BSE reduces m o r tality f r o m breast cancer in w o m e n of a n y age. Should we t h e n persist in massive cancer control intervention studies to increase m a m m o g r a p h y use in w o m e n y o u n g e r t h a n 50 or to i m p r o v e CBE or BSE? It does s e e m counterintuitive to d r o p CBE or BSE m e r e l y because w e h a v e no direct evidence that they m a k e an i m p a c t on breast cancer mortality. We do not really h a v e a n y direct evidence that t h e y do not m a k e such an impact. Mostly we h a v e no evidence. The issue is that if w e do not challenge the real utility of CBE or BSE, we m a y be lulled into a sense of false security that these modalities are a d e q u a t e to decrease mortality f r o m breast cancer. If w e a c k n o w l e d g e the lack of evidence s u p p o r t i n g the utility of these two modalities, p e r h a p s we can redirect e n e r g y into discovery a n d into testing of n e w a n d better screening modalities. The s p u r to such activity will surely be greater if w e are clear a b o u t the inadequacies of o u r current screening modalities a n d the inadequacies of their current application.
REFERENCES 1. Early Detection Branch. Working guidelines for early detection. Bethesda, Maryland: National Cancer Institute, 1987:9-13. 2. American Cancer Society. Summary of current guidelines for the cancer-related check-up: Recommendations. Atlanta: American Cancer Society, 1988. 3. United States Preventive Services Health Task Force. Guide to clinical prevention services: An assessment of the effectiveness of 169 interventions. Baltimore: Williams and Wilkins, 1989:26-31. 4. Morrison AS. Review of evidence on the early detection and treatment of breast cancer. Cancer 1989;64:2651-6. 5. Connor RJ, Prorok PC, Weed DL. The case-control design and the assessment of the cancer screening. J Clin Epidemiol 1991;44:1215-21. 6. Friedman DR, Dubin N. Case-control evaluation of breast cancer screening efficacy. Am J Epidemiol 1991;133:974-84. 7. Shapiro S, Strax P, Venet L, Roeser R. Ten to fourteen year effect of screening on breast cancer mortality. J Natl Cancer Inst 1982;69:349-55. 8. Tabar L, Fagerberg CK, Gad A, et al. Reduction in mortality from breast cancer after mass screening with mammography: Randomized trial from the Breast Cancer Screening Working Group of the Swedish National Board of Health and Welfare. Lancet 1985;1:829-32. 9. Andersson I, Aspergren K, Janzon L, et al. Mammographic screening and mortality from breast cancer: The Malmo mammographic screening trial. BMJ 1988;297:9438. 10. Roberts MM, Alexander FE, Anderson TJ, et al. Edinburgh trial of screening for breast cancer: Mortality at seven years. Lancet 1990;335:242-6. 11. Frisell J, Eklund G, HeUstrom L, Glas U, Somell A. The Stockholm Breast Cancer
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Screening Trial: 5-year results and stage at discovery. Breast Cancer Res Treat 1989;13:79-87. Baines CJ, McFarlane DV, Miller AB, et al. Sensitivity and specificity of first screen mammography in 15 NBSS centers. Can Assoc Radiol 1988;39:274-6. UK Trial of Early Detection of Cancer Group. First results of mortality reduction in the UK trial of early detection of breast cancer. Lancet 1988;2:411-6. Verbeek ALM, Hendricks JHCL, Holland R, et al. Reduction of breast cancer mortality through mass screening with m o d e m mammography: First results of the Nijmegen project, 1975-1981. Lancet 1984;2:1222-4. Collette HJA, Day NE, Rombach JJ, De Waard F. Evaluation of screening for breast cancer in a non-randomized study (the DOM project) by means of a case control study. Lancet 1984;1:1224-6. Palli D, Rosselli-Del Turco M, Buiatti E, et al. A case-control study of the efficacy of a non-randomized breast cancer screening program in Florence (Italy). Int J Cancer 1986;38:501-4. Shapiro S, Venet W, Stax P, et al. Periodic screening for breast cancer--the Health Insurance Plan Project and its sequelae, 1963-1986. Baltimore: Johns Hopkins University Press, 1988. Foster RS Jr, Worden JK, Costanza MC, Solomon LJ. Clinical breast examination and breast self-examination. Cancer 1992;69:1992-8. Day E. Cancer screening and detection: Medical aspects. J Chronic Dis 1963;16:397407. Gilbertsen VA. Detection of breast cancer in a specialized cancer detection center. Cancer 1969;24:1192-5. Seidman H, Gelb SK, Silverberg E, et al. Survival experience in the Breast Cancer Detection Demonstration Project. CA 1987;37:258-90. Baines CJ. Breast self-examination. Cancer 1992;69:1942-6. Champion V. The role of breast self-examination in breast cancer screening. Cancer 1992;69:1985-91. Foster RS Jr, Costanza MC. Breast self-examination practices and breast cancer survival. Cancer 1984;53:999-1005. Foster RS Jr, Lang SP, Costanza MC, et al. Breast self-examination practices and breast cancer stage. N Engl J Med 1978;299:265-70. Costanza MC, Foster RS. Relationship between breast self-examination and death from breast cancer by age groups. Cancer Detect Prev 1984;7:103-8. Phillip J, Harris WG, Flagerty C, et al. Breast self-examination: Clinical results from a population-based prospective study. Br J Cancer 1984;50:7-12. Dowle CS, Mitchell A, Elston CW, et al. Preliminary results of the Nottingham breast self-examination education program. Br J Surg 1987;74:217-9. Newcomb PA, Weiss NS, Storer BE, et al. Breast self-examination in relation to the occurrence of advanced breast cancer. J Natl Cancer Inst 1991;83:260-5. Greenwald P, Nasca PC, Lawrence CE, et al. Estimated effect of breast self-examination and routine physician examinations on breast cancer mortality. N Engl J Med 1978;299:271-3. Feldman JG, Carter AC, Nicastri AD, Hosat ST. Breast self-examination relationship to stage of breast cancer at diagnosis. Cancer 1981;17:2740-5. GIVIO (Interdisciplinary Group for Cancer Care Evaluation). Practice of breast self examination: Disease extent at diagnosis and patterns of surgical care. A report from an Italian study. J Epidemiol Community Health 1991;45:112-6. Huguley CM Jr, Brown RL, Greenberg RS, Clark WS. Breast self-examination and survival from breast cancer. Cancer 1988;62:1389-96. Foster RS, Costanza MC, Rathbun L. Breast self-examination practices: Twelve year survival and cause of death in breast cancer patients. International Cancer Congress, Hamburg, Germany, August 16-22, 1990. O'Malley MS, Fletcher SW. US Preventive Service Task Force: Screening for breast cancer with breast self-examination. JAMA 1987;257:2196-203. Smith EM, Frances AM, Polissar L. The effect of breast self-exam practices and physician examinations on extent of disease at diagnosis. Prev Med 1980;9:40917. Senie RT, Rosen PP, Lesser ML, Kinne DW. Breast self-examination and medical examination related to breast cancer stage. Am J Public Health 1981;71:583-90.
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38. Semiglazov VF, Moiseenko VM. Breast self-examination for the early detection of breast cancer: A USSR/WHO controlled trial in Leningrad. Bull WHO 1987;65:3916. 39. Koroltchouk V, Stanley K, Stjernsward J. The control of breast cancer: A World Health Organization perspective. Cancer 1990;65:2803-10. 40. Dowle CS, Mitchell A, Elston CW, et al. Preliminary results of the Nottingham Breast Self-Examination Education Program. Br J Surg 1987;74:217-9. 41. Adair F, Berg J, Joubert L, Robbins GF. Long-term follow-up of breast cancer patients: The 30-year report. Cancer 1974;33:1145-50. 42. Tabar L, Fagerberg G, Day NE, Duffy SW, Kitchin RM. Breast cancer treatment and natural history: New insights from results of screening. Lancet 1992;339: 412-4. 43. Henderson IG. Biologic variations of tumors. Cancer 1992;69:1888-95. 44. Zetter BR. The cellular basis of site-specific tumor metastasis. N Engl J Med 1990;322:605-12. 45. Liotta LA. Gene products which play a role in cancer invasion and metastasis. Breast Cancer Res Treat 1988;11:113-24. 46. Nicholson GL. Tumor cell instability, diversification and progression to the metastatic phenotype: From oncogene to oncofetal expression. Cancer Res 1987;47:1473. 47. American Cancer Society. Cancer statistics, 1992 [CA--A Journal for Clinicians]. Atlanta: ACS, 1992. 48. Baines CJ, Miller AB, Bassett AA. Physical examination: Its role as a single screening modality in the Canadian National Breast Screening Study. Cancer 1989;63:181622. 49. Fletcher SW, O'Malley MS, Bunce LA. Physicians' abilities to detect lumps in silicone breast models. JAMA 1985;253:2224-8. 50. Worden K, Solomon LJ, Flynn BS, et al. A community-wide program in breast self-examination training and maintenance. Prey Med 1990;19:254-69. 51. Fletcher SW, O'Malley MS, Earp JL, et al. How best to teach women breast selfexamination: A randomized controlled trial. Ann Intern Med 1990;112:772-9. 52. Winchester DP. Physical examination of the breast. Cancer 1992;69:1947-9. 53. Kahn KL. Screening for breast cancer in the ambulatory setting. Clin Res 1984;32:649A.
CLINICAL BREAST EXAMINATION A N D BREAST SELF-EXAMINATION Unlike m a m m o g r a p h y , w h o s e effectiveness for certain age groups is being called into question, there is a total lack of data confirming or d e n y i n g the benefits of clinical breast examination (CBE) and breast self-examination (BSE). Participants lamented that fact, yet m a n y clinicians rallied a r o u n d the clinical necessity of both screening modalities. The question of w h o should perform CBE and counsel about BSE was discussed, as well as directions for future research. Discussants included Elizabeth A n n Coleman, RNP, PhD, w h o discussed proficiency in technique, and Dr. Costanza, w h o s e paper is printed here. Mary A n n Braun, MSN, served as moderator.
Do we have any way of assessing the relative effectiveness of both screening techniques (eg, CBE and BSE)? Sally West Brooks, RN, MA, a c o m m u n i t y organizer, admitted that persons like herself are confused about w h a t to p u r s u e at the c o m m u n i t y level. "With the volunteers that we have, do we s p e n d a lot of time-teaching about BSE, or do we encourage w o m e n to get m a m m o g r a m s ? " she asked, adding, "we n e e d e d the data y e s t e r d a y . " Dr. Costanza referred to evidence p r e s e n t e d by Dr. Coleman that both CBE and BSE can reliably locate disease u n d e r 1 cm in size. "If that's the case, and it can be d e m o n s t r a t e d , then it's certainly w o r t h p u r s u i n g , " she said; however, in other remarks she also suggested that the issue of effectiveness c a n n o t be entertained separately from that of
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linical breast examination (CBE) and breast self-examination (BSE) are two of the three traditional time-honored methods of early breast cancer detection. Although the National Cancer Institute ~ and the American Cancer Society2 continue to recommend both CBE and BSE, other groups do not recommend BSE.3 It should be understood that the type of evidence supporting the utility of these two methods of detection are different and of unequal scientific merit compared with that supporting the efficacy of mammography. Because mammography is playing such an increasing role in breast cancer screening, it is timely to reconsider the role and merit of CBE and BSE. Evidence for the utility of a screening method should be reviewed on a scientific basis. This would include two key conditions: 1) the screening test must actually be able to detect cancers earlier, and 2) there must be evidence that treatment at that earlier stage of disease will result in a better outcome. These requirements are similar to those now used by the National Cancer Institute in reviewing their cancer screening guidelines (Barnett Kramer, MD, personal communication). Measures of improved outcome vary. The strongest evidence would be a decrease in cause-specific mortality. Weaker evidence would be a reduction in the incidence of later-stage cancer. Weakest of all would be a shift to a lower stage. The gold standard for evidence of utility would be several randomized, well-designed, well-controlled studies using cause-specific mortality as an end point in the screened versus the unscreened population. 4 Not many screening tests have met these strict requirements. Almost all of those are studies of breast cancer screening by mammography or by mammography and CBE against control. More common are case-control studies. These provide less direct evidence for utility because they only suggest mortality reduction and because bias cannot be controlled, s'6 Other common screening studies often use downshifts in stage or increase in survival or decrease in size or the number of positive lymph nodes as the end point to prove "effectiveness" of the proposed screening modality. Such studies may
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Table 1.
Study
STUDIES OF M A M M O G R A P H Y
Age (Years)
Screening Interval (Months)
Randomized controlled trials HIP 7 40-64 12 T w o - c o u n t y s 40-74 24-33 Malmo 9 45-69 18-24 Edinburgh 1° 45-64 12-24 Stockholm 11 40-64 24 Canadian 12 40-49 12 50-59 12 N o n r a n d o m i z e d controlled trials UK 13 45-64 24 12 Nijmegen TM 35-65 24 DOM 15 50-64 12-24 Florence t6 40-70 30
Decrease in Mortality
Modality M 2 + CBE M1
29% 31% 4% 17% 29% NA NA
M2
M 2 + CBE M1 M 2 + CBE M 2 + CBE
M CBE M1
Significance + +
NA NA
20% 49% 70% 47%
M2
M2
+
+ +
M ~, one-view m a m m o g r a m ; M 2, two-view m a m m o g r a m ; CBE, clinical breast examination; NA, not available.
be helpful in first noting a potentially effective screening test, but such studies cannot establish the utility of the screening test because of the absence of suitable controls. 4 Although there is an "intuitive" sense that downshifts in stage, smaller tumors, and less involved l y m p h nodes must be associated with a decrease in cause-specific mortality, it is not necessarily so. Relying on the related increase in survival as evidence of efficacy is likely to be treacherous because this increase may be accounted for by lead time bias. Put a n o t h e r way, finding a smaller breast cancer m a y not be associated with decreased mortality from breast cancer. Therefore, tests that are evaluated principally by their ability to detect smaller tumors at a less advanced stage m a y not alter the natural history of breast cancer.
E V I D E N C E REVIEWED Mammography (With or Without Clinical Breast Exam) A brief review of the published evidence concerning the efficacy of mamm o g r a p h y screening is informative. There is consistent evidence from controlled trials that breast cancer mortality is reduced by the use of m a m m o g raphy, with or w i t h o u t CBE (see Table 1). There are five r a n d o m i z e d controlled m a m m o g r a p h y trials, all with positive results (a decrease in mortality). 7-12 In two, the decrease in mortality reaches statistical significance. 7.s There are four n o n r a n d o m i z e d or case-controlled studies also consistently showing a decrease in breast cancer mortality. 13-16 Three of these reach statistical significance. There are several i m p o r t a n t issues involved regarding the efficacy of m a m m o g r a p h y in reducing mortality from breast cancer. These include the age at which m a m m o g r a p h y begins to confer a reduction in mortality, the intervals at which it should be performed, the n u m b e r of views of the breast to be taken, and w h e t h e r adding CBE to m a m m o g r a p h y improves the mortality reduction. Regarding the appropriate n u m b e r of views (one or two) or
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the appropriate interval (12-33 months), no clear answers can be given. There does not seem to be any consistent relationship between these variables and the size of mortality reduction. The age at which mammography begins to be useful is also unclear. The trials include a range of ages from 35-74, without stratifying for age. Accordingly, retrospective analyses of women below and above the age of 50 are less compelling. Nonetheless, in all but the Health Insurance Plan of New York (HIP) study, no decrease in breast cancer mortality with mammography was seen in women under the age of 50. The HIP study 17 has been analyzed differently by different authors, and the under age 50 benefit is a matter of controversy. The one trial of women randomized on the basis of age under 50 is the as yet unpublished Canadian trial. ~2 It is widely rumored to be a negative study, that is, there is no difference in breast cancer mortality whether women under age 50 receive annual mammography and CBE or receive only an initial baseline CBE. Clinical Breast Examination
With the exception of the Canadian study, 12 there are no randomized studies looking at CBE and its impact on the reduction of breast cancer mortality. The previously mentioned studies do not study the effects of CBE alone. The contribution of CBE to the reduction in mortality from breast cancer can therefore be only indirectly inferred. A recent review of CBETM notes that observational studies have associated CBE with downshift in stage, fewer positive axillary lymph nodes, and better survival.19,2° A review 7 of the HIP study notes that CBE alone detected a large percentage of breast cancers and suggests that CBE may have contributed up to two-thirds of the mortality reduction seen in that study. This large effect may be due to the poor technical quality of mammography available in the 1960s as compared with modern equipment. By the time of the Breast Cancer Detection Demonstration Project study 21 (which was done in the 1970s), only 9% of breast cancers were found by CBE alone. With the advent and increasing use of better mammography, the role of CBE may, in principle, be limited. Most radiologists now estimate that only 10% or less of breast cancers that are missed by mammography can be detected by CBE. The role of CBE appears to be complementary to mammography. However, the critical question is, even though CBE may be able to detect 10% of breast cancers missed by mammography screening, what is the evidence that the detection of these cancers leads to a decrease in mortality from the disease? The answer is that there is no direct evidence. Regarding indirect evidence, it seems that, if properly done, CBE can detect smaller tumors at earlier stages; evidence of this is available from various historical control studies. The next step is intuitive: a leap from a downward shift in stage to a decrease in death from breast cancer. This is a logically dangerous step. Is there any evidence that smaller size actually is associated with a true decrease in breast cancer mortality? Breast Self-Examination
Breast self-examination has not been the subject of prospective randomized trials until quite recently. 18'22'23 All past studies have been observational in nature. A fairly consistent finding has been the association of regular BSE with downshift in stage, size, number of positive axillary lymph nodes, 24-32 and, more recently, with an increase in survival. 33'34 However, there have been studies that failed to show any benefits. 3s-37 Breast self-examination has not been incorporated with mammography in any prospective randomized trials with breast cancer mortality as an end point, as has been the case with CBE. However, there are two new studies in progress that will illuminate 222
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this point. The Russian trial 38'39 is addressing the impact of BSE versus control. Currently there are no mortality data available but there does appear to be a downshift in stage and axillary node positivity. The other trial still in analysis is the Nottingham trial, 4° which has s h o w n no difference in breast cancer mortality w h e t h e r or not BSE was performed. Both of these were prospective randomized control trials, with strong scientific end points. Both will clearly add to our u n d e r s t a n d i n g of BSE.
POTENTIAL FOR DECREASING BREAST CANCER MORTALITY The potential for CBE and BSE to decrease breast cancer mortality must rest on a sound biologic base. Survival curves for the different stages and sizes of tumor show parallel curves. These parallel shapes show a shift "forward," that is, an increased survival time from diagnosis rather than increased cure. 41 This survival increase could simply be accounted for by lead-time bias. A recent analysis 42 of the data from the Swedish study suggests clinical evidence for a change in the slope of the survival curves with a breaking point at sizes smaller than 1 cm. This evidence, although indirect, suggests that finding tumors smaller than 1 cm m a y be associated with an increased cure rather than merely an increase in the survival time from diagnosis. Is there any evidence from a biologic basis that cure can be increased by finding tumors smaller than 1 cm? Tumors usually thought of as at the limit of clinical palpation (whether CBE or BSE) are approximately 1 cm. Such a size contains approximately 1 billion cancer cells. To get to this size, it took perhaps 30 doublings of tumor cells and perhaps as long as 6-8 years from the development of the first breast cancer cell. Hence, w h e n we detect a 1-cm tumor, we are not really detecting "early disease" in the life of the tumor. By the time the tumor is 1 cm the chances are considerable that it has developed metastatic capabilities and invaded lymphatics and blood vessel spaces within the breast primary itself. 43 Once the tumor has metastasized, even subclinically, chances for cure are significantly decreased. Finding a 3-cm tumor, for example (the average size found in BSE), means most likely finding a tumor that is associated with positive axillary lymph nodes and that already has established considerable micrometastases. The possibility that CBE or BSE could decrease breast cancer mortality would be greater if either examination could regularly discover lesions < 1 cm. The key to mortality from breast cancer rests with the acquired ability of breast cancer cells to metastasize and grow independently in other organs of the body. This ability is d e p e n d e n t on the acquisition of multiple biochemical and biologic characteristics or activities, such as the ability to secrete cathepsins, collagenases, autocrine motility factors, and tumor angiogenesis factor, to name but a few. 44"4sSuch capability or acquisition of characteristics appears to be time dependent; that is, it is not present in the cancer cells from the beginning. The successful expression of metastatic potential most likely requires the evolution of specific and successful tumor cell subpopulations. 46 It is unlikely that this h a p p e n s in the early "life" of the transformed cell (ie, within the first 20 doublings). It is more likely to begin between 20-30 doublings, and most likely to have h a p p e n e d by the time 30 doublings OCCUr. 43 In this sense, size could be surrogate for the likelihood of metastases occurring. Because we know that w o m e n can be cured of their breast cancer and that cure is more likely w h e n the cancer is small, it is an intuitive leap of faith to believe that there must be a continuous inverse relationship between tumor size and chance for a cure (or decrease in breast cancer mortality). Survival curves are quite parallel if d r a w n by size of the primary tumor at diagnosis, for tumors
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< 2 cm, 2-2.9 cm, 3-3.9 cm, 4-4.9 cm, or ~ 5 c m . 14 This suggests that the increase in survival is most likely related to lead-time bias. It is only in looking at tumors < 1 cm that the survival curve takes on a n e w shape. 42 One must be careful here in hypothesizing about "typical" breast cancers. We k n o w that there are large breast cancers that never seem to metastasize (although this is the exception rather than the rule), and we also k n o w that there are very small cancers that do metastasize (again the exception and not the rule). Breast cancers are h e t e r o g e n e o u s in their behavior. With this caveat, a 1-cm t u m o r is m u c h less likely to have showers of micrometastases than would a 3- or 4-cm tumor. In this sense, small size, particularly < 1 cm, could rationally be considered a proxy for the probability of associated mortality reduction.
WHAT TO DO? Although it is clear that m a m m o g r a p h y will decrease breast cancer mortality in w o m e n over 50, it is not at all clear that it has any beneficial effect for w o m e n y o u n g e r than 50. So, although we m a y feel comfortable doing regular m a m m o g r a p h y on w o m e n over 50 and ignoring the issue of exactly h o w useful c o m p l e m e n t a r y CBE is for the 10% of cases w h e r e m a m m o g r a p h y does not pick up a lesion, w h a t are we to do about the w o m e n y o u n g e r than 50? Even if the Canadian study does show that annual m a m m o g r a p h y and annual CBE is no better at reducing mortality than a single initial baseline CBE, it seems unlikely that investigators in this country will willingly give u p the use of routine m a m m o g r a p h y screening. But indeed, what good evidence is there that regularly applied m a m m o g r a p h y and CBE are useful in this y o u n g e r population? This year in the United States more than 50,000 w o m e n y o u n g e r than 50 will develop breast cancer. Approximately 16,000 w o m e n in this age g r o u p will die from breast cancer. 47 Saying that we do not have strong e n o u g h evidence to continue to do regular m a m m o g r a p h y , CBE, or BSE does not seem appropriate given the m a g n i t u d e of such disease. On the other hand, in the face of such n u m b e r s it seems inappropriate not to continue to study this question. Certainly there will be sufficient n u m b e r s of cases to a n s w e r any question we might w a n t to ask! In m a n y ways, the simplest solution would be to initiate prospective r a n d o m i z e d control trials in this country to answer issues regarding the relative roles of m a m m o g r a p h y , CBE, and BSE. But there are several i m p o r t a n t problems about developing such a study: first is the willingness of w o m e n or their physicians to be enrolled in a controlled or u n s c r e e n e d arm, or an arm that does not contain m a m m o g r a p h y . Second is the difficulty of ensuring that the screening modalities are technically optimal. A poor m a m m o g r a m , for example, will not detect early breast cancer and neither will i m p r o p e r l y or poorly performed CBE or BSE. We might wait for the current CBE and BSE r a n d o m i z e d studies to be matured or to be made public. Even then, we may not have our answer. If, for example, m a m m o g r a p h y is not state-of-theart as some allege of the Canadian study, or if BSE is not first rate, as might be true of the Russian or UK studies, t h e n a negative result m a y be interpreted to mean that the test has not been given a fair chance to prove its potential. Let us be clear that if we do u n d e r t a k e new studies, we must test stateof-the-art m a m m o g r a p h y and state-of-the-art breast examinations. Such technically optimal modalities are not universally available. 48-sl Currently, only a third of m a m m o g r a p h y facilities in the United States are accredited by the American College of Radiology (ACR). Although this is a laudable step, the standard applied by the ACR is not m e a n t to be a maximal one. Facilities 224
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could certainly do better t h a n m e r e l y m e e t the ACR accreditation standards. Clinical breast e x a m i n a t i o n as p e r f o r m e d b y physicians w h o h a v e no special training takes less t h a n 2 minutes, s2`s3 Surely, this is not an optimal exam. Breast self-examination that detects a typically sized 3-cm t u m o r is clearly not optimal BSE. If w e are to u n d e r t a k e further study, w e m u s t be sure that screening modalities u s e d are state-of-the-art (M. E. C o s t a n z a et al, u n p u b lished data, 1992).
CONCLUSION Barring further studies, w h a t are w e left with? There is no strong direct evidence that m a m m o g r a p h y reduces mortality from breast cancer in w o m e n y o u n g e r t h a n 50; no strong evidence that CBE reduces mortality from breast cancer in w o m e n of a n y age; a n d no strong evidence that BSE reduces m o r tality f r o m breast cancer in w o m e n of a n y age. Should we t h e n persist in massive cancer control intervention studies to increase m a m m o g r a p h y use in w o m e n y o u n g e r t h a n 50 or to i m p r o v e CBE or BSE? It does s e e m counterintuitive to d r o p CBE or BSE m e r e l y because w e h a v e no direct evidence that they m a k e an i m p a c t on breast cancer mortality. We do not really h a v e a n y direct evidence that t h e y do not m a k e such an impact. Mostly we h a v e no evidence. The issue is that if w e do not challenge the real utility of CBE or BSE, we m a y be lulled into a sense of false security that these modalities are a d e q u a t e to decrease mortality f r o m breast cancer. If w e a c k n o w l e d g e the lack of evidence s u p p o r t i n g the utility of these two modalities, p e r h a p s we can redirect e n e r g y into discovery a n d into testing of n e w a n d better screening modalities. The s p u r to such activity will surely be greater if w e are clear a b o u t the inadequacies of o u r current screening modalities a n d the inadequacies of their current application.
REFERENCES 1. Early Detection Branch. Working guidelines for early detection. Bethesda, Maryland: National Cancer Institute, 1987:9-13. 2. American Cancer Society. Summary of current guidelines for the cancer-related check-up: Recommendations. Atlanta: American Cancer Society, 1988. 3. United States Preventive Services Health Task Force. Guide to clinical prevention services: An assessment of the effectiveness of 169 interventions. Baltimore: Williams and Wilkins, 1989:26-31. 4. Morrison AS. Review of evidence on the early detection and treatment of breast cancer. Cancer 1989;64:2651-6. 5. Connor RJ, Prorok PC, Weed DL. The case-control design and the assessment of the cancer screening. J Clin Epidemiol 1991;44:1215-21. 6. Friedman DR, Dubin N. Case-control evaluation of breast cancer screening efficacy. Am J Epidemiol 1991;133:974-84. 7. Shapiro S, Strax P, Venet L, Roeser R. Ten to fourteen year effect of screening on breast cancer mortality. J Natl Cancer Inst 1982;69:349-55. 8. Tabar L, Fagerberg CK, Gad A, et al. Reduction in mortality from breast cancer after mass screening with mammography: Randomized trial from the Breast Cancer Screening Working Group of the Swedish National Board of Health and Welfare. Lancet 1985;1:829-32. 9. Andersson I, Aspergren K, Janzon L, et al. Mammographic screening and mortality from breast cancer: The Malmo mammographic screening trial. BMJ 1988;297:9438. 10. Roberts MM, Alexander FE, Anderson TJ, et al. Edinburgh trial of screening for breast cancer: Mortality at seven years. Lancet 1990;335:242-6. 11. Frisell J, Eklund G, HeUstrom L, Glas U, Somell A. The Stockholm Breast Cancer
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38. Semiglazov VF, Moiseenko VM. Breast self-examination for the early detection of breast cancer: A USSR/WHO controlled trial in Leningrad. Bull WHO 1987;65:3916. 39. Koroltchouk V, Stanley K, Stjernsward J. The control of breast cancer: A World Health Organization perspective. Cancer 1990;65:2803-10. 40. Dowle CS, Mitchell A, Elston CW, et al. Preliminary results of the Nottingham Breast Self-Examination Education Program. Br J Surg 1987;74:217-9. 41. Adair F, Berg J, Joubert L, Robbins GF. Long-term follow-up of breast cancer patients: The 30-year report. Cancer 1974;33:1145-50. 42. Tabar L, Fagerberg G, Day NE, Duffy SW, Kitchin RM. Breast cancer treatment and natural history: New insights from results of screening. Lancet 1992;339: 412-4. 43. Henderson IG. Biologic variations of tumors. Cancer 1992;69:1888-95. 44. Zetter BR. The cellular basis of site-specific tumor metastasis. N Engl J Med 1990;322:605-12. 45. Liotta LA. Gene products which play a role in cancer invasion and metastasis. Breast Cancer Res Treat 1988;11:113-24. 46. Nicholson GL. Tumor cell instability, diversification and progression to the metastatic phenotype: From oncogene to oncofetal expression. Cancer Res 1987;47:1473. 47. American Cancer Society. Cancer statistics, 1992 [CA--A Journal for Clinicians]. Atlanta: ACS, 1992. 48. Baines CJ, Miller AB, Bassett AA. Physical examination: Its role as a single screening modality in the Canadian National Breast Screening Study. Cancer 1989;63:181622. 49. Fletcher SW, O'Malley MS, Bunce LA. Physicians' abilities to detect lumps in silicone breast models. JAMA 1985;253:2224-8. 50. Worden K, Solomon LJ, Flynn BS, et al. A community-wide program in breast self-examination training and maintenance. Prey Med 1990;19:254-69. 51. Fletcher SW, O'Malley MS, Earp JL, et al. How best to teach women breast selfexamination: A randomized controlled trial. Ann Intern Med 1990;112:772-9. 52. Winchester DP. Physical examination of the breast. Cancer 1992;69:1947-9. 53. Kahn KL. Screening for breast cancer in the ambulatory setting. Clin Res 1984;32:649A.
CLINICAL BREAST EXAMINATION A N D BREAST SELF-EXAMINATION Unlike m a m m o g r a p h y , w h o s e effectiveness for certain age groups is being called into question, there is a total lack of data confirming or d e n y i n g the benefits of clinical breast examination (CBE) and breast self-examination (BSE). Participants lamented that fact, yet m a n y clinicians rallied a r o u n d the clinical necessity of both screening modalities. The question of w h o should perform CBE and counsel about BSE was discussed, as well as directions for future research. Discussants included Elizabeth A n n Coleman, RNP, PhD, w h o discussed proficiency in technique, and Dr. Costanza, w h o s e paper is printed here. Mary A n n Braun, MSN, served as moderator.
Do we have any way of assessing the relative effectiveness of both screening techniques (eg, CBE and BSE)? Sally West Brooks, RN, MA, a c o m m u n i t y organizer, admitted that persons like herself are confused about w h a t to p u r s u e at the c o m m u n i t y level. "With the volunteers that we have, do we s p e n d a lot of time-teaching about BSE, or do we encourage w o m e n to get m a m m o g r a m s ? " she asked, adding, "we n e e d e d the data y e s t e r d a y . " Dr. Costanza referred to evidence p r e s e n t e d by Dr. Coleman that both CBE and BSE can reliably locate disease u n d e r 1 cm in size. "If that's the case, and it can be d e m o n s t r a t e d , then it's certainly w o r t h p u r s u i n g , " she said; however, in other remarks she also suggested that the issue of effectiveness c a n n o t be entertained separately from that of
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