- Email: [email protected]
The mammography screening debate: time to move on
COMMENTARY
COMMENTARY
The mammography screening debate: time to move on See page 909 Last year at an oncology meeting in Cambridge (UK), a 53year-old American journalist confessed that she had not yet had a mammogram because she could not get a clear answer about its usefulness. She had read the research articles, talked to doctors on both sides of the Atlantic and both sides of the debate, and was still baffled. She is not alone. The literature on screening mammography provides ample opportunity for confusion and dogma, and can be interpreted to prove both benefit and harm. Is there a clear answer about whether a mammogram does affect mortality? An overview in the The Lancet this week gives further information. Lennarth Nyström and colleagues present 15·8-year data from the four Swedish randomised trials of screening mammography. The results of the included trials have been previously presented individually, used in meta-analyses of screening efficacy, and cited as a rationale for national screening programmes.1-7 With 247 010 women enrolled, these trials provide a database with long-term follow-up from which estimates of the efficacy of an invitation to screening mammography compared with no specific screening intervention can be derived. The trials were all population-based but differed in randomisation methods, ages of women included, number of radiological views, and intervals between screening assessments. The overall effect was 511 breast cancer deaths in 1 864 770 women-years of follow-up among women invited to screening, and 584 breast cancer deaths in 1 688 440 women-years in the controls. This translates into a statistically significant reduction in breast cancer mortality of 21% (relative risk 0·79, 95% CI 0·70–0·89). Nyström and colleagues provide data of sound quality that demonstrate the magnitude and age-specific effects of screening on breast cancer mortality. The benefits appear real but modest. Despite the reduction in breast cancer mortality, overall (all-cause) mortality showed a relative risk of just 0·98 (0·96–1·00) between the invited and control groups. How does this help the clinician and women who in recent years have been bombarded by media and scientific claims for and against screening mammography?8-11 Mammographic screening identifies small cancers several years before they can be detected by palpation. Clinicians, statisticians, health-care economists, and editors12 of major medical journals should recognise that the natural history of breast cancer tells us that avoiding deaths from breast cancer can only be measured many years and even decades after the start of screening. Confirmation of the stability of the reductions in breast cancer mortality over time is perhaps the most useful contribution of the paper by Nyström and colleagues. Critics of screening have cited fear, the increased diagnosis of in-situ disease, and the high number of false positives as harmful by-products of screening.13-15 The latest overview by Nyström and colleagues cannot address these issues. 904
From the latest overview, different levels of benefit and varied conclusions can be reached depending on how the 10-year age groups are defined. For example, women aged 45–54 years seemed to have the least benefit. However, when analysed by traditional decade cohorts (40–49, 50–59, &) it could be concluded that mammography was similarly beneficial across all age groups between age 40 and 74. Is this a reflection of reduced screening efficacy around the age of menopause due to hormonal changes, or is it simply a statistical variation? In recent weeks there has been considerable debate in academic journals about the issue of all-cause mortality in screening programmes,16–18 and the latest overview does address the possible biases and under-counting of mortality caused by screening. The 2·3% reduction of total mortality is reassuring and the small effect is not unexpected for a disease that contributes only modestly to all-cause mortality. The latest analysis does not tell us whether the massive effort to develop screening programmes3 in at least 22 countries and to encourage participation is worthwhile. That issue must be honestly confronted by those organisations and individuals with an interest in maintaining programmes for mammography screening. The extensive information in the latest overview about the selection and randomisation of the women goes a long way to address the concerns raised by Gøtzsche and Olsen.19,20 In addition, the overview by Nyström and colleagues, based on trial participant-specific data and outcomes, is methodologically a more robust meta-analysis than pooling of previously published data. There has been a reduction in breast cancer mortality of nearly 30% since 1990.21-23 How much of this is due to screening and early diagnosis and how much to improved therapy? During the era when most women were being accrued to the trials contributing to the latest analysis, systemic therapy was just beginning to be adopted and certainly was not as commonly used as today, when most women with breast cancer receive some sort of adjuvant systemic therapy. It is not known whether the benefits of screening and adjuvant therapy are additive. Populationbased analyses to tease out the relative effects of screening and treatment are needed. So where does this overview leave clinicians and women? What should the confused journalist be told? Both the American Society for Clinical Oncology and the PDQ group, which feeds into the US National Cancer Institute, are currently looking again at screening mammography. The latest analysis by Nyström and colleagues reassures us that the Swedish data are believable and that they can be used to develop guidelines and assist individual women to make informed health-care choices. The data confirm that screening mammography has a real but modest effect to decrease mortality from breast cancer and that this effect varies with age. The data confirm that women who are otherwise well, especially those aged 55–69 years, and who
THE LANCET • Vol 359 • March 16, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
are concerned about breast cancer should be encouraged to attend screening. Partly because of the controversy around mammography screening, less than half of such women, the age group most likely to benefit, access this service on a regular basis in many western countries. The focus of screening should be to ensure these women attend about every 2 years. Although individual younger women may benefit, debate continues on the size of the effect for women aged under 50. Since breast cancer accounts for only about 4% of all deaths annually, even a 21% reduction in breast cancer mortality is barely measurable when allcause mortality is the endpoint. It is time for the angst about breast cancer to move from screening to questions of molecular diagnoses, aetiology, selection of optimum therapy, and improved survival for women in a more timely and cost-effective way. *Karen A Gelmon, Ivo Olivotto *British Columbia Cancer Agency-Vancouver Cancer Centre, Vancouver BC, Canada V5Z 4E6; and BC Cancer Agency-Vancouver Island Centre, Victoria, BC, Canada (e-mail: [email protected]) 1
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Nyström L, Rutqvist LE, Wall S, et al. Breast cancer screening with mammography: overview of Swedish randomised studies. Lancet 1993; 341: 973–78. Shapiro S, Coleman EA, Broeders M, Codd M, de Koning H, Fracheboud J. Breast cancer screening programs in 22 countries: current policies, administration and guidelines. Int J Epidemiol 1998; 27: 735–42. Kerlikowske K, Grady D, Rubin SM, Sandrock C, Ernster VJ. Efficacy of screening mammography: a meta-analysis. JAMA 1995; 273: 149–54. Kerlikowske K. Efficacy of screening mammography among women aged 40–49 years and 50–69 years: comparison of relative and absolute benefit. Natl Cancer Inst Monogr 1997; 22: 79–86. Hendrick RE, Smite RA, Rutledge JH, Smart CR. Benefit of screening mammography in women aged 40-49: a new meta-analysis of randomized controlled trials. Natl Cancer Inst Monogr 1997; 22: 87–92. Smart CR, Hendrick RE, Rutledge JH, Smith RA. Benefit of mammography screening in women ages 40–49 years: current evidence from randomized controlled trials. Cancer 1995; 75: 1619–26. De Koning HJ. Assessment of nationwide cancer screening programmes. Lancet 2000; 355: 80–81. Taubes G. The breast screening brawl. Science 1997; 275: 1056–59. Wright CJ, Mueller CB. Screening mammography and public health policy: the need for perspective. Lancet 1995; 346: 29–32. Baum M. Screening for breast cancer: time to think and stop? Lancet 1995; 346: 436. Miller AB, To T, Baines CJ, Wall C. Canadian National Breast Screening Study 2: 13 year results of a randomized trial in women aged 50-59 years. J Natl Cancer Inst 2000; 92: 1400–09. Horton R. Screening mammography—an overview revisited. Lancet 2001; 358: 1284–85. Ernster VL, Barclay J. Increase in ductal carcinoma in situ (DCIS) of the breast in relation to mammography: a dilemma. Natl Cancer Inst Monogr 1997; 22: 151–56. Elmore JG, Barton MB, Moceri VM, Polk S, Arena PJ, Fletcher SW. Ten year risk of false positive screening mammograms and clinical breast examinations. N Engl J Med 1998; 338: 1089–96. Kerlikowske K, Ernster VL. Women should be fully informed of the potential benefit and harm before screening mammography. West J Med 2000; 173: 313–14. Baltic S. Analysis of mammography trials renews debate on mortality reduction. J Natl Cancer Inst 2001; 93: 1678–79. Black WC, Haggstrom DA, Welch HG. All cause mortality in randomised trials of cancer screening. J Natl Cancer Inst 2002; 94: 167–73. Juff HG, Tannock IF. Screening trials are even more difficult than we thought they were. J Natl Cancer Inst 2002; 94: 156–57. Gøtzsche PC, Olsen O. Is screening for breast cancer with mammography justifiable? Lancet 2000; 355: 129–34. Olson O, Gøtzsche PC. Cochrane review on screening for breast cancer with mammography. Lancet 2001; 358: 1340–42. Brown D. UK death rates from breast cancer fall by a third. BMJ 2000; 321: 849. Chu KC, Tarone RE, Kessler LG, et al. Recent trends in US breast cancer incidence, survival and mortality rates. JNCI 1996; 88: 1571–79. Peto R, Boreham J, Clarke M, Davies C, Beral V. UK and USA breast cancer deaths down 25% in year 2000 at ages 20–69 years. Lancet 2000; 355: 1822.
THE LANCET • Vol 359 • March 16, 2002 • www.thelancet.com
Dystrophin-associated protein complex and heart failure See page 936 Dystrophin is a member of the dystrophin-associated protein complex that includes the ␣ and  forms of dystroglycan and the ␣, , ␥, and ␦ forms of sarcoglycans (figure). ␣-dystroglycan is extracellular, linking laminin-2 with transmembrane -dystroglycan. Intracellularly the C-terminus of dystrophin links to -dystroglycan and the N-terminus to ␥-actin and talin, connecting the extracellular matrix with the cytoskeleton. The report by Matteo Vatta and colleagues in this issue of The Lancet demonstrates in human failing myocardium that immunofluorescence changes occur in the N-terminus region of dystrophin. This alteration in dystrophin, propose the authors, may be a final common pathway for contractile dysfunction, which is reversible by a reduction of mechanical stress. As they discuss, dystrophin-associated protein complex has been implicated in various cardiac diseases that present as dilated cardiomyopathies. Deficiencies of dystrophin or sarcoglycans may be the primary cause of congenital dilated cardiomyopathy.1 Cleavage of dystrophin by protease 2A is a primary cause of viral dilated cardiomyopathy.2 Vatta and colleagues raise the question of whether alterations in the N-terminal region of dystrophin cause contractile dysfunction or are they a manifestation of contractile dysfunction? Alterations in the N-terminus of dystrophin in most patients with end-stage failure, due to idiopathic and ischaemic cardiomyopathy, suggest that dystrophin-associated lesions occur secondary to failure. Ischaemic cardiomyopathy results from ischaemic infarct-associated loss of myocardium with scarring and ventricular remodelling. Thus defects in dystrophin are not a primary cause of heart failure. However, if the failing heart alters dystrophin (or other members of the dystrophin-associated protein complex) in a manner that reduces the mechanical efficiency of contraction, a vicious cycle might ensue that could be broken by a reduction of ventricular load. Such a reduction could then reverse myocyte hypertrophy and interstitial fibrosis, and restore function of the N-terminal region of dystrophin. Primary structural functions of dystrophin are to link the cytoskeleton of the cell to the extracellular matrix and to
Dystrophin-associated protein complex Extracellular matrix ␣-dystroglycan -dystroglycan
␣
 ␦
Sarcolemma
Sarcoglycans C-terminal
Signal transduction? Dystrophin N-terminal Cytoskeleton Linkage of extracellular matrix to cytoskeleton by dystrophin-associated protein complex provides mechanical stability for sarcolemma to resist contractile and osmotic stresses. Dystrophin-associated protein complex might also function as signal-transduction module, linking mechanical stresses in sarcolemma to protein kinase pathways.
905
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
The mammography screening debate: time to move on See page 909 Last year at an oncology meeting in Cambridge (UK), a 53year-old American journalist confessed that she had not yet had a mammogram because she could not get a clear answer about its usefulness. She had read the research articles, talked to doctors on both sides of the Atlantic and both sides of the debate, and was still baffled. She is not alone. The literature on screening mammography provides ample opportunity for confusion and dogma, and can be interpreted to prove both benefit and harm. Is there a clear answer about whether a mammogram does affect mortality? An overview in the The Lancet this week gives further information. Lennarth Nyström and colleagues present 15·8-year data from the four Swedish randomised trials of screening mammography. The results of the included trials have been previously presented individually, used in meta-analyses of screening efficacy, and cited as a rationale for national screening programmes.1-7 With 247 010 women enrolled, these trials provide a database with long-term follow-up from which estimates of the efficacy of an invitation to screening mammography compared with no specific screening intervention can be derived. The trials were all population-based but differed in randomisation methods, ages of women included, number of radiological views, and intervals between screening assessments. The overall effect was 511 breast cancer deaths in 1 864 770 women-years of follow-up among women invited to screening, and 584 breast cancer deaths in 1 688 440 women-years in the controls. This translates into a statistically significant reduction in breast cancer mortality of 21% (relative risk 0·79, 95% CI 0·70–0·89). Nyström and colleagues provide data of sound quality that demonstrate the magnitude and age-specific effects of screening on breast cancer mortality. The benefits appear real but modest. Despite the reduction in breast cancer mortality, overall (all-cause) mortality showed a relative risk of just 0·98 (0·96–1·00) between the invited and control groups. How does this help the clinician and women who in recent years have been bombarded by media and scientific claims for and against screening mammography?8-11 Mammographic screening identifies small cancers several years before they can be detected by palpation. Clinicians, statisticians, health-care economists, and editors12 of major medical journals should recognise that the natural history of breast cancer tells us that avoiding deaths from breast cancer can only be measured many years and even decades after the start of screening. Confirmation of the stability of the reductions in breast cancer mortality over time is perhaps the most useful contribution of the paper by Nyström and colleagues. Critics of screening have cited fear, the increased diagnosis of in-situ disease, and the high number of false positives as harmful by-products of screening.13-15 The latest overview by Nyström and colleagues cannot address these issues. 904
From the latest overview, different levels of benefit and varied conclusions can be reached depending on how the 10-year age groups are defined. For example, women aged 45–54 years seemed to have the least benefit. However, when analysed by traditional decade cohorts (40–49, 50–59, &) it could be concluded that mammography was similarly beneficial across all age groups between age 40 and 74. Is this a reflection of reduced screening efficacy around the age of menopause due to hormonal changes, or is it simply a statistical variation? In recent weeks there has been considerable debate in academic journals about the issue of all-cause mortality in screening programmes,16–18 and the latest overview does address the possible biases and under-counting of mortality caused by screening. The 2·3% reduction of total mortality is reassuring and the small effect is not unexpected for a disease that contributes only modestly to all-cause mortality. The latest analysis does not tell us whether the massive effort to develop screening programmes3 in at least 22 countries and to encourage participation is worthwhile. That issue must be honestly confronted by those organisations and individuals with an interest in maintaining programmes for mammography screening. The extensive information in the latest overview about the selection and randomisation of the women goes a long way to address the concerns raised by Gøtzsche and Olsen.19,20 In addition, the overview by Nyström and colleagues, based on trial participant-specific data and outcomes, is methodologically a more robust meta-analysis than pooling of previously published data. There has been a reduction in breast cancer mortality of nearly 30% since 1990.21-23 How much of this is due to screening and early diagnosis and how much to improved therapy? During the era when most women were being accrued to the trials contributing to the latest analysis, systemic therapy was just beginning to be adopted and certainly was not as commonly used as today, when most women with breast cancer receive some sort of adjuvant systemic therapy. It is not known whether the benefits of screening and adjuvant therapy are additive. Populationbased analyses to tease out the relative effects of screening and treatment are needed. So where does this overview leave clinicians and women? What should the confused journalist be told? Both the American Society for Clinical Oncology and the PDQ group, which feeds into the US National Cancer Institute, are currently looking again at screening mammography. The latest analysis by Nyström and colleagues reassures us that the Swedish data are believable and that they can be used to develop guidelines and assist individual women to make informed health-care choices. The data confirm that screening mammography has a real but modest effect to decrease mortality from breast cancer and that this effect varies with age. The data confirm that women who are otherwise well, especially those aged 55–69 years, and who
THE LANCET • Vol 359 • March 16, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
are concerned about breast cancer should be encouraged to attend screening. Partly because of the controversy around mammography screening, less than half of such women, the age group most likely to benefit, access this service on a regular basis in many western countries. The focus of screening should be to ensure these women attend about every 2 years. Although individual younger women may benefit, debate continues on the size of the effect for women aged under 50. Since breast cancer accounts for only about 4% of all deaths annually, even a 21% reduction in breast cancer mortality is barely measurable when allcause mortality is the endpoint. It is time for the angst about breast cancer to move from screening to questions of molecular diagnoses, aetiology, selection of optimum therapy, and improved survival for women in a more timely and cost-effective way. *Karen A Gelmon, Ivo Olivotto *British Columbia Cancer Agency-Vancouver Cancer Centre, Vancouver BC, Canada V5Z 4E6; and BC Cancer Agency-Vancouver Island Centre, Victoria, BC, Canada (e-mail: [email protected]) 1
2
3 4
5
6
7 8 9 10 11
12 13
14
15
16 17
18 19 20 21 22 23
Nyström L, Rutqvist LE, Wall S, et al. Breast cancer screening with mammography: overview of Swedish randomised studies. Lancet 1993; 341: 973–78. Shapiro S, Coleman EA, Broeders M, Codd M, de Koning H, Fracheboud J. Breast cancer screening programs in 22 countries: current policies, administration and guidelines. Int J Epidemiol 1998; 27: 735–42. Kerlikowske K, Grady D, Rubin SM, Sandrock C, Ernster VJ. Efficacy of screening mammography: a meta-analysis. JAMA 1995; 273: 149–54. Kerlikowske K. Efficacy of screening mammography among women aged 40–49 years and 50–69 years: comparison of relative and absolute benefit. Natl Cancer Inst Monogr 1997; 22: 79–86. Hendrick RE, Smite RA, Rutledge JH, Smart CR. Benefit of screening mammography in women aged 40-49: a new meta-analysis of randomized controlled trials. Natl Cancer Inst Monogr 1997; 22: 87–92. Smart CR, Hendrick RE, Rutledge JH, Smith RA. Benefit of mammography screening in women ages 40–49 years: current evidence from randomized controlled trials. Cancer 1995; 75: 1619–26. De Koning HJ. Assessment of nationwide cancer screening programmes. Lancet 2000; 355: 80–81. Taubes G. The breast screening brawl. Science 1997; 275: 1056–59. Wright CJ, Mueller CB. Screening mammography and public health policy: the need for perspective. Lancet 1995; 346: 29–32. Baum M. Screening for breast cancer: time to think and stop? Lancet 1995; 346: 436. Miller AB, To T, Baines CJ, Wall C. Canadian National Breast Screening Study 2: 13 year results of a randomized trial in women aged 50-59 years. J Natl Cancer Inst 2000; 92: 1400–09. Horton R. Screening mammography—an overview revisited. Lancet 2001; 358: 1284–85. Ernster VL, Barclay J. Increase in ductal carcinoma in situ (DCIS) of the breast in relation to mammography: a dilemma. Natl Cancer Inst Monogr 1997; 22: 151–56. Elmore JG, Barton MB, Moceri VM, Polk S, Arena PJ, Fletcher SW. Ten year risk of false positive screening mammograms and clinical breast examinations. N Engl J Med 1998; 338: 1089–96. Kerlikowske K, Ernster VL. Women should be fully informed of the potential benefit and harm before screening mammography. West J Med 2000; 173: 313–14. Baltic S. Analysis of mammography trials renews debate on mortality reduction. J Natl Cancer Inst 2001; 93: 1678–79. Black WC, Haggstrom DA, Welch HG. All cause mortality in randomised trials of cancer screening. J Natl Cancer Inst 2002; 94: 167–73. Juff HG, Tannock IF. Screening trials are even more difficult than we thought they were. J Natl Cancer Inst 2002; 94: 156–57. Gøtzsche PC, Olsen O. Is screening for breast cancer with mammography justifiable? Lancet 2000; 355: 129–34. Olson O, Gøtzsche PC. Cochrane review on screening for breast cancer with mammography. Lancet 2001; 358: 1340–42. Brown D. UK death rates from breast cancer fall by a third. BMJ 2000; 321: 849. Chu KC, Tarone RE, Kessler LG, et al. Recent trends in US breast cancer incidence, survival and mortality rates. JNCI 1996; 88: 1571–79. Peto R, Boreham J, Clarke M, Davies C, Beral V. UK and USA breast cancer deaths down 25% in year 2000 at ages 20–69 years. Lancet 2000; 355: 1822.
THE LANCET • Vol 359 • March 16, 2002 • www.thelancet.com
Dystrophin-associated protein complex and heart failure See page 936 Dystrophin is a member of the dystrophin-associated protein complex that includes the ␣ and  forms of dystroglycan and the ␣, , ␥, and ␦ forms of sarcoglycans (figure). ␣-dystroglycan is extracellular, linking laminin-2 with transmembrane -dystroglycan. Intracellularly the C-terminus of dystrophin links to -dystroglycan and the N-terminus to ␥-actin and talin, connecting the extracellular matrix with the cytoskeleton. The report by Matteo Vatta and colleagues in this issue of The Lancet demonstrates in human failing myocardium that immunofluorescence changes occur in the N-terminus region of dystrophin. This alteration in dystrophin, propose the authors, may be a final common pathway for contractile dysfunction, which is reversible by a reduction of mechanical stress. As they discuss, dystrophin-associated protein complex has been implicated in various cardiac diseases that present as dilated cardiomyopathies. Deficiencies of dystrophin or sarcoglycans may be the primary cause of congenital dilated cardiomyopathy.1 Cleavage of dystrophin by protease 2A is a primary cause of viral dilated cardiomyopathy.2 Vatta and colleagues raise the question of whether alterations in the N-terminal region of dystrophin cause contractile dysfunction or are they a manifestation of contractile dysfunction? Alterations in the N-terminus of dystrophin in most patients with end-stage failure, due to idiopathic and ischaemic cardiomyopathy, suggest that dystrophin-associated lesions occur secondary to failure. Ischaemic cardiomyopathy results from ischaemic infarct-associated loss of myocardium with scarring and ventricular remodelling. Thus defects in dystrophin are not a primary cause of heart failure. However, if the failing heart alters dystrophin (or other members of the dystrophin-associated protein complex) in a manner that reduces the mechanical efficiency of contraction, a vicious cycle might ensue that could be broken by a reduction of ventricular load. Such a reduction could then reverse myocyte hypertrophy and interstitial fibrosis, and restore function of the N-terminal region of dystrophin. Primary structural functions of dystrophin are to link the cytoskeleton of the cell to the extracellular matrix and to
Dystrophin-associated protein complex Extracellular matrix ␣-dystroglycan -dystroglycan
␣
 ␦
Sarcolemma
Sarcoglycans C-terminal
Signal transduction? Dystrophin N-terminal Cytoskeleton Linkage of extracellular matrix to cytoskeleton by dystrophin-associated protein complex provides mechanical stability for sarcolemma to resist contractile and osmotic stresses. Dystrophin-associated protein complex might also function as signal-transduction module, linking mechanical stresses in sarcolemma to protein kinase pathways.
905
For personal use. Only reproduce with permission from The Lancet Publishing Group.