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RESEARCH AND PRACTICE |
Gabriel M. Leung, Tai-Hing Lam, Thuan Q. Thach, and Anthony J. Hedley are with the Department of Community Medicine, University of Hong Kong Medical Centre, Hong Kong.
Correspondence: Requests for reprints should be sent to G. M. Leung, MD, MPH, Department of Community Medicine, 21 Sassoon Road, Patrick Manson Building, University of Hong Kong, Pokfulam, Hong Kong (e-mail: gmleung{at}hku.hk).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSCONCLUSIONSReferences |
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Objectives. We sought to systematically review the evidence for population-based mammography as applied to a Chinese population.
Methods. Primary reports for meta-analysis were identified by a search of MEDLINE and the Cochrane Library. Outcome measures included breast cancer–related mortality, the number needed to be screened to prevent 1 death, and the positive predictive value of mammography.
Results. Pooled relative risk for breast cancer–related death in the screened group was 0.80 (95% confidence interval = 0.71, 0.90). Applied to Hong Kong, this figure translates into a number needed to screen of 1 302 healthy women screened annually for 10 years to prevent 1 death. Conclusions. Evidence is insufficient to justify population-based breast cancer screening by mammography for women in Hong Kong and other Asian populations with low breast cancer prevalence.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSCONCLUSIONSReferences |
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We have reviewed the evidence for population-based screening for early breast cancer detection and examined the applicability of these results to a Chinese population. We first performed an updated systematic review and meta-analysis of clinical trials evaluating mammography screening. We then applied these results to women in Hong Kong, where 95% of the resident population are ethnic Chinese.4 We restricted our attention to mass screening at the population level, rather than issues relating to opportunistic screening or case finding. We also only examined this issue in women aged at least 50 years, given the lack of proven efficacy in screening women younger than 50 years, even in Western populations.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSCONCLUSIONSReferences |
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Two authors (G. M. L. and T. Q. T.) independently reviewed these 88 papers to identify studies that met eligibility criteria for inclusion in the meta-analysis. Inclusion criteria required: (1) an experimental RCT design that measured clinical endpoints, including breast cancer–related mortality; (2) a duration of follow-up lasting 5 years or more and a minimum of 10 breast cancer deaths; and (3) the reporting of relative risk (RR) or an odds ratio (OR) with 95% confidence intervals (CI), or data that would allow their calculation. We excluded studies that involved exclusively women younger than 50 years at the time of recruitment, were published in languages other than English or only in abstract form, or that enrolled primarily symptomatic patients with breast lumps, pain, nipple discharge, or enlarged lymph nodes.
Of 24 references that satisfied these criteria, we excluded 16 because of multiple publications from the same study. Thus, 8 articles from 7 studies were finally selected for quantitative pooling of results.5–12 The same 2 authors separately abstracted the relevant data. Disagreement was settled by consensus. For studies that reported more than 1 set of results due to updating of findings from longer periods of follow-up, we used the latest results published. A meta-analysis was performed using DerSimonian and Laird’s13 random effects model, Greenland’s14 fixed effects model, and Peto’s15 assumption-free method.
A test for heterogeneity was performed. Because the power of statistical tests of heterogeneity is low, a relatively high critical value for P of 0.2 was selected a priori to avoid underestimating the presence of heterogeneity.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSCONCLUSIONSReferences |
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). Based on the random effects model, the pooled relative risk was 0.80 (95% CI = 0.71, 0.90) for women invited for mammographic screening (Figure 1). Sensitivity analysis revealed that this estimate was robust with similar findings using the fixed effects model (RR = 0.81; 95% CI = 0.74, 0.88) and with the Peto assumption-free method (RR = 0.81; 95% CI = 0.74, 0.88). Our results were similar to those of a 1995 meta-analysis of the 8 primary trials (this review also included the Canadian National Breast Screening Study [CNBSS] I study involving exclusively women aged 40–49 years) under the fixed effects model (where RR = 0.79; 95% CI = 0.71, 0.87).16 A P value for heterogeneity of .14 indicated the appropriateness of the random effects model, which yielded a slightly wider confidence interval than the fixed effects model.15
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Geo-ethnic differences in breast cancer epidemiology.
Figure 2 shows the estimated age-specific incidences of breast cancer for the age group 50–69,19 comparing the rates of Asian regions with those of White populations from Canada, Scotland, Sweden, and the United States, where the primary studies were performed. There is a 1- to 2-fold difference in breast cancer risk between Asian women and North Americans and Europeans, on whom the original screening trials were carried out.19 These differences indicate that the positive predictive value (PPV) of any test, which depends on the underlying disease rates in the screened population, will be much lower in Asian regions than in the West.
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In Hong Kong, there were 868 new cases of breast cancer for women aged 50 years or more in 1996, an incidence of 123.3 per 100 000.24 From the International Agency for Research on Cancer’s GLOBOCAN database, we obtained corresponding rates per 100 000 of 361.6 (White) and 283.5 (Black), 299.5, 277.4, and 255.1 for the United States, Canada, Sweden, and the UK, respectively19 (arithmetic mean = 295.4 per 100 000). Assuming a linear relationship between prevalence ratio (P) and incidence rate (I), as per the formula D/(N–D) 
I, where N is the size of the population at risk for the disease, D the subset of the population with the disease, and D/(N–D) is the prevalence ratio,25 and a consistent relationship across different population groups (Western and Chinese women), we estimated Hong Kong’s breast cancer prevalence at screening to be around 146.1 per 100 000, according to the formula PWest/IWest = PHK/IHK.
Using the optimal ranges of sensitivity (83%–95%) and specificity (93.5%–99.1%) reported in a recent meta-analysis,21 the PPV for Hong Kong women ranges from 1.8% to 13.4%, assuming regular annual screening in those aged 50 years or more. So we would expect at least 86%, and as many as 98%, of positive screens to be false positives. In practice, we anticipate that the accuracy would be lower than these quoted ranges from trials. Because the average Chinese breast has a smaller volume (224.5 cm3 vs 585.1 cm3 in British women) and is denser with less fat content compared with Caucasians’ breasts,26,27 we believe that the true sensitivity and specificity in Hong Kong would correspond to the minimum values of these ranges.
Number needed to screen. The results of most clinical trials are presented as relative risk reductions but do not take into account the role of event rate or incidence of disease on overall clinical benefit. Statistical significance is often regarded as an index of clinical relevance, ignoring the effect of sample size on significance. Number needed to screen (NNS) is defined as the number of people that need to be screened to prevent 1 death or 1 adverse event.28 We calculated the NNS for breast cancer–related mortality for screening, using Hong Kong women aged 50 years or more in 1996, in whom there were 270 breast cancer–related deaths—a mortality rate of 38.4 per 100 000.24,29 Applying the pooled relative risk reduction from our meta-analysis, we estimated the absolute risk reduction of breast cancer–related mortality to be 0.106% over a screening period of 13.8 years and the NNS to be 1302 (95% CI = 898, 2604) women for 10 years to prevent 1 case of breast cancer death. This estimate compares unfavorably with the corresponding 10-year NNS of 666 in US women (the 1996 mortality rate for US women aged 50 years or more was 83.4 per 100 00030).
This extrapolation is valid only if we assume that the relative risk reduction observed in Western trials is independent of the baseline risk for developing breast cancer.31 Adjusting the NNS or number needed to treat for the baseline risk of the patient population implies, as underlined by Cook and Sackett,32 that the relative risk reduction is constant for all levels of disease incidence. Such an assumption may be valid for some diseases, such as hypertension treatment to prevent stroke,33 but not for others. For instance, in the overview of the effects of coronary artery bypass graft in patients with stable coronary artery disease, the relative risk reductions associated with surgery, instead of being equal to 39% in each third of risk, were around 45% in both the middle and highest thirds of risk, whereas there was a 17% relative risk increase in the lowest third.34 Therefore, there is a possibility that we may have underestimated the NNS to save 1 breast cancer–related death.
We used cancer statistics from 1996 for breast cancer incidence and mortality because they were the latest and the highest age-standardized numbers available. There is currently no population-based screening program for breast cancer in Hong Kong, only periodically advertised services in isolated hospitals and laboratory facilities since 1993. The intervening 3 years would not have allowed sufficient time for any effects of sporadic screening to influence breast cancer population statistics.35 So the PPV and NNS results derived from the 1996 statistics would not have been affected by widespread opportunistic screening, and may be biased toward higher PPV and lower NNS estimates.
Natural history of breast cancer. A dramatic increase in the incidence of ductal carcinoma in situ (DCIS) in asymptomatic women has been reported, coinciding with the widespread adoption of screening mammography. In the United States, the total recorded number of DCIS cases in 1992 was 200% higher than expected, based on rates in 1983 when mammographic screening became widespread36 according to trends between 1973 and 1983. In Hong Kong, similar findings were made in an audit of a hospital’s screening program.37 Of the asymptomatic, nonpalpable malignancies detected through mammography, 53% were DCIS, with the remainder being invasive cancer.37 Whereas early detection of invasive cancer has been shown to be beneficial in terms of survival, the prognostic value of DCIS detection is currently unknown. Increasing evidence suggests that most DCIS cases never progress to the invasive stage during a woman’s lifetime.38–43 Earlier autopsy studies first proposed this view,40–43 later supported by the large population-based Surveillance, Epidemiology, and End Results (SEER) program, in which the absolute risk of dying from breast cancer among women with DCIS was found to be very low (1.9% within 10 years).39 Miller et al.6 argued that the excellent survival (87.5% alive at 10 years) of women with DCIS and early impalpable invasive cancer in CNBSS II was almost certainly due to a combination of lead time and length bias. In the light of this, it is prudent to wait for more definitive evidence regarding improvements in survival from screening before recommending mass mammography in Hong Kong. For women who proceed with opportunistic screening in the meantime, we should at least inform them of the likelihood of being diagnosed with DCIS before mammographic examination, and that only some DCIS cases may be clinically significant.
Balance of benefit, harm and cost. The discussion of whether to screen cannot be limited to statistical validation of tests and histological staging of cancer types. We must also consider the harm inflicted by screening. Even though it is not known whether detection of DCIS actually contributes to lower mortality, it is clear that almost all women with mammographically detected DCIS undergo disfiguring operations. In the US SEER program, between 1983 and 1992, 43.8% of DCIS cases were treated with mastectomy and 53.3% with lumpectomy.36
High rates of false positivity are an important concern in screening mammography. Elmore et al.44 reported a 49.1% cumulative false-positive risk, and an 18.6% rate of biopsy in healthy women after 10 mammograms. They estimated that for every $100 spent on screening, an additional $33 was spent to evaluate these false-positive results. A positive screen inevitably leads to further confirmatory studies, ranging from a repeat mammogram to a fine-needle aspiration biopsy, or an open biopsy. The anxiety and psychological trauma associated with these interventions can be considerable.45
Women in a screening program deserve to know the complication rates of between 8%–10%46–48 for fine needle aspiration and open biopsy, because many will be subject to these investigations, given their low PPV of 1.8% to 13.4%. Complications ranged from prolonged bleeding and hematoma formation, to abscess and wound dishesion.46,48
The net balance of benefit, harm, and cost can be summarized for every 100 000 Hong Kong Chinese women aged 50 years or more screened annually for 10 years (Figure 3). With the best-case scenario of a sensitivity of 95% and specificity of 99.1% and a prevalence at screening of 146.1 per 100 000, we would expect 10 370 "positive" results, 8980 of which would be false-positive cases. Biopsies for 18.6%44 of women with false positives with a complication rate of 8%46–48 would lead to an avoidable iatrogenic adverse event in 134; however, according to our 10-year NNS estimate, fewer than 77 breast cancer–related deaths would have been avoided, even assuming optimal trial conditions with 100% uptake and follow-up. In practice, the number of lives saved as a result of screening is likely to be much smaller where uptake by and follow-up of women are often less than optimal.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSCONCLUSIONSReferences |
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There is an ongoing clinical trial in Singapore, mostly in Chinese women, to evaluate the efficacy of mammography screening in 50- to 64-year-old women. Although intermediate results are reported favorably, enrolled women have yet to be followed for a sufficiently long period to examine the relevant outcomes such as mortality reduction.22 Until then, health care professionals must maintain the ethical position of equipoise and counsel patients about both the potential benefits and hazards of screening.
Asian health systems should pay particular attention to the West’s experience with mammographic screening programs. Olsen and Gotzsche49 have recently raised serious doubts about the scientific validity of most of the original trials that led Western governments to promote organized screening. They, and the accompanying Lancet editorial,50 concluded that there was "no reliable evidence that screening for breast cancer reduces mortality." Now the Swedish, Canadian, and British national screening programs, among others, are facing the dilemma of whether to carry on an unproven clinical activity or to stop and dismantle the screening infrastructure they have worked so hard to put in place. As Wilson and Jungner18 cautioned 3 decades ago, screening should not be initiated until there is absolute, solid evidence supporting its effectiveness because organized programs are almost impossible to undo and stop. The East must not repeat the mistake of the West.
Our discussion has only dealt with mass, population-based mammographic screening of well women. For those at high risk for the disease, careful individual clinical assessment should guide the need for and frequency of mammographic screening. We suggest resources that may be allocated for a comprehensive population screening program in Asian populations would be better directed at raising public awareness of the issues exposed here, along with case-finding in targeted high-risk groups where mammography may be a truly beneficial, and necessary, intervention.
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Acknowledgments |
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Human Participant Protection
No institutional review board approval was needed for this study.
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Footnotes |
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Accepted for publication December 13, 2001.
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References |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSCONCLUSIONSReferences |
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