Correspondence to: Russell Harris, MD, MPH, Cecil G. Sheps Center for Health Services Research, University of North Carolina, Chapel Hill, NC 27599-7590 (e-mail: rharris{at}med.unc.edu).
The discussion about breast cancer screening has changed. Yesterday's question was about efficacywhether screening, under ideal circumstances, can reduce breast cancer mortality. Today's discussion is about a different question, effectiveness. To what extent is current screening, under usual conditions within the community, reducing mortality from breast cancer? The second question may prove to be as complex as the first.
The efficacy discussion largely concerned the internal validity of the eight randomized controlled trials (RCTs) of screening that were conducted between the mid-1960s and the mid-1980s. For the most part (there are still a few lingering issues), the question of efficacy is resolved. Careful observers, while acknowledging the presence of some bias in the RCTs, have concluded that the magnitude of these biases is not sufficient to invalidate the primary results of these trials, that periodic mammography, with or without clinical breast examination, reduces breast cancer mortality for women between 50 and 74 years of age. For women between the ages of 40 and 49 years, the absolute reduction in breast cancer mortality due to screening gradually increases over this decade of life, only appearing several years longer after the initiation of screening than for older women. Decision-makers must weigh these benefits against the harms of false-positive tests, overdiagnosis, and overtreatment. A meta-analysis of the RCTs for the U.S. Preventive Services Task Force found a 15% reduction in the risk of dying of breast cancer in the screened group (summary relative risk [RR] = 0.85, 95% credible interval [CrI] = 0.73 to 0.99) for women aged 4049 years after an average of 14 years of observation. For women aged 5074 years, the reduction was 22% (summary RR = 0.78, 95% CrI = 0.70 to 0.87) over the same period of observation (1).
Now that widespread screening has been under way for more than 15 years, the discussion has turned to the issue of effectiveness. This issue requires us to consider whether the RCTs have external validity for the general population, and to develop new evidence about the effects of current screening practices within the community. To what extent is widespread screening in the United States in 2005 contributing to reducing breast cancer mortality?
In this issue of the Journal, Elmore et al. (2) contribute to the effectiveness literature with an innovative casecontrol study of screening for breast cancer under usual conditions in six highly rated health plans in five statesone type of "real world" population. Using automated data systems, the investigators identified 1351 "case subjects" (women aged 4065 years who had died of breast cancer) and matched to them 2501 "control subjects" (women who had not been diagnosed with breast cancer). If screening does in factin these communities at this timeprotect women from dying from breast cancer, the case subjects would have undergone less prior screening than the control subjects. Previous casecontrol studies have shown a mortality benefit associated with breast cancer screening. For example, three European casecontrol studies published in the mid-1980s found that screening was associated with a reduced risk of dying of breast cancer of 40%70% (37).
Overall, however, Elmore et al. (2) found little difference in prior screening between case and control subjects. After adjustment for important covariates, the overall odds ratio (OR) of the association between prior screening and breast cancer mortality was 0.91 (95% confidence interval [CI] = 0.78 to 1.07). For women in their 40s, the odds ratio was 0.92 (95% CI = 0.76 to 1.13) and for women 5065 years old, it was 0.87 (95% CI = 0.68 to 1.12). None of these odds ratios show a statistically significant association between prior screening and breast cancer mortality, although the confidence intervals are fairly wide.
It is interesting that the authors also analyzed their data by breast cancer risk subgroups (average risk versus increased risk). They found that in both age groups, the association between prior screening and breast cancer mortality was stronger for women at increased risk than for women at average risk, although the differences in the odds ratios between the risk groups were not statistically significant.
In general, casecontrol studies are subject to greater threats to their internal validity than RCTs; bias is always a possible explanation for the results. But the study by Elmore et al. was particularly well conceived and conducted, and it was designed to mimic an RCT to the extent possible. The authors also analyzed their data in various ways to search for possible biases that would explain their largely negative results. It is therefore likely that the study is internally valid.
The study's biggest flaw is its limited power to detect small differences in the odds of screening between groups. The study was designed to have 80% power to detect an odds ratio of 0.75 or lower for screened versus unscreened women, not the weaker association it actually found. The study included case subjects who were diagnosed with breast cancer as early as 1983, well before screening was widespread. Thus, mammography screening rates in all of the groups were relatively low, contributing to the study's limited power. The weak associations (OR of 0.92 for women in their 40s and the OR of 0.87 for women aged 5065) could be real or due to random error. The authors wisely caution us not to overinterpret the results.
If the study by Elmore et al. does not resolve the issue of the effectiveness of screening within the community, it does raise at least three important questions about our current use of screening. First, could breast cancer screening be making a smaller contribution to the reduction of breast cancer mortality than the RCTs would lead us to believe? In other words, could effectiveness be less than efficacy? At least two issues may attenuate the effects of breast cancer screening in the community compared with those detected by the RCTs: implementation and contextual factors. Issues of implementation involve problems with such factors as patient nonadherence to screening, lack of access to screening, inaccurate screening, inadequate follow-up of abnormal screening tests, and inadequate short- and long-term treatment of women found to have breast cancer. In the real world outside of research studies, all of these problems probably exist to some extent; each could contribute to a reduction of the effectiveness of screening in the community.
A second issue that may attenuate the effects of screening when it is transferred to the community setting is contextual factors. The context for screening today is very different than it was during the era of the RCTs. First, women's risks for breast cancer may have changed because of differences in the levels of postmenopausal hormone use and the greater number of women who are overweight or obese. Second, women's awareness of the importance of small breast lumps found accidentally has changed. Thus, "background detection" has improved; an unscreened control group in an RCT of screening today would likely present with less advanced cancers than the control groups in RCTs in the past. Third, breast cancer treatment has markedly improved. Both hormonal and multiagent chemotherapy reduce breast cancer mortality (8); there are new agents being used, and the older agents are given in different ways than they were 20 years ago. Better treatment may mean that screening is less necessary than it was previously, because treatment of later stage cancers may still be effective.
The second question raised by the Elmore et al. study is, "Could we have a major impact on breast cancer mortality by focusing screening on women who are at increased risk of the disease?" Elmore et al. raise the issue of whether breast cancer screening may be more efficacious in women at increased risk of breast cancer. Even if the efficacy of screening were greater in women who are at increased risk, however, most breast cancers would still come from the group of women not at increased risk (9). The strategy of focusing screening on women at increased risk would be enhanced by improvements in our ability to assign risk. Targeted screening may gain importance in the future if we are able to target better.
The third question raised by the Elmore et al. study is, "Where should future research on breast cancer screening focus?" Elmore et al. label their study an efficacy study, yet it gives us information about effectiveness as well. They report data from a community population within functioning health plans that received no extra resources to participate in a research study. This is the aspect of the study that reflects the effectiveness of screening. Yet the casecontrol design also includes aspects of efficacy studies. Because casecontrol studies measure actual screening and do not take nonadherence (in the screening group) or contamination (in the control group) into account, they often find an association between exposure and mortality that is more extreme than that found in RCTs of the same issue (10).
Few studies provide pure evidence about efficacy or effectiveness. Moreover, the terms efficacy and effectiveness are imprecise because they represent two extreme poles on a continuum rather than a dichotomous classification. Most studies have some aspects of efficacy and some aspects of effectiveness; the study by Elmore et al. is no exception.
The results reported by Elmore et al. are consistent with a 20% or greater reduction in breast cancer mortality associated with screening. But this result is less likely than a much smaller effector no effect. Because of this uncertainty about interpretation, the study should not change our practicebut it should influence our research. It is time to emphasize research on the effectiveness of screening as currently practiced in the community.
The effectiveness discussion is taking place at an exciting time in the nation's battle against breast cancer. Breast cancer mortality is declining in the United States, as it is in other western countries. In 1990, the age-adjusted mortality rate for U.S. women was 33.2 deaths per 100 000 population. In 2002, the rate had fallen to 25.0 deaths per 100 000 population, a reduction of about 25% (11).
Much of the recent effectiveness research has focused on trying to explain this reduction in mortality (1222). Several ecologic and observational studies have compared breast cancer mortality in geographic areas before and after the start of a screening program. Other studies have compared breast cancer mortality in areas where screening has been more intense with that in areas where there has been less screening. These studies have produced variable results; some have attributed a 25% or larger reduction in breast cancer mortality to screening, whereas others have found that a smaller reduction is more likely. However, all of these studies had methodologic concerns. In particular, it has proven difficult to tease apart the effect of screening from the introduction of new and more effective treatment.
Making things even more complex is the understanding that the effectiveness of screening depends on factors that vary among countries and over time. The relationship between the population and the health care system; the country's philosophy toward avoiding false-positive tests, overdiagnosis, and overtreatment; the financing and coordination of the health care system; the interest of the health care system in quality improvement; and the contextual factors mentioned earlier are all likely to play a role in the degree to which screening actually does reduce breast cancer mortality in a given community.
Despite our preference for RCTs, effectiveness research sometimes demands study designs that are lower on the evidentiary hierarchy. We need ongoing ecologic analyses and large observational studies among countries and over time, using modeling to help us recognize and explain trends. Large and well-conducted casecontrol studies of the effects of screening in the real world also have an important role to play. This research agenda will require time and sustained effort.
Answering the effectiveness question is critically important. We need to recognize when issues of implementation (that can potentially be fixed) are limiting the effectiveness of our interventions. And we need to recognize when issues of context make a previously effective intervention no longer useful. The effectiveness question will not go away soon.
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