Decisions about cancer prognosis and therapy have historically been guided by anatomy — the size of the tumor and the extent of disease. However, it has become increasingly clear that the biologic characteristics of the tumor are more relevant to breast-cancer prognosis than the size of the tumor.7 Tumor size is, at best, a very crude manifestation of underlying biologic characteristics. A recent prospective trial involving women with breast cancer showed that the prognoses of those whose tumors had favorable molecular features were similar regardless of whether their tumors measured greater than or less than 2 cm.8 Although few clinicians would question that nodal status is a far better indicator of metastatic potential and biologic aggressiveness than tumor size, some even question whether advances in tumor biology will supplant the need to determine lymph-node status.9 However, while clinicians have moved on to focus on tumor biology, breast-cancer screening has remained rooted in anatomy.

The immediate focus of screening continues to be the detection of small lesions; in fact, the detection rate of so-called “minimal tumors” (i.e., invasive tumors measuring <1 cm or in situ carcinomas) is used as an indicator of the quality of mammography.10 However, the detection of additional small tumors is helpful only when it is accompanied by a reduction in the presentation of larger tumors. A reduction in the number of large tumors may, in turn, reduce the incidence of late-stage disease. Because tumor stage is a more important predictor of mortality than tumor size, trends in stage-specific incidence have been used in previous research that evaluated the effectiveness of screening.11-13 A reasonable concern was identified, however, that the disease stage (e.g., node-positive disease) may be subject to “upstaging” over time as technology and practice change (e.g., sentinel-node biopsy).14 To avoid the potentially confounding effect of disease-stage migration, we focused on tumor size, which has the advantage of being a metric that remains constant over time.

Our analysis of size-specific incidence highlights the fact that the introduction of screening mammography has produced a mixture of effects. A modest decrease in the incidence of large tumors (≥2 cm) was observed, which suggests that screening has had the desired effect of advancing the time of diagnosis of some tumors that were destined to become large. At the same time, a much larger increase in the incidence of small tumors (<2 cm) was observed, which suggests that screening has had the undesired effect of detecting tumors that otherwise would not have become clinically apparent. The magnitude of the imbalance indicates that women were considerably more likely to have tumors that were overdiagnosed than to have earlier detection of a tumor that was destined to become large.

Screening can result in the harm of overdiagnosis yet simultaneously result in the benefit of lower breast-cancer mortality. To focus on the effect of screening that would most likely reflect its benefit — a decline in the incidence of large tumors — we approximated the relative contribution of screening versus improved treatment to declining breast-cancer mortality. Because the rate of deaths averted as a result of a declining size-specific case fatality rate was larger than the rate of those averted as a result of the reduced incidence of large tumors, we conclude, as others have,15-19 that improved treatment must explain a majority of the reduction in mortality.

We should emphasize that our approximation of the contribution of screening mammography to the reduction in breast-cancer mortality is likely to be a highly favorable estimate. The screening-mediated reduction in the incidence of large tumors is unlikely to translate perfectly to a reduction in mortality. Screening can advance the time of diagnosis of a tumor, thereby detecting the tumor when it is still small, without changing its prognosis, a phenomenon termed “biologic predeterminism.” In particular, screening is known to selectively identify tumors that have favorable molecular features.20 Because tumors with favorable molecular features grow more slowly, they are disproportionately available to be detected by screening (so-called length-biased sampling). Thus, the expectation is that some tumors that are detected by screening when they are small would have favorable biologic characteristics and could have been treated equally effectively at clinical presentation.8 For this subset of tumors, earlier detection at a smaller size would not translate into a mortality reduction.

Furthermore, there are other reasons to believe that we have overstated the effect of screening relative to improved breast-cancer treatment. We attributed the observed shift in tumor-size distribution solely to screening mammography and did not take into consideration the possibility that women may have sought care earlier in the course of their disease. Indeed, evidence suggests that increased breast-cancer awareness in the general population has led women to present earlier with clinically evident disease than they did in the past.21 Finally, our analysis does not credit treatment for any improved prognosis in women with invasive tumors smaller than 2 cm. Although women with these small tumors have a generally favorable prognosis, 15 to 20% have node-positive disease, the category in which improved systemic therapy has exerted the greatest effect in declining breast-cancer mortality.22

Our findings are limited because a fundamental variable, the underlying true incidence of breast cancer (i.e., the true burden of disease), is unobservable. Observed breast-cancer incidence is influenced by observational intensity,23 which represents the combined effect of the frequency of screening, the resolution of the screening examination, and the threshold that is used to label the examination as abnormal. We assumed that the underlying incidence of breast cancer was unchanged and that the observed increase reflected the increased observational intensity associated with screening (information regarding a sensitivity analysis with alternative assumptions is provided in Section 4 in the Supplementary Appendix). Proponents of screening mammography have contended that the increase instead reflects genuine disease and that overdiagnosis has been greatly exaggerated.24 Those who postulate such substantial increases in underlying incidence, however, must explain why the increase coincides temporally with the introduction of screening, why the incidence of the most aggressive form of the disease — metastatic breast cancer — remains essentially unchanged,25 and why overdiagnosis is also evident in analyses that are based on a single point in time.26

There is no perfectly precise method to assess the population effects of cancer screening. Screening mammography performed in an asymptomatic population that has an average risk of cancer can, at best, have only a small absolute effect on cancer-specific mortality because the vast majority of women are not destined to die from the target cancer. Because the mortality effect is necessarily delayed in time, the availability of improving cancer treatment over time further complicates the assessment of the contribution of screening. Inferences regarding overdiagnosis are equally imprecise since overdiagnosis cannot be measured directly. Studies in which minimal overdiagnosis is reported are typically conducted under the assumption that all abnormalities that are given the pathologic diagnosis of cancer will, in fact, progress.27,28 Modeling all cancers as having lead time (i.e., as invariably progressing) ignores an important possibility, namely that some cancers are quiescent — or, in fact, regress.29 To avoid these problems, a recent review concluded that high-quality ecologic and cohort studies represent the best designs for investigating overdiagnosis.30

We do not pretend to present a precise estimate of either the amount of overdiagnosis or the contribution of screening mammography to the reduction in breast-cancer mortality. The data regarding size-specific incidence, however, make clear that the magnitude of overdiagnosis is larger than is generally recognized. Furthermore, the data regarding size-specific case fatality rate clarify that decreasing breast-cancer mortality largely reflects improved cancer treatment.