Our systematic review of 13 studies (14 datasets) in ten countries over six decades of 2363 autopsies and 99 cases of incidental cancer or neoplastic precursor lesions, found that incidental breast cancer and its precursors are common in women not known to have breast disease during life. The estimates from these autopsy studies represent the best available evidence to answer the important question on the size of the prevalence pool of incidental breast cancer and precursor lesions.

The majority of incidental lesions appear to be precursors for invasive cancer (cancer in-situ and atypical hyperplasia). However the smaller prevalence pool of incidental invasive cancers appeared easier to find, with even the least thorough studies reporting cases. Unlike invasive cancer which was unrelated to the number of sections submitted for pathology examination, the estimated prevalence of cancer in-situ and atypical hyperplasia was strongly related to the thoroughness of microscopic examination. The odds of finding in-situ cancer and atypical hyperplasia were 127 times and 21 times higher respectively, in the studies where at least 20 sections were examined compared to those where less than 20 sections were examined. We could find no other clear predictors, including age, although this may be attributed to a paucity of data on women ≥70 years.

Our study builds on the evidence from a previous systematic review of incidental cancer discovered at autopsy [16]. We included six of the seven studies in that review (we excluded one study [38] as those data were included in a later report [33]). Our sensitive search strategy uncovered a further six reports which were published at the time of the previous review, but not discovered by them. We also found one more recent study [25] which contributed 2 datasets. Pooling these data enabled us to report on the substantial prevalence pool of invasive cancer, situ-cancer and precursor lesions (ADH and ALH), and that the more thorough the microscopic examination, the more these lesions are discovered.

Autopsy rates are now much lower than previous decades; in addition, the widespread adoption of screening in many countries means that contemporary studies risk under-estimating the prevalence of incidental disease as much of this may have already been detected (and treated) during life. Although the primary studies were conducted over a long time period (from 1948 to 2010), all but one were conducted in largely unscreened populations. The most thorough studies were conducted in the 1970s and 1980s, and included both hospital and forensic studies.

Limitations to this review include variation in the prevalence of incidental breast cancer and precursors across the studies, which could in part be due to underlying differences within the populations studied. Pathologists may have differing thresholds for classifying lesions [39] and differing levels of scrutiny with which they analyse lesions - which, as already discussed, was the strongest predictor of incidental breast cancer in-situ and atypical hyperplasia. Our review was also limited by the absence of data on the age-specific prevalence in most of the studies. We compared older and younger women's prevalences of incidental cancer and precursors but had insufficient data to make any conclusions on this. Insufficient information also prevented us from being able to compare cancer prevalence across race groups. In particular, there was a paucity of data related to women of African descent (only one study).

The size of the prevalence pool of incidental invasive breast cancer in unscreened populations may be used to provide an approximate lower bound for the extent of overdiagnosis associated with mammography screening: true overdiagnosis rates are likely to be at least this large. Our estimate of the prevalence of incidental invasive cancer, at 0·85%, is much less than the current life-time prevalence of invasive cancer for women in the USA of 12·4% [40], or the life-time prevalence of screen-detected invasive cancer of ~7·4% (assuming that about 60% of invasive cancers diagnosed during life are detected by mammography screening [41, 42]). If we assume that all of the prevalence pool of incidental cancer would be detected through screening (which is reasonable given the apparent ease with which incidental invasive cancer was detected in the autopsy studies), then the implications may be that at least ~11% (~0·85/7·4%) of screen-detected invasive cancers, or at least ~7% (~0·85/12·4) of all invasive cancers, are overdiagnosed. Invasive cancers that would have regressed if not detected by screening [43, 44] however, will cause the lifetime prevalence of overdiagnosed cancers to be greater than the incidental cancer prevalence discovered at autopsy in unscreened populations.

The excess lifetime prevalence of breast cancer in a regularly screened population may be used to provide an approximate upper bound for the extent of overdiagnosis associated with mammography screening: true overdiagnosis rates are likely to be no larger than this. The lifetime prevalence of invasive breast cancer in the USA in 1975–1977 (prior to the introduction of screening) was 9.4% (1 in 10.6 women). Since 1987 after roll-out of nation-wide mammography screening the life time prevalence has been stable at around 12.5% (1 in 8 women). Some of the increased risk in more recent times is because women are now less likely to die of other causes and because of changing risk factor levels, but the main explanation appears to be increased detection through mammography screening [45]. The expected decline in lifetime prevalence as screening rates stabilized has not eventuated [46] and a large proportion of the excess 3% lifetime prevalence (12.4% - 9.4%), which has now persisted for 30 years, is likely to be due to overdiagnosis. The implications of this are that up to ~40% (~3%/7.4%) of screen-detected invasive cancers, or up to ~24% (~3/12.4%) of all invasive cancers, may be currently overdiagnosed. Others’ estimated overdiagnosis rates fall between our approximate lower and upper bounds [11, 43, 47,48,49,50].

For in-situ breast cancer, our estimate for the prevalence pool of incidental lesions is ~9%, much higher than the current life-time prevalence of ~2·0% [40], and lifetime prevalence of screen-detected in situ cancer of 1.6% (approximately 80–85% of in-situ cancers diagnosed during life are detected by screening [51]). This means there is a much higher probability of screen detected in-situ cancers being overdiagnosed (perhaps most are overdiagnosed), again consistent with estimates using other methods [11, 47].

The large pool of undetected cancer in-situ and atypical hyperplasia in these autopsy studies suggest caution for screening programs. First, as new breast screening technologies become more sensitive (e.g. digital mammography and breast tomosynthesis), it is likely that the proportion of overdiagnosed women will increase. Protocols for more intense biopsy sampling of screen detected abnormalities, or enhanced biopsy methods such as stereotactic vacuum-assisted core biopsy, are also likely to further increase overdiagnosis rates. Accordingly, new technologies and biopsy protocols should evaluate whether any increased sensitivity is for clinically important or overdiagnosed cancers, for example by examining interval cancer rates in randomised comparisons of alternative screening technologies [52]. Second, expansion of mammography screening programs to include those aged ≥70 years may also increase the risk of overdiagnosis and overtreatment [22]. The consequences of overtreating older women may also be more serious than for younger women because of their increased susceptibility to adverse effects of treatment [53].