For women with approximately 2-fold increased risks for breast cancer, the balance of benefits and harms (life-year gained vs. false positives) of starting biennial screening at age 40 approximates that of biennial screening for average-risk women starting at age 50. The models consistently showed that the additional benefits of adding annual screening are small and that there is greater harm relative to benefit from digital than from film mammography in women age 40–49. To obtain similar harm-benefit ratios as the one that results from the currently recommended screening, the false-positive rates for biennial screening with digital mammography would have to decrease substantially among women in their 40s.
The model results on the difference between annual and biennial screening are largely in line with previous work. A retrospective study found that women screened annually vs. biennially had similar distributions of prognostic factors (e.g., tumor size, lymph node status, and histological grade) (26
). However, another study found that among women age 40–49 years specifically, those undergoing biennial screening were more likely to have late-stage disease at diagnosis than those undergoing annual screening (27
). It has been suggested that for younger women annual screening would be more beneficial than biennial screening because of the faster tumor growth rates in this age group (28
). This is reflected in the model outcomes showing that adding annual screening to biennial screening in the 40–49 age group is somewhat more beneficial than in older age groups. For example, a previous study showed that 72–89% of the mortality benefit is maintained in these four models when women aged 50–74 move from annual to biennial screening scenarios (23
). The present study shows that in the 40–49 age group this percentage of mortality benefit maintained is somewhat lower (66–77%).
All four models found only small differences between film and digital mammography with regard to the benefits of screening, which is in line with a study that found that improvements in sensitivity did not have a marked effect on breast cancer mortality (31
). However, digital mammography did result in substantially more false-positive results than film. This translated into greater harm relative to benefits for digital than for film mammography in younger women. Therefore, it seems unlikely that data on the performance of digital mammography, if it had been available, would have led the USPSTF to recommend screening women starting at age 40. A recent study in the Netherlands found that referral and false-positive rates first increased after the implementation of digital mammography, but then these rates started to decrease over time and stabilized at a somewhat higher level than film mammography after a little more than one year (32
). However, in a recent US study comparing the screening performance of digital and film mammography, excluding the first year after the transition to digital mammographydid not influence results (33
). Another recent study found that the availability of a comparison mammogram halved the false-positive recall probability (34
). It remains to be investigated whether false-positive rates in the US can be reduced without also decreasing sensitivityor detection rates.
The results of the models are consistent regarding differences between outcome measures, predicting considerably higher threshold RRs when breast-cancer deaths averted is used instead of life-years gained, because in the 40–49 age group there are more life-years to gain by averting a death than in older age groups. Life-years gained may be considered preferable, because as a summary measure, it incorporates both the number of lives saved and the number of life-years gained per life saved. Our results indicate that the outcome measure used is a main determinant of the screening strategy that will be chosen for women aged 40–49, highlighting the importance of taking into account preferences of individual women about specific benefits and harms.
Several limitations in this study should be taken into account. Importantly, we calculated the harm-benefit ratios for women aged 50–74 screened biennially and used these as threshold values for younger women. However, it might be that younger women have different concerns and preferences than older women and that these preferences vary between individual women.
Additionally, in calculating the harm-benefit ratio we only included false-positive mammography screening examinations as the harm. Ideally, all harms and all benefits are taken into account when determining optimal screening scenarios. Besides false positives, harms of screening mammography include false-positive biopsies, radiation exposure, false reassurance, pain related to the procedure, overdiagnosis (the detection of lesions that would not have become clinically apparent without screening), overtreatment, and the burden of performing medical tests on healthy individuals. Several studies have shown that the risk of radiation is minimal (35
), and false reassurance has been found to play only a minor role in breast cancer screening (37
). Although many women experience pain during the procedure (range 1% to 77%), very few consider this a deterrent from future screening (8
). Estimates of overdiagnosis vary widely, ranging up to 54% (39
). Although a proportion of invasive cancer diagnosed by mammography may never have presented clinically, the proportion is likely to be small for women aged 40–49, ranging up to 7% (39
). For ductal carcinoma in situ
this proportion might be larger, but is surrounded by uncertainty. For these reasons we chose to focus on false-positive examinations as the main harm for women in their forties. We did, however, perform a sensitivity analysis in which we considered a more comprehensive measure of harm, QALYs lost. Although this measure is more comprehensive, capturing disutility of false positives and the impact of overdiagnosis, it is less transparent than the number of false-positives, and there is the possibility that the preferences of individual women diverge from the assumed societal utilities.
Also, the models differed for some outcomes. For biennial film screening, three models (E, G, and W) found comparable threshold RRs (1.5–1.6), whereas one model (D) estimated a threshold RR of 3.7. This discrepancy relates to differences in the estimated benefits, reflecting differences in model structures. In model D (19
) the stage distribution data are directly incorporated in constructing breast-cancer specific survival. Thus small incremental changes in stage shifts between annual/biennial or between film/digital led to smaller incremental benefits. The other models used a combination of sensitivity values and stage distribution to calibrate parameters and show larger benefits. Additionally, the models differed regarding the predicted incremental benefit of adding annual to biennial screening (range life-years gained 7–21), because the models make different assumptions for unobservable variables, such as sojourn time, which is the duration of the preclinical, screen-detectable phase of the tumor. No randomized controlled trials have directly compared annual and biennial screening. The range in model outcomes, thus, reflects uncertainties in current knowledge of the incremental benefits of screening women aged 40–49 and about shortening the screening interval.
Finally, model outcomes largely depended on the inputs and assumptions. One assumption was that the higher risk influenced only the incidence (onset of disease) and not the screening performance (sensitivity, specificity) or natural history of disease (e.g., the tumor growth rate, breast-cancer survival). However, at least some risk factors, including breast density and family history, have been found to influence both breast-cancer risk and screening performance (40
). If this is taken into account, the harm-benefit ratio could change for women with risk factors that influence performance. The psychological impact of false positives might also differ by risk group. For example, the amount of anxiety or distress might be higher for younger women and for women with a family history of breast cancer than for average-risk women (42
Our finding that women with increased risks for breast cancer have similar harm-benefit ratios from starting biennial screening mammography at age 40 is in line with studies finding that breast cancer risk or detection for women with a first-degree relative is similar to that for women a decade older without such a history (40
). Several other countries have risk-based screening guidelines. For example, guidelines in the Netherlands state that women with a moderately increased risk, defined as RR 2–3, should be offered annual screening starting at age 40. Similarly, in Australia, guidelines specify that a starting age below 50 or more frequent examinations should be considered individually for women with moderately increased risk, defined as RR 1.5–3.
A systematic review and meta-analysis of risk factors and their prevalence rates in women age 40–49 years in the U.S. was conducted jointly with the present study (43
). Two risk factors were associated with a 2-fold or higher RR: having a first-degree relative with breast cancer (9% of women in the U.S.) and extremely dense breasts on mammography (13% of women with Breast Imaging Reporting and Data System category 4 breast density). Results of these two studies imply that women with these characteristics could benefit from biennial screening starting at age 40, and that for them the balance of benefits and harms of screening would be similar to the balance of benefits and harms for average-risk women starting screening at age 50. In addition to these single risk factors, combinations of risk factors could potentially reach this risk threshold (16
). A potential difficulty with including breast density in screening recommendations is that breast density is not uniformly reported and requires baseline mammography examinations to determine breast density, introducing additional potential screening harms.
Our results provide important information towards more individualized, risk-based screening, suggesting that starting biennial screening at age 40 for women with an increased risk for breast cancer (RR ≥1.9) has a similar balance of benefits and harms as biennial screening for average-risk women aged 50–74 years. For women below this level of risk, the harm-benefit ratio of starting screening at age 40 is less favorable than that of biennial screening between ages 50–74. Reducing the false-positive rate is crucial to improving the balance of benefits and harms for screening regimens for women of all ages.