Long-term follow-up studies for estimating the screening effects of BC patients in Asian women are very limited. The current study reported that the rate of BC-specific deaths decreased by 35% among screened BC patients relative to their never-screened counterparts (HR = 0.65, 95% CI = 0.60–0.70) based on 10-year follow-up data. Besides the down stage effect of mammography screening shown in previous studies [8, 14, 21–24], this study provided additional evidence on the stage-specific screening effect on mortality; the BC mortality reductions after screening were 42%, 36%, and 26% for patients diagnosed with localized, regional, and distant stages, respectively. A study conducted in Finland involving participants predominantly aged ≥ 40 years reported that patients with BC detected during a screening program had a 41% lower risk of BC death than those with BC detected outside the screening program after 15 years of follow-up. Similarly, a large-scale study using data from the Swedish Cancer Registry highlighted that 40-69-year-old women who underwent mammography had a 41% lower risk of BC death within 10 years . A 57% BC mortality rate reduction in women aged 50–69 years was reported by Kaplan et al. for 5-year survival , which is expected to have further reduced at 10 years as the effect of lead-time bias. Kalager et al. reported a 14% reduction in the BC mortality rate after the introduction of the screening program relative to that before the program , which is lower than that reported by our study and other mentioned studies [24, 25]. The main reason for the differences was that Kalager et al mainly divided the BC patients into 2 groups (pre-program and post-program) for the analysis without considering the participation status. Therefore, the effect of mammography on survival may have been underestimated, as some patients in the post-program group did not participate in the screening program.
Mammography screening among women younger than 50 years is controversial, as limited evidence supports the cost and effectiveness among this age group [27, 28]. Notwithstanding, some Asian countries have included women in their 40s in their screening guidelines, given the different epidemiological characteristics of the Asian population [3–5, 29]. In the current study, we found that the youngest age group of 40–49 years received the least benefit from mammography screening related to long-term survival (HR = 0.71, 95% CI = 0.62–0.81). The higher prevalence of dense breasts in younger women had been addressed by a Korean study, whereas the proportion of women with dense breasts was approximately more than 80% for women in their 40s attending mammography screening; this decreased in the older age groups . The accuracy of mammography screening may be relatively lower for this age group [4, 31]. Therefore, screening for women in their 40s should have age-specific strategies including appropriate modality and screening interval [4, 27, 32–34]. The U.S. Preventive Services Task Force Recommendation indicated that screening at the age of 40 years should be based on the individual risk and benefits of mammography. According to the recommendation of the American Cancer Society, 40-44-year old women can undergo mammography screening every year; however, women aged 45–54 and ≥ 55 years should screen annually and biannually, respectively . The American College of Radiology also recommends annual mammography screening for women starting from 40 years old .
Overdiagnosis by BC screening is preferred for cases that are detected and diagnosed as BC but never progress to symptomatic and aggressive cancer cases. Therefore, the detection of these cases does not contribute to mortality reduction or cause more harm to patients such as psychological consequences or unnecessary treatments [35–37]. The DCIS cases are more likely to be associated with overdiagnosis due to screening than invasive BC cases [37, 38]. In the current study, we found a significantly higher proportion of DCIS cases among the screened group (13.9%) compared with the never-screened group (10.0%) but no significant reduction of the long-term BC mortality rate attributable to screening. While this can be associated with the successful treatment of early cancer, there may be several cases of overdiagnosis in this group. It is well known that DCIS patients have an excellent prognosis of more than 95% during the long-term follow-up [39, 40], which is consistent with the long-term survival rate of 96.4% in our study. Moreover, a study from SEER indicated that low-grade DCIS patients in the surgery and non-surgery groups had the same survival rates . In contrast, women diagnosed with DCIS are not well aware of the risk of developing invasive cancer, which worsens their screening-related psychological issues [42–44]. Given the increasing trend of DCIS associated with the widespread implementation of screening, it is essential to improve the understanding of DCIS in the population and the shared decision-making strategy for DCIS treatment between patients and physicians to minimize the risk of overdiagnosis and overtreatment.
Mammography screening has challenges that should be taken into careful consideration when evaluating its effectiveness. Firstly, the cancer cases detected by screening appear to have demonstrated longer survival, which is attributable to the earlier diagnosis, the so-called lead-time bias. In our cohort, the effect of lead-time bias may have been minimal due to the follow-up duration of at least 10 years for all patients. Secondly, the favorable outcomes for the screened population may have been attributable to the greater likelihood that slowly progressing cancers would be detected by screening. In addition, there is also the risk of selection bias stemming from the different baseline characteristics of people who show up for screening and those who do not. To partially control this in our study, we used several models with different population levels of adjustment of socioeconomic and tumor characteristics. Since the context of BC screening is universally provided with more than 80% of a lifetime screening rate , the selection bias would be small as indicated in the Handbook of Cancer Prevention by the International Agency for Research on Cancer (IARC) . Additionally, we also used the formula suggested by the previous study design to address self-selection bias in a cohort study , and the calculated net benefit from mammography screening in our study was reported at 12.2% for invasive cancer only (Table 2) and 17.6% after excluding DCIS and distant cancer cases (Supplement Table S3).
Nevertheless, our study had several limitations. First, our study could not combine the opportunistic screening information for the screening history. The non-attendants of KNCSP may have already undergone opportunistic screening, which is often used during ultrasonography as a screening test. Therefore, the effect of BC screening through the KNCSP could be underestimated. Second, our study only assessed the extent of BC based on the summary stage classification by the SEER Cancer Statistics Review of the National Cancer Institute , which had limitations in investigating the stage-specific effect of screening compared with classification systems widely used for cancer treatment, such as the Tumor, Node, Metastasis (TNM) staging system . Lastly, as our study covered all BC patients diagnosed in 2008 and 2009 in Korea, it was not possible to include information about treatment, which is a strong predictor of patient prognosis, in our analysis. However, we believe that the treatment statuses of the screened and never-screened groups are relatively similar at the same stage as all Korean residents are enrolled in the NHIS. Despite these limitations, this is one of the first studies evaluating the effect of mammography on the long-term survival of BC patients in Asia, to the best of our knowledge. Our study linked information at the individual level from 3 national databases with the nearly complete data on screening information, cancer information, and death information. This makes our findings relatively generalizable to the entire population of the country.
In conclusion, our study found a significant reduction of the BC-specific mortality rate after mammography screening of BC patients during a long-term follow-up of 10 years. Our results also indicated a reduced effect of mammography among women in their 40s, who require more detailed and specialized screening strategies. Future studies should have appropriate designs to directly address the overdiagnosis by mammography screening, especially among DCIS patients.