Equity in breast cancer screening for Asian women with dense breasts through ultrasonography: lessons learned from Japanese mammography screening and the J-START trial
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Introduction
Numerous randomized controlled trials (RCTs) conducted in Western countries have consistently shown a statistically significant reduction in breast cancer mortality rates [1,2]. Meta-analyses of these RCTs indicate that a screening sensitivity and participation rate exceeding 70% are key factors for demonstrating a decrease in breast cancer mortality rates [3]. This evidence highlights the vital importance of maintaining high standards in both the accuracy of screening methods and the effectiveness of public health initiatives that encourage participation in these screenings. Therefore, these findings strongly support the continuous improvement and backing of breast cancer screening programs to ensure they achieve these critical benchmarks, ultimately increasing their effectiveness in saving lives.
In contrast, Japan has not observed a corresponding decline in breast cancer mortality, despite implementing population-based mammography screening programs for over two decades [4,5]. It is imperative to consider the diverse patient populations, including those with both dense and non-dense breast tissue, when conducting mammography screenings.
Over the past 24 years, Japan has accumulated extensive experience in mammography screening, highlighted by the results from the Japan Strategic Anti-cancer Randomized Trial (J-START). These findings provide invaluable insights into the nuances of mammography and the potential benefits of implementing supplemental ultrasonography. This wealth of knowledge is a vital educational resource that can increase the efficacy and precision of breast cancer screening methods globally, particularly for Asian women with dense breasts.
Global Incidence and Mortality Rates of Breast Cancer
In 2022, breast cancer was the second most diagnosed cancer worldwide and the fourth leading cause of cancer-related deaths [1]. Although developed countries have experienced a decline in mortality rates due to enhanced screening and treatment options, developing countries are facing increasing incidence and mortality rates, signaling a shift in the global breast cancer landscape [1]. This trend is also observed in affluent Asian countries, such as Japan and Korea [1].
Mammography screening is acknowledged as a key strategy for reducing breast cancer mortality rates in many Western countries [2,6,7]. The statement "Mammography screening saves lives" is a firmly held conviction, frequently emphasized by healthcare professionals, researchers, and civil society advocates [8]. In the United States, breast cancer deaths have decreased significantly, by 37%-58%, due to mammography and enhanced therapies [9,10]. Of this reduction, 25%-44% is attributed solely to mammography, underscoring its critical role in the early detection and successful treatment of the disease [9,10].
It is widely acknowledged that both a screening sensitivity and a participation rate exceeding 70% are essential [3]. However, real-world data indicates that one might be considered more crucial than the other. This data relates to breast cancer screening and mortality rates in Switzerland. Despite the participation rate for breast cancer screening being just over 20% [11], the sensitivity of mammography screenings approaches 70% [12]. Additionally, the breast cancer mortality rate in Switzerland has been on a decline since the late 1980s, a trend that persists today. This decrease is consistent with that observed in other Western countries that have achieved both a screening sensitivity and a participation rate above 70% [13]. This scenario provides a scientific foundation for the argument that a screening sensitivity of over 70% is a more significant factor than a participation rate of over 70% in reducing mortality rates from breast cancer through screening programs.
Incidence and Mortality Rates of Breast Cancer in Japan
Breast cancer is the most common type of cancer in Japanese women, with 94,000 new cases reported in 2019 and a lifetime risk of one in nine. Although healthcare has advanced, it remains the fourth deadliest cancer, responsible for 15,000 deaths in 2020 [4,5]. Notably, mortality rates are on the rise, particularly among women in their fifties. In contrast to Western countries, the incidence of breast cancer in Japan peaks between the ages of 45 and 49, highlighting distinct trends and underscoring the need for tailored healthcare strategies. Despite the long-term implementation of mammography screenings, the mortality rate has not decreased [4,5].
In Japan, cases of breast cancer detected through screening generally have more favorable outcomes than those that are self-detected. Screen-detected cancers are significantly more likely to be early-stage, node-negative, and estrogen receptor-positive [14]. Between 2004 and 2011, the proportion of cancers identified by screening increased from 21.7% to 37.1%, accompanied by a rise in the detection of early-stage and hormone receptor-positive cancers. The biological differences between screen-detected and self-detected breast cancers may partially account for why mammography screening programs have a limited effect on reducing breast cancer mortality in Japan.
Some experts argue that the lack of a decrease in the mortality rate is an inevitable consequence of the sharp rise in breast cancer incidence among Japanese women. However, this view is incorrect. In Western countries, including the United States, there is clear evidence that mammography screening has led to a reduction in mortality rates despite increasing incidence of breast cancer. Notably, the decline in breast cancer mortality became apparent well before the incidence rates stabilized, occurring more than a decade earlier [2]. If mammography screening is effective, it should demonstrate a decrease in breast cancer mortality rates even as the incidence of the disease continues to increase. Without such evidence, the rationale for implementing mammography screening is undermined.
In Japan, the sensitivity of mammography for detecting breast cancer in asymptomatic women in their 40s is reported to be 47.4% [15]. Similarly, the participation rate in mammography screening is also low, at 47% [4]. Both of these figures fall significantly below the benchmark of over 70% for sensitivity and participation rates. Consequently, this aligns with findings that show no discernible reduction in breast cancer mortality rates, despite 24 years of mammography screening implementation.
Considering the previous discussions on the importance of sensitivity versus the participation rate, using Switzerland as a reference, it is reasonable to conclude that the primary reason for the lack of observed reduction in breast cancer mortality rates among Japanese women through mammography screening is the insufficient sensitivity of mammography in detecting breast cancer in this population.
External Validity: Key to Extrapolating Evidence from RCTs Conducted in Other Countries
External validity (generalizability) is essential for the extrapolation of research from international RCTs to local contexts, a key part of evidence-based practice in medicine and public health. It is vital for creating guidelines from new evidence-based medicine and evaluating the transferability of RCT results to different settings and populations.
RCTs in the West have shown that mammography reduces breast cancer deaths, and RCTs represent the most reliable level of scientific evidence influencing medical policy and practice. Yet, applying this Western-based evidence to Japanese women without assessing its relevance may be harmful. Studies indicate Japanese women have denser breasts than Western women, affecting the effectiveness of mammography [4,5]. Automated volumetric mammographic density assessment software has revealed that 78% of Japanese women have dense breasts, in contrast to 28% of Norwegian women, which affects screening results [16,17]. Therefore, the direct application of Western mammography screening evidence to the Japanese population lacks external validity due to these differences in breast density profiles. Specialized knowledge in breast imaging and radiology is essential to assess such evidence, a task that falls outside the expertise of public health and epidemiology experts.
Since mammography screening is less effective for women with dense breasts, Western countries with well-established mammography evidence have started implementing specific measures for this group. On March 10, 2023, the Food and Drug Administration acknowledged the limitations of mammograms in detecting abnormalities in dense breast tissue and amended the Mammography Quality Standards Act. This amendment, which takes effect on September 10, 2024, mandates that mammogram reports include the Breast Imaging Reporting & Data System category of breast density. It also ensures that physicians discuss the benefits and limitations of mammography and explore additional screening options with their patients [18]. In 2022, the European Society of Breast Imaging (EUSOBI) identified dense breast tissue as an independent risk factor for breast cancer, which diminishes the effectiveness of mammography. Women with very dense breasts face a higher risk of late cancer detection. EUSOBI recommends that these women be offered the option of undergoing contrast-enhanced breast magnetic resonance imaging (MRI) screenings. These screenings not only potentially reduce mortality but are also cost-effective, provided the women are fully informed of the advantages and disadvantages [19].
Underdiagnosis: Critical Harm to Women with Dense Breasts in Mammography Screening
Mammography screening has several drawbacks, including false positives and negatives, overdiagnosis, radiation risks, and psychological impacts, all of which are crucial in assessing its value [2,4,5]. However, underdiagnosis in dense breasts, a known limitation of mammography, has not yet been formally recognized as harmful. This oversight is significant given the widespread use of mammography and its acknowledged inefficacy in dense tissue, suggesting that underdiagnosis should be newly acknowledged as a harm in mammography screening.
In breast cancer screening, sensitivity is undoubtedly important, but the significance of specificity cannot be overstated in terms of preventing unnecessary stress and additional tests for healthy individuals. Japan adopts a cautious approach to minimize overdiagnosis resulting from high sensitivity. However, the severe consequences of late cancer detection make it imperative to prioritize disease identification over the risk of overdiagnosis. Missed diagnoses can lead to irreversible, fatal outcomes, which are far more concerning than overdiagnosis. It is crucial to recognize the substantial risks associated with failing to detect cancers through mammography, particularly in women with dense breasts.
A major issue with Japan's mammography screening program is the absence of a database system, which is essential for providing accurate and objective information about its sensitivity, specificity, and participation rates. As a method for breast cancer screening, the mammography program in Japan is problematic, with both its effectiveness and cost-benefit analysis still unverified.
Established Evidence of Breast Cancer Screening for Japanese Women from the J-START Trial
J-START is the world’s first large-scale RCT of supplemental ultrasonography for population screening, specifically targeting asymptomatic average-risk women without prior imaging-based selection [20,21]. The study demonstrated that incorporating ultrasonography into breast cancer screening significantly enhances early cancer detection among Japanese women aged 40-49. This approach not only improves sensitivity but also halves the rates of interval cancers. The interval cancer rate serves as a proxy for mortality in the evaluation of new screening methods [22]. While mortality reduction remains the definitive benchmark for screening efficacy, the findings from J-START regarding sensitivity are crucial for reducing mortality among women with dense breasts worldwide. Moreover, ultrasonography proved more effective than mammography in identifying early-stage and node-negative invasive cancers across both dense and non-dense breasts [21]. The consistent benefits of ultrasonography, irrespective of breast density, establish J-START as a crucial risk-based screening tool for Japanese women, who face a higher risk due to increased breast density and a peak cancer incidence between the ages of 45 and 49 [4,21].
J-START is the only RCT that has employed mammography screening in a Japanese female control group, offering highly relevant and specific evidence for Japanese women. This stands in contrast to RCTs conducted in Western countries, the results of which are less applicable to Japanese women due to concerns about external validity.
Equity in Breast Cancer Screening through Ultrasonography
The current global strategy for breast cancer screening typically involves offering uniform mammography to women aged over 40 or 50, without considering breast density. This approach does not have the necessary sensitivity for women with dense breasts, which is crucial for effectively reducing mortality rates. To improve this, achieving 'equity' in screening means incorporating additional methods for those with dense breasts, ensuring that all women receive the most effective protection against breast cancer mortality (Fig. 1). Uniform screening policies have not succeeded in reducing mortality rates among Japanese women, highlighting the need for a more equitable approach in future screenings that is tailored to individual needs. A risk-stratified and personalized screening strategy that considers both breast density and cancer risk may represent the best approach to achieving equitable breast cancer screening [23].
Equity versus equality in breast cancer screening.
Breast cancer screening worldwide uses mammography uniformly (represented by the same step stool in the left diagram), but this method lacks sensitivity (depicted as the red fruit) for women with dense breasts, leading to unchanged mortality rates. To improve this, an approach focusing on equity in breast cancer screening suggests extra tests (symbolized by providing a higher step stool: adding a pink step stool) for these women, ensuring they receive adequate screening sensitivity, promoting fairness in healthcare outcomes.
Several supplemental breast cancer screening methods, such as ultrasonography, digital breast tomosynthesis, and MRI, are recommended to enhance detection in women with dense breasts [24]. However, there is no consensus on the adoption of these methods. Ultrasonography is particularly recommended for Asian women due to its cost-effectiveness, convenience, and non-invasive nature, which make it a favorable option in regions where mammography is less sensitive. In Japan, following the results of J-START, there is ongoing discussion and consideration among relevant academic societies and the Ministry of Health, Labour and Welfare's expert panel regarding the implementation of ultrasonography-based screening to leverage its advantages.
Enhancing Quality Assurance and Quality Control in Ultrasonography-Based Breast Cancer Screening
Ultrasonography is a cost-effective and accessible method for breast cancer screening in Asia, depending heavily on the operator's expertise in adjusting imaging parameters and positioning. Quality control is critical in screening settings, requiring strong quality assurance protocols that include equipment standards, technician training, and interpretation guidelines to uphold diagnostic accuracy and patient care. Japan has established comprehensive guidelines to support these efforts [25,26].
Ultrasonography in Japan is conducted by technologists or physicians, and the images are interpreted by physicians. Therefore, it would be ideal that only physicians and technicians who have completed a specialized training course in ultrasonography, which includes image interpretation, and have passed the final examination, perform ultrasonography-based screening in Japan.
Conclusion
Personalized breast cancer screening through ultrasonography can help reduce disparities, particularly for Asian women with dense breasts. Ensuring equitable access to these services is essential. For these women, supplemental ultrasonography is crucial as it decreases the risk of false negatives associated with mammography, without requiring substantial effort, time, or cost. Advocacy for this initiative is important.
Notes
No potential conflict of interest relevant to this article was reported.
References
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Key points
The direct application of Western mammography screening evidence to Japan lacks external validity due to differing breast density profiles. Applying this Western-based evidence to Japanese women without assessing its relevance could be harmful. Personalized breast cancer screening with ultrasonography can help reduce disparities, particularly among Asian women with dense breasts.