Highlights
– Adjunctive ultrasonography (US) combined with mammography (MG) reduced the cumulative incidence of advanced breast cancer (Stage 2 or higher) by 17% compared to MG alone (HR 0.83, p=0.026).
– The divergence in advanced cancer incidence between the two groups became significant after 48 months, suggesting a long-term benefit from early detection.
– This study provides robust evidence for the integration of US into screening programs for women aged 40-49, particularly in Asian populations where dense breast tissue is common.
Introduction: Addressing the Screening Gap in Younger Women
In many Asian countries, the peak incidence of breast cancer occurs among women in their 40s, a demographic that often presents with dense breast tissue. Traditional mammography (MG) screening faces significant limitations in this population; the high density of fibroglandular tissue can mask malignant lesions, leading to a higher rate of false negatives. To address this diagnostic gap, the Japan Strategic Anti-cancer Randomised Trial (J-START) was initiated to evaluate whether adjunctive ultrasonography (US) could improve screening outcomes. While initial reports confirmed that the addition of US significantly increased the detection rate and sensitivity of screening, the long-term impact on advanced cancer incidence remained a critical unanswered question until now.
Study Design: The J-START Methodology
J-START is a large-scale, multicenter, randomized controlled trial conducted across 42 sites in Japan. The study enrolled 72,661 asymptomatic women aged 40-49 years with no history of breast cancer and a life expectancy of at least five years. Participants were randomized in a 1:1 ratio into two groups:
1. Intervention Group (n=36,723): Received both ultrasonography and mammography.
2. Control Group (n=35,938): Received mammography alone.
Screening was performed twice during a two-year period. This prespecified secondary analysis focused on the cumulative incidence of advanced breast cancer (defined as Stage 2 or higher according to the TNM classification). Data were collected over a median follow-up period of approximately 11.4 years, providing a comprehensive look at the clinical trajectory of these patients.
Key Findings: Impact on Cumulative Incidence of Advanced Breast Cancer
Over the follow-up period, 894 breast cancers were detected in the intervention group and 843 in the control group. The critical finding of this analysis lies in the stage distribution of these detected cancers:
– In the intervention group, 234 of the 894 detected cancers (26%) were classified as advanced (Stage 2+).
– In the control group, 277 of the 843 detected cancers (33%) were advanced.
The statistical analysis revealed a hazard ratio (HR) of 0.83 (95.6% CI 0.70–0.98; p=0.026), indicating a 17% reduction in the risk of being diagnosed with advanced breast cancer when adjunctive ultrasonography was utilized. This reduction is clinically significant, as Stage 2 or higher cancers typically require more aggressive systemic therapy and are associated with lower survival rates compared to Stage 1 or in-situ lesions.
Temporal Trends and the Proportional Hazards Assumption
An interesting observation in the J-START data was the violation of the proportional hazards assumption. Kaplan-Meier curves showed that the incidence of advanced cancer did not diverge immediately. Instead, the groups began to separate around the 48-month mark. The gap widened until approximately 96 months (8 years) and then remained stable.
This delay suggests that the benefit of adjunctive US in the 40-49 age group is realized through the detection of small, invasive cancers that would have otherwise progressed to an advanced stage several years later. The stability of the difference after eight years suggests that the primary benefit of the two screening rounds was concentrated in preventing the progression of lesions present during the active screening window.
Expert Commentary: Clinical Implications for Dense Breast Populations
For clinicians and health policy experts, the results of this secondary analysis provide the necessary evidence to support a shift in screening paradigms. The masking effect of dense breasts is a well-documented phenomenon; by using sound waves rather than X-rays, ultrasonography can identify masses that are isodense with surrounding tissue.
In Asian populations, where breast density is significantly higher than in Western cohorts, the J-START findings are particularly relevant. The reduction in advanced cancer suggests that adjunctive US is not merely increasing the detection of indolent or overdiagnosed cases, but is actually catching clinically relevant tumors at a point where they are still localized. This shift toward earlier stage detection is a prerequisite for reducing breast cancer mortality, although mortality data itself will require even longer follow-up to mature.
Strengths and Limitations
The primary strength of this study is its randomized, controlled design and the large sample size, which provides high statistical power. The long-term follow-up (median >11 years) is also a significant asset, allowing for a realistic assessment of cumulative incidence beyond the immediate screening interval.
However, limitations must be acknowledged. The study was conducted specifically in a Japanese population, and while the findings are likely generalizable to other Asian populations or women with high breast density, they may differ in populations with lower average breast density. Furthermore, the screening was limited to two rounds; the impact of sustained, annual, or biennial adjunctive US over a longer duration remains to be explored. Finally, while advanced cancer incidence is a strong surrogate, the ultimate goal of screening—mortality reduction—was not the primary endpoint of this specific analysis.
Conclusion
The J-START secondary analysis confirms that for women aged 40-49, the addition of ultrasonography to mammography reduces the cumulative incidence of Stage 2 or higher breast cancers. These findings highlight the potential value of integrating adjunctive US into national screening programs, particularly in regions where dense breast tissue is common. By shifting the stage at diagnosis toward earlier, more treatable phases, this intervention represents a significant step forward in optimizing breast cancer outcomes for younger women.
Funding and Trial Registration
This study was funded by the Ministry of Health, Labor, and Welfare of Japan and the Japan Agency for Medical Research and Development (AMED). The J-START trial is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), number UMIN000000757.
References
Harada-Shoji N, Suzuki A, Ishida T, et al. Cumulative incidence of advanced breast cancer in women aged 40-49 years in the Japan Strategic Anti-cancer Randomised Trial (J-START) of adjunctive ultrasonography: a prespecified secondary analysis. Lancet. 2026 Feb 21;407(10530):784-793. doi: 10.1016/S0140-6736(25)02319-0.
