Work

Family history-adjusted age recommendation for initiating breast cancer screening: 7-year follow-up from a prospective cohort study

Year: 2025

Type: article

Abstract: To the Editor: Breast cancer remains a leading cause of cancer incidence and mortality among women globally.[1] While population-based screening programs in countries like the U.S., Germany, and Japan have reduced mortality through early detection,[2] Family history—a major nonmodifiable risk factor—significantly influences individual breast cancer risk and age of onset, warranting tailored screening strategies. In China, national initiatives such as the Cancer Screening Program in Urban China and the Breast and Cervical Cancer Project for Rural Women have improved early detection. Nevertheless, current guidelines remain largely age-centered, with limited integration of family history for personalized screening. This study aims to provide empirical evidence for optimizing breast cancer screening initiation based on familial risk in a large Chinese cohort. This population-based cohort study is part of the Urban China Cancer Screening Program. Women aged 40–74 were recruited in Zhejiang, covering Hangzhou, Ningbo, Quzhou, and Jinhua, from 2014 to 2019, with follow-up until June 30, 2021. Ethical approval was obtained from the institutional review boards of the National Cancer Center in China (No. 15-070/997) and Zhejiang Cancer Hospital (No. IRB-2022-271). All participants gave informed consent. Participants underwent baseline interviews and risk assessments using the Harvard Cancer Risk Index. High-risk individuals were referred for screening via mammography and ultrasound. The detailed screening and follow-up strategies are shown in Supplementary Figure 1, https://links.lww.com/CM9/C598. Data on first-degree (FDR) and second-degree relatives (SDR) with breast cancer were collected. Breast cancer incidence and age at diagnosis were the primary outcomes. Cox proportional hazards models were used to estimate hazard ratios (HRs), adjusting for confounders such as age, smoking, alcohol use, reproductive history, and menopause. The family history-adjusted initiation age was defined as the age at which the 10-year cumulative risk matched that of average-risk women at age 50 years. Sensitivity analyses used 10- and 5-year cumulative risk thresholds at ages 45 and 50 years. The detailed calculation method is presented in Supplementary Text 1, https://links.lww.com/CM9/C598. Among 70,520 women (391,076.5 person-years; median follow-up: 6.43 years), 447 breast cancer cases were diagnosed. At baseline, 7.1% (n = 4997) reported a family history of breast cancer. Of these, 923 had ≥2 affected FDRs or SDRs, and 2792 had a FDR diagnosed at ≤50 years [Figure 1 and Supplementary Figure 2, https://links.lww.com/CM9/C598]. The baseline characteristics of the screening cohort were presented in Supplementary Table 1, https://links.lww.com/CM9/C598. Women with any affected FDR or SDR had an elevated risk (HR: 1.51, 95% CI: 1.09–2.11) compared to those without family history. Risk increased with more affected relatives (HR for ≥2 affected: 2.47, 95% CI: 1.35–4.52) and earlier age of diagnosis in relatives (HR for FDR diagnosed ≤50 years: 1.60, 95% CI: 1.05–2.45) [Figure 1]. The mean age at diagnosis was 58.0 years in the general population. In contrast, women with affected FDRs or SDRs had a significantly earlier mean age at diagnosis (52.9 years), and those with a FDR diagnosed at ≤50 had an onset age of 51.6 years. Women with FDRs or SDRs had a mean onset age that was 5.2 years earlier, and 6.4 years earlier for women whose FDRs were diagnosed before 50 years of age [Supplementary Table 2 and Supplementary Figure 3, https://links.lww.com/CM9/C598]. The 10-year accumulated risk for women with a familial history of breast cancer undergoes prominent changes predominantly before they reach the age of 50, subsequently stabilizing and aligning more closely with the risk observed in the general populace, as well as those without a familial history. When breast cancer screening was recommended to start at the age of 50 years for all females with a 10-year cumulative risk of breast cancer, women without a family history reached this risk threshold level at 50 years. Conversely, women with affected FDRs or SDRs attained the benchmark risk level before the age of 40, while those with a FDR diagnosed at the age of 50 years or younger similarly achieved this risk threshold before turning 40 [Supplementary Tables 3 and 4, https://links.lww.com/CM9/C598].Figure 1: Risk of breast cancer in women with a family history. CI: Confidence interval; FDR: First-degree relatives with breast cancer; HR: Hazard ratio; SDR: Second-degree relatives with breast cancer.When breast cancer screening was recommended to start at age 45 years for average-risk females according to their 10-year cumulative risk of breast cancer, women without family history reached the benchmark risk level at 46 years, whereas those with affected FDRs or SDRs and those with affected FDRs diagnosed at age ≤50 years both achieved comparable risk before 40 years old [Supplementary Table 3, https://links.lww.com/CM9/C598]. Comparing the 5-year cumulative risk of breast cancer in the general population at age 50 and 45 years as reference points, we observed that women with affected FDRs or SDRs, as well as women with a FDR diagnosed at ≤50 years of age, reached this risk threshold before turning 40 years old [Supplementary Tables 3 and 5, https://links.lww.com/CM9/C598]. These findings highlight the need for tailored screening initiation based on familial risk. While many current guidelines suggest starting screening at age 40 or 45 years for average-risk women, our data support initiating screening before age 40 years for women with familial risk. Specifically, the adjusted starting age for screening could be determined based on the number and degree of affected relatives and age at diagnosis. Authoritative guidelines and recommendations on the initiation age of breast cancer screening in the general population and in women with familial risk are presented in Supplementary Tables 6–8, https://links.lww.com/CM9/C598. International guidelines vary in recommendations for high-risk women. The Society of Breast Imaging suggests initiating screening at age 30 or 10 years earlier than the youngest affected relative (but not before age 25 years).[3] The American Cancer Society recommends starting at age 30 years for women with an FDR and a BRCA1/2 mutation.[4] China’s national guideline recommends beginning at age 40 years for women with FDRs, ≥2 SDRs diagnosed before age 50 years, or those with BRCA1/2 mutations.[5] However, these recommendations lack granularity in stratifying familial risk. Supporting our findings, a Swedish cohort study suggested starting screening between ages 27 and 45 years, depending on the family history constellation.[6] Other studies have shown that women with any family history reach comparable risk thresholds by age 43 years.[7] The Breast Cancer Surveillance Consortium suggests screening should begin 5–8 years before the age at diagnosis of the youngest affected relative.[7] Several practical recommendations are proposed. (1) Women with ≥2 affected relatives or FDRs diagnosed at ≤50 years should begin screening by age 40 or earlier, depending on risk thresholds. (2) Incorporate family history into validated risk models for individualized screening strategies. Where feasible, add genetic testing for BRCA mutations to refine stratification. (3) Implement tiered screening approaches that align with regional healthcare capacity. Primary care systems should be strengthened to deliver risk-informed services equitably. (4) Establish systems to update family history over time and integrate emerging genetic risk data, improving long-term surveillance and responsiveness. This study provides a large-scale, prospective cohort evidence from China to support risk-adapted screening initiation based on family history, including both FDRs and SDRs. Our findings are aligned with principles of equitable risk management and offer a cost-effective, personalized screening strategy, especially relevant for resource-limited settings. However, several limitations should be noted. First, participants were aged 40–74 years at enrollment, limiting the ability to assess risk below age 40 years. Second, family history was collected only at baseline and not updated during follow-up. Third, the relative contributions of FDRs versus SDRs were not separately analyzed. Fourth, the number of breast cancer cases with a positive family history was relatively small, and BRCA mutation data were unavailable, potentially limiting generalizability to hereditary breast cancer syndromes. In conclusion, this study supports the incorporation of detailed familial risk assessments into breast cancer screening guidelines. Women with ≥2 affected FDRs or SDRs had a 2.47-fold increased risk and were diagnosed 5.15 years earlier than women without family history. Using the principle of equal cumulative risk, screening could start 10 years earlier for women with a family history. These findings provide important evidence to refine screening guidelines and improve early detection in high-risk women, especially in Asian populations. Funding This work was supported by the Cancer Screening Program in Urban China, the Natural Science Foundation of Zhejiang Province (No. LQN25H260001) and the Medical and Health Research Project of Zhejiang Province (Nos. 2024KY050 and 2025KY043). Conflicts of interest None.

Source: Chinese Medical Journal

DOI: 10.1097/cm9.0000000000003797