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Use of Breast Cancer Risk Factors to Identify Risk-Adapted Starting Age of Screening in China

Key Points Question At what age should women with varying levels of breast cancer risk start screening? Findings In this cohort study of 1 549 988 women in China, participants were divided into groups according to breast cancer risk scores (driven by risk factors including first-degree family history of breast cancer, benign breast disease, breastfeeding, age at menarche, and body mass index). Using the 10-year cumulative risk of breast cancer at age 50 years in the general population as a benchmark, the optimal starting age of screening was identified as 43, 48, or after 55 years for women with high, medium, or low risk, respectively. Meaning These results identify the risk-adapted starting age at which to begin screening in women with varying levels of breast cancer risk in China, which may inform updates of current screening guidelines.


Introduction
Breast cancer in female individuals is the leading cause of cancer incidence and the fifth leading cause of cancer mortality worldwide, accounting for 11.7% of new cancer cases and 6.9% of cancer deaths in 2020. Among women, breast cancer ranks first for cancer incidence and mortality in most countries. 1 From 2000 to 2016, there was a significant increase in age-standardized breast cancer incidence rates among female individuals and an upward trend in breast cancer mortality rates in China. 2 Evidence has consistently shown that screening and early detection reduce breast cancer mortality. 3 In theory, screening interventions should be applied to high-risk populations based on a risk-adapted screening strategy 4,5 ; however, the evidence is limited worldwide. 6 To our knowledge, most randomized clinical trials and guidelines for breast cancer screening have recommended a one-size-fits-all approach in which all women are advised to begin screening at age 50 years, even those with risk factors (eg, a family history of breast cancer). 3,7-11 A one-size-fits-all or age-oriented screening strategy does not consider individual variation in terms of breast cancer risk, 12 which is not beneficial for young women at increased risk whose breast cancer incidence rate has gradually increased with distant-stage diseases in recent years. 13,14 Therefore, a risk-adapted starting age of screening is warranted to ensure the fairness and effectiveness of breast cancer screening applications.
The recommended initial age for breast cancer screening in most guidelines is 50 years, which is consistent with the peak age of breast cancer diagnosis in China. 15 To explore the risk-adapted starting age of breast cancer screening in China, we used data from the Cancer Screening Program in Urban China (CanSPUC)-the largest nationwide multicenter community-based screening cohort-and treated 10-year cumulative risk at age 50 years as the benchmark. We hypothesized that women with different levels of breast cancer risk should be screened at a risk-adapted age.

Methods
This cohort study was approved by the ethics committees of the China National Cancer Center/ Cancer Hospital, the Chinese Academy of Medical Sciences, and Peking Union Medical College and of all hospitals involved. All participants provided written informed consent. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Study Design and Participants
We performed this multicenter community-based cohort study under the framework of the CanSPUC government-supported cancer screening program initiated in October 2012. In brief, residents aged 40 to 74 years living in participating cities who did not have a history of cancer, kidney dysfunction, or severe disease of the heart (coronary atherosclerotic, congenital, rheumatic, or hypertensive heart disease), brain (ischemic or hemorrhagic cerebrovascular disease), or lungs (chronic obstructive pulmonary disease, pneumoconiosis, or silicosis) were recruited through telephone calls, personal encounters, social media, and community advertisements. Participants answered a comprehensive questionnaire about their exposure to risk factors, and women with increased breast cancer risk were recommended to undergo ultrasound or mammography screening. Unscreened participants who entered the cohort from January 1, 2013, to December 31, 2018, were analyzed for this study, which covered a total of 19 provinces in China.

Statistical Analysis
Continuous variables are expressed as the mean (SD), and the t or Wilcoxon rank-sum test was used to compare differences between groups. Categorical variables are expressed as percentages, and the χ 2 or Fisher exact test was used to compare differences between groups. Breast cancer risk factors were identified with Cox proportional hazards regression models and clinical significance. The multivariable Cox proportional hazards regression model including breast cancer risk factors was used to calculate the risk score for each participant. Risk division was performed according to risk score. Risk scores were divided into different risk levels according to the number of participants and the trends in 10-year cumulative risk curves.
Ten-year cumulative risks were calculated as follows. 17 The age-specific annual incidence rate equaled the number of cases for each age divided by person-years for that age. The 10-year cumulative incidence rate was calculated as the sum of each subsequent 10-year age-specific annual incidence rate at each age. Finally, 10-year cumulative risk equaled 1 -exp (-the 10-year cumulative incidence rate). The risk-adapted starting age of screening was defined as the age at which women with a particular risk of breast cancer attained a similar level of 10-year cumulative risk to the general population at age 50 years.
A 2-fold cross-validation method 18 for internal validation of 10-year cumulative risk for different risk levels was conducted to assess the stability of the model used to calculate risk scores. Data analysis was performed from October 1, 2021, to August 16, 2022. In China, current guidelines recommend that women at average risk receive breast cancer screening starting at age 45 years, although this is based on expert opinion and lacks population-based evidence. 19 Therefore, 10-year cumulative risk at age 45 years was also treated as the alternative benchmark for sensitivity analysis.
All analyses were conducted using R version 4.1.2 (R Foundation for Statistical Computing). All statistical tests were 2 sided, and P < .05 was considered statistically significant.

Population Characteristics
Of the 1 731 422 women in the CanSPUC cohort, 1 549 988 were included in this study (Figure 1).  Risk scores were first divided into 10 levels from low to high, then classified into 5 risk levels due to the small number of participants in the lower-and higher-level groups (eFigure 1 in the Supplement).

Risk Factors and Risk Scores for Breast Cancer Incidence
Because of similar trends in the 10-year cumulative risk curves, we further classified risk scores into 3 levels (low, medium, or high) (Figure 2).
Compared with women in the low-risk group, those in the medium-risk  Table 2). The mean (SD) age of diagnosed breast cancer in the general population was 58 (8) years, which was significantly older than that for the high-risk group (57 [7] years; P < .001) and similar to that for the low-risk (59 [8]; P = .07) and medium-risk (58 [8] years; P = .28) groups (eTable 2 in the Supplement).

Evaluation of Risk-Adapted Starting Age of Breast Cancer Screening
Women with low, medium, or high breast cancer risk (aged >55, 48, or 43 years, respectively) reached 10-year cumulative breast cancer risk equal to that of women with average risk at age 50 years in the general population ( Figure 2 and Table 2). Comparable results were found in the 2-fold cross-validation analysis. As a result, 10-year cumulative risk curves for women with different risk levels in both the development and validation data sets were analogous across age (eFigure 2 in the Supplement). We also developed an online tool to calculate an individual's starting age of breast cancer screening. 20

Sensitivity Analysis
Using 10-year cumulative risk at age 45 years as an alternative risk benchmark, our proposed breast cancer risk stratification demonstrated consistent breast cancer incidence trends in unscreened women in the CanSPUC cohort. As a result, risk equal to that of women at average risk at age 45 years in the general population was achieved 3 years later in the low-risk group and 1 and 3 years earlier in the medium-risk and high-risk groups, respectively (Table 2 and eFigure 3 in the Supplement).

Discussion
This cohort study examined the risk-adapted starting age of breast cancer screening in China by using CanSPUC population-based national cancer screening program data, with more than 1 million women eligible. Women with low breast cancer risk were proposed to start screening after age 55 years, whereas those with medium or high risk were proposed to begin screening at age 48 or 43 years, respectively. We also generated an online tool (http://cancerrc.ncsis.org.cn/#/utilshome) to calculate an individual's optimal starting age and to support decision-making in breast cancer screening.
In this study, breast cancer risk factors used for risk division included first-degree family history of breast cancer, benign breast disease, breastfeeding, age at menarche, and BMI. A family history of breast cancer is a well-demonstrated risk factor 10,21,22 and remains a major factor for screening and prevention counseling. Individuals with benign breast disease are also reported to have a higher risk of breast cancer. 23 25 and exerts a notable protective effect against hormone receptor-negative breast cancers. 26 Younger age at menarche is also associated with a higher risk of breast cancer. A meta-analysis of 117 studies showed a 5.0% reduction in breast cancer risk for every year older at menarche. 9 Furthermore, the results of a meta-analysis of studies in East Asian women showed that obesity is independently associated with increased risk of breast cancer in postmenopausal women. 27 Although all of these factors were considered in the China Guideline for the Screening and Early Detection of Female Breast Cancer, 19 the recommended starting age of screening for women at average and increased risk was based on expert opinion and lacked population-based evidence in Chinese women. Evidence of a risk-adapted starting age of screening is needed to determine populations at high risk and promote screening of  To date, studies focused on risk-adapted starting ages of breast cancer screening have been conducted with the Swedish family cancer data sets by Mukama et al. 11,18,28 These authors considered a family history of breast cancer, reproductive profile (eg, age at first live birth and parity), and other family history of cancers separately in their study, which makes it difficult for individuals with more than 1 category of risk factors to decide when to screen.
Several improvements were made in our study. First, we analyzed more than 1 million community-dwelling women from a multicenter, population-based, prospective cohort. Baseline characteristics in our study (eg, age and marital status) were also similar to data from the 2020 China Population Census Yearbook, 29 which also means that the population analyzed here is representative of Chinese women in the general population. Second, all cancer-related examinations and results were obtained from hospital medical records, the China National Central Cancer Registry, and the health insurance system, which contributed to study reliability. Third, we combined 5 factors associated with breast cancer and classified women into groups with different risk levels according to combined risk scores, which is more practical for clinical use. In addition, although the median follow-up time of the study was no more than 5 years, we found that the incident age of breast cancer in women in the general Chinese population was significantly older compared with women at high risk, which supports the recommendation of a risk-adapted starting age of breast cancer screening.
We believe that a difference would also be found between the medium-risk or low-risk groups and the general population of women with longer follow-up. Finally, we generated an online calculator based on the proposed risk-adapted age to support individual decision-making.

Limitations
This study has some limitations. First, the age of 40 years recommended by certain guidelines was not explored due to the limitation of the starting age in this study. 30,31 Second, although 5 factors were selected for risk division in our study according to clinical and statistical significance, more key variables associated with breast cancer (eg, mammographic density 32,33 ) should be collected and used for risk division in future research. In addition, risk-adapted starting age in our study was defined as the age at which women with different risk levels attained a 10-year cumulative risk comparable to the average risk for women at the recommended age in the general population. The cost-effectiveness of this approach was not taken into consideration and should be assessed in further studies. In addition, external validation should also be conducted. Screening methods such as mammography 34 and clinical breast examination 35 are proven to be effective for breast cancer screening. Screening strategies include not only the starting age of screening but also screening methods and screening intervals, which should be investigated for risk-adapted breast cancer screening in the future to detect women at high risk for breast cancer. Doing so helps to focus limited resources on these individuals, especially in developing countries such as China.

Conclusions
This cohort study reports the risk-adapted starting age of breast cancer screening in China. In addition, we developed a website to calculate an individual's optimal starting age of screening, which may support the decision-making process and inform the update of current breast cancer screening guidelines. Our findings contribute to the principle of equal management of equal risks in breast cancer prevention and may help narrow the focus to women at high risk. Doing so may optimize the allocation of limited screening resources, especially in developing countries like China. Future research on risk-adapted screening methods and screening intervals is needed.