Clinical practice guidelines for risk assessment to identify women at high risk of breast cancer: Chinese Society of Breast Surgery (CSBrS) practice guidelines 2021



## Level of evidence and recommendation strength
Level of evidence standard [bib_ref] Clinical practice guidelines for sentinel lymph node biopsy in patients with early-stage..., Ye [/bib_ref] Recommendation strength standard [bib_ref] Clinical practice guidelines for sentinel lymph node biopsy in patients with early-stage..., Ye [/bib_ref] Recommendation strength review committee There were 83 voting committee members for this guideline, including 69 breast surgeons (83.1%), four oncologists (4.8%), four radiologists (4.8%), two pathologists (2.4%), two radiation therapists (2.4%), and two epidemiologists (2.4%).

## Target audience
Clinicians specializing in breast diseases in China. Women with a likelihood of inherited predisposition to breast cancer based on personal or family history  should be offered genetic counseling, in order to guide decision-making of genetic testing for BRCA1/2 genetic mutations [bib_ref] Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US preventive..., Owens [/bib_ref] I A

## Recommendations

## Indications
Level of evidence Recommendation strength

## 3.2
Priority of genetic testing should be offered to the cancer patient(s) among the family members (index case) [bib_ref] Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US preventive..., Owens [/bib_ref] I A * The indications listed in this guideline apply only to healthy women at high risk of breast cancer. Indications of genetic testing for BRCA1/2 mutations in patients with breast cancer can be found in the "Clinical Practice Guidelines for BRCA1/2 Testing for Patients with Breast Cancer: Chinese Society of Breast Surgery (CSBrS) Practice Guidelines 2021."  Individuals with one or more factors with respect to family history, as below, can be considered to have a likelihood of inherited predisposition to breast cancer: confirmed carriers of harmful BRCA1/2 mutations among close family members (lineal blood relative, up to three generations); multiple cases of breast cancer in the family; male family members with breast cancer; close family members with a breast cancer diagnosis before age 50 years; close family members with two primary types (such as ovarian cancer and breast cancer) or two primary tumors (such as bilateral breast cancer or multifocal/multicentric breast cancer) of BRCA-related cancer. BRCA1/2: Breast cancer susceptibility gene 1/2.

# Discussion
Assessment of breast cancer risk status is aimed to distinguish individuals at greater risk of breast cancer from those with average risk and to guide personalized risk reduction through risk stratification.Currently, there is no single cutoff for defining increased absolute risk of breast cancer for all women worldwide. A risk assessment tool is a kind of statistical method based on epidemiological risk factors, which can be used to predict individual probability of developing breast cancer over the next 5 or 10 years or a lifetime. [bib_ref] Assessment tools of individual breast cancer risk: clinical practice and study advances..., Huang [/bib_ref] The modified Gail model is now one of the most widely used breast cancer risk assessment tools, which sets risk thresholds of at least 1.67% for 5-year risk of breast cancer.Because it was initially developed for white women, the Gail model has been modified and validated for female Asian and Pacific Islander immigrants. [bib_ref] Projecting individualized absolute invasive breast cancer risk in Asian and Pacific Islander..., Matsuno [/bib_ref] However, the cutoff of the Gail model is still largely based on population reference standards of women from the United States. [bib_ref] Projecting individualized probabilities of developing breast cancer for White females who are..., Gail [/bib_ref] A metaanalysis showed that the Gail model may substantially overestimate the absolute breast cancer risk of Asian women and is therefore not suitable for use in this population. [bib_ref] Assessment of performance of the Gail model for predicting breast cancer risk:..., Wang [/bib_ref] Our panel of experts proposes that development of a high-risk threshold exclusively for predicting breast cancer probability among Chinese women is warranted.
Limited breast cancer risk assessment tools have been developed for Chinese women. CSBrS guideline experts reviewed seven good-and fair-quality studies using six risk stratification models (Appendix, http://links.lww.com/CM9/ A546). [bib_ref] Risk prediction for breast Cancer in Han Chinese women based on a..., Wang [/bib_ref] [bib_ref] Risk factors related to female breast cancer in regions of Northeast China:..., Yu [/bib_ref] [bib_ref] Genetic and clinical predictors for breast cancer risk assessment and stratification among..., Zheng [/bib_ref] [bib_ref] Breast cancer risk assessment with five independent genetic variants and two risk..., Dai [/bib_ref] [bib_ref] Prediction of breast cancer risk based on common genetic variants in women..., Wen [/bib_ref] [bib_ref] BCRAM: a socialnetwork-inspired breast cancer risk assessment model, Li [/bib_ref] Similar to other international studies, most of these models reported only modest discriminatory accuracy, with C statistic values ranging from 0.61 to 0.66. [bib_ref] Genetic and clinical predictors for breast cancer risk assessment and stratification among..., Zheng [/bib_ref] [bib_ref] Breast cancer risk assessment with five independent genetic variants and two risk..., Dai [/bib_ref] [bib_ref] Prediction of breast cancer risk based on common genetic variants in women..., Wen [/bib_ref] However, for one model under review, levels of discriminatory accuracy above 0.70 were reported in both development and validation populations, with C statistic values of 0.73 and 0.72, respectively. Risk predictors included in this model are age, history of benign breast tumor, diabetes, residence, body mass index, life satisfaction score, and number of abortions. [bib_ref] Risk prediction for breast Cancer in Han Chinese women based on a..., Wang [/bib_ref] [bib_ref] Risk factors related to female breast cancer in regions of Northeast China:..., Yu [/bib_ref] Online risk assessment services based on this model are now available to the public (http://sd2y.pingjiaxitong.com).
With reference to the USPSTF (medication use to reduce risk of breast cancer) [bib_ref] Medication use to reduce risk of breast cancer: US preventive services task..., Owens [/bib_ref] and NCCN (breast cancer risk reduction)guidelines on populations under consideration of breast cancer risk assessment, the experts recommend that the present guideline on breast cancer risk assessment apply to all asymptomatic women aged 35 years and older who have no current or previous diagnosis of breast cancer or ductal carcinoma in situ. Retrospective studies have shown that both atypical hyperplasia and lobular carcinoma in situ are important risk predictors, rather than precancerous diseases of breast cancer. [bib_ref] Cancer statistics: breast cancer in situ, Ward [/bib_ref] [bib_ref] Bilateral risk for subsequent breast cancer after lobular carcinoma-insitu: analysis of surveillance,..., Chuba [/bib_ref] Thus, the experts recommend that women with a history of atypical hyperplasia or lobular carcinoma in situ are also candidates for breast cancer risk assessment. Although direct evidence is unavailable regarding the optimal age or frequency for risk assessment or the best interval at which to reassess risk, the experts suggest that repeating risk assessment should be considered when there is a significant change in breast cancer risk factors (eg, when a family member is diagnosed with breast cancer or when there is a new diagnosis of breast disease on biopsy) or when any risk-reducing intervention (eg, lifestyle changes, control of body weight, or risk-reducing medications) has been undertaken. Considering that evidence for Chinese populations is still unavailable, no recommendation on riskreducing medications for women with increased risk of breast cancer is made in the present guideline.
One large epidemiological survey showed that the prevalence of BRCA1 or BRCA2 mutations was 5.37% among women diagnosed with sporadic breast cancer in China. [bib_ref] Breast cancer risk in Chinese women with BRCA1 or BRCA2 mutations, Yao [/bib_ref] The probability of developing breast cancer before age 79 years among Chinese women who are carriers of BRCA1 or BRCA2 mutations is 37.9% and 36.5%, respectively, remarkably higher than that of the general population. [bib_ref] Breast cancer risk in Chinese women with BRCA1 or BRCA2 mutations, Yao [/bib_ref] Currently, both international and Chinese guidelines or expert consensus recommend that specific populations at high risk of cancer should be referred for genetic counseling and genetic testing to detect BRCA1/2 mutations. [bib_ref] Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US preventive..., Owens [/bib_ref] Several familial risk stratification tools (eg, BOADICEA and BRCAPRO) have been developed and validated to predict the individual probability of carrying harmful BRCA1/2 mutations among women with a family history of breast cancer. [bib_ref] 10-year performance of four models of breast cancer risk: a validation study, Terry [/bib_ref] As shown in section 3.1, this guideline puts forth recommendations on the characteristics of a personal family history suggestive of high inherited susceptibility to cancer. These characteristics are based on predictors included in the abovementioned international familial risk stratification tools, factors associated with increased likelihood of potential harmful BRCA1/2 mutations, as indicated by USPSTF as well as the diagnostic criteria of populations at high risk of inheritable cancer, as defined by the Chinese Anti-Cancer Association. [bib_ref] Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US preventive..., Owens [/bib_ref] To date, limited familial risk stratification tools are available to evaluate whether a family history of breast cancer is related to BRCA1/2 mutations in Chinese women. [bib_ref] Evaluating the performance of models for predicting the BRCA germline mutations in..., Rao [/bib_ref] The experts suggest that pretest genetic counseling should be offered before testing for BRCA1/2 mutations, to balance both benefits and harm of this service for individuals with the above characteristics of family history. For women with confirmed harmful mutations in the BRCA genes, a variety of risk-reducing interventions may be considered. Detailed recommendations on these interventions can be found in the "Clinical Practice Guidelines for BRCA1/2 Testing for Patients with Breast Cancer: CSBrS Practice Guidelines 2021." [bib_ref] Clinical practice guidelines for BRCA1/2 testing for patients with breast cancer: Chinese..., Xie [/bib_ref] The experts recognize that risk assessment of breast cancer is a preventive measure designated for healthy women. Considering that current high-level evidence specific to Chinese women is still lacking, clinical decisions should involve additional considerations and should not rely on evidence alone. Clinicians and primary care providers should hold discussions with women undergoing risk assessment to address the aims of assessment, limitations of the current evidence, potential risk-reducing

## Conflicts of interest
The expert committee for these guidelines declares no conflict of interest. These guidelines are a reference for breast disease specialists in clinical practice. However, the guidelines are not to be used as the basis for medical evaluation, and should not play an arbitrating role in the handling of any medical disputes. The guidelines are not a reference for patients or non-breast specialists. The Chinese Society of Breast Surgery assumes no responsibility for results involving the inappropriate application of these guidelines, and reserves the right to interpret and revise the guidelines.