Clinical practice guidelines for multigene assays in patients with early-stage breast cancer: Chinese Society of Breast Surgery (CSBrS) practice guidelines 2021

 [bib_ref] Use of biomarkers to guide decisions on adjuvant systemic therapy for women..., Krop [/bib_ref] 

## 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 81 voting committee members for these guidelines: 70 from breast surgery departments (86.4%), 2 from medical oncology departments (2.5%), 4 from medical imaging departments (4.9%), 2 from a pathology department (2.5%), 2 from a radiotherapy department (2.5%), and 1 epidemiologist (1.2%).

## Target audience
Clinicians specializing in breast diseases in China. I [bib_ref] Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive..., Paik [/bib_ref] B * Oncotype Dx  Recurrence Score.

## Recommendations

# Discussion
In recent years, the US Food and Drug Administration (FDA) and numerous international bodies have approved and recommended the 70-gene (MammaPrint  ) and 21gene (Oncotype Dx  ) assays for clinical practice with highlevel evidence. [bib_ref] Use of biomarkers to guide decisions on adjuvant systemic therapy for women..., Krop [/bib_ref] [bib_ref] Breast cancer, version 3.2020, nccn clinical practice guidelines in oncology, Gradishar [/bib_ref] The expert panel agreed that multigene assays are of great value in adjuvant treatment decisionmaking, with 97% of experts voting for a strong recommendation for the 70-gene assay and 73% for a weaker recommendation for the 21-gene assay. Several points need to be noted for this study. First, T3-T4 patients only accounted for 1.2% of the enrolled patients, the expert panel recommended that chemotherapy is appropriate for patients with T1-T2 disease. Second, majority of patients were node-negative (79%), while node-positive patients with 1-3 nodes accounted for 14.1%, 4.5%, and 2.3%, respectively, suggesting that this study is mainly applicable to 0-3 nodes-positive patients. Up to 88.4% of patients were HR-positive, and up to 90.3% were HER2-negative, suggesting that this study is mainly applicable to HR-positive and HER2-negative patients. Third, the clinical "risk" stratification of this study is based on the improved Adjuvant! Online tool, which includes tumor size, node stage, histological grade, HR and HER2 status, but does not include age and tumor thrombus. The so-called clinical "low-risk" or "high-risk" differs from the conventional St. Gallen expert consensus on the risk of recurrence after breast cancer surgery. [bib_ref] Progress and promise: Highlights of the international expert consensus on the primary..., Goldhirsch [/bib_ref] The 21-gene assay (Oncotype Dx  ) is currently the most widely used multigene panel and prognosis analysis method for HR-positive breast cancer patients in the USA.
The result of the TAILORx study provides high-level evidence for the clinical application of the 21-gene assay in practice (See details in the Supplementary file, http://links. lww.com/CM9/A820).
In recent years, three other breast cancer assay tools, EndoPredict, [bib_ref] Prediction of chemotherapy benefit by endopredict in patients with breast cancer who..., Sestak [/bib_ref] PAM50,  [bib_ref] Pam50 risk of recurrence score predicts 10-year distant recurrence in a comprehensive..., Laenkholm [/bib_ref] [bib_ref] Comparison of the performance of 6 prognostic signatures for estrogen receptor-positive breast..., Sestak [/bib_ref] and BCI, [bib_ref] Breast cancer index and prediction of benefit from extended endocrine therapy in..., Bartlett [/bib_ref] have also been widely recommended. These tools are not yet predictive of chemotherapy benefits and are not available in China, so they were not discussed by the expert panel.
The expert panel explicitly recommended that multigene assay indications include: T1-T2 and HR-positive, HER-2negative, node-negative or limited metastasis (1-3), and high-risk patients. The expert panel emphasized that ER, PR, and HER-2 status should be determined before assay. The assays are not recommended for TNBC and HER-2positive patients nor are they recommended for patients with >3 positive nodes. Decisions for chemotherapy are also not recommended for ER/PR-positive, HER-2-negative, node-negative, and clinically low-risk patients. Extended endocrine therapy based on gene test results is not recommended. Patients who are not suitable for chemotherapy due to complications, tumor stage, risk level, and other factors and who clearly need chemotherapy do not need routine genetic testing.
Multigene assays including the 70-gene and 21-gene assay have uniform and strict technology standards. The analysis and interpretation of biological data is tightly controlled, which provides an important guarantee for rigorous and credible results and lays the foundation for reasonable clinical application. The expert panel stressed that any 70-gene and 21-gene assay not labeled Mammaprint  or Oncotype Dx  is different from the genuine Mammaprint  and Oncotype Dx  assays. Clinicians should be cautious about evaluating the clinical value of these assays. www.cmj.org
The expert panel suggested that the following should be clarified when recommending polygenic testing for patients.
First, accurate multigene assay information is helpful for clinicians to make treatment decisions based on clinical and pathological data. Gene information acquired from clinical pathology may be inconsistent, and clinicians should combine genetic and clinical-pathological results to formulate treatment plans. Multidisciplinary consultations (MDT) should be conducted when necessary.
Second, the sample used for polygenic testing should be the primary tumor of invasive cancer tissue in patients with indications. The accuracy of the test is closely related to the amount of tissue, and the representative and pathological fixation status. The specific slice requirements may vary according to different tools. It is recommended that doctors should have a detailed understanding of the methods used and the tissue section requirements of the cancer tissue sectioning before testing.
Third, the consistency of the results among the different tools is controversial. [bib_ref] Molecular drivers of oncotype dx, prosigna, endopredict, and the breast cancer index:..., Buus [/bib_ref] That is, for the same patient, using different multigene assays, the results may not be the same.
Fourth, it must be objectively recognized that the current multigene research is mainly based on the results of the Western population, and the research on the Chinese population is still relatively small. The expert panel recommended that, with the support of national policies, multi-center research on multigene panels should be carried out to formulate national standards suitable for China's national conditions.
Fifth, the costs of gene assays are relatively expensive, and, as results between the different assays may be inconsistent, doctors need to make individualized selections according to the specific clinical conditions.
List of Compiling Committee Members (in alphabetical order by surname)