# GUIDELINE OBJECTIVES
To update clinical guidance on the use of multigene profiling assays in individuals with earlystage invasive breast cancer.

# TARGET POPULATION
Individuals diagnosed with early-stage invasive breast cancer for whom further information is needed for prognosis and treatment decision making. In this guideline, early-stage invasive breast cancer is defined as stage I to III breast cancers that are surgically operable and do not have evidence of inflammatory, locally recurrent or distant metastatic disease with pT1-T3, pN0-N1a based on surgical pathologic staging.

# INTENDED USERS
This guideline is targeted for clinicians and policy makers involved in the diagnosis and treatment of breast cancer.
The purpose of this guideline is to determine the clinical utility of multigene profiling assays (i.e., Oncotype DX, MammaPrint, Prosigna, EndoPredict, and Breast Cancer Index), not to identify which assay is better. No prospective studies have compared these head-to-head.
Given that the assays use different scoring systems and classification systems, please refer to Table 1-1 for a summary of each of the assays. Further, this guideline does not cover the utility of multigene profiling assays in helping to guide clinical treatment decisions regarding the use of either neoadjuvant chemotherapy or radiation.

# RECOMMENDATIONS, KEY EVIDENCE, AND JUSTIFICATION Recommendation 1
In patients with early-stage estrogen receptor (ER)-positive/human epidermal growth factor 2 (HER2)-negative breast cancer, clinicians should consider using multigene profiling assays (i.e., Oncotype DX, MammaPrint, Prosigna, EndoPredict, and Breast Cancer Index) to help guide the use of systemic therapy.

# Qualifying Statements for Recommendation 1
- There is currently insufficient evidence to use multigene profiling assays among patients with either HER2-positive or triple negative breast cancers. - Multigene profiling assays are recommended for use in patients with lymph nodenegative or lymph node-positive (1-3 lymph nodes) disease who are under consideration for adjuvant chemotherapy if the use is supported by other clinical, pathological, or patient-related factors. Clinical and pathological features include patient age, tumour grade, tumour size and nodal status.
- One multigene profiling assay should be requested per patient to guide a specific treatment decision. Requesting multiple tests with different multigene profiling assays on an individual tumour specimen to guide a single treatment decision is discouraged. Additional testing may be considered for patients with either repeat metachronous breast cancer diagnoses or synchronous breast cancer diagnoses where tumour specimens display varying morphologies, grade or hormone receptor status. - Multigene profiling assays should be interpreted cautiously in premenopausal patients where a significant benefit from adjuvant chemotherapy may still exist despite a lowrisk score. - It is uncertain whether at least some of the benefit of chemotherapy among premenopausal patients may be due to chemotherapy induced amenorrhea versus the cytotoxic effects of treatment.
- The Prosigna, EndoPredict/EPclin, and Breast Cancer Index assays can identify low-risk node-positive patients whose prognostic outcomes are favourable; however, these assays have not demonstrated predictive evidence to support withholding adjuvant chemotherapy among higher risk, node-positive, ER-positive, HER2-negative breast cancer patients.

# Recommendation 5
The evidence to support the use of molecular profiling to select the duration of endocrine therapy is evolving. In patients with ER-positive disease, clinicians may consider using a Breast Cancer Index (BCI) (H/I) high assay result to support a decision to extend adjuvant endocrine therapy if the decision is supported by other clinical, pathological, or patientrelated factors.

# Qualifying Statements for Recommendation 5
- While a number of studies have demonstrated clinical utility of BCI for extending adjuvant endocrine therapy, the preliminary results of the NSABP B42 trial are negative leading to some uncertainty. Treatment decisions should be based on all available clinical and pathological information for each patient, rather than depending only on multigene profiling tests. - MammaPrint, Oncotype DX, Prosigna, and EndoPredict currently have insufficient evidence to guide extension of adjuvant endocrine therapy; however, these molecular assays may prognosticate a very low rate of disease recurrence that might not justify an extension of endocrine therapy.