All immunohistochemistry (IHC) assessments were performed locally as per routine practice in each institution and were reported in the central database. All 18 Comprehensive Cancer Centres used the same guidelines (i.e. updated ASCO-CAP recommendations and their adaptation issued by the French GEFPICS Group) for tumour testing regarding ER, PR and HER222,34, and were participating to mandatory external proficiency tests performed each year in the frame of quality assurance programs (AFAQAP, UKNEQAS). Tumours were reported as ER-positive and PR positive, respectively, if ER and PR expression was observed in ≥10% of tumour cells by IHC, following French guidelines35. A global HR-positive (HR+) status was considered if ER and/or PR were expressed. A global HR-negative (HR−) status was defined by absence of both ER and PR detectable expressions. HER2-positive (HER2+) breast cancer was defined by a 3+ HER2 IHC score, or a 2+ IHC score associated with HER2 gene amplification by in situ hybridization. Multifocal heterogeneous tumors showing a different status for a given biomarker (either HR or HER2) between the different primary tumors were excluded from the analysis only for this biomarker. The primary tumour status was defined on the first surgical histology sample available. In the absence of surgery of the primary tumour, pathological data from the initial core needle biopsy were selected. The first metastatic HR/HER2 status was obtained on the first available sample within the first 6 months of metastatic diagnosis and prior to any tumour progression. When available, the second metastatic HR/HER2 status was obtained on histology sample within the first 6 months after first progression. Global HR status was considered as discordant if the primary tumour was positive (ER and/or PR positive) and the metastasis negative (ER and PR negative); or reverse. The same rules were applied to HER2 status.

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