The Residual Cancer Burden (RCB) quantifies residual disease after neoadjuvant chemotherapy (NAC). Its predictive value has not been validated on large cohorts with long term follow up. The objective of this work is to independently evaluate the prognostic value of the RCB index depending on BC subtypes (Luminal, HER2 positive and triple negative (TNBCs)). Methods: We retrospectively evaluated the RCB index on surgical specimens from a cohort of T1T3NxM0 BC patients treated with NAC between

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... and 2012. We analyzed the association between RCB index and relapse-free survival (RFS), overall survival (OS) among the global population, after stratification by BC subtypes. Results: 717 patients were included (luminal BC (n = 222, 31%), TNBC (n = 319, 44.5%), HER2 positive (n = 176, 24.5%)). After a median follow up of 99.9 months, RCB index was significantly associated with RFS. The RCB0 patients displayed similar prognosis when compared to the RCBI group, while patients from the RCBII and RCBIII classes were at increased risk of relapse (RCBII versus RCB0: HR=3.25 CI [2.1;5.1] p < 0.001; RCBIII versus RCB0: HR=5.6 CI [3.5;8.9] p < 0.001). The prognostic impact of RCB index was significant for TNBC and HER2 positive cancers; but not for luminal cancers (Pinteraction = 0.07). The prognosis of RCBIII patients was poor (8 years RFS: 52.7%, 95% CI [44.8 ; 62.0]) particularly in the TNBC subgroup, where the median RFS was 12.7 months. Conclusion: RCB index is a reliable prognostic score. RCB accurately identifies patients at a high risk of recurrence (RCBIII) with TNBC or HER2 positive BC who must be offered second-line adjuvant therapies.