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Simple Summary  Little is known about whether residual axillary disease after neoadjuvant chemotherapy carries a different prognostic value by breast cancer subtype. We retrospectively evaluated the axillary involvement (0, 1 to 3 positive nodes, ≥4 positive nodes) on surgical specimens from a cohort of 1197 patients treated with neoadjuvant chemotherapy, and analyzed its association with survival outcomes. Relapse free survival was significantly associated with the number of positive nodes, but this effect was different by breast cancer subtype (Pinteraction = 0.004). High risk patients were those with 4 or more nodes involved in the luminal subgroup, whereas patients with 1 node or more involved had a decreased prognosis in triple negative and  HER2  positive breast cancer subgroups. The prognostic value of residual axillary disease should be interpreted according to breast cancer subtype to accurately stratify patients with a high risk of recurrence after neoadjuvant chemotherapy who should be offered second line therapies.    Abstract  Introduction: The three different breast cancer subtypes (Luminal,  HER2- positive, and triple negative (TNBCs) display different natural history and sensitivity to treatment, but little is known about whether residual axillary disease after neoadjuvant chemotherapy (NAC) carries a different prognostic value by BC subtype. Methods: We retrospectively evaluated the axillary involvement (0, 1 to 3 positive nodes, ≥4 positive nodes) on surgical specimens from a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012. We analyzed the association between nodal involvement (ypN) binned into three classes (0; 1 to 3; 4 or more), relapse-free survival (RFS) and overall survival (OS) among the global population, and according to BC subtypes. Results: 1197 patients were included in the analysis (luminal ( n  = 526, 43.9%), TNBCs ( n  = 376, 31.4%),  HER2 -positive BCs ( n  = 295, 24.6%)). After a median follow-up of 110.5 months, ypN was significantly associated with RFS, but this effect was different by BC subtype ( P  interaction  = 0.004), and this effect was nonlinear. In the luminal subgroup, RFS was impaired in patients with 4 or more nodes involved (HR 2.8; 95% CI [1.93; 4.06],  p  < 0.001) when compared with ypN0, while it was not in patients with 1 to 3 nodes (HR = 1.24, 95% CI = [0.86; 1.79]). In patients with TNBC, both 1-3N+ and ≥4 N+ classes were associated with a decreased RFS (HR = 3.19, 95% CI = [2.05; 4.98] and HR = 4.83, 95% CI = [3.06; 7.63], respectively  versus  ypN0,  p  < 0.001). Similar decreased prognosis were observed among patients with  HER2 -positive BC (1-3N +: HR = 2.7, 95% CI = [1.64; 4.43] and ≥4 N +: HR = 2.69, 95% CI = [1.24; 5.8] respectively,  p  = 0.003). Conclusion: The prognostic value of residual axillary disease should be considered differently in the 3 BC subtypes to accurately stratify patients with a high risk of recurrence after NAC who should be offered second line therapies.

The Prognostic Value of Lymph Node Involvement after Neoadjuvant Chemotherapy Is Different among Breast Cancer Subtypes