| Summary: | Introduction: The three different breast cancer subtypes (Luminal, <i>HER2-</i>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 (<i>n</i> = 526, 43.9%), TNBCs (<i>n</i> = 376, 31.4%), <i>HER2</i>-positive BCs (<i>n</i> = 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 (<i>P</i><sub>interaction</sub> = 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], <i>p</i> < 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 <i>versus</i> ypN0, <i>p</i> < 0.001). Similar decreased prognosis were observed among patients with <i>HER2</i>-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, <i>p</i> = 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.
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