Changes in HER2, ER, PR, and Ki-67 in HER2-Negative Breast Cancer After Neoadjuvant Chemotherapy: A Case–Control Study

<b>Purpose</b>: This study investigates receptor status changes following neoadjuvant chemotherapy (NAC) in breast cancer, aiming to identify new therapeutic opportunities and improve human epidermal growth factor receptor 2 (HER2) detection and categorization methods. <b>Methods</b>: This retrospective analysis was conducted on patients with breast cancer who underwent NAC and surgery between July 2022 and June 2024. Chi-square tests and logistic regression models were applied to assess the associations between HER2 status changes and clinicopathological features. <b>Results</b>: Among 508 patients, the receptor discordance rates after NAC were 5.3% for estrogen receptor (ER), 21.3% for progesterone receptor (PR), and 43.7% for HER2. Ki-67 expression decreased in 64.6% of cases and increased in 6.8%. Of the 103 patients with HER2-0, 47 (45.6%) transitioned to IHC 1+, 9 (8.7%) to IHC 2+/ISH-, and 1 (1.0%) to IHC 2+/ISH+. Among 256 patients with HER2 IHC 1+, 58 (22.7%) transitioned to IHC 2+/ISH-, 36 (14.1%) to IHC 0, and 9 (3.5%) to IHC 2+/ISH+. For 149 patients with HER2 IHC 2+/ISH-, 50 (33.6%) transitioned to IHC 1+, 6 (4.0%) to IHC 2+/ISH+, 5 (3.4%) to IHC 0, and 1 (0.7%) to IHC 3+. Univariate analysis revealed that, when compared to grade III tumors, grade I-II tumors exhibited a higher rate of HER2-0 to HER2-low conversion (66.7% vs. 36.8%, <i>p</i> = 0.027). HER2-low to HER2-0 conversion was associated with ER negativity (<i>p</i> = 0.028), PR negativity (<i>p</i> = 0.021), HER2 IHC 1+ (vs. IHC 2+, <i>p</i> = 0.001), and TIL >10% (<i>p</i> = 0.049). Multivariate analysis revealed that tumors with HER2 IHC 1+ were more likely to convert to HER2-0 after NAC than those with HER2 IHC 2+ (<i>p</i> = 0.020). <b>Conclusions</b>: Following NAC, ER gain, PR loss, and Ki-67 reduction were common. HER2 and ER status changes predominantly occurred within adjacent expression intensity levels.