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

## TL;DR

This study finds that breast cancer receptor statuses like HER2, ER, and PR often change after chemotherapy, which could help improve detection and treatment strategies.

## Contribution

The study reveals significant receptor status changes in breast cancer after neoadjuvant chemotherapy, offering insights into potential therapeutic adjustments.

## Key findings

- HER2 discordance rates were 43.7% after neoadjuvant chemotherapy, with notable transitions between IHC categories.
- ER and PR status changes were common, with Ki-67 expression decreasing in 64.6% of cases.
- Tumors with HER2 IHC 1+ were more likely to convert to HER2-0 after chemotherapy compared to those with HER2 IHC 2+.

## Abstract

To identify new therapeutic opportunities, this study investigates receptor status changes following neoadjuvant chemotherapy in breast cancer. Among 508 patients, the receptor discordance rates after neoadjuvant chemotherapy were 5.3% for estrogen receptor, 21.3% for progesterone receptor, and 43.7% for HER2. Ki-67 expression decreased in 64.6% and increased in 6.8% of all cases. 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+. Tumors with HER2 IHC 1+ were more likely to convert to HER2-0 after neoadjuvant chemotherapy than those with HER2 IHC 2+ (p = 0.020). The changes in receptors were common. HER2 and estrogen receptor status changes predominantly occurred within adjacent expression intensity levels. These findings provide insights into the mechanisms underlying estrogen receptor and HER2 transitions.

Purpose: 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. Methods: 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. Results: 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%, p = 0.027). HER2-low to HER2-0 conversion was associated with ER negativity (p = 0.028), PR negativity (p = 0.021), HER2 IHC 1+ (vs. IHC 2+, p = 0.001), and TIL >10% (p = 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+ (p = 0.020). Conclusions: Following NAC, ER gain, PR loss, and Ki-67 reduction were common. HER2 and ER status changes predominantly occurred within adjacent expression intensity levels.