Distinguishing Low Expression Levels of Human Epidermal Growth Factor Receptor 2 in Breast Cancer: Insights from Qualitative and Quantitative Magnetic Resonance Imaging Analysis

Abstract

Background: The discovery of novel antibody-drug conjugates for low-expression human epidermal growth factor receptor 2 (HER2-low) breast cancer highlights the inadequacy of the conventional binary classification of HER2 status as either negative or positive. Identification of HER2-low breast cancer is crucial for selecting patients who may benefit from targeted therapies. This study aims to determine whether qualitative and quantitative magnetic resonance imaging (MRI) features can effectively reflect low-HER2-expression breast cancer.

Methods: Pre-treatment breast MRI images from 232 patients with pathologically confirmed breast cancer were retrospectively analyzed. Both clinicopathologic and MRI features were recorded. Qualitative MRI features included Breast Imaging Reporting and Data System (BI-RADS) descriptors from dynamic contrast-enhanced MRI (DCE-MRI), as well as intratumoral T2 hyperintensity and peritumoral edema observed in T2-weighted imaging (T2WI). Quantitative features were derived from diffusion kurtosis imaging (DKI) using multiple b-values and included statistics such as mean, median, 5th and 95th percentiles, skewness, kurtosis, and entropy from apparent diffusion coefficient (ADC), D_app, and K_app histograms. Differences in clinicopathologic, qualitative, and quantitative MRI features were compared across groups, with multivariable logistic regression used to identify significant independent predictors of HER2-low breast cancer. The discriminative power of MRI features was assessed using receiver operating characteristic (ROC) curves.

Results: HER2 status was categorized as HER2-zero (n = 60), HER2-low (n = 91), and HER2-overexpressed (n = 81). Clinically, estrogen receptor (ER), progesterone receptor (PR), hormone receptor (HR), and Ki-67 levels significantly differed between the HER2-low group and others (all p < 0.001). In MRI analyses, intratumoral T2 hyperintensity was more prevalent in HER2-low cases (p = 0.009, p = 0.008). Mass lesions were more common in the HER2-zero group than in the HER2-low group (p = 0.038), and mass shape (p < 0.001) and margin (p < 0.001) significantly varied between the HER2 groups, with mass shape emerging as an independent predictive factor (HER2-low vs. HER2-zero: p = 0.010, HER2-low vs. HER2-over: p = 0.012). Qualitative MRI features demonstrated an area under the curve (AUC) of 0.763 (95% confidence interval [CI]: 0.667-0.859) for distinguishing HER2-low from HER2-zero status. Quantitative features showed distinct differences between HER2-low and HER2-overexpression groups, particularly in non-mass enhancement (NME) lesions. Combined variables achieved the highest predictive accuracy for HER2-low status, with an AUC of 0.802 (95% CI: 0.701-0.903).

Conclusions: Qualitative and quantitative MRI features offer valuable insights into low-HER2-expression breast cancer. While qualitative features are more effective for mass lesions, quantitative features are more suitable for NME lesions. These findings provide a more accessible and cost-effective approach to noninvasively identifying patients who may benefit from targeted therapy.

Keywords: breast cancer; human epidermal growth factor receptor 2; low HER2 expression; magnetic resonance imaging.

Figure 1

Flowchart of the study.

Figure 2

Representative images of qualitative MRI features in HER2-zero, HER2-low, and HER2-overexpression breast cancer. Case 1 (a–c) and Case 2 (d–f) show HER2-zero breast cancer, Case 3 (g–i) and Case 4 (j–l) show HER2-low breast cancer, and Case 5 (m–o) and Case 6 (p–r) show HER2-overexpression breast cancer. Case 1 (a–c): A 59-year-old female with HER2-zero expression breast cancer. The lesion is located in the left breast, has a rounded shape with circumscribed margins, and shows no NME (a). There is no intratumoral hyperintensity on T2WI (b). The HE staining image (×20, (c) left) shows invasive ductal carcinoma, and the IHC result (×20, (c) right) shows an HER2 score of 0. Case 2 (d–f): A 51-year-old female with HER2-zero expression breast cancer. The lesion is located in the left breast, has a rounded shape with circumscribed margins, and shows no NME (d). There is no intratumoral hyperintensity on T2WI (e). The HE staining image (×20, (f) left) shows invasive ductal carcinoma, and the IHC result (×20, (f) right) shows an HER2 score of 0. Case 3 (g–i): A 67-year-old female with low-HER2-expression breast cancer. The lesion is located in the left breast, has an irregular shape and uncircumscribed margins, and shows no NME (g). There is an intratumoral hyperintensity area (arrow) on T2WI (h). The HE staining image (×20, (i) left) shows invasive ductal carcinoma, and the IHC result (×20, (i) right) shows an HER2 score of 1+. Case 4 (j–l): A 59-year-old female with low-HER2-expression breast cancer. The lesion is located in the right breast, has an irregular shape and uncircumscribed margins, and shows no NME (j). There is an intratumoral hyperintensity area (arrow) on T2WI (k). The HE staining image (×20, (l) left) shows invasive ductal carcinoma, and the IHC result (×20, (l) left right) shows an HER2 score of 1+. Case 5 (m–o): A 61-year-old female with HER2-overexpression breast cancer. The lesion is located in the left breast, has an irregular shape and uncircumscribed margins, and shows NME (m). There is no intratumoral hyperintensity on T2WI (n). The HE staining image (×20, (o) left) shows invasive ductal carcinoma, and the IHC result (×20, (o) right) shows an HER2 score of 3+. Case 6 (p–r): A 55-year-old female with HER2-overexpression breast cancer. The lesion is located in the left breast, and shows as an NME lesion (p). There is no intratumoral hyperintensity on T2WI (q). The HE staining image (×20, (r) left) shows invasive ductal carcinoma, and the IHC result (×20, (r) right) shows an HER2 score of 3+. NME: non-mass enhancement; DCE-1: enhancement during the first phase.

Figure 3

Violin graph of significant quantitative MRI features in NME-related lesions among the HER2-zero, -low, and -overexpression groups. (a–c) Histogram features of ADC; (d–f) histogram features of D_app; (g–j) histogram features of K_app. Significance levels: *: p < 0.05, **: p < 0.01, ***: p < 0.001; NS: not significant.