Editor's Note: In recent years, the accurate detection of HER2 (human epidermal growth factor receptor 2) expression in breast cancer has become crucial for guiding personalized treatment strategies. However, the heterogeneity of HER2 expression, including spatial and temporal heterogeneity, poses challenges for clinical decision-making. In this article, Professor Songqing Ye from Fujian Provincial Hospital delves into the impact of tumor HER2 expression heterogeneity and how to select appropriate samples (primary or metastatic lesions) for testing to utilize novel ADC drugs effectively, aiming to provide more precise guidance for personalized treatment of breast cancer patients.

Oncology Frontier: Given that HER2 expression can change during treatment and testing results can be inconsistent, which sample (primary or metastatic lesion) do you rely on for using novel ADC drugs in clinical decision-making? How do you approach this?

Professor Songqing Ye: Tumor development and progression exhibit heterogeneity, including spatial and temporal heterogeneity. Spatial heterogeneity encompasses differences between metastatic and primary lesions, as well as pathological heterogeneity within the same lesion. Temporal heterogeneity refers to changes occurring at different stages of disease progression. For instance, in HER2 expression, it is not uniformly distributed within the same tumor tissue, and biopsy samples or pathological slides may not accurately reflect the overall HER2 expression in the entire tumor.

The 2023 ASCO HEROD-BC study explored HER2 detection discrepancies between primary and paired recurrent/metastatic lesions in 1299 breast cancer cases. It was found that 28.5% of patients (370 cases) exhibited HER2 status heterogeneity between primary and metastatic lesions, with 31.7% of HER2-0 breast cancer patients (144 cases) converting to low HER2 expression. The percentage of spatial heterogeneity in HER2 status among different metastatic lesions was approximately 16.7%.

In the DESTINY-Breast04 study, 35% (n=196) of HER2 IHC samples came from primary lesions, and 65% (n=359) from metastatic lesions. Among patients whose samples came from primary lesions, the median progression-free survival (mPFS) was 9.6 months in the T-DXd group, compared to 4.2 months in the chemotherapy group, with a hazard ratio (HR) of 0.47 (95% CI: 0.32-0.70). For patients with samples from metastatic lesions, the mPFS was 10.9 months in the T-DXd group and 5.4 months in the chemotherapy group, with an HR of 0.50 (95% CI: 0.38-0.66). These results indicate that T-DXd improves efficacy regardless of whether HER2 low expression is detected in primary or metastatic lesion samples.

At the 7th International Consensus Conference on Advanced Breast Cancer (ABC7), 94.7% of experts agreed that “regardless of the stage of the disease or the sample location (primary or metastatic lesion), if HER2 low expression is detected in any sample, the patient qualifies for T-DXd treatment.”

Oncology Frontier: Considering the spatial and temporal heterogeneity of HER2 expression in breast cancer, and given that HER2 IHC low/ultralow expression patients can benefit more from T-DXd, is there a need for re-biopsy of HER2 IHC 0 patients in current clinical practice? What factors affect HER2 expression detection results?

Professor Songqing Ye: The need for re-biopsy in HER2 IHC 0 patients can be considered based on HER2 expression, drug benefit, and HER2 interpretation.

HER2 expression is a continuous variable. T-DXd has continuously expanded the benefit population of anti-HER2 targeted therapy, with patients exhibiting low/ultralow HER2 expression benefiting from T-DXd treatment. Defining the threshold for HER2 expression has become a focus for clinical and pathological doctors. Not all patients defined as HER2 IHC 0 lack HER2 expression; some exhibit ultralow HER2 expression (Ultralow, 0<IHC<1+), indicating that IHC 0 can be further categorized into HER2 ultralow and HER2 pure zero expression.

In the DB-06 study, 20-25% of HR+/HER2- advanced breast cancer patients were identified as HER2 Ultralow. Previous literature evaluations of HER2 IHC 0 samples showed that approximately 60% of these samples were assessed by at least one pathologist as HER2 Ultralow. Data from the national HER2 PATH study, conducted in 10 pathology centers, indicated that among HR+/HER2- patients, 13.1% (249/1908) exhibited HER2 Ultralow; among previously evaluated IHC 0 patients, 44.4% (303/682) showed HER2 Ultralow, with variations in HER2 Ultralow proportions across different centers.

The emergence of HER2 Ultralow poses interpretive challenges for pathologists, particularly between “0” and “HER2 Ultralow.” In the HER2 PATH study, only 74.1% (158/229) of samples assessed as IHC 0 were consistently interpreted. Therefore, for patients initially interpreted as HER2 IHC 0 with no membrane staining, re-biopsy, reassessment of the primary lesion, or switching paraffin blocks may increase the likelihood of detecting HER2 Ultralow or low expression.

A retrospective study presented at ASCO 2023 showed that among 512 TNBC MBC patients who underwent HER2 testing with biopsy samples at least once, one-third of previously HER2 0 patients could be re-detected as HER2 low expression, with the probability of HER2 low expression detection increasing with the number of biopsies.

The accurate detection of HER2 expression status is a prerequisite for formulating ADC drug treatment plans. Factors affecting detection results include pre-analytical processes (fixation time, sampling, preservation), differences between core needle biopsy (CNB) and surgical excision biopsy (SEB) samples, techniques used (antibodies, detection platforms, staining reagents), and interpretive accuracy.

Currently, IHC remains the best method for detecting low-level HER2 expression, though not ideal. Standardizing the detection process and refining interpretation standards are necessary. Ongoing research in AI-assisted diagnostics may further improve accuracy. New HER2 detection technologies, such as qRT-PCR, AQUA analysis, novel quantitative IHC methods, and deep learning techniques, are being explored and validated to enhance precision in HER2 expression detection.

Given the benefit of HER2 Ultralow in T-DXd treatment, noting HER2 IHC 0 staining status in pathology reports (0, no membrane staining or 0, membrane staining) may help clinicians identify HER2 ultralow patients more easily. The lower limit of HER2 benefit remains under exploration.

Professor Songqing Ye

Chief Physician, Department of Breast Surgery, Fujian Provincial Hospital Administrative Deputy Director (in charge of daily work) Member of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association Member of the Breast Cancer Expert Committee of the Chinese Society of Clinical Oncology (CSCO) Member of the Breast Cancer Group of the Chinese Medical Doctor Association Oncology Branch Deputy Director of the Yangtze River Academic Breast Cancer Alliance Deputy Director of the Breast Disease Branch of the Fujian Medical Association Editorial Board Member of “Gland Surgery” Guest Editor of “Chinese Journal of Breast Disease”