Editor’s Note: With the success of antibody-drug conjugates (ADCs) in treating HER2-low breast cancer patients, this patient group is receiving increased attention. The latest 2024 CSCO BC guidelines were released on April 12 in Beijing, featuring the first recommendations for treating HER2-low patients. “Oncology Frontier” invited Professor Shusen Wang from Sun Yat-sen University Cancer Center to discuss the current treatment landscape for HER2-low patients and the recommendations in the 2024 CSCO BC guidelines.

Oncology Frontier: First, could you introduce the current treatment status and options for patients with HER2-low advanced breast cancer?

Professor Shusen Wang: In the early years, we did not differentiate the treatment of breast cancer patients and provided general treatment recommendations. With the advancement of times, we realized that breast cancer should be molecularly classified, and treatment should be guided based on these classifications. HER2, known as the human epidermal growth factor receptor 2, is a complex group when it comes to low expression. From a treatment perspective, HER2-low expression is a treatment classification, not an independent molecular classification. The gene that drives HER2 protein expression is associated with the development of breast cancer, but if the gene is overly amplified, it can lead to breast cancer.

About 20% of breast cancer patients show gene amplification[1], where HER2 gene amplification results in protein overexpression. According to existing detection guidelines[2], HER2 overexpression (HER2-positive) is defined as immunohistochemistry (IHC) 3+, but some patients have gene amplification with weaker protein expression: IHC 2+ and in situ hybridization (ISH) positive (amplification). Previously, patients without HER2 gene amplification or IHC 3+ expression were classified as HER2-negative breast cancer. This created a treatment dichotomy of either negative or positive for HER2 breast cancer patients.

HER2 protein expression is dynamic and continuous; even HER2-negative patients may have some HER2 protein expression. However, previous treatment choices did not consider protein expression. With advancements in new drug development, we have further distinguished HER2-low expression (IHC 1+ or IHC 2+/ISH-) patients and provided additional treatments with very good results. Therefore, from a treatment perspective, the concept of HER2-low expression is meaningful. The 2024 CSCO BC guidelines have recommended treatments for HER2-low patients, and thus the HER2-low expression guidelines were established.

The concept of HER2-low expression is specific to the HER2 marker, but we also need to consider other markers that might differ among HER2-low patients, such as hormone receptor-positive (HR+)/HER2-low or hormone receptor-negative (HR-)/HER2-low. Hormone receptor-positive patients are sensitive to endocrine therapy, so for HR+/HER2-low patients, endocrine therapy drugs must be included in the treatment regimen. For hormone receptor-negative patients, previously classified under triple-negative breast cancer, the HR-/HER2-low classification should also be reconsidered for treatment.

For HER2-low patients, treatment options should consider the differences in hormone receptor status, whether in advanced or early-stage patients. For HR+/HER2-low breast cancer patients who fail endocrine therapy, the DB-04 clinical study suggests[3] that chemotherapy is less effective than T-DXd treatment; the DB-04 study also included some triple-negative breast cancer patients and showed good efficacy. Therefore, for HER2-low patients, we must consider their hormone receptor status comprehensively and make appropriate treatment decisions.

Oncology Frontier: With the development of new HER2-targeted therapies in recent years, more research is focusing on HER2-low patients. What changes have occurred in the treatment of HER2-low breast cancer patients in the 2024 CSCO BC guidelines?

Professor Shusen Wang: Previous CSCO BC guidelines did not provide specific treatment recommendations for HER2-low patients, who often followed the treatment recommendations for triple-negative breast cancer or hormone receptor-positive breast cancer. Now, with new drug options (such as T-DXd), the 2024 CSCO BC guidelines have provided recommendations for this treatment classification.

For HR+/HER2-low patients, we must emphasize the standard status of endocrine therapy in treatment choices. For patients who fail endocrine therapy, especially those who progress after endocrine + CDK4/6 inhibitor treatment and have HER2-low expression, ADC drugs (T-DXd) should be prioritized. However, if HR+/HER2-low patients have not undergone endocrine therapy, the endocrine treatment pathway should be prioritized according to the CSCO BC guidelines for HR+/HER2- breast cancer patients.

Oncology Frontier: The emergence of ADC drugs has provided more treatment options for HER2-low breast cancer patients. What aspects of treatment for HER2-low breast cancer patients can be further explored in the future?

Professor Shusen Wang: Among hormone receptor-positive breast cancer patients, about 2/3 are HER2-low; among triple-negative breast cancer patients, about 1/3 are HER2-low[4]. Fortunately, we have more effective drug treatment options for HER2-low patients, and new treatments are continuously being developed. The success of the DB-04 study[3] for HER2-low patients has indeed changed clinical practice. Following the success of the DB-04 study, there is a significant focus on drug exploration in the HER2-low field, including ADC drugs and new treatment combinations. I believe that drug development in the HER2-low field will provide more treatment options for HER2-low patients, and we look forward to these options bringing better outcomes for these patients.