Redefining Breast Cancer Treatment: The Emergence of 'Low Expression' as a New Target and the Era of Chronic Disease Management

The classification system for HER2 breast cancer is undergoing a fundamental shift. The long-standing dichotomy of 'positive' or 'negative' is collapsing, giving rise to a new treatable category: 'HER2-low'. This change is not merely an evolution in terminology. It signifies that, with the advent of advanced Antibody-Drug Conjugate (ADC) drugs, effective targeted therapy is now possible for a patient group that previously had limited treatment options. Furthermore, the treatment paradigm, especially for stage 4 metastatic breast cancer, is clearly shifting from 'cure' to 'chronic disease management for long-term coexistence with the illness'.

Current Status: Investigated Facts and Data

HER2-low breast cancer is defined as cases with an Immunohistochemistry (IHC) test result of 1+ or 2+ while being negative on in situ hybridization (ISH) gene amplification testing. This group was previously part of the patient population collectively referred to as HER2-negative but is biologically distinct from HER2-positive due to the absence of HER2 gene amplification. The key difference is that these tumors are now recognized as a new category that can respond to specific targeted therapies.

This paradigm shift has been driven by the ADC drug 'Enhertu (Trastuzumab Deruxtecan)'. This drug binds to the HER2 receptor on the cancer cell surface and then delivers a potent chemotherapy agent (payload) inside the cell. A particularly crucial mechanism is the 'bystander effect', where the released payload can cross cell membranes and kill neighboring cancer cells with low HER2 expression. The results of the DESTINY-Breast04 Phase 3 clinical trial clinically demonstrated this effect. In patients with HER2-low metastatic breast cancer, Enhertu extended progression-free survival to 9.9 months, representing a 50% reduction in the risk of disease progression compared to 5.1 months in the standard therapy group. Overall survival also significantly increased to 23.4 months, compared to 16.8 months in the control group.

This expansion of the treatment landscape is part of a broader trend observed across various cancers, including metastatic breast cancer. Advances in targeted therapies and immunotherapies for metastatic breast cancer, some lung cancers, chronic myeloid leukemia, and others are establishing a 'chronic disease' management paradigm. Research indicates that as disease progression is delayed, the worsening of patient-reported health-related quality of life is also significantly postponed, with positive effects confirmed on pain improvement and maintenance of daily function.

Analysis: Implications and Impact

The introduction of the HER2-low category is not merely a sub-classification but a redefinition of the treatable population. It demonstrates that precision medicine is evolving beyond diagnostic precision into a practical classification based on treatment responsiveness. As the definition of a 'target' expands from genetic mutations to protein expression levels, a path has opened for more patients to benefit from personalized treatment.

Simultaneously, the change in treatment goals for stage 4 breast cancer requires a shift in societal perception of medical success. 'Cure' is no longer the sole measure of success; instead, cancer is approached as a chronic condition to be managed long-term while maintaining quality of life, similar to hypertension or diabetes. This paradigm necessitates a new standard of care framework encompassing not only treatment strategies but also patient psychological support, management of economic burden, and continuous monitoring systems.

Practical Application: How Readers Can Utilize This

It is essential for patients and healthcare providers to understand this changed classification system. Patients diagnosed with breast cancer must carefully check their HER2 status on their pathology report, including both IHC and ISH results. Even if diagnosed as 'HER2-negative', it may correspond to 'HER2-low' if the result is IHC 1+ or 2+/ISH negative, which creates a significant difference in treatment options.

Healthcare providers are continuously required to update their treatment algorithms. The use of Enhertu in HER2-low metastatic breast cancer is now an evidence-based standard treatment option. Furthermore, under the chronic disease management paradigm, treatment decisions must consider not only tumor response but also long-term tolerability and impact on the patient's quality of life.

FAQ: 3 Questions

Q: Is HER2-low breast cancer the same disease as HER2-positive breast cancer? A: No. There are fundamental biological differences. HER2-positive involves amplification of the HER2 gene, making the HER2 signaling pathway crucial for cancer cell growth and survival. In contrast, HER2-low lacks such gene amplification. From a therapeutic perspective, both groups can benefit from ADC drugs targeting HER2, but the mechanisms and degree of response may differ.

Q: Does 'chronic disease' management apply to all metastatic breast cancer patients? A: Currently, it is not guaranteed for all cases. This paradigm is more realistic for specific cancer subtypes where effective targeted therapies or immunotherapies exist, allowing long-term control of disease progression. HER2-low breast cancer is a representative case where such management has become possible thanks to new drugs like Enhertu.

Q: When treatment shifts to chronic disease management, does the patient's quality of life actually improve? A: Research results indicate yes. Analysis of patient-reported outcomes in clinical trials has confirmed that treatments that effectively delay disease progression also postpone the time to deterioration in health-related quality of life. Positive associations have been reported, particularly in aspects like symptom control (e.g., pain) and maintenance of daily function.

Conclusion: Summary + Actionable Suggestions

The breast cancer treatment landscape is rapidly being reshaped alongside the discovery of the new therapeutic realm of HER2-low. This change has not only expanded the scope of targeted therapy but also promotes a fundamental shift in thinking, viewing many cancers, including metastatic breast cancer, as manageable chronic diseases. Patients and caregivers must actively ask questions based on accurate pathological information, and the medical community must now build comprehensive treatment and support systems aligned with this new paradigm.

Aionda

Redefining Breast Cancer: HER2-Low and the Chronic Disease Era