Epidemiological characteristics, clinical management and prognosis analysis of breast cancer with low HER2 expression

I. Research Background and Clinical Significance
As a key indicator for molecular subtyping of breast cancer, the accurate assessment of human epidermal growth factor receptor 2 (HER2) expression levels plays a decisive role in treatment decision-making. With the publication of landmark studies such as DESTINY-Breast04, the clinical value of HER2-low (IHC 1+ or 2+/ISH-) breast cancer has become increasingly prominent. This study, based on cancer registry data from North Carolina, USA, systematically evaluates for the first time the epidemiological characteristics, healthcare utilization patterns, and survival outcomes of HER2-low breast cancer, providing important evidence-based guidance for clinical practice in the era of precision medicine.

II. Study Methodology Design
This study adopted a retrospective cohort design with the following inclusion criteria:

• Timeframe: Diagnosed between 2010-2016

• Geographical scope: Statewide coverage of North Carolina

• Study population: Female breast cancer patients aged ≥18 years

• Grouping criteria:

  • HER2-negative group (IHC 0)

  • HER2-low group (IHC 1+ or 2+/ISH-)

III. Primary Endpoints:

Prevalence of HER2-low expression

Demographic/clinical characteristic differences

Healthcare utilization patterns

1. 3-year all-cause mortality (Stage IV subgroup)

IV. Statistical Methods:

• Categorical variables: χ² test

• Continuous variables: t-test/Mann-Whitney U test

• Survival analysis: Cox proportional hazards model

• Adjustment factors: Age, race, stage, HR status

V. Key Research Findings
1. Epidemiological Characteristics
In the overall cohort of 12,965 cases:

• HER2-low accounted for 59% (n=7,649)

• HR positivity rate was significantly higher than IHC 0 group (82% vs 68%, p<0.001)

In the Stage IV subgroup of 635 cases:

• HER2-low accounted for 53% (n=337)

• Black patient proportion was significantly higher than IHC 0 group (26% vs 16%, p=0.016)

Table 1. Baseline Characteristics Comparison (Overall Cohort)

2. Healthcare Utilization

• Hospitalization rate: HER2-low vs IHC 0

  • Overall cohort: 32% vs 29% (p=0.008)

  • Stage IV cohort: 58% vs 51% (p=0.047)

• No significant difference in ER visit rates (p>0.05)

3. Survival Analysis
3-year survival rate in Stage IV patients:

• HER2-low group: 41.2% (95%CI 36.8-45.6)

• IHC 0 group: 38.7% (95%CI 34.3-43.1)
  (HR=0.93, p=0.42)

VI. Discussion and Clinical Implications
1. New Epidemiological Findings
This study first confirmed:

• HER2-low accounts for 59% of HER2-negative breast cancers

• Black Stage IV patients show significantly higher HER2-low prevalence (+10%)
  These findings are highly consistent with previous single-center studies (e.g., Tarantino et al. reported 57%).

2. Treatment Strategy Optimization
Based on DESTINY-Breast04 evidence:

• HER2-low mBC patients receiving DS-8201 achieved 4.8-month PFS extension (HR 0.50)

• This population constitutes 53% of Stage IV patients, indicating novel ADCs will significantly change clinical practice

3. Racial Disparity Alert
Potential mechanisms for higher HER2-low in Black patients:

• Tumor biology differences: Basal-like subtype distribution

• Detection standard variations: IHC interpretation subjectivity

• Socioeconomic factors: Healthcare accessibility

4. Clinical Management Challenges
Current practical issues:

• Pathology standardization: Need for more precise IHC/ISH criteria

• Treatment decision complexity: Dual-target strategies for HR+/HER2-low patients

• Economic toxicity considerations: Cost-effectiveness analysis of ADCs

VII. Future Research Directions

1. Molecular Mechanism Exploration

   • Genomic/transcriptomic features of HER2-low

   • Epigenetic regulation mechanisms

2. Clinical Translation Research

   • Real-world efficacy validation of novel ADCs

   • Optimization of dual-target combinations (e.g., CDK4/6 inhibitors + ADCs)

3. Health Equity Research

   • Development of disparity-reducing interventions

   • More accessible detection technologies

VIII. Conclusions and Recommendations
Through large-scale population data analysis, this study establishes the important clinical status of HER2-low breast cancer. Key conclusions:

HER2-low represents 59% of HER2-negative breast cancers, constituting a crucial therapeutic target population

Significantly higher HER2-low prevalence in Black Stage IV patients necessitates attention to healthcare equity

Current comparable survival outcomes may be altered by novel ADCs

Clinical Practice Recommendations:

Routine HER2-low testing for all newly diagnosed breast cancers

Establish multidisciplinary teams for optimized treatment decisions

Strengthen pathology quality control

Incorporate racial factors into treatment considerations

Study Limitations:

Inherent information bias in retrospective design

Lack of treatment details (e.g., specific regimens, dosages)

Limited follow-up duration (median 42 months)