Odzer on ERBB2 Copy Number Ratio as a Predictive Biomarker in HER2+ Breast Cancer

“We were able to show that copy number ratio did correlate with overall immunohistochemistry scores as we would have hoped, so we’re hoping that this helps us better understand copy number ratios as a possible biomarker to use in the future.”

Nicole Odzer, third-year medical student, Yale University School of Medicine, discusses findings from a retrospective study evaluating ERBB2 copy number ratio as a predictive biomarker in metastatic breast cancer treated with conjugated and unconjugated HER2-targeting therapies.

In this study, investigators used the Flatiron Health and Foundation Medicine clinico-genomic database to assess the predictive value of ERBB2 copy number ratio in 2 cohorts of patients with metastatic breast cancer. Cohort 1 (n = 121) included patients with HER2-positive disease treated with trastuzumab (Herceptin), pertuzumab (Perjeta), and taxane chemotherapy in the first-line setting, whereas cohort 2 (n = 95) included patients with HER2-low or HER2-negative disease treated with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in later-line settings.

Results presented at the 2024 San Antonio Breast Cancer Symposium revealed significant associations between ERBB2 copy number ratio and clinical outcomes. In cohort 1, patients with a copy number ratio of greater than 5 experienced superior outcomes across all end points, including real-world time to treatment discontinuation (rwTTD; copy number > 5, median 8.4 months; copy number ≤ 5, median 5.3 months; HR, 0.55; 95% CI, 0.36-0.84; P = .006), real-world progression-free survival (rwPFS), and real-world overall survival (rwOS) compared with those with a copy number ratio of 5 or lower. These findings indicate that a higher ERBB2 copy number ratio is associated with longer response to first-line trastuzumab-based regimens.

In cohort 2, exploratory analyses evaluated ERBB2 copy number ratio in patients with HER2-low/negative metastatic breast cancer treated with T-DXd in the second-line or later settings. Patients with an ERBB2 copy number ratio of 0.5 or lower had poorer outcomes across all key end points compared with those with a copy number ratio greater than 0.5. The median rwTTD, rwPFS, and rwOS for patients with an ERBB2 copy number ratio of 0.5 or less were 1.6 months, 2.5 months, and 6.5 months, respectively, compared with 4.8 months, 6 months, and 25.2 months for those with a copy number ratio of greater than 0.5.

Multivariate analyses of cohort 2 confirmed the independent predictive value of ERBB2 copy number ratio for rwPFS (HR, 0.21; 95% CI, 0.076-0.58; P = .003), even when accounting for imbalances in baseline factors, including disease stage, ECOG performance status, estrogen receptor status, and age at treatment initiation. Trends favoring superior outcomes with a higher copy number ratio were also observed for rwTTD (HR, 0.71; 95% CI, 0.28-1.7; P = .45) and rwOS (HR, 0.53; 95% CI, 0.17-1.64; P = .27).

Mechanistically, the study confirmed a strong correlation between ERBB2 copy number ratio and HER2 immunohistochemistry scores, supporting its relevance as a complementary biomarker. Odzer concludes that these findings indicate that ERBB2 copy number ratio could guide treatment escalation and surveillance strategies in patients with HER2-positive and HER2-low disease.