Impact of HER2 Status on CDK4/6 Inhibitor Outcomes for HR-Positive, HER2-Negative Metastatic Breast Cancer
According to a retrospective analysis, the HER2 status did not impact treatment outcomes with CDK4/6 inhibitors among patients with HR-positive, HER2-negative metastatic breast cancer.
Study authors commented, “HER2 expression, even at low levels, may influence the efficacy of CDK4/6 [inhibitors] through bidirectional crosstalk with HR signaling pathways,” adding that some data suggests, “HER2-low tumors may show distinct PFS [progression-free survival] patterns compared with HER2-zero though their prognostic significance remains unclear.”
This multicenter retrospective analysis included 212 patients with HR-positive, HER2-negative metastatic breast cancer who had been treated with CDK4/6 inhibitors (palbociclib or ribociclib) within the first 4 lines of therapy, between 2018 and 2022. Based on immunohistochemistry (IHC) results, patients were classified as either HER2-zero, defined as IHC 0 (n = 100), or HER2-low, defined as IHC 1+ or 2+ without HER2 genetic amplification as confirmed by ISH (n = 112). Outcomes compared between the 2 groups included PFS, objective response rate, and disease control rate.
The median follow-up time was 24.7 months and the overall PFS was 15.0 months. In the HER2-low group, the median PFS was 16.0 months, compared to 13.9 months in the HER2-zero group, which did not represent a statistically significant difference (P = .40). For patients treated with CDK4/6 inhibitors in the first line, the PFS was 18.6 months in the HER2-low group vs 14.9 months in the HER2-zero group, which did not represent a statistically significant benefit (P = .26). For those who received a CDK4/6 inhibitor in the second line or later, the median PFS was 12.3 months in both the HER2-low and the HER2-zero group. The ORR was 71.4% in the HER2-low group and 62% in the HER2-zero group, and the disease control rates were 86.6% and 82%, respectively — neither of which represents a significant difference between the groups. Multivariate analysis confirmed the presence of visceral metastases and the line of CDK4/6 inhibitor therapy as independent prognostic factors for PFS — an association between both limited metastatic burden and the absence of visceral involvement with longer PFS.
Within the HER2-low group, there was a longer PFS among those with recurrent metastases (17.9 months) compared to those with de novo metastases (13.4 months; P = .04). Study authors noted this data “should be interpreted with caution due to the limited sample size and possible confounders” and that the trend “lacks sufficient statistical power to suggest a meaningful conclusion.” Patients with HER2-low disease who had a single metastatic site also had a longer PFS (20.2 months) when compared to those with 2 or more metastatic sites (14.1 months, P = .02). There was no similar effect from metastasis type or number of metastasis sites observed in the HER2-zero group.
Study authors concluded that data from this analysis “suggest that HER2 expression alone is not a definitive predictor of treatment response in HR-positive, HER2-negative [metastatic breast cancer] patients receiving CDK4/6 [inhibitors].” They also noted that “relying solely on IHC scoring to define HER2-low status may be insufficient,” and recommended “the identification of advanced biomarkers for subclassifying HER2-negative patients should be considered a key objective for future research.”
Source:
Ozcan E, Gokmen I, Akgul F, et al. Clinical outcomes of CDK4/6 inhibitor therapy in HR+/HER2– metastatic breast cancer: A multicenter comparison of HER2-low and HER2-zero subgroups. Breast J. Published online: June 27, 2025. doi:10.1155/tbj/5577345
