High p95HER2/HER2 Ratio Associated With Poor Outcome in Trastuzumab-Treated HER2-Positive Metastatic Breast Cancer NCCTG N0337 and NCCTG 98-32-52 (Alliance)

Abstract

Purpose: p95HER2 is a truncated form of HER2 that confers resistance to trastuzumab in vitro, but clinical results have been conflicting to date. Given that p95HER2 levels correlate with total HER2 expression levels, which confer better outcomes, we sought to evaluate the p95HER2/HER2 ratio in the North Central Cancer Treatment Group N0337 and N98-32-52 trials.Experimental Design: The HERmark assay and VeraTag technology (Monogram Biosciences) were used to measure total HER2 and p95HER2 expression levels in 91 patient samples.Results: In the multivariate model, increasing total HER2 level was significantly associated with longer (OS; HR, 0.33; P = 0.002) and decreasing p95HER2 level was significantly associated with longer OS (HR, 4.2; P = 0.01). Total HER2 expression level was significantly associated with longer progression-free survival (PFS) (HR, 0.57; P = 0.04), whereas p95HER2 level was not (HR, 1.7; P = 0.25). However, there was a positive association between p95HER2 and total HER2 expression levels (R2 = 0.48; P < 0.001). Consistent with our hypothesis, the ratio of p95HER2/HER2 was significantly associated with worsening PFS (HR, 1.7; P = 0.04) and OS (HR, 2.8; P = 0.002). Patients with the highest tertile of p95HER2/HER2 values had significantly less favorable PFS (HR, 1.8; P = 0.06) and OS (HR, 2.3; P = 0.02).Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 24(13); 3053-8. ©2018 AACR.

Trial registration: ClinicalTrials.gov NCT00093808 NCT00003612.

Conflict of interest statement

Conflict of interest: Drs. Chumsri, Liu, Gligorov, Spano, Antoine, Moreno Aspitia, Tan, Bates and Weidler have no conflict of interest to report. Drs. Sperinde, Winslow, Petropoulos, Chenna, and Huang work for Monogram Biosciences. Dr. Perez works for Genentech.

©2018 American Association for Cancer Research.

Figures

Figure 1:

HER2 FISH, HER2 Protein, and p95HER2 Protein. A, HER2 protein expression vs. HER2/CEP17 FISH ratio; lines correspond to cutoffs for HER2 FISH-negative vs positive (solid) and HERmark-negative vs. equivocal vs. positive (dashed). B, p95HER2 protein expression vs. HER2 protein expression; lines correspond to HERmark cutoffs (dotted) and p95HER2-negative vs. positive (dashed). Abbreviations: FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2.

Figure 2:

HER2 and p95HER2 vs. Number of Metastatic Sites. A, HER2 protein expression vs number of metastatic sites. B, p95HER2 protein expression versus number of metastatic sites. Measurements below the limit of detection are shown as

Figure 3:

Kaplan-Meier Plots by Tertile for A, Progression-Free Survival and B, Overall Survival for Tertiles of p95/HER2 Ratio.