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

<b>Purpose:</b> p95HER2 is a truncated form of HER2 that confers resistance to trastuzumab <i>in vitro</i>, 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.<b>Experimental Design:</b> The HERmark assay and VeraTag technology (Monogram Biosciences) were used to measure total HER2 and p95HER2 expression levels in 91 patient samples.<b>Results:</b> In the multivariate model, increasing total HER2 level was significantly associated with longer (OS; HR, 0.33; <i>P</i> = 0.002) and decreasing p95HER2 level was significantly associated with longer OS (HR, 4.2; <i>P</i> = 0.01). Total HER2 expression level was significantly associated with longer progression-free survival (PFS) (HR, 0.57; <i>P</i> = 0.04), whereas p95HER2 level was not (HR, 1.7; <i>P</i> = 0.25). However, there was a positive association between p95HER2 and total HER2 expression levels (<i>R</i>² = 0.48; <i>P</i> < 0.001). Consistent with our hypothesis, the ratio of p95HER2/HER2 was significantly associated with worsening PFS (HR, 1.7; <i>P</i> = 0.04) and OS (HR, 2.8; <i>P</i> = 0.002). Patients with the highest tertile of p95HER2/HER2 values had significantly less favorable PFS (HR, 1.8; <i>P</i> = 0.06) and OS (HR, 2.3; <i>P</i> = 0.02).<b>Conclusions:</b> 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. <i>Clin Cancer Res; 24(13); 3053-8. ©2018 AACR</i>.