Quantitative P95her2 Protein Expression Is Predictive Of Trastuzumab Response In Her2-Positive Metastatic Breast Cancer

Background : Expression of p95HER2 (p95), a truncated form of the HER2 receptor that lacks the trastuzumab binding site but retains kinase activity, has been reported as a prognostic biomarker for poor outcome in trastuzumab-treated HER2-positive metastatic breast cancer (MBC). However, the ability of p95 to predict trastuzumab benefit has not been demonstrated due to the difficulty in obtaining the appropriate control group, namely HER2+ MBC patients not treated with trastuzumab. In the current study, the predictive value of p95 expression was tested in a cohort comprised of HER2-positive MBC patients treated before the availability of trastuzumab and trastuzumab-treated HER2-positive MBC patients. Methods : The current cohort was derived from 206 HER2-positive MBC patients in the Munich Cancer Registry with a median follow up of 64 months. Cases were divided between those that received trastuzumab (n=115) and those that were treated before the availability of trastuzumab (n=91). Quantitative p95 protein expression was measured in formalin-fixed paraffin-embedded samples using the p95 VeraTag ® assay (Monogram Biosciences), which is specific for the active M611 form of p95. Quantitative total HER2 protein expression was measured using the HERmark ® assay (Monogram Biosciences). p95 and HERmark cutoffs were pre-specified (Duchnowska, Clin Cancer Res, 20:2805, 2014 and Huang, Am J Clin Pathol, 134:303, 2010). Analyses with p95 were restricted to samples with confirmed HER2 overexpression by HERmark. All hazard ratios (HR) were stratified by estrogen receptor status and grade. Results : Consistent with previous training (Sperinde, Clin Cancer Res, 16:4226, 2010) and validation (Duchnowska, Clin Cancer Res, 20:2805, 2014) datasets, subjects treated with trastuzumab experienced a shorter time to progression (TTP) when p95 expression levels were above the cutoff versus below the cutoff (HR = 3.8, p = 0.019). However, only a trend was observed between p95 expression levels and overall survival (HR = 2.2, p = 0.20), possibly due to a lower frequency of events and relatively small sample size. The predictive value of p95 was assessed by determining the benefit of adding trastuzumab to chemotherapy treatment in subsets below and above the p95 cutoff. As expected, patients with p95 below the cutoff experienced significant benefit in TTP from adding trastuzumab (HR = 0.13, p Conclusions: In this dataset, quantitative p95 expression was predictive of trastuzumab treatment benefit in MBC. Patients with high p95 expression may be particularly good candidates for dual HER2 blockade, as reported in the NeoALTTO trial (Scaltriti, Clin Cancer Res, 21:569, 2015), or other additional therapies. Citation Format: Sperinde J, Bachmeier B, Weidler JM, Lie Y, Chenna A, Winslow J, Engel J, Schubert-Fritschle G, Sommerhoff C, Petropoulos C, Bates M, Huang W, Nerlich A. Quantitative p95HER2 protein expression is predictive of trastuzumab response in HER2-positive metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-09.