Prognostic and predictive value of phosphorylated HER2, HER3 and PTEN expression in patients with HER2-positive breast cancer treated with trastuzumab

Background: Trastuzumab improves survival in HER2-positive breast cancer patients. But there are no other predictive markers for the treatment and only half of patients benefit from it. Our aim is to evaluate an association between expression of proteins engaged into HER2-signaling pathway and overall survival of patients treated with trastuzumab. Methods: A retrospective analysis of 81 patients with breast cancer treated with trastuzumab in adjuvant (n = 45) or palliative (as a 1st to 5th line; n = 36) regimens in our institution from 2003 to 2010 was done. Immunohistochemistry staining for expression of phosphorylated HER2 (p-HER2), HER3 and PTEN was performed. We analyzed an association between expression of the proteins and overall survival (OS) and overall survival from start of trastuzumab treatment (OStrast) defined, respectively, as a time from date of diagnosis or time from start of trastuzumab to date of death or last observation. The relationship between tested parameters and survival was analyzed by the Cox regression models. We used Kruskall-Wallis analysis of variance and Fisher's exact test to verify correlation between the proteins expression and clinical features of the patients. Statistical significance was assumed when p < 0.05. Results: 55.6%, 32% and 34.6% of the tumors were positive for HER3, PTEN and p-HER2, respectively. Positivity of HER3 and PTEN correlated with larger size of tumors (p = 0.016 and p = 0.008, respectively) and p-HER2-positivity - with more advanced clinical stage (p = 0.032). Median follow-up was 141 months. We recorded, respectively, 14 and 34 deaths in adjuvant and in palliative group. We have not found any correlation between the expressions of the proteins and survival neither for patients treated with palliative nor adjuvant regimen. For 27 patients treated palliatively with trastuzumab in 1st or 2nd line we have shown a trend toward worse OStrast in p-HER2-positive subgroup (HR 2.39; 95%: 0.99 to 5.79; p = 0.053). For patients treated with adjuvant trastuzumab numerically higher mortality rate was recorded for p-HER2-positive patients (7/15 v. 7/30). Conclusions: p-HER2 may have predictive value for trastuzumab treatment but this observation needs validation. Legal entity responsible for the study: Medical University of Lodz Study was approved by Bioethical Committee of Medical University of Lodz (No. RNN/138/09/KE 12-05-.2009). Funding: Study was financed by means of European Social Fund (Integrated Regional Operational Program - Grants for innovative PhD studies) and statutory activities no. 503-1034-2. Disclosure: M. Krakowska: Sponsorship of a participation in conferences: Merck, Roche. R. Czyzykowski, U. Czernek: Investigator in clinical trial sponsored by Roche. P. Potemski: Lecture fees, travel support: Roche. All other authors have declared no conflicts of interest.