P1-12-15: Adjuvant Trastuzumab Effect on HER2−Positive Breast Cancers According to Hormonal Receptor (HR) Status: Crosstalk between ER and EGFR/HER2 Pathway May Prevent Trastuzumab from Improving Outcomes in HER2−Positive and HR-Positive Breast Cancers.
Authors: YH Park, EY Cho, JE Lee, SJ Nam, JH Yang, JS Ahn, Y-H Im
Journal: Cancer Research (2011)

Abstract Background: Crosstalk between growth factor receptor, especially the EGFR/HER2 pathway, and ER pathways has been associated with endocrine resistance. Thus, combination therapy targeting both ER and EGFR/HER2 signaling to block the crosstalk between these pathways and eliminate escape routes have been proven effective in both preclinical and clinical models. Anti-HER2 directed therapy has been reported to restore hormone sensitivity in HER2−positive breast cancers. Adding trastuzumab to conventional treatment has been a standard treatment of choice in HER2−positive breast cancer irrespective of hormonal receptor (HR) status. The purpose of the study is to evaluate adding effect of 1 year of trastuzumab to conventional adjuvant treatment in patients with HER2−positive breast cancer who received surgery according to HR status. Patients and Methods: We retrospectively analyzed the clinicopathologic characteristics and outcomes of 618 postoperative HER2−positive breast cancer patients between 2001 and 2008 at the Samsung Medical Center. Most of HER2−positive patients in our institute were treated with 1 year of trastuzumab as a part of adjuvant therapy since 2007 (post-trastuzumab era) compared with 2000–2006 (pre-trastuzumab era). Clinical outcomes including recurrence-free survival (RFS) were analyzed between pre-trastuzumab and post-trastuzumab era according to HR status. We performed Cox regression multivariate analysis for relapse using variables from univariate analysis by log-rank test for relapse. Clinical presentations and clinicopathologic characteristics were evaluated at the time of recurrence between both eras. Results: The median age at diagnosis was 46 years (range, 22–79). During the median 60.0 months of follow-up, the 5-year recurrence rate was 20.2%. The 618 patients were divided into two groups (patients who received (n=175) and did not receive (n=443) adjuvant trastuzumab). Recurrence rate was much lower in post-trastuzumab era than in pre-trastuzumab era (13.6% vs. 32.3%, p&amp;lt;0.0001). Improving outcomes due to adding trastuzumab in patients with HER2+ve/HR-ve patients showed significant benefit from trastuzumab throughout the follow-up period (p=0.004). However, this improving effect appeared not to be consistent with statistical significance in HER2+ve/HR+ve patients (p=0.135). The analyses were performed according to quantitative ER Allred scores in HER2+ve/ER+ve patients, the effect of adding trastuzumab appeared to be mitigated as time over without any statistical significance (p=0.975). Young age (≤35) (hazard ratio (HR) 2.4, p&amp;lt;0.0001), trastuzumab use (HR 0.4, p=0.001), and node positivity (HR 2.8, p&amp;lt;0.0001) were identified as independent prognostic factors for recurrence in Cox-regression multivariate analysis. Limiting to HER2+ve/ER+ve patients, the statistical significances of trastuzumab use as independent factors were not maintained in Cox-regression models (p=0.074 for trastuzumab use). Conclusion: Cross-talk between ER and EGFR/HER2 pathways may mitigate trastuzumab effect in HER2+ve/ER+ve breast cancers. Further study is warranted. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-15.