Abstract P1-18-13: Impact of prior (neo)adjuvant trastuzumab exposure on the efficacy of HER2 targeted therapy for metastatic breast cancer
Authors: Kanjanapan Yada , Tran Dan , Lok Sheau Wen , Gibbs Peter , De Boer Richard , Yeo Belinda , Greenberg Sally , Barnett Frances , Knott Louise , Richardson Gary , Wong Rachel , Nottage Michelle , Collins Ian , Torres Javier , Lombard Janine , Johns Julie , Harold Michael , Malik Laeeq 
Published: March 2020

Abstract
Background: HER2 targeted therapies, such as trastuzumab, pertuzumab and trastuzumab-emtansine (TDM-1), have improved survival of patients (pts) with HER2+ metastatic breast cancer (MBC). In the pivotal phase III study of pertuzumab/trastuzumab/docetaxel in MBC (NCT00567190), only 10% of pts received prior trastuzumab, whereas in modern practice the majority of recurrent HER2+ MBC pts have received neo(adjuvant) trastuzumab [NAT]. Survival outcomes in the real world setting have not been well described.
Methods: Pts were part of a prospective national registry collecting clinicopathologic, treatment and outcome data for HER2+ MBC pts diagnosed between 10/2006 and 1/2019. Survival was estimated by the Kaplan-Meier method and compared among groups by log-rank test. A multivariable analysis was used to assess the impact of prior trastuzumab-use on survival. Analysis was stratified by estrogen receptor (ER) status to exclude the impact of concurrent endocrine therapy in the ER positive (ER+) subgroup. The TABITHA registry is sponsored by BioGrid Australia with financial support from Roche Products Pty Limited.
Results: Of 254 HER2+ MBC pts in the registry, 225 received HER2 directed therapy in the first-line advanced disease setting and were included for analysis. Median age was 58 years, 100 (44%) had de novo metastatic disease, 131 (58%) had ER+ disease and 24 (11%) had brain metastases. Of the 125 (56%) pts with recurrent disease, 89 (71%) pts received NAT. First-line HER2 therapy was pertuzumab plus trastuzumab in 176 (78%), trastuzumab in 38 (17%), TDM-1 in 9 (4%), and lapatinib or pertuzumab alone in single pts (&lt;1%). Concurrent chemotherapy was given in 205 (91%) pts, all but one case was taxane-based.
The response rate to anti-HER2 therapy among all MBC pts evaluable for response was 42% in pts who received NAT, and 53% in pts who did not (p=0.20). Median progression free survival (PFS) was 16.4 months and 22.6 months, in pts who were trastuzumab-treated and trastuzumab-naïve, respectively (HR 1.44 [95%CI 0.99 - 2.10], p=0.05). The median overall survival (OS) from first-line HER2-directed therapy for MBC was 41.2 months in pts who had prior NAT, and 52.0 months in trastuzumab-naïve pts (HR 1.73 [95%CI 1.04 - 2.86], p=0.03). On multivariable analysis, prior trastuzumab-exposure was no longer significantly associated with survival. Factors significantly associated with PFS were ER status (HR 0.63, p=0.02) and age (HR 1.02, p=0.04), while only age was significantly associated with OS (see table). Among the subset of 93 ER negative (ER-) pts, prior NAT was significantly associated with inferior PFS (HR 1.97 [95%CI 1.11 - 3.52], p=0.02) and OS (HR 2.13 [95% CI 1.00 - 4.57], p=0.046). Multivariable analysis found only age and presence of brain metastases to be significantly associated with OS in the ER- subgroup. NAT exposure did not impact on PFS (HR 1.15, [95% CI 0.70 - 1.90], p=0.58) or OS (HR 1.37, [95% CI 0.68 - 2.73], p=0.37) in ER+ pts.
Conclusions: In pts with HER2+ MBC, receipt of NAT was associated with inferior survival when HER2 targeted therapy was used in the metastatic setting on univariate analysis, but this finding was not seen in a multivariable analysis. Furthermore, the impact of NAT was only observed in the subset of pts with ER- tumors, raising the possibility that the disease-course in ER+ subgroup is not entirely HER2 driven. Survival rates of these HER2+ MBC pts treated in the community are comparable to that reported in clinical trials.
Cox proportional hazard models for OS in MBC on HER2-targeted therapyUnivariableMultivariableHR95% CIPHR95% CIPAdjuvant trastuzumab Y vs N1.731.04 – 2.850.031.370.64 – 2.940.42De novo metastatic disease Y vs N0.610.37 – 1.020.060.810.38 – 1.730.59Estrogen receptor positive vs negative0.880.53 – 1.440.600.690.41 – 1.180.18Brain metastases Y vs N1.800.88 – 3.670.111.960.90 – 4.260.09Age (years)1.021.00 – 1.040.051.031.01 – 1.060.003
Citation Format: Yada Kanjanapan, Dan Tran, Sheau Wen Lok, Peter Gibbs, Richard De Boer, Belinda Yeo, Sally Greenberg, Frances Barnett, Louise Knott, Gary Richardson, Rachel Wong, Michelle Nottage, Ian Collins, Javier Torres, Janine Lombard, Julie Johns, Michael Harold, Laeeq Malik. Impact of prior (neo)adjuvant trastuzumab exposure on the efficacy of HER2 targeted therapy for metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-13.