Abstract P2-13-05: Central nervous system metastases as a site of first recurrence in adjuvant therapy trials of HER2+ early breast cancer (EBC)
Authors: Lin Nancy U , Lueftner Diana , Brufsky Adam M , Tolaney Sara M , Melisko Michelle E , Holmes Frankie Ann , Awada Ahmad 
Published: March 2022

Abstract
Background: Among patients (pts) with HER2+ early breast cancer (EBC), the CNS continues to serve as a sanctuary for distant metastases following trastuzumab-based adjuvant treatment (von Minckwitz 2017, Piccart 2020, von Minckwitz 2019). Since the initial trastuzumab adjuvant trials, several other HER2-directed agents, including pertuzumab, lapatinib, ado-trastuzumab emtansine, and neratinib have been evaluated in EBC. We sought to describe the incidence of CNS metastases as a site of first recurrence in pts with HER2+ EBC who have received a HER2 directed agent, in order to evaluate whether there is any evidence of CNS prevention. Methods: A literature analysis was performed to identify controlled pivotal trials of HER2-directed adjuvant therapy in pts with HER2+ EBC and with or without prior neoadjuvant therapy. Data regarding CNS metastases as the first site of recurrence was extracted along with data from a meta-analysis of trastuzumab adjuvant trials. Due to differences in trial design, populations studied and differences in the use of neoadjuvant therapy, a descriptive summary of data is presented in lieu of statistical cross-trial comparisons. Results: Results from adjuvant trials of trastuzumab, lapatinib, neratinib, pertuzumab, and ado-trastuzumab emtansine in pts with HER2+ EBC (meta-analysis of trastuzumab trials, ALLTO, ExteNET, APHINITY and KATHERINE, respectively) are summarized (Table). In the trastuzumab adjuvant trials the incidence of CNS metastases was ~2.5% (Olson 2013). No pts had prior neoadjuvant therapy in APHINITY and neoadjuvant use was limited in ALLTO (8%). The addition of lapatinib, a reversible TKI, or pertuzumab, a HER2 monoclonal antibody, to trastuzumab had no impact on the incidence of CNS metastases. In the lapatinib and pertuzumab studies, the incidence of CNS metastases in all study groups was ~2%. The proportion of pts with CNS recurrence as a first site of metastasis among placebo pts in the ExteNET trial was similar to that reported in the other 3 trials (Table). Numerical improvements in the incidence of CNS as a site of first recurrence were seen in the intention-to-treat (ITT) population as well as in pts with hormone receptor positive (HR+) disease. The 5-year cumulative incidence of CNS metastases as a site of first recurrence in the ExteNET ITT population was 1.3% and in pts with HR+ disease who initiated neratinib ≤1 year post trastuzumab (HR+/≤1yr) was 0.7% (Table). The KATHERINE study, which enrolled higher risk patients, reported a higher incidence of CNS metastases as site of first recurrence, but without a reduction in the intervention arm (5.9% ado-trastuzumab emtansine and 4.3% trastuzumab). In a descriptive analysis of the subgroup of pts in ExteNET who were HR+/≤1yr and had residual disease after neoadjuvant therapy (n=295), the incidence of CNS metastases was 0.8% in the neratinib arm vs 3.6% in the placebo arm. Conclusions: The risk of developing a CNS metastasis as the site of first recurrence is generally low; however, it is higher in those with residual disease after neoadjuvant therapy. The ExteNET trial of neratinib is the only study to show a signal decrease in the incidence of CNS recurrence as the first site of relapse among HER2+ EBC pts. These data are consistent with other trials showing CNS activity with neratinib in the metastatic setting.
CNS Recurrence as the First Site of Metastasis in Studies of Adjuvant Therapy in HER2+ EBCTrial and PopulationAnalysis TimepointNNeoadjuvant Population CNS Recurrence, %ComparatorTreatmentAdjuvant trast Meta-analysis1-9020N/A1.942.56ALLTO23 yr5190~822ExteNET3ITT5 yr284026%1.81.3HR+/≤1yr post trast.5 yr133427%2.10.7APHINITY4 node (+) or high-risk node ()3 yr480501.91.9No pCR Post Neoadjuvant TxKATHERINE5 high-risk3 yr1486N/A4.35.9ExteNET3 HR+/≤1yr post trast5 yr295N/A3.60.8HR+/≤1yr, hormone receptor positive with start of neratinib ≤1 year following trastuzumab adjuvant therapy; ITT, intent-to-treat; PLB, placebo; T-DM1, ado trastuzumab emtansine; trast, trastuzumab; pCR, pathologic complete responsea.Using all patients in the trials as a denominator1.Olson 2013; 2. Piccart-Gebhart 2015; 3. Chan 2021; 4. Von Minckwitz 2017; 5. Mamounas 2020
Citation Format: Nancy U Lin, Diana Lueftner, Adam M Brufsky, Sara M Tolaney, Michelle E Melisko, Frankie Ann Holmes, Ahmad Awada. Central nervous system metastases as a site of first recurrence in adjuvant therapy trials of HER2+ early breast cancer (EBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-05.