Abstract P4-02-01: Efficacy of HER2 ADCs against HER2 inhibitor resistance alterations in the PI3K and MAPK pathways in HER2-positive breast cancer
Authors: Ferraro Emanuela , Safonov Anton , Chen Yuan , White Charlie , Marra Antonio , Ahmed Mehnaj , Acevedo Barbara , Dang Chau T , Modi Shanu , Solit David B. , Norton Larry , Robson Mark E. , Reis-Filho Jorge , Chandarlapaty Sarat , Razavi Pedram 
Published: March 2023

Abstract
Background: HER2 positive (HER2+) breast cancers harboring downstream MAPK or PI3K pathway alterations manifest persistent downstream signaling on anti-HER2 inhibitors with metastatic patients having worse outcomes on first line trastuzumab and pertuzumab (HP) therapy. However, HER2 antibody-drug conjugates (ADCs) are not as dependent upon potent signal transduction inhibition to exert their antitumor effects. To further investigate, we sought to determine whether MAPK and/or PI3K alterations affect the biologic or clinical outcomes of patients and models receiving HER2 ADCs. Methods: We performed prospective genomic sequencing using MSK-IMPACT on patients with advanced HER2+ breast cancer who received trastuzumab emtansine (T-DM1) in the metastatic setting between March 2013 and July 2021. We collected detailed information on clinical outcomes and correlates through our institutional IRB-approved retrieval process. HER2/ER/PR status at the time of metastatic recurrence were defined as per ASCO/CAP guidelines. Cox proportional hazard models were used to determine the association between MAPK and PI3K pathways alterations and progression-free survival (PFS) on T-DM1. Common mutations associated with outcomes were modeled in HER2+ breast cancer cell lines using short hairpin RNAs and CRISPR/Cas9, and the sensitivity to HER2 ADC was evaluated via cell proliferation and xenograft assays. Results: We identified 185 HER2+ breast cancer patients treated with T-DM1 at any line (median: 5) whose primary (N=65) or metastatic (N=120) tumor samples were sequenced. Median age was 55 (range: 20-87). The majority of the patients received T-DM1 in 2nd or 3rd line (52%) and received prior trastuzumab or HER2 TKI in metastatic setting (96%). 74/185 (40%) had de novo metastatic breast cancer and 119/185 (64%) had ER/PR+/HER2+ disease. Pathogenic activating alterations involving the MAPK pathway were observed in 14% of patients with the most frequent alterations being ERBB2 activating mutations (42%) and NF1 loss (34%). PI3K pathway alterations were identified in 42% of the patients, the majority being activating mutations of PIK3CA (87%). MAPK alterations were significantly enriched in the metastatic tumors compared to the treatment-naïve primaries (20% vs 3%, p=0.001), while PI3K alterations were not (44% vs 40%, p=0.6). To reduce the possible confounding resistance mechanisms induced by prior treatment, we restricted the survival analyses to patients who received T-DM1 up to 3rd line of therapy (N=100). On multivariable analysis adjusted for ER/PR status (positive vs negative), stage at the presentation of metastatic disease (de novo metastatic vs recurrence), treatment line and type of sequenced sample (primary vs metastatic), patients with MAPK (N=14) and PI3K (N= 38) alterations had similar PFS compared to wild type (HR 1.20, 95%CI 0.62-2.30, p=0.6 and HR 1.23, 95%CI 0.77-1.95, p=0.4, respectively). Similar results were found in the combined analysis including alterations in either pathway (N=48, HR 1.28, 95%CI 0.81-2.04, p=0.3). To verify the antiproliferative effect of HER2 ADCs on breast cancer cells with MAPK pathway activation, we depleted NF1 in a panel of HER2+ breast cancer cell lines. Consistently, MAPK-altered cell lines were sensitive to FDA-approved HER2 ADCs including trastuzumab deruxtecan (T-DXd). Conclusions: In contrast to H/P therapy, T-DM1 therapy was equally effective in tumors with downstream PI3K or MAPK alterations and wild type tumors. Expanded analysis on a larger cohort, including a subgroup of patients treated with novel HER2 ADCs such as T-DXd will be presented. The characterization of PI3K and MAPK pathways status in metastatic HER2+ breast cancer may inform prioritization of treatment options.
Citation Format: Emanuela Ferraro, Anton Safonov, Yuan Chen, Charlie White, Antonio Marra, Mehnaj Ahmed, Barbara Acevedo, Chau T Dang, Shanu Modi, David B. Solit, Larry Norton, Mark E. Robson, Jorge Reis-Filho, Sarat Chandarlapaty, Pedram Razavi. Efficacy of HER2 ADCs against HER2 inhibitor resistance alterations in the PI3K and MAPK pathways in HER2-positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-01.