Abstract OT1-12-01: Solti-1804 HER2-PREDICT: Translational study of tumor samples from breast cancer patients treated with trastuzumab deruxtecan in the metastatic setting
Authors: Prat Aleix , Saura Cristina , Cruz Josefina , Fernández Esteban Nogales , Bofill Javier Salvador , Gavilá Joaquin , Bermejo-Perez Maria José , Quiroga Vanesa , Morales Serafin , Servitja Sonia , de Toro Ruben , Zamora Pilar , Galván Patricia , Chic Nuria , Martínez Débora , Brasó-Maristany Fara , Canes Jordi , Paré Laia , Ferrero-Cafiero Juan M , Pascual Tomás , Pernas Sonia 
Published: March 2022

Background: Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in 15-20% of breast cancers (BC). At the same time, HER2-low tumors (immunohistochemistry 1+ or 2+ with no gene amplification) comprise ~50% of all BC. Trastuzumab Deruxtecan (T-DXd) is an anti-HER2 antibody drug conjugate that has shown impressive and durable response rates not only in HER2+ and HER2low BC, but also in other cancer subtypes expressing the HER2 receptor. However, not all patients respond or benefit to the same extent. Thus, there is a need to identify predictive biomarkers. Here, we hypothesize that by performing several molecular studies in both tissue and plasma samples of those patients participating in the DESTINY studies receiving T-DXd, we will shed more light on the molecular features of HER2 expressing BC and will better characterize the patient population that benefits benefit from this promising new anti-HER2 agent. Methods: HER2-PREDICT is a multi-center, observational study within the biomarker program of SOLTI group, which will include patients who received T-DXd-only while participating in DESTINY trials. Both HER2-positive and HER2-low unresectable and/or metastatic breast cancer may be included in SOLTI-1804 HER2-PREDICT study (NCT04257162). All patients need to consent to obtain a fresh tumor biopsy or donate an archival metastatic biopsy. Primary tumors may be allowed under SOLTI acceptance. Additionally, for patients included before initiating T-DXd treatment blood samples for biomarker analyses on Cycle 1 Day 1 (C1D1), C2D1 and end of treatment will be obtained. Collection of tumor biopsies is an essential part of this study. Pathological analyses will include hematoxylin and eosin (H&E) staining of formalin-fixed paraffin-embedded (FFPE) tissue, identification of areas with the greater amount of tumor cells and determination of their tumor cell percentage. RNA will be isolated and analyzed using the nCounter platform (Nanostring Technologies). Molecular intrinsic subtypes will be identified by a research-based version of PAM50. Furthermore, we aim to evaluate 771 additional genes (+5 housekeeping genes) that encompass genomic signatures and individual genes of importance in breast cancer by means of the nCounter®Breast Cancer 360 Panel. Somatic mutations in PIK3CA, TP53, and additional genes (e.g., GATA3 and ERBB2) will be identified using next-generation sequencing (NGS) in FFPE tumor blocks and plasma samples. Objectives: The primary objectives are (1) to identify an optimal ERBB2 mRNA cut-off point predictive of T-DXd response and (2) to evaluate the correlation of baseline ERBB2 mRNA levels (as a continuous variable) with overall response rate (ORR). Secondary objectives include: to evaluate the association of ERBB2 mRNA levels, PAM50 intrinsic subtypes and immune-related genes with ORR, progression-free survival (PFS) and overall survival (OS); to design a new gene expression signature predictive of clinical benefit; to evaluate the correlation in early changes in circulating tumor DNA (ctDNA) with ORR, PFS and OS; and to identify acquired somatic mutations of resistance upon progression in plasma samples. The study is active in 13 sites in Spain, and 39 patients have been included in the trial since December 2019 until June 2021. Acknowledgments: We thank Daiichi Sankyo Inc. for their financial support for the study.

Citation Format: Aleix Prat, Cristina Saura, Josefina Cruz, Esteban Nogales Fernández, Javier Salvador Bofill, Joaquin Gavilá, Maria José Bermejo-Perez, Vanesa Quiroga, Serafin Morales, Sonia Servitja, Ruben de Toro, Pilar Zamora, Patricia Galván, Nuria Chic, Débora Martínez, Fara Brasó-Maristany, Jordi Canes, Laia Paré, Juan M Ferrero-Cafiero, Tomás Pascual, Sonia Pernas. Solti-1804 HER2-PREDICT: Translational study of tumor samples from breast cancer patients treated with trastuzumab deruxtecan in the metastatic setting [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 OT1-12-01.