Abstract OT-03-07: Solti-1804 HER2-PREDICT: A biomarker research study of DS8201-A-U301 -U302 and -U303 trials
Authors: Prat Aleix , Gavilá Joaquin , Pernas Sonia , Cruz Josefina , Saura Cristina , Nogales Esteban , Bermejo Maria , Bofill Javier Salvador , Quiroga Vanesa , Garcia-Estévez Laura , Morales Serafin , Servitja Sonia , del Toro Rubén , Galván Patricia , Chic Núria , Martinez Débora , Brasó-Maristany Fara , Canes Jordi , Paré Laia , Ferrero-Cafiero Juan M , Villagrasa Patricia 
Published: February 2021

Abstract
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. DS-8201a is an anti-HER2 antibody drug conjugate that has shown very promising response rates both in HER2+ and HER2low BC. However, not all patients respond or benefit to the same extend. 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 pivotal DESTINY-Breast trials, we will shed more light about the molecular features of HER2+ BC and better characterized the patient population according to their 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 will participate, are participating or previously participated in the Daiichi Sankyo INC sponsored phase III trials: DS8201-A-U301 (NCT03523585), -U302 (NCT03529110) and -U303 (NCT03734029). Patients with HER2-positive or HER2-low unresectable and/or metastatic breast cancer may be included in SOLTI-1804 HER2-PREDICT study if randomized to the DS-8201a arm. All patients need to consent for obtaining a fresh tumor biopsy or donating an archival metastatic biopsy. Primary tumors are allowed under SOLTI acceptance. Additionally, patients included before initiating DS-8201a therapy will provide blood samples for biomarker analyses on Cycle 1 Day 1 (C1D1), C2D1 and end of treatment. The primary objectives are (1) to identify an optimal ERBB2 mRNA cut-off point predictive of Ds-8201a response and (2) to evaluate the correlation of baseline ERBB2 mRNA levels (as a continuous variable) with overall response rate (ORR) in the Ds-8201a-treated cohorts. Secondary objectives includes: to evaluate the association of ERBB2 mRNA levels, PAM50 intrinsic subtypes and immune-related genes with ORR, progression-free survival and overall survival; to design a new gene expression signature predictive of Ds-8201a benefit; to correlate early changes in ctDNA with Ds-8201a benefit and to identify acquired somatic mutations of resistance to DS8201a upon progression in plasma samples. Collection of tumor biopsies is an essential part of this study. Pathological analysis includes hematoxylin and eosin (H&E) staining, identification of areas with greater amount of tumor cells and determination of their tumor cell percentage. RNA will be isolated and analyzed at the nCounter (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 important genomic signatures and individual genes of importance for 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). Also, a comprehensive NGS gene panel will be performed under the Ion Torrent or Illumina platforms to DNA extracted from FFPE tumor blocks and to circulating tumor DNA (ctDNA) in plasma samples. Current status: Since December 13th, 2019, a total of 10 patients have been included, 5 of them with blood samples. As of today, 13 out of 15 Spanish sites are recruiting patients. Clinical trial identification: NCT04257162
Citation Format: Aleix Prat, Joaquin Gavilá, Sonia Pernas, Josefina Cruz, Cristina Saura, Esteban Nogales, Maria Bermejo, Javier Salvador Bofill, Vanesa Quiroga, Laura Garcia-Estévez, Serafin Morales, Sonia Servitja, Rubén del Toro, Patricia Galván, Núria Chic, Débora Martinez, Fara Brasó-Maristany, Jordi Canes, Laia Paré, Juan M Ferrero-Cafiero, Patricia Villagrasa. Solti-1804 HER2-PREDICT: A biomarker research study of DS8201-A-U301 -U302 and -U303 trials [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-07.