Abstract PS2-33: Investigating oncogenic signaling pathways in inflammatory metastatic breast cancer (MBC) though circulating tumor DNA (ctDNA) next-generation sequencing (NGS)
Authors: Gerratana Lorenzo , Davis Andrew A , Mina Marco , Jacob Saya L , Zhang Qiang , Shah Ami N , D’Amico Paolo , Katam Neelima , Wehbe Firas , Vagia Elena , Flaum Lisa , Platanias Leonidas , Behdad Amir , Puglisi Fabio , Gradishar William J , Ciriello Giovanni , Cristofanilli Massimo 
Published: February 2021

Abstract
Background: Inflammatory breast cancer (IBC) has a distinctive and aggressive clinical behavior but its underlying biological characteristics have not been fully elucidated. The extended analysis of somatic alterations in The Cancer Genome Atlas (TCGA) highlighted canonical oncogenic pathways that were consistently represented across different tumor subtypes. The aim of this study was to translate such pathway-based characterization to the clinical setting through ctDNA NGS to dissect IBC’s biology and prognosis.
Methods: The study retrospectively analyzed 255 metastatic breast cancer (MBC) patients (pts) treated and characterized for ctDNA at Northwestern University (Chicago, IL). ctDNA was analyzed using the Guardant360 NGS assay (Guardant Health). Only non-synonymous alterations were analyzed. Pathway classification was defined based on prior work (Sanchez-Vega F et al, Cell. 2018). Associations among clinical characteristics, pathway classification, and IBC were explored through uni- and multivariate logistic regression; survival was tested though uni- and multivariate Cox regression both for progression-free survival (PFS) and overall survival (OS).
Results: Of 255 enrolled pts, 124 (48%) were diagnosed with hormone receptor positive (HR pos) MBC, 75 (30%) with HER2-positive (HER2_pos) MBC and 56 (22%) with triple negative (TNBC) MBC. IBC was diagnosed in 74 pts (30%). Receptor-tyrosine kinase, RTK (130 pts, 51%), p53 (130 pts, 51%), PI3K/Akt (116 pts, 46%), and cell cycle (91 pts, 36%) were the most often altered pathways. The multivariate model highlighted the association of IBC with HER2_pos (OR: 2.19; 95%CI: 1.09 - 4.38; P=0.0276), an increased number of alterations in the p53 pathway (OR: 2.05; 95%CI: 1.12 - 3.75; P=0.0197) and a decreased number of alterations in the RAS pathway (OR: 0.34; 95%CI: 0.14 - 0.80; P=0.0137). Decreased alterations in the ER pathway were borderline significant (OR: 0.48; 95%CI: 0.22 - 1.03; P=0.0584). Only cell cycle alterations had an impact on PFS for IBC (HR: 2.20; 95%CI: 1.18 - 4.08; P=0.0127), while p53 and Wnt had an impact on nonIBC (respectively HR: 2.00; 95%CI: 1.23 - 3.25; P=0.0052 and HR: 3.40; 95%CI: 1.20 - 9.64; P=0.0212). The univariate model showed a significant impact on OS RAF, ER, and cell cycle pathways alterations for IBC, the role of ER and cell cycle pathways alterations was confirmed in the multivariate model (respectively HR: 6.19; 95%CI: 1.63 - 23.48; P=0.0073 and HR: 3.79; 95%CI: 1.04 - 13.75; P=0.0431). The multivariate model showed a prognostic impact only for p53 in the nonIBC subgroup (HR: 2.20; 95%CI: 1.11 - 4.36; P=0.0237)
Conclusion: The ctDNA-based oncogenic signaling pathway characterization showed different biological and prognostic features across IBC and nonIBC MBC patients. Alterations of the p53 pathway were more likely to be present in IBC pts, while alterations in the RAS pathway were less represented in this cohort. ER and cell cycle pathways’ alterations impacted the OS of IBC MBC patients. Although preliminary, these results suggest a more comprehensive biological characterization based on ctDNA for treatment selection and clinical decision-making.
Main alterations and pathwayGeneNumber of alterations%PathwayTP5318815.58p53PIK3CA14111.68PI3K/AktERBB2725.97RTKESR1705.8ERMYC574.72MycFGFR1463.81RTKEGFR453.73RTKCCNE1383.15Cell cycleMET322.65RTKNF1322.65RAS
Citation Format: Lorenzo Gerratana, Andrew A Davis, Marco Mina, Saya L Jacob, Qiang Zhang, Ami N Shah, Paolo D’Amico, Neelima Katam, Firas Wehbe, Elena Vagia, Lisa Flaum, Leonidas Platanias, Amir Behdad, Fabio Puglisi, William J Gradishar, Giovanni Ciriello, Massimo Cristofanilli. Investigating oncogenic signaling pathways in inflammatory metastatic breast cancer (MBC) though circulating tumor DNA (ctDNA) next-generation sequencing (NGS) [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 PS2-33.