Abstract PD14-04: Circulating tumor DNA characterization of invasive lobular carcinoma in patients with metastatic breast cancer
Authors: Davis Andrew A , Gerratana Lorenzo , Clifton Katherine , Velimirovic Marko , Hensing Whitney L , Shah Ami N , D’Amico Paolo , Reduzzi Carolina , Zhang Qiang , Dai Charles S , Denault Elyssa N , Bagegni Nusayba A , Opyrchal Mateusz , Ademuyiwa Foluso O , Bose Ron , Gradishar William J , Behdad Amir , Ma Cynthia X , Bardia Aditya , Cristofanilli Massimo 
Published: March 2022

Abstract
Background:Invasive lobular carcinoma (ILC) is the second most common histology of breast cancer, accounting for approximately 10-15% of cases. Prior studies have demonstrated that loss of E-cadherin, as well as alterations in tissue including CDH1, FOXA1, TBX3 and PTEN loss, that were more commonly observed in Luminal A ILC, while GATA3 was more commonly observed in invasive ductal carcinoma (IDC) (Ciriello et al., Cell 2015). However, data regarding the characterization of circulating tumor DNA (ctDNA) in patients (pts) with metastatic ILC are limited. We hypothesized that there would be distinct mutational profiles between pts with metastatic ILC and IDC that could be characterized using ctDNA. Methods:This retrospective cohort study included de-identified clinical, pathological, and ctDNA data from pts with metastatic breast cancer (MBC) combined under a data use agreement and approved by the institutional review boards of three sites: Washington University in St. Louis (MO), Northwestern University (Chicago, IL), and Massachusetts General Hospital (Boston, MA). All pts included in the study had ctDNA testing per standard of care with plasma-based genotyping performed by Guardant360 (Redwood City, CA) between 2015-2020. Histological classification (ILC vs. IDC) was defined based on review of pathology reports from the primary tumor or from breast biopsies of de novo MBC, and additional clinical and pathological variables were obtained via electronic medical record review. Single nucleotide variants (SNVs) were annotated using OncoKB and ClinVar and only pathogenic variants were included. Mutational profiles were compared across histologic subtypes using Fisher’s exact test to assess differences in alteration frequency across subtypes. Multivariable analysis was performed. Results:A total of 994 pts with MBC underwent ctDNA testing and were included in the analysis. 10.7% of pts had ILC (N=106) and 89.3% had IDC (N=888). 89.4% of ILC cases were categorized as hormone-receptor positive (HR+) compared with 67.1% of IDC cases. Pts with ILC had a lower frequency of triple-negative (6.7% vs. 17.7%) and HER2 positive (3.9% vs. 15.2%) breast cancer compared with IDC. Pts with ILC had a significantly higher number of pathogenic SNVs compared with IDC (mean 4.45 vs. 2.77; P=0.0037). In contrast, pts with ILC had a significantly lower number of copy number alterations as compared to pts with IDC (mean 0.40 vs. 1.03; P=0.0017). No differences were observed in mutant allele frequency between pts with ILC and IDC. The 5 most common alterations observed in pts with ILC were the following: PIK3CA, TP53, ESR1, ERBB2, and ARID1A. Alterations in AR, BRAF, CDH1, ERBB2, FGFR2, IDH2, KRAS, NF1, PIK3CA, SMAD4, and TERT were significantly higher in ILC than IDC (all P&lt;0.05). In contrast, mutations in GATA3, and amplifications in ERBB2 and MYC were significantly more common in pts with IDC (all P&lt;0.05). In multivariable analysis, mutations in BRAF, CDH1, ERBB2, IDH2, TERT remained significantly higher in ILC, while amplification of MYC was significantly higher in IDC (all P&lt;0.05). After restricting the analysis to pts with HR+ HER2 negative MBC, the following genes were significant in multivariate analysis: CDH1 and ERBB2 for pts with ILC and MYC amplification for pts with IDC (all P&lt;0.05). Discussion:In this large, multi-institutional dataset, pts with metastatic ILC were characterized by a significantly higher number of SNVs in ctDNA compared to pts with IDC, suggesting higher mutational burden. We report several alterations that were significantly different in ILC vs. IDC. These results demonstrate the ctDNA profile of pts with ILC, and future studies should explore serial plasma-based genotyping to track ILC evolution to develop targeted precision medicine based therapeutic approaches for this unique subset of pts with MBC.
Citation Format: Andrew A Davis, Lorenzo Gerratana, Katherine Clifton, Marko Velimirovic, Whitney L Hensing, Ami N Shah, Paolo D’Amico, Carolina Reduzzi, Qiang Zhang, Charles S Dai, Elyssa N Denault, Nusayba A Bagegni, Mateusz Opyrchal, Foluso O Ademuyiwa, Ron Bose, William J Gradishar, Amir Behdad, Cynthia X Ma, Aditya Bardia, Massimo Cristofanilli. Circulating tumor DNA characterization of invasive lobular carcinoma in patients with metastatic breast cancer [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 PD14-04.