Abstract P1-05-16: Differential ctDNA-based genomic features of Triple-Negative Metastatic Lobular Breast carcinoma: insights into a rare and poorly understood disease

Abstract Background: Invasive lobular carcinoma (ILC) comprises 10-15% of all breast cancers (BC), predominantly presenting as low grade and hormone receptor positive (HRpos). Triple-negative ILC (TN-ILC) is rare, accounting for approximately 2% of all triple-negative BC (TNBC) and 0.1% of all BC. Due to its rarity, TN-ILC is poorly understood and lacks well-established treatment standards. This study aims to investigate the genomic characteristics of TN-ILC through circulating tumor DNA (ctDNA) profiling within a large multi-center consortium. Methods: The study analyzed a retrospective cohort of 750 patients (pts) with HER2 negative metastatic BC with ctDNA testing using the Guardant360 NGS panel within a large multicenter academic consortium. HR and HER2 status were defined based on the most recent biopsy. Associations across single nucleotide and copy number variations (SNVs and CNVs), histology, and HR status were tested by multinomial logistic regression in terms of Relative Risk Ratio (RRR), adjusting for significant clinical characteristics (i.e., lines of treatment, metastatic sites). Oncogenic pathway analysis was defined based on Sanchez-Vega F et al, Cell. 2018. Prognosis was analyzed for overall survival (OS) defined from the time of ctDNA collection. Results: Among the 750 pts analyzed, the cohort consisted of TN-ILC (N:16, 2%), HRpos-ILC (N:91, 12%), TN-invasive ductal carcinoma (IDC) (N:186, 25%), and HRpos-IDC (N:457, 61%). In TN-ILC, the most frequently altered genes were PIK3CA (50%), TP53 (44%), ERBB2 (25%), and CDH1 (25%). Less frequent alterations included BRAF, ALK, ARID1A, MET, RB1, and SMAD4, each occurring in 12-19% of cases. PIK3CA (48%) and TP53 (39%) had a similar alteration frequency in HRpos-ILC, and ESR1alterations were also common (36%). Multivariable multinomial logistic regression, designed with TN-IDC as reference, investigated differences in oncogenic pathway alterations across histologies and subtypes. In TN-ILC, a significant association was observed for RAS SNVs (RRR = 7.9, p = 0.038) and PI3K SNVs (RRR = 4.32, P = 0.015). In HRpos-ILC, cell cycle CNVs (RRR = 0.3, P = 0.013) and P53 SNVs (RRR = 0.26, P < 0.001) had a significantly lower prevalence than in TN-IDC, while RAS SNVs (RRR = 4.94, P = 0.022) and PI3K SNVs (RRR = 2.6, P = 0.003) were more common. Single gene alterations were investigated across significantly altered pathways. PIK3CA SNVs were more common in TN-ILC (50%) compared to TN-IDC (16%), but similar in frequency to HRpos-ILC (42%) (P<0.001). PTEN SNVs were higher in HRpos-ILC (11%) than in TN-IDC and TN-ILC (respectively 0% and 6%). KRAS SNVs were more represented in HRpos- and TN-ILC (respectively 6% and 8%), with respect to TN-IDC (1%) (P= 0.017). TP53 SNVs were significantly more detected in TN-IDC (68%) than in HRpos and TN-ILC (respectively 44% and 35%, P<0.001). A similarly unfavorable outcome was observed for TN-ILC and TN-IDC (median OS 12 and 13 months, respectively), compared to their HRpos counterparts (median OS 31 and 33 months, respectively) (P<0.001). Conclusions: Our study highlights distinct genomic features of triple-negative ILC detectable through ctDNA. These findings reinforce the need for improved understanding of TN-ILC to define personalized treatment options for this aggressive and rare subtype. Citation Format: Lorenzo Gerratana,Andrew A. Davis, Lorenzo Foffano, Carolina Reduzzi, Emily Podany, Arielle J. Medford, Marko Velimirovic, Katherine Clifton, Annika Putur, Laura Munoz-Arcos, Letizia Pontolillo, Rachel O Abelman, Caterina Gianni, Shaili Tapiavala, Elisabetta Molteni, Marla D Lipsyc-Sharf, Eleonora Nicolò, Eleni Andreopoulou, William J Gradishar, Fabio Puglisi, Cynthia X. Ma, Aditya Bardia, Massimo Cristofanilli. Differential ctDNA-based genomic features of Triple-Negative Metastatic Lobular Breast carcinoma: insights into a rare and poorly understood disease [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-05-16.