Dissecting primary endocrine resistance through ctDNA profiling of a hybrid real-world and clinical trial dataset in hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (MBC)

Background: New targeted therapies, including novel endocrine agents and antibody drug conjugates, are revolutionizing the treatment of HR+/HER2- metastatic breast cancer (MBC). However, questions surrounding primary and secondary endocrine resistance (R1 and R2, respectively) still hinder the development of personalized treatment strategies. This study aimed to investigate R1 by leveraging liquid biopsy in a hybrid real-world and clinical trial dataset. Methods: This study used the nationwide (US-based) deidentified Flatiron Health-Foundation Medicine MBC clinicogenomic database (FH-FMI CGDB), comprising data originated from ~ 280 US cancer clinics (~800 sites of care), and analyzed a cohort of 855 patients (pts) profiled through the FoundationOne Liquid CDx NGS panel, combining it with the first 65 pts enrolled in the GIM-24-PalboBP study (NCT04318223). R1 was defined as 1-line PFS of < 6 months. A 1:3 Propensity Score Matching was applied to balance key factors (i.e. age, ECOG performance status, visceral, lymph node, multiple metastasis, type of CDK6/4i). Pathogenic alterations with a > 10% prevalence were tested singularly and according to oncogenic pathways based on Sanchez-Vega F et al, Cell. 2018. Associations between ctDNA alterations, R1, and R2 were assessed using logistic regression, while prognosis was evaluated through Cox regression. Results: A set of 528 pts (respectively 132 and 396 for R1 and R2) was selected from the original cohort of 855 pts. Top detected alterations were PIK3CA SNV (46%), TP53 SNV (33%) and ESR1 SNV (24%). R1 was associated with TP53 SNV (OR = 2.30, P < 0.001), CCND1, FGF19, FGF3 and FGF4 CNVs (respectively OR = 1.75, P = 0.018; OR = 1.62, P = 0.044; OR = 1.80, P = 0.015; OR = 1.73, P = 0.024). On the other hand, ESR1 SNV was associated with R2 (OR = 0.47, P = 0.005). CCND1, FGF19, FGF3 and FGF4 CNVs were significantly co-occurring (P < 0.001) and located in the chromosome (chr)11q13.3 region. In multivariable analysis, TP53 SNV, ESR1 SNV and chr11q13.3 CNV maintained their association with R1 (respectively OR = 2.22, P < 0.001; OR = 0.47, P = 0.006 and OR = 1.94, P = 0.006). Pathway analysis was consistent, showing a significant association between R1 and SNVs in the P53 and in the ER pathways (respectively OR = 1.92, P = 0.002; OR = 0.58, P = 0.024) and CNVs in the cell cycle pathway (OR = 2.18, P = 0.001). No differences were observed for 2-line (PFS2) across R1 and R2 (median PFS2 8.89 vs 8.03 months P = 0.589). Chemotherapy was prevalent in the R1 group (35% vs 15%). Within pts receiving 2-line endocrine therapy, TP53 SNV was the only prognostic factor in R1 (HR = 2.02, P = 0.008), while SNVs in TP53 and ESR1 had an impact on PFS2 in R2 (respectively HR = 1.50, P = 0.003 and HR = 1.45, P = 0.008). Conclusions: This study confirms TP53 and ESR1 as key factors for R1 and R2, respectively, with ESR1 showing a prognostic impact on PFS2 in R2 only. Additionally, chr11q13.3 emerges as a new candidate region for R1. These results provide critical data for both decision making and 2-line clinical trial design.