ctDNA mutational profiles in luminal breast cancer with early vs late distant relapse: Geicam/2014-03.
Authors: Guerrero Angel , Alvarez Isabel , Tibau Ariadna , Cruz Jurado Josefina , Rodríguez Sánchez César A , Martinez Purificacion , Falo Catalina , Hernández Sosa Maria , Margelí Mireia , Miguel Ana , Chacon Jose Ignacio , Andres Raquel , Adrover Encarna , Corbellas Aparicio Miguel , Caballero Rosalia , Herranz Jesus , Fernández García Daniel , Antolín Novoa Silvia , López-Tarruella Sara , Rojo Federico 
Published: June 2023

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Background: Patients with hormone receptor-positive early breast cancer (BC) can develop resistance to endocrine therapies (ET) and face a continuous risk of relapse, which can occur anywhere from a few months (m) to several decades after surgery. The causes of early vs late relapses are not well understood. Our research examines the presence of oncogenic drivers in circulating tumor DNA (ctDNA) at the time of relapse in patients with luminal BC who have either an early or late distant recurrence. Methods: We identified pts included in the GEICAM/2014-03 study (NCT02819882) with: 1) HR-positive BC, 2) metastatic relapse either <36m (early relapse, [early-R]) or >120m (late relapse, [late-R]) from diagnosis, and 3) ctDNA obtained before first line treatment for advanced disease. The AVENIO ctDNA assay was used for identifying genomic aberrations in 77 cancer-related genes. Results: Eighty-four pts, 36 in early-R and 48 in late-R groups, were selected. Median time to relapse was 24.97m in early-R vs 151.84m in late-R. Median time from last dose of adjuvant ET to relapse was 0.03m for early-R vs 74.06m for late-R. Median PFS to first line treatment was 7.62m in early-R and 35.15m in late-R. With a median follow-up of 32.08m, median OS after diagnosis of metastatic disease was 27.74m for early-R and not reached for late-R. ctDNA analysis detected at least 1 mutation (mut) in 71/84 (85%) pts (89% in early-R vs 81% in late-R). Early-R pts were enriched in mut in TP53 (44% vs 19%), ESR1 (11% vs 4%), MAPK_ERK pathway (14% vs 6%), and ERBB2 copy number alterations (CNA) (25% vs 2%). PI3K/AKT pathway alterations had similar frequency in both recurrence groups (38% vs 42%) and they were not associated with OS. Seven ESR1 mut were detected in 6 pts. In the early-R group there were 5 ESR1 mut (71% of total ESR1 mut), median mutant allele frequency (mMAF): 0.64%; while in the late-R, 2 ESR1 mut (29%), mMAF: 0.4%. ESR1 mut were associated with worse OS (median OS 48.48m vs 12.84m wild-type vs mutant; p=0.0025). There were 10 pts with E RBB2 CNA at metastatic relapse; 9 (25%) in the early-R and 1 pts (2%) in the late-R. Seven pts (70%) had HER2-positive. Pts with ctDNA ERBB2 CNA had worse OS (median OS 48.48m vs 20.52m wild-type vs mutant; p-adj=0.025). Conclusions: In luminal breast cancer (BC), early and late distant relapse differ at both the clinical and genomic levels. Early relapse is a highly aggressive form of the disease and is enriched in TP53 mutations and actionable genetic alterations, such as mutations in the ESR1 and CNA in ERBB2, as detected by ctDNA analysis at the time of metastatic relapse diagnosis. Clinical trial information: NCT02819882 . [Table: see text]