Abstract PS5-22: Mutational profile from circulating tumor DNA in triple negative breast cancer: Results from the prospective registry of unresectable locally advanced or metastatic breast cancer GEICAM/2014-03 (RegistEM)
Authors: Guerrero-Zotano Angel , Jara Carlos , López-Tarruella Sara , Rodríguez César A , Adrover Encarna , Falo Catalina , Martínez Purificación , Antolín Silvia , Margeli Mireia , Cruz Josefina , Rodríguez-Lescure Alvaro , Iranzo Vega , Gómez-Raposo César , Illarramendi Jose Juan , Malón Diego , Alonso Jose Luis , Antón Antonio , Andrés Raquel , Herranz Jesús , Bezares Susana , Caballero Rosalía , Álvarez Isabel , Rojo Federico 
Published: February 2021

Abstract
Background: The RegistEM is a non-interventional cohort study enrolling 1,867 patients (pts) (males or females) with advanced breast cancer diagnosed from January 2016 to December 2019, either after recurrence or as first diagnosis, in 38 Spanish sites. Triple negative BC (TNBC) is clinically defined based on lack of expression of both estrogen and progesterone receptors, and HER2 overexpression, and constitutes approximately 16% of BC cases. It is a particularly proliferative and aggressive BC subtype characterized by higher rates of relapse, greater metastatic potential, and shorter overall survival compared with other BC subtypes. Recent studies have shown hormone receptor status can change from the primary (P) to the recurrence tumor (M) in a proportion of cases, inducing a switch to TNBC in the recurrence, while other remains TNBC both in the P and M setting. This feature might impact survival and treatment options. Methods: We selected TNBC pts from the RegistEM study with ctDNA plasma samples available from the relapse. TNBC pts were classified into 2 groups according to clinical subtype (CS): 1) CS-converted (CS-C), with a discordant phenotype (TN subtype in M but not in P); and 2) CS-non-converted (CS-NC), with TN phenotype in P and M. To compare the mutation profiles of the 2 groups, next-generation sequencing (NGS) was performed using the AVENIO Expanded ctDNA Analysis Kit (Roche Sequencing Solutions, Inc; 77 genes; SNPs, indels, fusions and CNVs). Genomics alterations at individual level and grouped by pathway were explored for pathogenic and probably pathogenics variants. Genomics findings were correlated with clinicopathological data and outcomes, in terms of progression-free survival (PFS) and response to first line chemotherapy treatment. Kaplan-Meier estimator and Cox regression model were used to analyze PFS, and Fisher’s test to analyze contingency tables. Bonferroni correction was used for multiple testing. Results: NGS data was available from 32 (17%) TNBC pts; 22 (69%) pts CS-NC and 10 (31%) CS-C. The time from diagnosis to relapse was 29.2 months (m) for CS-NC and 60.2m for CS-C (HR=4.81, 95% confidence interval (CI) (1.59-14.59), p=0.0055; adjusted for confounders: menopausal status, grade, stage). In the metastatic setting, CS-NC had similar PFS than CS-C (8.3m CS-C vs 5.3m CS-NC; HR=1.63, 95% CI (0.71-3.72), p=0.2442). A median of 3 genomic alterations were found, similar in both groups. The most frequent somatic alterations were TP53 (50%), MAP2K1 (25%) and APC (25%). CS-C were enriched for MAP2K1 (60% vs. 9% in CS-NC; p=0.0243). No single genomic alteration was associated with outcome. Forty-percent of tumors harbored at least 1 mutation in PI3K-AKT-mTOR pathway (PIK3CA, PIK3R1, AKT1, AKT2, PTEN or MTOR genes), with similar incidence between CS-NC and CS-C. Pts with an altered PI3K-AKT-mTOR pathway had poor PFS (3.9m mutant vs 6.7m wild-type (WT); HR=3.02, 95% CI (1.4-6.56), p=0.0033) and a trend to worse response (complete or parcial response and stable disease: 23% mutant vs 77% WT, p=0.1581). CS-C tumors presented an altered MAPK-ERK pathway (mutations in KRAS, NRAS, BRAF, MAP2K1 or RAF1 genes) more frequently in comparison to CS-NC (60% vs 23%, p=0.0557), with no differences in response or PFS. Finally tumors with a high mutation allele frequency (≥mean) showed poor PFS (HR=3.64, 95% CI (1.52-8.75), p=0.0038). Conclusion: Analysis of ctDNA reveals diverse mutational spectrum in metastatic TNBC, suggesting that the presence of PI3K-AKT-mTOR pathway alterations associates with worse outcome and poor response to standard therapies. The clinical subtype conversions from luminal primary tumor are enriched in MAPK-ERK pathway alterations.
Citation Format: Angel Guerrero-Zotano, Carlos Jara, Sara López-Tarruella, César A Rodríguez, Encarna Adrover, Catalina Falo, Purificación Martínez, Silvia Antolín, Mireia Margeli, Josefina Cruz, Alvaro Rodríguez-Lescure, Vega Iranzo, César Gómez-Raposo, Jose Juan Illarramendi, Diego Malón, Jose Luis Alonso, Antonio Antón, Raquel Andrés, Jesús Herranz, Susana Bezares, Rosalía Caballero, Isabel Álvarez, Federico Rojo. Mutational profile from circulating tumor DNA in triple negative breast cancer: Results from the prospective registry of unresectable locally advanced or metastatic breast cancer GEICAM/2014-03 (RegistEM) [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 PS5-22.