Predictors of fulvestrant long-term benefit in hormone receptor-positive/HER2 negative advanced breast cancer

• Published in: Scientific reports Vol. 12; no. 1; p. 12789
• Main Authors: Torrisi, Rosalba, Vaira, Valentina, Giordano, Laura, Destro, Annarita, Basilico, Vera, Mazzara, Saveria, Salvini, Piermario, Gaudioso, Gabriella, Fernandes, Bethania, Rudini, Noemi, Masci, Giovanna, Santoro, Armando
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 27.07.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Breast cancer; ErbB-2 protein; ESR1 protein; Fulvestrant; Metastases; Molecular modelling; Mutation; Paraffin; Patients; Tumors; Wnt protein
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-16409-7

Abstract We retrospectively investigated in women treated with fulvestrant for HR+/HER2 negative advanced breast cancer clinical, pathological and molecular features associated with long-term benefit from treatment defined as being progression-free at 18 months. Specifically, we analyzed on formalin-fixed paraffin-embedded tumor samples ESR1 and PI3KCA mutations and miRNAs profiles. 59 patients were evaluable (median age of 67 years, range 32–92). 18-month PFS rate was 27%; the lack of visceral metastases significantly predicted the likelihood of being progression-free at 18 months, while PI3KCA mutations, found in 36% of patients, were not associated with 18-month PFS. As of miRNAs, miR-549a , miR-644a, miR-16-5p were negatively while let-7c-5p was positively associated with 18-month PFS. In addition , miR-520d-3p and miR-548g-3p values were significantly lower while miR-603, miR-181a-5p and miR-199a-miR-199b-3p values were significantly higher in patients achieving 18-month PFS. In silico analysis of targets modulated by these two latter groups of miRNAs show that in patients achieving 18-month PFS the Hippo and Wnt signaling pathways were predicted to be upregulated while endocrine resistance was potentially repressed by miR-603, miR-181a-5p and miR-199a-miR-199b-3p. Our results provide additional clues on the molecular mechanisms involved in fulvestrant activity and resistance. Underlying pathways should be further elucidated and confirmed in larger cohorts.