Clinical, pathological and molecular predictors of Fulvestrant long-term benefit in Hormone Receptor-positive / HER2 negative advanced breast cancer

Purpose: The identification of factors predicting the benefit of treatments is a major goal for medical oncologists. Methods We retrospectively investigated in metastatic tumor tissues of 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 ESR1 and PI3KCA mutations and miRNA profiles. Results: Fifty-nine patients were evaluable (median age 67 yrs, range 32-92). Overall mPFS was 10.7 months (range 2.2-14) while 18-month PFS rate was 27%; only the lack of visceral metastases significantly predicted the likelihood of being progression-free at 18 months (OR=0.25 95%CI 0.07-0.9 p=.035). PI3KCA mutations were found in 36% of patients and were associated with a numerically shorter mPFS but not with a lower likelihood of being progression-free at 18 months. As of miRNAs, miR-549a , miR-644a, miR-16-5p were negatively associated with 18-month PFS while let-7c-5p was positively associated with outcome. In addition , miR-520d-3p and miR-548g-3p values were significantly lower while miR-603, miR-181a and miR-199a-miR-199b-3p values were significantly higher in patients achieving 18-month PFS. In silico analysis of predicted targets suggested that miR-520d-3p and miR-548g-3p decrease might induce Hippo and Wnt signaling, while high levels of miR-603, mir-181a-5p,miR-199a-miR-199b-3p might repress endocrine resistance thus potentially promoting the response to treatment. Conclusions: Our clinical findings are consistent with literature data, while the mutation and miRNA results provide some clues on the molecular mechanisms involved in fulvestrant activity and resistance to be confirmed in larger cohorts of breast cancer patients.