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

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.

maGENEgerZ: An Efficient Artificial Intelligence-Based Framework Can Extract More Expressed Genes and Biological Insights Underlying Breast Cancer Drug Response Mechanism

“…Also, genes linked to the positive regulation of epithelial cell proliferation biological processes are related to the induction of metastasis and inhibition of breast cancer cell apoptosis through the promotion of epithelial cell proliferation via estrogen [44,45]. These results demonstrate the effectiveness of our computational method in unveiling important molecular mechanisms pertaining to breast cancer therapy) that have been approved for breast cancer treatment (see Figure 3) [61][62][63]. Both drugs identified two drug targets, PGR and ATP1A2.…”

“…Consequently, we encoded the dataset as a 736 × 119 matrix, including a column vector for drug responses, in which 256 BC patients achieved a complete response (CR) while 480 had a failed complete response (FCR). We had 11 treatments in which the 736 samples were distributed accordingly as follows: paclitaxel (169), paclitaxel + ABT 888 + carboplatin (63), paclitaxel + AMG-386 (110), paclitaxel + AMG-386 + trastuzumab (18), paclitaxel + MK-2206 (56), paclitaxel + MK-2206 + trastuzumab (31), paclitaxel + neratinib (105), paclitaxel + pembrolizumab (67), paclitaxel + pertuzumab + trastuzumab (43), paclitaxel + trastuzumab (25), and T-DM1 + pertuzumab (49). The gene expression data were performed using a reverse phase protein array (RPPA) microarray at George Mason University.…”

“…In Table 3, we report terms (i.e., drugs) and expressed genes (i.e., drug targets) within IDG Drug Targets 2022. Tamoxifen and Fulvestrant are antiestrogen inhibitors (hormone therapy) that have been approved for breast cancer treatment (see Figure 3) [61][62][63]. Both drugs identified two drug targets, PGR and ATP1A2.…”

Identification of a Panel of miRNAs Associated with Resistance to Palbociclib and Endocrine Therapy

“…RNA quality and quantity was measured with the High-Sensitivity RNA ScreenTape system (Agilent Technologies, Cernusco Sul Naviglio (Mi), Italy). Then, 50 ng of total RNA were used for miRNA profiling using the nCounter Human v3 miRNA Panel (NanoString Technologies, Seattle, WA, USA), as previously described [36]. The nCounter Flex instrument was used and all counts were gathered by scanning for 280 fields of view per sample.…”

Non-Coding RNAs Modulating Estrogen Signaling and Response to Endocrine Therapy in Breast Cancer

“…Downregulation of ESR1 gene expression by miRNAs has been shown to be one mechanism of fulvestrant resistance. A recent study examining predictors of fulvestrant long-term benefits reported the ESR1 -targeting miR-520d-3p to be negatively associated with 18-month progression-free survival (PFS) [ 48 , 146 ].…”