ER-CCDC170 fusion

CGP detects a wide spectrum of mutations in ESR1, including missense and indel mutations and fusions. When LBx TF is < 1%, sensitivity for ESR1mut is reduced and repeat testing should be considered. ESR1mut can coexist with complementary or competing resistance mechanisms, particularly when ESR1 is a minor allele, which could impact benefit from novel ET approved for patients with ESR1 mutations.

These models, designated ST4565C, ST4565D, STM148B, STM148C, STM148D, and ST4480B/EHR were developed and characterized for receptor expression, genomics, and drug sensitivities toward chemotherapies and targeted agents including T-DXd, T-DM1, and margetuximab. ST4565C/D was established from a patient with ER+/HER2+, metastatic BC who was T-DXd treatment naïve. ST4565C was collected post chemo- and HER2-targeted therapies; ST4565D was collected following eribulin/margetuximab... We established and characterized six breast XPDX models representing innate or acquired resistance to T-DXd. These models are valuable tools in understanding resistance mechanisms and in developing novel therapies for T-DXd-resistant patients.

Examples of the most significant recurrent gene fusions to date include (1) ESR1::CCDC170 gene fusions in luminal B and endocrine-resistant breast cancer that exert oncogenic function via modulating the HER2/HER3/SRC Proto-Oncogene (SRC) complex, (2) ESR1 exon 6 fusions in metastatic disease that drive estrogen-independent estrogen-receptor transcriptional activity, (3) BCL2L14::ETV6 fusions in a more aggressive form of the triple-negative subtype that prime epithelial-mesenchymal transition and endow paclitaxel resistance, (4) the ETV6::NTRK3 fusion in secretory breast carcinoma that constitutively activates NTRK3 kinase, (5) the oncogenic MYB-NFIB fusion as a genetic driver underpinning adenoid cystic carcinomas of the breast that activates MYB Proto-Oncogene (MYB) pathway, and (6) the NOTCH/microtubule-associated serine-threonine (MAST) kinase gene fusions that activate NOTCH and MAST signaling...Thus, these gene fusions could be utilized as genetic biomarkers to identify patients that require more intensive treatment and surveillance. In addition, kinase fusions are currently being evaluated in breast cancer clinical trials and on-going mechanistic investigation is exposing therapeutic vulnerabilities in patients with fusion positive disease.

Our study shows that in primary BC only ESR1-CCDC170 exon 8 gene fusion transcript carries prognostic value. None of the ESR1 fusion transcripts, which are considered to have constitutive ER activity, was predictive for outcome in BC with advanced disease treated with endocrine treatment.

Methods : ST4480B and ST4480C were established from a 70-year-old Caucasian female with ER+/HER2+ metastatic breast cancer pretreated with chemotherapy and targeted agents including T-DM1 for nine months followed by capecitabine/trastuzumab/tucatinib combination for one year prior to sample collections...For in vivo studies, both models were evaluated with several chemotherapy and targeted agents alone and in combination including: trastuzumab, pertuzumab, T-DM1, DS-8201a, neratinib, tucatinib, alpelisib, everolimus, and irinotecan...Conclusion : We established two XPDX models representing T-DM1-resistant, ER+/HER2+ breast cancer from both tissue and fluid samples collected simultaneously from the same patient which were found differentially responsive to DS-8201a. These models can be utilized as a valuable tool in better understanding innate resistance to DS-8201a.

Further investigation revealed that nine genes (AURKB, HDAC2, PLK1, CENPA, CHEK1, CHEK2, RB1, CCNA2, and MDM2) in coordination with E:C fusion were found to be common denominators in three or more of these pathways, thereby making them promising gene biomarkers for target therapy. Among the 21 putative actionable drugs inferred by drug-target network analysis, palbociclib, alpelisib, ribociclib, dexamethasone, checkpoint kinase inhibitor AXD 7762, irinotecan, milademetan tosylate, R05045337, cisplatin, prexasertib, and olaparib were considered promising drug candidates targeting genes involved in at least two E:C fusion-related pathways.

ESR1-CCDC170 may endow breast cancer cell survival under endocrine therapy via maintaining/activating HER2/HER3/SRC/AKT signaling which implies a potential therapeutic strategy for managing these fusion positive tumors.