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Kinase Fusions in ESR1 Wild-Type Metastatic Breast Cancer

Pathology analysis found enrichment of fusions after progression on endocrine therapy
29 Apr 2020
Breast cancer;  Pathology/Molecular biology

Results of the study published on 26 April 2020 in the Annals of Oncology by Dr Dara S. Ross of the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, US and colleagues show that kinase fusions are enriched in ESR1 wild-type metastatic breast cancer after progression on endocrine therapy. The authors emphasised that fusion testing of metastatic breast cancers upon progression to endocrine therapy may provide new therapeutic options in this setting.

Kinase fusions in breast cancer are extremely rare. The study team led by Dr Ross aimed to characterise kinase fusions within a large cohort of patients with advanced breast cancer. They analyzed samples from 4854 patients with breast cancer by MSK-IMPACT targeted DNAseq and MSK-Fusion targeted RNAseq.

The study team found 27 patients (0,6%) whose tumours harboured fusions, in particular 11 patients with FGFR fusions, 5 patients with BRAF fusions, 4 patients with NTRK1 fusions, 2 patients with RET fusions, 2 patients with ROS1 fusions, 1 patient with ALK fusions, 1 patient with ERBB2 fusions and 1 patient with MET fusions. Among patients whose tumours harboured FGFR fusions, there were 5 patients with FGFR2 fusions, 3 patients with FGFR3 fusions and 3 patients with FGFR1 fusions.

In total, 15 patients (56%) with fusion-positive breast cancers had a history of previous endocrine therapy. From those, 8 patients had available pre-treatment samples of which 6 were fusion negative. None of the fusion-positive breast cancer samples harboured ESR1 hotspot mutations. Two patients with acquired LMNA-NTRK1 fusions and metastatic disease received larotrectinib and demonstrated clinical benefit.

The authors concluded that kinase fusions are rare in breast cancer, but they are enriched in hormone-resistant, metastatic carcinomas and mutually exclusive with ESR1 mutations. They wrote that their study expands the spectrum of genetic alterations activating MAPK signaling that can substitute for ESR1 mutations in this setting.

As an effort to identify additional therapeutic options which may provide substantial clinical benefit, the study team advocates that molecular testing in metastatic breast cancer at progression after endocrine therapy should include fusion testing, especially in case of absence of ESR1 hotspot alterations.  

Reference

Ross DS, Liu B, Schram AM, et al. Enrichment of Kinase Fusions in ESR1 Wild Type, Metastatic Breast Cancer Revealed by a Systematic Analysis of 4,854 Patients. Annals of Oncology; Published online 26 April 2020. DOI: https://doi.org/10.1016/j.annonc.2020.04.008 

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