We present the case of a 41-year-old premenopausal woman not harboring pathogenic germline BRCA mutation who was diagnosed in 2009, at the age of 29, with an early stage, HR+/HER2- BC. She underwent radical surgery, taxane-anthracycline based adjuvant chemotherapy and adjuvant ET with ovarian function suppression (OFS) and tamoxifen for 5 years.
In July 2015, less than 1 year after finishing endocrine treatment, a histological HR+/HER2- proven bone relapse was diagnosed. Endocrine first palliative line treatment with OFS and an aromatase inhibitor (AI) was started, achieving a 26-month period of disease control and then, new bone and liver metastases were observed. Second ET line with Palbociclib, OFS and Fulvestrant was started obtaining a clinical benefit and a 9 month progression free survival (PFS). PIK3CA status at this time revealed a PIK3CA-wild type bone recurrence, so she started a third ET line with exemestane plus everolimus and OFS for 11 months. A subsequent line of abemaciclib, tamoxifen and OFS was started, obtaining 13 months of disease control.
A comprehensive genomic profiling, using the Foundation Medicine  platform was performed in order to look for actionable targets, and a BRAF p.V600E mutation was found. The patient refused to undertake chemotherapy due to potential side effects and was eager to explore other options; so, once discussed in our institution molecular board and adequately explained to the patient the current evidence of tyrosine kinase therapy in BC, she agreed to start an off-label treatment targeting BRAF pathway. The combination of dabrafenib 150mg every 12 hours and trametinib 2mg daily was initiated in March, 2021.
The treatment related adverse events (trAEs) were similar to those reported in previous studies: with grade 2 nausea and pyrexia as the main toxicities after 10 days of treatment, which lead to temporary treatment discontinuation. As grade 2 pyrexia recurred and persisted after restarting therapy, the doses of both drugs were lowered to dabrafenib 100 mg every 12 hours and trametinib 1.5 mg daily, with no new trAEs in the following months.
First imaging reevaluation was performed in June, 2021 using a CT-PET scan that showed hepatic and bone complete response ( Figures 1 ,  2 ). The patient experienced clinical benefit and no further significant toxicity, maintaining her quality of life, until December 2021, when bone progression was documented. Therefore, a PFS of 9 months was achieved with excellent performance status during treatment.
Since the beginning of treatment, the patient has been monitored by liquid biopsy, studying blood-circulating DNA harboring BRAF V600E mutation (ctBRAF). Blood was collected in EDTA tubes at 4 initiating time points, and plasma was processed before one hour after extraction. BRAF V600E mutation in plasma was evaluated by Idylla  ctBRAF Mutation assay (Biocartis ) ( Figure 3 ). Mutant allele frequency (MAF) of 16.9% was detected before start the dabrafenib/trametinib treatment. In a second time point (+8 days of treatment), mutation was reduced to 6.7%, which could suggest a benefit of this treatment. During temporary treatment discontinuation by trAEs, the liquid biopsy showed an increase of mutation frequency (MAF of 13.3%). Lastly, mutation was undetectable in plasma after 43 days after the beginning of the treatment, and maintained until disease progression was observed and a slight elevation of MAF to 0.1% was documented in December 2021.