Ottavia Bernocchi, Marianna Sirico, Silvia Paola Corona, Carla Strina, Manuela Milani, Maria Rosa Cappelletti, Giuseppina Ferrero, Nicoletta Ziglioli, Valeria Cervoni, Andrea Macchiavelli, Giandomenico Roviello and Daniele Generali
MDPI Pharmaceuticals (2021)


Background: Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment. BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types. Tumor type agnostic therapy is based on targeting genomic alterations, regardless of tumor origin. In this context, novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape in solid tumors have been investigated. Case presentation, Case 1: The first case is chemotherapy-refractory, BRAF V600E mutated intrahepaticcholangiocarcinoma treated with vemurafenib and cobimetinib as third line therapy. In this setting the dual BRAF and MEK inhibition resulted in improved progression-free survival and quality of life; Case 2: The second case shows aBRAF G466A mutated Bellini duct carcinoma (BDC), treated with dabrafenib and trametinib in second line therapy.

The disease remained under control for 11 months after the first relapse. Discussion: In the literature there is strong evidence
that melanoma, colorectal cancer, non small cell lung cancer and anaplastic thyroid cancer with BRAF mutations are good targets for BRAF/MEK pathway inhibitors. The VE-BASKET and ROAR basket trials explored the efficacy of vemurafenib and the combination of dabrafenib/trametinib, respectively, in BRAF V600 mutation-positive cancers other than melanoma, papillary thyroid cancer, colorectal cancer and non small cell lung cancer. Within the concept of tumor type agnostic therapy, we decided to treat our BRAF-mutated tumors with the association of BRAF and MEK inhibitors.
Conclusions: Our results confirm the emerging importance of molecular tumor profiling for the successful management of cancer, and the potential of BRAF-targeted therapy in the treatment of rare solid tumors with poor prognosis and no clinical benefit from systemic therapies with.


In the last few years, there have been increasing efforts to understand the molecular biology of several rare tumors with limited treatment options. Genome analysis could, in these cases, help find specific genomic alterations which can be targeted. Precision
medicine allows a personalized approach based on biomarker individualization.
The approval of the first-in-class tumor agnostic therapies shows that identification of biomarkers independent from tumor origin could offer new treatment options with drugs already on the market.
In the literature, there is strong evidence that different tumors with BRAF mutations are good targets for BRAF/MEK pathway inhibitors and our work adds to this evidence.

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