Tumor Type Agnostic Therapy Carrying BRAF Mutation: Case Reports and Review of Literature

Abstract

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.

Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial

“…The findings from the ROAR study are also complementary to available case reports supporting the efficacy of dabrafenib plus trametinib in various BRAFV600E mutation-positive tumors, including breast cancer 21 , pancreatic cancer 22,23 , salivary duct cancer 24 , Bellini duct cancer 25 , pituitary tumor 26 , ameloblastoma 27 , histiocytic sarcoma 28 and gynecological malignancies 29,30 . Some of the cancers reported here are ultra-rare cancers and have never been studied before with BRAFV600 inhibitors in clinical trials.…”

Vemurafenib effectively controlled Chemotherapy-refractory Intrahepatic Cholangiocarcinoma with BRAF V600E Mutation: a case report and literature review

“…This research reveals that treated ICC patients with combined inhibition of BRAF and MEK showed favorable outcomes and tolerable side effects. Furthermore, there have been 6 cases reporting inhibition of BRAF and MEK combined in treating cholangiocarcinoma (CC) with BRAF V600E mutation (summarized in ▶ Table 1 [28,29,30,31,32]). These 6 patients all achieved obvious tumor remission, progression-free, and one of them survived tumorfree with no signs of recurrence for 2 years.…”

Evolution of Treatment in Advanced Cholangiocarcinoma: Old and New towards Precision Oncology

“…In this study, a dismal response rate of 12% (one partial response/eight total patients) was reported with vemurafenib, likely related to the high burden of disease and poor patient conditions. Later, successful combination therapies involving BRAF inhibitors (i.e., vemurafenib or dabrafenib) for the treatment of metastatic CCAs were reported [ 52 , 53 ]. In most cancers bearing BRAF mutations, patients treated with BRAF inhibitors develop disease progression within a few months from the start of treatment.…”