Response to Dabrafenib and Trametinib of a Patient with Metaplastic Breast Carcinoma Harboring a BRAF V600E Mutation.
ABSTRACT: Background:Metaplastic breast carcinomas are rare and carry poor prognoses. They are also more aggressive than other breast cancers and are known for their resistance to chemotherapy. Prolonged treatment with dabrafenib and trametinib is a therapy for malignant melanoma that improves the progression-free survival and overall survival. Such molecular-targeted therapies are also being developed for cancers with BRAF mutation, a driver of malignant melanoma. Case Presentation. A 57-year-old woman with metaplastic breast cancer and chemotherapy-refractory massive pleural effusion. After contained anthracycline regimen failure, her breast cancer progressed to an advanced stage. We ordered next-generation sequencing- (NGS-) based tumor molecular profiling from core needle biopsy of the breast. The NGS report indicated the presence of a BRAF V600E mutation. After initiation of dabrafenib and trametinib, her symptom and the pleural effusion were decreased. The first assessment of CT scans showed a decreased pleural effusion and shrunken subcutaneous lesions. Approximately 2 weeks later, a new lesion appeared. She died from 12 weeks after initiation of dabrafenib and trametinib treatment. Conclusion:To the best of our knowledge, this is the first report of BRAF mutation breast cancer treated with dabrafenib and trametinib and it heralds the possibility of targeted therapy for rare breast cancers.
Project description:RATIONALE:BRAF and MEK inhibitors (BRAF/MEKi) are targeted therapy for proto-oncogene BRAF mutated metastatic unresectable melanoma. Compared to monotherapy, an increased cardiovascular toxicity is reported with the combination of Dabrafenib and Trametinib. This case report documents Grade 4 cardiac treatment emergent adverse effect of pericardial effusion and cardiac tamponade induced by this combination therapy. PATIENT CONCERNS:A 52 year old man presented with clinical stage II unresectable melanoma with BRAF mutation, was initiated on treatement with Dabrafenib and Trametinib. He complained of generalised edema and increased his weight by 27 kg. This progressed to shortness of breath and he underwent echocardiogram which revealed cardiac tamponade. DIAGNOSES:Emergent pericardiocentesis was performed. No definited pathology was demonstrated in laboratory analysis of pericardial fluid. Re- initiating treatment resulted in cardiac tamponade and pericardiotomy was performed by video-assisted thoracic surgical (VATS). Pericardial biopsy revealed nonspecific chronic inflammation. INTERVENTIONS:Discontinuation of treatment with Dabrafenib and Trametinib and diuretics resolved peripheral edema. Cardiac function normalized after pericardiocentesis and pericardiotomy. OUTCOMES:Treatment with Dabrafenib and Trametinib caused significant peripheral edema and pericardial effusion resulting in cardiac tamponade. Naranjo score suggests probable association of treatment induced pericardial effusion and cardiac tamponade. LESSONS:This is the first documented report of pericardial effusion and cardiac tamponade induced by Dabrafenib and Trametinib. Cardiac toxicity of BRAF/MEK inhibitors is rare but clinicans must monitor for treatment emergent adverse effects.
Project description:Dabrafenib plus trametinib is US Food and Drug Administration approved combination therapy for use in patients with BRAF V600E-mutant non-small cell lung cancer, but information on use outside of clinical trials is limited. We report the case of a 70-year-old Asian woman (never smoker) who was diagnosed with lung adenocarcinoma in May 2014. Testing at diagnosis was negative for programmed death ligand 1 or EGFR, ALK, and ROS1 alterations. She was started on carboplatin-pemetrexed-bevacizumab and maintenance bevacizumab but progressed in September 2015. Subsequently, she progressed on second-line nivolumab and third-line docetaxel. In March 2016, pleural fluid obtained at diagnosis tested positive for the BRAF V600E mutation and she received dabrafenib plus trametinib. She experienced rapid tumor shrinkage and symptom improvement and became able to participate in regular daily activities with no notable adverse events. In December 2016, she died from a hemorrhagic stroke considered unrelated to treatment. In this heavily pretreated patient with non-small cell lung cancer, dabrafenib plus trametinib elicited an excellent response.
Project description:Approximately half of BRAF-mutated Non-small cell lung cancers (NSCLCs) harbor a non-V600 BRAF mutation, accounting for ?40,000 annual deaths worldwide. Recent studies have revealed the benefits of combined targeted therapy with a RAF-inhibitor (Dabrafenib) and a MEK-inhibitor (Trametinib) in treating V600 BRAF mutant cancers, including NSCLC. In contrast, sensitivity of non-V600 BRAF mutations to these inhibitors is not documented. Non-V600 mutations can either increase or impair BRAF kinase activity. However, impaired BRAF kinases can still activate the ERK pathway in a CRAF-dependent manner. Herein, beyond describing a cohort of BRAF mutant NSCLC patients and functionally analyzing 13 tumor-derived BRAF mutations, we demonstrate that both types of non-V600 BRAF mutations can be sensitive to clinically relevant doses of Dabrafenib and Trametinib in HEK293T cells, in lung epithelial cellular model (BEAS-2B) and in human cancer cell lines harboring non-V600 BRAF mutations. ERK activity induced by both types of these mutations is further reduced by combinatorial drug treatment. Moreover, the combination leads to more prolonged ERK inhibition and has anti-proliferative and pro-apoptotic effects in cells harboring both types of non-V600 BRAF mutations. This study provides a basis for the clinical exploration of non-V600 BRAF mutant lung cancers upon treatment with Trametinib and Dabrafenib.
Project description:Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.
Project description:INTRODUCTION:The present study aimed to inform an economic evaluation of dabrafenib and trametinib combination as first-line treatment of metastatic melanoma in a Canadian setting. A network meta-analysis was conducted to estimate hazard ratios (HRs) for progression-free survival (PFS)and overall survival (OS) of dabrafenib plus trametinib versus other first-line treatments of BRAF mutation-positive metastatic melanoma including dabrafenib, trametinib, vemurafenib, ipilimumab, and dacarbazine (DTIC). METHODS:HRs for PFS and OS were from randomized controlled trials identified from systematic literature reviews. HRs for PFS and OS (adjusted for crossover as appropriate) were analyzed using multivariate and univariate Bayesian network meta-analysis. RESULTS:In multivariate network-meta analyses (HRs for PFS and OS estimated simultaneously to account for the correlation of treatment effects on PFS and OS), HRs (95% credible interval) for PFS and OS favored dabrafenib plus trametinib [PFS: 0.23 (0.18-0.29) versus DTIC, 0.32 (0.24-0.42) versus ipilimumab plus DTIC, 0.52 (0.32-0.83) versus trametinib, 0.57 (0.48-0.69) versus vemurafenib, and 0.59 (0.50-0.71) versus dabrafenib]; OS [0.41 (0.29-0.56) versus DTIC, 0.52 (0.38-0.71) versus ipilimumab plus DTIC, 0.68 (0.47-0.95) versus trametinib, 0.69 (0.57-0.84) versus vemurafenib, and 0.72 (0.60-0.85) versus dabrafenib]. The beneficial effects on OS of dabrafenib plus trametinib versus ipilimumab plus DTIC and versus trametinib were attenuated when HRs were estimated using univariate network meta-analysis (HRs for PFS and OS estimated separately). CONCLUSION:This analysis demonstrates improved PFS and OS with dabrafenib + trametinib versus dabrafenib, trametinib, vemurafenib, ipilimumab plus DTIC, and DTIC as first-line treatment for patients with BRAF mutation-positive metastatic melanoma. FUNDING:Novartis Pharmaceuticals.
Project description:BACKGROUND:Targeting BRAF V600E mutation has been proven effective in the treatment of several types of cancer. In endometrial adenocarcinoma, the BRAF V600E mutation has been rarely reported. Whether targeting BRAF oncogene may represent a plausible therapeutic strategy for the rare patients with BRAF-mutated endometrial cancer remains to be ascertained in prospective studies. CASE PRESENTATION:We report herein the case of a heavily pre-treated patient with recurrent microsatellite instability high (MSI-H) BRAF V600E mutated endometrial adenocarcinoma, which was successfully treated with the V600E targeting agent dabrafenib. After developing resistance to this agent, the MEK targeting agent trametinib was added to dabrafenib achieving again a therapeutic response. CONCLUSIONS:This case shows that dabrafenib both as monotherapy and when combined with trametinib may exert significant therapeutic activity in heavily pretreated BRAF V600E mutated endometrial adenocarcinoma, and highlight potential benefits of personalized treatment in this disease.
Project description:A large fraction of somatic driver BRAF mutations in lung cancer are non-V600 and impaired-kinase. Non-V600 BRAF mutations predict sensitivity to combination of a type I RAF inhibitor, Dabrafenib, and a MEK inhibitor, Trametinib. Singly, Dabrafenib only weakly suppresses mutant BRAF-induced ERK signaling and can induce ERK paradoxical activation in CRAF-overexpressing cells. The present study compared the effects of Dabrafenib and a type II RAF inhibitor, AZ628, on ERK activity in HEK293T cells expressing several tumor-derived BRAF mutants, and in a non-V600 and impaired-kinase BRAF-mutant lung cancer cell line (H1666). Unlike Dabrafenib, AZ628 did not induce paradoxical ERK activation in CRAF-overexpressing cells and BRAF-mutant cells overexpressing CRAF were more responsive to AZ628 compared to Dabrafenib in terms of ERK inhibition. AZ628 inhibited ERK more effectively than Dabrafenib in both H1666 cells and HEK293T cells co-expressing several different BRAF-mutants with CRAF. Similarly, AZ628 plus Trametinib had better MEK-inhibitory and pro-apoptotic effects in H1666 cells than Dabrafenib plus Trametinib. Moreover, prolonged treatment of H1666 cells with AZ628 plus Trametinib produced greater inhibition of cell growth than Dabrafenib plus Trametinib. These results indicate that AZ628 has greater potential than Dabrafenib, both as a single agent and combined with Trametinib, for the treatment of non-V600 BRAF mutant lung cancer.
Project description:The first clinical trial testing the combination of targeted therapy with a BRAF inhibitor vemurafenib and immunotherapy with a CTLA-4 antibody ipilimumab was terminated early due to significant liver toxicities, possibly due to paradoxical activation of the MAPK pathway by BRAF inhibitors in tumors with wild type BRAF. MEK inhibitors can potentiate the MAPK inhibition in tumor, while potentially alleviating the unwanted paradoxical MAPK activation. With a mouse model of syngeneic BRAFV600E driven melanoma (SM1), we tested whether the addition of the MEK inhibitor trametinib would enhance the immunosensitization effects of the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression. Bioluminescent imaging and tumor infiltrating lymphocyte (TIL) phenotyping showed increased effector infiltration to tumors with dabrafenib, trametinib or dabrafenib plus trametinib with pmel-1 ACT combination. Intracellular IFN gamma staining of the TILs and in vivo cytotoxicity studies showed trametinib was not detrimental to the effector functions in vivo. Dabrafenib increased tumor associated macrophages and T regulatory cells (Tregs) in the tumors, which can be overcome by addition of trametinib. Microarray analysis revealed increased melanoma antigen, MHC expression, and global immune-related gene upregulation with the triple combination therapy. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen specific ACT, we tested the triple combination of dabrafenib, trametinib with anti-PD1 therapy, and observed superior anti-tumor effect to SM1 tumors. Our findings support the testing of these combinations in patients with BRAFV600E mutant metastatic melanoma. SM1 tumors were implanted into C57BL/6 mice. Mice were treated by ACT of pmel-1 splenocytes or C57BL/6 splenocytes as control. Pmel-1 treated mice were additionally treated with either vehicle, dabrafenib, trametinib, or combination of both drugs and control mice were treated with vehicle or combination of both drugs.
Project description:PURPOSE:To investigate the safety and efficacy of dabrafenib and trametinib combination therapy for BRAF V600 mutation-positive unresectable and metastatic melanoma in over 100 Japanese patients of a real-world clinical setting. PATIENTS:The surveillance period of interim post-marketing surveillance (PMS) analysis was from June 2016 to November 2018, and 112 patients with unresectable and metastatic BRAF V600 melanoma who received dabrafenib and trametinib were enrolled. RESULTS:The safety analysis set included 112 patients whom almost all patients had stage IV disease (n?=?97, 86.61%) with an Eastern Cooperative Oncology Group performance status 0 or 1 (n?=?102, 91.07%), and mean (standard deviation) lactate dehydrogenase level was 354.3 (456.4) U/L (n?=?105) at baseline. Median daily dose of dabrafenib was 300.0 mg/day (118-300), and median daily dose of trametinib was 2.00 mg/day (1.0-4.0). Adverse drug reactions (ADRs) were reported in 84 patients (75%), and common ADRs (incidence???5%) were pyrexia (n?=?49, 43.75%), hepatic function abnormal (n?=?11, 9.82%), rash and blood creatine phosphokinase increased (n?=?9 each, 8.04%), and erythema nodosum (n?=?6, 5.36%). Majority of ADRs reported in this study were consistent with that reported in previous trials. In the efficacy analysis set of 110 patients, the objective response rate was 55.45% (95% confidence interval 45.67-64.93%), and median progression-free survival was 384.0 days (251.0 days-not reached). CONCLUSIONS:No new safety or efficacy concerns were observed in this interim PMS analysis in Japanese patients with unresectable and metastatic melanoma with BRAF gene mutation who received dabrafenib and trametinib combination therapy.
Project description:The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAF (V600E) mutant melanoma, but responses are not durable. In addition, the impressive clinical benefits with anti-PD-1 and anti-PD-L1 antibodies (Ab) in patients with heavily pretreated metastatic melanoma and the synergistic effect of dabrafenib, trametinib and anti-PD-1 compared with single therapy alone groups support the idea that combining dabrafenib, trametinib and immunotherapy based on PD-1 blockade could be an interesting approach in the treatment of metastatic melanoma. With our mouse model of syngeneic BRAF (V600E) driven melanoma (SM1), we tested whether the addition of an immunostimulatory Ab targeting CD137 (4-1BB) and/or CD134 (OX40) would enhance the antitumor effect of dabrafenib, trametinib and anti-PD-1 or anti-PD-L1 therapy. In vitro studies showed that the combination group of dabrafenib, trametinib and anti-PD-1 increases CD8(+) tumor infiltrating lymphocytes (TILs), as well as CD4(+) T cells and tumor-associated macrophages (TAMs). An upregulation of PD-L1 was observed in the combination of dabrafenib, trametinib and anti-PD-1 therapy. Combination of dabrafenib, trametinib and anti-PD-1, with either anti-CD137 or anti-CD134, showed a superior antitumor effect, but the five-agent combination was not superior to the four-agent combinations. In conclusion, the combination of dabrafenib, trametinib, anti-PD1 or anti-PD-L1 therapy results in robust antitumor activity, which is further improved by adding the immune-stimulating Ab anti-CD137 or anti-CD134. Our findings support the testing of these combinations in patients with BRAF (V600E) mutant metastatic melanoma.