Panniculitis With Necrotizing Granulomata in a Patient on BRAF Inhibitor (Dabrafenib) Therapy for Metastatic Melanoma
Nisha S. RamaniJonathan L. CurryJyoti KapilRonald P. RapiniMichael T. TetzlaffVíctor G. PrietoCarlos A. Torres‐Cabala
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Abstract:
There have been major developments in targeted therapeutics with the clinical development of selective BRAF inhibitors (BRAFi) for patients with metastatic BRAF V600E mutant melanoma. Objective response rate of almost 50% has been witnessed in BRAFi clinical trials. Frequent side effects range from squamoproliferative lesions, including hyperplasia, keratoacanthomas, and squamous cell carcinomas to second primary melanomas. We describe a 50-year-old Hispanic woman with BRAF V600E mutant metastatic melanoma who was treated with surgery, radiation therapy, interleukin-2, and was enrolled on a BRAFi (dabrafenib) trial. Two months after initiation, she developed multiple erythematous, indurated, tender subcutaneous nodules bilaterally on the anterior thighs, posterior arms, and left dorsal forearm without overlying epidermal change. Punch biopsy revealed panniculitis with necrotizing granulomata. Infectious and other causes for panniculitis were excluded. We believe the histology likely represents a reaction to BRAFi therapy based on the temporal relationship of its onset to initiation of BRAFi therapy and previously reported cases of neutrophilic panniculitis associated with BRAFi therapy. Panniculitis has been emerging as an important unusual side effect of BRAFi therapy. Our case illustrates a unique presentation of BRAFi-associated panniculitis demonstrating necrotizing granulomata.Keywords:
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Dabrafenib is a kinase inhibitor used in the treatment of patients with unresectable or metastatic melanoma with specific BRAF variants. Dabrafenib can be used as a single agent to treat melanoma with the BRAF V600E variant, or in combination with the MEK inhibitor trametinib to treat melanoma with BRAF V600E or V600K variants.BRAF is an intracellular kinase in the mitogen-activated protein kinases (MAPK) pathway. BRAF is involved in regulating important cell functions such as cell growth, division, differentiation, and apoptosis. BRAF is also a proto-oncogene—when mutated it has the ability to transform normal cells into cancerous cells.Variation in the kinase domain of BRAF have been associated with various cancers. The most common BRAF variant, V600E, constitutively activates the kinase, and causes cell proliferation in the absence of growth factors that would normally be required. The V600E variant is detected in approximately 50% of melanomas (1, 2).The FDA-approved label for dabrafenib states that the presence of BRAF mutation in tumor specimens (V600E for dabrafenib monotherapy; V600E or V600K for dabrafenib plus trametinib) should be confirmed, using an FDA-approved test, before starting treatment with dabrafenib. Dabrafenib is not indicated for treatment of patients with wild-type BRAF melanoma.The label also states that patients who have glucose-6-phosphate dehydrogenase (G6PD) deficiency should be monitored for signs of hemolytic anemia while taking dabrafenib (3).
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Abstract V‐raf murine sarcoma viral oncogene homologue B1 (BRAF) is a proto‐oncogene that regulates cell proliferation and survival. BRAF V600E‐mutated lung cancer has aggressive characteristics and is resistant to chemotherapies. Combination of BRAF‐specific inhibitor dabrafenib and mitogen‐activated protein kinase kinase (MEK) inhibitor trametinib is the standard treatment for BRAF V600E‐mutated lung cancer. We report a case of BRAF V600E‐mutated lung adenocarcinoma, which presented with respiratory distress due to deterioration of advanced cancer. The tumour responded rapidly and significantly to BRAF/MEK inhibitors, and the patient's symptoms improved within 2 weeks. BRAF/MEK inhibitors are effective treatment in BRAF‐mutated lung cancer even under critical conditions.
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Combination use of BRAF V600E inhibitor dabrafenib and MEK inhibitor trametinib has become a standard treatment for human cancers harboring BRAF V600E. Its anticancer efficacies vary, however, with dramatic efficacy in some patients and drug resistance/tumor recurrence in others, which is poorly understood. Using thyroid cancer, melanoma, and colon cancer cell models, we showed that dabrafenib and trametinib induced robust apoptosis of cancer cells harboring both BRAF V600E and TERT promoter mutations but had little proapoptotic effect in cells harboring only BRAF V600E. Correspondingly, the inhibitors nearly completely abolished the growth of in vivo tumors harboring both mutations but had little effect on tumors harboring only BRAF V600E. Upon drug withdrawal, tumors harboring both mutations remained hardly measurable but tumors harboring only BRAF V600E regrew rapidly. BRAF V600E/MAP kinase pathway is known to robustly activate mutant promoter of TERT, a strong apoptosis suppressor. Thus, for survival, cancer cells harboring both mutations may have evolved to rely on BRAF V600E-promoted and high-TERT expression-mediated suppression of apoptosis. As such, inhibition of BRAF/MEK can trigger strong apoptosis-induced cell death and hence tumor abolishment. This does not happen in cells harboring only BRAF V600E as they have not developed reliance on TERT-mediated suppression of apoptosis due to the lack of mutant promoter-driven high-TERT expression. TERT promoter mutation governs BRAF-mutant cancer cells' apoptotic and hence therapeutic responses to BRAF/MEK inhibitors. Thus, the genetic duet of BRAF V600E and TERT promoter mutation represents an Achilles Heel for effective therapeutic targeting and response prediction in cancer.
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We report on a patient with an adenocarcinoma of the lung harbouring a BRAF V600E mutation who benefited from combination therapy with dabrafenib-trametinib after developing resistance to vemurafenib. To our knowledge, our report shows, for the first time, that combination therapy with dabrafenib-trametinib can overcome vemurafenib resistance in a BRAF V600E-mutated adenocarcinoma of the lung.
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Enteric-type adenocarcinoma of the lung (lung-ETAC) is a rare form of lung cancer with histologic similarities to colorectal cancer, with aggressive behavior and unfavorable prognosis.An 81-year-old man presented with discolored skin lesions on the chest and abdomen. After comprehensive evaluation, including skin biopsy and molecular profiling, the patient was diagnosed with having lung-ETAC with a BRAF p.V600E mutation. Treatment with dabrafenib and trametinib initially resulted in positive results, with improvement in skin lesions and overall clinical condition. Nevertheless, approximately 6 months after, the disease had progression with new skin lesions reappearing.We reported a unique case of a patient with BRAF p.V600E-mutant lung-ETAC with metastatic skin lesions achieving complete cutaneous response after targeted treatment with dabrafenib and trametinib, highlighting the potential for targeted therapy in patients with lung-ETAC harboring a BRAF p.V600E mutation.
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Combination dabrafenib and trametinib in the management of advanced melanoma with BRAFV600 mutations
In the 40-50% of advanced melanoma patients with tumors harboring BRAF V600E and V600 K mutations, BRAF inhibitors such as dabrafenib are a highly effective treatment. However, most patients develop resistance after several months on treatment. The addition of a MEK inhibitor, such as trametinib, to BRAF inhibition mitigates one key pathway of resistance, further increasing response rates and improving survival.This article summarizes the mechanism of action of the combination of dabrafenib and trametinib, its evolution through Phase I, II and III clinical trials and discusses its current use in the management of patients with advanced melanoma.Combination therapy with dabrafenib and trametinib improves response rate, progression-free survival and overall survival when compared to dabrafenib or vemurafenib alone. The addition of trametinib to dabrafenib changes the adverse event profile, making hyperkeratosis and cutaneous squamous cell carcinomas less common but side effects such as fever and nausea more common. How dabrafenib/trametinib is best sequenced with other effective treatments such as immune checkpoint blockade remains uncertain.
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At present, two selective BRAF inhibitors (dabrafenib and vemurafenib) and one MEK inhibitor (trametinib) are FDA-approved for treating stage IV BRAFV600E -mutated metastatic melanoma. Single-agent dabrafenib but not vemurafenib has been tested against combination dabrafenib/trametinib. Vemurafenib monotherapy is in current use; these investigators studied its efficacy relative to combination dabrafenib/trametinib.
A total of 704 patients were randomized to receive either oral …
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Inhibitors targeting active protein kinases, such as EGFR or ALK, have demonstrated significant efficacy in the treatment of lung cancer. Activating mutations in the MAPK pathway, which includes the enzymes RAS, RAF, MEK, and ERK, result in constitutive signalling, leading to oncogenic cell proliferation and escape from apoptosis; therefore this pathway is a focus of crucial interest for the development of cancer drugs. In melanoma, the most commonly mutated gene is BRAF, with mutations usually occurring in about 50% of all tumours. The BRAF Val600Glu (V600E) mutation constitutes more than 90% of mutations in melanoma. V600E BRAF mutation shows a great dependency on MEK activity, and offers a rational therapeutic strategy for this genetically defined tumour subtype. The use of vemurafenib and dabrafenib, agents that block MAPK signaling in patients with melanoma and the BRAF V600E mutation, has been associated with prolonged survival and progression-free survival. The frequency of V600E BRAF mutation in lung adenocarcinoma is 1.5% to 2.8%. Treatment of V600E BRAF-mutant lung adenocarcinomas with dabrafenib is under evaluation in a phase 2 trial, and could represent another milestone in individualized therapy for lung cancer patients. The next step will be a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib.
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