Cutaneous Toxic Effects Associated With Vemurafenib and Inhibition of the BRAF Pathway

Huang, Victor; Hepper, Donna M.; Anadkat, Milan J.; Cornelius, Lynn A.

doi:10.1001/archdermatol.2012.125

Cited by 94 publications

(66 citation statements)

References 28 publications

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“…5). Patients who develop cutaneous tumors frequently acquire multiple primary lesions, which can affect entire limbs or chest (29,30), a phenotype consistent with an infectious disease. Furthermore, the pathology of tumors is also not limited to cSCC and keratoacanthoma.…”

Section: Discussionmentioning

confidence: 99%

Vemurafenib Cooperates with HPV to Promote Initiation of Cutaneous Tumors

et al. 2014

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Treatment with RAF inhibitors such as vemurafenib causes the development of cutaneous squamous cell carcinomas (cSCC) or keratoacanthomas as a side effect in 18% to 30% of patients. It is known that RAF inhibitors activate the mitogen-activated protein kinase (MAPK) pathway and stimulate growth of RAS-mutated cells, possibly accounting for up to 60% of cSCC or keratoacanthoma lesions with RAS mutations, but other contributing events are obscure. To identify such events, we evaluated tumors from patients treated with vemurafenib for the presence of human papilloma virus (HPV) DNA and identified 13% to be positive. Using a transgenic murine model of HPV-driven cSCC (K14-HPV16 mice), we conducted a functional test to determine whether administration of RAF inhibitors could promote cSCC in HPV-infected tissues. Vemurafenib treatment elevated MAPK markers and increased cSCC incidence from 22% to 70% in this model. Furthermore, 55% of the cSCCs arising in vemurafenib-treated mice exhibited a wild-type Ras genotype, consistent with the frequency observed in human patients. Our results argue that HPV cooperates with vemurafenib to promote tumorigenesis, in either the presence or absence of RAS mutations. Cancer Res; 74(8); 2238-45. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Vemurafenib Cooperates with HPV to Promote Initiation of Cutaneous Tumors

et al. 2014

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“…Interestingly, BRAF inhibitor was found to have radio sensitization effect (132,133). However, the radiosensitization effect of BRAF inhibitor also increased the risk of skin toxicities with radiation (133)(134)(135)(136). Due to the minimum skin dose from SRS, several studies that evaluated BRAF inhibitor with SRS for patients with brain metastases reported favorable outcome (137)(138)(139).…”

Section: Rt With Concomitant Agentsmentioning

confidence: 99%

Radiation Therapy for Melanoma

Shi

2017

Cutaneous Melanoma: Etiology and Therapy

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Although melanoma is a relative radioresistant tumor, radiation therapy (RT) remains a valid and effective treatment option for the management of melanoma. RT as a primary treatment is often offered in well-defined situations, such as medical inoperability, lentiginous melanoma, mucosal melanoma, and ocular melanoma. Adjuvant RT following lymphadenectomy in node-positive melanoma patients prevents local and regional recurrence; however, the role of adjuvant RT remains controversial and underutilized due to lack of overall survival benefit. On the other hand, RT is highly effective in providing symptom palliation for metastatic melanoma and is widely used. Advanced RT technologies such as stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT) can achieve excellent local control with minimum toxicities. They are commonly used in the management of brain, lung, spine, and liver metastases. Most recently, it is under active investigation on combining RT with new systemic options, such as targeted therapy, or immunotherapy. The advancements in the treatment of patients with melanoma highlight the importance of multidisciplinary management in this disease. Radiation therapy will continue to be one of the key therapeutic options.

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“…50 Interestingly, this paradoxical activation has been proposed as an etiologic factor in the development of squamous cell carcinomas of the skin, which may occur in patients treated with BRAF inhibitors. 51,52 …”

Section: Issues In Specific Tumor Typesmentioning

confidence: 99%

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

Venook¹,

Arcila²,

Benson³

et al. 2014

J Natl Compr Canc Netw

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Defining treatment susceptible or resistant populations of cancer patients through the use of genetically defined biomarkers has revolutionized cancer care in recent years for some disease/patient groups. Research continues to show that histologically defined diseases are diverse in their expression of unique mutations or other genetic alterations, however, which presents both opportunities for the development of personalized cancer treatments, but increased difficulty in testing these therapies because potential patient populations are divided into ever-smaller numbers. To address some of the growing challenges in biomarker development and clinical trial design, NCCN assembled a group of experts across specialties and solid tumor disease types to begin to define the problems and to consider alternate ways of designing clinical trials in the era of multiple biomarkers and targeted therapies. Results from that discussion are presented, focusing on issues of clinical trial design from the perspective of statisticians, clinical researchers, regulators, pathologists and information developers.

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Cutaneous Toxic Effects Associated With Vemurafenib and Inhibition of the BRAF Pathway

Cited by 94 publications

References 28 publications

Vemurafenib Cooperates with HPV to Promote Initiation of Cutaneous Tumors

Vemurafenib Cooperates with HPV to Promote Initiation of Cutaneous Tumors

Radiation Therapy for Melanoma

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

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