Letter

Keratoacanthomas associated with sorafenib therapy

As cancer treatment evolves in the era of precision oncology, molecularly targeted agents (MTAs) have become frontline therapy for many cancers. MTAs are biologically targeted and thought to have less off-target toxicity; however, the eye is particularly susceptible to off-target toxicities given its unique microenvironment. In this review, we present commonly used FDA-approved MTAs, any associated ocular toxicities and review the mechanisms, frequency, severity, and management. Increased awareness and communication between clinicians caring for cancer patients is needed for individualized risk assessment, earlier diagnosis, and mitigation of ocular toxicities.

Recent advancements in anticancer therapy have produced an array of highly specialized therapeutics that prolong disease-free survival, improve tolerability of treatment, and individualize care. With improved treatments and longer survival, treatment-related toxicities are gaining importance. Dermatologic toxicities are common, with therapy-induced secondary cutaneous malignancies of the most frequent and serious for targeted therapies, immunotherapy, and radiotherapy. Often, these eruptive malignant lesions can be treatment limiting and detrimental to quality of life. As such, dermatologists play an important role in multidisciplinary oncologic care teams for surveillance and management of secondary cutaneous malignancies. Proactive dermatologic supervision yields early diagnosis and treatment of secondary cutaneous malignancies, which limits therapy discontinuation and thus optimizes treatment through both therapeutic achievement and overall well-being.

There has been a rapid emergence of numerous targeted agents in the oncology community in the last decade. This exciting paradigm shift in drug development lends promise for the future of individualized medicine. Given the pace of development and clinical deployment of targeted agents with novel mechanisms of action, dermatology providers may not be familiar with the full spectrum of associated skin-related toxicities. Cutaneous adverse effects are among the most frequently observed toxicities with many targeted agents, and their intensity can be dose-limiting or lead to therapy discontinuation. In light of the often life-saving nature of emerging oncotherapeutics, it is critical that dermatologists both understand the mechanisms and recognize clinical signs and symptoms of such toxicities in order to provide effective clinical management. Part I of this continuing medical education article will review in detail the potential skin-related adverse sequelae, the frequency of occurrence, and the implications associated with on- and off-target cutaneous toxicities of inhibitors acting at the cell membrane level, chiefly inhibitors of epidermal growth factor receptor, KIT, and BCR-ABL, angiogenesis, and multikinase inhibitors.

Con el empleo de las nuevas terapias antiangiogénicas y su incorporación en el arsenal terapéutico de los distintos tipos de cáncer, se han detectado nuevos efectos adversos, no conocidos previamente, que afectan a la calidad de vida de los pacientes e incluso pueden obligar a suspender el tratamiento. Los efectos secundarios cutáneos ocurren en un 90% de los pacientes tratados con fármacos inhibidores de angiogénesis. En algunas ocasiones la severidad de las reacciones cutáneas se ha correlacionado con la eficacia y respuesta tumoral al tratamiento, por lo que resulta extremadamente importante para el dermatólogo ser capaz de reconocer y manejar este tipo de reacciones, diferenciar aquellas que pueden ser peligrosas para la vida del paciente y que obliguen a interrumpir el tratamiento de las que no lo son, evitando de esta forma la supresión no justificada de estas terapias que potencialmente pueden prolongar la vida del paciente. En esta revisión se analizan los efectos adversos cutáneos más importantes de los principales fármacos antiangiogénicos.

As new antiangiogenic therapies have been introduced and added to the therapeutic arsenal against various types of cancer, previously unknown adverse effects have been detected. These effects negatively impact patients’ quality of life and can even make it necessary to suspend treatment. Adverse skin reactions occur in 90% of patients treated with angiogenesis inhibitors. In some cases, a correlation has been observed between the severity of reactions and treatment efficacy and tumor response. It is therefore extremely important that dermatologists be able to recognize and manage these reactions. Moreover, in order to avoid the unjustified withdrawal of potentially life-extending treatments, dermatologists must be able to differentiate between non-life-threatening reactions and life-threatening reactions that necessitate the suspension of treatment. In this review article, we analyze the main cutaneous adverse effects of the most common antiangiogenic agents.

Somatic mutations in the BRAF gene have been identified as the most frequent and relevant to develop targeted molecular therapies in melanoma. Recently, seminal clinical trials have provided indisputable evidence that BRAF inhibitors improve response rate, progression free and overall survival in BRAFV600 mutated metastatic melanoma patients, thus representing the novel standard of care. Dermatological “off target” effects of these so-called ‘targeted therapies’ have to be considered, however, and among them the most intriguing are cutaneous adverse reactions. Skin toxicity is of relevance for at least three reasons: (1) it worsens the patient's quality of life and may be difficult to manage, (2) its heterogeneous clinical presentation differs from the clinico-pathological pictures observed in patients who do not receive BRAF inhibitors, and; (3) onset of skin cancer represents a model of carcinogenesis which may help to better understand the potential visceral tumorigenesis induced by BRAF inhibitors. This manuscript summarizes and critically reviews the state of the art of skin toxicity associated with BRAF inhibitors. Special attention will be paid to clinical presentation and histopathological findings, as well as related challenges for clinicians, pathologists, and basic scientists.

Since the discovery of activating mutations in the BRAF oncogene in melanoma, there has been remarkable progress in the development of targeted therapies for unresectable and metastatic melanoma. We review the latest developments in our understanding of the role of BRAF/MEK/ERK pathway signaling in melanoma, and the development of inhibitors of this pathway. We also explore alternative mutations seen in melanoma, such as NRAS, KIT, GNAQ, and GNA11, and the drug development that is ongoing based on this biology. Strategies for the management of the vexing clinical problem of BRAF inhibitor resistance, primarily via combination therapy, are outlined. With the recent approval of the BRAF inhibitor vemurafenib for stage IV metastatic melanoma, use of this agent is expanding in the United States. Thus, management of the skin toxicities of this agent, such as squamous cell carcinomas, “acneiform” eruptions, hand-foot syndrome, and panniculitis, will be a growing problem facing dermatologists today. We discuss the toxicities of targeted agents in use for melanoma, in particular the dermatologic effects and the management of these skin toxicities.