Oncology

Editorial introductions No abstract available

Targeted therapies in melanoma beyond BRAF: targeting NRAS-mutated and KIT-mutated melanoma Purpose of review Melanoma treatment have been revolutionized since 2010 by the development of immune checkpoint inhibitors, and, for BRAF-mutated melanoma, targeted therapies based on BRAF and MEK inhibitors, which is a model of effective targeted therapy in cancer. However, patients with BRAF wild type cannot benefit for such treatments. In this review, we will focus on the current clinical development of targeted therapies beyond BRAF, in NRAS-mutated and KIT-altered melanoma. Recent findings In NRAS-mutated melanoma, targeted therapies based on MEK inhibition are being developed as monotherapy or in combination with MAPK, PI3K or CDK4/6 inhibitor. Targeted therapies of KIT-altered melanoma patients is based in KIT inhibitor (mostly imatinib, nilotinib), although for both melanoma subtypes, results are for now disappointing as compared with BRAF and MEK inhibitors in BRAF-mutated melanoma. Summary Combined therapeutic targeted strategies are awaited in NRAS-mutated and KIT-altered melanoma and could provide additional benefit.

Targeting BRAF and MEK inhibitors in melanoma in the metastatic, neoadjuvant and adjuvant setting Purpose of review Better understanding of the biology of BRAF-mutated melanoma has led to the development of highly effective therapy, BRAF and MEK inhibitors, targeting abnormally activated protein kinases for patient with BRAF-mutated melanoma. The purpose of this article was to review the recent published data on BRAF and MEK inhibitors in melanoma in the metastatic, adjuvant and neoadjuvant setting to facilitate the management of melanoma patients in clinical practice. Recent findings The spectacular outcomes of targeted therapy in advanced melanoma patients have led to their development in the adjuvant setting with substantial improvements in recurrence-free and overall survival. The neoadjuvant strategy is already used in many cancers to decrease tumor load, improve resectability and prevent relapse. Targeted therapy in the neoadjuvant setting is a therapeutic approach being explored in subsequent studies. Summary We hope that this review will help clinicians to manage melanoma patients in routine practice.

Mechanisms of resistance and predictive biomarkers of response to targeted therapies and immunotherapies in metastatic melanoma Purpose of review Thanks to mitogen-activated protein kinase inhibitors (MAPKi) and immune checkpoint inhibitors (ICI), major progress has been made in the field of melanoma treatment. However, long-term success is still scarce because of the development of resistance. Understanding these mechanisms of resistance and identifying predictive genomic biomarkers are now key points in the therapeutic management of melanoma patients. Recent findings Multiple and complex mechanisms of resistance to MAPKi or ICI have been uncovered in the past few years. The lack of response can be driven by mutations and nonmutational events in tumor cells, as well as by changes in the tumor microenvironment. Melanoma cells are also capable of rapidly switching their molecular and cellular phenotype, leading to an initial drug-tolerant favorizing melanoma resistance. Tumor molecular profiling and circulating tumor cell analyses are of high interest as predictive biomarkers as well as studying immunogenic changes and microbiome in ICI-treated patients. Summary Resistance to MAPKi and ICI is a key point in therapeutic management of metastatic melanoma patients. Validated biomarkers predicting response to therapy are urgently needed to move toward personalized medicine. Combinatory treatments guided by the understanding of resistance mechanisms will be of major importance in the future of melanoma therapy.

Use of noninvasive imaging in the management of skin cancer Purpose of review To evaluate noninvasive imaging techniques in the management of skin cancers. Recent findings In the last decades, a wide range of noninvasive imaging methods has been developed in the field of dermatooncology with the aim to detect and assess the several structural and molecular changes that characterize skin cancer development and progression. Summary In this review, we discuss the current and emerging applications of noninvasive imaging approaches in skin cancer management, such as digital photography, dermoscopy, ultrasound sonography, reflectance confocal microscopy, optical coherence tomography, electrical impedance techniques, Raman spectroscopy, multispectral imaging, fluorescence imaging, and multispectral optoacustic tomography.

Immune checkpoint inhibitors in melanoma in the metastatic, neoadjuvant, and adjuvant setting Purpose of review Immune checkpoint inhibitors (ICI) are now standards of care in metastatic melanoma. We highlight here the dramatic improvement that these drugs brought in the history of melanoma care. Recent findings The monoclonal antibody directed against cytotoxic T-lymphocyte-associated protein 4, ipilimumab, was approved in 2011. Antiprogramed death cell protein 1 antibodies, nivolumab and pembrolizumab, were developed afterward and approved in 2014, demonstrating an improved efficacy/safety ratio as compared with ipilimumab. The association of ipilimumab and nivolumab now appears as the most efficient immunotherapy but the toxicity of this regimen is a limitation. These drugs have also been evaluated in the adjuvant setting for patients with stage III or IV resected melanoma where they have shown a significant benefit in terms of relapse-free survival. Summary ICI-based immunotherapy radically modified melanoma management and now appear as the most efficient treatment for patients with metastatic melanoma with characterized by long-lasting cancer remissions, and a distinct spectrum of immune-related adverse events. Their efficacy is now also established in the adjuvant setting and they are now actively evaluated as neoadjuvant treatment with promising early results. Intensive translational work is ongoing to identify predictive biomarkers of efficacy and toxicity to improve ICI benefit/risk ratio.

Immunobiology of Merkel cell carcinoma Purpose of review Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer, which is associated in 80% of cases with the Merkel cell polyomavirus (MCPyV). Advanced stages respond to immune checkpoint inhibitors in 50% of cases. Major issues remain unanswered regarding its oncogenesis and optimal treatment. Recent findings MCPyV-negative and MCPyV-positive MCCs have been hypothesized to derive from distinct cells, although the cell of origin remains a matter of debate. The crucial role the MCPyV small T oncoprotein was recently confirmed by its ability to inactivate p53, together with its contribution to the metastatic progression. In advanced cases, tumoral microenvironment may adequately predict responses to immunotherapies, and several mechanisms of primary and secondary resistance have been investigated. Summary Identifying the mechanisms of oncogenesis allow experimentation of new therapeutic targets, which remain mandatory even at the era of immunotherapies. Although new insights in the mechanisms of primary and secondary resistance pave the way for development of further immunotherapy strategies, neoadjuvant strategies may challenge our whole approach of the disease.

Update on oncogenesis and therapy for Kaposi sarcoma Purpose of review This review is an update of the recent findings on pathophysiology of Kaposi sarcoma, the role of HHV-8 in Kaposi sarcoma pathogenesis and to summarize the recent advances in the treatment of Kaposi sarcoma and the role of immunity to control the disease. Recent findings The causal agent of Kaposi sarcoma is HHV-8 and the mechanism by which HHV-8 drives the tumor development is unique. HHV-8 is not a classic oncogenic virus and the disease is an opportunistic tumor responding to immune restoration when it is possible. Summary Five epidemiologic types of Kaposi are recognized and HHV-8 is associated to all epidemiologic forms of Kaposi. HHV-8 is a virus favoring both angiogenesis and cellular proliferation, which are the two main histological features of Kaposi sarcoma. Although in many cases, treatment of Kaposi sarcoma is not necessary, specific chemotherapy, immunomodulation and immune stimulation are the tools for treating Kaposi sarcoma. Monochemotherapy has been shown to be as efficient as polychemotherapy and less toxic. Immune checkpoint inhibitors gave some promising results, which should be confirmed by prospective studies.

Molecular prediction of metastasis in cutaneous squamous cell carcinoma Purpose of review Cutaneous squamous cell carcinoma (cSCC) is a highly prevalent malignancy frequently occurring on body surfaces chronically exposed to ultraviolet radiation. While a large majority of tumors remain localized to the skin and immediate subcutaneous tissue and are cured with surgical excision, a small subset of patients with cSCC will develop metastatic disease. Risk stratification for cSCC is performed using clinical staging systems, but given a high mutational burden and advances in targeted and immunotherapy, there is growing interest in molecular predictors of high-risk disease. Recent findings Recent literature on the risk for metastasis in cSCC includes notable findings in genes involved in cell-cycle regulation, tumor suppression, tissue invasion and microenvironment, interactions with the host-immune system, and epigenetic regulation. Summary cSCC is a highly mutated tumor with complex carcinogenesis. Regulators of tumor growth and local invasion are numerous and increasingly well-understood but drivers of metastasis are less established. Areas of importance include central system regulators (NOTCH, miRNAs), proteins involved in tissue invasion (podoplanin, E-cadherin), and targets of existing and emerging therapeutics (PD-1, epidermal growth factor receptor). Given the complexity of cSCC carcinogenesis, the use of machine learning algorithms and computational genomics may provide ultimate insight and prospective studies are needed to verify clinical relevance.

Editorial: Dissecting the pathological bone marrow niche through single-cell omics and artificial intelligence No abstract available