Submit to Cancers Review for Cancers Propose a Special Issue

Journal Browser

► Journal Browser

Therapeutic Strategies for Metastatic Melanomas

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (1 May 2021) | Viewed by 21579

Share This Special Issue

Special Issue Editors

Dr. Andrea Forschner

E-Mail Website
Guest Editor

University Hospital Tuebingen, Eberhard Karls University of Tübingen, D-72076 Tübingen, Germany
Interests: immune checkpoint inhibitors of melanoma; targeted therapies of melanoma; resistance to melanoma therapies; psychooncology

Dr. Elisabeth Livingstone

E-Mail Website
Co-Guest Editor

Department of Dermatology, University Hospital Essen, 45122 Essen, Germany
Interests: immune checkpoint inhibitors of melanoma; targeted therapies of melanoma; treatment sequencing; adverse events; drug repurposing; quality of life

Special Issue Information

Dear Colleagues,

Over the last few years, the prognosis of metastatic melanoma patients has improved significantly due to new treatment options, such as checkpoint inhibition and targeted therapy. However, most efficacy data were obtained from randomized phase III trials with strict inclusion and exclusion criteria. As a consequence, there is a great need for data from clinical practice (real world data), for example, from registries that also address patients with, e.g., comorbidities or noncutaneous melanomas that were excluded in the clinical trials.
This Special Issue will highlight the current status of metastatic melanoma therapy and potential future prospects.
Manuscripts are welcome that report on original data or updated, comprehensive literature reviews in the field of melanoma therapy.
The following topics are of particular interest:

Long term survival of melanoma patients under checkpoint inhibition and/or targeted therapy;
Real world data on adjuvant therapy of metastatic melanoma patients;
New possibilities for therapy monitoring of melanoma patients, such as liquid biopsies;
Real world data/therapy options for difficult-to-treat melanoma subtypes such as mucosal melanoma, acral melanoma, and uveal melanoma;
- Therapy options for advanced liver metastasis, such as chemosaturation, SIRT, stereotaxy, surgery.

Other topics may also be of interest and will be considered.

Dr. Andrea Forschner
Dr. Elisabeth Livingstone
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Advanced melanoma
Adjuvant therapy
Neoadjuvant therapy
Immune checkpoint inhibition
Targeted therapy
BRAF/MEK inhibitor
Next generation sequencing (NGS)
Liquid biopsy
Melanoma biomarker

Published Papers (6 papers)

Download All Papers

Research

Jump to: Review

15 pages, 284 KiB

Open AccessArticle

Primary Melanoma Characteristics of Metastatic Disease: A Nationwide Cancer Registry Study

by Catherine Zhou, Marieke Louwman, Marlies Wakkee, Astrid van der Veldt, Dirk Grünhagen, Cornelis Verhoef, Antien Mooyaart, Tamar Nijsten and Loes Hollestein

Cancers 2021, 13(17), 4431; https://doi.org/10.3390/cancers13174431 - 02 Sep 2021

Cited by 12 | Viewed by 1907

Abstract

The characteristics and disease patterns of primary stage I and II cutaneous melanomas that progress to stage III or IV disease were investigated based on data from the Netherlands Cancer Registry (NCR). Data on stage III or IV melanomas at first diagnosis or during follow-up between 2017 and 2019 were retrieved. Patient and primary tumour characteristics were investigated in relation to time to disease progression and the number of organ sites with metastatic disease using regression models. In total, 2763 patients were included, of whom 1613 were diagnosed with stage IV disease. Among the patients with stage IV disease, 60% (n = 963) were initially diagnosed with stage I or II disease. The proportion of patients who received a sentinel lymph node biopsy increased after the introduction of adjuvant therapy in 2019 from 61% to 87%. Among all patients with stage III disease who were eligible for adjuvant systemic therapy (n = 453) after 2019, 37% were not treated with this therapy. Among patients with stage IV disease, lung metastases were most often detected as the first metastatic site and females presented with more metastatic sites than males. Most patient and primary tumour characteristics were not associated with the distant metastatic organ site, except melanoma localisation in the lower extremities and the head or neck. Our observation that most stage IV patients were initially diagnosed with early-stage disease highlights the need for more accurate risk prediction models. Full article

(This article belongs to the Special Issue Therapeutic Strategies for Metastatic Melanomas)

19 pages, 291 KiB

Open AccessArticle

Factors Influencing the Adjuvant Therapy Decision: Results of a Real-World Multicenter Data Analysis of 904 Melanoma Patients

by Georg Lodde, Andrea Forschner, Jessica Hassel, Lena M. Wulfken, Friedegund Meier, Peter Mohr, Katharina Kähler, Bastian Schilling, Carmen Loquai, Carola Berking, Svea Hüning, Kerstin Schatton, Christoffer Gebhardt, Julia Eckardt, Ralf Gutzmer, Lydia Reinhardt, Valerie Glutsch, Ulrike Nikfarjam, Michael Erdmann, Andreas Stang, Bernd Kowall, Alexander Roesch, Selma Ugurel, Lisa Zimmer, Dirk Schadendorf and Elisabeth Livingstone Show full author list Hide full author list

Cancers 2021, 13(10), 2319; https://doi.org/10.3390/cancers13102319 - 12 May 2021

Cited by 16 | Viewed by 2967

Abstract

Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in BRAF mutant patients). Of these patients, 76.9% (95% CI 74–80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26% lower in patients >65 years (RR 0.74, 95% CI 68–80). The most common reasons against adjuvant treatment given by patients were age (29.4%, 95% CI 24–38), and fear of adverse events (21.1%, 95% CI 16–28) and impaired quality of life (11.9%, 95% CI 7–16). Of all BRAF-mutated patients who opted for adjuvant treatment, 52.9% (95% CI 47–59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI. Full article

(This article belongs to the Special Issue Therapeutic Strategies for Metastatic Melanomas)

19 pages, 1278 KiB

Open AccessArticle

Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma—A Retrospective Multicenter ADOReg Study

by Henner Stege, Maximilian Haist, Michael Schultheis, Maria Isabel Fleischer, Peter Mohr, Friedegund Meier, Dirk Schadendorf, Selma Ugurel, Elisabeth Livingstone, Lisa Zimmer, Rudolf Herbst, Claudia Pföhler, Katharina Kähler, Michael Weichenthal, Patrick Terheyden, Dorothée Nashan, Dirk Debus, Martin Kaatz, Fabian Ziller, Sebastian Haferkamp, Andrea Forschner, Ulrike Leiter, Alexander Kreuter, Jens Ulrich, Johannes Kleemann, Fabienne Bradfisch, Stephan Grabbe and Carmen Loquai Show full author list Hide full author list

Cancers 2021, 13(10), 2312; https://doi.org/10.3390/cancers13102312 - 12 May 2021

Cited by 11 | Viewed by 3107

Abstract

The advent of BRAF/MEK inhibitors (BRAFi/MEKi) has significantly improved progression-free (PFS) and overall survival (OS) for patients with advanced BRAF-V600-mutant melanoma. Long-term survivors have been identified particularly among patients with a complete response (CR) to BRAF/MEK-directed targeted therapy (TT). However, it remains unclear which patients who achieved a CR maintain a durable response and whether treatment cessation might be a safe option in these patients. Therefore, this study investigated the impact of treatment cessation on the clinical course of patients with a CR upon BRAF/MEK-directed-TT. We retrospectively selected patients with BRAF-V600-mutant advanced non-resectable melanoma who had been treated with BRAFi ± MEKi therapy and achieved a CR upon treatment out of the multicentric skin cancer registry ADOReg. Data on baseline patient characteristics, duration of TT, treatment cessation, tumor progression (TP) and response to second-line treatments were collected and analyzed. Of 461 patients who received BRAF/MEK-directed TT 37 achieved a CR. TP after initial CR was observed in 22 patients (60%) mainly affecting patients who discontinued TT (n = 22/26), whereas all patients with ongoing TT (n = 11) maintained their CR. Accordingly, patients who discontinued TT had a higher risk of TP compared to patients with ongoing treatment (p < 0.001). However, our data also show that patients who received TT for more than 16 months and who discontinued TT for other reasons than TP or toxicity did not have a shorter PFS compared to patients with ongoing treatment. Response rates to second-line treatment being initiated in 21 patients, varied between 27% for immune-checkpoint inhibitors (ICI) and 60% for BRAFi/MEKi rechallenge. In summary, we identified a considerable number of patients who achieved a CR upon BRAF/MEK-directed TT in this contemporary real-world cohort of patients with BRAF-V600-mutant melanoma. Sustained PFS was not restricted to ongoing TT but was also found in patients who discontinued TT. Full article

(This article belongs to the Special Issue Therapeutic Strategies for Metastatic Melanomas)

► Show Figures

Figure 1

12 pages, 2814 KiB

Open AccessArticle

Allosteric and ATP-Competitive MEK-Inhibition in a Novel Spitzoid Melanoma Model with a RAF- and Phosphorylation-Independent Mutation

by Luca Hegedüs, Özlem Okumus, Elisabeth Livingstone, Marcell Baranyi, Ildikó Kovács, Balázs Döme, József Tóvári, Ágnes Bánkfalvi, Dirk Schadendorf, Clemens Aigner and Balázs Hegedüs

Cancers 2021, 13(4), 829; https://doi.org/10.3390/cancers13040829 - 16 Feb 2021

Cited by 4 | Viewed by 2095

Abstract

Spitzoid melanoma is a rare malignancy with histological characteristics similar to Spitz nevus. It has a diverse genetic background and in adults, a similarly grim clinical outcome as conventional malignant melanoma. We established a spitzoid melanoma cell line (PF130) from the pleural effusion sample of a 37-year-old male patient. We found that the cell line carries a rare MEK1 mutation (pGlu102_Lys104delinsGln) that belongs to the RAF- and phosphorylation-independent subgroup of MEK1 alternations supposedly insensitive to allosteric MEK inhibitors. The in vivo tumorigenicity was tested in three different models by injecting the cells subcutaneously, intravenously or into the thoracic cavity of SCID mice. In the intrapleural model, macroscopic tumors formed in the chest cavity after two months, while subcutaneously and intravenously delivered cells showed limited growth. In vitro, trametinib—but not selumentinib—and the ATP-competitive MEK inhibitor MAP855 strongly decreased the viability of the cells and induced cell death. In vivo, trametinib but not MAP855 significantly reduced tumor growth in the intrapleural model. To the best of our knowledge, this is the first patient-derived melanoma model with RAF- and phosphorylation-independent MEK mutation and we demonstrated its sensitivity to trametinib. Full article

(This article belongs to the Special Issue Therapeutic Strategies for Metastatic Melanomas)

► Show Figures

Figure 1

Review

Jump to: Research

39 pages, 2076 KiB

Open AccessReview

RTK Inhibitors in Melanoma: From Bench to Bedside

by Malak Sabbah, Ahmad Najem, Mohammad Krayem, Ahmad Awada, Fabrice Journe and Ghanem E. Ghanem

Cancers 2021, 13(7), 1685; https://doi.org/10.3390/cancers13071685 - 02 Apr 2021

Cited by 23 | Viewed by 3634

Abstract

MAPK (mitogen activated protein kinase) and PI3K/AKT (Phosphatidylinositol-3-Kinase and Protein Kinase B) pathways play a key role in melanoma progression and metastasis that are regulated by receptor tyrosine kinases (RTKs). Although RTKs are mutated in a small percentage of melanomas, several receptors were found up regulated/altered in various stages of melanoma initiation, progression, or metastasis. Targeting RTKs remains a significant challenge in melanoma, due to their variable expression across different melanoma stages of progression and among melanoma subtypes that consequently affect response to treatment and disease progression. In this review, we discuss in details the activation mechanism of several key RTKs: type III: c-KIT (mast/stem cell growth factor receptor); type I: EGFR (Epidermal growth factor receptor); type VIII: HGFR (hepatocyte growth factor receptor); type V: VEGFR (Vascular endothelial growth factor), structure variants, the function of their structural domains, and their alteration and its association with melanoma initiation and progression. Furthermore, several RTK inhibitors targeting the same receptor were tested alone or in combination with other therapies, yielding variable responses among different melanoma groups. Here, we classified RTK inhibitors by families and summarized all tested drugs in melanoma indicating the rationale behind the use of these drugs in each melanoma subgroups from preclinical studies to clinical trials with a specific focus on their purpose of treatment, resulted effect, and outcomes. Full article

(This article belongs to the Special Issue Therapeutic Strategies for Metastatic Melanomas)

► Show Figures

Figure 1

26 pages, 1945 KiB

Open AccessReview

Systemic Therapy of Metastatic Melanoma: On the Road to Cure

by Julian Steininger, Frank Friedrich Gellrich, Alexander Schulz, Dana Westphal, Stefan Beissert and Friedegund Meier

Cancers 2021, 13(6), 1430; https://doi.org/10.3390/cancers13061430 - 20 Mar 2021

Cited by 48 | Viewed by 7184

Abstract

This decade has brought significant survival improvement in patients with metastatic melanoma with targeted therapies and immunotherapies. As our understanding of the mechanisms of action of these therapeutics evolves, even more impressive therapeutic success is being achieved through various combination strategies, including combinations of different immunotherapies as well as with other modalities. This review summarizes prospectively and retrospectively generated clinical evidence on modern melanoma therapy, focusing on immunotherapy and targeted therapy with BRAF kinase inhibitors and MEK kinase inhibitors (BRAF/MEK inhibitors), including recent data presented at major conference meetings. The combination of the anti-PD-1 directed monoclonal antibody nivolumab and of the CTLA-4 antagonist ipilimumab achieves unprecedented 5-year overall survival (OS) rates above 50%; however, toxicity is high. For PD-1 monotherapy (nivolumab or pembrolizumab), toxicities are in general well manageable. Today, novel combinations of such immune checkpoint inhibitors (ICIs) are under investigation, for example with cytokines and oncolytic viruses (i.e., pegylated interleukin-2, talimogene laherparepvec). Furthermore, current studies investigate the combined or sequential use of ICIs plus BRAF/MEK inhibitors. Several studies focus particularly on poor prognosis patients, as e.g., on anti-PD-1 refractory melanoma, patients with brain metastases, or uveal melanoma. It is hoped, on the road to cure, that these new approaches further improve long term survival in patients with advanced or metastatic melanoma. Full article

(This article belongs to the Special Issue Therapeutic Strategies for Metastatic Melanomas)

► Show Figures