Targeted Therapies and Immunotherapies in Metastatic Melanoma

A topical collection in Cancers (ISSN 2072-6694). This collection belongs to the section "Cancer Therapy".

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Editors

1. Department of Pharmacology and Solid Tumor Genomics, Hôpital Saint-Louis, AP-HP, F-75010 Paris, France
2. INSERM UMR-S 976, Team 1, Human Immunology Pathophysiology and Immunotherapy, F-75010 Paris, France
3. Université de Paris, F-75010 Paris, France
Interests: cancer; melanoma; biomarkers; pharmacogenomics; targeted therapies; resistance; angiogenesis and metastasis
1. Assitance Publique des Hôpitaux de Paris Dermatology, Department of Dermatology, Hôpital Saint-Louis, 75010 Paris, France
2. INSERM U976, Paris 7 Diderot University, 75475 Paris, France
Interests: melanoma; nonmelanoma skin cancer; immune checkpoint inhibitors; immunotherapy; immune-related adverse events

Topical Collection Information

Dear Colleague,

Melanoma is a highly malignant skin cancer with a strong tendency to metastasize and develop drug resistance. In recent years, many efficient therapies have emerged in the management of advanced melanoma, which have profoundly transformed the therapeutic landscape and the prognosis of this disease. Several BRAF and MEK inhibitors as well as immune checkpoint inhibitors have been developed and have improved the survival of melanoma patients. Despite these unprecedented advances, resistance to these therapies is often inevitable due to pre-exiting or emerging resistance mechanisms. Comprehensive molecular deciphering revealed genomic alterations in tumor cells and their microenvironment accounting for this resistance. Better understanding of the mechanisms of therapy escape will undoubtedly improve clinical response and guide future therapeutic development.

Prof. Samia Mourah
Dr. Barouyr Baroudjian
Collection Editors

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Keywords

  • melanoma
  • targeted therapies
  • immunotherapies
  • resistance
  • comprehensive molecular deciphering

Published Papers (10 papers)

2023

Jump to: 2022, 2021

10 pages, 280 KiB  
Article
Combined Nivolumab and Ipilimumab in Octogenarian and Nonagenarian Melanoma Patients
by Constance Reichert, Capucine Baldini, Sarah Mezghani, Eve Maubec, Christine Longvert, Laurent Mortier, Gaëlle Quereux, Arnaud Jannic, Laurent Machet, Julie de Quatrebarbes, Charlée Nardin, Nathalie Beneton, Mona Amini Adle, Elisa Funck-Brentano, Vincent Descamps, Lorry Hachon, Nausicaa Malissen, Barouyr Baroudjian and Florence Brunet-Possenti
Cancers 2023, 15(17), 4330; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15174330 - 30 Aug 2023
Cited by 2 | Viewed by 765
Abstract
Data regarding elderly melanoma patients treated with anti-PD-1 or anti-CTLA-4 antibodies are in favor of tolerability outcomes that are similar to those of younger counterparts. However, there are very few studies focusing on elderly patients receiving nivolumab combined with ipilimumab (NIVO + IPI). [...] Read more.
Data regarding elderly melanoma patients treated with anti-PD-1 or anti-CTLA-4 antibodies are in favor of tolerability outcomes that are similar to those of younger counterparts. However, there are very few studies focusing on elderly patients receiving nivolumab combined with ipilimumab (NIVO + IPI). Here, we ask what are the current prescribing patterns of NIVO + IPI in the very elderly population and analyze the tolerance profile. This French multicenter retrospective study was conducted on 60 melanoma patients aged 80 years and older treated with NIVO + IPI between January 2011 and June 2022. The mean age at first NIVO + IPI administration was 83.7 years (range: 79.3–93.3 years). Fifty-five patients (92%) were in good general condition and lived at home. Two dosing regimens were used: NIVO 1 mg/kg + IPI 3 mg/kg Q3W (NIVO1 + IPI3) in 27 patients (45%) and NIVO 3 mg/kg + IPI 1 mg/kg Q3W (NIVO3 + IPI1) in 33 patients (55%). NIVO + IPI was a first-line treatment in 39 patients (65%). The global prevalence of immune-related adverse events was 63% (38/60), with 27% (16/60) being of grade 3 or higher. Grade ≥ 3 adverse events were less frequent in patients treated with NIVO3 + IPI1 compared with those treated with NIVO1 + IPI3 (12% versus 44%, p = 0.04). In conclusion, the prescribing patterns of NIVO + IPI in very elderly patients are heterogeneous in terms of the dosing regimen and line of treatment. The safety profile of NIVO + IPI is reassuring; whether or not the low-dose regimen NIVO3 + IPI1 should be preferred over NIVO1 + IPI3 in patients aged 80 years or older remains an open question. Full article

2022

Jump to: 2023, 2021

18 pages, 2389 KiB  
Article
Monitoring of Dabrafenib and Trametinib in Serum and Self-Sampled Capillary Blood in Patients with BRAFV600-Mutant Melanoma
by Nora Isberner, Anja Gesierich, David Balakirouchenane, Bastian Schilling, Fatemeh Aghai-Trommeschlaeger, Sebastian Zimmermann, Max Kurlbaum, Alicja Puszkiel, Benoit Blanchet, Hartwig Klinker and Oliver Scherf-Clavel
Cancers 2022, 14(19), 4566; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194566 - 20 Sep 2022
Cited by 3 | Viewed by 1822
Abstract
Patients treated with dabrafenib and trametinib for BRAFV600-mutant melanoma often experience dose reductions and treatment discontinuations. Current knowledge about the associations between patient characteristics, adverse events (AE), and exposure is inconclusive. Our study included 27 patients (including 18 patients for micro-sampling). [...] Read more.
Patients treated with dabrafenib and trametinib for BRAFV600-mutant melanoma often experience dose reductions and treatment discontinuations. Current knowledge about the associations between patient characteristics, adverse events (AE), and exposure is inconclusive. Our study included 27 patients (including 18 patients for micro-sampling). Dabrafenib and trametinib exposure was prospectively analyzed, and the relevant patient characteristics and AE were reported. Their association with the observed concentrations and Bayesian estimates of the pharmacokinetic (PK) parameters of (hydroxy-)dabrafenib and trametinib were investigated. Further, the feasibility of at-home sampling of capillary blood was assessed. A population pharmacokinetic (popPK) model-informed conversion model was developed to derive serum PK parameters from self-sampled capillary blood. Results showed that (hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or toxicity. Co-medication with P-glycoprotein inducers was associated with significantly lower trough concentrations of trametinib (p = 0.027) but not (hydroxy-)dabrafenib. Self-sampling of capillary blood was feasible for use in routine care. Our conversion model was adequate for estimating serum PK parameters from micro-samples. Findings do not support a general recommendation for monitoring dabrafenib and trametinib but suggest that monitoring can facilitate making decisions about dosage adjustments. To this end, micro-sampling and the newly developed conversion model may be useful for estimating precise PK parameters. Full article
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25 pages, 4035 KiB  
Review
Treatment of Metastatic Melanoma with a Combination of Immunotherapies and Molecularly Targeted Therapies
by Taylor Rager, Adam Eckburg, Meet Patel, Rong Qiu, Shahina Gantiwala, Katrina Dovalovsky, Kelly Fan, Katie Lam, Claire Roesler, Aayush Rastogi, Shruti Gautam, Namrata Dube, Bridget Morgan, S M Nasifuzzaman, Dhruv Ramaswami, Varun Gnanasekar, Jeffrey Smith, Aftab Merchant and Neelu Puri
Cancers 2022, 14(15), 3779; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14153779 - 03 Aug 2022
Cited by 19 | Viewed by 4323
Abstract
Melanoma possesses invasive metastatic growth patterns and is one of the most aggressive types of skin cancer. In 2021, it is estimated that 7180 deaths were attributed to melanoma in the United States alone. Once melanoma metastasizes, traditional therapies are no longer effective. [...] Read more.
Melanoma possesses invasive metastatic growth patterns and is one of the most aggressive types of skin cancer. In 2021, it is estimated that 7180 deaths were attributed to melanoma in the United States alone. Once melanoma metastasizes, traditional therapies are no longer effective. Instead, immunotherapies, such as ipilimumab, pembrolizumab, and nivolumab, are the treatment options for malignant melanoma. Several biomarkers involved in tumorigenesis have been identified as potential targets for molecularly targeted melanoma therapy, such as tyrosine kinase inhibitors (TKIs). Unfortunately, melanoma quickly acquires resistance to these molecularly targeted therapies. To bypass resistance, combination treatment with immunotherapies and single or multiple TKIs have been employed and have been shown to improve the prognosis of melanoma patients compared to monotherapy. This review discusses several combination therapies that target melanoma biomarkers, such as BRAF, MEK, RAS, c-KIT, VEGFR, c-MET and PI3K. Several of these regimens are already FDA-approved for treating metastatic melanoma, while others are still in clinical trials. Continued research into the causes of resistance and factors influencing the efficacy of these combination treatments, such as specific mutations in oncogenic proteins, may further improve the effectiveness of combination therapies, providing a better prognosis for melanoma patients. Full article
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14 pages, 1639 KiB  
Article
18FDG PET Assessment of Therapeutic Response in Patients with Advanced or Metastatic Melanoma Treated with First-Line Immune Checkpoint Inhibitors
by Alexia Rivas, Julie Delyon, Antoine Martineau, Estelle Blanc, Clara Allayous, Laetitia Da Meda, Pascal Merlet, Céleste Lebbé, Barouyr Baroudjian and Laetitia Vercellino
Cancers 2022, 14(13), 3190; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133190 - 29 Jun 2022
Cited by 5 | Viewed by 1542
Abstract
Background: Immune checkpoint inhibitors (ICI) are currently the first-line treatment for patients with metastatic melanoma. We investigated the value of positron emission tomography (PET) response criteria to assess the therapeutic response to first-line ICI in this clinical context and explore the potential contribution [...] Read more.
Background: Immune checkpoint inhibitors (ICI) are currently the first-line treatment for patients with metastatic melanoma. We investigated the value of positron emission tomography (PET) response criteria to assess the therapeutic response to first-line ICI in this clinical context and explore the potential contribution of total tumor metabolic volume (TMTV) analysis. Methods: We conducted a retrospective study in patients treated with first-line ICI for advanced or metastatic melanoma, with 18F-FDG PET/CT performed at baseline and 3 months after starting treatment. Patients’ metabolic response was classified according to PERCIST5 and imPERCIST 5 criteria. TMTV was recorded for each examination. Results: Twenty-nine patients were included. The median overall survival (OS) was 51.2 months (IQR 13.6—not reached), and the OS rate at 2 years was 58.6%. Patients classified as responders (complete and partial response) had a 90.9% 2-year OS rate versus 38.9% for non-responders (stable disease and progressive disease) (p = 0.03), for PERCIST5 and imPERCIST 5 criteria. The median change in metabolic volume was 9.8% (IQR −59–+140%). No significant correlation between OS and changes in TMTV was found. Conclusion: The evaluation of response to immunotherapy using metabolic imaging with PERCIST5 and imPERCIST5 was significantly associated with OS in patients with advanced or metastatic melanoma. Full article
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21 pages, 301 KiB  
Article
Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma
by Marcus Wölffer, Florian Battke, Martin Schulze, Magdalena Feldhahn, Lukas Flatz, Peter Martus and Andrea Forschner
Cancers 2022, 14(2), 302; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020302 - 08 Jan 2022
Cited by 14 | Viewed by 3063
Abstract
Immune checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of metastatic melanoma. However, ICI are often associated with immune-related adverse events (IRAE) such as colitis, hepatitis, pancreatitis, hypophysitis, pneumonitis, thyroiditis, exanthema, nephritis, myositis, encephalitis, or myocarditis. Biomarkers associated with the occurrence of IRAE [...] Read more.
Immune checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of metastatic melanoma. However, ICI are often associated with immune-related adverse events (IRAE) such as colitis, hepatitis, pancreatitis, hypophysitis, pneumonitis, thyroiditis, exanthema, nephritis, myositis, encephalitis, or myocarditis. Biomarkers associated with the occurrence of IRAE would be desirable. In the literature, there is only little data available and furthermore mostly speculative, especially in view of genetic alterations. Our major aim was to check for possible associations between NGS-based genetic alterations and IRAE. We therefore analyzed 95 melanoma patients with ICI and evaluated their NGS results. We checked the data in view of potential associations between copy number variations (CNVs), small variations (VARs), human leucocyte antigen (HLA), sex, blood count parameters, pre-existing autoimmune diseases and the occurrence of IRAE. We conducted a literature research on genetic alterations hypothesized to be associated with the occurrence of IRAE. In total, we identified 39 genes that have been discussed as hypothetical biomarkers. We compared the list of these 39 genes with the tumor panel that our patients had received and focused our study on those 16 genes that were also included in the tumor panel used for NGS. Therefore, we focused our analyses on the following genes: AIRE, TERT, SH2B3, LRRK2, IKZF1, SMAD3, JAK2, PRDM1, CTLA4, TSHR, FAN1, SLCO1B1, PDCD1, IL1RN, CD274, UNG. We obtained relevant results: female sex was significantly associated with the development of hepatitis, combined immunotherapy with colitis, increased total and relative monocytes at therapy initiation were significantly associated with the development of pancreatitis, the same, pre-existing autoimmune diseases. Further significant associations were as follows: HLA homozygosity (hepatitis), and VARs on SMAD3 (pancreatitis). Regarding CNVs, significant markers included PRDM1 deletions and IL1RN (IRAE), CD274 duplications and SLCO1B1 (hepatitis), PRDM1 and CD274 (encephalitis), and PRDM1, CD274, TSHR, and FAN1 (myositis). Myositis and encephalitis, both, were associated with alterations of PRDM1 and CD274, which might explain their joined appearance in clinical practice. The association between HLA homozygosity and IRAE was clarified by finding HLA-A homozygosity as determining factor. We identified several genetic alterations hypothesized in the literature to be associated with the development of IRAE and found significant results concerning pre-existing autoimmune diseases and specific blood count parameters. Our findings can help to better understand the development of IRAE in melanoma patients. NGS might be a useful screening tool, however, our findings have yet to be confirmed in larger studies. Full article

2021

Jump to: 2023, 2022

31 pages, 1718 KiB  
Review
Melanoma Targeted Therapies beyond BRAF-Mutant Melanoma: Potential Druggable Mutations and Novel Treatment Approaches
by Karam Khaddour, Lucas Maahs, Ana Maria Avila-Rodriguez, Yazan Maamar, Sami Samaan and George Ansstas
Cancers 2021, 13(22), 5847; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225847 - 22 Nov 2021
Cited by 13 | Viewed by 3778
Abstract
Melanomas exhibit the highest rate of somatic mutations among all different types of cancers (with the exception of BCC and SCC). The accumulation of a multimode of mutations in the driver oncogenes are responsible for the proliferative, invasive, and aggressive nature of melanomas. [...] Read more.
Melanomas exhibit the highest rate of somatic mutations among all different types of cancers (with the exception of BCC and SCC). The accumulation of a multimode of mutations in the driver oncogenes are responsible for the proliferative, invasive, and aggressive nature of melanomas. High-resolution and high-throughput technology has led to the identification of distinct mutational signatures and their downstream alterations in several key pathways that contribute to melanomagenesis. This has enabled the development of individualized treatments by targeting specific molecular alterations that are vital for cancer cell survival, which has resulted in improved outcomes in several cancers, including melanomas. To date, BRAF and MEK inhibitors remain the only approved targeted therapy with a high level of evidence in BRAFV600E/K mutant melanomas. The lack of approved precision drugs in melanomas, relative to other cancers, despite harboring one of the highest rates of somatic mutations, advocates for further research to unveil effective therapeutics. In this review, we will discuss potential druggable mutations and the ongoing research of novel individualized treatment approaches targeting non-BRAF mutations in melanomas. Full article
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22 pages, 2265 KiB  
Review
Melanoma Immunotherapy and Precision Medicine in the Era of Tumor Micro-Tissue Engineering: Where Are We Now and Where Are We Going?
by Francesca Varrone, Luigi Mandrich and Emilia Caputo
Cancers 2021, 13(22), 5788; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225788 - 18 Nov 2021
Cited by 4 | Viewed by 2461
Abstract
Malignant melanoma still remains a cancer with very poor survival rates, although it is at the forefront of personalized medicine. Most patients show partial responses and disease progressed due to adaptative resistance mechanisms, preventing long-lasting clinical benefits to the current treatments. The response [...] Read more.
Malignant melanoma still remains a cancer with very poor survival rates, although it is at the forefront of personalized medicine. Most patients show partial responses and disease progressed due to adaptative resistance mechanisms, preventing long-lasting clinical benefits to the current treatments. The response to therapies can be shaped by not only taking into account cancer cell heterogeneity and plasticity, but also by its structural context as well as the cellular component of the tumor microenvironment (TME). Here, we review the recent development in the field of immunotherapy and target-based therapy and how, in the era of tumor micro-tissue engineering, ex-vivo assays could help to enhance our melanoma biology knowledge in its complexity, translating it in the development of successful therapeutic strategies, as well as in the prediction of therapeutic benefits. Full article
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12 pages, 437 KiB  
Article
Severe Late-Onset Grade III-IV Adverse Events under Immunotherapy: A Retrospective Study of 79 Cases
by Jean-Matthieu L’Orphelin, Emilie Varey, Amir Khammari, Brigitte Dreno and Anne Dompmartin
Cancers 2021, 13(19), 4928; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13194928 - 30 Sep 2021
Cited by 10 | Viewed by 1829
Abstract
Background: For several decades, PD-1 has been a target in malignant melanoma (MM). PD-1 inhibitors (nivolumab, pembrolizumab) and anti-CTLA-4 (CD152) (ipilimumab) have revolutionized cancer therapy. PD-1 and CTLA-4 inhibition leads to prolonged lymphocyte effects, which explains the cytotoxicity underlying immune-reaction-based adverse events (irAEs). [...] Read more.
Background: For several decades, PD-1 has been a target in malignant melanoma (MM). PD-1 inhibitors (nivolumab, pembrolizumab) and anti-CTLA-4 (CD152) (ipilimumab) have revolutionized cancer therapy. PD-1 and CTLA-4 inhibition leads to prolonged lymphocyte effects, which explains the cytotoxicity underlying immune-reaction-based adverse events (irAEs). Most irAEs occur in the first cycle of treatment at a median of 40 days. IrAEs of any grade have been observed in 68.2% of patients, with 10% of patients experiencing severe grade III/IV irAEs. Data on late-onset irAEs are lacking. Methods: Data on patients with advanced melanoma (N = 1862) from March 2016 to March 2021 were obtained from the RicMel database, a French national multicentric biobank dedicated to the follow-up of MM patients. Patients who received anti-PD-1 therapy or a combination therapy and experienced grade III-IV irAEs were selected and analyzed at 7 months, one year and two years after treatment was initiated. Results: Superficial spreading melanoma (SSM) and previous oncological drug administration before immunotherapy are significant risk factors for late-onset irAEs over 2 years after beginning immunotherapy in the univariate and multivariate analysis. The other parameters—sex, mutational status, association of immunotherapy (PD-1i and CTLA-4i) and overall response—were not significantly associated with late-onset irAEs. In our real-life data study, the median onset time of grade III-IV irAES was 128 days after the initiation of immune checkpoint inhibitors (ICI) therapy. Conclusions: Our study, using real-life data, suggests that patients with SSM and those who have received previous oncological treatments are more likely to experience late-onset grade III-IV irAES. Further multicentric studies with wider recruitment of patients should be performed to confirm our findings, potentially leading to changes in the recommended treatment for carefully monitored at-risk patients. Full article
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15 pages, 971 KiB  
Article
Tolerance and Effectiveness of Targeted Therapies in Aged Patients with Metastatic Melanoma
by Ondine Becquart, Bastien Oriano, Stéphane Dalle, Laurent Mortier, Marie Thérèse Leccia, Caroline Dutriaux, Sophie Dalac, Henri Montaudié, Julie De Quatrebarbes, Florence Brunet-Possenti, Philippe Saiag, Thierry Lesimple, Marie Beylot-Barry, Francois Aubin, Pierre-Emmanuel Stoebner, Jean-Philippe Arnault, Brigitte Dreno, Raphael Porcher, Celeste Lebbe and Bernard Guillot
Cancers 2021, 13(12), 3042; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13123042 - 18 Jun 2021
Cited by 4 | Viewed by 1742
Abstract
Purpose: Melanoma’s incidence is increasing, and elderly people could be significantly impacted since the majority occurs in people over 65 years of age. Combined BRAF and MEK targeted therapies (TT) are current standard regimen for BRAF mutated metastatic melanoma (MM). Except for subgroups [...] Read more.
Purpose: Melanoma’s incidence is increasing, and elderly people could be significantly impacted since the majority occurs in people over 65 years of age. Combined BRAF and MEK targeted therapies (TT) are current standard regimen for BRAF mutated metastatic melanoma (MM). Except for subgroups of pivotal trials, little data are available for TT in this population. Materials and Methods: Outcomes were explored in real life patients from MelBase, a French multicentric biobank dedicated to the prospective follow-up of unresectable stage III or IV melanoma. Patients treated by BRAF TT and/or MEK TT combined or not, were included from 2013 to 2017 in 2 groups: group 1 ≤ 65-year-old (yo), group 2 > 65 yo, analyzed for tolerance and efficacy. Results: 353 patients were included: 231 in group 1, 122 in group 2. Median follow-up was 12 months (M). Median time of treatment was 6.9 M. A total of 80% had at least one Adverse Effect (AE). Most frequent AE (all grades) were mainly skin and subcutaneous, general, and gastrointestinal disorders. A total of 31% of AE were grade 3–4: 28% in group 1 and 39% in group 2 (p = 0.05). No differences were observed in all AE grades proportion, dose modifications, interruptions, and discontinuations. For each group, median overall survival was 20.3 M (CI 95%: 15.5–27.9) and 16.3 M (CI: 14.5–26.9), respectively (p = 0.8). Median progression free survival was 7.8 M (6.4–9.9) and 7.7 M (CI: 5.8–11.3) (p = 0.4). Objective response rate was 59% and 50% (p = 0.6). Conclusion: This study on a large multicentric cohort is the first to assess that TT is well tolerated in elderly BRAF-mutated patients such as in patients younger than 65. Efficacy was similar between groups with outcomes reaching those from pivotal studies. There is thus no argument against using TT in elderly people, although an onco-geriatric opinion is welcome for the most vulnerable. Full article
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16 pages, 3590 KiB  
Article
Identifying High-Risk Tumors within AJCC Stage IB–III Melanomas Using a Seven-Marker Immunohistochemical Signature
by Robin Reschke, Philipp Gussek and Mirjana Ziemer
Cancers 2021, 13(12), 2902; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13122902 - 10 Jun 2021
Cited by 6 | Viewed by 2428
Abstract
Background: We aim to validate a seven-marker immunohistochemical signature, consisting of Bax, Bcl-X, PTEN, COX-2, (loss of) ß-Catenin, (loss of) MTAP and (presence of) CD20, in an independent patient cohort and test clinical feasibility. Methods: We performed staining of the mentioned antibodies in [...] Read more.
Background: We aim to validate a seven-marker immunohistochemical signature, consisting of Bax, Bcl-X, PTEN, COX-2, (loss of) ß-Catenin, (loss of) MTAP and (presence of) CD20, in an independent patient cohort and test clinical feasibility. Methods: We performed staining of the mentioned antibodies in tissue of 88 primary melanomas and calculated a risk score for each patient. Data were correlated with clinical parameters and outcome (recurrence-free, distant metastasis-free and melanoma-specific survival). Results: The seven-marker signature was able to identify high-risk patients within stages IB-III melanoma patients that have a significantly higher risk of disease recurrence, metastasis, and death. In particular, the high sensitivity of relapse prediction (>94%) in sentinel negative patients (stages IB–IIC) was striking (negative predictive value of 100% for melanoma-specific survival and distant metastasis-free survival, and 97.5% for relapse-free survival). For stage III patients (positive nodal status), the negative predictive value was 100% with the seven-marker signature. Conclusions: The seven-marker signature can help to further select high-risk patients in stages IIB-C but also in earlier stages IB–IIA and be a useful tool for therapy decisions in the adjuvant and future neo-adjuvant settings. Stage III patients with measurable lymph node disease classified as high-risk with the seven-marker signature are potential candidates for neoadjuvant immunotherapy. Full article
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