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Fager A, Samuelsson M, Olofsson Bagge R, Pivodic A, Bjursten S, Levin M, Jespersen H, Ny L. Immune checkpoint inhibitor therapy is associated with a decreased risk of developing melanoma brain metastases. BJC REPORTS 2025; 3:22. [PMID: 40217072 PMCID: PMC11992042 DOI: 10.1038/s44276-025-00137-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 02/27/2025] [Accepted: 03/23/2025] [Indexed: 04/14/2025]
Abstract
BACKGROUND Despite recent advancements in metastatic melanoma treatment, the emergence of melanoma brain metastases (MBM) continues to pose a challenge. This study aimed to explore factors associated with MBM development. METHODS This retrospective study included patients diagnosed with advanced melanoma (unresectable stages III and IV [M1a-c]) between 2013 and 2019 at Sahlgrenska University Hospital, Gothenburg, Sweden. Differences in baseline and primary tumor characteristics, mutational status, biomarker levels, and first-line treatment between patients who developed MBM (BM+) and patients who did not develop MBM (BM-) were analyzed using univariable and multivariable Cox proportional hazard regression. RESULT Of 395 patients, 91 subsequently developed MBM. Patients who received immune checkpoint inhibitors (ICI) as first-line treatment had a reduced risk of MBM development (p ≤ 0.001). None of the eleven patients who received CTLA-4 inhibitors as monotherapy or in combination with PD-1 inhibitors as first-line treatment developed brain metastases. Elevated plasma levels of S100B (p = 0.021) and higher metastatic stage (p = 0.047) were also associated with an increased risk of MBM development. CONCLUSION ICI treatment is associated with a decreased risk of MBM development, suggesting a protective role. Elevated S100B levels and stage IV disease at advanced melanoma diagnosis might indicate an increased risk of MBM development.
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Affiliation(s)
- Anna Fager
- Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
| | - Matilda Samuelsson
- Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Roger Olofsson Bagge
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | | | - Sara Bjursten
- Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Max Levin
- Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Henrik Jespersen
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Lars Ny
- Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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2
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Giesler S, Riemer R, Lowinus T, Zeiser R. Immune-mediated colitis after immune checkpoint inhibitor therapy. Trends Mol Med 2025; 31:265-280. [PMID: 39477757 DOI: 10.1016/j.molmed.2024.09.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 09/23/2024] [Accepted: 09/30/2024] [Indexed: 03/15/2025]
Abstract
Immune checkpoint inhibitors (ICIs) have led to improved outcome in patients with various types of cancer. Due to inhibition of physiological anti-inflammatory mechanisms, patients treated with ICIs may develop autoimmune inflammation of the colon, associated with morbidity, decreased quality of life (QoL), and mortality. In this review, we summarize clinical and pathophysiological aspects of immune-mediated colitis (ImC), highlighting novel treatment options. In the colon, ICIs trigger resident and circulating T cell activation and infiltration of myeloid cells. In addition, the gut microbiota critically contribute to intestinal immune dysregulation and loss of barrier function, thereby propagating local and systemic inflammation. Currently available therapies for ImC include corticosteroids, antitumor necrosis factor-α (TNF-α)- and anti-integrin α4β7 antibodies. Given that systemic immunosuppression might impair antitumor immune responses, novel therapeutic approaches are urgently needed.
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Affiliation(s)
- Sophie Giesler
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Roxane Riemer
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Theresa Lowinus
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Robert Zeiser
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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Prkačin I, Mokos M, Ferara N, Šitum M. Melanoma's New Frontier: Exploring the Latest Advances in Blood-Based Biomarkers for Melanoma. Cancers (Basel) 2024; 16:4219. [PMID: 39766118 PMCID: PMC11727356 DOI: 10.3390/cancers16244219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/11/2024] [Accepted: 12/16/2024] [Indexed: 01/06/2025] Open
Abstract
Melanoma is one of the most malignant cancers, and the global incidence of cutaneous melanoma is increasing. While melanomas are highly prone to metastasize if diagnosed late, early detection and treatment significantly reduce the risk of mortality. Identifying patients at higher risk of metastasis, who might benefit from early adjuvant therapies, is particularly important, especially with the advent of new melanoma treatments. Therefore, there is a pressing need to develop additional prognostic biomarkers for melanoma to improve early stratification of patients and accurately identify high-risk subgroups, ultimately enabling more effective personalized treatments. Recent advances in melanoma therapy, including targeted treatments and immunotherapy, have underscored the importance of biomarkers in determining prognosis and predicting treatment response. The clinical application of these markers holds the potential for significant advancements in melanoma management. Various tumor-derived genetic, proteomic, and cellular components are continuously released into the bloodstream of cancer patients. These molecules, including circulating tumor DNA and RNA, proteins, tumor cells, and immune cells, are emerging as practical and precise liquid biomarkers for cancer. In the current era of effective molecular-targeted therapies and immunotherapies, there is an urgent need to integrate these circulating biomarkers into clinical practice to facilitate personalized treatment. This review highlights recent discoveries in circulating melanoma biomarkers, explores the challenges and potentials of emerging technologies for liquid biomarker discovery, and discusses future directions in melanoma biomarker research.
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Affiliation(s)
- Ivana Prkačin
- Department of Dermatology and Venereology, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia; (M.M.); (N.F.); (M.Š.)
- School of Medicine, University of Split, 21000 Split, Croatia
| | - Mislav Mokos
- Department of Dermatology and Venereology, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia; (M.M.); (N.F.); (M.Š.)
| | - Nikola Ferara
- Department of Dermatology and Venereology, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia; (M.M.); (N.F.); (M.Š.)
| | - Mirna Šitum
- Department of Dermatology and Venereology, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia; (M.M.); (N.F.); (M.Š.)
- School of Dental Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Croatian Academy of Sciences and Arts, 10000 Zagreb, Croatia
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Guo AJ, Deng QY, Dong P, Zhou L, Shi L. Biomarkers associated with immune-related adverse events induced by immune checkpoint inhibitors. World J Clin Oncol 2024; 15:1002-1020. [PMID: 39193157 PMCID: PMC11346067 DOI: 10.5306/wjco.v15.i8.1002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 05/13/2024] [Accepted: 06/21/2024] [Indexed: 08/16/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) constitute a pivotal class of immunotherapeutic drugs in cancer treatment. However, their widespread clinical application has led to a notable surge in immune-related adverse events (irAEs), significantly affecting the efficacy and survival rates of patients undergoing ICI therapy. While conventional hematological and imaging tests are adept at detecting organ-specific toxicities, distinguishing adverse reactions from those induced by viruses, bacteria, or immune diseases remains a formidable challenge. Consequently, there exists an urgent imperative for reliable biomarkers capable of accurately predicting or diagnosing irAEs. Thus, a thorough review of existing studies on irAEs biomarkers is indispensable. Our review commences by providing a succinct overview of major irAEs, followed by a comprehensive summary of irAEs biomarkers across various dimensions. Furthermore, we delve into innovative methodologies such as machine learning, single-cell RNA sequencing, multiomics analysis, and gut microbiota profiling to identify novel, robust biomarkers that can facilitate precise irAEs diagnosis or prediction. Lastly, this review furnishes a concise exposition of irAEs mechanisms to augment understanding of irAEs prediction, diagnosis, and treatment strategies.
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Affiliation(s)
- An-Jie Guo
- School of Life Sciences, Chongqing University, Chongqing 400044, China
| | - Qing-Yuan Deng
- School of Life Sciences, Chongqing University, Chongqing 400044, China
| | - Pan Dong
- School of Life Sciences, Chongqing University, Chongqing 400044, China
| | - Lian Zhou
- Head and Neck Cancer Center, Chongqing University Cancer Hospital, Chongqing 400000, China
| | - Lei Shi
- School of Life Sciences, Chongqing University, Chongqing 400044, China
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Slusher N, Jones N, Nonaka T. Liquid biopsy for diagnostic and prognostic evaluation of melanoma. Front Cell Dev Biol 2024; 12:1420360. [PMID: 39156972 PMCID: PMC11327088 DOI: 10.3389/fcell.2024.1420360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 07/03/2024] [Indexed: 08/20/2024] Open
Abstract
Melanoma is the most aggressive form of skin cancer, and the majority of cases are associated with chronic or intermittent sun exposure. The incidence of melanoma has grown exponentially over the last 50 years, especially in populations of fairer skin, at lower altitudes and in geriatric populations. The gold standard for diagnosis of melanoma is performing an excisional biopsy with full resection or an incisional tissue biopsy. However, due to their invasiveness, conventional biopsy techniques are not suitable for continuous disease monitoring. Utilization of liquid biopsy techniques represent substantial promise in early detection of melanoma. Through this procedure, tumor-specific components shed into circulation can be analyzed for not only diagnosis but also treatment selection and risk assessment. Additionally, liquid biopsy is significantly less invasive than tissue biopsy and offers a novel way to monitor the treatment response and disease relapse, predicting metastasis.
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Affiliation(s)
- Nicholas Slusher
- School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Nicholas Jones
- School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Taichiro Nonaka
- Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA, United States
- Feist-Weiller Cancer Center, Louisiana State University Health Shreveport, Shreveport, LA, United States
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Janka EA, Ványai B, Szabó IL, Toka-Farkas T, Várvölgyi T, Kapitány A, Szegedi A, Emri G. Primary tumour category, site of metastasis, and baseline serum S100B and LDH are independent prognostic factors for survival in metastatic melanoma patients treated with anti-PD-1. Front Oncol 2023; 13:1237643. [PMID: 37664072 PMCID: PMC10472446 DOI: 10.3389/fonc.2023.1237643] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 08/03/2023] [Indexed: 09/05/2023] Open
Abstract
Background Prognostic classification of metastatic melanoma patients treated with anti-PD-1 is of great interest to clinicians. Objective We aimed to determine the anti-PD-1 treatment related prognostic performance of demographics, clinical and histological prognostic markers and baseline serum S100B and LDH levels in advanced melanoma. Methods A total of 200 patients with unresectable metastatic melanoma were included in this retrospective study. 34.5% had stage M1c disease and 11.5% had stage M1d disease at the start of therapy. 30% had pT4b primary melanoma. 55.5% had elevated baseline serum S100B levels and 62.5% had elevated baseline serum LDH levels. We analysed the risk of death using univariate and multivariate Cox proportional-hazards models and the median overall (OS) and progression-free (PFS) survival using the Kaplan-Meier estimator. Results The median follow-up time from the start of anti-PD-1 treatment in patients who were alive at the end of the study (N=81) was 37 months (range: 6.1-95.9). The multivariate Cox regression analysis showed that M1c stage (vs. M1a, p=0.005) or M1d stage at the start of therapy (vs. M1a, p=0.001), pT4b category (vs. pT1a, p=0.036), elevated baseline serum S100B levels (vs. normal S100B, p=0.008) and elevated LDH levels (vs. normal LDH, p=0.049) were independently associated with poor survival. The combination of M1d stage, elevated baseline serum S100B and LDH levels and pT4b category was associated with a very high risk of death (HR 4.72 [1.81; 12.33]). In the subgroup of patients with pT4b primary melanoma, the median OS of patients with normal serum S100B levels was 37.25 months [95% CI 11.04; 63.46]), while the median OS of patients with elevated serum S100B levels was 8.00 months [95% CI 3.49; 12.51]) (p<0.001); the median OS of patients with normal serum LDH levels was 41.82 months [95% CI 11.33; 72.32]), while the median OS of patients with elevated serum LDH levels was 12.29 months [95% CI 4.35; 20.23]) (p=0.002). Conclusion Our real-world study indicates that the prognostic role of primary melanoma parameters is preserved in anti-PD-1 treated stage IV patients. Furthermore, there seems to be perspective in combining clinical, histological and serum prognostic markers in a prognostic model.
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Affiliation(s)
- Eszter Anna Janka
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- ELKH-DE Allergology Research Group, Debrecen, Hungary
| | - Beatrix Ványai
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Doctoral School of Health Sciences, University of Debrecen, Debrecen, Hungary
| | - Imre Lőrinc Szabó
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tünde Toka-Farkas
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tünde Várvölgyi
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Anikó Kapitány
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- ELKH-DE Allergology Research Group, Debrecen, Hungary
| | - Andrea Szegedi
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- ELKH-DE Allergology Research Group, Debrecen, Hungary
| | - Gabriella Emri
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- ELKH-DE Allergology Research Group, Debrecen, Hungary
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Zhang Y, Liu B, Kotenko S, Li W. Prognostic value of neutrophil-lymphocyte ratio and lactate dehydrogenase in melanoma patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis. Medicine (Baltimore) 2022; 101:e29536. [PMID: 35960066 PMCID: PMC9371534 DOI: 10.1097/md.0000000000029536] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) showed promising therapeutic efficacy on melanoma. Neutrophil-to-lymphocyte ratio (NLR) and serum lactate dehydrogenase (LDH) showed predictive values on prognosis of various tumors, but not on melanoma yet. This meta-analysis was conducted to investigate the prognostic role of NLR and LDH levels in melanoma treated with ICIs. METHODS A search was conducted for all reports published till March 2020 in PubMed, Web of Science, Cochrane Library, EMBASE, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP). Studies were included if they investigated the association between pretreatment NLR/LDH and prognosis in melanoma patients treated with ICIs. Subgroup analysis, publication bias, and meta-regression were conducted to investigate heterogeneity. RESULTS A total of 6817 melanoma patients were included. Overall, high pretreatment NLR and LDH were associated with poor overall survival (OS) (P < .001) and PFS (P < .001). Subgroup analyses revealed that elevated NLR and LDH levels were associated with poor OS and PFS in patients treated with anti-CTLA-4 or anti-PD-1/PD-L1 alone. NLR level was superior in predicting OS if compared with LDH level in patients treated with anti-PD-1/PD-L1 + anti-CTLA-4. In subgroup analysis stratified by cutoff value, high NLR level was associated with poor OS and PFS regardless of cutoff value, but LDH works when cutoff value = upper normal limit (UNL). The predictive value of NLR and LDH levels on OS and PFS was partially compromised in the Asian populations, compared with the Western countries. CONCLUSION Blood NLR and LDH levels showed great potential to be used as early prognostic biomarkers in melanoma patients treated with ICIs.
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Affiliation(s)
- Yongchao Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Bozhi Liu
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Sergei Kotenko
- Department of Microbiology, Biochemistry and Molecular Genetics, Newark, NJ
- Center for Cell Signaling, Newark, NJ
- Center for Immunity and Inflammation, Rutgers New Jersey Medical School, RBHS, Newark, NJ
| | - Wei Li
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- * Correspondence: Wei Li, PhD, Cancer Center, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, 100015 Beijing, People’s Republic of China (e-mail: )
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Chennamadhavuni A, Abushahin L, Jin N, Presley CJ, Manne A. Risk Factors and Biomarkers for Immune-Related Adverse Events: A Practical Guide to Identifying High-Risk Patients and Rechallenging Immune Checkpoint Inhibitors. Front Immunol 2022; 13:779691. [PMID: 35558065 PMCID: PMC9086893 DOI: 10.3389/fimmu.2022.779691] [Citation(s) in RCA: 187] [Impact Index Per Article: 62.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 03/31/2022] [Indexed: 12/19/2022] Open
Abstract
Immune-related adverse events (irAEs) are a range of complications associated with the use of immune-checkpoint inhibitors (ICIs). Two major classes of ICIs widely used are Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Programmed Cell death-1 (PD-1)/Programmed death-ligand 1 (PD-L1) inhibitors. High-grade irAEs are life-threatening and often cause a severe decline in performance status in such that patients do not qualify for any further anticancer treatments. It is difficult to generalize the evidence in the current literature on risk factors or biomarkers for the entire class of ICIs as the studies so far are either disease-specific (e.g., lung cancer or melanoma) or ICI agent-specific (e.g., pembrolizumab, ipilimumab) or irAE-specific (e.g., pneumonitis or gastritis). In this review, risk factors and biomarkers to consider before initiating or monitoring ICI are listed with a practical purpose in day-to-day practice. Risk factors are grouped into demographics and social history, medical history, and medication history, tumor-specific and agent-specific risk factors. A higher risk of irAE is associated with age <60 years, high body mass index, women on CTLA4 and men on PD-1/PD-L1 agents, and chronic smokers. Patients with significant kidney (Stage IV-V), cardiac (heart failure, coronary artery disease, myocardial infarction, hypertension), and lung (asthma, pulmonary fibrosis, and chronic obstructive pulmonary disease) are at a higher risk of respective organ-specific irAEs. Pre-existing autoimmune disease and chronic use of certain drugs (proton pump inhibitors, diuretics, anti-inflammatory drugs) also increase the irAE-risk. Biomarkers are categorized into circulating blood counts, cytokines, autoantibodies, HLA genotypes, microRNA, gene expression profiling, and serum proteins. The blood counts and certain protein markers (albumin and thyroid-stimulating hormone) are readily accessible in current practice. High neutrophil-lymphocyte ratio, eosinophil/monocyte/lymphocyte counts; TSH and troponins at diagnosis and drop in the white count and lymphocyte count can predict irAE. Other biomarkers with limited evidence are cytokines, autoantibodies, HLA genotypes, microRNA, and gene expression profiling. With fast-expanding approvals for ICIs in various cancer types, knowledge on risk factors and biomarkers can help providers assess the irAE-risk of their patients. Prospective disease and agent-specific studies are needed to provide further insight on this essential aspect of ICI therapy.
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Affiliation(s)
- Adithya Chennamadhavuni
- University of Iowa Hospitals and Clinics, Holden Comprehensive Cancer Center, Iowa City, IA, United States
| | - Laith Abushahin
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - Ning Jin
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - Carolyn J. Presley
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
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Zhang H, Chen Z, Zhang A, Gupte AA, Hamilton DJ. The Role of Calcium Signaling in Melanoma. Int J Mol Sci 2022; 23:ijms23031010. [PMID: 35162934 PMCID: PMC8835635 DOI: 10.3390/ijms23031010] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/12/2022] [Accepted: 01/13/2022] [Indexed: 02/04/2023] Open
Abstract
Calcium signaling plays important roles in physiological and pathological conditions, including cutaneous melanoma, the most lethal type of skin cancer. Intracellular calcium concentration ([Ca2+]i), cell membrane calcium channels, calcium related proteins (S100 family, E-cadherin, and calpain), and Wnt/Ca2+ pathways are related to melanogenesis and melanoma tumorigenesis and progression. Calcium signaling influences the melanoma microenvironment, including immune cells, extracellular matrix (ECM), the vascular network, and chemical and physical surroundings. Other ionic channels, such as sodium and potassium channels, are engaged in calcium-mediated pathways in melanoma. Calcium signaling serves as a promising pharmacological target in melanoma treatment, and its dysregulation might serve as a marker for melanoma prediction. We documented calcium-dependent endoplasmic reticulum (ER) stress and mitochondria dysfunction, by targeting calcium channels and influencing [Ca2+]i and calcium homeostasis, and attenuated drug resistance in melanoma management.
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Affiliation(s)
- Haoran Zhang
- Center for Bioenergetics, Houston Methodist Research Institute, Houston, TX 77030, USA; (H.Z.); (A.Z.); (A.A.G.)
- Xiangya Hospital, Central South University, Changsha 410008, China;
| | - Zhe Chen
- Xiangya Hospital, Central South University, Changsha 410008, China;
| | - Aijun Zhang
- Center for Bioenergetics, Houston Methodist Research Institute, Houston, TX 77030, USA; (H.Z.); (A.Z.); (A.A.G.)
- Department of Medicine, Houston Methodist, Weill Cornell Medicine Affiliate, Houston, TX 77030, USA
| | - Anisha A. Gupte
- Center for Bioenergetics, Houston Methodist Research Institute, Houston, TX 77030, USA; (H.Z.); (A.Z.); (A.A.G.)
- Department of Medicine, Houston Methodist, Weill Cornell Medicine Affiliate, Houston, TX 77030, USA
| | - Dale J. Hamilton
- Center for Bioenergetics, Houston Methodist Research Institute, Houston, TX 77030, USA; (H.Z.); (A.Z.); (A.A.G.)
- Department of Medicine, Houston Methodist, Weill Cornell Medicine Affiliate, Houston, TX 77030, USA
- Correspondence: ; Tel.: +1-(713)-441-4483
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Janka EA, Várvölgyi T, Sipos Z, Soós A, Hegyi P, Kiss S, Dembrovszky F, Csupor D, Kéringer P, Pécsi D, Solymár M, Emri G. Predictive Performance of Serum S100B Versus LDH in Melanoma Patients: A Systematic Review and Meta-Analysis. Front Oncol 2021; 11:772165. [PMID: 34950582 PMCID: PMC8688362 DOI: 10.3389/fonc.2021.772165] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/11/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Currently, no consensus on the use of blood tests for monitoring disease recurrence in patients with resected melanoma exists. The only meta-analysis conducted in 2008 found that elevated serum S100B levels were associated with significantly worse survival in melanoma patients. Serum LDH is an established prognostic factor in patients with advanced melanoma. OBJECTIVE To compare the discriminative and prognostic ability of serum S100B with that of serum LDH in patients with melanoma. METHODS This systematic review and meta-analysis were reported in accordance with the PRISMA Statement. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42019137138). RESULTS A quantitative analysis of data from 6 eligible studies included 1,033 patients with cutaneous melanoma. The discriminative ability of serum S100B at identifying disease relapse [pooled Area Under the ROC (AUROC) 78.64 (95% CI 70.28; 87.01)] was significantly greater than the discriminative ability of serum LDH [AUROC 64.41 (95% CI 56.05; 7278)] (p=0.013). Ten eligible studies with 1,987 patients were included in the risk of death analysis. The prognostic performance of serum S100B [pooled estimate of adjusted hazard ratio (HR) 1.78 (95% CI 1.38; 2.29)] was independent but not superior to that of serum LDH [HR 1.60 (95% CI 1.36; 2.29)]. LIMITATIONS A relatively small number of articles were eligible and there was considerable heterogeneity across the included studies. CONCLUSIONS Serum biomarkers may provide relevant information on melanoma patient status and should be further researched. Serum S100B is a valid marker for diagnosis of melanoma recurrence. SYSTEMATIC REVIEW REGISTRATION The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42019137138).
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Affiliation(s)
- Eszter Anna Janka
- Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tünde Várvölgyi
- Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zoltán Sipos
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Alexandra Soós
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Szabolcs Kiss
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
| | - Fanni Dembrovszky
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Dezső Csupor
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Department of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary
| | - Patrik Kéringer
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Dániel Pécsi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Margit Solymár
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Gabriella Emri
- Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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11
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Zaremba A, Philip M, Hassel JC, Glutsch V, Fiocco Z, Loquai C, Rafei-Shamsabadi D, Gutzmer R, Utikal J, Haferkamp S, Reinhardt L, Kähler KC, Weishaupt C, Moreira A, Thoms KM, Wilhelm T, Pföhler C, Roesch A, Ugurel S, Zimmer L, Stadtler N, Sucker A, Kiecker F, Heinzerling L, Meier F, Meiss F, Schlaak M, Schilling B, Horn S, Schadendorf D, Livingstone E. Clinical characteristics and therapy response in unresectable melanoma patients stage IIIB-IIID with in-transit and satellite metastases. Eur J Cancer 2021; 152:139-154. [PMID: 34102453 DOI: 10.1016/j.ejca.2021.04.032] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/07/2021] [Accepted: 04/22/2021] [Indexed: 11/26/2022]
Abstract
INTRODUCTION Cutaneous melanoma is notorious for the development of in-transit metastases (ITM). For unknown biological reasons, ITM remain the leading tumour manifestation without progression to distant sites in some patients. METHODS In total, 191 patients with initially unresectable stage III ITM and satellite metastases from 16 skin cancer centres were retrospectively evaluated for their tumour characteristics, survival and therapy response. Three groups according to disease kinetics (no distant progress, slow (>6 months) and fast (<6 months) distant progression) were analysed separately. RESULTS Median follow-up time was 30.5 (range 0.8-154.0) months from unresectable ITM. Progression to stage IV was observed in 56.5% of cases. Patients without distant metastasis were more often female, older (>70 years) and presented as stage III with lymph node or ITM at initial diagnosis in 45.7% of cases. Melanoma located on the leg had a significantly better overall survival (OS) from time of initial diagnosis compared to non-leg localised primaries (hazard ratio [HR] = 0.61, 95% confidence interval [CI] 0.40-0.91; p = 0.017), but not from diagnosis of unresectable stage III (HR = 0.67, 95% CI 0.45-1.02; p = 0.06). Forty percent of patients received local therapy for satellite and ITM. Overall response rate (ORR) to all local first-line treatments was 38%; disease control rate (DCR) was 49%. In total, 72.3% of patients received systemic therapy for unresectable stage IIIB-D. ORR for targeted therapy (n = 19) was highest with 63.2% and DCR was 84.2% compared to an ORR of 31.4% and a DCR of 54.3% in PD-1 treated patients (n = 70). Patients receiving PD-1 and intralesional talimogene laherparepvec (n = 12) had an ORR of 41.7% and a DCR of 75%. CONCLUSION Patients with unresectable ITM and without distant progression are more often female, older, and have a primary on the leg. Response to PD-1 inhibitors in this cohort was lower than expected, but further investigation is required to elucidate the biology of ITM development and the interplay with the immune system.
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Affiliation(s)
- Anne Zaremba
- Dept. of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
| | - Manuel Philip
- Dept. of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Jessica C Hassel
- Dept. of Dermatology, National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany
| | - Valerie Glutsch
- Dept. of Dermatology, University of Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany
| | - Zeno Fiocco
- Dept. of Dermatology and Allergology, University Hospital, LMU Munich, Frauenlobstraße 9-11, 80337 Munich, Germany
| | - Carmen Loquai
- Dept. of Dermatology, Venerology and Allergology, University Medical Center Mainz, Germany
| | | | - Ralf Gutzmer
- Dept. of Dermatology, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, 30625, Hannover, Germany
| | - Jochen Utikal
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 58167, Mannheim, Germany
| | | | - Lydia Reinhardt
- Skin Cancer Center at the University Cancer Centre Dresden, National Center for Tumor Diseases, Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - Katharina C Kähler
- Dept. of Dermatology, Venerology and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, Germany
| | - Carsten Weishaupt
- Dept. of Dermatology, University Hospital Münster, Von Esmarch Str. 58, 48149, Münster, Germany
| | - Alvaro Moreira
- Dept. of Dermatology, Venerology and Allergology, University Hospital Erlangen, Germany; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; The Kimberly and Eric J. Waldman Department of Dermatology at Mount Sinai, New York, NY, 10029, USA
| | - Kai-Martin Thoms
- Dept. of Dermatology, University Medical Center Goettingen Goettingen, Germany
| | - Tabea Wilhelm
- Clinic for Dermatology, Venerology and Allergology, Havelklinik Berlin, Germany
| | - Claudia Pföhler
- Saarland University Medical School, Department of Dermatology, Homburg, Saar, Germany
| | - Alexander Roesch
- Dept. of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Selma Ugurel
- Dept. of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Lisa Zimmer
- Dept. of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Nadine Stadtler
- Dept. of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Antje Sucker
- Dept. of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Felix Kiecker
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Department of Dermatology, Venerology and Allergology, Berlin, Germany
| | - Lucie Heinzerling
- Dept. of Dermatology and Allergology, University Hospital, LMU Munich, Frauenlobstraße 9-11, 80337 Munich, Germany; Dept. of Dermatology, Venerology and Allergology, University Hospital Erlangen, Germany
| | - Friedegund Meier
- Skin Cancer Center at the University Cancer Centre Dresden, National Center for Tumor Diseases, Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - Frank Meiss
- Dept. of Dermatology, Venerology and Allergology, University Hospital Freiburg, Germany
| | - Max Schlaak
- Dept. of Dermatology and Allergology, University Hospital, LMU Munich, Frauenlobstraße 9-11, 80337 Munich, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Department of Dermatology, Venerology and Allergology, Berlin, Germany
| | - Bastian Schilling
- Dept. of Dermatology, University of Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany
| | - Susanne Horn
- Dept. of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Rudolf-Schönheimer-Institute of Biochemistry, Medical Faculty of the University Leipzig, Johannisallee 30, 04103, Leipzig, Germany
| | - Dirk Schadendorf
- Dept. of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Elisabeth Livingstone
- Dept. of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany
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12
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Karlsson MJ, Costa Svedman F, Tebani A, Kotol D, Höiom V, Fagerberg L, Edfors F, Uhlén M, Egyhazi Brage S, Maddalo G. Inflammation and Apolipoproteins Are Potential Biomarkers for Stratification of Cutaneous Melanoma Patients for Immunotherapy and Targeted Therapy. Cancer Res 2021; 81:2545-2555. [PMID: 33574091 DOI: 10.1158/0008-5472.can-20-2000] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 09/22/2020] [Accepted: 02/09/2021] [Indexed: 11/16/2022]
Abstract
Malignant cutaneous melanoma is one of the most common cancers in young adults. During the last decade, targeted and immunotherapies have significantly increased the overall survival of patients with malignant cutaneous melanoma. Nevertheless, disease progression is common, and a lack of predictive biomarkers of patient response to therapy hinders individualized treatment strategies. To address this issue, we performed a longitudinal study using an unbiased proteomics approach to identify and quantify proteins in plasma both before and during treatment from 109 patients treated with either targeted or immunotherapy. Linear modeling and machine learning approaches identified 43 potential prognostic and predictive biomarkers. A reverse correlation between apolipoproteins and proteins related to inflammation was observed. In the immunotherapy group, patients with low pretreatment expression of apolipoproteins and high expression of inflammation markers had shorter progression-free survival. Similarly, increased expression of LDHB during treatment elicited a significant impact on response to immunotherapy. Overall, we identified potential common and treatment-specific biomarkers in malignant cutaneous melanoma, paving the way for clinical use of these biomarkers following validation on a larger cohort. SIGNIFICANCE: This study identifies a potential biomarker panel that could improve the selection of therapy for patients with cutaneous melanoma.
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Affiliation(s)
- Max J Karlsson
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
| | | | - Abdellah Tebani
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
| | - David Kotol
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Veronica Höiom
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Linn Fagerberg
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Fredrik Edfors
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Mathias Uhlén
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
- Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
- Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark
| | | | - Gianluca Maddalo
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden.
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13
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Xu Y, Fu Y, Zhu B, Wang J, Zhang B. Predictive Biomarkers of Immune Checkpoint Inhibitors-Related Toxicities. Front Immunol 2020; 11:2023. [PMID: 33123120 PMCID: PMC7572846 DOI: 10.3389/fimmu.2020.02023] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 07/27/2020] [Indexed: 12/12/2022] Open
Abstract
The emergence and continuous development of immune checkpoint inhibitors (ICIs) therapy brings a revolution in cancer therapy history, but the major hurdle associated with their usage is the concomitant ICIs-related toxicities that present a challenge for oncologists. The toxicities may involve non-specific symptoms of multiple systems as for the unique mechanism of formation, which are not easily distinguishable from traditional toxicities. A few of these adverse events are self-limiting and readily manageable, but others may limit treatment, cause interruption and need to be treated with methylprednisolone or tumor necrosis factor-α (TNF-α) antibody infliximab, and even directly threaten life. Early accurate recognition and adequate management are critical to the patient's prognosis and overall survival (OS). Several biomarkers such as the expression of programmed cell death ligand 1 (PD-L1), tumor mutation burden (TMB), and microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) have been proved to be the predictors for anti-tumor efficacy of ICIs, but there is a gap in clinical needs for effective biomarkers that predict toxicities and help filter out the patients who may benefit most from these costly therapies while avoiding major risks of toxicities. Here, we summarize several types of risk factors correlated with ICIs-related toxicities to provide a reference for oncologists to predict the occurrence of ICIs-related toxicities resulting in a timely process in clinical practice.
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Affiliation(s)
- Ya Xu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yang Fu
- Department of Oncology, Xiangyang Hospital, Hubei University of Chinese Medicine, Xiangyang, China
| | - Bo Zhu
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Jun Wang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Bicheng Zhang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
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14
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Biomarkers, measured during therapy, for response of melanoma patients to immune checkpoint inhibitors: a systematic review. Melanoma Res 2020; 29:453-464. [PMID: 30855527 PMCID: PMC6727956 DOI: 10.1097/cmr.0000000000000589] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Immune checkpoint inhibitors (ICIs), which target CTLA-4 or PD-(L)1 molecules, have shown impressive therapeutic results. Durable responses, however, are only observed in a segment of the patient population and must be offset against severe off-target immune toxicity and high costs. This calls for biomarkers that predict response during ICI treatment. Although many candidate biomarkers exist, as yet, there has been no systematic overview of biomarkers predictive during. Here, we provide a systematic review of the current literature of ICI treatment to establish an overview of candidate predictive biomarkers during ICI treatment in melanoma patients. We performed a systematic Medline search (2000-2018, 1 January) on biomarkers for survival or response to ICI treatment in melanoma patients. We retrieved 735 publications, of which 79 were finally included in this systematic review. Blood markers were largely studied for CTLA-4 ICI, whereas tumor tissue markers were analyzed for PD-(L)1 ICI. Blood cytology and soluble factors were more frequently correlated to overall survival (OS) than response, indicating their prognostic rather than predictive nature. An increase in tumor-infiltrating CD8 + T-cells and a decrease in regulatory T-cells were correlated to response, in addition to mutational load, neoantigen load, and immune-related gene expression. Immune-related adverse events were also associated frequently with a favorable response and OS. This review shows the great variety of potential biomarkers published to date, in an attempt to better understand response to ICI therapy; it also highlights the candidate markers for future research. The most promising biomarkers for response to ICI treatment are the occurrence of immune-related adverse events (especially vitiligo), lowering of lactate dehydrogenase, and increase in activated CD8 + and decrease in regulatory T-cells.
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15
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Development of thrombocytopenia is associated with improved survival in patients treated with immunotherapy. Future Sci OA 2020; 6:FSO581. [PMID: 32802390 PMCID: PMC7421541 DOI: 10.2144/fsoa-2020-0021] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background: Immune-related adverse events are associated with efficacy of immune checkpoint inhibitors (ICIs). We hypothesize that immune-mediated thrombocytopenia could be a biomarker for response to ICIs. Materials & methods: This retrospective study included 215 patients with metastatic malignancies treated with ICIs. Patients were stratified by nadir platelet count. Outcomes of interest were progression-free survival and overall survival. Results: On multivariate analysis, grade 1 thrombocytopenia was positively associated with overall survival compared with patients who did not develop thrombocytopenia (hazard ratio [HR]= 0.28 [95% CI: 0.13–0.60]; p = 0.001), while grade 2–4 thrombocytopenia was not (HR= 0.36 [95% CI: 0.13–1.04]; p = 0.060). There was no association between degree of thrombocytopenia and progression-free survival. Conclusion: Follow-up studies are warranted to substantiate the predictive significance of thrombocytopenia in patients receiving ICIs. Immune checkpoint inhibitors (ICIs) are a class of drug that are increasingly being used in different cancers. The extent of response to treatment with ICIs differs among individuals. There is a lack of biomarkers, which would help clinicians predict response to ICIs. In our study, we aimed to explore the development of low platelets as a potential biomarker. Our findings suggest that cancer patients receiving ICIs who develop a mild decrease in platelet count tend to live longer than those who do not. However, this was not true for those who developed a severe decrease in platelet count. The mechanism of how ICIs affect platelets may be related to the interaction between the immune system and platelets. More studies are needed to validate our results and better understand the role of platelets in cancer biology.
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16
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Boyer M, Cayrefourcq L, Dereure O, Meunier L, Becquart O, Alix-Panabières C. Clinical Relevance of Liquid Biopsy in Melanoma and Merkel Cell Carcinoma. Cancers (Basel) 2020; 12:cancers12040960. [PMID: 32295074 PMCID: PMC7226137 DOI: 10.3390/cancers12040960] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/09/2020] [Accepted: 04/10/2020] [Indexed: 12/14/2022] Open
Abstract
Melanoma and Merkel cell carcinoma are two aggressive skin malignancies with high disease-related mortality and increasing incidence rates. Currently, invasive tumor tissue biopsy is the gold standard for their diagnosis, and no reliable easily accessible biomarker is available to monitor patients with melanoma or Merkel cell carcinoma during the disease course. In these last years, liquid biopsy has emerged as a candidate approach to overcome this limit and to identify biomarkers for early cancer diagnosis, prognosis, therapeutic response prediction, and patient follow-up. Liquid biopsy is a blood-based non-invasive procedure that allows the sequential analysis of circulating tumor cells, circulating cell-free and tumor DNA, and extracellular vesicles. These innovative biosources show similar features as the primary tumor from where they originated and represent an alternative to invasive solid tumor biopsy. In this review, the biology and technical challenges linked to the detection and analysis of the different circulating candidate biomarkers for melanoma and Merkel cell carcinoma are discussed as well as their clinical relevance.
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Affiliation(s)
- Magali Boyer
- Laboratory of Rare Human Circulating Cells, University Medical Centre of Montpellier, 34093 Montpellier, France; (M.B.); (L.C.)
| | - Laure Cayrefourcq
- Laboratory of Rare Human Circulating Cells, University Medical Centre of Montpellier, 34093 Montpellier, France; (M.B.); (L.C.)
| | - Olivier Dereure
- Department of Dermatology and INSERM 1058 Pathogenesis and Control of Chronic Infections, University of Montpellier, 34090 Montpellier, France;
| | - Laurent Meunier
- Department of Dermatology, University of Montpellier, 34090 Montpellier, France; (L.M.); (O.B.)
| | - Ondine Becquart
- Department of Dermatology, University of Montpellier, 34090 Montpellier, France; (L.M.); (O.B.)
| | - Catherine Alix-Panabières
- Laboratory of Rare Human Circulating Cells, University Medical Centre of Montpellier, 34093 Montpellier, France; (M.B.); (L.C.)
- Correspondence: ; Tel.: +33-4-1175-99-31; Fax: +33-4-1175-99-33
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17
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Ben Chaaben A, Ouni N, Douik H, Ayari F, Abaza H, Mamoghli T, Harzallah L, Fortier C, Boukouaci W, Krishnamoorthy R, Charron D, Gara S, Guemira F, Tamouza R. Soluble MICA and anti-MICA Antibodies as Biomarkers of Nasopharyngeal Carcinoma Disease. Immunol Invest 2019; 49:498-509. [PMID: 31814472 DOI: 10.1080/08820139.2019.1690506] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The MHC class I chain-related molecule A (MICA) is a ligand for the activating natural killer (NK) cell receptor NKG2D. A part from its genetic diversity, MICA is characterized by the presence of membrane-bound and soluble isoform (sMICA) and by the propensity to elicit antibody-mediated allogeneicity (MICA Abs). Altogether such properties are important in the cancer setting. Here, we investigated whether MICA polymorphism, serum level of sMICA and MICA antibodies (Abs) may influence nasopharyngeal carcinoma (NPC) risk. 274 NPC naïve of treatment patients and 275 healthy individuals, all originating from Tunisia were included and genotyped. Among them, 160 sera from patients and 51 from controls were analyzed for the sMICA level by ELISA and were tested for the presence of MICA Abs by Luminex assay. The statistical analysis showed that: (1) we extend and confer our previous finding concerning Val/Val association with risk of NPC (p = .02, OR = 1.56; 95%CI [1.12-2.11]). (2) The higher level of sMICA characterized patients advanced stage of the disease. (3) The 18 (78%) of patients having MICA Abs exhibit all a non-advanced stage of the tumor extension at presentation. MICA129 Met /Val, sMICA and MICA Abs could be potential biomarkers of prediction, the diverse staging of NPC and hence prognostic and treatment.
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Affiliation(s)
- Arij Ben Chaaben
- Clinical Biology Department, Salah Azaiz Institut , Tunis, Tunisia.,Immunology and Histocompatibility Department, CIH-HOG, AP-HP/GHU-Nord, IUH and INSERM, U940, Saint-Louis Hospital , Paris, France
| | - Nesrine Ouni
- Clinical Biology Department, Salah Azaiz Institut , Tunis, Tunisia.,Faculty of Mathematics, Physics and Natural Sciences, University of Tunis El Manar , Tunis, Tunisia
| | - Hayet Douik
- Clinical Biology Department, Salah Azaiz Institut , Tunis, Tunisia
| | - Fayza Ayari
- Clinical Biology Department, Salah Azaiz Institut , Tunis, Tunisia
| | - Hajer Abaza
- Clinical Biology Department, Salah Azaiz Institut , Tunis, Tunisia
| | - Tesnim Mamoghli
- Clinical Biology Department, Salah Azaiz Institut , Tunis, Tunisia
| | - Latifa Harzallah
- Clinical Biology Department, Salah Azaiz Institut , Tunis, Tunisia
| | - Cathy Fortier
- Immunology and Histocompatibility Department, CIH-HOG, AP-HP/GHU-Nord, IUH and INSERM, U940, Saint-Louis Hospital , Paris, France
| | - Wahid Boukouaci
- Immunology and Histocompatibility Department, CIH-HOG, AP-HP/GHU-Nord, IUH and INSERM, U940, Saint-Louis Hospital , Paris, France
| | | | - Dominique Charron
- Immunology and Histocompatibility Department, CIH-HOG, AP-HP/GHU-Nord, IUH and INSERM, U940, Saint-Louis Hospital , Paris, France
| | - Sonia Gara
- Clinical Biology Department, Salah Azaiz Institut , Tunis, Tunisia
| | - Fethi Guemira
- Clinical Biology Department, Salah Azaiz Institut , Tunis, Tunisia
| | - Ryad Tamouza
- INSERM, U955, Translational Psychiatry, Paris-East University , Creteil, France.,AP-HP, DHU PePSY, Department of Psychiatry, Hôpital Henri Mondor, Université Paris-Est-Creteil , Creteil, France.,Fondation FondaMental , Creteil F94000, France
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18
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Forthun RB, Hovland R, Schuster C, Puntervoll H, Brodal HP, Namløs HM, Aasheim LB, Meza-Zepeda LA, Gjertsen BT, Knappskog S, Straume O. ctDNA detected by ddPCR reveals changes in tumour load in metastatic malignant melanoma treated with bevacizumab. Sci Rep 2019; 9:17471. [PMID: 31767937 PMCID: PMC6877652 DOI: 10.1038/s41598-019-53917-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 11/05/2019] [Indexed: 12/26/2022] Open
Abstract
Bevacizumab is included in an increasing number of clinical trials. To find biomarkers to predict and monitor treatment response, cancer and angiogenesis relevant mutations in tumour and circulating tumour DNA (ctDNA) were investigated in 26 metastatic melanoma patients treated with bevacizumab. Patients with >1% BRAF/NRAS ctDNA at treatment start had significantly decreased progression free survival (PFS) and overall survival (OS) (PFS: p = 0.019, median 54 vs 774 days, OS: p = 0.026, median 209 vs 1064 days). Patients with >1% BRAF/NRAS ctDNA during treatment showed similar results (PFS: p = 0.002, OS: p = 0.003). ≤1% BRAF/NRAS ctDNA and normal lactate dehydrogenase (LDH) levels both significantly predicted increased response to treatment, but BRAF/NRAS ctDNA was better at predicting response compared to LDH at treatment start (OR 16.94, p = 0.032 vs OR 4.57, p = 0.190), and at predicting PFS (HR 6.76, p = 0.002) and OS (HR 6.78, p = 0.002) during therapy. ctDNA BRAF p.V600D/E/K and NRAS p.G12V/p.Q61K/L/R were better biomarkers for response prediction than TERT promoter mutations (OR 1.50, p = 0.657). Next generation sequencing showed that all patients with ≥2 mutations in angiogenesis-relevant genes had progressive disease, but did not reveal other biomarkers identifying responders. To conclude, ctDNA and LDH are useful biomarkers for both monitoring and predicting response to bevacizumab.
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Affiliation(s)
- Rakel Brendsdal Forthun
- Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway
| | - Randi Hovland
- Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
- Department of Biosciences, University of Bergen, Bergen, Norway
| | - Cornelia Schuster
- Centre of Cancer Biomarkers, CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Hanne Puntervoll
- Centre of Cancer Biomarkers, CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Hans Petter Brodal
- Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway
| | - Heidi Maria Namløs
- Department of Tumour Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Lars Birger Aasheim
- Norwegian Cancer Genomics Consortium, Institute for Cancer Research, The Norwegian Radium Hospital/Oslo University Hospital, Oslo, Norway
| | - Leonardo A Meza-Zepeda
- Department of Tumour Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Norwegian Cancer Genomics Consortium, Institute for Cancer Research, The Norwegian Radium Hospital/Oslo University Hospital, Oslo, Norway
- Genomics Core Facility, Department of Core Facilities, Oslo University Hospital, Oslo, Norway
| | - Bjørn Tore Gjertsen
- Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway
- Centre of Cancer Biomarkers, CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Stian Knappskog
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
- K.G. Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Oddbjørn Straume
- Centre of Cancer Biomarkers, CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.
- Department of Oncology, Haukeland University Hospital, Bergen, Norway.
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19
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Gambichler T, Chatzipantazi M, Schröter U, Stockfleth E, Gedik C. Patients with melanoma of unknown primary show better outcome under immune checkpoint inhibitor therapy than patients with known primary: preliminary results. Oncoimmunology 2019; 8:e1677139. [PMID: 31741779 PMCID: PMC6844308 DOI: 10.1080/2162402x.2019.1677139] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 10/02/2019] [Accepted: 10/03/2019] [Indexed: 12/18/2022] Open
Abstract
Background: Melanoma of unknown primary (MUP) is an uncommon clinical subtype of melanoma of known primary (MKP). Objectives: We aimed to compare treatment outcomes of MUP and MKP patients who had undergone therapy with immune checkpoint inhibitors (ICPI). Methods: We studied 41 metastatic melanoma patients (32 with MKP and 9 with MUP) with an indication for ICPI. Results: Clinical characteristics such as age, gender, stage of disease, etc., did not significantly differ (P < .05) between MUP and MKP patients. 20/32 (62.5%) melanoma-specific deaths (MSD) were observed in the MKP group, whereas 2/9 (22.2%) were detected in the MUP group (P = .035). On logistic regression, the MUP status proved to be an independent predictor for a more favorable outcome under immunotherapy when compared to MKP (P = .030). Conclusion: Our preliminary results indicate that MUP patients show better clinical outcome under ICPI when compared to MKP.
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Affiliation(s)
- Thilo Gambichler
- Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany
| | - Maria Chatzipantazi
- Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany
| | - Ulrike Schröter
- Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany
| | - E Stockfleth
- Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany
| | - Cansu Gedik
- Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany
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20
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Prognostic and predictive role of elevated lactate dehydrogenase in patients with melanoma treated with immunotherapy and BRAF inhibitors: a systematic review and meta-analysis. Melanoma Res 2019; 29:1-12. [PMID: 30308577 DOI: 10.1097/cmr.0000000000000520] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Levels of serum lactate dehydrogenase (LDH) are a recognized prognostic factor in malignant melanoma (MM). It is relevant to confirm its prognostic role in patients treated with targeted therapies [BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi)] and immunotherapy (IT). Furthermore, its role as a predictive marker in patients treated with these drugs had still not been investigated. We performed an electronic search for studies reporting information on overall survival (OS) or progression-free survival (PFS) according to LDH levels and on their predictive effect in patients treated with targeted therapies (BRAFi and MEKi) and IT. Data were pooled using hazard ratios (HRs) for OS and HRs for PFS according to a fixed-effect or a random-effect model. For predictive analysys, effect of new agents versus standard therapy was evaluated in LDH high population. A total of 71 publications were retrieved for a total of 16 159 patients. Overall, elevated LDH levels were associated with an HR for OS of 1.72 [95% confidence interval (CI): 1.6-1.85; P<0.0001]. Similarly, HR for PFS was 1.83 (95% CI: 1.53-2.2; P<0.0001). In the LDH elevated subgroup, new agents improved OS significantly (HR: 0.71; 95% CI: 0.62-0.82; P<0.0001) and PFS (HR: 0.63; 95% CI: 0.55-0.72; P<0.0001). In advanced MM treated with IT or BRAFi±MEKi, elevated LDH level at baseline represents a poor prognostic factor. However, patients with increased LDH levels and treated with these drugs gain significant benefits in terms of PFS and OS.
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21
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Abstract
Malignant melanoma is a cancer with increasing incidence worldwide with relevant socioeconomic impact. Despite progress in prevention and early detection, it is one of the most lethal forms of skin cancer. Therefore it is urgent need to identify suitable biomarkers in order to improve early diagnosis, precise staging, and prognosis, as well as for therapy selection and monitoring. In this book chapter, we are focusing on S100B and discuss its clinical relevance in melanoma.
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Affiliation(s)
| | - Reinhard Dummer
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
| | - Joanna Mangana
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
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22
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Wei XL, Wu QN, Chen DL, Zeng ZL, Lu JB, Liu ZX, Ju HQ, Ren C, Pan ZZ, Wang FH, Xu RH. The Clinical and Biomarker Association of Programmed Death Ligand 1 and its Spatial Heterogeneous Expression in Colorectal Cancer. J Cancer 2018; 9:4325-4333. [PMID: 30519336 PMCID: PMC6277645 DOI: 10.7150/jca.27735] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 08/10/2018] [Indexed: 02/06/2023] Open
Abstract
Background: Programmed death ligand 1 (PD-L1) expression has been shown to predict benefit from anti-PD-1 treatment in several cancers. However, its predictive value in colorectal cancer seems limited. This study was aimed to explore the clinical and biomarker association of programmed death ligand 1 and its spatial heterogeneous expression in colorectal cancer. Methods: Tissue microarrays of 422 primary colorectal cancers from our hospital were used for the interpretation of PD-L1 and programmed death 1 (PD-1) expression, cluster of differentiation 4 (CD4) and CD8 density and microsatellite instability (MSI) status by immunohistochemistry. To assess the spatial heterogeneity of PD-L1 expression, Tissue microarrays of 383 paired intra-primary-tumor tissues, and 105 paired lymph node metastatic tumors and 64 paired distant metastatic tumors were also used. Results: PD-L1 was positive in 188 (44.5%) primary colorectal cancers. PD-L1 expression was associated with less advanced N category (P<0.001), less advanced TNM stage (P<0.001) and less nervous invasion (P=0.04). Higher PD-L1 expression was associated with higher PD-1 expression (P<0.001), higher CD4 (P<0.001) and CD8 (P<0.001) density and DNA mismatch repair deficiency (P=0.01). PD-L1 expression was associated with better disease-free survival and overall survival, but it was only an independent prognostic factor for disease-free survival (hazard ratio and 95% confidence interval: 0.42 [0.25-0.72], P<0.001). The probability of inconsistent PD-L1 expression was respectively 17.8%, 31.4% and 39.1% within primary tumors, between primary tumors and lymph node metastatic tumors, and between primary tumors and distant metastatic tumors. All the three differences were statistically significant (P<0.001, P<0.001 and P=0.05, respectively). Conclusions: PD-L1 expression was a marker of pre-existing immune responses in colorectal cancer, however, it was heterogeneously expressed in colorectal cancer, especially between primary and metastatic tumors. This might partially explain the low-efficiency of its predictive value for benefit from anti-PD-1 treatment.
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Affiliation(s)
- Xiao-Li Wei
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Qi-Nian Wu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Dong-Liang Chen
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Zhao-Lei Zeng
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Jia-Bin Lu
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Ze-Xian Liu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Huai-Qiang Ju
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Chao Ren
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Zhi-Zhong Pan
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Feng-Hua Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Rui-Hua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
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23
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Capone M, Giannarelli D, Mallardo D, Madonna G, Festino L, Grimaldi AM, Vanella V, Simeone E, Paone M, Palmieri G, Cavalcanti E, Caracò C, Ascierto PA. Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab. J Immunother Cancer 2018; 6:74. [PMID: 30012216 PMCID: PMC6048712 DOI: 10.1186/s40425-018-0383-1] [Citation(s) in RCA: 340] [Impact Index Per Article: 48.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 06/27/2018] [Indexed: 11/10/2022] Open
Abstract
Background Previous studies have suggested that elevated neutrophil-to-lymphocyte ratio (NLR) is prognostic for worse outcomes in patients with a variety of solid cancers, including those treated with immune checkpoint inhibitors. Methods This was a retrospective analysis of 97 consecutive patients with stage IV melanoma who were treated with nivolumab. Baseline NLR and derived (d) NLR were calculated and, along with other characteristics, correlated with progression-free survival (PFS) and overall survival (OS) in univariate and multivariate analyses. The best cutoff values for NLR and dNLR were derived using Cutoff Finder software based on an R routine which optimized the significance of the split between Kaplan-Meier survival curves. Results In univariate analysis, increasing absolute neutrophil count (ANC), NLR, dNLR and lactate dehydrogenase (LDH) (continuous variables) were all significantly associated with OS. Only NLR (hazard ratio [HR] = 2.85; 95% CI 1.60–5.08; p < 0.0001) and LDH (HR = 2.51; 95% CI 1.36–4.64; p < 0.0001) maintained a significant association with OS in multivariate analysis. Patients with baseline NLR ≥5 had significantly worse OS and PFS than patients with NLR < 5, as did patients with baseline dNLR ≥3 versus < 3. Optimal cut-off values were ≥ 4.7 for NLR and ≥ 3.8 for dNLR. Using this ≥4.7 cut-off for NLR, the values for OS and PFS were overlapping to the canonical cut-off for values, and dNLR< 3.8 was also associated with better OS and PFS. Conclusion Both Neutrophil-to-lymphocyte ratio (NLR) and derived (d) NLR were associated with improved survival when baseline levels were lower than cut-off values. NLR and dNLR are simple, inexpensive and readily available biomarkers that could be used to help predict response to immunotherapy in patients with advanced melanoma. Electronic supplementary material The online version of this article (10.1186/s40425-018-0383-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Mariaelena Capone
- Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy
| | - Diana Giannarelli
- Statistical Unit, Regina Elena National Cancer Institute, Rome, Italy
| | - Domenico Mallardo
- Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy
| | - Gabriele Madonna
- Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy
| | - Lucia Festino
- Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy
| | - Antonio Maria Grimaldi
- Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy
| | - Vito Vanella
- Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy
| | - Ester Simeone
- Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy
| | - Miriam Paone
- Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy
| | - Giuseppe Palmieri
- Unit of Cancer Genetics, Institute of Biomolecular Chemistry, CNR, I-07100, Sassari, Italy
| | - Ernesta Cavalcanti
- Department of Diagnostic Pathology and Laboratory, Istituto Nazionale Tumori- IRCCS -Fondazione G. Pascale, Napoli, Italy
| | - Corrado Caracò
- Melanoma and Skin Cancers Surgery Unit, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Napoli, Italy
| | - Paolo Antonio Ascierto
- Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy.
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24
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Wagner NB, Forschner A, Leiter U, Garbe C, Eigentler TK. S100B and LDH as early prognostic markers for response and overall survival in melanoma patients treated with anti-PD-1 or combined anti-PD-1 plus anti-CTLA-4 antibodies. Br J Cancer 2018; 119:339-346. [PMID: 29950611 PMCID: PMC6070917 DOI: 10.1038/s41416-018-0167-x] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 06/07/2018] [Accepted: 06/07/2018] [Indexed: 01/19/2023] Open
Abstract
Background Immunotherapy with PD-1 antibodies has greatly increased prognosis of patients with advanced melanoma. Identifying biomarkers that predict overall survival (OS) and response to immunotherapy is important. Methods OS and best overall response according to RECIST version 1.1 were analysed, and S100B and lactate dehydrogenase (LDH) serum levels were assessed retrospectively in 152 patients treated with anti-PD-1, and in 86 patients treated with anti-PD-1 plus anti-CTLA-4 antibodies at University Hospital Tuebingen, Germany. Results In the pembrolizumab group, patients with elevated baseline S100B or LDH exhibited significantly impaired OS compared with patients with normal S100B (1-year OS: 51.1% vs 83.1%, log-rank P < .0001) and normal LDH (1-year OS: 44.4% vs 80.8%, P = .00022), respectively. LDH increases of >25% and S100B increases of >145% compared to baseline were significantly associated with impaired OS (both P < .0001). In patients treated with ipilimumab and nivolumab, baseline S100B and increasing S100B levels of >145% as well as baseline LDH were associated with impaired OS (P < .0001, P = .00060, and P = .0050, respectively), whereas increasing LDH of >25% was not (P = .64). Conclusions S100B could serve as a strong baseline marker for OS in melanoma patients receiving anti-PD-1 therapy. Rising S100B levels during the first weeks of therapy could help guide treatment decisions.
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Affiliation(s)
- Nikolaus B Wagner
- Department of Dermatology, University Hospital Tuebingen, Liebermeisterstrasse 25, 72076, Tuebingen, Germany.
| | - Andrea Forschner
- Department of Dermatology, University Hospital Tuebingen, Liebermeisterstrasse 25, 72076, Tuebingen, Germany
| | - Ulrike Leiter
- Department of Dermatology, University Hospital Tuebingen, Liebermeisterstrasse 25, 72076, Tuebingen, Germany
| | - Claus Garbe
- Department of Dermatology, University Hospital Tuebingen, Liebermeisterstrasse 25, 72076, Tuebingen, Germany
| | - Thomas K Eigentler
- Department of Dermatology, University Hospital Tuebingen, Liebermeisterstrasse 25, 72076, Tuebingen, Germany
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25
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Andrews MC, Wargo JA. Predictors of Response to Immune Checkpoint Blockade. Oncoimmunology 2018. [DOI: 10.1007/978-3-319-62431-0_31] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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26
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Gambichler T, Brown V, Steuke AK, Schmitz L, Stockfleth E, Susok L. Baseline laboratory parameters predicting clinical outcome in melanoma patients treated with ipilimumab: a single-centre analysis. J Eur Acad Dermatol Venereol 2017; 32:972-977. [DOI: 10.1111/jdv.14629] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 09/22/2017] [Indexed: 12/19/2022]
Affiliation(s)
- T. Gambichler
- Skin Cancer Center of the Department of Dermatology; Ruhr-University Bochum; Bochum Germany
| | - V. Brown
- Skin Cancer Center of the Department of Dermatology; Ruhr-University Bochum; Bochum Germany
| | - A.-K. Steuke
- Skin Cancer Center of the Department of Dermatology; Ruhr-University Bochum; Bochum Germany
| | - L. Schmitz
- Skin Cancer Center of the Department of Dermatology; Ruhr-University Bochum; Bochum Germany
| | - E. Stockfleth
- Skin Cancer Center of the Department of Dermatology; Ruhr-University Bochum; Bochum Germany
| | - L. Susok
- Skin Cancer Center of the Department of Dermatology; Ruhr-University Bochum; Bochum Germany
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27
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Maccalli C, Giannarelli D, Chiarucci C, Cutaia O, Giacobini G, Hendrickx W, Amato G, Annesi D, Bedognetti D, Altomonte M, Danielli R, Calabrò L, Di Giacomo AM, Marincola FM, Parmiani G, Maio M. Soluble NKG2D ligands are biomarkers associated with the clinical outcome to immune checkpoint blockade therapy of metastatic melanoma patients. Oncoimmunology 2017; 6:e1323618. [PMID: 28811958 DOI: 10.1080/2162402x.2017.1323618] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 04/20/2017] [Accepted: 04/21/2017] [Indexed: 12/23/2022] Open
Abstract
The introduction of immune checkpoint blockade into the clinical practice resulted in improvement of survival of a significant portion of melanoma patients. Consequently, predictive biomarkers of response are needed to optimize patient's stratification and the development of combination therapies. The aim of this study was to determine whether levels of soluble NKG2D ligands (MICA, MICB, ULBP1, 2 and 3; sNKG2DLs) in the serum of melanoma patients can serve as useful predictors of response to the treatment with immune checkpoint blockade. sNKG2DLs were measured by ELISA in baseline and post-treatment serum and these results were correlated with the clinical outcome of melanoma patients (N = 194). The same determinations were performed also in a cohort of patients (N = 65) treated with either chemotherapy, radiotherapy, or mutated BRAF inhibitors (BRAFi). Absence of soluble MICB and ULBP-1 in baseline serum correlated with improved survival (OS = 21.6 and 25.3 mo and p = 0.02 and 0.01, respectively) of patients treated with immunological therapies while detectable levels of these molecules were found in poor survivors (OS = 8.8 and 12.1 mo, respectively). Multivariate analysis showed that LDH (p <0.0001), sULBP-1 (p = 0.02), and sULBP-2 (p = 0.02) were independent predictors of clinical outcome for the cohort of melanoma patients treated with immune checkpoint blockade. Only LDH but not sNKG2DLs was significantly associated with the clinical outcome of patients treated with standard or BRAFi regimens. These findings highlight the relevance of sNKG2DLs in the serum of melanoma patients as biomarkers for patients' stratification and optimization of immune checkpoint inhibition regimens.
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Affiliation(s)
- Cristina Maccalli
- Research Branch, Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar
| | - Diana Giannarelli
- Unit of Statistics, Regina Elena National Cancer Institute, Rome, Italy
| | - Carla Chiarucci
- Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.,University of Siena, Siena, Italy
| | - Ornella Cutaia
- Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.,University of Siena, Siena, Italy
| | - Gianluca Giacobini
- Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.,University of Siena, Siena, Italy
| | - Wouter Hendrickx
- Research Branch, Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar
| | - Giovanni Amato
- Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy
| | - Diego Annesi
- Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy
| | - Davide Bedognetti
- Research Branch, Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar
| | - Maresa Altomonte
- Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy
| | - Riccardo Danielli
- Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy
| | - Luana Calabrò
- Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy
| | - Anna Maria Di Giacomo
- Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy
| | - Francesco M Marincola
- Office of the Chief Research Officer (CRO), Research Branch, Sidra Medical and Research Center, Doha, Qatar
| | - Giorgio Parmiani
- Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.,Italian Network for Bio-therapy of Tumors-(NIBIT)-Laboratory, Siena, Italy
| | - Michele Maio
- Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy
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