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Hyngstrom JR. Neoadjuvant Therapy: Changes in the Management of Macroscopic Stage III/Resectable Stage IV Melanoma. Surg Oncol Clin N Am 2025; 34:375-392. [PMID: 40413005 DOI: 10.1016/j.soc.2024.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2025]
Abstract
Existing adjuvant therapies improve outcomes for resected stage III and IV melanoma patients but fail in almost half to prevent recurrence and death. Large, multi-institution, randomized studies firmly establish the superiority of neoadjuvant to adjuvant therapy alone. Checkpoint inhibition, either anti-programmed cell death protein 1 monotherapy or combination with CTLA-4/LAG-3 blockage, demonstrates more durable event-free survival compared to targeted or targeted/immunotherapy combination therapies. Novel combinations of intralesional immunotherapies and other agents aim to increase clinical efficacy and limit toxicity of therapies. Pathologic response to treatment remains as the best prognostic surrogate for clinical outcomes for patients.
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Affiliation(s)
- John R Hyngstrom
- Division of Surgical Oncology, Department of Surgery, Rush University Medical Center, 1725 West Harrison Street, Suite 818, Chicago, IL 60612, USA.
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Schumann K, Klespe KC, Mauch C, Loquai C, Schultheis U, Börger S, Thiem A, Emmert S, Hoellwerth M, Koelbinger P, Nguyen VA, Wanner M, Richtig E, Peitsch WK, Harth W, Zenderowski V, Braun AD, Mengoni M, Dummer R, Mangana J, Maul LV, Meis F, Rappersberger K, Persa OD, Biedermann T, Posch C. Switching PD-1 to BRAF + MEK inhibition improves recurrence-free survival in patients receiving a second course of adjuvant melanoma therapy. J Eur Acad Dermatol Venereol 2025. [PMID: 40331873 DOI: 10.1111/jdv.20708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 04/04/2025] [Indexed: 05/08/2025]
Abstract
BACKGROUND PD-1 or BRAF + MEK inhibition is considered the current gold standard in adjuvant melanoma therapy. Little is known if, after the recurrence of the disease and surgery, a second course of adjuvant therapy might be beneficial. METHODS A multicenter, retrospective study investigating a second course of adjuvant therapy after recurrence and surgery in stage III-IV melanoma patients. Patients received nivolumab (NIV), pembrolizumab (PEM) or dabrafenib plus trametinib (D + T) between 01/2017 and 10/2021. The primary endpoint was 12-month recurrence-free survival (RFS2). Further analyses included descriptive and correlative statistics. RESULTS Sixty-six patients from 22 centers in Germany, Austria and Switzerland were included. Thirty-two patients received D + T as second-course adjuvant therapy, 9 patients received PEM and 25 patients received NIV. Recurrence-free survival for the second-course adjuvant treatment (RFS2) was assessed after 12 and 24 months and showed a superiority of adjuvant BRAF + MEK over PD-1 therapy (12-months RFS2: 90.6% vs. 70.6%, HR 4.226 [95% CI 1.154-15.48]; p = 0.030; 24-months RFS2 71.9% vs. 52.9%, HR 3.154 [95% CI 1.374-7.242]; p = 0.007). There was no significant decrease in OS with either BRAF + MEK or PD-1 treatment (12-months OS: 100% both, 24-months OS: 100% vs. 93.8%). Furthermore, therapy sequences were investigated. For better comparability, only BRAF V600 mutated patients were assessed: RFS2 was significantly better for patients with a class switch from PD-1 to BRAF + MEK compared to BRAF + MEK to PD-1 (HR 4.401 (1.04-18.63), p = 0.044). No new safety signals were detected. CONCLUSION In the investigated cohort, a second course of adjuvant melanoma treatment is feasible and provides similar RFS compared to an initial course of adjuvant therapy using BRAF + MEK inhibitors; however, RFS2 is reduced for PD-1 antibodies. In addition, both treatments were convincing with a 24-month OS of almost 100%. Switching from adjuvant PD-1 to BRAF + MEK treatment provided better overall RFS compared to switching from adjuvant BRAF + MEK to PD-1 treatment.
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Affiliation(s)
- Katharina Schumann
- Department of Dermatology and Allergy, School of Medicine, German Cancer Consortium (DKTK), Technical University of Munich, Munich, Germany
- Department for Phlebology and Venerology, Artemed Hospital, Munich, Germany
| | - Kai Christian Klespe
- Department of Dermatology and Allergology, University Hospital RWTH Aachen, Aachen, Germany
- Department of Dermatology and Venereology, University Hospital Cologne, Cologne, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Cologne, Germany
| | - Cornelia Mauch
- Department of Dermatology and Venereology, University Hospital Cologne, Cologne, Germany
| | - Carmen Loquai
- Department for Dermatology and Allergology, Clinic Bremen Ost, Bremen, Germany
| | - Ulrike Schultheis
- Department for Dermatology, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Sevil Börger
- Department for Dermatology, University Hospital Kassel, Kassel, Germany
| | - Alexander Thiem
- Clinic and Policlinic for Dermatology and Venereology, University Medical Center Rostock, Rostock, Germany
| | - Steffen Emmert
- Clinic and Policlinic for Dermatology and Venereology, University Medical Center Rostock, Rostock, Germany
| | - Magdalena Hoellwerth
- Department for Dermatology and Allergology, Paracelsus Medical University, Salzburg, Austria
| | - Peter Koelbinger
- Department for Dermatology and Allergology, Paracelsus Medical University, Salzburg, Austria
| | - Van Anh Nguyen
- Department for Dermatology, Venereology and Allergology, Medical University Innsbruck, Innsbruck, Austria
| | - Marina Wanner
- Department for Dermatology, Venereology and Allergology, Medical University Innsbruck, Innsbruck, Austria
| | - Erika Richtig
- Department of Dermatology and Venereology, Medical University Graz, Graz, Austria
| | - Wiebke K Peitsch
- Department of Dermatology and Venereology, Vivantes Skin Cancer Center, Berlin, Germany
| | - Wolfgang Harth
- Department of Dermatology and Venereology, Vivantes Skin Cancer Center, Berlin, Germany
| | | | | | - Miriam Mengoni
- Department of Dermatology, University Hospital Magdeburg, Magdeburg, Germany
| | - Reinhard Dummer
- Dermatology Clinic, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Johanna Mangana
- Dermatology Clinic, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Lara Valeska Maul
- Dermatology Clinic, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Frank Meis
- Department for Dermatology and Venereology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | | | - Oana Diana Persa
- Department of Dermatology and Allergy, School of Medicine, German Cancer Consortium (DKTK), Technical University of Munich, Munich, Germany
| | - Tilo Biedermann
- Department of Dermatology and Allergy, School of Medicine, German Cancer Consortium (DKTK), Technical University of Munich, Munich, Germany
| | - Christian Posch
- Department of Dermatology and Allergy, School of Medicine, German Cancer Consortium (DKTK), Technical University of Munich, Munich, Germany
- Faculty of Medicine, Sigmund Freud University Vienna, Vienna, Austria
- Department for Dermatology, Clinic Hietzing, Vienna Healthcare Group, Vienna, Austria
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3
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Martínez-Vila C, Teixido C, Aya F, Martín R, González-Navarro EA, Alos L, Castrejon N, Arance A. Detection of Circulating Tumor DNA in Liquid Biopsy: Current Techniques and Potential Applications in Melanoma. Int J Mol Sci 2025; 26:861. [PMID: 39859576 PMCID: PMC11766255 DOI: 10.3390/ijms26020861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 01/10/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025] Open
Abstract
The treatment landscape for advanced melanoma has transformed significantly with the advent of BRAF and MEK inhibitors (BRAF/MEKi) targeting BRAFV600 mutations, as well as immune checkpoint inhibitors (ICI) like anti-PD-1 monotherapy or its combinations with anti-CTLA-4 or anti-LAG-3. Despite that, many patients still do not benefit from these treatments at all or develop resistance mechanisms. Therefore, prognostic and predictive biomarkers are needed to identify patients who should switch or escalate their treatment strategies or initiate an intensive follow-up. In melanoma, liquid biopsy has shown promising results, with a potential role in predicting relapse in resected high-risk patients or in disease monitoring during the treatment of advanced disease. Several components in peripheral blood have been analyzed, such as circulating tumor cells (CTCs), cell-free DNA (cfDNA), and circulant tumoral DNA (ctDNA), which have turned out to be particularly promising. To analyze ctDNA in blood, different techniques have proven to be useful, including digital droplet polymerase chain reaction (ddPCR) to detect specific mutations and, more recently, next-generation sequencing (NGS) techniques, which allow analyzing a broader repertoire of the mutation landscape of each patient. In this review, our goal is to update the current understanding of liquid biopsy, focusing on the use of ctDNA as a biological material in the daily clinical management of melanoma patients, in particular those with advanced disease treated with ICI.
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Affiliation(s)
- Clara Martínez-Vila
- Department of Medical Oncology, Althaia Xarxa Assistencial Universitària de Manresa, Dr. Joan Soler, 1–3, 08243 Manresa, Spain;
- Programa de Doctorat en Medicina i Recerca Translacional, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain
- Institut de Recerca i Innovació en Ciències de la Vida i de la Salut a la Catalunya Central (IRIS-CC), Roda 70, 08500 Vic, Spain
| | - Cristina Teixido
- Department of Pathology, Hospital Clínic of Barcelona, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain; (C.T.); (L.A.); (N.C.)
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149, 08036 Barcelona, Spain; (F.A.); (R.M.); (E.A.G.-N.)
| | - Francisco Aya
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149, 08036 Barcelona, Spain; (F.A.); (R.M.); (E.A.G.-N.)
- Department of Medical Oncology, Hospital Clínic of Barcelona, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain
| | - Roberto Martín
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149, 08036 Barcelona, Spain; (F.A.); (R.M.); (E.A.G.-N.)
- Department of Medical Oncology, Hospital Clínic of Barcelona, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain
| | - Europa Azucena González-Navarro
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149, 08036 Barcelona, Spain; (F.A.); (R.M.); (E.A.G.-N.)
- Department of Immunology, Hospital Clínic of Barcelona, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain
| | - Llucia Alos
- Department of Pathology, Hospital Clínic of Barcelona, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain; (C.T.); (L.A.); (N.C.)
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149, 08036 Barcelona, Spain; (F.A.); (R.M.); (E.A.G.-N.)
| | - Natalia Castrejon
- Department of Pathology, Hospital Clínic of Barcelona, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain; (C.T.); (L.A.); (N.C.)
| | - Ana Arance
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149, 08036 Barcelona, Spain; (F.A.); (R.M.); (E.A.G.-N.)
- Department of Medical Oncology, Hospital Clínic of Barcelona, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain
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Dougherty SC, Flowers WL, Gaughan EM. Precision Oncology in Melanoma: Changing Practices. J Nucl Med 2024; 65:1838-1845. [PMID: 39542696 PMCID: PMC11619585 DOI: 10.2967/jnumed.124.267781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 10/22/2024] [Indexed: 11/17/2024] Open
Abstract
Over the last 2 decades, significant progress has been made in our understanding of the genomics, tumor immune microenvironment, and immunogenicity of malignant melanoma. Historically, the prognosis for metastatic melanoma was poor because of limited treatment options. However, after multiple landmark clinical trials displaying the efficacy of combined BRAF/MEK inhibition for BRAF-mutant melanoma and the application of immune checkpoint inhibitors targeting the programmed death-1, cytotoxic T-lymphocyte antigen-4, and lymphocyte activation gene-3 molecules, overall survival rates have dramatically improved. The role of immune checkpoint inhibition has since expanded to the neoadjuvant and adjuvant settings with multiple regimens in routine use. Personalized therapies, including tumor-infiltrating lymphocytes that are extracted from a patient's melanoma and eventually reinfused into the patient, and messenger RNA vaccines used to target neoantigens unique to a patient's tumor, show promise. Improvements in accompanying imaging modalities, particularly within the field of nuclear medicine, have allowed for more accurate staging of disease and assessment of treatment response. Continued growth in the role of nuclear medicine in the evaluation of melanoma, including the incorporation of artificial intelligence into image interpretation and use of radiolabeled tracers allowing for intricate imaging of the tumor immune microenvironment, is expected in the coming years.
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Affiliation(s)
- Sean C Dougherty
- Division of Hematology/Oncology, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia; and
| | - William L Flowers
- Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, Virginia
| | - Elizabeth M Gaughan
- Division of Hematology/Oncology, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia; and
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Senechal I, Andres MS, Tong J, Ramalingam S, Nazir MS, Rosen SD, Young K, Idaikkadar P, Larkin J, Lyon AR. Risk Stratification, Screening and Treatment of BRAF/MEK Inhibitors-Associated Cardiotoxicity. Curr Oncol Rep 2024; 26:1431-1441. [PMID: 39316222 DOI: 10.1007/s11912-024-01599-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2024] [Indexed: 09/25/2024]
Abstract
PURPOSE OF REVIEW In this review article we describe the cardiovascular adverse events associated with BRAF and MEK inhibitors as well as their pathophysiologic mechanisms and provide up to date guidance for risk stratified surveillance of patients on treatment and the optimal management of emergent cardiotoxicities. RECENT FINDINGS Combination BRAF/MEK inhibition has become an established standard treatment option for patients with a wide variety of BRAF mutant haematological and solid organ cancers, its use is most commonly associated with stage three and metastatic melanoma. The introduction of these targeted drugs has significantly improved the prognosis of previously treatment resistant cancers. It is increasingly recognised that these drugs have a number of cardiovascular toxicities including left ventricular systolic dysfunction, hypertension and QTc interval prolongation. Whilst cardiotoxicity is largely reversible and manageable with medical therapy, it does limit the effective use of these highly active agents.
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Affiliation(s)
- Isabelle Senechal
- Cardio-Oncology Service, Royal Brompton Hospital, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
- Centre Hospitalier Universitaire de Québec, Québec City, Québec, Canada.
| | - Maria Sol Andres
- Cardio-Oncology Service, Royal Brompton Hospital, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Jieli Tong
- Cardio-Oncology Service, Royal Brompton Hospital, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Sivatharshini Ramalingam
- Cardio-Oncology Service, Royal Brompton Hospital, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Muhummad Sohaib Nazir
- Cardio-Oncology Service, Royal Brompton Hospital, Guy's and St. Thomas' NHS Foundation Trust, London, UK
- School of Biomedical Engineering and Imaging Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Stuart D Rosen
- Cardio-Oncology Service, Royal Brompton Hospital, Guy's and St. Thomas' NHS Foundation Trust, London, UK
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Kate Young
- Royal Marsden Hospital Foundation Trust, London, UK
| | | | - James Larkin
- Royal Marsden Hospital Foundation Trust, London, UK
| | - Alexander R Lyon
- Cardio-Oncology Service, Royal Brompton Hospital, Guy's and St. Thomas' NHS Foundation Trust, London, UK
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Czarnecka AM, Ostaszewski K, Błoński PJ, Szumera-Ciećkiewicz A, Świtaj T, Kozak K, Koseła-Patreczyk H, Rogala P, Kalinowska I, Zaborowski K, Krotewicz M, Borkowska A, Rutkowski P. Long-term efficacy of neoadjuvant-adjuvant targeted therapy in borderline resectable stage IIIB-D and IV melanoma. Cancer 2024; 130:3463-3472. [PMID: 38843386 DOI: 10.1002/cncr.35425] [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: 11/23/2023] [Revised: 03/16/2024] [Accepted: 03/19/2024] [Indexed: 09/28/2024]
Abstract
BACKGROUND Neoadjuvant-adjuvant therapy for locally advanced or potentially resectable metastatic melanoma was expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment only. METHODS Forty-seven consecutive patients were treated with neoadjuvant-adjuvant BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi) and surgery. RESULTS Twelve (26%) patients achieved a pathological complete response and 10 (21%) patients achieved a near-complete response. In the whole group, median recurrence-free survival was 19.4 months and median distant metastasis-free survival (mDMFS) was 21.9 months. In patients with a pathological complete response (pCR)/near-pCR median recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were significantly longer than in patients with minor pathological response with hazard ratio (HR) = 0.37 (p = .005) for RFS and HR = 0.33 (p = .002) for DMFS. After median follow-up of 52.5 months, median progression-free survival since BRAFi/MEKi therapy initiation was 25.1 months. The median time-to-treatment-failure since initiation of neoadjuvant therapy was 22.2 months and was significantly longer in patients with pCR/near-pCR (HR = 0.45; p = .022). Neoadjuvant therapy did not result in any new specific complications of surgery. After 48 months, RFS and overall survival were 36.3% and 64.8% or 20% and 37.4% in patients with pCR/near-pCR and pathological partial response/pathological nonresponse, respectively. CONCLUSIONS The authors confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of stage III/IV melanoma. Major pathological response to neoadjuvant treatment is a surrogate marker of recurrence including DMFS in these patients. PLAIN LANGUAGE SUMMARY Our study presents a large comprehensive analysis of neoadjuvant-adjuvant systemic therapy in patients diagnosed with marginally resectable stage III or IV melanoma. Neoadjuvant therapy effectively reduced the volume of the disease, which facilitated subsequent surgical resection. After median follow-up of 52.5 months, median progression-free survival since therapy initiation was 25.1 months. Twelve patients had complete pathological response and 10 patients had a near-complete pathological response-and together they had median recurrence-free survival and distant metastasis-free survival significantly longer than in patients with pathological partial response or nonresponse. Complete/near-complete pathological response to neoadjuvant treatment is a surrogate marker of recurrence-free, including distant metastasis-free, survival in these patients.
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Affiliation(s)
- Anna M Czarnecka
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Krzysztof Ostaszewski
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Piotr J Błoński
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
- Faculty of Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Anna Szumera-Ciećkiewicz
- Department of Pathology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Tomasz Świtaj
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Katarzyna Kozak
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Hanna Koseła-Patreczyk
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Paweł Rogala
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Iwona Kalinowska
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Konrad Zaborowski
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Maria Krotewicz
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Aneta Borkowska
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Piotr Rutkowski
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
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Shen S, Hong Y, Huang J, Qu X, Sooranna SR, Lu S, Li T, Niu B. Targeting PD-1/PD-L1 in tumor immunotherapy: Mechanisms and interactions with host growth regulatory pathways. Cytokine Growth Factor Rev 2024; 79:16-28. [PMID: 39179486 DOI: 10.1016/j.cytogfr.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 08/06/2024] [Accepted: 08/07/2024] [Indexed: 08/26/2024]
Abstract
Tumor immunotherapy has garnered considerable attention, emerging as a new standard of care in cancer treatment. The conventional targets, such as VEGF and EGFR, have been extended to others including BRAF and PD-1/PD-L1, which have shown significant potential in recent cancer treatments. This review aims to succinctly overview the impact and mechanisms of therapies that modulate PD-1/PD-L1 expression by targeting VEGF, EGFR, LAG-3, CTLA-4 and BRAF. We investigated how modulation of PD-1/PD-L1 expression impacts growth factor signaling, shedding light on the interplay between immunomodulatory pathways and growth factor networks within the tumor microenvironment. By elucidating these interactions, we aim to provide insights into novel potential synergistic therapeutic strategies for cancer immunotherapy.
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Affiliation(s)
- Songyu Shen
- School of life Science, Shanghai University, 99 Shangda Road, 200444, China
| | - Yihan Hong
- School of life Science, Shanghai University, 99 Shangda Road, 200444, China
| | - Jiajun Huang
- School of life Science, Shanghai University, 99 Shangda Road, 200444, China
| | - Xiaosheng Qu
- Guangxi Botanical Garden of Medicinal Plants, Nanning, Guangxi 530023, China
| | - Suren Rao Sooranna
- Department of Metabolism, Digestion and Reproduction, Imperial College London, 369 Fulham Road, London SW10 9NH, United Kingdom
| | - Sheng Lu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Tian Li
- School of Basic Medicine, Fourth Military Medical University, 169 Changle West Rd, Xi'an 710032, China.
| | - Bing Niu
- School of life Science, Shanghai University, 99 Shangda Road, 200444, China.
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Taglialatela I, Indini A, Santanelli G, Di Liberti G, Di Guardo L, De Braud F, Del Vecchio M. Melanoma and sex hormones: Pathogenesis, progressive disease and response to treatments. TUMORI JOURNAL 2024; 110:309-318. [PMID: 38372040 DOI: 10.1177/03008916241231687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/20/2024]
Abstract
Cutaneous melanoma represents the fifth tumor in terms of incidence in young adults, with a major involvement of males than females. Despite the significant changes in available effective treatments for cutaneous melanoma, there is still a proportion of patients that do not benefit long-term disease control with immune checkpoint inhibitors and/or BRAF/MEK inhibitors, and eventually develop progressive disease. In addition to the emerging biomarkers under investigation to understand resistance to treatments, recent studies resumed the role of sex hormones (estrogens, progesterone and androgens) in melanoma patients. In the last decades, the impact of sex hormones has been considered controversial in melanoma patients, but actual growing preclinical and clinical evidence underline the potential influence on melanoma cells' growth, tumor microenvironment, the immune system and consequently on the course of disease.This review will provide available insights on the role of sex hormones in melanoma pathogenesis, disease progression and response/resistance to systemic treatments. We will also offer an overview on the recent studies on the theme, describing the hormonal contribution to disease response and the interaction with targeted therapies and immune-checkpoint inhibitors in cutaneous melanoma patients, illustrating an insight into future research in this field.
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Affiliation(s)
- Ida Taglialatela
- Melanoma Medical Oncology Unit, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Alice Indini
- Melanoma Medical Oncology Unit, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Giulia Santanelli
- Melanoma Medical Oncology Unit, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Giorgia Di Liberti
- Melanoma Medical Oncology Unit, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Lorenza Di Guardo
- Melanoma Medical Oncology Unit, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Filippo De Braud
- Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
- Università degli studi di Milano, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Michele Del Vecchio
- Melanoma Medical Oncology Unit, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
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Amouzegar A, Tawbi HA. Local and Systemic Management Options for Melanoma Brain Metastases. Cancer J 2024; 30:102-107. [PMID: 38527263 DOI: 10.1097/ppo.0000000000000711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2024]
Abstract
ABSTRACT Development of brain metastasis is one of the most serious complications of advanced melanoma, carrying a significant burden of morbidity and mortality. Although advances in local treatment modalities such as stereotactic radiosurgery and breakthrough systemic therapies including immunotherapy and targeted therapies have improved the outcomes of patients with metastatic melanoma, management of patients with melanoma brain metastases (MBMs) remains challenging. Notably, patients with MBMs have historically been excluded from clinical trials, limiting insights into their specific treatment responses. Encouragingly, a growing body of evidence shows the potential of systemic therapies to yield durable intracranial responses in these patients, highlighting the need for inclusion of patients with MBMs in future clinical trials. This is pivotal for expediting the advancement of novel therapies tailored to this distinct patient population. In this review, we will highlight the evolving landscape of MBM management, focusing on local and systemic treatment strategies.
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Affiliation(s)
- Afsaneh Amouzegar
- From the Division of Cancer Medicine, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
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Dunsche L, Ivanisenko N, Riemann S, Schindler S, Beissert S, Angeli C, Kreis S, Tavassoli M, Lavrik I, Kulms D. A cytosolic mutp53(E285K) variant confers chemoresistance of malignant melanoma. Cell Death Dis 2023; 14:831. [PMID: 38097548 PMCID: PMC10721616 DOI: 10.1038/s41419-023-06360-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 11/29/2023] [Accepted: 11/30/2023] [Indexed: 12/17/2023]
Abstract
Malignant melanoma (MM) is known to be intrinsically chemoresistant, even though only ~20% of MM carry mutations of the tumor suppressor p53. Despite improvement of systemic therapy the mortality rate of patients suffering from metastatic MM is still ~70%, highlighting the need for alternative treatment options or for the re-establishment of conventional therapeutic approaches, including chemotherapy. Screening the p53 mutation status in a cohort of 19 patient-derived melanoma samples, we identified one rarely described missense mutation of p53 leading to E285K amino acid exchange (mutp53(E285K)). Employing structural and computational analysis we revealed a major role of E285 residue in maintaining stable conformation of wild-type p53 (wtp53). E285K mutation was predicted to cause interruption of a salt-bridge network affecting the conformation of the C-terminal helix of the DNA-binding domain (DBD) thereby preventing DNA interaction. In this context, a cluster of frequently mutated amino acid residues in cancer was identified to putatively lead to similar structural effects as E285K substitution (E285 cluster). Functional analysis, including knockdown of endogenous p53 and reconstitution with diverse p53 missense mutants confirmed mutp53(E285K) to have lost transcriptional activity, to be localized in the cytosol of cancer cells, by both means conferring chemoresistance. Re-sensitization to cisplatin-induced cell death was achieved using clinically approved compounds aiming to restore p53 wild-type function (PRIMA1-Met), or inhibition of AKT-driven MAPK survival pathways (afuresertib), in both cases being partially due to ferroptosis induction. Consequently, active ferroptosis induction using the GPX4 inhibitor RSL3 proved superior in tumorselectively fighting MM cells. Due to high prevalence of the E285-cluster mutations in MM as well as in a variety of other tumor types, we conclude this cluster to serve an important function in tumor development and therapy and suggest new implications for ferroptosis induction in therapeutic applications fighting MM in particular and cancer in general.
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Affiliation(s)
- Luise Dunsche
- Experimental Dermatology, Department of Dermatology, TU-Dresden, 01307, Dresden, Germany
- National Center for Tumor Diseases, TU-Dresden, 01307, Dresden, Germany
| | - Nikita Ivanisenko
- Translational Inflammation Research, Medical Faculty, Center of Dynamic Systems, Otto von Guericke University, 39106, Magdeburg, Germany
| | - Shamala Riemann
- Experimental Dermatology, Department of Dermatology, TU-Dresden, 01307, Dresden, Germany
- National Center for Tumor Diseases, TU-Dresden, 01307, Dresden, Germany
| | - Sebastian Schindler
- Experimental Dermatology, Department of Dermatology, TU-Dresden, 01307, Dresden, Germany
- National Center for Tumor Diseases, TU-Dresden, 01307, Dresden, Germany
| | - Stefan Beissert
- Experimental Dermatology, Department of Dermatology, TU-Dresden, 01307, Dresden, Germany
| | - Cristian Angeli
- Department of Life Science and Medicine, University of Luxembourg, Belvaux, 4367, Luxembourg
| | - Stephanie Kreis
- Department of Life Science and Medicine, University of Luxembourg, Belvaux, 4367, Luxembourg
| | - Mahvash Tavassoli
- Molecular Oncology, Guy's Hospital, Kings College London, London, SE1 1UL, UK
| | - Inna Lavrik
- Translational Inflammation Research, Medical Faculty, Center of Dynamic Systems, Otto von Guericke University, 39106, Magdeburg, Germany
| | - Dagmar Kulms
- Experimental Dermatology, Department of Dermatology, TU-Dresden, 01307, Dresden, Germany.
- National Center for Tumor Diseases, TU-Dresden, 01307, Dresden, Germany.
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Rose MA, Miura J, Sharon C, Ermer JP, Karakousis G, Wachtel H. Current Patterns of Treatment and Outcomes in Advanced Melanoma at a Single Institution. J Surg Res 2023; 291:25-33. [PMID: 37331189 PMCID: PMC10524477 DOI: 10.1016/j.jss.2023.05.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 05/17/2023] [Accepted: 05/18/2023] [Indexed: 06/20/2023]
Abstract
INTRODUCTION Treatment of advanced melanoma has been transformed by novel systemic therapies. The purpose of this study is to describe the current utilization patterns of immunotherapies with respect to survival outcomes in advanced melanoma. METHODS We performed a retrospective cohort study of patients with Stage 3 and 4 melanoma at our institution (2009-2019). Primary outcomes included overall survival (OS) and progression free survival (PFS). Kaplan-Meier survival analysis and Cox proportional hazards regression analysis evaluated associations between covariates and survival outcomes. RESULTS Of 244 patients, 5-y OS was 62.4%. Lymphovascular invasion (hazard ratio [HR] = 2.462, P = 0.030) was associated with shorter PFS whereas female gender (HR = 0.324, P = 0.010) was associated with longer PFS. Residual tumor (HR = 146, P = 0.006) and Stage 4 disease (HR = 3.349, P = 0.011) were associated with shorter OS. Use of immunotherapy increased from 2% to 23% over the study period, and use of neoadjuvant immunotherapy also increased up to 2016. Timing of immunotherapy administration was not significantly associated with survival. Of the 193 patients who received 2 or more treatment types, the most common treatment sequence was surgery followed by immunotherapy (n = 117, 60.6%). CONCLUSIONS Immunotherapy is increasingly used for treatment of advanced melanoma. In this heterogeneous cohort, there was no significant association between timing of immunotherapy and survival outcomes.
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Affiliation(s)
- Michelle A Rose
- Perelman School of Medicine, University of Pennsylvania, Philadelphia Pennsylvania
| | - John Miura
- Perelman School of Medicine, University of Pennsylvania, Philadelphia Pennsylvania; Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Cimarron Sharon
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jae P Ermer
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Giorgos Karakousis
- Perelman School of Medicine, University of Pennsylvania, Philadelphia Pennsylvania; Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Heather Wachtel
- Perelman School of Medicine, University of Pennsylvania, Philadelphia Pennsylvania; Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
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12
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Cummins DD, Garcia JH, Nguyen MP, Saggi S, Chung JE, Goldschmidt E, Berger MS, Theodosopoulos PV, Chang EF, Daras M, Hervey-Jumper SL, Aghi MK, Morshed RA. Association of CDKN2A alterations with increased postoperative seizure risk after resection of brain metastases. Neurosurg Focus 2023; 55:E14. [PMID: 37527678 PMCID: PMC11128027 DOI: 10.3171/2023.5.focus23133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/16/2023] [Indexed: 08/03/2023]
Abstract
OBJECTIVE Seizures are common and significantly disabling for patients with brain metastases (BMs). Although resection can provide seizure control, a subset of patients with BMs may continue to suffer seizures postoperatively. Genomic BM characteristics may influence which patients are at risk for postoperative seizures. This work explores correlations between genomic alterations and risk of postoperative seizures following BM resection. METHODS All patients underwent BM resection at a single institution, with available clinical and sequencing data on more than 500 oncogenes. Clinical seizures were documented pre- and postoperatively. A random forest machine learning classification was used to determine candidate genomic alterations associated with postoperative seizures, and clinical and top genomic variables were correlated with postoperative seizures by using Cox proportional hazards models. RESULTS There were 112 patients with BMs who underwent 114 surgeries and had at least 1 month of postoperative follow-up. Seizures occurred preoperatively in 26 (22.8%) patients and postoperatively in 25 (21.9%). The Engel classification achieved at 6 months for those with preoperative seizures was class I in 13 (50%); class II in 6 (23.1%); class III in 5 (19.2%), and class IV in 2 (7.7%). In those with postoperative seizures, only 8 (32.0%) had seizures preoperatively, and preoperative seizures were not a significant predictor of postoperative seizures (HR 1.84; 95% CI 0.79-4.37; p = 0.156). On random forest classification and multivariate Cox analysis controlling for factors including recurrence, extent of resection, and number of BMs, CDKN2A alterations were associated with postoperative seizures (HR 3.22; 95% CI 1.27-8.16; p = 0.014). Melanoma BMs were associated with higher risk of postoperative seizures compared with all other primary malignancies (HR 5.23; 95% CI 1.37-19.98; p = 0.016). Of 39 BMs with CDKN2A alteration, 35.9% (14/39) had postoperative seizures, compared to 14.7% (11/75) without CDKN2A alteration. The overall rate of postoperative seizures in melanoma BMs was 42.9% (15/35), compared with 12.7% (10/79) for all other primary malignancies. CONCLUSIONS CDKN2A alterations and melanoma primary malignancy are associated with increased postoperative seizure risk following resection of BMs. These results may help guide postoperative seizure prophylaxis in patients undergoing resection of BMs.
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Affiliation(s)
- Daniel D. Cummins
- Department of Neurological Surgery, University of California, San Francisco, California
| | - Joseph H. Garcia
- Department of Neurological Surgery, University of California, San Francisco, California
| | - Minh P. Nguyen
- Department of Neurological Surgery, University of California, San Francisco, California
| | - Satvir Saggi
- Department of Neurological Surgery, University of California, San Francisco, California
| | - Jason E. Chung
- Department of Neurological Surgery, University of California, San Francisco, California
| | - Ezequiel Goldschmidt
- Department of Neurological Surgery, University of California, San Francisco, California
| | - Mitchel S. Berger
- Department of Neurological Surgery, University of California, San Francisco, California
| | | | - Edward F. Chang
- Department of Neurological Surgery, University of California, San Francisco, California
| | - Mariza Daras
- Department of Neurological Surgery, University of California, San Francisco, California
- Department of Neurology, University of California, San Francisco, California
| | | | - Manish K. Aghi
- Department of Neurological Surgery, University of California, San Francisco, California
| | - Ramin A. Morshed
- Department of Neurological Surgery, University of California, San Francisco, California
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Abstract
Gliomas are a heterogeneous group of brain tumors with limited therapeutic options. However, identification of BRAF V600E mutations in a subset of gliomas has provided a genomic-targeted approach for management of these diseases. In this review, we aimed to review the role of BRAF V600E in gliomagenesis, to characterize concurrent genomic alterations and their potential prognostic implications, and to review comprehensively the efficacy data of BRAF inhibitors (combined or not with MEK inhibitors) for the treatment of low- and high-grade gliomas. We also provide a summary of the toxicity of these agents and describe resistance mechanisms that may be circumvented by alternative genomic approaches. Although the efficacy of targeted therapy for management of BRAF V600E-mutant gliomas has mostly been assessed in small retrospective and phase 2 studies with heterogeneous populations, the data generated so far are a proof of concept that genomic-directed therapies improve outcomes of patients with refractory/relapsed glioma and underpin the need of comprehensive genomic assessments for these difficult-to-treat diseases. In the future, the role of targeted therapy in the first-line setting and of genomic-directed therapies to overcome resistance mechanisms should be assessed in well-designed clinical trials.
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Affiliation(s)
- Thiago P Muniz
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
| | - Warren P Mason
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
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14
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Broman KK, Hughes TM, Bredbeck BC, Sun J, Kirichenko D, Carr MJ, Sharma A, Bartlett EK, Nijhuis AAG, Thompson JF, Hieken TJ, Kottschade L, Downs J, Gyorki DE, Stahlie E, van Akkooi A, Ollila DW, O'shea K, Song Y, Karakousis G, Moncrieff M, Nobes J, Vetto J, Han D, Hotz M, Farma JM, Deneve JL, Fleming MD, Perez M, Baecher K, Lowe M, Bagge RO, Mattsson J, Lee AY, Berman RS, Chai H, Kroon HM, Teras J, Teras RM, Farrow NE, Beasley GM, Hui JYC, Been L, Kruijff S, Sinco B, Sarnaik AA, Sondak VK, Zager JS, Dossett LA. International Center-Level Variation in Utilization of Completion Lymph Node Dissection and Adjuvant Systemic Therapy for Sentinel Lymph Node-Positive Melanoma at Major Referral Centers. Ann Surg 2023; 277:e1106-e1115. [PMID: 35129464 PMCID: PMC10097464 DOI: 10.1097/sla.0000000000005370] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The aim of this study was to determine overall trends and center-level variation in utilization of completion lymph node dissection (CLND) and adjuvant systemic therapy for sentinel lymph node (SLN)-positive melanoma. SUMMARY BACKGROUND DATA Based on recent clinical trials, management options for SLN-positive melanoma now include effective adjuvant systemic therapy and nodal observation instead of CLND. It is unknown how these findings have shaped practice or how these contemporaneous developments have influenced their respective utilization. METHODS We performed an international cohort study at 21 melanoma referral centers in Australia, Europe, and the United States that treated adults with SLN-positive melanoma and negative distant staging from July 2017 to June 2019. We used generalized linear and multinomial logistic regression models with random intercepts for each center to assess center-level variation in CLND and adjuvant systemic treatment, adjusting for patient and disease-specific characteristics. RESULTS Among 1109 patients, performance of CLND decreased from 28% to 8% and adjuvant systemic therapy use increased from 29 to 60%. For both CLND and adjuvant systemic treatment, the most influential factors were nodal tumor size, stage, and location of treating center. There was notable variation among treating centers in management of stage IIIA patients and use of CLND with adjuvant systemic therapy versus nodal observation alone for similar risk patients. CONCLUSIONS There has been an overall decline in CLND and simultaneous adoption of adjuvant systemic therapy for patients with SLN-positive melanoma though wide variation in practice remains. Accounting for differences in patient mix, location of care contributed significantly to the observed variation.
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Affiliation(s)
- Kristy K Broman
- Moffitt Cancer Center, Tampa, FL
- University of South Florida Morsani College of Medicine, Tampa, FL
- University of Alabama at Birmingham, Birmingham, AL
| | | | | | | | | | | | | | | | - Amanda A G Nijhuis
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia
| | - John F Thompson
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia
| | | | | | | | | | - Emma Stahlie
- Netherlands Cancer institute, Amsterdam, The Netherlands
| | | | | | | | - Yun Song
- University of Gothenburg, Gothenburg, Sweden
| | | | - Marc Moncrieff
- Norfolk and Norwich University Hospital, Norwich, United Kingdom
| | - Jenny Nobes
- Norfolk and Norwich University Hospital, Norwich, United Kingdom
| | - John Vetto
- Oregon Health & Science University, Portland, OR
| | - Dale Han
- Oregon Health & Science University, Portland, OR
| | | | | | | | | | | | | | | | | | - Jan Mattsson
- University Medical Center, Groningen, Netherlands
| | | | | | - Harvey Chai
- Royal Adelaide Hospital, University of Adelaide, Adelaide, Australia
| | - Hidde M Kroon
- Royal Adelaide Hospital, University of Adelaide, Adelaide, Australia
| | - Juri Teras
- North Estonia Medical Centre Foundation, Tallinn, Estonia
| | - Roland M Teras
- North Estonia Medical Centre Foundation, Tallinn, Estonia
| | | | | | | | | | | | | | - Amod A Sarnaik
- Moffitt Cancer Center, Tampa, FL
- University of South Florida Morsani College of Medicine, Tampa, FL
| | - Vernon K Sondak
- Moffitt Cancer Center, Tampa, FL
- University of South Florida Morsani College of Medicine, Tampa, FL
| | - Jonathan S Zager
- Moffitt Cancer Center, Tampa, FL
- University of South Florida Morsani College of Medicine, Tampa, FL
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15
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Ascierto PA, Cioli E, Chiarion-Sileni V, Quaglino P, Spagnolo F, Guidoboni M, Del Vecchio M, Peris K, Queirolo P, Fioretto L, Caracò C, Paone M, Sorrentino A, Capone M, Giannarelli D, Ferrara G, Massi D, Trojaniello C. Neoadjuvant plus adjuvant combined or sequenced vemurafenib, cobimetinib and atezolizumab in patients with high-risk, resectable BRAF-mutated and wild-type melanoma: NEO-TIM, a phase II randomized non-comparative study. Front Oncol 2023; 13:1107307. [PMID: 36845751 PMCID: PMC9949553 DOI: 10.3389/fonc.2023.1107307] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 01/25/2023] [Indexed: 02/11/2023] Open
Abstract
Background Following the increased survival of patients with metastatic melanoma thanks to immunotherapy and targeted therapy, neoadjuvant approaches are being investigated to address the unmet needs of unresponsive and intolerant patients. We aim to investigate the efficacy of neoadjuvant plus adjuvant combined or sequenced vemurafenib, cobimetinib and atezolizumab in patients with high-risk, resectable BRAF-mutated and wild-type melanoma. Methods The study is a phase II, open-label, randomized non-comparative trial in patients with stage IIIB/C/D surgically resectable, BRAF-mutated and wild-type melanoma, with three possible treatments: (1) vemurafenib 960 mg twice daily from day 1 to 42; (2) vemurafenib 720 mg twice daily from day 1 to 42; (3) cobimetinib 60 mg once daily from day 1 to 21 and from day 29 to 42; and (4) atezolizumab 840 mg for two cycles (day 22 and day 43).Patients will be randomized to three different arms: A) BRAF-mutated patients will receive over 6 weeks (1) + (3); B) BRAF-mutated patients will receive over 6 weeks (2) + (3) + (4); C) BRAF wild-type patients will receive over 6 weeks (3) + (4). All patients will also receive atezolizumab 1200 mg every 3 weeks for 17 cycles after surgery and after a second screening period (up to 6 weeks). Discussion Neoadjuvant therapy for regional metastases may improve operability and outcomes and facilitate the identification of biomarkers that can guide further lines of treatment. Patients with clinical stage III melanoma may especially benefit from neoadjuvant treatment, as the outcomes of surgery alone are very poor. It is expected that the combination of neoadjuvant and adjuvant treatment may reduce the incidence of relapse and improve survival. Clinical trial registration eudract.ema.europa.eu/protocol.htm, identifier 2018-004841-17.
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Affiliation(s)
- Paolo A. Ascierto
- Department of Melanoma, Cancer Immunotherapy and Development Therapeutics. Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale” Napoli, Naples, Italy,*Correspondence: Paolo A. Ascierto,
| | - Eleonora Cioli
- Department of Melanoma, Cancer Immunotherapy and Development Therapeutics. Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale” Napoli, Naples, Italy
| | | | - Pietro Quaglino
- Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy
| | | | - Massimo Guidoboni
- Immunotherapy and Cell Therapy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Michele Del Vecchio
- Unit of Melanoma Medical Oncology, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Ketty Peris
- Catholic University of the Sacred Heart and Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy
| | - Paola Queirolo
- Skin Cancer Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy,Division of Melanoma Sarcoma and Rare Tumors, IEO European Institute of Oncology IRCCS Milan, Milan, Italy
| | - Luisa Fioretto
- Medical Oncology Unit, Department of Oncology, Santa Maria Annunziata Hospital, Azienda USL Toscana Centro, Florence, Italy
| | - Corrado Caracò
- Melanoma and Skin Cancers Surgery Unit, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Napoli, Italy
| | - Miriam Paone
- Department of Melanoma, Cancer Immunotherapy and Development Therapeutics. Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale” Napoli, Naples, Italy
| | - Antonio Sorrentino
- Department of Melanoma, Cancer Immunotherapy and Development Therapeutics. Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale” Napoli, Naples, Italy
| | - Mariaelena Capone
- Department of Melanoma, Cancer Immunotherapy and Development Therapeutics. Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale” Napoli, Naples, Italy
| | - Diana Giannarelli
- Fondazione Policlinico Universitario A. Gemelli, IRCCS – Facility of Epidemiology & Biostatistics, Rome, Italy
| | - Gerardo Ferrara
- Department of Pathology and Cytopathology, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Napoli, Italy
| | - Daniela Massi
- Section of Pathology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Claudia Trojaniello
- Department of Melanoma, Cancer Immunotherapy and Development Therapeutics. Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale” Napoli, Naples, Italy
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16
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Abstract
PURPOSE OF REVIEW Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm for patients with metastatic melanoma; however, there remains an unmet clinical need for alternative treatment options for those patients who are either intolerant or refractory to immunotherapy. Here we review the role and clinical efficacy of targeted therapies for BRAFV600 wild-type melanoma. RECENT FINDINGS Genomic analyses in BRAFV600 wild-type melanoma have previously identified driver mutations along the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT pathways that can be targeted with small molecule inhibitors. New drugs such as bispecific antibodies and antibody drug conjugates may have significant clinical activity even in rare subtypes of melanoma that are less responsive to ICIs. Historically, molecular-targeted therapies have modest clinical success in treating BRAFV600 wild-type melanoma; nevertheless, they may have a significant clinical role in select, genetically distinct groups of patients. Next-generation immunotherapies or immunomodulators may represent the latest breakthrough in the treatment of melanoma. Additional studies are needed to identify novel drug targets and synergistic drug combinations to expand treatment options and optimize clinical outcomes.
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Long Term Results and Prognostic Biomarkers for Anti-PD1 Immunotherapy Used after BRAFi/MEKi Combination in Advanced Cutaneous Melanoma Patients. Cancers (Basel) 2022; 14:cancers14092123. [PMID: 35565255 PMCID: PMC9101360 DOI: 10.3390/cancers14092123] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 04/20/2022] [Accepted: 04/23/2022] [Indexed: 02/01/2023] Open
Abstract
(1) Background: BRAFi/MEKi are usually offered as a first line treatment for patients requiring rapid response; with elevated lactate dehydrogenase (LDH) activity, large tumor burden, and with brain metastases. The efficacy of second line therapies after BRAFi/MEKI failure is now well defined. (2) Methods: Patients treated with first line target BRAFi/MEKi therapy (vemurafenib plus cobimetinib, dabrafenib plus trametinib or encorafenib plus binimetinib); and for the second line treatment immunotherapy with programmed cell death 1 (PD-1) checkpoint inhibitors (nivolumab or pembrolizumab) with at least one cycle of second line were analyzed for survival and prognostic biomarkers. (3) Results: There were no statistically significant differences in ORR between the treatment groups with nivolumab and pembrolizumab, as well as median progression free-survival (PSF) and overall survival (OS) since the initiation of second line therapy; on nivolumab OS was 6.6 months, and on pembrolizumab 5.0 months. The greatest clinical benefit with second line immunotherapy was observed in patients with LDH ≤ ULN and <3 organ sites with metastasis at baseline. Longer OS was also noted in patients with time to PD >6 months in first line (slow progression). (4) Conclusions: Second line anti-PD1 immunotherapy is effective in BRAF-mutated melanoma patients after BRAFi/MEKi therapy failure.
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18
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Del Mistro G, Riemann S, Schindler S, Beissert S, Kontermann RE, Ginolhac A, Halder R, Presta L, Sinkkonen L, Sauter T, Kulms D. Focal adhesion kinase plays a dual role in TRAIL resistance and metastatic outgrowth of malignant melanoma. Cell Death Dis 2022; 13:54. [PMID: 35022419 PMCID: PMC8755828 DOI: 10.1038/s41419-022-04502-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 10/26/2021] [Accepted: 12/07/2021] [Indexed: 12/19/2022]
Abstract
Despite remarkable advances in therapeutic interventions, malignant melanoma (MM) remains a life-threating disease. Following high initial response rates to targeted kinase-inhibition metastases quickly acquire resistance and present with enhanced tumor progression and invasion, demanding alternative treatment options. We show 2nd generation hexameric TRAIL-receptor-agonist IZI1551 (IZI) to effectively induce apoptosis in MM cells irrespective of the intrinsic BRAF/NRAS mutation status. Conditioning to the EC50 dose of IZI converted the phenotype of IZI-sensitive parental MM cells into a fast proliferating and invasive, IZI-resistant metastasis. Mechanistically, we identified focal adhesion kinase (FAK) to play a dual role in phenotype-switching. In the cytosol, activated FAK triggers survival pathways in a PI3K- and MAPK-dependent manner. In the nucleus, the FERM domain of FAK prevents activation of wtp53, as being expressed in the majority of MM, and consequently intrinsic apoptosis. Caspase-8-mediated cleavage of FAK as well as FAK knockdown, and pharmacological inhibition, respectively, reverted the metastatic phenotype-switch and restored IZI responsiveness. FAK inhibition also re-sensitized MM cells isolated from patient metastasis that had relapsed from targeted kinase inhibition to cell death, irrespective of the intrinsic BRAF/NRAS mutation status. Hence, FAK-inhibition alone or in combination with 2nd generation TRAIL-receptor agonists may be recommended for treatment of initially resistant and relapsed MM, respectively.
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Affiliation(s)
- Greta Del Mistro
- Experimental Dermatology, Department of Dermatology, TU-Dresden, 01307, Dresden, Germany
| | - Shamala Riemann
- Experimental Dermatology, Department of Dermatology, TU-Dresden, 01307, Dresden, Germany
| | - Sebastian Schindler
- Experimental Dermatology, Department of Dermatology, TU-Dresden, 01307, Dresden, Germany
- National Center for Tumor Diseases Dresden, TU-Dresden, 01307, Dresden, Germany
| | - Stefan Beissert
- Experimental Dermatology, Department of Dermatology, TU-Dresden, 01307, Dresden, Germany
| | - Roland E Kontermann
- Institute of Cell Biology and Immunology and Stuttgart Research Centre Systems Biology, University of Stuttgart, 70569, Stuttgart, Germany
| | - Aurelien Ginolhac
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, 4367, Luxembourg
| | - Rashi Halder
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, 4367, Luxembourg
| | - Luana Presta
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, 4367, Luxembourg
| | - Lasse Sinkkonen
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, 4367, Luxembourg
| | - Thomas Sauter
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, 4367, Luxembourg
| | - Dagmar Kulms
- Experimental Dermatology, Department of Dermatology, TU-Dresden, 01307, Dresden, Germany.
- National Center for Tumor Diseases Dresden, TU-Dresden, 01307, Dresden, Germany.
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19
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Ferroptosis-Associated Classifier and Indicator for Prognostic Prediction in Cutaneous Melanoma. JOURNAL OF ONCOLOGY 2021; 2021:3658196. [PMID: 34745259 PMCID: PMC8568558 DOI: 10.1155/2021/3658196] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/16/2021] [Accepted: 10/01/2021] [Indexed: 02/07/2023]
Abstract
Ferroptosis plays a critical role in different types of cancers, but the prognostic impact of ferroptosis in cutaneous melanoma remains lacking. Therefore, ferroptosis-related genes (FRGs) were firstly obtained from the FerrDb database and the differentially expressed FRGs were identified by the “limma” algorithm. Next, the prognostic differentially expressed FRGs were screened out by univariate Cox regression, which were subsequently used to cluster melanomas into two subtypes (clusters A and B). Besides, the Boruta algorithm and principal component analysis (PCA) were performed to build a 15-FRGs indicator, which can robustly predict patients' overall survival (OS) and be considered as an independent prognostic factor in melanoma. The melanoma patients were further divided into high- and low-FRGs score groups. The high score group have a good prognosis, with higher T cell immune infiltrating and lower mutation frequencies in NRAS, KRAS, and NF1. Finally, we discovered that many immune processes and several chemotherapy drugs were closely associated with FRGs score. Thus, our study provides a novel ferroptosis-associated classifier and indicator to predict the prognosis of melanoma. Besides, we identified several potential chemotherapy drugs to induce ferroptosis and could supply additional effective treatments.
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20
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Katsandris A, Ziogas DC, Kontouri M, Staikoglou S, Gogas H. Atezolizumab plus vemurafenib and cobimetinib for the treatment of BRAF V600-mutant advanced melanoma: from an hypothetic triplet to an approved regimen. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2021. [DOI: 10.1080/23808993.2021.1976637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Aikaterini Katsandris
- First Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Laiko General Hospital, Athens, Greece
| | - Dimitrios C. Ziogas
- First Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Laiko General Hospital, Athens, Greece
| | - Maria Kontouri
- First Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Laiko General Hospital, Athens, Greece
| | - Stavroula Staikoglou
- First Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Laiko General Hospital, Athens, Greece
| | - Helen Gogas
- First Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Laiko General Hospital, Athens, Greece
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21
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Lee CS, Miao E, Das K, Seetharamu N. Clinical efficacy with dabrafenib and trametinib in a T599_V600insT poorly differentiated metastatic thyroid carcinoma. BMJ Case Rep 2021; 14:e243264. [PMID: 34413035 PMCID: PMC8378374 DOI: 10.1136/bcr-2021-243264] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2021] [Indexed: 11/04/2022] Open
Abstract
BRAF (v-raf murine sarcoma viral oncogene homolog B1) and MEK (mitogen-activated protein kinase kinase) inhibitors have been shown to improve clinical outcomes in tumours presenting with mutations in the BRAF gene. The most common form of BRAF mutation is V600E/K and has been shown to occur in thyroid cancers. Treatment data for patients harbouring less frequent BRAF mutations are limited. In vitro studies have shown that mutations in codons 599-601 increase kinase activity similar to that in V600E mutations, which suggests that BRAF and MEK inhibitors could be an effective treatment option. Here, we report a case of a patient with thyroid carcinoma harbouring a rare amino acid insertion in codon 599 of the BRAF gene (T599_V600insT) treated with a BRAF and MEK inhibitor.
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Affiliation(s)
- Chung-Shien Lee
- Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, Lake Success, New York, USA
- Clinical Health Professions, St John's University, Queens, New York, USA
| | - Emily Miao
- Pharmacy Department, North Shore University Hospital, Manhasset, New York, USA
| | - Kasturi Das
- Division of Cytopathology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Greenvale, New York, USA
| | - Nagashree Seetharamu
- Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, Lake Success, New York, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
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22
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Broman KK, Bettampadi D, Pérez-Morales J, Sun J, Kirichenko D, Carr MJ, Eroglu Z, Tarhini AA, Khushalani N, Schabath MB, Sarnaik A, Sondak VK, Zager JS. Surveillance of Sentinel Node-Positive Melanoma Patients Who Receive Adjuvant Therapy Without Undergoing Completion Lymph Node Dissection. Ann Surg Oncol 2021; 28:6978-6985. [PMID: 34363118 DOI: 10.1245/s10434-021-10570-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 06/24/2021] [Indexed: 11/18/2022]
Abstract
INTRODUCTION Adjuvant therapy trials required completion lymph node dissection (CLND) for sentinel lymph node (SLN)-positive melanoma prior to systemic treatment, but nodal surveillance without CLND is now common. For patients receiving adjuvant therapy without CLND, patterns of recurrence are unknown and the value of regional nodal ultrasound alongside cross-sectional imaging is not well-defined. METHODS In a retrospective cohort of SLN-positive melanoma patients managed with nodal surveillance from June 2014 to June 2019, we evaluated the association between adjuvant treatment and location of first recurrence (locoregional, nodal, distant, or multisite) using Chi-square tests. We compared methods of recurrence detection and cost by surveillance intensity using Chi-square and Dunn's tests. RESULTS Among 177 nodal surveillance patients, 66 (37%) received adjuvant therapy. Median follow-up was 24 months, during which 48 patients (27%) recurred. Adjuvant treatment did not alter patterns of initial recurrence (p = 0.76). Adjuvant therapy recipients more often had both nodal ultrasound and cross-sectional imaging surveillance (p < 0.01). Among 13 isolated nodal recurrences, 85% were within the first year and 85% were detected by examination and/or ultrasound. Increasing surveillance intensity was not associated with recurrence detection rates but increased overall cost and cost per detected recurrence. CONCLUSION Regardless of adjuvant treatment, most nodal recurrences occurred in the first year and were initially detected clinically or by ultrasound. Findings support continued use of examination and nodal basin ultrasound in addition to any planned cross-sectional imaging surveillance.
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Affiliation(s)
- Kristy K Broman
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. .,University of South Florida Morsani College of Medicine, Tampa, FL, USA. .,University of Alabama at Birmingham, Birmingham, AL, USA.
| | | | | | - James Sun
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.,University Hospital Cleveland Medical Center, Cleveland, OH, USA
| | - Dennis Kirichenko
- University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Michael J Carr
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Zeynep Eroglu
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.,University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Ahmad A Tarhini
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.,University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Nikhil Khushalani
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.,University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Matthew B Schabath
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.,University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Amod Sarnaik
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.,University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Vernon K Sondak
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.,University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Jonathan S Zager
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.,University of South Florida Morsani College of Medicine, Tampa, FL, USA
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Revythis A, Shah S, Kutka M, Moschetta M, Ozturk MA, Pappas-Gogos G, Ioannidou E, Sheriff M, Rassy E, Boussios S. Unraveling the Wide Spectrum of Melanoma Biomarkers. Diagnostics (Basel) 2021; 11:diagnostics11081341. [PMID: 34441278 PMCID: PMC8391989 DOI: 10.3390/diagnostics11081341] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 12/24/2022] Open
Abstract
The use of biomarkers in medicine has become essential in clinical practice in order to help with diagnosis, prognostication and prediction of treatment response. Since Alexander Breslow’s original report on “melanoma and prognostic values of thickness”, providing the first biomarker for melanoma, many promising new biomarkers have followed. These include serum markers, such as lactate dehydrogenase and S100 calcium-binding protein B. However, as our understanding of the DNA mutational profile progresses, new gene targets and proteins have been identified. These include point mutations, such as mutations of the BRAF gene and tumour suppressor gene tP53. At present, only a small number of the available biomarkers are being utilised, but this may soon change as more studies are published. The aim of this article is to provide a comprehensive review of melanoma biomarkers and their utility for current and, potentially, future clinical practice.
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Affiliation(s)
- Antonios Revythis
- Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK; (A.R.); (S.S.); (M.K.)
| | - Sidrah Shah
- Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK; (A.R.); (S.S.); (M.K.)
| | - Mikolaj Kutka
- Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK; (A.R.); (S.S.); (M.K.)
| | - Michele Moschetta
- CHUV, Lausanne University Hospital, Rue du Bugnon, 21 CH-1011 Lausanne, Switzerland;
| | - Mehmet Akif Ozturk
- Department of Internal Medicine, School of Medicine, Bahcesehir University, Istanbul 34353, Turkey;
| | - George Pappas-Gogos
- Department of Surgery, University Hospital of Ioannina, 45111 Ioannina, Greece;
| | - Evangelia Ioannidou
- Department of Paediatrics and Child Health, West Suffolk Hospital NHS Foundation Trust, Hardwick Lane, Bury St Edmunds IP33 2QZ, UK;
| | - Matin Sheriff
- Department of Urology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK;
| | - Elie Rassy
- Department of Cancer Medicine, Gustave Roussy Institut, 94805 Villejuif, France;
| | - Stergios Boussios
- Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK; (A.R.); (S.S.); (M.K.)
- Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, King’s College London, London SE1 9RT, UK
- AELIA Organization, 9th Km Thessaloniki-Thermi, 57001 Thessaloniki, Greece
- Correspondence: or or
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24
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The Pan-Immune-Inflammation Value in Patients with Metastatic Melanoma Receiving First-Line Therapy. Target Oncol 2021; 16:529-536. [PMID: 34076798 DOI: 10.1007/s11523-021-00819-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Since a non-negligible fraction of patients with metastatic melanoma does not experience long-term disease control, even with immunotherapy and targeted therapy, new biomarkers for patient stratification and treatment tailoring are needed in this setting. OBJECTIVE We investigated the association of a novel immune-inflammatory blood-based biomarker, the Pan-Immune-Inflammation Value (PIV), with clinical outcomes of patients with metastatic melanoma receiving first-line therapy. PATIENTS AND METHODS We retrospectively included patients treated at the Fondazione IRCCS Istituto Nazionale dei Tumori of Milan and having an available baseline complete blood cell count (CBC). PIV was calculated as: [neutrophil count (103/mm3) × platelet count (103/mm3) × monocyte count (103/mm3)]/lymphocyte count (103/mm3). RESULTS A total of 228 patients were included: 119 (52%) had been treated with immunotherapy and 109 (48%) with targeted therapy. PIV was significantly higher in patients with ECOG PS ≥ 1, high disease burden, synchronous metastases, and elevated baseline LDH level. High baseline PIV was independently associated with poor overall survival (adjusted hazard ratio [HR]: 2.06; 95% confidence interval [CI]: 1.30-3.29; adjusted P = 0.002) and progression-free survival (adjusted HR 1.56; 95% CI 1.01-2.41; adjusted P = 0.044). High PIV was also associated with primary resistance to both immunotherapy (odds ratio [OR]: 3.98; 95% CI 1.45-12.32; P = 0.005) and targeted therapy (OR: 8.42; 95% CI 2.50-34.5; P < 0.001). PIV showed a promising discrimination ability in terms of AIC and c-index when compared with other CBC-based biomarkers. CONCLUSIONS PIV may guide the treatment decision process and the development of novel first-line treatment strategies in melanoma, but warrants further study and validation.
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25
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Krishnan T, Menzies AM, Roberts-Thomson R. Recent advancements in melanoma management. Intern Med J 2021; 51:327-333. [PMID: 33738950 DOI: 10.1111/imj.15228] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 11/11/2020] [Accepted: 11/11/2020] [Indexed: 01/11/2023]
Abstract
The treatment options for patients with melanoma have expanded significantly over the past decade. In particular, the use of targeted therapy and immunotherapy has dramatically transformed the outlook for patients with advanced disease. These treatments are now being utilised as adjuvant therapy for patients with earlier stage melanoma after surgical resection. We review the latest updates for melanoma staging, surgical resection, radiotherapy and systemic therapies.
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Affiliation(s)
- Tharani Krishnan
- Medical Oncology Department, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia
| | - Alexander M Menzies
- Medical Oncology Department, Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.,Medical Oncology Department, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia
| | - Rachel Roberts-Thomson
- Medical Oncology Department, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia
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26
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Ziogas DC, Konstantinou F, Bouros S, Theochari M, Gogas H. Combining BRAF/MEK Inhibitors with Immunotherapy in the Treatment of Metastatic Melanoma. Am J Clin Dermatol 2021; 22:301-314. [PMID: 33765322 DOI: 10.1007/s40257-021-00593-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/15/2021] [Indexed: 12/11/2022]
Abstract
The management and prognosis of BRAF-mutant metastatic melanoma have changed drastically following the introduction of immune checkpoint inhibitors and molecularly targeted agents. These treatment options present different mechanisms of action and toxicities but also totally distinct kinetics of their response, including a "relatively" short-lasting benefit in subsets of patients treated with BRAF/MEK inhibitors and a lower response rate in patients treated with immune checkpoint inhibitors. BRAF/MEK inhibitors, when administered prior to or concurrently with immune checkpoint inhibitors, at least transiently alter some immunosuppressive parameters of the tumor microenvironment and theoretically improve sensitivity to immunotherapy. Preclinical data from mouse models with oncogene-addicted melanoma confirmed this beneficial immune/targeted synergy and supported the clinical testing of combinations of BRAF/MEK inhibitors and immune checkpoint inhibitors to improve the activity of upfront anti-melanoma therapies. The first positive phase III results were published in 2020, and triggered the discussion about the benefits, the limitations, as well as the possible implications of combining or sequencing targeted therapies with immune checkpoint inhibitors in everyday practice. Beginning from the interplay of immune/targeted agents within the melanoma microenvironment, this review outlines available information from the retrospective experience up to the late-stage randomized evidence on combinatorial treatments. Many clinical trials are currently underway exploring open questions about optimal timing, new immune biomarkers, and eligible patient subsets for these immune/targeted regimens. Awaiting these results, decision making in the first-line setting for BRAF-mutant melanoma is still guided by the patients' characteristics and the biological aspects of melanoma.
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Affiliation(s)
- Dimitrios C Ziogas
- School of Medicine, First Department of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, 75, Mikras Asias str., Goudi, 11527, Athens, Greece
| | - Frosso Konstantinou
- School of Medicine, First Department of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, 75, Mikras Asias str., Goudi, 11527, Athens, Greece
| | - Spyros Bouros
- School of Medicine, First Department of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, 75, Mikras Asias str., Goudi, 11527, Athens, Greece
| | - Maria Theochari
- School of Medicine, First Department of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, 75, Mikras Asias str., Goudi, 11527, Athens, Greece
| | - Helen Gogas
- School of Medicine, First Department of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, 75, Mikras Asias str., Goudi, 11527, Athens, Greece.
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27
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Wang Y, Lian B, Cui CL. Long-term control of melanoma brain metastases with co-occurring intracranial infection and involuntary drug reduction during COVID-19 pandemic: A case report. World J Clin Cases 2021; 9:2373-2379. [PMID: 33869616 PMCID: PMC8026827 DOI: 10.12998/wjcc.v9.i10.2373] [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: 11/24/2020] [Revised: 12/27/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Melanoma brain metastasis is a common cause of death in melanoma patients and is associated with a poor prognosis. There are relatively few reports on intracranial infections after brain metastasis resection.
CASE SUMMARY Here we report a case of melanoma brain metastases in a patient harboring a BRAF V600E mutation, who experienced intracranial tumor progression despite previous combined treatment with a programmed death (PD)-1 inhibitor, axitinib, and vemurafenib. She repeatedly underwent local therapy, including stereotactic radiosurgery and intracranial surgery, and developed central nervous system infection. Treatment with vemurafenib combined with cobimetinib resulted in an intracranial progression-free survival of 10 mo. During the coronavirus disease 2019 (COVID-19) pandemic, the patient did not visit the hospital for regular vemurafenib treatment, and experienced intracranial progression after involuntary drug reduction for 1 mo. The patient subsequently received various systemic treatments including vemurafenib, PD-1 inhibitor, and chemotherapy, with an overall survival of 29 mo as of September 2020.
CONCLUSION We report the first case of melanoma brain metastases with co-occurring intracranial infection and unintended drug reduction during the COVID-19 outbreak. Long-term control of the intracranial lesions was achieved with systemic and local therapies.
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Affiliation(s)
- Yang Wang
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Bin Lian
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Chuan-Liang Cui
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China
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28
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Fullmer T, Cabanillas ME, Zafereo M. Novel Therapeutics in Radioactive Iodine-Resistant Thyroid Cancer. Front Endocrinol (Lausanne) 2021; 12:720723. [PMID: 34335481 PMCID: PMC8321684 DOI: 10.3389/fendo.2021.720723] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 06/24/2021] [Indexed: 01/18/2023] Open
Abstract
Iodine-resistant cancers account for the vast majority of thyroid related mortality and, until recently, there were limited therapeutic options. However, over the last decade our understanding of the molecular foundation of thyroid function and carcinogenesis has driven the development of many novel therapeutics. These include FDA approved tyrosine kinase inhibitors and small molecular inhibitors of VEGFR, BRAF, MEK, NTRK and RET, which collectively have significantly changed the prognostic outlook for this patient population. Some therapeutics can re-sensitize de-differentiated cancers to iodine, allowing for radioactive iodine treatment and improved disease control. Remarkably, there is now an FDA approved treatment for BRAF-mutated patients with anaplastic thyroid cancer, previously considered invariably and rapidly fatal. The treatment landscape for iodine-resistant thyroid cancer is changing rapidly with many new targets, therapeutics, clinical trials, and approved treatments. We provide an up-to-date review of novel therapeutic options in the treatment of iodine-resistant thyroid cancer.
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Affiliation(s)
- Tanner Fullmer
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Maria E. Cabanillas
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Mark Zafereo
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- *Correspondence: Mark Zafereo,
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29
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Abstract
PURPOSE OF REVIEW Management of metastasis to the central nervous system (CNS) has evolved, and molecular characterization of metastatic disease is now routinely done. Targeted therapies, once few in number with limited penetration into the CNS, have multiplied in number and increased in CNS coverage. This article addresses recent advances in the evaluation and clinical management of patients with CNS metastasis. RECENT FINDINGS Metastasis of cancer to the CNS can be diagnosed and characterized with novel techniques, including molecular analyses of the spinal fluid, so-called liquid biopsies. Resected parenchymal CNS metastases are now routinely subjected to genomic sequencing. For patients with CNS metastases displaying targetable mutations, a wide variety of treatment options are available, including deferral of radiation therapy in favor of a trial of an orally bioavailable targeted therapy or immunotherapy. For patients without a molecularly targetable lesion, local treatment in the form of radiation therapy, now most often stereotactic radiosurgery, is supplanting untargeted whole-brain radiation therapy. SUMMARY Technologic advances in diagnosis and management have resulted in new diagnostic and therapeutic approaches to patients with metastasis to the CNS, with resulting improvements in progression-free and overall survival.
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30
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Granados K, Poelchen J, Novak D, Utikal J. Cellular Reprogramming-A Model for Melanoma Cellular Plasticity. Int J Mol Sci 2020; 21:E8274. [PMID: 33167306 PMCID: PMC7663830 DOI: 10.3390/ijms21218274] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 10/29/2020] [Accepted: 10/31/2020] [Indexed: 12/14/2022] Open
Abstract
Cellular plasticity of cancer cells is often associated with phenotypic heterogeneity and drug resistance and thus remains a major challenge for the treatment of melanoma and other types of cancer. Melanoma cells have the capacity to switch their phenotype during tumor progression, from a proliferative and differentiated phenotype to a more invasive and dedifferentiated phenotype. However, the molecular mechanisms driving this phenotype switch are not yet fully understood. Considering that cellular heterogeneity within the tumor contributes to the high plasticity typically observed in melanoma, it is crucial to generate suitable models to investigate this phenomenon in detail. Here, we discuss the use of complete and partial reprogramming into induced pluripotent cancer (iPC) cells as a tool to obtain new insights into melanoma cellular plasticity. We consider this a relevant topic due to the high plasticity of melanoma cells and its association with a strong resistance to standard anticancer treatments.
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Affiliation(s)
- Karol Granados
- Skin Cancer Unit, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany; (K.G.); (J.P.); (D.N.)
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, D-68135 Mannheim, Germany
- Department of Biochemistry, School of Medicine, University of Costa Rica (UCR), Rodrigo Facio Campus, San Pedro Montes Oca, San Jose 2060, Costa Rica
| | - Juliane Poelchen
- Skin Cancer Unit, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany; (K.G.); (J.P.); (D.N.)
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, D-68135 Mannheim, Germany
| | - Daniel Novak
- Skin Cancer Unit, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany; (K.G.); (J.P.); (D.N.)
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, D-68135 Mannheim, Germany
| | - Jochen Utikal
- Skin Cancer Unit, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany; (K.G.); (J.P.); (D.N.)
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, D-68135 Mannheim, Germany
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31
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Soffietti R, Ahluwalia M, Lin N, Rudà R. Management of brain metastases according to molecular subtypes. Nat Rev Neurol 2020; 16:557-574. [PMID: 32873927 DOI: 10.1038/s41582-020-0391-x] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/14/2020] [Indexed: 12/25/2022]
Abstract
The incidence of brain metastases has markedly increased in the past 20 years owing to progress in the treatment of malignant solid tumours, earlier diagnosis by MRI and an ageing population. Although local therapies remain the mainstay of treatment for many patients with brain metastases, a growing number of systemic options are now available and/or are under active investigation. HER2-targeted therapies (lapatinib, neratinib, tucatinib and trastuzumab emtansine), alone or in combination, yield a number of intracranial responses in patients with HER2-positive breast cancer brain metastases. New inhibitors are being investigated in brain metastases from ER-positive or triple-negative breast cancer. Several generations of EGFR and ALK inhibitors have shown activity on brain metastases from EGFR and ALK mutant non-small-cell lung cancer. Immune-checkpoint inhibitors (ICIs) hold promise in patients with non-small-cell lung cancer without druggable mutations and in patients with triple-negative breast cancer. The survival of patients with brain metastases from melanoma has substantially improved after the advent of BRAF inhibitors and ICIs (ipilimumab, nivolumab and pembrolizumab). The combination of targeted agents or ICIs with stereotactic radiosurgery could further improve the response rates and survival but the risk of radiation necrosis should be monitored. Advanced neuroimaging and liquid biopsy will hopefully improve response evaluation.
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Affiliation(s)
- Riccardo Soffietti
- Department of Neuro-Oncology, University and City of Health and Science Hospital, Turin, Italy.
| | - Manmeet Ahluwalia
- Burkhardt Brain Tumor and Neuro-Oncology Center, Taussig Center Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Nancy Lin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Roberta Rudà
- Department of Neuro-Oncology, University and City of Health and Science Hospital, Turin, Italy
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32
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Li ZN, Zhao L, Yu LF, Wei MJ. BRAF and KRAS mutations in metastatic colorectal cancer: future perspectives for personalized therapy. Gastroenterol Rep (Oxf) 2020; 8:192-205. [PMID: 32665851 PMCID: PMC7333923 DOI: 10.1093/gastro/goaa022] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/02/2020] [Accepted: 04/09/2020] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide and 30% of patients with CRC experience metastasis. Patients with metastatic colorectal cancer (mCRC) have a 5-year overall survival rate of <10%. V-raf murine sarcoma viral oncogene homolog B1 (BRAF) and V-Ki-ras2 Kirsten ratsarcoma viral oncogene homolog (KRAS) mutations are mostly studied in mCRC, as clinical trials found that first-line chemotherapy with anti-epidermal growth factor receptor agent confers limited efficacy for mCRC. Treatment decisions for early-stage mCRC do not consider BRAF or KRAS mutations, given the dramatically poor prognosis conferred by these mutations in clinical trials. Thus, it is necessary to identify patients with mCRC harboring BRAF or KRAS mutations to formulate rational therapeutic strategies to improve prognosis and survival. BRAF and KRAS mutations occur in ∼10% and ∼44% of patients with mCRC, respectively. Although the survival rate of patients with mCRC has improved in recent years, the response and prognosis of patients with the aforementioned mutations are still poor. There is a substantial unmet need for prospective personalized therapies for patients with BRAF- or KRAS-mutant mCRC. In this review, we focus on BRAF and KRAS mutations to understand the mechanisms underlying resistance and improving the response rate, outcomes, and prognosis of patients with mCRC bearing these mutations and to discuss prospective personalized therapies for BRAF- and KRAS-mutant mCRC.
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Affiliation(s)
- Zi-Nan Li
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, P. R. China.,Liaoning Engineering Technology Research Center, China Medical University, Shenyang, Liaoning, P. R. China
| | - Lin Zhao
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, P. R. China.,Liaoning Engineering Technology Research Center, China Medical University, Shenyang, Liaoning, P. R. China
| | - Li-Feng Yu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, P. R. China.,Liaoning Engineering Technology Research Center, China Medical University, Shenyang, Liaoning, P. R. China
| | - Min-Jie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, P. R. China.,Liaoning Engineering Technology Research Center, China Medical University, Shenyang, Liaoning, P. R. China
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Medina BD, Choi BH, Rodogiannis KG, Moran U, Shapiro RL, Pavlick A, Osman I, Berman RS, Lee AY. Metastasectomy for melanoma is associated with improved overall survival in responders to targeted molecular or immunotherapy. J Surg Oncol 2020; 122:555-561. [DOI: 10.1002/jso.25987] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 05/11/2020] [Indexed: 12/12/2022]
Affiliation(s)
- Benjamin D. Medina
- Division of Surgical Oncology, Department of Surgery New York University Langone Health New York New York
| | - Beatrix Hyemin Choi
- Division of Surgical Oncology, Department of Surgery New York University Langone Health New York New York
| | - Kathy G. Rodogiannis
- Interdisciplinary Melanoma Cooperative Group New York University Langone Health New York New York
| | - Una Moran
- Interdisciplinary Melanoma Cooperative Group New York University Langone Health New York New York
- Ronald O. Perelman Department of Dermatology New York University Langone Health New York New York
| | - Richard L. Shapiro
- Division of Surgical Oncology, Department of Surgery New York University Langone Health New York New York
- Interdisciplinary Melanoma Cooperative Group New York University Langone Health New York New York
| | - Anna Pavlick
- Interdisciplinary Melanoma Cooperative Group New York University Langone Health New York New York
- Division of Hematology and Oncology, Department of Medicine New York University Langone Health New York New York
| | - Iman Osman
- Interdisciplinary Melanoma Cooperative Group New York University Langone Health New York New York
- Ronald O. Perelman Department of Dermatology New York University Langone Health New York New York
| | - Russell S. Berman
- Division of Surgical Oncology, Department of Surgery New York University Langone Health New York New York
- Interdisciplinary Melanoma Cooperative Group New York University Langone Health New York New York
| | - Ann Y. Lee
- Division of Surgical Oncology, Department of Surgery New York University Langone Health New York New York
- Interdisciplinary Melanoma Cooperative Group New York University Langone Health New York New York
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Spillane AJ, Menzies AM, van Akkooi ACJ. The Landmark Series: Neoadjuvant Systemic Therapy (NAST) for Stage 3 Melanoma Patients - A Potential Paradigm Shift in Management. Ann Surg Oncol 2020; 27:2188-2200. [PMID: 32409966 DOI: 10.1245/s10434-020-08566-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Indexed: 12/22/2022]
Abstract
Since the advent of effective systemic therapy, quantum changes have occurred in the multidisciplinary management strategies used for patients with American Joint Committee on Cancer stages 3 and 4 melanoma. For high-risk stage 3 patients, neoadjuvant immune checkpoint blockade (ICB) and targeted therapies present a promising novel approach to improving survival outcomes. In particular, patients who respond to ICB have an excellent prognosis, and clinical trials are ongoing to investigate whether those with a pathologic complete response (pCR) or near-pCR in a single node may avoid therapeutic lymph node dissection and adjuvant therapy. Toxicities currently are acceptably low, but when toxic events occur, they can have an enduring impact on a patient's quality of life. To date, nearly all patients evaluated after treatment with neoadjuvant dabrafenib plus trametinib have some clinical and pathologic response. Patients who achieve pCR have improved prognosis, but pCR is not as reliable a predictor of improved outcome as pCR or near-pCR after neoadjuvant ICB. Ongoing studies should ideally be coordinated through the International Neoadjuvant Melanoma Consortium to ensure maximal efficiency at improving outcomes for melanoma patients.
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Affiliation(s)
- Andrew J Spillane
- Faculty of Medicine and Health, The University of Sydney, North Sydney, NSW, Australia. .,Melanoma Institute Australia, The University of Sydney, Sydney, Australia. .,Mater Hospital Sydney, Sydney, Australia. .,Royal North Shore Hospital, Sydney, Australia.
| | - Alexander M Menzies
- Faculty of Medicine and Health, The University of Sydney, North Sydney, NSW, Australia.,Melanoma Institute Australia, The University of Sydney, Sydney, Australia.,Mater Hospital Sydney, Sydney, Australia.,Royal North Shore Hospital, Sydney, Australia
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Ali A, Dumbrava M, Riddell K, Stewart N, Ward R, Ibrahim AK, Chin M. Correlation between initial tumour volume and treatment duration on Dabrafenib: observation study of subjects with BRAF mutant melanoma on the BRF112680 trial. BMC Cancer 2020; 20:342. [PMID: 32321474 PMCID: PMC7179008 DOI: 10.1186/s12885-020-06848-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 04/07/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Planar-based measurements of lesions in metastatic melanoma have limitations in estimating tumor burden of a patient and in predicting response to treatment. Volumetric imaging might add predictive value to Response criteria in Solid Tumor (RECIST)-measurement. Based on clinical observations, we explored the association between baseline tumor volume (TV) and duration of treatment with dabrafenib in patients with metastatic melanoma. We have also explored the prognostic value of TV for overall survival (OS) and progression free survival (PFS). METHODS This is a retrospective, chart-review of primary source documents and medical imaging of a cohort of patients participating in the BRF112680 phase 1 clinical trial at the Prince of Wales Hospital. TV was quantified by contouring all the measurable baseline target lesions in the standard manner for radiation planning using Voxxar™ software. We used Cox regression models to analyse associations between TV and duration of treatment with dabrafenib and between TV, PFS and OS. RESULTS Among 13 patients of BRAF 112680 trial, 10 were included in the retrospective analysis. Target lesion sum volume ranged from 0.3 to 1065.5 cm3 (cc), with a median of 27.5 cc. The median PFS and OS were 420 days (range 109-1765) and 1680 days (range 390-2940), respectively. The initial TV was inversely correlated with duration of treatment with dabrafenib (rho - 0.6; P 0.03). In multivariate analysis, TV was a predictor for OS (HR 2.81 CI 1.06-6.19) and PFS (8.76 (CI 1.05-43.58). Patients with tumour volume above the median had significantly lower OS of 6-months compared to 56-months survival for patients with smaller volumes; P = 0.019. CONCLUSIONS TV is a predictor for treatment duration and is prognostic of OS and PFS in patients with metastatic melanoma. These findings need to be validated prospectively in clinical trials.
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Affiliation(s)
- Arwa Ali
- Medical Oncology, Nelune Comprehensive Cancer Centre/The Bright Alliance Building, Prince Of Wales Hospital, Randwick, NSW, 2031, Australia. .,Medical Oncology Department, South Egypt Cancer Institute, Assiut University, Asyut, Egypt.
| | - Monica Dumbrava
- Medical Oncology Department, North West Regional Hospital, Burnie, Tasmania, Australia
| | - Kylie Riddell
- GlaxoSmithKline Research and Development, Ermington, Australia
| | - Nina Stewart
- Radiation Oncology Department, Fiona Stanley Hospital, Murdoch, WA, Australia
| | - Robyn Ward
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Ahmed K Ibrahim
- Community Health School, Faculty of Medicine, Assiut University, Asyut, Egypt
| | - Melvin Chin
- Medical Oncology, Nelune Comprehensive Cancer Centre/The Bright Alliance Building, Prince Of Wales Hospital, Randwick, NSW, 2031, Australia
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