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1. Neoadjuvant pembrolizumab, dabrafenib and trametinib in BRAFV600-mutant resectable melanoma: the randomized phase 2 NeoTrio trial

Author

Long, Georgina V., Carlino, Matteo S., Au-Yeung, George, Spillane, Andrew J., Shannon, Kerwin F., Gyorki, David E., Hsiao, Edward, Kapoor, Rony, Thompson, Jake R., Batula, Iris, Howle, Julie, Ch’ng, Sydney, Gonzalez, Maria, Saw, Robyn P. M., Pennington, Thomas E., Lo, Serigne N., Scolyer, Richard A., and Menzies, Alexander M.

Published
2024
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5. Interobserver agreement in the histopathological classification of desmoplastic melanomas.

Author

Lezcano, Cecilia, Berwick, Marianne, Luo, Li, Barnhill, Raymond, Duncan, Lyn, Gerami, Pedram, Lowe, Lori, Messina, Jane, Scolyer, Richard, Wood, Benjamin, Yeh, Iwei, Zembowicz, Artur, and Busam, Klaus

Subjects
Desmoplastic, angiotropism, melanoma, mixed, neurotropism, pure, Humans, Skin Neoplasms, Observer Variation, Melanoma, Prognosis
Abstract

Desmoplastic melanoma is a subtype of melanoma characterised by amelanotic fusiform melanocytes dispersed in a collagenous stroma. Cell-poor and fibrous stroma-rich pure variants have been distinguished from mixed variants with areas of higher cell density and/or less desmoplastic stroma. This distinction is relevant because patients whose tumours display a pure phenotype have a lower risk for regional lymph node metastasis and distant recurrence. However, little is known about interobserver agreement among pathologists in the subclassification of desmoplastic melanoma. To address this issue, we conducted a study in which eleven dermatopathologists independently evaluated whole slide scanned images of excisions from 30 desmoplastic melanomas. The participating pathologists were asked to classify the tumours as pure or mixed. They were also asked to record the presence or absence of neurotropism and angiotropism. We found substantial interobserver agreement between the 11 dermatopathologists in the classification of tumours as pure versus mixed desmoplastic melanoma (kappa=0.64; p

Published
2023

6. Clinical Features Associated with Outcomes and Biomarker Analysis of Dabrafenib plus Trametinib Treatment in Patients with BRAF-Mutant Melanoma Brain Metastases.

Author

Wilmott, James, Tawbi, Hussein, Engh, Johnathan, Amankulor, Nduka, Shivalingam, Brindha, Banerjee, Hiya, Vergara, Ismael, Lee, Hansol, Johansson, Peter, Ferguson, Peter, Saiag, Philippe, Robert, Caroline, Grob, Jean-Jacques, Scolyer, Richard, Kirkwood, John, Long, Georgina, Davies, Michael, and Butterfield, Lisa

Subjects
Humans, Proto-Oncogene Proteins B-raf, Melanoma, Oximes, Pyridones, Brain Neoplasms, Biomarkers, Antineoplastic Combined Chemotherapy Protocols, Mutation, Skin Neoplasms
Abstract

PURPOSE: This study aimed to identify baseline clinical features associated with the outcomes of patients enrolled in the COMBI-MB phase II study of dabrafenib and trametinib treatment in patients with V600 BRAF-mutant metastatic melanoma with melanoma brain metastases (MBM). Exploratory biomarker analysis was also conducted as part of the synergistic COMBI-BRV trial (BRV116521), to identify molecular and immunologic changes associated with dabrafenib in MBMs and extracranial metastases (ECM). PATIENTS AND METHODS: Post hoc analysis was performed for baseline features of patients (n = 125) enrolled in COMBI-MB. Analyses were performed to identify baseline clinical features associated with intracranial response rate (ICRR), progression-free survival (PFS), and overall survival (OS). UNLABELLED: Exploratory biomarker analysis was performed on biospecimen collected in the COMBI-BRV trial in which patients with BRAF-mutant, resectable MBM were treated with dabrafenib for 10 to 14 days prior to craniotomy. Accessible ECM were resected or biopsied at the time of craniotomy. Biospecimens underwent molecular and immunologic profiling for comparative analyses. RESULTS: In COMBI-MB baseline treatment with corticosteroids was independently associated with lower ICRR [39% vs. 63%; OR, 0.323; 95 % confidence interval (CI), 0.105-0.996; P = 0.049] and shorter PFS (HR, 1.93; 95% CI, 1.06-3.51; P = 0.031). Additional significant associations identified in the multivariate analysis were improved PFS in patients with a BRAFV600E genotype (HR, 0.565; 95% CI, 0.321-0.996; P = 0.048) and improved OS in patients with Eastern Cooperative Oncology Group 0 (HR, 0.44; 95% CI, 0.25-0.78; P = 0.005). CONCLUSIONS: Corticosteroid treatment was associated with reduced ICRR and PFS in COMBI-MB, similar to results with immunotherapy for MBMs. Baseline corticosteroid treatment is a key factor to consider in MBM patient management and clinical trial design/interpretation.

Published
2023

7. Revision of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis Classification Schema for Melanocytic Lesions

Author

Barnhill, Raymond L, Elder, David E, Piepkorn, Michael W, Knezevich, Stevan R, Reisch, Lisa M, Eguchi, Megan M, Bastian, Boris C, Blokx, Willeke, Bosenberg, Marcus, Busam, Klaus J, Carr, Richard, Cochran, Alistair, Cook, Martin G, Duncan, Lyn M, Elenitsas, Rosalie, de la Fouchardière, Arnaud, Gerami, Pedram, Johansson, Iva, Ko, Jennifer, Landman, Gilles, Lazar, Alexander J, Lowe, Lori, Massi, Daniela, Messina, Jane, Mihic-Probst, Daniela, Parker, Douglas C, Schmidt, Birgitta, Shea, Christopher R, Scolyer, Richard A, Tetzlaff, Michael, Xu, Xiaowei, Yeh, Iwei, Zembowicz, Artur, and Elmore, Joann G

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Clinical Research, Cancer, Humans, Skin Neoplasms, Melanoma, Pathologists, Consensus, Health Facilities, Biomedical and clinical sciences, Health sciences
Abstract

ImportanceA standardized pathology classification system for melanocytic lesions is needed to aid both pathologists and clinicians in cataloging currently existing diverse terminologies and in the diagnosis and treatment of patients. The Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) has been developed for this purpose.ObjectiveTo revise the MPATH-Dx version 1.0 classification tool, using feedback from dermatopathologists participating in the National Institutes of Health-funded Reducing Errors in Melanocytic Interpretations (REMI) Study and from members of the International Melanoma Pathology Study Group (IMPSG).Evidence reviewPracticing dermatopathologists recruited from 40 US states participated in the 2-year REMI study and provided feedback on the MPATH-Dx version 1.0 tool. Independently, member dermatopathologists participating in an IMPSG workshop dedicated to the MPATH-Dx schema provided additional input for refining the MPATH-Dx tool. A reference panel of 3 dermatopathologists, the original authors of the MPATH-Dx version 1.0 tool, integrated all feedback into an updated and refined MPATH-Dx version 2.0.FindingsThe new MPATH-Dx version 2.0 schema simplifies the original 5-class hierarchy into 4 classes to improve diagnostic concordance and to provide more explicit guidance in the treatment of patients. This new version also has clearly defined histopathological criteria for classification of classes I and II lesions; has specific provisions for the most frequently encountered low-cumulative sun damage pathway of melanoma progression, as well as other, less common World Health Organization pathways to melanoma; provides guidance for classifying intermediate class II tumors vs melanoma; and recognizes a subset of pT1a melanomas with very low risk and possible eventual reclassification as neoplasms lacking criteria for melanoma.Conclusions and relevanceThe implementation of the newly revised MPATH-Dx version 2.0 schema into clinical practice is anticipated to provide a robust tool and adjunct for standardized diagnostic reporting of melanocytic lesions and management of patients to the benefit of both health care practitioners and patients.

Published
2023

9. Uncovering the complex relationship between balding, testosterone and skin cancers in men

Author

Ong, Jue-Sheng, Seviiri, Mathias, Dusingize, Jean Claude, Wu, Yeda, Han, Xikun, Shi, Jianxin, Olsen, Catherine M., Neale, Rachel E., Thompson, John F., Saw, Robyn P. M., Shannon, Kerwin F., Mann, Graham J., Martin, Nicholas G., Medland, Sarah E., Gordon, Scott D., Scolyer, Richard A., Long, Georgina V., Iles, Mark M., Landi, Maria Teresa, Whiteman, David C., MacGregor, Stuart, and Law, Matthew H.

Published
2023
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10. Cross-platform comparison of immune signatures in immunotherapy-treated patients with advanced melanoma using a rank-based scoring approach

Author

Mao, Yizhe, Gide, Tuba N., Adegoke, Nurudeen A., Quek, Camelia, Maher, Nigel, Potter, Alison, Patrick, Ellis, Saw, Robyn P. M., Thompson, John F., Spillane, Andrew J., Shannon, Kerwin F., Carlino, Matteo S., Lo, Serigne N., Menzies, Alexander M., da Silva, Inês Pires, Long, Georgina V., Scolyer, Richard A., and Wilmott, James S.

Published
2023
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12. Neoadjuvant immunotherapy for melanoma is now ready for clinical practice

Author

Garbe, Claus, Dummer, Reinhard, Amaral, Teresa, Amaria, Rodabe N., Ascierto, Paolo A., Burton, Elizabeth M., Dreno, Brigitte, Eggermont, Alexander M. M., Hauschild, Axel, Hoeller, Christoph, Kaufmann, Roland, Lebbe, Celeste, Mandala, Mario, Menzies, Alexander M., Moreno, David, Michielin, Olivier, Nathan, Paul, Patel, Sapna P., Robert, Caroline, Schadendorf, Dirk, Lorigan, Paul C., Scolyer, Richard A., Tawbi, Hussein A., van de Wiel, Bart A., Blank, Christian, and Long, Georgina V.

Published
2023
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13. Comparison of humans versus mobile phone-powered artificial intelligence for the diagnosis and management of pigmented skin cancer in secondary care: a multicentre, prospective, diagnostic, clinical trial

Author

Menzies, Scott W, Sinz, Christoph, Menzies, Michelle, Lo, Serigne N, Yolland, William, Lingohr, Johann, Razmara, Majid, Tschandl, Philipp, Guitera, Pascale, Scolyer, Richard A, Boltz, Florentina, Borik-Heil, Liliane, Herbert Chan, Hsien, Chromy, David, Coker, David J, Collgros, Helena, Eghtedari, Maryam, Corral Forteza, Marina, Forward, Emily, Gallo, Bruna, Geisler, Stephanie, Gibson, Matthew, Hampel, Amelie, Ho, Genevieve, Junez, Laura, Kienzl, Philipp, Martin, Arthur, Moloney, Fergal J, Regio Pereira, Amanda, Ressler, Julia Maria, Richter, Susanne, Silic, Katharina, Silly, Thomas, Skoll, Michael, Tittes, Julia, Weber, Philipp, Weninger, Wolfgang, Weiss, Doris, Woo-Sampson, Ping, Zilberg, Catherine, and Kittler, Harald

Published
2023
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14. L1CAM and laminin vascular network: Association with the high-risk replacement histopathologic growth pattern in uveal melanoma liver metastases

Author

Barnhill, Raymond, van Laere, Steven, Vermeulen, Peter, Roman-Roman, Sergio, Gardrat, Sophie, Alsafadi, Samar, Tarin, Malcy, Champenois, Gabriel, Nicolas, André, Matet, Alexandre, Cassoux, Nathalie, Servois, Vincent, Rodrigues, Manuel, Scolyer, Richard, Lazar, Alexander, Romano, Emanuela, Piperno-Neumann, Sophie, Mariani, Pascale, and Lugassy, Claire

Published
2022
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15. Diet-driven microbial ecology underpins associations between cancer immunotherapy outcomes and the gut microbiome

Author

Simpson, Rebecca C., Shanahan, Erin R., Batten, Marcel, Reijers, Irene L. M., Read, Mark, Silva, Ines P., Versluis, Judith M., Ribeiro, Rosilene, Angelatos, Alexandra S., Tan, Jian, Adhikari, Chandra, Menzies, Alexander M., Saw, Robyn P. M., Gonzalez, Maria, Shannon, Kerwin F., Spillane, Andrew J., Velickovic, Rebecca, Lazar, Alexander J., Damania, Ashish V., Mishra, Aditya K., Chelvanambi, Manoj, Banerjee, Anik, Ajami, Nadim J., Wargo, Jennifer A., Macia, Laurence, Holmes, Andrew J., Wilmott, James S., Blank, Christian U., Scolyer, Richard A., and Long, Georgina V.

Published
2022
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17. Prognostic Gene Expression Profiling in Cutaneous Melanoma

Author

Grossman, Douglas, Okwundu, Nwanneka, Bartlett, Edmund K, Marchetti, Michael A, Othus, Megan, Coit, Daniel G, Hartman, Rebecca I, Leachman, Sancy A, Berry, Elizabeth G, Korde, Larissa, Lee, Sandra J, Bar-Eli, Menashe, Berwick, Marianne, Bowles, Tawnya, Buchbinder, Elizabeth I, Burton, Elizabeth M, Chu, Emily Y, Curiel-Lewandrowski, Clara, Curtis, Julia A, Daud, Adil, Deacon, Dekker C, Ferris, Laura K, Gershenwald, Jeffrey E, Grossmann, Kenneth F, Hu-Lieskovan, Siwen, Hyngstrom, John, Jeter, Joanne M, Judson-Torres, Robert L, Kendra, Kari L, Kim, Caroline C, Kirkwood, John M, Lawson, David H, Leming, Philip D, Long, Georgina V, Marghoob, Ashfaq A, Mehnert, Janice M, Ming, Michael E, Nelson, Kelly C, Polsky, David, Scolyer, Richard A, Smith, Eric A, Sondak, Vernon K, Stark, Mitchell S, Stein, Jennifer A, Thompson, John A, Thompson, John F, Venna, Suraj S, Wei, Maria L, and Swetter, Susan M

Subjects
Cancer, Clinical Research, Patient Safety, Prevention, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Good Health and Well Being, Clinical Decision-Making, Consensus, Consensus Development Conferences as Topic, Gene Expression Profiling, Humans, Melanoma, Neoplasm Staging, Practice Guidelines as Topic, Prognosis, Sentinel Lymph Node Biopsy, Skin Neoplasms, Clinical Sciences, Oncology and Carcinogenesis
Abstract

ImportanceUse of prognostic gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care.ObjectiveTo develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies.Evidence reviewThe MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed.FindingsThe MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility.Conclusions and relevanceMore evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.

Published
2020

18. Hypoxia Controls the Glycome Signature and Galectin-8–Ligand Axis to Promote Protumorigenic Properties of Metastatic Melanoma

Author

Chakraborty, Asmi, Perez, Mariana, Carroll, Jordan D., Antonopoulos, Aristotelis, Dell, Anne, Ortega, Liettel, Mohammed, Norhan B.B., Wells, Michael, Staudinger, Caleb, Griswold, Anthony, Chandler, Kevin B., Marrero, Cristina, Jimenez, Ramon, Tani, Yoshihiko, Wilmott, James S., Thompson, John F., Wang, Wei, Sackstein, Robert, Scolyer, Richard A., Murphy, George F., Haslam, Stuart M., and Dimitroff, Charles J.

Published
2023
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20. Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma

Author

Menzies, Alexander M., primary, Lo, Serigne N., additional, Saw, Robyn P.M., additional, Gonzalez, Maria, additional, Ch’ng, Sydney, additional, Nieweg, Omgo E., additional, Shannon, Kerwin F., additional, Ferguson, Peter M., additional, Lee, Jenny, additional, Emmett, Louise, additional, Kapoor, Rony, additional, Rawson, Robert V., additional, Stretch, Jonathan R., additional, Thompson, John F., additional, Spillane, Andrew J., additional, Rizos, Helen, additional, Scolyer, Richard A., additional, and Long, Georgina V., additional

Published
2024
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21. Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial

Author

Reijers, Irene L. M., Menzies, Alexander M., van Akkooi, Alexander C. J., Versluis, Judith M., van den Heuvel, Noëlle M. J., Saw, Robyn P. M., Pennington, Thomas E., Kapiteijn, Ellen, van der Veldt, Astrid A. M., Suijkerbuijk, Karijn P. M., Hospers, Geke A. P., Rozeman, Elisa A., Klop, Willem M. C., van Houdt, Winan J., Sikorska, Karolina, van der Hage, Jos A., Grünhagen, Dirk J., Wouters, Michel W., Witkamp, Arjen J., Zuur, Charlotte L., Lijnsvelt, Judith M., Torres Acosta, Alejandro, Grijpink-Ongering, Lindsay G., Gonzalez, Maria, Jóźwiak, Katarzyna, Bierman, Carolien, Shannon, Kerwin F., Ch’ng, Sydney, Colebatch, Andrew J., Spillane, Andrew J., Haanen, John B. A. G., Rawson, Robert V., van de Wiel, Bart A., van de Poll-Franse, Lonneke V., Scolyer, Richard A., Boekhout, Annelies H., Long, Georgina V., and Blank, Christian U.

Published
2022
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22. Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets.

Author

Newell, Felicity, Kong, Yan, Wilmott, James S, Johansson, Peter A, Ferguson, Peter M, Cui, Chuanliang, Li, Zhongwu, Kazakoff, Stephen H, Burke, Hazel, Dodds, Tristan J, Patch, Ann-Marie, Nones, Katia, Tembe, Varsha, Shang, Ping, van der Weyden, Louise, Wong, Kim, Holmes, Oliver, Lo, Serigne, Leonard, Conrad, Wood, Scott, Xu, Qinying, Rawson, Robert V, Mukhopadhyay, Pamela, Dummer, Reinhard, Levesque, Mitchell P, Jönsson, Göran, Wang, Xuan, Yeh, Iwei, Wu, Hong, Joseph, Nancy, Bastian, Boris C, Long, Georgina V, Spillane, Andrew J, Shannon, Kerwin F, Thompson, John F, Saw, Robyn PM, Adams, David J, Si, Lu, Pearson, John V, Hayward, Nicholas K, Waddell, Nicola, Mann, Graham J, Guo, Jun, and Scolyer, Richard A

Subjects
Melanocytes, Humans, Melanoma, Telomerase, Signal Transduction, Point Mutation, Female, Male, Cyclin-Dependent Kinase 4, Proto-Oncogene Proteins c-mdm2, DNA Copy Number Variations, Biomarkers, Tumor, Whole Genome Sequencing, Biomarkers, Tumor
Abstract

Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.

Published
2019

23. LNK suppresses interferon signaling in melanoma.

Author

Ding, Ling-Wen, Sun, Qiao-Yang, Edwards, Jarem J, Fernández, Lucia Torres, Ran, Xue-Bin, Zhou, Si-Qin, Scolyer, Richard A, Wilmott, James S, Thompson, John F, Doan, Ngan, Said, Jonathan W, Venkatachalam, Nachiyappan, Xiao, Jin-Fen, Loh, Xin-Yi, Pein, Maren, Xu, Liang, Mullins, David W, Yang, Henry, Lin, De-Chen, and Koeffler, H Phillip

Subjects
Cell Line, Tumor, Animals, Mice, Inbred C57BL, Mice, Inbred NOD, Humans, Mice, Mice, SCID, Melanoma, Skin Neoplasms, Intracellular Signaling Peptides and Proteins, Proteins, Interferons, Xenograft Model Antitumor Assays, Apoptosis, STAT1 Transcription Factor, HEK293 Cells, Cell Cycle Checkpoints, Membrane Proteins, Cell Line, Tumor, Inbred C57BL, Inbred NOD, SCID
Abstract

LNK (SH2B3) is a key negative regulator of JAK-STAT signaling which has been extensively studied in malignant hematopoietic diseases. We found that LNK is significantly elevated in cutaneous melanoma; this elevation is correlated with hyperactive signaling of the RAS-RAF-MEK pathway. Elevated LNK enhances cell growth and survival in adverse conditions. Forced expression of LNK inhibits signaling by interferon-STAT1 and suppresses interferon (IFN) induced cell cycle arrest and cell apoptosis. In contrast, silencing LNK expression by either shRNA or CRISPR-Cas9 potentiates the killing effect of IFN. The IFN-LNK signaling is tightly regulated by a negative feedback mechanism; melanoma cells exposed to IFN upregulate expression of LNK to prevent overactivation of this signaling pathway. Our study reveals an unappreciated function of LNK in melanoma and highlights the critical role of the IFN-STAT1-LNK signaling axis in this potentially devastating disease. LNK may be further explored as a potential therapeutic target for melanoma immunotherapy.

Published
2019

25. Multi-Trait Genetic Analysis Identifies Autoimmune Loci Associated with Cutaneous Melanoma

Author

Agee, Michelle, Aslibekyan, Stella, Auton, Adam, Babalola, Elizabeth, Bell, Robert K., Bielenberg, Jessica, Bryc, Katarzyna, Bullis, Emily, Cameron, Briana, Coker, Daniella, Cuellar Partida, Gabriel, Dhamija, Devika, Das, Sayantan, Elson, Sarah L., Filshtein, Teresa, Fletez-Brant, Kipper, Fontanillas, Pierre, Freyman, Will, Gandhi, Pooja M., Heilbron, Karl, Hicks, Barry, Hinds, David A., Huber, Karen E., Jewett, Ethan M., Kleinman, Aaron, Kukar, Katelyn, Lin, Keng-Han, Lowe, Maya, Luff, Marie K., McCreight, Jennifer C., McIntyre, Matthew H., McManus, Kimberly F., Micheletti, Steven J., Moreno, Meghan E., Mountain, Joanna L., Mozaffari, Sahar V., Nandakumar, Priyanka, Noblin, Elizabeth S., O'Connell, Jared, Petrakovitz, Aaron A., Poznik, G. David, Shastri, Anjali J., Shelton, Janie F., Shi, Jingchunzi, Shringarpure, Suyash, Tran, Vinh, Tung, Joyce Y., Wang, Xin, Wang, Wei, Weldon, Catherine H., Wilton, Peter, Liyanage, Upekha E., MacGregor, Stuart, Bishop, D. Timothy, Shi, Jianxin, An, Jiyuan, Ong, Jue Sheng, Han, Xikun, Scolyer, Richard A., Martin, Nicholas G., Medland, Sarah E., Byrne, Enda M., Green, Adèle C., Saw, Robyn P.M., Thompson, John F., Stretch, Jonathan, Spillane, Andrew, Jiang, Yunxuan, Tian, Chao, Gordon, Scott G., Duffy, David L., Olsen, Catherine M., Whiteman, David C., Long, Georgina V., Iles, Mark M., Landi, Maria Teresa, and Law, Matthew H.

Published
2022
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26. Anatomic position determines oncogenic specificity in melanoma

Author

Weiss, Joshua M., Hunter, Miranda V., Cruz, Nelly M., Baggiolini, Arianna, Tagore, Mohita, Ma, Yilun, Misale, Sandra, Marasco, Michelangelo, Simon-Vermot, Theresa, Campbell, Nathaniel R., Newell, Felicity, Wilmott, James S., Johansson, Peter A., Thompson, John F., Long, Georgina V., Pearson, John V., Mann, Graham J., Scolyer, Richard A., Waddell, Nicola, Montal, Emily D., Huang, Ting-Hsiang, Jonsson, Philip, Donoghue, Mark T. A., Harris, Christopher C., Taylor, Barry S., Xu, Tianhao, Chaligné, Ronan, Shliaha, Pavel V., Hendrickson, Ronald, Jungbluth, Achim A., Lezcano, Cecilia, Koche, Richard, Studer, Lorenz, Ariyan, Charlotte E., Solit, David B., Wolchok, Jedd D., Merghoub, Taha, Rosen, Neal, Hayward, Nicholas K., and White, Richard M.

Published
2022
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28. Author Correction: Tumour gene expression signature in primary melanoma predicts long-term outcomes

Author

Garg, Manik, Couturier, Dominique-Laurent, Nsengimana, Jérémie, Fonseca, Nuno A., Wongchenko, Matthew, Yan, Yibing, Lauss, Martin, Jönsson, Göran B., Newton-Bishop, Julia, Parkinson, Christine, Middleton, Mark R., Bishop, D. Timothy, McDonald, Sarah, Stefanos, Nikki, Tadross, John, Vergara, Ismael A., Lo, Serigne, Newell, Felicity, Wilmott, James S., Thompson, John F., Long, Georgina V., Scolyer, Richard A., Corrie, Pippa, Adams, David J., Brazma, Alvis, and Rabbie, Roy

Published
2022
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30. Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting

Author

Seviiri, Mathias, Scolyer, Richard A., Bishop, D. Timothy, Newton-Bishop, Julia A., Iles, Mark M., Lo, Serigne N., Stretch, Johnathan R., Saw, Robyn P. M., Nieweg, Omgo E., Shannon, Kerwin F., Spillane, Andrew J., Gordon, Scott D., Olsen, Catherine M., Whiteman, David C., Landi, Maria Teresa, Thompson, John F., Long, Georgina V., MacGregor, Stuart, and Law, Matthew H.

Published
2022
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33. High response rate to PD-1 blockade in desmoplastic melanomas.

Author

Eroglu, Zeynep, Zaretsky, Jesse M, Hu-Lieskovan, Siwen, Kim, Dae Won, Algazi, Alain, Johnson, Douglas B, Liniker, Elizabeth, Ben Kong, Munhoz, Rodrigo, Rapisuwon, Suthee, Gherardini, Pier Federico, Chmielowski, Bartosz, Wang, Xiaoyan, Shintaku, I Peter, Wei, Cody, Sosman, Jeffrey A, Joseph, Richard W, Postow, Michael A, Carlino, Matteo S, Hwu, Wen-Jen, Scolyer, Richard A, Messina, Jane, Cochran, Alistair J, Long, Georgina V, and Ribas, Antoni

Subjects
CD8-Positive T-Lymphocytes, Humans, Melanoma, Neurofibromin 1, Biopsy, Immunotherapy, Retrospective Studies, Mutation, Programmed Cell Death 1 Receptor, Cell Cycle Checkpoints, B7-H1 Antigen, Genetics, Human Genome, Cancer, 2.1 Biological and endogenous factors, General Science & Technology
Abstract

Desmoplastic melanoma is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, and is highly associated with ultraviolet light-induced DNA damage. We analysed sixty patients with advanced desmoplastic melanoma who had been treated with antibodies to block programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1). Objective tumour responses were observed in forty-two of the sixty patients (70%; 95% confidence interval 57-81%), including nineteen patients (32%) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF1 mutations (fourteen out of seventeen cases) in these tumours. Immunohistochemistry analysis from nineteen desmoplastic melanomas and thirteen non-desmoplastic melanomas revealed a higher percentage of PD-L1-positive cells in the tumour parenchyma in desmoplastic melanomas (P = 0.04); these cells were highly associated with increased CD8 density and PD-L1 expression in the tumour invasive margin. Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.

Published
2018

34. The Prognostic Significance of Low-Frequency Somatic Mutations in Metastatic Cutaneous Melanoma.

Author

Zhao, Xiaobei, Little, Paul, Hoyle, Alan, Pegna, Guillaume, Hayward, Michele, Ivanova, Anastasia, Parker, Joel, Marron, David, Soloway, Matthew, Jo, Heejoon, Salazar, Ashley, Papakonstantinou, Michael, Bouchard, Deeanna, Jefferys, Stuart, Hoadley, Katherine, Ollila, David, Frank, Jill, Thomas, Nancy, Googe, Paul, Ezzell, Ashley, Collichio, Frances, Lee, Carrie, Earp, H, Sharpless, Norman, Hugo, Willy, Wilmott, James, Quek, Camelia, Waddell, Nicola, Johansson, Peter, Thompson, John, Hayward, Nicholas, Mann, Graham, Lo, Roger, Johnson, Douglas, Scolyer, Richard, Hayes, D, and Moschos, Stergios

Subjects
RAC1, RNA sequencing, SPEN, The Cancer Genome Atlas Project, UV signature, cutaneous melanoma, next generation sequencing, prognostic significance
Abstract

Background: Little is known about the prognostic significance of somatically mutated genes in metastatic melanoma (MM). We have employed a combined clinical and bioinformatics approach on tumor samples from cutaneous melanoma (SKCM) as part of The Cancer Genome Atlas project (TCGA) to identify mutated genes with potential clinical relevance. Methods: After limiting our DNA sequencing analysis to MM samples (n = 356) and to the CANCER CENSUS gene list, we filtered out mutations with low functional significance (snpEFF). We performed Cox analysis on 53 genes that were mutated in ≥3% of samples, and had ≥50% difference in incidence of mutations in deceased subjects versus alive subjects. Results: Four genes were potentially prognostic [RAC1, FGFR1, CARD11, CIITA; false discovery rate (FDR) < 0.2]. We identified 18 additional genes (e.g., SPEN, PDGFRB, GNAS, MAP2K1, EGFR, TSC2) that were less likely to have prognostic value (FDR < 0.4). Most somatic mutations in these 22 genes were infrequent (< 10%), associated with high somatic mutation burden, and were evenly distributed across all exons, except for RAC1 and MAP2K1. Mutations in only 9 of these 22 genes were also identified by RNA sequencing in >75% of the samples that exhibited corresponding DNA mutations. The low frequency, UV signature type and RNA expression of the 22 genes in MM samples were confirmed in a separate multi-institution validation cohort (n = 413). An underpowered analysis within a subset of this validation cohort with available patient follow-up (n = 224) showed that somatic mutations in SPEN and RAC1 reached borderline prognostic significance [log-rank favorable (p = 0.09) and adverse (p = 0.07), respectively]. Somatic mutations in SPEN, and to a lesser extent RAC1, were not associated with definite gene copy number or RNA expression alterations. High (>2+) nuclear plus cytoplasmic expression intensity for SPEN was associated with longer melanoma-specific overall survival (OS) compared to lower (≤ 2+) nuclear intensity (p = 0.048). We conclude that expressed somatic mutations in infrequently mutated genes beyond the well-characterized ones (e.g., BRAF, RAS, CDKN2A, PTEN, TP53), such as RAC1 and SPEN, may have prognostic significance in MM.

Published
2018

35. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Outcomes in histopathologic subgroups from the randomized, double-blind, phase 3 KEYNOTE-716 trial

Author

Schadendorf, Dirk, primary, Luke, Jason John, additional, Ascierto, Paolo A, additional, Long, Georgina V, additional, Rutkowski, Piotr, additional, Khattak, Adnan, additional, Del Vecchio, Michele, additional, de la Cruz-Merino, Luis, additional, Mackiewicz, Jacek, additional, Sileni, Vanna Chiarion, additional, Kirkwood, John M, additional, Robert, Caroline, additional, Grob, Jean-Jacques, additional, Dummer, Reinhard, additional, Carlino, Matteo S, additional, Zhao, Yujie, additional, Kalabis, Mizuho, additional, Krepler, Clemens, additional, Eggermont, Alexander, additional, and Scolyer, Richard A, additional

Published
2024
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36. Health Economic Consequences Associated With COVID-19–Related Delay in Melanoma Diagnosis in Europe

Author

Maul, Lara V., primary, Jamiolkowski, Dagmar, additional, Lapides, Rebecca A., additional, Mueller, Alina M., additional, Hauschild, Axel, additional, Garbe, Claus, additional, Lorigan, Paul, additional, Gershenwald, Jeffrey E., additional, Ascierto, Paolo Antonio, additional, Long, Georgina V., additional, Wang-Evers, Michael, additional, Scolyer, Richard A., additional, Saravi, Babak, additional, Augustin, Matthias, additional, Navarini, Alexander A., additional, Legge, Stefan, additional, Németh, István B., additional, Jánosi, Ágnes J., additional, Mocellin, Simone, additional, Feller, Anita, additional, Manstein, Dieter, additional, Zink, Alexander, additional, Maul, Julia-Tatjana, additional, Buja, Alessandra, additional, Adhikari, Kaustubh, additional, and Roider, Elisabeth, additional

Published
2024
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38. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Outcomes in histopathologic subgroups from the randomized, double-blind, phase 3 KEYNOTE-716 trial

Author

Universidad de Sevilla. Departamento de Medicina, Schadendorf, Dirk, Luke, Jason John, Ascierto, Paolo A., Long, Georgina V., Rutkowski, Piotr, Khattak, Adnan, Cruz Merino, Luis de la, Scolyer, Richard A., Universidad de Sevilla. Departamento de Medicina, Schadendorf, Dirk, Luke, Jason John, Ascierto, Paolo A., Long, Georgina V., Rutkowski, Piotr, Khattak, Adnan, Cruz Merino, Luis de la, and Scolyer, Richard A.

Abstract

Background Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics. Methods Patients aged ≥12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness (≤4 mm vs >4 mm), presence of ulceration (yes vs no), mitotic rate (<5 per mm2 (median) vs ≥5 per mm2), and presence of tumor-infiltrating lymphocytes (TILs; absent vs present). Results Between September 23, 2018, and November 4, 2020, 976 patients were assigned to pembrolizumab (n=487) or placebo (n=489). Median follow-up was 27.4 months (range, 14.0–39.4). The HR (95% CI) for RFS was 0.54 (0.37 to 0.79) for nodular and 0.77 (0.53 to 1.11) for non-nodular melanoma; 0.57 (0.37 to 0.89) for thickness ≤4 mm and 0.69 (0.50 to 0.96) for >4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate <5 per mm2 and 0.57 (0.40 to 0.80) for ≥5 per mm2; and 0.89 (0.52 to 1.54) for TILs absent and 0.51 (0.34 to 0.76) for TILs present. DMFS results were similar. In a Cox multivariate analysis, treatment arm, tumor thickness, and mitotic rate were significant independent factors for RFS, and treatment arm and mitotic rate were significant independent factors for DMFS. Conclusions In this post hoc analysis, the benefit

Published
2024

39. Population-Based Validation of the MIA and MSKCC Tools for Predicting Sentinel Lymph Node Status

Author

Bagge, Roger Olofsson, Mikiver, Rasmus, Marchetti, Michael A., Lo, Serigne N., van Akkooi, Alexander C. J., Coit, Daniel G., Ingvar, Christian, Isaksson, Karolin, Scolyer, Richard A., Thompson, John F., Varey, Alexander H. R., Wong, Sandra L., Lyth, Johan, Bartlett, Edmund K., Bagge, Roger Olofsson, Mikiver, Rasmus, Marchetti, Michael A., Lo, Serigne N., van Akkooi, Alexander C. J., Coit, Daniel G., Ingvar, Christian, Isaksson, Karolin, Scolyer, Richard A., Thompson, John F., Varey, Alexander H. R., Wong, Sandra L., Lyth, Johan, and Bartlett, Edmund K.

Abstract

Importance Patients with melanoma are selected for sentinel lymph node biopsy (SLNB) based on their risk of a positive SLN. To improve selection, the Memorial Sloan Kettering Cancer Center (MSKCC) and Melanoma Institute Australia (MIA) developed predictive models, but the utility of these models remains to be tested.Objective To determine the clinical utility of the MIA and MSKCC models.Design, Setting, and Participants This was a population-based comparative effectiveness research study including 10 089 consecutive patients with cutaneous melanoma undergoing SLNB from the Swedish Melanoma Registry from January 2007 to December 2021. Data were analyzed from May to August 2023.Main Outcomes and Measures, The predicted probability of SLN positivity was calculated using the MSKCC model and a limited MIA model (using mitotic rate as absent/present instead of count/mm(2) and excluding the optional variable lymphovascular invasion) for each patient. The operating characteristics of the models were assessed and compared. The clinical utility of each model was assessed using decision curve analysis and compared with a strategy of performing SLNB on all patients.Results Among 10 089 included patients, the median (IQR) age was 64.0 (52.0-73.0) years, and 5340 (52.9%) were male. The median Breslow thickness was 1.8 mm, and 1802 patients (17.9%) had a positive SLN. Both models were well calibrated across the full range of predicted probabilities and had similar external area under the receiver operating characteristic curves (AUC; MSKCC: 70.8%; 95% CI, 69.5-72.1 and limited MIA: 69.7%; 95% CI, 68.4-71.1). At a risk threshold of 5%, decision curve analysis indicated no added net benefit for either model compared to performing SLNB for all patients. At risk thresholds of 10% or higher, both models added net benefit compared to SLNB for all patients. The greatest benefit was observed in patients with T2 melanomas using a threshold of 10%; in that setting, the use of the nomograms, Funding Agencies|Knut and Alice Wallenberg Foundation

Published
2024
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40. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Outcomes in histopathologic subgroups from the randomized, double-blind, phase 3 KEYNOTE-716 trial

Author

Schadendorf, Dirk; https://orcid.org/0000-0003-3524-7858, Luke, Jason John; https://orcid.org/0000-0002-1182-4908, Ascierto, Paolo A; https://orcid.org/0000-0002-8322-475X, Long, Georgina V; https://orcid.org/0000-0001-8894-3545, Rutkowski, Piotr; https://orcid.org/0000-0002-8920-5429, Khattak, Adnan, Del Vecchio, Michele, de la Cruz-Merino, Luis; https://orcid.org/0000-0002-5333-0535, Mackiewicz, Jacek, Sileni, Vanna Chiarion, Kirkwood, John M; https://orcid.org/0000-0002-3570-4476, Robert, Caroline; https://orcid.org/0000-0002-9493-0238, Grob, Jean-Jacques; https://orcid.org/0000-0002-0667-153X, Dummer, Reinhard; https://orcid.org/0000-0002-2279-6906, Carlino, Matteo S, Zhao, Yujie; https://orcid.org/0000-0003-2896-4955, Kalabis, Mizuho, Krepler, Clemens, Eggermont, Alexander, Scolyer, Richard A; https://orcid.org/0000-0002-8991-0013, Schadendorf, Dirk; https://orcid.org/0000-0003-3524-7858, Luke, Jason John; https://orcid.org/0000-0002-1182-4908, Ascierto, Paolo A; https://orcid.org/0000-0002-8322-475X, Long, Georgina V; https://orcid.org/0000-0001-8894-3545, Rutkowski, Piotr; https://orcid.org/0000-0002-8920-5429, Khattak, Adnan, Del Vecchio, Michele, de la Cruz-Merino, Luis; https://orcid.org/0000-0002-5333-0535, Mackiewicz, Jacek, Sileni, Vanna Chiarion, Kirkwood, John M; https://orcid.org/0000-0002-3570-4476, Robert, Caroline; https://orcid.org/0000-0002-9493-0238, Grob, Jean-Jacques; https://orcid.org/0000-0002-0667-153X, Dummer, Reinhard; https://orcid.org/0000-0002-2279-6906, Carlino, Matteo S, Zhao, Yujie; https://orcid.org/0000-0003-2896-4955, Kalabis, Mizuho, Krepler, Clemens, Eggermont, Alexander, and Scolyer, Richard A; https://orcid.org/0000-0002-8991-0013

Abstract

Background: Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics. Methods: Patients aged ≥12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness (≤4 mm vs >4 mm), presence of ulceration (yes vs no), mitotic rate (<5 per mm$^{2}$(median) vs ≥5 per mm$^{2}$), and presence of tumor-infiltrating lymphocytes (TILs; absent vs present). Results: Between September 23, 2018, and November 4, 2020, 976 patients were assigned to pembrolizumab (n=487) or placebo (n=489). Median follow-up was 27.4 months (range, 14.0–39.4). The HR (95% CI) for RFS was 0.54 (0.37 to 0.79) for nodular and 0.77 (0.53 to 1.11) for non-nodular melanoma; 0.57 (0.37 to 0.89) for thickness ≤4 mm and 0.69 (0.50 to 0.96) for >4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate <5 per mm$^{2}$and 0.57 (0.40 to 0.80) for ≥5 per mm$^{2}$; and 0.89 (0.52 to 1.54) for TILs absent and 0.51 (0.34 to 0.76) for TILs present. DMFS results were similar. In a Cox multivariate analysis, treatment arm, tumor thickness, and mitotic rate were significant independent factors for RFS, and treatment arm and mitotic rate were significant independent factors for DMFS. Conclusions: In this post hoc

Published
2024

41. Predicting Recurrence-Free and Overall Survival for Patients With Stage II Melanoma: The MIA Calculator

Author

Pathologie Groep Van Diest, Pathologie, Cancer, Varey, Alexander H R, Li, Isabel, El Sharouni, Mary-Ann, Simon, Julie, Dedeilia, Aikaterini, Ch'ng, Sydney, Saw, Robyn P M, Spillane, Andrew J, Shannon, Kerwin F, Pennington, Thomas E, Rtshiladze, Michael, Stretch, Jonathan R, Nieweg, Omgo E, van Akkooi, Alexander, Sullivan, Ryan J, Boland, Genevieve M, Gershenwald, Jeffrey E, van Diest, Paul J, Scolyer, Richard A, Long, Georgina V, Thompson, John F, Lo, Serigne N, Pathologie Groep Van Diest, Pathologie, Cancer, Varey, Alexander H R, Li, Isabel, El Sharouni, Mary-Ann, Simon, Julie, Dedeilia, Aikaterini, Ch'ng, Sydney, Saw, Robyn P M, Spillane, Andrew J, Shannon, Kerwin F, Pennington, Thomas E, Rtshiladze, Michael, Stretch, Jonathan R, Nieweg, Omgo E, van Akkooi, Alexander, Sullivan, Ryan J, Boland, Genevieve M, Gershenwald, Jeffrey E, van Diest, Paul J, Scolyer, Richard A, Long, Georgina V, Thompson, John F, and Lo, Serigne N

Published
2024

42. Interferon-gamma signature as prognostic and predictive marker in macroscopic stage III melanoma

Author

Pathologie Pathologen staf, Cancer, MS Medische Oncologie, Infection & Immunity, Versluis, Judith M, Blankenstein, Stephanie A, Dimitriadis, Petros, Wilmott, James S, Elens, Robert, Blokx, Willeke A M, van Houdt, Winan, Menzies, Alexander Maxwell, Schrage, Yvonne M, Wouters, Michel W J M, Sanders, Joyce, Broeks, Annegien, Scolyer, Richard A, Suijkerbuijk, Karijn P M, Long, Georgina V, Akkooi, Alexander C J van, Blank, Christian U, Pathologie Pathologen staf, Cancer, MS Medische Oncologie, Infection & Immunity, Versluis, Judith M, Blankenstein, Stephanie A, Dimitriadis, Petros, Wilmott, James S, Elens, Robert, Blokx, Willeke A M, van Houdt, Winan, Menzies, Alexander Maxwell, Schrage, Yvonne M, Wouters, Michel W J M, Sanders, Joyce, Broeks, Annegien, Scolyer, Richard A, Suijkerbuijk, Karijn P M, Long, Georgina V, Akkooi, Alexander C J van, and Blank, Christian U

Published
2024

43. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Outcomes in histopathologic subgroups from the randomized, double-blind, phase 3 KEYNOTE-716 trial

Author

Schadendorf, Dirk, Luke, Jason J., Ascierto, Paolo A., Long, Georgina V., Rutkowski, Piotr, Khattak, Adnan, Del Vecchio, Michele, De La Cruz-Merino, Luis, Mackiewicz, Jacek, Sileni, Vanna C., Kirkwood, John M., Robert, Caroline, Grob, Jean-Jacques, Dummer, Reinhard, Carlino, Matteo S., Zhao, Yujie, Kalabis, Mizuho, Krepler, Clemens, Eggermont, Alexander, Scolyer, Richard A., Schadendorf, Dirk, Luke, Jason J., Ascierto, Paolo A., Long, Georgina V., Rutkowski, Piotr, Khattak, Adnan, Del Vecchio, Michele, De La Cruz-Merino, Luis, Mackiewicz, Jacek, Sileni, Vanna C., Kirkwood, John M., Robert, Caroline, Grob, Jean-Jacques, Dummer, Reinhard, Carlino, Matteo S., Zhao, Yujie, Kalabis, Mizuho, Krepler, Clemens, Eggermont, Alexander, and Scolyer, Richard A.

Abstract

Background Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics. Methods Patients aged ≥ 12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness ( ≤ 4 mm vs > 4 mm), presence of ulceration (yes vs no), mitotic rate ( < 5 per mm 2 (median) vs ≥ 5 per mm 2), and presence of tumor-infiltrating lymphocytes (TILs; absent vs present). Results Between September 23, 2018, and November 4, 2020, 976 patients were assigned to pembrolizumab (n=487) or placebo (n=489). Median follow-up was 27.4 months (range, 14.0-39.4). The HR (95% CI) for RFS was 0.54 (0.37 to 0.79) for nodular and 0.77 (0.53 to 1.11) for non-nodular melanoma; 0.57 (0.37 to 0.89) for thickness ≤ 4 mm and 0.69 (0.50 to 0.96) for > 4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate < 5 per mm 2 and 0.57 (0.40 to 0.80) for ≥ 5 per mm 2; and 0.89 (0.52 to 1.54) for TILs absent and 0.51 (0.34 to 0.76) for TILs present. DMFS results were similar. In a Cox multivariate analysis, treatment arm, tumor thickness, and mitotic rate were significant independent factors for RFS, and treatment arm and mitotic rate were significant independent factors for DMFS. Conclusions In this post hoc analysi

Published
2024

44. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC)

Author

Menzies, Alexander M., Amaria, Rodabe N., Rozeman, Elisa A., Huang, Alexander C., Tetzlaff, Michael T., van de Wiel, Bart A., Lo, Serigne, Tarhini, Ahmad A., Burton, Elizabeth M., Pennington, Thomas E., Saw, Robyn P. M., Xu, Xiaowei, Karakousis, Giorgos C., Ascierto, Paolo A., Spillane, Andrew J., van Akkooi, Alexander C. J., Davies, Michael A., Mitchell, Tara C., Tawbi, Hussein A., Scolyer, Richard A., Wargo, Jennifer A., Blank, Christian U., and Long, Georgina V.

Published
2021
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50. Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms

Author

Johnson, Douglas B, Menzies, Alexander M, Zimmer, Lisa, Eroglu, Zeynep, Ye, Fei, Zhao, Shilin, Rizos, Helen, Sucker, Antje, Scolyer, Richard A, Gutzmer, Ralf, Gogas, Helen, Kefford, Richard F, Thompson, John F, Becker, Jürgen C, Berking, Carola, Egberts, Friederike, Loquai, Carmen, Goldinger, Simone M, Pupo, Gulietta M, Hugo, Willy, Kong, Xiangju, Garraway, Levi A, Sosman, Jeffrey A, Ribas, Antoni, Lo, Roger S, Long, Georgina V, and Schadendorf, Dirk

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Genetics, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Antineoplastic Agents, Australia, Biomarkers, Tumor, DNA Mutational Analysis, Disease Progression, Disease-Free Survival, Drug Resistance, Neoplasm, Europe, Female, Genetic Predisposition to Disease, Humans, Kaplan-Meier Estimate, Male, Melanoma, Middle Aged, Mutation, Phenotype, Proportional Hazards Models, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Risk Factors, Signal Transduction, Skin Neoplasms, Time Factors, Treatment Outcome, United States, BRAF, Vemurafenib, Dabrafenib, Resistance, Acquired, MAPK, NRAS, Splice, MEK1, Meta-analysis, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundAcquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance.MethodsWe compiled clinical and genetic data from 100 patients with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole-exome sequencing and/or polymerase chain reaction-based genetic testing.ResultsAmong 132 samples, putative resistance mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAF(V600E/K) amplifications (13%), MEK1/2 mutations (7%), and non-mitogen-activated protein kinase pathway alterations (11%). Marked heterogeneity was observed within tumors and patients; 18 of 19 patients (95%) with more than one progression biopsy had distinct/unknown drivers of resistance between samples. NRAS mutations were associated with vemurafenib use (p = 0.045) and intracranial metastases (p = 0.036), and MEK1/2 mutations correlated with hepatic progression (p = 0.011). Progression-free survival and overall survival were similar across resistance mechanisms. The median survival after disease progression was 6.9 months, and responses to subsequent BRAF and MEK inhibition were uncommon (2 of 15; 13%). Post-progression outcomes did not correlate with specific acquired BRAFi-resistance mechanisms.ConclusionsThis is the first study to systematically characterise the clinical implications of particular acquired BRAFi-resistance mechanisms in patients with BRAF-mutant melanoma largest study to compile the landscape of resistance. Despite marked heterogeneity of resistance mechanisms within patients, NRAS mutations correlated with vemurafenib use and intracranial disease involvement.

Published
2015

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