Cancer Research and Treatment

Original Articles

Clinical Outcomes of Immune Checkpoint Blocker Therapy for Malignant Melanoma in Korean Patients: Potential Clinical Implications for a Combination Strategy Involving Radiotherapy: Jeongshim Lee, Jee Suk Chang, Mi Ryung Roh, Minkyu Jung, Choong-Kun Lee, Byung Ho Oh, Kee Yang Chung, Woong Sub Koom, Sang Joon Shin; Cancer Res Treat. 2020;52(3):730-738. Published online February 13, 2020; DOI: https://doi.org/10.4143/crt.2019.598

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Purpose
We investigated the clinical efficacy of immune checkpoint blocker (ICB) therapy for metastatic or advanced melanoma in Korean patients. As well, we assessed whether the effects of ICBs can be enhanced by combination therapy with palliative radiotherapy (RT).
Materials and Methods
We retrospectively reviewed the records of 127 patients with metastatic melanoma who received ICB with or without palliative RT between 2014 and 2018. The melanoma subtypes were classified as follows: chronic sun-damaged (CSD), acral, mucosal, and uveal. The primary endpoint was the objective response rate (ORR).
Results
The overall ORR was 15%, with 11 complete and eight partial responses. ORRs for CSD, acral/mucosal, and uveal melanomas were 50%, 16.5%, and 0%, respectively (p=0.009). In addition to the subtype, stage at treatment, total tumor burden at treatment, and ICB type were significantly associated with ORR (all p < 0.05). Palliative RT was administered in 44% of patients during the treatment, and it did not affect ORR. Clinical responders to ICB therapy exhibited significantly higher 1-year progression-free and overall survival rates than nonresponders.
Conclusion
ORR for ICB monotherapy in Korean patients with melanoma is relatively modest compared with that in Western patients because the non-CSD subtypes are predominant in the Korean population. Our findings regarding combination therapy with ICB provided a rationale for the initiation of our phase II study (NCT04017897).

Citations

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Hydrogels as a Potential Biomaterial for Multimodal Therapeutic Applications
Harpreet Kaur, Bishmita Gogoi, Ira Sharma, Deepak Kumar Das, Mohd Ashif Azad, Devlina Das Pramanik, Arindam Pramanik
Molecular Pharmaceutics.2024; 21(10): 4827. CrossRef
Injectable hydrogels for personalized cancer immunotherapies
Neda Mohaghegh, Amir Ahari, Fatemeh Zehtabi, Claire Buttles, Saya Davani, Hanna Hoang, Kaylee Tseng, Benjamin Zamanian, Safoora Khosravi, Ariella Daniali, Negar Hosseinzadeh Kouchehbaghi, Isabel Thomas, Hamed Serati Nouri, Danial Khorsandi, Reza Abbasghol
Acta Biomaterialia.2023; 172: 67. CrossRef
Efficacy of radiotherapy combined with immune checkpoint inhibitors in patients with melanoma: a systemic review and meta-analysis
Gaofei Yin, Wei Guo, Zhigang Huang, Xiaohong Chen
Melanoma Research.2022; 32(2): 71. CrossRef
The pharmacotherapeutic management of nail unit and acral melanomas
Julianne M. Falotico, Shari R. Lipner
Expert Opinion on Pharmacotherapy.2022; 23(11): 1273. CrossRef
A Comparison of 2 Disease Burden Assessment Methods (3D Volume Versus the Number of Lesions) for Prognostication of Survival in Metastatic Melanoma: Implications for the Characterization of Oligometastatic Disease
Jina Kim, Jee Suk Chang, Wonmo Sung, Jin Sung Kim, Tae Hyung Kim, Seo Hee Choi, Kyung Hwan Kim, Heejoo Ko, Hye Sun Lee, Soyoung Jeon, Sang Joon Shin, Mitchell Liu, Robert Olson
International Journal of Radiation Oncology*Biology*Physics.2022; 114(5): 883. CrossRef
Prediction of Immune-Checkpoint Blockade Monotherapy Response in Patients With Melanoma Based on Easily Accessible Clinical Indicators
Hwa Kyung Byun, Jee Suk Chang, Minkyu Jung, Woong Sub Koom, Kee Yang Chung, Byung Ho Oh, Mi Ryung Roh, Kyung Hwan Kim, Choong-Kun Lee, Sang Joon Shin
Frontiers in Oncology.2021;[Epub] CrossRef
Effectiveness and safety of immune checkpoint inhibitors in combination with palliative radiotherapy in advanced melanoma: A systematic review
Jennifer Ben Shimol, Yuli Guzman-Prado, Maria Karlinskaya, Tima Davidson
Critical Reviews in Oncology/Hematology.2021; 167: 103499. CrossRef

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Genetic Alterations among Korean Melanoma Patients Showing Tumor Heterogeneity: A Comparison between Primary Tumors and Corresponding Metastatic Lesions: Si-Hyung Lee, Jee Eun Kim, Hong Sun Jang, Kyu Hyun Park, Byung Ho Oh, Sang Joon Shin, Kee Yang Chung, Mi Ryung Roh, Sun Young Rha; Cancer Res Treat. 2018;50(4):1378-1387. Published online January 22, 2018; DOI: https://doi.org/10.4143/crt.2017.535

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Purpose
Melanoma is a highly heterogeneous neoplasm, composed of subpopulations of tumor cells with distinct molecular and biological phenotypes and genotypes. In this study, to determine the genetic heterogeneity between primary and metastatic melanoma in Korean melanoma patients, we evaluated several well-known genetic alterations of melanoma. In addition, to elucidate the clinical relevance of each genetic alteration and heterogeneity between primary and metastatic lesions, clinical features and patient outcome were collected.
Materials and Methods
In addition to clinical data, BRAF, NRAS, GNAQ/11 mutation and KIT amplification data was acquired from an archived primary Korean melanoma cohort (KMC) of 188 patients. Among these patients, 43 patients were included for investigation of tumor heterogeneity between primary melanoma and its corresponding metastatic lesions.
Results
Overall incidence of genetic aberrations of the primary melanomas in KMC was 17.6% of BRAF V600, 12.6% of NRAS mutation, and 28.6% of KIT amplification. GNAQ/11 mutation was seen in 66.6% of the uveal melanoma patients. Patients with BRAF mutation were associated with advanced stage and correlated to poor prognosis (p < 0.01). Among 43 patients, 55.8% showed heterogeneity between primary and metastatic lesion. The frequency of BRAF mutation and KIT amplification significantly increased in the metastatic lesions compared to primary melanomas. Conclusion
Our data demonstrated heterogeneity between primary melanomas and corresponding metastatic lesions for BRAF, NRAS mutation and KIT amplification. However, GNAQ/11 mutation was genetically homogeneous between primary and metastatic melanoma lesions in uveal melanoma.

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Elucidation of anti-human melanoma and anti-aging mechanisms of compounds from green seaweed Caulerpa racemosa
Danar Wicaksono, Nurpudji Astuti Taslim, Vincent Lau, Rony Abdi Syahputra, Aiman Idrus Alatas, Purnawan Pontana Putra, Trina Ekawati Tallei, Raymond Rubianto Tjandrawinata, Apollinaire Tsopmo, Bonglee Kim, Fahrul Nurkolis
Scientific Reports.2024;[Epub] CrossRef
Évolution du statut braf dans le melanome : mythe ou Réalité ?
Elicia Molines, Aurélie Haffner, Frédéric Fina, Nausicaa Malissen, L’Houcine Ouafik, Jean-Jacques Grob, Nicolas Macagno
Annales de Pathologie.2022; 42(2): 113. CrossRef
Metastatic uveal melanoma: The final frontier
Elina S. Rantala, Micaela M. Hernberg, Sophie Piperno-Neumann, Hans E. Grossniklaus, Tero T. Kivelä
Progress in Retinal and Eye Research.2022; 90: 101041. CrossRef
Variations in genetics, biology, and phenotype of cutaneous disorders in skin of color – Part I: Genetic, biologic, and structural differences in skin of color
Jessica B. Brown-Korsah, Shanice McKenzie, Deega Omar, Nicole C. Syder, Nada Elbuluk, Susan C. Taylor
Journal of the American Academy of Dermatology.2022; 87(6): 1239. CrossRef
PTEN Promoter Hypermethylation Is Associated with Breslow Thickness in Acral Melanoma on the Heel, Forefoot, and Hallux
Hae Seok Park, Jong Hoon Kim, Mi Yeon Cho, Kee Yang Chung, Mi Ryung Roh
Annals of Dermatology.2021; 33(1): 18. CrossRef
Heterogeneity of GNAQ/11 mutation inversely correlates with the metastatic rate in uveal melanoma
Chen Liang, Lan ya Peng, Ming Zou, Xuemei Chen, Yingying Chen, Hou Chen, Lirong Xiao, Naihong Yan, Junjun Zhang, Qing Zhao, Xi Huang
British Journal of Ophthalmology.2021; 105(4): 587. CrossRef
Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition
Jian-Ching Wu, Han-En Tsai, Yi-Hsiang Hsiao, Ji-Syuan Wu, Chieh-Shan Wu, Ming-Hong Tai
International Journal of Molecular Sciences.2020; 21(2): 681. CrossRef
Male sex and Breslow thickness are important risk factors for recurrence of localized melanoma in Korean populations
Yeongjoo Oh, Sooyie Choi, Mi Yeon Cho, Kyoung Ae Nam, Sang Joon Shin, Jee Suk Chang, Byung Ho Oh, Mi Ryung Roh, Kee Yang Chung
Journal of the American Academy of Dermatology.2020; 83(4): 1071. CrossRef
Tumor Heterogeneity on FDG PET/CT and Immunotherapy: An Imaging Biomarker for Predicting Treatment Response in Patients With Metastatic Melanoma
Y. Sanli, J. Leake, A. Odu, Y. Xi, R. M. Subramaniam
American Journal of Roentgenology.2019; 212(6): 1318. CrossRef
BRAF and NRAS mutations and antitumor immunity in Korean malignant melanomas and their prognostic relevance: Gene set enrichment analysis and CIBERSORT analysis
Kyueng-Whan Min, Ji-Young Choe, Mi Jung Kwon, Hye Kyung Lee, Ho Suk Kang, Eun Sook Nam, Seong Jin Cho, Hye-Rim Park, Soo Kee Min, Jinwon Seo, Yun Joong Kim, Nan Young Kim, Ho Young Kim
Pathology - Research and Practice.2019; 215(12): 152671. CrossRef
Molecular and genetic diversity in melanoma of eye
N. N. Mazurenko, I. V. Tsyganova, V. V. Nazarova, I. A. Utyashev, K. V. Orlova, D. A. Ponkratova, D. V. Martinkov, L. V. Demidov
Advances in molecular oncology.2018; 5(3): 51. CrossRef

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Case Report

PTEN Methylation Dependent Sinonasal Mucosal Melanoma: Sang Hee Lee, Mi Ryung Roh, Beodeul Kang, Kyu Hyun Park, Soo Hee Kim, Sang Eun Lee, Sun Young Rha; Cancer Res Treat. 2016;48(2):853-858. Published online March 18, 2015; DOI: https://doi.org/10.4143/crt.2014.356

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Sinonasal mucosal melanoma (SMM) is an aggressive and rare type of melanoma. Although the classic RAS-RAF-MEK pathway is thought to be the main pathway involved in melanoma pathogenesis, genetic alterations in the phosphatidylinositol 3-kinase–AKT pathway, including PTEN-regulated signaling, are also thought to contribute. So far, data regarding altered PTEN expression and epigenetic mechanism of PTEN silencing in development of SMM is extremely limited. Herein we report on a case of SMM with liver and bone metastases with an epigenetic alteration of PTEN. Results of mutation analysis for BRAF, NRAS, HRAS, KRAS, PIK3CA, c-Kit, and PTEN were negative; however, methylation of PTEN CpG islands was observed. Our case not only supports PTEN as a major tumor suppressor involved in melanoma tumorigenesis, but also a potential epigenetic mechanism of PTEN silencing in development of SMM.

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Mucosal Melanoma: Epidemiology, Clinical Features, and Treatment
Maria Chiara Sergi, Elisabetta Filoni, Giacomo Triggiano, Gerardo Cazzato, Valeria Internò, Camillo Porta, Marco Tucci
Current Oncology Reports.2023; 25(11): 1247. CrossRef
Mucosal melanomas of different anatomic sites share a common global DNA methylation profile with cutaneous melanoma but show location‐dependent patterns of genetic and epigenetic alterations
Philipp Jurmeister, Niklas Wrede, Inga Hoffmann, Claudia Vollbrecht, Daniel Heim, Michael Hummel, Peggy Wolkenstein, Ines Koch, Verena Heynol, Wolfgang Daniel Schmitt, Anne Thieme, Daniel Teichmann, Christine Sers, Andreas von Deimling, Julia Cara Thierau
The Journal of Pathology.2022; 256(1): 61. CrossRef
Actionable Mutation Profile of Sun-Protected Melanomas in South America
Ricardo Hsieh, Marcello M. S. Nico, Cláudia M. C. Camillo, Kátia K. Oliveira, Dirce M. Carraro, Martin Sangueza, Silvia V. Lourenço
The American Journal of Dermatopathology.2022; 44(10): 741. CrossRef
Mucosal melanoma: current strategies and future directions
Shaheer Khan, Richard D. Carvajal
Expert Opinion on Orphan Drugs.2019; 7(10): 427. CrossRef

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Original Article

Results of a Phase II Study to Evaluate the Efficacy of Docetaxel and Carboplatin in Metastatic Malignant Melanoma Patients Who Failed First-Line Therapy Containing Dacarbazine: Choong-kun Lee, Minkyu Jung, Hye Jin Choi, Hye Ryun Kim, Hyo Song Kim, Mi Ryung Roh, Joong Bae Ahn, Hyun Cheol Chung, Su Jin Heo, Sun Young Rha, Sang Joon Shin; Cancer Res Treat. 2015;47(4):781-789. Published online February 16, 2015; DOI: https://doi.org/10.4143/crt.2014.261

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Purpose
There is no standard second-line regimen for malignant melanoma patients with disease progression after first-line chemotherapy, and platinum-alkylating agents combined with paclitaxel have shown modest efficacy. Materials and Methods We conducted a phase II, open-label, single-arm study to test the efficacy of docetaxel combined with carboplatin for malignant melanoma patients who failed previous treatment with dacarbazine. Intravenous docetaxel (35 mg/m2 on days 1 and 8 of each cycle) and carboplatin (area under the curve 3 on days 1 and 8 of each cycle) was administered every 21 days. Primary end point was objective response rate (ORR).
Results
Thirty patients were enrolled in the study, and the median follow-up duration was 19.8 months. Among 25 per-protocol patients, there were three responders (1 with complete response and 2 with partial response) and 17 stable disease patients (ORR, 12.0%). Among the per-protocol population, the median progression-free survival (PFS) was 4.3 months and the median overall survival (OS) was 9.6 months. Uveal melanoma patients (n=9) showed the best prognosis compared to other subtypes (median PFS, 7.6 months; OS, 9.9 months). The most common grade 3 or 4 adverse event was neutropenia (n=15, 50.0%). Conclusion Docetaxel combined with carboplatin showed association with an acceptable safety profile and overall efficacy for patients with malignant melanoma who had progressed on chemotherapy containing dacarbazine.

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Signaling pathways driving ocular malignancies and their targeting by bioactive phytochemicals
Courtney R. Croley, Joshua Pumarol, Blake E. Delgadillo, Andrew C. Cook, Faith Day, Tea Kaceli, Caroline C. Ward, Imran Husain, Ali Husain, Sabyasachi Banerjee, Anupam Bishayee
Pharmacology & Therapeutics.2023; 248: 108479. CrossRef
A Phase 1 study of ADI‐PEG20 (pegargiminase) combined with cisplatin and pemetrexed in ASS1‐negative metastatic uveal melanoma
Pui Ying Chan, Melissa M. Phillips, Stephen Ellis, Amanda Johnston, Xiaoxing Feng, Amit Arora, Gordon Hay, Victoria M. L. Cohen, Mandeep S. Sagoo, John S. Bomalaski, Michael T. Sheaff, Peter W. Szlosarek
Pigment Cell & Melanoma Research.2022; 35(4): 461. CrossRef
iUMRG: multi-layered network-guided propagation modeling for the inference of susceptibility genes and potential drugs against uveal melanoma
Yueping Ren, Congcong Yan, Lili Wu, Jingting Zhao, Mingwei Chen, Meng Zhou, Xiaoyan Wang, Tonghua Liu, Quanyong Yi, Jie Sun
npj Systems Biology and Applications.2022;[Epub] CrossRef
Systemic and Liver-Directed Therapies in Metastatic Uveal Melanoma: State-of-the-Art and Novel Perspectives
Francesca Comito, Paola Valeria Marchese, Angela Dalia Ricci, Nastassja Tober, Chiara Peterle, Francesca Sperandi, Barbara Melotti
Future Oncology.2021; 17(33): 4583. CrossRef
New Therapeutic Perspectives in the Treatment of Uveal Melanoma: A Systematic Review
Mario Damiano Toro, Lucia Gozzo, Luciano Tracia, Marco Cicciù, Filippo Drago, Claudio Bucolo, Teresio Avitabile, Robert Rejdak, Katarzyna Nowomiejska, Sandrine Zweifel, Yacoub A. Yousef, Rashed Nazzal, Giovanni Luca Romano
Biomedicines.2021; 9(10): 1311. CrossRef
Interferon-α versus interleukin-2 in Chinese patients with malignant melanoma
Shenglong Li, Xixi Wu, Peng Chen, Yi Pei, Ke Zheng, Wei Wang, Enduo Qiu, Xiaojing Zhang
Anti-Cancer Drugs.2019; 30(4): 402. CrossRef
Mechanism of HN‑3 cell apoptosis induced by carboplatin: Combination of mitochondrial pathway associated with Ca2+ and the nucleus pathways
Bo Shen, Wenjing Mao, Jin‑Chul Ahn, Phil‑Sang Chung, Peijie He
Molecular Medicine Reports.2018;[Epub] CrossRef
Endoplasmic reticulum stress-mediated pathways to both apoptosis and autophagy: Significance for melanoma treatment
Mohamed Hassan
World Journal of Experimental Medicine.2015; 5(4): 206. CrossRef

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