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Cancer Research and Treatment > Accepted Articles
doi: https://doi.org/10.4143/crt.2022.251    [Accepted]
Comprehensive Molecular Characterization of Soft Tissue Sarcoma for Prediction of Pazopanib-Based Treatment Response
Jung Yong Hong1 , Hee Jin Cho2,3, Kum-Hee Yun4, Young Han Lee5, Seung Hyun Kim6, Wooyeol Baek7, Sang Kyum Kim8, Yurimi Lee9, Yoon-La Choi9, Minsuk Kwon10, Hyo Song Kim4 , Jeeyun Lee1
1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2Department of Biomedical Convergence Science and Technology, Kyungpook National University, Daegu, Korea
3Cell and Matrix Research Institute, Kyungpook National University, Daegu, Korea
4Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
5Department of Radiology, Yonsei University College of Medicine, Seoul, Korea
6Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul, Korea
7Institute for Human Tissue Restoration, Department of Plastic & Reconstructive Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
8Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
9Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
10Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, Korea
Correspondence  Hyo Song Kim ,Tel: 82-2-2228-8124, Fax: 82-2-393-3652, Email: hyosong77@yuhs.ac
Received: April 21, 2022;  Accepted: September 25, 2022.  Published online: September 27, 2022.
*Jung Yong Hong and Hee Jin Cho contributed equally to this work.
ABSTRACT
Purpose
Even though pazopanib, a multitargeted tyrosine kinase inhibitor, has been approved for refractory soft tissue sarcoma (STS), little is known about the molecular determinants of the response to pazopanib. We performed integrative molecular characterization to identify potential predictors of pazopanib efficacy.
Materials and Methods
We obtained fresh pre-treatment tumor tissue from 35 patients with advanced STS receiving pazopanib-based treatment. Among those, 18 (51.4%) received pazopanib monotherapy, and the remaining 17 (48.6%) received pazopanib in combination with durvalumab, PD-L1 blockade. Whole-exome and transcriptome sequencing were performed for each tumor and patient germline DNA.
Results
Of the 35 patients receiving pazopanib-based treatment, 9 achieved a partial response (PR), resulting in an objective response rate (ORR) of 27.3%, and the median progression-free survival (PFS) was 6.0 months. Patients with CDK4 amplification (copy ratio tumor to normal > 2) exhibited shorter PFS (3.7 vs 7.9 months, p=2.09 x10-4) and a poorer response (ORR; 0% vs 33.3%) compared to those without a gene amplification (copy ratio ≤ 2). Moreover, non-responders demonstrated transcriptional activation of CDK4 via DNA amplification, resulting in cell cycle activation. In the durvalumab combination cohort, 7 (41.2%) of the 17 patients achieved a PR, and gene expression analysis revealed that durvalumab responders exhibited high immune/stromal cell infiltration, mainly comprising NK cells, compared to non-responders as well as increased expression of CD19, a B cell marker.
Conclusion
Despite the limitation of heterogeneity in the study population and treatment, we identified possible molecular predictors of pazopanib efficacy that can be employed in future clinical trials aimed at evaluating therapeutic strategies.
Key words: Soft tissue sarcoma, Pazopanib, Immune Checkpoint Inhibitor, Whole Exome Sequencings, Whole Transcriptome Sequencing
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