Exploring potential molecular resistance and clonal evolution in advanced HER2-positive gastric cancer under trastuzumab therapy
Abstract HER2-positive gastric cancer (GC) makes up 15–20% of all GC incidences, and targeted therapy with trastuzumab is the standard of treatment. However, the mechanisms of resistance to trastuzumab are still not fully understood and presents a significant challenge in clinical practice. In this...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-04-01
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| Series: | Oncogenesis |
| Online Access: | https://doi.org/10.1038/s41389-023-00466-2 |
| _version_ | 1797840770624913408 |
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| author | Qi Xu Xiaoqing Xu Haimeng Tang Junrong Yan Jingjing Li Hua Bao Xue Wu Yang Shao Cong Luo Haimin Wen Jianying Jin Jieer Ying |
| author_facet | Qi Xu Xiaoqing Xu Haimeng Tang Junrong Yan Jingjing Li Hua Bao Xue Wu Yang Shao Cong Luo Haimin Wen Jianying Jin Jieer Ying |
| author_sort | Qi Xu |
| collection | DOAJ |
| description | Abstract HER2-positive gastric cancer (GC) makes up 15–20% of all GC incidences, and targeted therapy with trastuzumab is the standard of treatment. However, the mechanisms of resistance to trastuzumab are still not fully understood and presents a significant challenge in clinical practice. In this study, whole exome sequencing (WES) was performed on paired tumor tissues before trastuzumab treatment (at baseline) and at progressive disease (PD) in 23 GC patients. Clinicopathological and molecular features that may be associated with primary and/or acquired resistance to trastuzumab were identified. Lauren classification of intestinal type was associated with a more prolonged progression-free survival (PFS) than diffuse type (HR = 0.29, P = 0.019). Patients with low tumor mutation burden (TMB) showed significantly worse PFS, while high chromosome instability (CIN) was correlated with prolonged OS (HR = 0.27; P = 0.044). Patients who responded to treatment had a higher CIN than nonresponders, and a positive trend towards increasing CIN was observed as response improved (P = 0.019). In our cohort, the most common genes to acquire mutations are AURKA, MYC, STK11, and LRP6 with four patients each. We also discovered an association between clonal branching pattern and survival, with an extensive clonal branching pattern being more closely related to a shorter PFS than other branching patterns (HR = 4.71; P = 0.008). We identified potential molecular and clinical factors that provide insight regarding potential association to trastuzumab resistance in advanced HER2-positive GC patients. |
| first_indexed | 2024-04-09T16:20:06Z |
| format | Article |
| id | doaj.art-211540b0891f454994f2b4c2afd6bc6d |
| institution | Directory Open Access Journal |
| issn | 2157-9024 |
| language | English |
| last_indexed | 2024-04-09T16:20:06Z |
| publishDate | 2023-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Oncogenesis |
| spelling | doaj.art-211540b0891f454994f2b4c2afd6bc6d2023-04-23T11:28:39ZengNature Publishing GroupOncogenesis2157-90242023-04-0112111110.1038/s41389-023-00466-2Exploring potential molecular resistance and clonal evolution in advanced HER2-positive gastric cancer under trastuzumab therapyQi Xu0Xiaoqing Xu1Haimeng Tang2Junrong Yan3Jingjing Li4Hua Bao5Xue Wu6Yang Shao7Cong Luo8Haimin Wen9Jianying Jin10Jieer Ying11Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer HospitalDepartment of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer HospitalGeneseeq Research Institute, Nanjing Geneseeq Technology Inc.Geneseeq Research Institute, Nanjing Geneseeq Technology Inc.Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer HospitalGeneseeq Research Institute, Nanjing Geneseeq Technology Inc.Geneseeq Research Institute, Nanjing Geneseeq Technology Inc.Geneseeq Research Institute, Nanjing Geneseeq Technology Inc.Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer HospitalDepartment of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer HospitalDepartment of Medical Oncology, Taizhou Hospital of Zhejiang ProvinceDepartment of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer HospitalAbstract HER2-positive gastric cancer (GC) makes up 15–20% of all GC incidences, and targeted therapy with trastuzumab is the standard of treatment. However, the mechanisms of resistance to trastuzumab are still not fully understood and presents a significant challenge in clinical practice. In this study, whole exome sequencing (WES) was performed on paired tumor tissues before trastuzumab treatment (at baseline) and at progressive disease (PD) in 23 GC patients. Clinicopathological and molecular features that may be associated with primary and/or acquired resistance to trastuzumab were identified. Lauren classification of intestinal type was associated with a more prolonged progression-free survival (PFS) than diffuse type (HR = 0.29, P = 0.019). Patients with low tumor mutation burden (TMB) showed significantly worse PFS, while high chromosome instability (CIN) was correlated with prolonged OS (HR = 0.27; P = 0.044). Patients who responded to treatment had a higher CIN than nonresponders, and a positive trend towards increasing CIN was observed as response improved (P = 0.019). In our cohort, the most common genes to acquire mutations are AURKA, MYC, STK11, and LRP6 with four patients each. We also discovered an association between clonal branching pattern and survival, with an extensive clonal branching pattern being more closely related to a shorter PFS than other branching patterns (HR = 4.71; P = 0.008). We identified potential molecular and clinical factors that provide insight regarding potential association to trastuzumab resistance in advanced HER2-positive GC patients.https://doi.org/10.1038/s41389-023-00466-2 |
| spellingShingle | Qi Xu Xiaoqing Xu Haimeng Tang Junrong Yan Jingjing Li Hua Bao Xue Wu Yang Shao Cong Luo Haimin Wen Jianying Jin Jieer Ying Exploring potential molecular resistance and clonal evolution in advanced HER2-positive gastric cancer under trastuzumab therapy Oncogenesis |
| title | Exploring potential molecular resistance and clonal evolution in advanced HER2-positive gastric cancer under trastuzumab therapy |
| title_full | Exploring potential molecular resistance and clonal evolution in advanced HER2-positive gastric cancer under trastuzumab therapy |
| title_fullStr | Exploring potential molecular resistance and clonal evolution in advanced HER2-positive gastric cancer under trastuzumab therapy |
| title_full_unstemmed | Exploring potential molecular resistance and clonal evolution in advanced HER2-positive gastric cancer under trastuzumab therapy |
| title_short | Exploring potential molecular resistance and clonal evolution in advanced HER2-positive gastric cancer under trastuzumab therapy |
| title_sort | exploring potential molecular resistance and clonal evolution in advanced her2 positive gastric cancer under trastuzumab therapy |
| url | https://doi.org/10.1038/s41389-023-00466-2 |
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