MicroRNAs as biomarkers for trastuzumab-based therapy in HER2-positive advanced oesophago-gastric cancer patients
BackgroundThis study aimed to identify microRNAs (miRs) as circulating biomarkers of resistance to first-line trastuzumab-based therapy in advanced HER2-positive oesophago-gastric cancer patients.MethodsA high-throughput 1015 Exiqon miRCURY LNA™ microRNA inhibitor library screen was performed in tra...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1258365/full |
| _version_ | 1797448289191198720 |
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| author | Hazel Lote Hazel Lote Florentia Mousoullou George Vlachogiannis Andrea Lampis Laura Satchwell Clare Peckitt Caroline Fong Ruwaida Begum Shannon Kidd Susan Cromarty Anderley Gordon Charlotte Fribbens Sheela Rao Naureen Starling Ian Chau David Cunningham Nicola Valeri Nicola Valeri |
| author_facet | Hazel Lote Hazel Lote Florentia Mousoullou George Vlachogiannis Andrea Lampis Laura Satchwell Clare Peckitt Caroline Fong Ruwaida Begum Shannon Kidd Susan Cromarty Anderley Gordon Charlotte Fribbens Sheela Rao Naureen Starling Ian Chau David Cunningham Nicola Valeri Nicola Valeri |
| author_sort | Hazel Lote |
| collection | DOAJ |
| description | BackgroundThis study aimed to identify microRNAs (miRs) as circulating biomarkers of resistance to first-line trastuzumab-based therapy in advanced HER2-positive oesophago-gastric cancer patients.MethodsA high-throughput 1015 Exiqon miRCURY LNA™ microRNA inhibitor library screen was performed in trastuzumab-treated HER2-positive NCI-N87 and HER2-negative FLO-1 oesophago-gastric cancer cell lines. NanoString nCounter® miR analysis was performed in NCI-N87, FLO-1, and MAGIC trial (ISRCTN93793971) formalin-fixed paraffin-embedded (FFPE) oesophago-gastric cancer patient samples. MiR-148a-3p copies in plasma samples were quantified using digital droplet polymerase chain reaction (ddPCR) from HER2-positive oesophago-gastric cancer patients treated with standard-of-care trastuzumab-based therapy within the FOrMAT (NCT02112357) and PLATFORM (NCT02678182) clinical trials. The primary endpoints were overall survival (OS) for plasma miR-148a-3p HIGH (>median) versus LOW (≤median). The secondary endpoints were progression-free survival (PFS) and 3-month progression-free rates (PFRs) miR-148a-3p HIGH versus LOW. PLATFORM sensitivity analysis normalised miR-148a-3p (NmiR-148a-3p).ResultsThe inhibition of miR-148a-3p reduced NCI-N87 relative cell viability (<0.6) and expression was high (>242) in NCI-N87 and HER2-positive MAGIC trial patients (n=5). Normalised-miR-148a-3p (NmiR-148a-3p) LOW versus HIGH demonstrated a statistically significant difference in 3-month PFRs (n=23; OR, 0.11 [0.02–0.78]; p=0.027; aOR, 0.03 [0.001–0.71], p=0.029) but no difference in OS or PFS. There was no statistically significant relationship between miR-148-3p LOW versus HIGH for OS (PLATFORM, n=62; hazard ratio [HR], 0.98 [0.57–1.66]; p=0.933; FOrMAT, n=8; HR, 0.54 [0.13–2.31]; p=0.322), PFS (n=62; HR, 1.08 [0.65–1.81]; p=0.759; FOrMAT, n=8; HR, 1.26 [0.31–5.07]; p=0.714), or PFRs (PLATFORM, n=31; odds ratio [OR], 0.67 [0.2–2.8]; p=0.577).ConclusionNormalised miR-148a-3p may be a relevant biomarker for trastuzumab-based therapy in advanced HER2-positive oesophago-gastric cancer patients. |
| first_indexed | 2024-03-09T14:08:12Z |
| format | Article |
| id | doaj.art-ce00e101c55741ff998c109728418068 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-03-09T14:08:12Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-ce00e101c55741ff998c1097284180682023-11-29T21:07:23ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-11-011310.3389/fonc.2023.12583651258365MicroRNAs as biomarkers for trastuzumab-based therapy in HER2-positive advanced oesophago-gastric cancer patientsHazel Lote0Hazel Lote1Florentia Mousoullou2George Vlachogiannis3Andrea Lampis4Laura Satchwell5Clare Peckitt6Caroline Fong7Ruwaida Begum8Shannon Kidd9Susan Cromarty10Anderley Gordon11Charlotte Fribbens12Sheela Rao13Naureen Starling14Ian Chau15David Cunningham16Nicola Valeri17Nicola Valeri18Division of Molecular Pathology, The Institute of Cancer Research, London, United KingdomDepartment of Gastrointestinal Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United KingdomDepartment of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United KingdomDivision of Molecular Pathology, The Institute of Cancer Research, London, United KingdomDivision of Molecular Pathology, The Institute of Cancer Research, London, United KingdomDepartment of Gastrointestinal Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United KingdomDepartment of Gastrointestinal Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United KingdomDepartment of Gastrointestinal Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United KingdomDepartment of Gastrointestinal Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United KingdomDepartment of Gastrointestinal Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United KingdomDepartment of Gastrointestinal Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United KingdomDepartment of Gastrointestinal Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United KingdomDepartment of Gastrointestinal Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United KingdomDepartment of Gastrointestinal Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United KingdomDepartment of Gastrointestinal Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United KingdomDepartment of Gastrointestinal Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United KingdomDepartment of Gastrointestinal Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United KingdomDivision of Molecular Pathology, The Institute of Cancer Research, London, United KingdomDepartment of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United KingdomBackgroundThis study aimed to identify microRNAs (miRs) as circulating biomarkers of resistance to first-line trastuzumab-based therapy in advanced HER2-positive oesophago-gastric cancer patients.MethodsA high-throughput 1015 Exiqon miRCURY LNA™ microRNA inhibitor library screen was performed in trastuzumab-treated HER2-positive NCI-N87 and HER2-negative FLO-1 oesophago-gastric cancer cell lines. NanoString nCounter® miR analysis was performed in NCI-N87, FLO-1, and MAGIC trial (ISRCTN93793971) formalin-fixed paraffin-embedded (FFPE) oesophago-gastric cancer patient samples. MiR-148a-3p copies in plasma samples were quantified using digital droplet polymerase chain reaction (ddPCR) from HER2-positive oesophago-gastric cancer patients treated with standard-of-care trastuzumab-based therapy within the FOrMAT (NCT02112357) and PLATFORM (NCT02678182) clinical trials. The primary endpoints were overall survival (OS) for plasma miR-148a-3p HIGH (>median) versus LOW (≤median). The secondary endpoints were progression-free survival (PFS) and 3-month progression-free rates (PFRs) miR-148a-3p HIGH versus LOW. PLATFORM sensitivity analysis normalised miR-148a-3p (NmiR-148a-3p).ResultsThe inhibition of miR-148a-3p reduced NCI-N87 relative cell viability (<0.6) and expression was high (>242) in NCI-N87 and HER2-positive MAGIC trial patients (n=5). Normalised-miR-148a-3p (NmiR-148a-3p) LOW versus HIGH demonstrated a statistically significant difference in 3-month PFRs (n=23; OR, 0.11 [0.02–0.78]; p=0.027; aOR, 0.03 [0.001–0.71], p=0.029) but no difference in OS or PFS. There was no statistically significant relationship between miR-148-3p LOW versus HIGH for OS (PLATFORM, n=62; hazard ratio [HR], 0.98 [0.57–1.66]; p=0.933; FOrMAT, n=8; HR, 0.54 [0.13–2.31]; p=0.322), PFS (n=62; HR, 1.08 [0.65–1.81]; p=0.759; FOrMAT, n=8; HR, 1.26 [0.31–5.07]; p=0.714), or PFRs (PLATFORM, n=31; odds ratio [OR], 0.67 [0.2–2.8]; p=0.577).ConclusionNormalised miR-148a-3p may be a relevant biomarker for trastuzumab-based therapy in advanced HER2-positive oesophago-gastric cancer patients.https://www.frontiersin.org/articles/10.3389/fonc.2023.1258365/fulloesophageal adenocarcinomagastric cancermicroRNAHER2biomarkerstrastuzumab |
| spellingShingle | Hazel Lote Hazel Lote Florentia Mousoullou George Vlachogiannis Andrea Lampis Laura Satchwell Clare Peckitt Caroline Fong Ruwaida Begum Shannon Kidd Susan Cromarty Anderley Gordon Charlotte Fribbens Sheela Rao Naureen Starling Ian Chau David Cunningham Nicola Valeri Nicola Valeri MicroRNAs as biomarkers for trastuzumab-based therapy in HER2-positive advanced oesophago-gastric cancer patients Frontiers in Oncology oesophageal adenocarcinoma gastric cancer microRNA HER2 biomarkers trastuzumab |
| title | MicroRNAs as biomarkers for trastuzumab-based therapy in HER2-positive advanced oesophago-gastric cancer patients |
| title_full | MicroRNAs as biomarkers for trastuzumab-based therapy in HER2-positive advanced oesophago-gastric cancer patients |
| title_fullStr | MicroRNAs as biomarkers for trastuzumab-based therapy in HER2-positive advanced oesophago-gastric cancer patients |
| title_full_unstemmed | MicroRNAs as biomarkers for trastuzumab-based therapy in HER2-positive advanced oesophago-gastric cancer patients |
| title_short | MicroRNAs as biomarkers for trastuzumab-based therapy in HER2-positive advanced oesophago-gastric cancer patients |
| title_sort | micrornas as biomarkers for trastuzumab based therapy in her2 positive advanced oesophago gastric cancer patients |
| topic | oesophageal adenocarcinoma gastric cancer microRNA HER2 biomarkers trastuzumab |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1258365/full |
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