HER2 Copy Number and Resistance Mechanisms in Patients with HER2-positive Advanced Gastric Cancer Receiving Initial Trastuzumab-based Therapy in JACOB Trial
| العنوان: | HER2 Copy Number and Resistance Mechanisms in Patients with HER2-positive Advanced Gastric Cancer Receiving Initial Trastuzumab-based Therapy in JACOB Trial |
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| المؤلفون: | Filippo Pietrantonio, Paolo Manca, Sara Erika Bellomo, Simona Corso, Alessandra Raimondi, Enrico Berrino, Federica Morano, Cristina Migliore, Monica Niger, Lorenzo Castagnoli, Serenella Maria Pupa, Caterina Marchiò, Maria Di Bartolomeo, Eleonora Restuccia, Chiara Lambertini, Josep Tabernero, Silvia Giordano |
| المساهمون: | Institut Català de la Salut, [Pietrantonio F, Manca P, Raimondi A] Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. [Bellomo SE, Corso S] Department of Oncology, University of Turin, Turin, Italy. Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy. [Berrino E] Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy. Department of Medical Sciences, University of Turin, Turin, Italy. [Tabernero J] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Uvic-UCC, IOB-Quiron, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| المصدر: | Scientia |
| بيانات النشر: | American Association for Cancer Research (AACR), 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias gástricas [ENFERMEDADES], Cancer Research, Estómac - Càncer - Tractament, Oncology, Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Medicaments antineoplàstics - Ús terapèutic, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Stomach Neoplasms [DISEASES], Other subheadings::Other subheadings::/drug therapy [Other subheadings], Estómac - Càncer - Aspectes genètics |
| الوصف: | Purpose: In JACOB trial, pertuzumab added to trastuzumab-chemotherapy did not significantly improve survival of patients with HER2-positive metastatic gastric cancer, despite 3.3 months increase versus placebo. HER2 copy-number variation (CNV) and AMNESIA panel encompassing primary resistance alterations (KRAS/PIK3CA/MET mutations, KRAS/EGFR/MET amplifications) may improve patients’ selection for HER2 inhibition. Experimental Design: In a post hoc analysis of JACOB on 327 samples successfully sequenced by next-generation sequencing (NGS; Oncomine Focus DNA), HER2 CNV, HER2 expression by IHC, and AMNESIA were correlated with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) by univariable/multivariable models. Results: Median HER2 CNV was 4.7 (interquartile range, 2.2–16.9). HER2 CNV-high versus low using the median as cutoff was associated with longer median PFS (10.5 vs. 6.4 months; HR = 0.48; 95% confidence interval: 0.38–0.62; P < 0.001) and OS (20.3 vs. 13.0 months; HR = 0.54; 0.42–0.72; P < 0.001). Combining HER2 CNV and IHC improved discriminative ability, with better outcomes restricted to HER2-high/HER2 3+ subgroup. AMNESIA positivity was found in 51 (16%), with unadjusted HR = 1.35 (0.98–1.86) for PFS; 1.43 (1.00–2.03) for OS. In multivariable models, only HER2 CNV status remained significant for PFS (P < 0.001) and OS (P = 0.004). Higher ORR was significantly associated with IHC 3+ [61% vs. 34% in 2+; OR = 3.11 (1.89–5.17)] and HER2-high [59% vs. 43% in HER2-low; OR = 1.84 (1.16–2.94)], with highest OR in the top CNV quartile. These biomarkers were not associated with treatment effect of pertuzumab. Conclusions: HER2 CNV-high assessed by NGS may be associated with better ORR, PFS, and OS in a JACOB subgroup, especially if combined with HER2 3+. The negative prognostic role of AMNESIA requires further clinical validation. |
| وصف الملف: | application/pdf |
| تدمد: | 1557-3265 1078-0432 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9373e9d52e6015dc17110ec5965cd97cTest https://doi.org/10.1158/1078-0432.ccr-22-2533Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9373e9d52e6015dc17110ec5965cd97c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573265 10780432 |
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