HER2 Copy Number and Resistance Mechanisms in Patients with HER2-positive Advanced Gastric Cancer Receiving Initial Trastuzumab-based Therapy in JACOB Trial

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 altera...

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Detalles Bibliográficos
Autores principales: Pietrantonio, Filippo, Manca, Paolo, Bellomo, Sara Erika, Corso, Simona, Raimondi, Alessandra, Berrino, Enrico, Morano, Federica, Migliore, Cristina, Niger, Monica, Castagnoli, Lorenzo, Pupa, Serenella Maria, Marchiò, Caterina, Di Bartolomeo, Maria, Restuccia, Eleonora, Lambertini, Chiara, Tabernero, Josep, Giordano, Silvia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
Materias:
Precision Medicine and Imaging
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9890129/
https://www.ncbi.nlm.nih.gov/pubmed/36413222
http://dx.doi.org/10.1158/1078-0432.CCR-22-2533
Descripción
Sumario: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.

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