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

Abstract

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 NGS (Oncomine Focus DNA), HER2 CNV, HER2 expression by IHC and AMNESIA were correlated with ORR, PFS and OS by uni/multivariable models. Results: Median HER2 CNV was 4.7 (IQR 2.2-16.9). HER2 CNV-high vs low using the median as cut-off was associated with longer median PFS (10.5 vs 6.4 months; HR=0.48, 95%CI: 0.38-0.62; p<.001) and OS (20.3 vs 13.0 months; HR=0.54, 0.42-0.72; p<.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<.001)/OS (p=.004). Higher ORR was significantly associated with IHC 3+ [61% vs 34% in 2+; odds ratio (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, OS in a JACOB subgroup, especially if combined with HER2 3+. The negative prognostic role of AMNESIA requires further clinical validation.

Clinical application of targeted tumour sequencing tests for detecting ERBB2 amplification and optimizing anti-HER2 therapy in gastric cancer

“…However, the optimal cut-off value of ERBB2 CNA for predicting prognosis in patients receiving trastuzumab therapy remains undetermined. Previous studies have demonstrated that elevated continuous copy numbers of ERBB2 correlate significantly with extended PFS [ 25 , 26 ], and higher cut-off values of ERBB2 CNA, compared to those employed in the current study, have proven advantageous for prognostic categorization in patients undergoing trastuzumab therapy [ 26 , 27 ]. Further exploration aimed at delineating the optimal cut-off values capable of predicting the efficacy of trastuzumab therapy specifically in patients with GC will advance anti-HER2 therapy for unresectable metastatic disease.…”

“…In the present study, compared with no ERBB2 AMP, ERBB2 AMP was associated with better PFS and a higher ORR for trastuzumab therapy. Furthermore, several reports attest to the association of ERBB2 AMP, as determined through copy number analysis using NGS, with more favourable prognosis in trastuzumab therapy [ 22 , 25 – 27 ]. Assessment of ERBB2 CNA via a targeted tumour sequencing test is advantageous for identifying patients likely to exhibit a favourable response to trastuzumab therapy.…”

Characterization of MET Alterations in 37 Gastroesophageal Cancer Cell Lines for MET-Targeted Therapy

“…Tmab monotherapy does not significantly inhibit ERK and S6 activity on OE33 cells [ 25 ]. Consistently, MET co-amplifications are significantly associated with worse outcomes, indicating resistance to anti-HER2 targeted therapy for HER2+ GC in a post hoc analysis of 327 samples from the JACOB trial [ 26 ]. Here, treatment of OE33 cells with Tmab, savolitinib, or their combination effectively suppressed the growth of colonies ( Figure 5 a) and the downstream molecules, AKT, ERK, and S6 ( Figure 5 b).…”

Negative Hyperselection of Patients with HER2+ and RAS Wild-Type Metastatic Colorectal Cancer Receiving Dual HER2 Blockade: the PRESSING-HER2 Study

“…Second, the reproducibility of HER2 CNV assessment may have been negatively influenced by the heterogeneity of the NGS assays. It should be also kept in mind that NGS may underestimate the HER2 CNV because of the stromal dilution as compared with standard morphologic assays such as ISH ( 25 ). Finally, a substantial proportion of patients with primary resistance did not display any PRESSING-HER2 alteration nor low HER2 CNV by tissue NGS.…”