Biomarkers of Primary Resistance to Trastuzumab in HER2-Positive Metastatic Gastric Cancer Patients: the AMNESIA Case-Control Study

Pietrantonio, Filippo; Fucà, Giovanni; Morano, Federica; Gloghini, Annunziata; Corso, Simona; Aprile, Giuseppe; Perrone, Federica; Vita, Ferdinando De; Tamborini, Elena; Tomasello, Gianluca; Gualeni, Ambra Vittoria; Ongaro, Elena; Busico, Adele; Giommoni, Elisa; Volpi, Chiara Costanza; Laterza, Maria Maddalena; Corallo, Salvatore; Prisciandaro, Michele; Antista, Maria; Pellegrinelli, Alessandro; Castagnoli, Lorenzo; Pupa, Serenella M.; Pruneri, Giancarlo; Braud, Filippo de; Giordano, Silvia; Cremolini, Chiara; Bartolomeo, Maria Di

doi:10.1158/1078-0432.ccr-17-2781

Cited by 81 publications

(58 citation statements)

References 29 publications

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“…1A). These data are consistent with prior results demonstrating that mutations in the RAS and PI3K pathways are associated with trastuzumab resistance in ERBB2-amplified EG cancer (8,12,(22)(23)(24)(25). MYC amplification, although identified in only 3 patients, was associated with a lower likelihood of RECIST response (P = 0.04, one-sided Wilcoxon rank-sum test; Fig.…”

Section: Tumor Regression On Afatinib Is Associated With Coamplificatsupporting

confidence: 92%

EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer

et al. 2019

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The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with ERBB2 (HER2) amplifi cation or overexpression, but intrinsic and acquired resistance are common. We conducted a phase II study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib response was associated with coamplifi cation of EGFR and ERBB2. Heterogeneous 89 Zr-trastuzumab PET uptake was associated with genomic heterogeneity and mixed clinical response to afatinib. Resistance to afatinib was associated with selection for tumor cells lacking EGFR amplifi cation or with acquisition of MET amplifi cation, which could be detected in plasma cell-free DNA. The combination of afatinib and a MET inhibitor induced complete tumor regression in ERBB2 and MET coamplifi ed patient-derived xenograft models established from a metastatic lesion progressing on afatinib. Collectively, differential intrapatient and interpatient expression of HER2, EGFR, and MET may determine clinical response to HER kinase inhibitors in ERBB2-amplifi ed EG cancer. SIGNIFICANCE: Analysis of patients with ERBB2-amplifi ed, trastuzumab-resistant EG cancer who were treated with the HER kinase inhibitor afatinib revealed that sensitivity and resistance to therapy were associated with EGFR / ERBB2 coamplifi cation and MET amplifi cation, respectively. HER2-directed PET imaging and cell-free DNA sequencing could help guide strategies to overcome the emergence of resistant clones.

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Section: Tumor Regression On Afatinib Is Associated With Coamplificatsupporting

confidence: 92%

EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer

et al. 2019

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“…Beyond co‐occurring RTK alterations, changes in cell cycle genes, PI‐3‐kinase, and MAP‐kinase pathway genes are implicated in innate and acquired resistance to HER2‐targeted therapies in GEA . We observed alterations in MYC (17%), KRAS (10%), and PIK3CA (5.6%) frequently across FGFR2 ‐altered cases, paralleling HER2 observations (Fig.…”

Section: Resultssupporting

confidence: 64%

FGFR2-Altered Gastroesophageal Adenocarcinomas Are an Uncommon Clinicopathologic Entity with a Distinct Genomic Landscape

Klempner

Madison²,

Pujara

et al. 2019

The Oncologist

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Background With the exception of trastuzumab, therapies directed at receptor tyrosine kinases (RTKs) in gastroesophageal adenocarcinomas (GEA) have had limited success. Recurrent fibroblast growth factor receptor 2 (FGFR2) alterations exist in GEA; however, little is known about the genomic landscape of FGFR2‐altered GEA. We examined FGFR2 alteration frequency and frequency of co‐occurring alterations in GEA. Subjects, Materials, and Methods A total of 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture‐based genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA, and microsatellite instability was determined on 95 or 114 loci. Descriptive statistics were used to compare subgroups. Results We identified a total of 269 (4.0%) FGFR2‐altered cases consisting of FGFR2‐amplified (amp; 193, 72% of FGFR2‐altered), FGFR2‐mutated (36, 13%), FGFR2‐rearranged (re; 23, 8.6%), and cases with multiple FGFR2 alterations (17, 6.3%). Co‐occurring alterations in other GEA RTK targets including ERBB2 (10%), EGFR (8%), and MET (3%) were observed across all classes of FGFR2‐altered GEA. Co‐occurring alterations in MYC (17%), KRAS (10%), and PIK3CA (5.6%) were also observed frequently. Cases with FGFR2amp and FGFR2re were exclusively microsatellite stable. The median TMB for FGFR2‐altered GEA was 3.6 mut/mb, not significantly different from a median of 4.3 mut/mb seen in FGFR2 wild‐type samples. Conclusion FGFR2‐altered GEA is a heterogenous subgroup with approximately 20% of FGFR2‐altered samples harboring concurrent RTK alterations. Putative co‐occurring modifiers of FGFR2‐directed therapy including oncogenic MYC, KRAS, and PIK3CA alterations were also frequent, suggesting that pretreatment molecular analyses may be needed to facilitate rational combination therapies and optimize patient selection for clinical trials. Implications for Practice Actionable receptor tyrosine kinase alterations assayed within a genomic context with therapeutic implications remain limited to HER2 amplification in gastroesophageal adenocarcinomas (GEA). Composite biomarkers and heterogeneity assessment are critical in optimizing patients selected for targeted therapies in GEA. Comprehensive genomic profiling in FGFR2‐altered GEA parallels the heterogeneity findings in HER2‐amplified GEA and adds support to the utility of genomic profiling in advanced gastroesophageal adenocarcinomas.

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“…Recently, studies evaluating trastuzumab resistance mechanisms have highlighted certain pathways for resistance. In the multicenter, prospective, case-control AMNESIA study in patients with HER2+ metastatic gastric cancer, genomic alterations in the epidermal growth factor receptor (EGFR)/MET/KRAS/ PI3K/PTEN pathway were significantly more frequent in trastuzumab-resistant (55%) patients than in trastuzumabsensitive (0%) patients, and patients without these genomic alterations had a significantly longer median progressionfree survival (PFS) (5.2 vs 2.6 months, hazard ratio [HR], 0.34 [95% confidence interval (CI), 0.07-0.48]; P = 0.001) and overall survival (OS) (16.1 vs 7.6 months; HR, 0.38 [95% CI 0.09-0.75]; P = 0.015) than those with alterations [11]. At present, however, no chemotherapy regimen specific to HER2+ G/GEJ cancer patients has been established in the second-or later-line treatment setting.…”

Section: Introductionmentioning

confidence: 99%

Exploratory subgroup analysis of patients with prior trastuzumab use in the ATTRACTION-2 trial: a randomized phase III clinical trial investigating the efficacy and safety of nivolumab in patients with advanced gastric/gastroesophageal junction cancer

et al. 2019

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Background Data on immune checkpoint inhibitor efficacy in patients with human epidermal growth factor receptor 2-positive (HER2+) advanced gastric/gastroesophageal junction (G/GEJ) cancer are lacking. Because HER2 status was not captured in the ATT RAC TION-2 trial, we used patients with prior trastuzumab use (Tmab+) as surrogate for HER2 expression status to evaluate the efficacy and safety of nivolumab as third-or later-line therapy in these patients. Methods In ATT RAC TION-2, a randomized, double-blind, placebo-controlled, phase 3 multicenter trial, patients were randomized (2:1) to receive nivolumab (3 mg/kg) or placebo every 2 weeks until disease progression or toxicity requiring study discontinuation. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were assessed. Results Of 493 enrolled patients, 81 (nivolumab, n = 59; placebo, n = 22) were Tmab+ and 412 (nivolumab, n = 271; placebo, n = 141) were Tmab−. In both groups, patients receiving nivolumab showed a longer median OS vs placebo (Tmab+, 8.3 [95% confidence interval, 5.3-12.9] vs 3.1 [1.9-5.3] months, hazard ratio, 0.38 [0.22-0.66]; P = 0.0006; Tmab−, 4.8 [4.1-6.0] vs 4.2 [3.6-4.9] months, 0.71 [0.57-0.88]; P = 0.0022). PFS was longer in both groups receiving nivolumab vs placebo (Tmab+,.0] vs 1.5 [1.3-2.9] months, 0.49 [0.29-0.85]; P = 0.0111; Tmab−, 1.6 [1.5-2.4] vs 1.5 [1.5-1.5] months, 0.64 [0.51-0.80]; P = 0.0001). Conclusions Nivolumab was efficacious and safe as third-or later-line therapy regardless of prior trastuzumab use in patients with advanced G/GEJ cancer.

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Biomarkers of Primary Resistance to Trastuzumab in HER2-Positive Metastatic Gastric Cancer Patients: the AMNESIA Case-Control Study

Cited by 81 publications

References 29 publications

EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer

EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer

FGFR2-Altered Gastroesophageal Adenocarcinomas Are an Uncommon Clinicopathologic Entity with a Distinct Genomic Landscape

Exploratory subgroup analysis of patients with prior trastuzumab use in the ATTRACTION-2 trial: a randomized phase III clinical trial investigating the efficacy and safety of nivolumab in patients with advanced gastric/gastroesophageal junction cancer

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