Comprehensive analyses using next-generation sequencing and immunohistochemistry enable precise treatment in advanced gastric cancer

Kuboki, Yasutoshi; Yamashita, Satoshi; Niwa, Tohru; Ushijima, Toshikazu; Nagatsuma, Akiko Kawano; Kuwata, Takeshi; Yoshino, Takayuki; Doi, Toshihiko; Ochiai, Atsushi; Ohtsu, Atsushi

doi:10.1093/annonc/mdv508

Cited by 67 publications

(56 citation statements)

References 24 publications

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“…Dent et al also showed that EGFR, HER2, MET, and FGFR2 were amplified in GC using an SNP [33]. Recently, protein expression (using IHC) and copy numbers (using next-generation sequencing) have been used, and high-level amplification was correlated with protein expression in mutually exclusive way [34, 35]. In our study, although several RTKs were overexpressed simultaneously, 73.4% (160 out of 218) of cases had overexpression of only one RTK.…”

Section: Discussionmentioning

confidence: 99%

“…In patient-derived xenograft models of GC, cases with EGFR amplification and overexpression (3+) benefitted from cetuximab treatment, an EGFR-directed monoclonal antibody [37]. High levels of RTK amplification show high protein overexpression using IHC in most cases of GC [35]. Because amplifications occur at a low frequency, it is important to develop a reliable IHC assay to screen the right population for RTK inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive expression profiles of gastric cancer molecular subtypes by immunohistochemistry: implications for individualized therapy

et al. 2016

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Gastric cancer (GC) is a leading cause of death. We aim to establish a clinically relevant assay that encompasses recent molecular classifications and provides useful clinical information in a large cohort of GC patients. A consecutive series of 438 GC patients that underwent palliative chemotherapy between 2014 and 2015 were assessed using 10 GC panels: EBER in-situ hybridization, immunohistochemistry for mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), receptor tyrosine kinases (RTKs; HER2, EGFR, and MET), PTEN, and p53 protein. With a median of one aberration, 3.3 % of samples analyzed were Epstein-Barr virus (EBV)-positive; 4.8%, MMR-deficient. RTKs were overexpressed in 218 patients; EGFR was most commonly overexpressed (39.9%), followed by HER2 (13.5%) and MET (12.1%). Furthermore, 2.5 % and 10.7 % of cases had simultaneous overexpression of three and two RTKs, respectively. p53 overexpression/null tumors were identified in 259 patients (59.1%), and PTEN loss was identified in 89 patients (20.3%). EBV-positivity was mutually exclusive with MMR-deficiency, predominantly identified in male patients, and these tumors were undifferentiated with proximal location. p53 mutant type was significantly found predominantly in the EBV-negative (60.6% vs 14.3%, P=0.001) and HER2-positive (78.0% vs 56.2%, P=0.002) groups. We described a molecular spectrum of distinct GC subtypes using clinically applicable assay. This assay will provide a convenient screening tool and facilitate the development of targeted agents in clinical trials.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comprehensive expression profiles of gastric cancer molecular subtypes by immunohistochemistry: implications for individualized therapy

et al. 2016

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“…New molecular classification systems now provide a critical basis for the design of precision medicine clinical trials. Similarly, continuously updated molecular genetic profiling of GC has yielded promising new therapeutic targets such as RTKs or RAS and PI(3)-kinase signaling proteins 8, 9, 129. Although various new agents are still being investigated for targeted GC therapy, several ongoing clinical trials are already targeting STAT3 , c-MET , mTOR , CLDN18.2, and PD-1/PD-L1 52, 130, 131.…”

Section: Precision Medicine In Gastric Cancermentioning

confidence: 99%

Gastric Cancer in the Era of Precision Medicine

Liu

Meltzer

2017

Cellular and Molecular Gastroenterology and Hepatology

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Gastric cancer (GC) remains the third most common cause of cancer death worldwide, with limited therapeutic strategies available. With the advent of next-generation sequencing and new preclinical model technologies, our understanding of its pathogenesis and molecular alterations continues to be revolutionized. Recently, the genomic landscape of GC has been delineated. Molecular characterization and novel therapeutic targets of each molecular subtype have been identified. At the same time, patient-derived tumor xenografts and organoids now comprise effective tools for genetic evolution studies, biomarker identification, drug screening, and preclinical evaluation of personalized medicine strategies for GC patients. These advances are making it feasible to integrate clinical, genome-based and phenotype-based diagnostic and therapeutic methods and apply them to individual GC patients in the era of precision medicine.

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“…Despite the known difficulty of reliable CNA detection from amplicon-based targeted sequencing data (because of variable amplification efficiency across targets) [14, 18], OFA with a proprietary analysis pipeline with in silico reference normal tissue data could identify 17 CNAs, 16 (94.1%) of which were validated by ISH. However, the IHC panel was able to identify an additional 5 ERBB2 amplified cases, which were confirmed by ISH.…”

Section: Discussionmentioning

confidence: 99%

“…Regarding GC, despite recent studies with comprehensive molecular profiling [3, 4, 14, 15], no clinical data demonstrating target-drug efficacy in the context of umbrella studies have been published yet. In addition, the very small sizes of FFPE gastric biopsy specimens pose practical and technical challenges often result in sequencing assay failures due to low yield and poor quality of extracted DNA.…”

Section: Introductionmentioning

confidence: 99%

Complementary utility of targeted next-generation sequencing and immunohistochemistry panels as a screening platform to select targeted therapy for advanced gastric cancer

et al. 2017

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We tested the clinical utility of combined profiling of Ion Torrent PGM based next-generation sequencing (NGS) and immunohistochemistry (IHC) for assignment to molecularly targeted therapies. A consecutive cohort of 93 patients with advanced/metastatic GC who underwent palliative chemotherapy between March and December 2015 were prospectively enrolled. Formalin fixed paraffin embedded tumor biopsy specimens were subjected to a 10 GC panels [Epstein Barr virus encoding RNA in-situ hybridization, IHC for mismatch repair proteins (MMR; MLH1, PMS2, MSH2, and MSH6), receptor tyrosine kinases (HER2, EGFR, and MET), PTEN, and p53 protein], and a commercial targeted NGS panel of 52 genes (Oncomine Focus Assay). Treatment was based on availability of targeted agents at the time of molecular diagnosis. Among the 81 cases with available tumor samples, complete NGS and IHC profiles were successfully achieved in 66 cases (81.5%); only IHC results were available for 15 cases. Eight cases received matched therapy based on sequencing results; ERBB2 amplification, trastuzumab (n = 4); PIK3CA mutation, Akt inhibitor (n = 2); and FGFR2 amplification, FGFR2b inhibitor (n = 2). Eleven cases received matched therapy based on IHC; ERBB2 positivity, trastuzumab (n = 5); PTEN loss (n = 2), PI3Kβ inhibitor; MMR deficiency (n = 2), PD-1 inhibitor; and EGFR positivity (n = 2), pan-ERBB inhibitor. A total of 19 (23.5%) and 62 (76.5%) cases were treated with matched and non-matched therapy, respectively. Matched therapy had significantly higher overall response rate than non-matched therapy (55.6% vs 13.1%, P = 0.001). NGS and IHC markers provide complementary utility in identifying patients who may benefit from targeted therapies.

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Comprehensive analyses using next-generation sequencing and immunohistochemistry enable precise treatment in advanced gastric cancer

Cited by 67 publications

References 24 publications

Comprehensive expression profiles of gastric cancer molecular subtypes by immunohistochemistry: implications for individualized therapy

Comprehensive expression profiles of gastric cancer molecular subtypes by immunohistochemistry: implications for individualized therapy

Gastric Cancer in the Era of Precision Medicine

Complementary utility of targeted next-generation sequencing and immunohistochemistry panels as a screening platform to select targeted therapy for advanced gastric cancer

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