Mismatch Repair Deficiency, Microsatellite Instability, and Survival

Smyth, Elizabeth; Wotherspoon, Andrew; Peckitt, Clare; González, David; Hulkki-Wilson, Sanna; Eltahir, Zakaria; Fassan, Matteo; Rugge, Massimo; Valeri, Nicola; Okines, Alicia; Hewish, Madeleine; Allum, William; Stenning, Sally; Nankivell, Matthew; Langley, Ruth E.; Cunningham, David

doi:10.1001/jamaoncol.2016.6762

Cited by 433 publications

(295 citation statements)

References 35 publications

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“…Here we showed that MSI is associated with specific clinical and pathological features of GC [3-5], even if the lack of association with N0 disease in this series may be related to the enrollment of patients with poorer disease stage. In multivariable analysis, a nonsignificant trend for better DFS and OS in MSI-high Asian GC patients was still evident following adjuvant chemo(radio)therapy treatment, even if the small number of patients with MSI-high status may have halted the formal achievement of a statistically significant result.…”

Section: Discussionmentioning

confidence: 86%

“…However, the clinical translation of MSI as a prognostic biomarker for GC patients has been hampered by the retrospective and heterogeneous nature of available series, the relatively low frequency of MSI-high status, and the potential detrimental effect of “over-treatments” with perioperative chemotherapy in MSI-high GC patients. The post hoc analysis of the MAGIC trial [5] showed that MSI-high status is a good prognostic factor in GC patients treated with surgery alone, whereas it may be a negative predictive marker in patients randomized to perioperative combination chemotherapy. However, it must be pointed out that disease outcomes and treatment efficacy are markedly different in Western versus Eastern countries and, consequently, there may be a possible differential prognostic or even predictive role of MSI-high status that still remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Given the hypermutated status of MSI-high GC, a typical lymphocyte-rich histology is often observed [3]. Since several studies showed that MSI may be associated with a better prognosis of patients with resected GC [4, 5], we aimed at specifically assessing the prognostic role of MSI status in Asian ARTIST trial patients.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic Impact of Microsatellite Instability in Asian Gastric Cancer Patients Enrolled in the ARTIST Trial

Miceli

An²,

Bartolomeo

et al. 2019

Oncology

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Background: Caucasian patients with microsatellite instability (MSI)-high gastric cancer (GC) may have better prognosis but worse outcomes. Objective: Here we explored the prognostic role of MSI in Asian patients. Methods: This post hoc analysis comprehended radically resected GC patients randomized to XP (capecitabine/cisplatin) or XPRT. MSI status was assessed by combining immunohistochemistry with multiplex polymerase chain reaction. The MSI prognostic effect on disease-free survival (DFS) and overall survival (OS) was evaluated. Results: 393 tissue samples were analyzed and 35 (9%) were MSI-high. This subgroup was characterized by: older age, Borrmann classification 1–2, antral localization, T3–4 stage, and intestinal type. At univariable analysis, the microsatellite-stable subgroup showed a trend toward a worse prognosis as compared to the MSI-high group: 3-year DFS was 76.3 versus 85.4% (p = 0.122); 3-year OS was 81.7 versus 91.4% (p = 0.046). Multivariable analyses confirmed it in both DFS (hazard ratio, HR = 2.32 [95% CI 0.91, 5.88]; p = 0.077) and OS (HR = 3.17 [95% CI 0.97, 10.43]; p = 0.057). Conclusions: MSI-high status was associated with specific clinical-pathological features and a trend toward better outcomes of Asian GC patients.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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Prognostic Impact of Microsatellite Instability in Asian Gastric Cancer Patients Enrolled in the ARTIST Trial

Miceli

An²,

Bartolomeo

et al. 2019

Oncology

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“…In February 2017, an exploratory post hoc analysis from the MAGIC trial was published [12]. The goal was to evaluate the proportion of patients with high MSI (MSI-H) or mismatch repair deficiency (MMRD) in the 2 cohorts, and if these biomarkers had prognostic effect on survival.…”

Section: Discussionmentioning

confidence: 99%

Perioperative Treatment in Gastric Cancer—Developments in Patient Selection

Machado¹,

Magalhães²,

Fontes‐Sousa³

2018

JCT

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Gastric cancer (GC) is a major public health issue. It is considered the 5 th most common cancer diagnosed worldwide and it is one of the main causes of malignant disease-associated morbidity and mortality. The cornerstone of curative treatment is still surgery, and since the rate of relapse is high, a multidisciplinary approach is warranted in most developed countries. And while there have been recent developments in the perioperative scenario namely the FLOT regimen, little has advanced considering patient selection. We have reviewed the major trials in this setting and provide some insights from recently reported microsatellite instability (MSI) in a subgroup analysis in the MAGIC trial patients that seem to suggest an opportunity to patient selection. Furthermore, GC subtyping may prove helpful selecting candidates to immunotherapy or even multimodal therapy in the future. As the paradigm is moving towards a precision oncology model, GC patient selection remains one the biggest challenges in oncology but seems closer to clinical practice reality as new developments are being reported.

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“…Při-pravovaná studie EORTC 1707 plánuje srovnat efekt pooperační chemoterapie s kombinací nivolumab + ipilimumab u prognosticky nepříznivé skupiny pa cientů, která operací po neoadjuvanci dosáhla pouze R1 resekce, nebo s N+ stavem po operaci. Post-hoc analýza studie MAGIC [21] stejné skupiny autorů provedla rozbor v souvislosti s MSI/ dMMR stavem. Pa cienti, kteří mají nádory s MSI--high (tato skupina představovala ve zmiňované studii okolo 10 % pa cientů), mají lepší prognózu a neprofitují z chemoterapie, naopak analogicky pa cienti, kteří nemají MSI-high nebo dMMR, měli benefit z aplikované chemoterapie.…”

Section: Checkpoint Inhibitory U Potenciálně Operabilního Karcinomu žunclassified

Checkpoint Inhibitors in the Treatment of Upper Gastrointestinal Tract Tumors

Obermannová¹

2017

Klin Onkol

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Klinika komplexní onkologické péče Masarykova onkologického ústavu, Brno Lékařská fakulta MU, Brno SouhrnKombinovaná chemoterapeutická léčba vedla u metastatického karcinomu jícnu (esophageal cancer -EC) a žaludku (gastric cancer -GC) k prodloužení celkového přežití (over all survival -OS). Neuspokojivý přínos terapie klasickými cytostatiky inicioval hledání nových možností léčby. U metastatického onemocnění byla neúspěšně testována řada cílených léků, jako například EGFR protilátky/ inhibitory, inhibitory angiogeneze (bevacizumab), multikinázové inhibitory, met inhibitory, mTOR, atd. Trastuzumab zůstává jediným cíleným lékem se známým prediktorem, který prodloužil OS u metastatického adenokarcinomu gastroezofageální junkce (gastroesophageal junction -GEJ) a ža-ludku. V minulých 2 letech publikovala skupina The Cancer Genome Atlas analýzu založenou na genomické charakteristice GC a EC. Lepší porozumění nádorové bio logii může být cestou ke stratifikaci léčby na základě genetických znaků nádorové buňky a nikoliv pouze na podkladě anatomickém nebo histologickém. Rychlý vývoj výzkumu protinádorové imunity poslední dekády a úspěchy na poli využití checkpoint inhibitorů u maligního melanomu umožnily také výzkum jejich účinku u dalších nádo-rových chorob vč. gastrointestinálních malignit. Checkpoints jsou součástí komplexního a složitého procesu imunitního systému a současně klíčovými body ve vzniku nádorové tolerance. Jejich aktivace chrání organizmus před vznikem autoimunitních reakcí, ale současně umožňuje navození nádorové tolerance. Mezi tyto kontrolní body patří cytotoxický T lymfocytární antigen 4 (CTLA-4) a programmed death-1 (PD-1) receptory a ligand PD-1 receptoru programmed death ligand-1 (PD-L1). V tomto sdělení shrnuji současné poznatky o aktuálních výsledcích léčby checkpoint inhibitory u EC a GC. Klíčová slova karcinom jícnu -karcinom žaludku -checkpoint inhibitory SummaryChemotherapy prolongs overall survival (OS) in esophageal (EC) and gastric cancer (GC). Unsatisfactory results of systemic therapy initiated a search for new treatment options. In metastatic disease, a number of targeted drugs were tested; however, several phase III studies assessing receptor tyrosin kinase-related signaling pathways, such as EGFR, MET/HGF or mTOR, failed. Trastuzumab remains the only targeted drug with a known molecular predictor, which extended the OS in metastatic gastric adenocarcinoma and adenocarcinoma of esophago-gastric junction. In the past two years, The Cancer Genome Atlas group published an analysis based on the genomic characteristics of GC and EC. Therefore, a better understanding of tumor biology may be a way towards stratification of treatment based on genetic and molecular characteristics and not merely on anatomical or histological basis. The rapid development in research of anti-tumor immunity and an achievement in the field of checkpoint inhibitors use in malignant melanoma have also enabled research in other cancers, including gastrointestinal malignancies. Checkpoints are part of a comprehensive a...

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Mismatch Repair Deficiency, Microsatellite Instability, and Survival

Cited by 433 publications

References 35 publications

Prognostic Impact of Microsatellite Instability in Asian Gastric Cancer Patients Enrolled in the ARTIST Trial

Prognostic Impact of Microsatellite Instability in Asian Gastric Cancer Patients Enrolled in the ARTIST Trial

Perioperative Treatment in Gastric Cancer—Developments in Patient Selection

Checkpoint Inhibitors in the Treatment of Upper Gastrointestinal Tract Tumors

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