Recent clinical trials have shown the promising therapeutic effects of pembrolizumab and nivolumab in patients with advanced gastric cancer. Currently, the programmed death ligand-1 (PD-L1) 22C3 ...pharmDx assay is the only companion diagnostic assay for assessing the safety and effectiveness of pembrolizumab. The purpose of this study was to compare 22C3 pharmDx and 28-8 pharmDx, a complementary diagnostic assay for nivolumab, in gastric cancer. In this study, 22C3 and 28-8 pharmDx assays were performed on the same formalin-fixed, paraffin-embedded tissue blocks of gastric adenocarcinoma clinical samples (n = 55). The concordance rate was evaluated using combined positive score (CPS) cutoffs of 1, 10, and 50. PD-L1 positivity with CPS ≥ 1 was 45.5% using the 22C3 pharmDx assay and 49.1% using the 28-8 pharmDx assay. At a CPS cutoff of 1, the overall percentage agreement was 96.4%. The positive and negative percentage agreements were 93.3% and 100%, respectively. All cases positive for PD-L1 using the 22C3 pharmDx assay were also positive using the 28-8 pharmDx assay. At a CPS cutoff of 10, the overall percentage agreement was 96.4%. At a CPS cutoff of 50, the two assays exhibited 100% concordance. Nonspecific cytoplasmic staining in the background tissues and tumor cells was often observed in the 28-8 pharmDx assay. When the results of the two assays were matched for response to immunotherapy, the overall response rate was higher in patients with a PD-L1 CPS ≥ 1 than in PD-L1-negative patients (22C3 pharmDx, P = 0.001; 28-8 pharmDx, P = 0.002). In conclusion, PD-L1 22C3 and 28-8 pharmDx assays were highly comparable at CPS cutoffs of 1, 10, and 50 in gastric cancer. These results provide evidence for the potential interchangeability of the two PD-L1 assays in gastric cancer.
Accurate detection of genomic alterations using high-throughput sequencing is an essential component of precision cancer medicine. We characterize the variant allele fractions (VAFs) of somatic ...single nucleotide variants and indels across 5095 clinical samples profiled using a custom panel, CancerSCAN. Our results demonstrate that a significant fraction of clinically actionable variants have low VAFs, often due to low tumor purity and treatment-induced mutations. The percentages of mutations under 5% VAF across hotspots in EGFR, KRAS, PIK3CA, and BRAF are 16%, 11%, 12%, and 10%, respectively, with 24% for EGFR T790M and 17% for PIK3CA E545. For clinical relevance, we describe two patients for whom targeted therapy achieved remission despite low VAF mutations. We also characterize the read depths necessary to achieve sensitivity and specificity comparable to current laboratory assays. These results show that capturing low VAF mutations at hotspots by sufficient sequencing coverage and carefully tuned algorithms is imperative for a clinical assay.
Exosomes are a subtype of extracellular vesicles ranging from 30 to 150 nm and comprising many cellular components, including DNA, RNA, proteins, and metabolites, encapsulated in a lipid bilayer. ...Exosomes are secreted by many cell types and play important roles in intercellular communication in cancer. Viruses can hijack the exosomal pathway to regulate viral propagation, cellular immunity, and the microenvironment. Cells infected with Epstein-Barr virus (EBV), one of the most common oncogenic viruses, have also been found to actively secrete exosomes, and studies on their roles in EBV-related malignancies are ongoing. In this review, we focus on the role of exosomes in EBV-associated gastric cancer and their clinical applicability in diagnosis and treatment.
In the CLASSIC and MAGIC trials, microsatellite instability (MSI)-high status was a favorable prognostic and potential negative predictive factor for neoadjuvant/adjuvant chemotherapy in resectable ...gastric cancer (GC). Given the low prevalence of MSI-high status in GC and its association with other positive prognostic variables, large data sets are needed to draw robust evidence of its prognostic/predictive value.
We performed a multinational, individual-patient-data meta-analysis of the prognostic/predictive role of MSI in patients with resectable GC enrolled in the MAGIC, CLASSIC, ARTIST, and ITACA-S trials. Prognostic analyses used multivariable Cox models (MVM). The predictive role of MSI was assessed both in an all-comer population and in MAGIC and CLASSIC trials by MVM testing of the interaction of treatment (chemotherapy plus surgery
surgery) with MSI.
MSI status was available for 1,556 patients: 121 (7.8%) had MSI-high status; 576 were European, and 980 were Asian. In MSI-high versus MSI-low/microsatellite stable (MSS) comparisons, the 5-year disease-free survival (DFS) was 71.8% (95% CI, 63.8% to 80.7%) versus 52.3% (95% CI, 49.7% to 55.1%); the 5-year overall survival (OS) was 77.5% (95% CI, 70.0% to 85.8%) versus 59.3% (95% CI, 56.6% to 62.1%). In MVM, MSI was associated with longer DFS (hazard ratio HR, 1.88; 95% CI, 1.28 to 2.76;
< .001) and OS (HR, 1.78; 95% CI, 1.17 to 2.73;
= .008), as were pT, pN, ethnicity, and treatment. Patients with MSI-low/MSS GC benefitted from chemotherapy plus surgery: the 5-year DFS compared with surgery only was 57% versus 41% (HR, 0.65; 95% CI, 0.53 to 0.79), and the 5-year OS was 62% versus 53% (HR, 0.75; 95% CI, 0.60 to 0.94). Conversely, those with MSI-high GC did not: the 5-year DFS was 70% versus 77% (HR, 1.27; 95% CI, 0.53 to 3.04), and the 5-year OS was 75% versus 83% (HR, 1.50; 95% CI, 0.55 to 4.12).
In patients with resectable primary GC, MSI is a robust prognostic marker that should be adopted as a stratification factor by clinical trials. Chemotherapy omission and/or immune checkpoint blockade should be investigated prospectively in MSI-high GCs according to clinically and pathologically defined risk of relapse.
Intestinal-type gastric carcinoma exhibits a multistep carcinogenic sequence from adenoma to carcinoma with a gradual increase in genomic alterations. But the roles of microRNAs (miRNA) in this ...multistage cascade are not fully explored. To identify differentially expressed miRNA (DEM) during early gastric carcinogenesis, we performed miRNA microarray profiling with 24 gastric cancers and precursor lesions (7 early gastric cancer EGC, 3 adenomas with high-grade dysplasia, 4 adenomas with low-grade dysplasia, and 10 adjacent normal tissues). Alterations in the expression of 132 miRNA were detected; these were categorized into three groups based on their expression patterns. Of these, 42 miRNAs were aberrantly expressed in EGC. Five miRNA (miR-26a, miR-375, miR-574-3p, miR-145, and miR-15b) showed decreased expression since adenoma. Expression of two miRNA, miR-200C and miR-29a, was down-regulated in EGCs compared to normal mucosa or adenomas. Six miRNA (miR-601, miR-107, miR-18a, miR-370, miR-300, and miR-96) showed increased expression in gastric cancer compared to normal or adenoma samples. Five representative miRNAs were further validated with RT-qPCR in independent 77 samples. Taken together, these results suggest that the dysregulated miRNA show alterations at the early stages of gastric tumorigenesis and may be used as a candidate biomarker.
Background
Sarcopenia has been underscored as a significant predictor of poor prognosis in cancer patients undergoing immunotherapy with programmed death-1 (PD-1) inhibitors. We aimed to investigate ...the prognostic significance of computed tomography (CT)-determined sarcopenia in patients with microsatellite-stable (MSS) gastric cancer (GC) treated with PD-1 inhibitors.
Methods
We retrospectively assessed patients with MSS GC who had been treated with PD-1 inhibitors from March 2016 to June 2019. Pre-treatment sarcopenic status was determined by analyzing L3 skeletal muscle index with abdominal CT. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method, and the differences in survival probability according to sarcopenic status were compared using the log-rank test. Cox proportional hazards regression analyses were performed to identify predictors of PFS and OS.
Results
Of 149 patients with MSS GC (mean age, 57.0 ± 12.3 years; 93 men), 79 (53.0%) had sarcopenia. Patients with sarcopenia had significantly shorter PFS than patients without sarcopenia (median, 1.4 months vs. 2.6 months;
P
= 0.026). Sarcopenia was independently associated with shorter PFS (adjusted hazard ratio HR, 1.79; 95% confidence interval CI, 1.10−2.93;
P
= 0.020). Patients with sarcopenia had shorter OS than patients without sarcopenia (median, 3.6 months vs. 4.9 months;
P
= 0.052), but sarcopenia itself was not a significant prognostic factor for OS (adjusted HR, 1.01; 95% CI, 0.58−1.75;
P
= 0.974).
Conclusions
CT-determined sarcopenia is an independent prognostic factor for PFS in patients with MSS GC treated with PD-1 inhibitors.
Tumors exhibiting DNA mismatch repair (MMR) deficiency and microsatellite instability (MSI) are responsive to immune checkpoint blockade. MSI is frequently diagnosed using five quasimonomorphic ...mononucleotide (pentaplex) markers; however, the assays have several technical limitations, including the lack of sensitivity of some of the markers. Although markers with increased sensitivity, such as CAT25 and BAT40, have been introduced, the majority of multiplex MSI tests have only been studied in Western populations and require further evaluation in an Asian cohort.
This study tested the efficacy of BAT26, CAT25, and BAT40 mononucleotide MSI markers via triplex PCR on 300 samples from patients with advanced cancers from a Korean clinical population. The results were directly compared with those of a pentaplex MSI test and tumor mutation burden (TMB) status, and an additional 60 MSI‐H cancers were used for further validation.
Four (1.3%) out of 300 advanced tumors were MSI‐high (MSI‐H). In the pentaplex PCR assay, two colorectal cancers (0.7%) exhibited instability only with the BAT25 mononucleotide marker and were interpreted as MSI‐low (MSI‐L). In the triplex PCR assay, BAT40 was unstable in 64 cases (21%) and the results did not overlap with those of MSI‐L from pentaplex. Given the high frequency of isolated BAT40 instability, we performed the same triplex PCR with DNA obtained from normal controls and found BAT40 polymorphisms in 37 cases (90%). Interestingly, the median TMB of the cases with BAT40 polymorphism was significantly higher (7.0 mt/Mb) than that of BAT40 wild‐type cases (5.5 mt/Mb) (p = 0.003). The triplex PCR results from 60 additional MSI‐H cancers correlated perfectly (100%) with those of pentaplex PCR, and the results were consistent for two (BAT26 and CAT25) markers.
BAT40 germline polymorphism is common in the Korean population and is associated with higher TMB values. The simple duplex (BAT26 and CAT25) MSI test provided the same sensitivity and specificity as pentaplex PCR tests.
Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers and associated with clinical response to anti-PD-1 antibodies. However, 50% of ...microsatellite instability-high (MSI-H) cancers are intrinsically resistant to PD-1 therapies. We conducted a phase II trial of pembrolizumab in patients with advanced MSI-H gastric cancer and included serial and multi-region tissue samples in addition to serial peripheral blood analyses. The number of whole-exome sequencing (WES)-derived nonsynonymous mutations correlated with antitumor activity and prolonged progression-free survival (PFS). Coupling WES to single-cell RNA sequencing, we identified dynamic tumor evolution with greater on-treatment collapse of mutational architecture in responders. Diverse T-cell receptor repertoire was associated with longer PFS to pembrolizumab. In addition, an increase in PD-1
CD8
T cells correlated with durable clinical benefit. Our findings highlight the genomic, immunologic, and clinical outcome heterogeneity within MSI-H gastric cancer and may inform development of strategies to enhance responsiveness. SIGNIFICANCE: This study highlights response heterogeneity within MSI-H gastric cancer treated with pembrolizumab monotherapy and underscores the potential for extended baseline and early on-treatment biomarker analyses to identify responders. The observed markers of intrinsic resistance have implications for patient stratification to inform novel combinations among patients with intrinsically resistant features.
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Detecting microsatellite instability (MSI) in advanced cancers is crucial for clinical decision-making, as it helps in identifying patients with differential treatment responses and prognoses. BAT26 ...is a highly sensitive MSI marker that defines the mismatch repair (MMR) status with high sensitivity and specificity. However, isolated BAT26-only instability is rare and has not been previously reported. Of the 6476 cases tested using pentaplex MSI polymerase chain reaction, we identified two BAT26-only instability cases (0.03%) in this study. The case #1 patient was diagnosed with endometrial adenocarcinoma without MMR germline mutations. The endometrial tumor showed BAT26-only instability, partial loss of MLH1/PMS2 protein expression, and a high programmed cell death ligand 1 (PD-L1) combined positive score (CPS = 8). The tumor exhibited a somatic phosphatase and tensin homolog (PTEN) R303P missense mutation and loss of the PTEN protein. On a comprehensive cancer panel sequencing with ≥500 genes, the tumor showed an MSI score of 11.38% and high tumor mutation burden (TMB) (19.5 mt/mb). The case #2 patient was diagnosed with colorectal carcinoma with proficient MMR and PTEN protein loss without PTEN alteration, as well as a high PD-L1 CPS (CPS = 10). A pathogenic KRAS A146T mutation was detected with an MSI score of 3.36% and high TMB (13 mt/mb). In conclusion, BAT26-only instability is very rare and associated with PTEN protein loss, high TMB, and a high PD-L1 score. Our results suggest that patients with BAT26-only instability may show good responses to immunotherapy.
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