MSI and EBV Positive Gastric Cancer’s Subgroups and Their Link with Novel Immunotherapy
Abstract
:1. Introduction
2. Molecular Landscape and Classification of Gastric Cancer
3. EBV Positive GCs
4. MSI Positive GCs
5. Immunotherapy in EBV Positive and MSI-H GCs
6. How to Better Select Patients for Immunotherapy: Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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SUBTYPES | MOLECULAR FEATURES | |
---|---|---|
TCGA (The Cancer Genome Atlas) | EBV (9%) | - DNA hypermethylation, including CDKN2A (p16) but not MLH1 promoters |
- PIK3CA mutations | ||
- JAK2 gene amplification | ||
- PDL1/PDL2 overexpression | ||
MSI (22%) | - high mutation rate | |
- DNA methylation with epigenetic silencing of MLH1 | ||
- Hypermutation of many genes including HLA class 1 factors | ||
GS (20%) | - molecular alterations in cell adhesion/ cell migration pathways | |
- ARID1 and BCOR mutations | ||
CIN (50%) | - chromosomal instability (CIN) | |
- amplification of genes (most encoding tyrosine kinase receptors) | ||
ACRG (Asian Cancer Research Group) | MSS/TP53 + (26%) | - frequent EBV positivity |
- intermediate mutation rate | ||
MSI (23%) | - high mutation rate | |
EMT (15%) | - low mutation rate | |
- loss of epithelial markers | ||
MSS/TP53- (36%) | - TP53 mutations | |
- genomic instability | ||
Li et al. Classification | REGULAR C1 | - 2.4 mutations /megabase; range, 0–8.3 |
- TP53, XIRP2, APC mutations | ||
REGULAR C2 | - 2.4 mutations /megabase; range, 0–8.3 | |
- ARID1A, CDH1, PIK3CA, ERBB2, RHOA mutations | ||
- | ||
HYPERMUTATED | - 20.5 mutations/megabase; range, 9.6–200.2) |
Trial/Author | Target | Agent | Line | Control | Endpoint | Result | Difference mOS (m) (HR) |
---|---|---|---|---|---|---|---|
Keynote061 | PD1 | Pembrolizumab | 2nd | Paclitaxel | OS | Negative | +0.8 (HR 0.82) |
JAVELIN300 | PD1 | Avelumab | 3rd | Irinotecan/taxanes | OS | Negative | −0.4 (HR 1.1) |
ATTRACTION-2 | PD1 | Nivolumab | 3rd | Placebo | OS | Positive | +1.2 (HR 0.63) |
AVAGAST | VEGF-A | Bevacizumab | 1st | Placebo (+chemo) | OS | Negative | +2 (HR 0.87) |
RAINFALL | VEGFR2 | Ramucirumab | 1st | Placebo (+chemo) | OS | Negative | +0.4 (HR 0.96) |
REGARD | VEGFR2 | Ramucirumab | 2nd | Placebo | OS | Positive | +1.4 (HR 0.776) |
RAINBOW | VEGFR2 | Ramucirumab | 2nd | Placebo (+chemo) | OS | Positive | +2.2 (HR 0.807) |
Li. et al. | VEGFR2 | Apatinib | 3rd | Placebo | OS | Positive | +1.8 (HR 0.71) |
REAL-3 | EGFR | Panitumumab | 1st | (+chemo) | OS | Negative | −2.5 (HR 1.37) |
EXPAND | EGFR | Cetuximab | 1st | Placebo (+chemo) | PFS | Negative | −1.3 (HR 1.0) |
ToGA | HER2 | Trastuzumab | 1st | (+chemo) | OS | Positive | +2.7 (HR 0.74) |
Logic | HER2 | Lapatinib | 1st | Placebo (+chemo) | OS | Negative | +1.7 (HR 0.91) |
JACOB | HER2 | Pertuzumab | 1st | Placebo (+chemo + Tmab) | OS | Negative | +3.3 (HR 0.84) |
TyTAN | HER2 | Lapatinib | 2nd | (+chemo) | OS | Negative | +3 (HR 0.84) |
GATSBY | HER2 | T-DM1 | 2nd | Taxanes | OS | Negative | −0.7 (HR 1.15) |
GRANITE-1 | mTOR | Everolimus | 2nd/3rd | Placebo | OS | Negative | +1.05 (HR 0.9) |
GRANITE-2 | mTOR | Everolimus | 2nd | Placebo (+chemo) | OS | Negative | +1.0 (HR 0.92) |
RILOMET1 | HGF | Rilotumumab | 1st | Placebo (+chemo) | OS | Negative | −2.9 (HR 1.36) |
METgastric | MET | Onartuzumab | 1st | Placebo (+chemo) | OS | Negative | −0.3 (HR 0.82) |
GOLD | PARP | Olaparib | 2nd | Placebo (+chemo) | OS | Negative | +1.9 (HR 0.79) |
BRIGHTER | STAT3 | Napabucasin | 2nd | Placebo (+chemo) | OS | Negative | −0.4 (HR 1.01) |
Next-Generation Sequencing Techniques | |
---|---|
Whole-genome sequencing (WGS) | Single-nucleotide resolution of all genome bases |
Whole-exome sequencing (WES) | Single-nucleotide resolution of protein-codon areas of the genome |
Targeted sequencing | Covers limited subsets of candidate genes |
RNA sequencing | Sequencing of each RNA transcript |
Gene expression profiling | Evaluates the RNA level of a single gene with further functional associations; cell environment as potential bias |
Esophageal Cancer | Gastroesophageal Cancer | ||
---|---|---|---|
Gene | Frequency (%) | Gene | Frequency (%) |
TP53 | 60–93 | TP53 | 14–59 |
CCND1 | 33–46 | PIK3CA | 7–36 |
CDKN2A | 12–47 | CDH1 | 4–36 |
KMT2D | 19–26 | HER2 | 2–32 |
FAT1 | 14–27 | ARID1A | 8–27 |
KRAS | 5–27 | KRAS | 0–27 |
EGFR | 6–24 | PTEN | 0–27 |
NOTCH | 9–19 | RHOA | 0–23 |
PIK3CA | 4–10 | APC | 3–14 |
ERBB3 | 0–10 | ||
CTNNB1 | 2–9 | ||
MET | 0–9 | ||
SMAD4 | 4–6 | ||
FBXW7 | 2–6 |
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Rodriquenz, M.G.; Roviello, G.; D’Angelo, A.; Lavacchi, D.; Roviello, F.; Polom, K. MSI and EBV Positive Gastric Cancer’s Subgroups and Their Link with Novel Immunotherapy. J. Clin. Med. 2020, 9, 1427. https://doi.org/10.3390/jcm9051427
Rodriquenz MG, Roviello G, D’Angelo A, Lavacchi D, Roviello F, Polom K. MSI and EBV Positive Gastric Cancer’s Subgroups and Their Link with Novel Immunotherapy. Journal of Clinical Medicine. 2020; 9(5):1427. https://doi.org/10.3390/jcm9051427
Chicago/Turabian StyleRodriquenz, Maria Grazia, Giandomenico Roviello, Alberto D’Angelo, Daniele Lavacchi, Franco Roviello, and Karol Polom. 2020. "MSI and EBV Positive Gastric Cancer’s Subgroups and Their Link with Novel Immunotherapy" Journal of Clinical Medicine 9, no. 5: 1427. https://doi.org/10.3390/jcm9051427