| Molecular classification | Grade I recommendations | Grade II recommendations | Grade III recommendations |
|---|---|---|---|
| After a pathological diagnosis of gastric cancer, molecular profilinga should be conducted and treatment should be guided according to the molecular classification. |
Evaluation of PD‐L1 expression status for patients intended to be treated with PD‐1/PD‐L1 inhibitors is recommendedh (Evidence 2A) |
Detection of NTRK fusion genei (Evidence 2B) |
Abbreviations: HER2, human epidermal growth factor receptor 2; MSI, microsatellite instability; dMMR, deficient DNA mismatch repair; PD‐L1, programmed death‐ligand 1; NTRK, neurotrophic tyrosine receptor kinase;
Notes:
aFor patients with advanced gastric cancer who experienced treatment failure after standard treatment, NGS can be used to identify potential therapeutic targets. It is emphasized that certified platforms and products abiding by strict quality control and standardized operation process are recommended to ensure the reliability of obtained results.
bHER2 status has been associated with response and survival prediction of patients with advanced gastric cancer to trastuzumab treatment. Therefore, HER2 status testing is recommended for all gastric cancer [24, 25, 26, 27].
cAccording to some reports [28, 29], high‐throughput sequencing‐based serial circulating tumor DNA (ctDNA) genotyping was found to be an efficient approach to monitor resistance to trastuzumab based on differences in HER2 copy numbers in HER2 positive gastric cancer. If tissue biopsy cannot be obtained, assessment of HER2 amplification via liquid biopsy could be an effective alternative. HER2 amplification from ctDNA can also be used to monitor gastric cancer patients’ response to trastuzumab.
dIHC and in situ hybridization (ISH) techniques for HER2 assessment should be strictly performed according to the “Guidelines for HER2 detection in gastric cancer (2016)” [30]. These and related tests (IHC, FISH/double signal in situ hybridization [DSISH]) should be performed using the China Food and Drug Administration (CFDA) approved kits.
eImmune checkpoint inhibitors targeting programmed death protein‐1 (PD‐1) and its ligand‐1 (PD‐L1) have become a research hotspot in tumor immunotherapy in recent years. For patients who are to undergo immunotherapy, evaluation of MSI/MMR status and the association of PD‐L1 expression to tumor mutational burden (TMB) is recommended. The association of Epstein‐Barr virus (EBV) status with immunotherapy is still to be fully elucidated.
fMMR protein detection: immunohistochemistry detection of MLH1, PMS2, MSH2, MSH6 proteins in the nucleus of the tumor should be performed. If absence of any one of these four proteins is observed, the patient can be classified as dMMR, and if all four are present, the patient can be classified as proficient MMR (pMMR).
gMSI detection: it is recommended to use the 5 microsatellite loci (BAT25, BAT26, D5S346, D2S123, D17S250) proposed by the US National Cancer Institute (NCI). The grading criteria are as follows: MSS, if all the 5 loci are found as stable; MSI‐L, if 1 locus is found unstable; high MSI status (MSI‐H) if ≥2 loci are unstable. MSI is mostly caused by MMR gene mutation and functional defect, and its status can be reflected based on MMR protein analysis. Thus, dMMR can be considered equivalent to MSI‐H, and pMMR to low MSI status (MSI‐L) or microsatellite stability (MSS).
hFor a sample to be deemed suitable for PD‐L1 assessment, there should be at least 100 tumor cells present in the sample. PD‐L1 combined positive score (CPS) = total number of PD‐L1‐stained cells (including tumor cells, macrophages, and lymphocytes) / total number of tumor cells under microscope (× 100) [31].
iThe U.S.FDA has authorized the use of TRK inhibitors (i.e., larotrectinib or entrectinib) in patients with neurotrophic tyrosine receptor kinase (NTRK) gene fusion‐positive solid tumors. For gastric cancer patients who have failed with standard treatment, NTRK gene fusion can be detected via multiple methods. Immunohistochemistry is a fast and convenient preliminary screening method, but it still needs to be verified by FISH or NGS.