Gastric cancer is the fifth most prevalent malignant tumor in the world, and the third most deadly after lung cancer and liver cancer. Chemotherapy is the main treatment for progressive gastric cancer, and the median survival time of patients with progressive gastric cancer is only about 11 months with the combination of cytotoxic drugs. Currently, there is no unanimously accepted standard chemotherapy regimen for progressive gastric cancer internationally.
Therefore, changing the existing drug strategy and finding more effective combination chemotherapy regimens are important research directions for gastric cancer. Among the tens of thousands of genomes in tumor tissues, genes related to tumor development are called driver genes, and when the driver genes are changed, they will “drive” the tumor cells. Therefore, if we can select appropriate molecular targeted drugs for individualized treatment of tumor development, we will get twice the result with half the effort. However, the exploration of molecularly targeted therapies for gastric cancer has been a bumpy road, and most studies have ended in failure. In this paper, we mainly review the driver genes of gastric cancer with potential clinical application and their related targeted drugs.
1.Human epidermal growth factor receptor 2 (HER-2)
HER-2 is a proto-oncogene. 10%-22% of gastric cancers have amplification of HER-2 gene and overexpression of its protein product related to cell proliferation and cell activity. HER-2 is highly expressed in intestinal gastric cancer and gastroesophageal junction tumors. Unlike breast cancer, HER-2 positivity is not a factor of poor prognosis in gastric cancer.
(1) Trastuzumab
Trastuzumab (Trastuzumab) is a recombinant DNA-derived humanized monoclonal antibody that has been approved for marketing by the U.S. Food and Drug Administration for the treatment of HER-2 overexpressed malignancies. In the ToGA study, a multicenter randomized phase III clinical study of trastuzumab in patients with inoperable, locally advanced, recurrent and/or metastatic HER-2-positive gastric cancer, the median overall survival (OS) was significantly longer in the trastuzumab-chemotherapy group (13.8 months vs. 11.1 months, p=0.0048), and the objective There was also a significant increase in objective efficacy (47.3% vs. 34.5%, P=0.0017). In terms of safety, there were no unanticipated side effects in the trastuzumab group.
Subgroup analysis showed that treatment with trastuzumab resulted in further prolongation of median OS in patients with positive immunohistochemistry (IHC)2+/fluorescence in situ hybridization (FISH) or IHC3+ ( 16.0 The ToGA trial is a landmark phase III clinical trial in targeted therapy for gastric cancer, which for the first time extended the overall survival of patients to more than 1 year, greatly improving the quality of life of patients with progressive gastric cancer and fully demonstrating the advantages of individualized therapy.
(2) Lapatinib
Lapatinib is an oral inhibitor of EGFR/HER-2 receptor tyrosine kinase. Results from a phase III clinical trial of lapatinib for gastric cancer (TyTAN) showed that lapatinib in combination with paclitaxel as a second-line treatment option for patients with progressive HER-2 amplified (FISH-positive) gastric cancer improved response rates by 18% (27% vs. 9%), OS by 2.1 months, and median disease-free progression (progress Free Survival (PFS) improved by 1 month, with no statistical difference. Subgroup analysis showed that the median OS of patients in the HER-2 IHC 3+ subgroup increased from 7.6 months to 14.0 months, with a difference of 6.4 months between the two groups (P= 0.0176). However, 35% of patients with FISH-confirmed HER-2 amplification had an IHC score of 0 or 1+. The TyTAN study demonstrated that lapatinib prolonged survival in patients with progressive gastric cancer undergoing second-line therapy, but this finding was limited to individuals with HER-2-positive (IHC3+) disease by immunohistochemistry.
Another phase III clinical trial (LOGiC) investigated the efficacy of lapatinib in combination with capecitabine plus oxaliplatin or capecitabine plus oxaliplatin for HER-2-positive progressive gastroesophageal and gastroesophageal junction tumors. The results found that the combination of lapatinib did not result in an OS benefit compared with chemotherapy alone. Although the objective remission rate increased from 40% to 53%, the incidence of diarrhea and skin toxicity was higher in the combination chemotherapy group.
The efficacy of lapatinib in gastric cancer may be inferior to that of trastuzumab, and the reasons for this may be related to differences in metabolism and bioavailability of lapatinib in different patients and resistance to lapatinib in some patients. Studies have shown that resistance to lapatinib may be associated with secondary mutations in HER-2, overexpression of MET and loss of phosphatase and tensin homolog deleted on chromosome ten (PTEN) downstream and the murine sarcoma virus oncogene ( kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were associated.
The possible survival benefit of lapatinib in specific subgroups of the population warrants further investigation. In addition, the oral second-generation EGFR/HER-2 dual receptor tyrosine kinase inhibitors afatinib and dacomitinib are in clinical trials in chemotherapy-resistant patients with HER-2 overexpression.
(3) Trastuzumab emtansine (T-DM1)
T-DM1 is an antibody-drug conjugate that couples trastuzumab, a target drug that acts on HER-2, with DM1, a cytotoxic microtubule inhibitor. Given the good performance of T-DM1 in breast cancer, the role of this drug in patients with progressive gastric cancer is expected.
2 .Epidermal growth factor receptor (EGFR)
EGFR belongs to HER/erbB family, a multifunctional glycoprotein widely distributed in cell membranes of various tissues in human body. the positive rate of FISH for EGFR in gastric cancer is 4.9%, and the positive rate of IHC (2+ and 3+) is 27.4%.
(1) Cetuximab
Cetuximab (Cetuximab) is a human-mouse chimeric monoclonal antibody that acts on EGFR. The phase III EXPAND clinical trial evaluated the efficacy of cetuximab in combination with cisplatin and capecitabine in the first-line treatment of progressive gastric cancer. However, the differences in PFS and OS were not statistically significant (4.4 months vs. 5.6 months, P=0.32; 9.4 months vs. 10.7 months, P=0.95), while the incidence of grade 3/4 adverse reactions was higher in the experimental group than in the control group.
Multifactorial analysis showed that KRAS mutation (P=0.025) as well as PIK3CA mutation (P=0.04) were both factors of poor prognosis. In colon cancer, patients with KRAS wild type had better outcomes with cetuximab, while patients with KRAS mutations were resistant to cetuximab, but clinical studies have not yet shown evidence of a correlation between KRAS gene status and outcomes in patients with gastric cancer.
(2) Panitumumab
Panitumumab, a fully humanized IgG2 monoclonal antibody that blocks the binding of EGFR to its ligand, has shown efficacy in the treatment of EGFR-positive progressive colorectal cancer in REAL-3, a multicenter, randomized, phase II/III clinical trial. Application of panitumumab in combination with a modified epirubicin, oxaliplatin, and cabecitabine (EOX) regimen did not improve outcomes in patients with untreated esophageal, esophagogastric union, and gastric adenocarcinoma or undifferentiated cancer (median OS of 8.8 months), with significantly lower OS compared with the standard EOX regimen (median OS of 11.3 months) and a trend toward lower PFS (6.0 months vs. 7.4 months, P = 0.068). The absence of biomarker screening may be the main reason for the failure of panitumumab to benefit patients.
The worse survival propensity of patients may be associated with inadequate doses of chemotherapy drugs, accelerated tumor progression after discontinuation, and deterioration of the patient’s underlying condition to continue treatment.
(3) Nitrozumab
Nitrozumab (Nimotuzumab) is a humanized monoclonal antibody that targets EGFR. The results of a phase II clinical trial on nitrozumab in combination with irinotecan for gastric cancer showed a potential improvement in PFS and overall survival in patients with EGFR IHC 2+ or 3+ gastric cancer treated with nitrozumab. This is consistent with evidence that nituzumab selectively targets EGFR overexpressing tissues. Based on the results of the Phase II clinical trial, a Phase III clinical trial (ENRICH) selecting the EGFR IHC 2+ or 3+ population is underway.
The clinical trial FLEX in non-small cell lung cancer showed that IHC levels of EGFR may be a predictor of effective patient application of EGFR monoclonal antibodies as well as a prognostic factor for prolonged OS after application of EGFR monoclonal antibodies. Unfortunately, neither IHC nor FISH was applied to assess EGFR expression in the EXPAND nor in the REAL-3 trials. Although unscreened patient populations did not achieve an overall survival benefit with targeted therapies targeting the EGFR signaling pathway, there is growing evidence that such agents do benefit patients when treating specific subgroups of the population.
3. Fibroblast growth factor receptor (FGFR)
FGFR belongs to the tyrosine kinase receptor family, located on human chromosome 10 (10q26), and has autophosphorylation activity. %), HER-2 (7.2%) and MET (4.3%) were more common.
Kilgour et al. examined the amplification of FGFR2, HER-2 and MET in 764 postoperative specimens of gastric cancer. 45/764 (5.9%) of the samples had FGFR amplification. there was a significant decrease in OS (P=0.0001) in the FGFR amplified population. amplification of FGFR was also associated with lymph node metastasis (P< 0.0007) and was more common in the Korean population more commonly in diffuse gastric cancer in the Korean population.
Little is known about the effect of FGFR4 in gastric cancer. A study showed that 38% of gastric cancer patients had high FGFR4 expression in tumor tissue, 40.8% had moderate expression, 14.1% had low expression, and 7% had no expression. five-year survival rate of gastric cancer patients with low FGFR4 expression reached 61.5%, while only 42% of gastric cancer patients had high FGFR4 expression (P = 0.058). Analysis of subgroups of gastric cancer patients showed that patients in stages III and IV had a poorer prognosis, which was associated with high FGFR4 expression (P = 0.044).
Starting with molecular targeting of FGFR, promising results have been obtained from in vivo as well as in vitro trials targeting gastric cancer with high FGFR expression. The inhibitors against FGFR, ponatinib, dovitinib, NVP-BGJ396 and AZD4547, showed significant inhibition in gastric cancer cell lines with high FGFR expression as well as in a nude mouse suppressor tumor model established with high FGFR expressing gastric cancer cell lines. These findings will provide a strong basis for the application of FGFR-targeted targeted drugs in the future 5% of gastric cancer population with high FGFR expression.
4. Hepatocyte growth factor receptor proto-oncogene MET
MET receptor and its ligand hepatocyte growth factor (HGF) are involved in cell signaling associated with regulatory proteins and oncogene products. In gastric cancer, MET amplification rates ranged from 0% to 20%, with wide variations reported in different literature, which may stem from differences in experimental methodologies.
(1) Foretinib
Foretinib is a dual inhibitor of MET and VEGFR2/KDR with antitumor activity in MET-amplified tumor cell lines and xenograft tumor models. Results from a multicenter phase II clinical study showed that the best outcome was stable disease in 74 patients with a duration of stable disease of 1.9-7.2 months (median 3.2 months). c-MET gene amplification was detected by FISH at a rate of 4.5% (3/67 cases), of which 1 case was stable. Although Foretinib inhibits c-MET gene expression, gastric cancer is rarely regulated by MET and VEGFR2 alone, and definitive efficacy of single agent Foretinib in unselected progressive gastric cancer is difficult.
(2) Onartuzumab
Onartuzumab (MetMAb) is a recombinant humanized monovalent monoclonal antibody that exerts antitumor effects by blocking the binding of HGF to MET. Catenacci et al. found that MET IHC-positive patients had a full 2-year duration of effectiveness for Onartuzumab. In addition to this, a phase III clinical study of Onartuzumab in combination with mFOLFOX6 for HER-2 negative but MET positive (IHC2+/3+) progressive gastric cancer has been conducted.
(3) Rilotumumab
The results of the clinical phase II study of rilotumumab showed that the combination of epirubicin, cisplatin, and capecitabine (ECX) as a first-line treatment regimen with rilotumumab resulted in greater clinical benefit in patients with higher levels of MET expression than ECX alone (11.1 patients). clinical benefit compared with ECX alone (11.1 months vs. 5.7 months, P = 0.012). In contrast, patients with low MET expression plus Rilotumumab treatment did not have a favorable outcome.
A separate phase III study is evaluating the safety and efficacy of Rilotumumab in combination with the ECX regimen for first-line treatment based on the results of the phase II study. This study is ongoing and is expected to yield positive results and screen for a benefit population.
5. insulin 1 like growth factor 1 receptor (IGF-1R)
IGF-1R is a tyrosine kinase transmembrane protein receptor that plays an important role in cell division and differentiation and proliferation through its downstream regulated Raf-MEK-ERK and AKT-mTOR-S6K signaling pathways.
Jiang et al. examined 86 surgically resected specimens of gastric cancer and found that 62% of the specimens had IGF-1R overexpression, and patients overexpressing IGF-1R were more likely to develop lymph node metastasis. Matsubara et al. examined surgical specimens of 87 patients with progressive gastric cancer, and 77% of the patients expressed IGF-1R, and the IGF-1R IHC positivity rate was 29% (25/87 ), which was associated with poor prognosis (P=0.03). This study also noted a correlation between IGF-1R, EGFR and HER-2 expression: 55% of gastric cancer patients expressed both IGF-1R and EGFR, 18% of HER-2-positive patients expressed IGF-1R, and patients with low expression of both IGF-1R and EGFR had a longer OS.
Figitumumab is a fully humanized IgG2 monoclonal antibody that acts on IGF-1R, inducing receptor internalization and inhibiting autophosphorylation. The drug is still in phase I clinical study in gastric cancer treatment, and its efficacy and safety need to be confirmed by further trial data.
6.Vascular endothelial growth factor (VEGF)
VEGF is a growth factor that acts specifically on vascular endothelial cells to induce the growth of blood vessels and is directly involved in inducing the formation of tumor blood vessels. Studies have confirmed that VEGF expression is associated with tumor recurrence and poor prognosis in patients with gastric cancer and adenocarcinoma of the gastroesophageal junction, and those with high VEGF expression have a relatively poor prognosis.
(1) Bevacizumab
The phase III clinical trial of AVAGAST evaluated the efficacy of capecitabine and cisplatin in combination with bevacizumab as a first-line treatment for progressive gastric cancer. The results showed that bevacizumab did not significantly prolong OS (12.1 months vs. 10.1 months, P= 0.10), but PFS was significantly prolonged (6.7 months vs. 5.3 months, P= 0.0037) and the objective response rate was significantly higher (46% vs. 37%, P= 0.0315). use. The results showed that the efficacy of bevacizumab correlated with plasma VEGF-A levels at baseline and tumor neurofibrillary protein-1 expression.
In non-Asian populations, OS was longer in those with higher baseline VEGF-A levels and those with lower baseline neurofibrillary protein-1 expression. These findings suggest that the most important thing in the future development of gastrointestinal tumor therapy is to find the corresponding biomarkers and explore individualized treatment options is the trend.
(2) Ramulizumab
Ramucirumab is a novel humanized IgG1 monoclonal antibody that exerts its biological effects by targeting vascular endothelial growth factor receptor-2 (VEGFR-2). The use of ramolutumab was supported in the phase III clinical trial REGARD. The drug combined with best Supportive Care (BSC) as second-line therapy resulted in a significant prolongation of median OS (3.8 months vs. 5.2 months, p=0.047), meeting the trial’s primary endpoint. Remolimumab combined with BSC treatment also significantly prolonged patients’ median PFS (1.3 months vs. 2.1 months, P<0.001).
Also, the disease control rate was twice as high with the combination regimen as with the BSC-only regimen (48.7% vs. 23.1%, P< 0.0001). In addition, the 2014 American Society of Clinical Oncology (ASCO) Gastrointestinal Oncology Symposium reported results from the global phase III RAINBOW trial. The results of the study showed that ramolutumab, when used in second-line therapy, resulted in PFS and OS benefits for patients.
The median OS in the ramolutumab and paclitaxel combination group was 9.6 months compared to 7.4 months in the paclitaxel monotherapy group (P=0.017). The results of the RAINBOW trial suggest that ramolutumab is effective in patients with metastatic or locally progressive gastric cancer who have failed first-line standard combination chemotherapy (platinum and fluorouracil) and significantly improves OS when used as a second-line treatment. The positive results of the RAINBOW and REGARD trials are certainly encouraging, and after trastuzumab, ramolutumab becomes the second targeted agent proven to be effective in the treatment of progressive gastric cancer.
7. Conclusion
Gastric cancer is highly heterogeneous, with poor sensitivity to chemotherapeutic drugs and poor prognosis, and is a tumor that requires high individualized treatment. In the treatment of tumors, the selection of target drugs corresponding to them based on molecular markers of tumors will become one of the important research directions in tumor treatment. Therefore, only by paying attention to patients’ tumor characteristics in clinical practice work and clinical research for individualized and rational drug selection, it is possible to prolong survival and make patients really benefit.