Early changes in soluble intracellular adhesion molecule-1 as prognostic biomarkers to immune checkpoint inhibitor.

Serologic biomarker to predict clinical outcome is needed for immune checkpoint inhibitors (ICIs). We evaluated soluble intercellular adhesion molecules-1 (sICAM-1) as a predictor of response to ICIs treatment. Ninety-five patients with cancer treated with ICI were studied. The serum sICAM-1 levels of baseline, post two cycle therapy and end of therapy (EOT) were measured by enzyme-linked immunoassay. We randomly assigned the patients into the primary cohort (n = 47) and validation cohort (n = 48). Serum sICAM-1 post two cycle (277.7 ± 181.6 ng/mL) and EOT (403.9 ± 218.9 ng/mL) were significantly elevated compared to baseline (244.8 ± 153.8 ng/mL, p = 0.008 and p = 0.004, respectively). Early changes of sICAM-1 (ΔsICAM-1), deemed as sICAM-1 after two cycles minus baseline, were assessed. Following ICI treatments, responders had significantly lower ΔsICAM-1 compared with nonresponders in the primary cohort (p = 0.040) and the validation cohort (p = 0.026). High ΔsICAM-1 was strongly associated with inferior progression-free survival (PFS; (primary cohort: p = 0.001 and validation cohort: p = 0.002) and overall survival (OS; (primary cohort: p < 0.001 and validation cohort: p = 0.007). The ΔsICAM-1 remained independently associated with worse PFS and OS in the primary cohort and the validation cohort. Subgroup analysis indicated patients whose sICAM-1 significantly elevated had shorter PFS and OS in both anti-PD-1 and anti-PD-L1 treatment groups. Early change of serum sICAM-1 could be used to monitor and predict clinical benefit of ICI therapy in patients with solid cancer.

Phase I study of A166, an antibody‒drug conjugate in advanced HER2-expressing solid tumours.

In this phase I study, the safety, pharmacokinetics, and antitumour activity of the HER2-targeted antibody-drug conjugate A166 were evaluated in patients with HER2-expressing advanced solid tumours. Patients with advanced solid tumours refractory to standard therapies received A166 at doses of 0.1, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8 or 6.0 mg/kg Q3W in a standard "3 + 3" design. Dose cohorts were expanded at 4.8 and 6.0 mg/kg Q3W. Primary endpoints were assessment of the safety and tolerability of A166 and identification of the maximum tolerated dose or recommended phase II dose. In total, 81 patients were enroled and received A166 (n = 1 for 0.1 mg/kg; n = 3 for each of 0.3, 0.6, 1.2, 2.4 and 3.6 mg/kg doses; n = 27 for 4.8 mg/kg; n = 38 for 6.0 mg/kg). No dose-limiting toxicity or drug-related deaths occurred. The most common treatment-related adverse events at grade 3 or higher were corneal epitheliopathy (30.9%), blurred vision (18.5%), dry eyes (7.4%), and peripheral sensory neuropathy (6.2%). The Cmax and area under the curve of Duo-5, its free payload, were approximately 0.1% and 0.2% of those of the ADC, respectively. For all assessable HER2-positive breast cancer patients enroled in the 4.8 mg/kg and 6.0 mg/kg cohorts, the corresponding ORRs were 73.9% (17/23) and 68.6% (24/35), respectively, and the median PFS was 12.3 and 9.4 months, respectively. A166 has a recommended phase II dose of 4.8 mg/kg Q3W, manageable toxicity, good stability in the circulation and promising antitumour activities in HER2-positive breast cancer patients.

Hsa_circ_0001944 enhanced GSPT1 expression via sponging miR-498 to promote proliferation and invasion of gastric cancer.

BACKGROUND: Gastric cancer (GC) is the fifth most common malignant tumor and the third leading cause of cancer-related deaths worldwide. CircRNAs may provide new insights into the development of GC by acting as oncogenes or tumor suppressors. In this study, we aim to examine the biological role of hsa_circ_0001944 (circFIRRE) in tumor progression of GC. METHODS: The bioinformatic analysis, qPCR, Western blotting, and immunohistochemistry were fulfilled to detect the expression of hsa_circ_0001944, miR-498, and GSPT1 in gastric cancer. Gain or loss of function approaches were used to investigate the biological functions of hsa_circ_0001944. MTS, EDU, wound healing, and transwell assays were performed to study the proliferation, invasion, and migration of GC cells. These molecular mechanisms were detected by luciferase reporter assays and chromatin immunoprecipitation assays. RESULTS: We screened out hsa_circ_0001944, whose expression was significantly increased in gastric cancer tissues. Knockdown of hsa_circ_0001944 significantly suppressed the cell proliferation, invasion, and migration. Mechanistic investigations showed that hsa_circ_0001944 can bind to and sponge miR-498. Moreover, hsa_circ_0001944 sponged miR-498 to increase GSPT1 expression, thereby promoted excessive proliferation and maintained the malignant phenotype of GC cells. CONCLUSION: The present study demonstrates the hsa_circ_0001944/miR-498/GSPT1 axis contributes to GC development. This may provide a target for GC therapy and potential prognostic biomarker.

Lack of bombesin receptor-activated protein homologous protein impairs hippocampal synaptic plasticity and promotes chronic unpredictable mild stress induced behavioral changes in mice.

Bombesin receptor-activated protein (BRAP) and its homologous protein in mice, which is encoded by bc004004 gene, were expressed abundantly in brain tissues with unknown functions. We treated bc004004-/- mice with chronic unpredictable mild stress (CUMS) to test whether those mice were more vulnerable to stress-related disorders. The results of forced swimming test, sucrose preference test, and open field test showed that after being treated with CUMS for 28 days or 35 days both bc004004-/- and bc004004+/+ mice exhibited behavioural changes and there was no significant difference between bc004004+/+ and bc004004-/-. However, behavioural changes were observed only in bc004004-/- mice after being exposed to CUMS for 21 days, but not in bc004004+/+ after 21-day CUMS exposure, indicating that lack of BRAP homologous protein may cause vulnerability to stress-related disorders in mice. In addition, bc004004-/- mice showed a reduction in recognition memory as revealed by novel object recognition test. Since memory changes and stress related behavioural changes are all closely related to the hippocampus function we further analyzed the changes of dendrites and synapses of hippocampal neurons as well as expression levels of some proteins closely related to synaptic function. bc004004-/- mice exhibited decreased dendritic lengths and increased amount of immature spines, as well as altered expression pattern of synaptic related proteins including GluN2A, synaptophysin and BDNF in the hippocampus. Those findings suggest that BRAP homologous protein may have a protective effect on the behavioural response to stress via regulating dendritic spine formation and synaptic plasticity in the hippocampus.

Lack of bombesin receptor-activated protein attenuates bleomycin-induced pulmonary fibrosis in mice.

Bombesin receptor-activated protein (BRAP) was found to express in the interstitial cells of human fibrotic lungs with unknown function. Its homologous protein, encoded by BC004004 gene, was also present in mouse lung tissues. We used BC004004 -/- mice which lack BRAP homologous protein expression to establish a bleomycin-induced lung fibrotic model. After bleomycin treatment, BC004004 -/- mice exhibited attenuation of pulmonary injury and less pulmonary fibrosis. Fibroblasts from BC004004 -/- mice proliferated at a lower rate and produced less collagen. Autophagy-related gene 5 (ATG5) was identified as a partner interacting with human BRAP. Lacking BRAP homologous protein led to enhanced autophagy activity in mouse lung tissues as well as in isolated lung fibroblasts, indicating a negative regulatory role of this protein in autophagy via interaction with ATG5. Enhanced autophagy process in fibroblasts due to lack of BRAP homologous protein might contribute to the resistance of BC004004 -/- mice to pulmonary fibrosis.

Corrigendum: Longitudinal Circulating Tumor DNA Profiling in Metastatic Colorectal Cancer During Anti-EGFR Therapy.

[This corrects the article DOI: 10.3389/fonc.2022.830816.].

Longitudinal Circulating Tumor DNA Profiling in Metastatic Colorectal Cancer During Anti-EGFR Therapy.

Background: Metastatic colorectal cancer (mCRC) is a heterogenous disease with limited precision medicine and targeted therapy options. Monoclonal antibodies against epidermal growth factor receptor (EGFR) have been a crucial treatment option for mCRC. However, proper biomarkers for predicting therapeutic response remain unknown. As a non-invasive test, circulating tumor DNA (ctDNA) is appropriately positioned to reveal tumor heterogeneity and evolution, as it can be used in real-time genomic profiling. To evaluate the significance of ctDNA in monitoring the dynamic therapeutic response and prognosis of mCRC, we detected the baseline and dynamic changes of ctDNA in mCRC patients receiving anti-EGFR therapies. Methods: A single-center study was conducted retrospectively. Plasma samples from mCRC patients who received anti-EGFR therapies were collected at baseline and continuous treatment points. The ctDNA was extracted and sequenced with a target panel of tumor-related genes via next-generation sequencing (NGS). Clinical information was also collected and analyzed. Results: We conducted dynamic sampling of 22 mCRC patients, analyzed 130 plasma samples, obtained a baseline genomic mutation profile of the patients. In total, 54 variations were detected in 22 plasma samples, with a positive rate of 77.3% (17/22). TP53 was the most mutated gene (59.1%, 13/22), followed by APC (18.2%, 4/22). There was a high concordance rate of genomic characteristics between the tumor tissue test by polymerase chain reaction and ctDNA test by NGS. The mutation discrepancy increased with an extended course of treatment. During remission TP53 and APC were the most frequently decreased clonal mutations and KRAS, NRAS, ERBB2 and PIK3CA were the most decreased subclonal mutations. Both mutation types were increased during progression. The ctDNA decreased earlier than did the responses of computed tomography and traditional tumor markers (carbohydrate antigen 19-9 and carcinoembryonic antigen [CEA]). Lactate dehydrogenase level (P = 0.041), CEA level (P = 0.038), and primary lesion site (P = 0.038) were independent risk factors that influenced overall survival. Moreover, patients with RAS mutations tended to have a worse prognosis (P = 0.072). Conclusions: This study demonstrates that ctDNA is a promising biomarker for monitoring the dynamic response to treatment and determining the prognosis of mCRC.

Cation Lipid-Assisted PEG6-PLGA Polymer Nanoparticles Encapsulated Knocking Down Long ncRNAs Reverse Non-Coding RNA of Xist Through the Support Vector Machine Model to Regulate the Molecular Mechanisms of Gastric Cancer Cell Apoptosis.

Gastric adenocarcinoma (GAC) is one kind of gastric cancer with a high incidence rate and mortality. It is essential to study the etiology of GAC and provide theoretical guidance for the prevention and treatment of GAC. Bioinformatics was used via differential expression analysis, weighted gene co-expression network analysis, gene set enrichment analysis, and a training support vector machine (SVM) model to construct a TSIX/mir-320a/Rad51 network as the research index of GAC disease. On the basis of CRISPR/Cas9 gene editing technology, the present study utilizes the Cation lipid-assisted PEG-6-PLGA polymer nanoparticle (CLAN) drug carrier system to prepare the target knock-out TSIX drug with CRISPR/CaS9 nucleic acid. Knocking down lncRNA TSIX restored the suppression role of miR-320a on Rad51 and inhibited the Rad51 expression. Simultaneously, this ceRNA network activated the ATF6 signaling pathway after endoplasmic reticulum stress to promote GAC cells' apoptosis and inhibit the disease. TSIX/miR-320a/Rad51 network may be a potential biological target of GAC disease and provides a new strategy for treating GAC disease.

Phase I study of pucotenlimab (HX008), an anti-PD-1 antibody, for patients with advanced solid tumors.

BACKGROUND: Pucotenlimab is a humanized immunoglobulin G4 (IgG4) anti programmed cell death protein 1 (anti-PD-1) monoclonal antibody (mAb) with a S228P hinge mutation and an engineered Fc domain. Preclinical data suggests that pucotenlimab exerts antitumor effects. In this phase I study, which was prospectively registered on www.chinadrugtrials.org.cn (CTR20180125), the safety, maximum tolerated dose, preliminary antitumor activity, pharmacokinetics, and immunogenicity of pucotenlimab were evaluated in patients with advanced solid tumors. METHODS: Patients with advanced solid tumors refractory to standard therapies were recruited. In a 3+3 dose escalation study, 13 patients received pucotenlimab intravenously every 3 weeks (Q3W) until disease progression or unacceptable toxicity occurred at doses of 1 mg/kg, 3 mg/kg, 10 mg/kg, and 200 mg. 17 additional patients were assigned in the expansion period. RESULTS: A total of 30 patients were enrolled. No dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common treatment-related adverse events of any grade were proteinuria (40%), fatigue (36.7%), weight loss (26.7%), fever (26.7%), increased aspartate aminotransferase (26.7%), rash (23.3%), and anorexia (20.0%). Partial responses occurred in five patients, with an objective response rate of 16.7%. Pharmacokinetics analysis showed rapid absorption followed by slow terminal elimination, with a mean half-life of 17.1-23.5 days across all dose groups. CONCLUSIONS: Pucotenlimab had an acceptable toxicity profile at doses up to 10 mg/kg and the maximum tolerated dose was not reached. Based on the pharmacokinetics, efficacy, and safety profile, 3 mg/kg Q3W or 200 mg Q3W are optimal for further drug development.

Short-form RON (sf-RON) enhances glucose metabolism to promote cell proliferation via activating ß-catenin/SIX1 signaling pathway in gastric cancer.

Recepteur d'origine nantais (RON) has been implicated in cell proliferation, metastasis, and chemoresistance of various human malignancies. The short-form RON (sf-RON) encoded by RON transcripts was overexpressed in gastric cancer tissues, but its regulatory functions remain illustrated. Here, we found that sf-RON promoted gastric cancer cell proliferation by enhancing glucose metabolism. Furthermore, sf-RON was proved to induce the ß-catenin expression level through the AKT1/GSK3ß signaling pathway. Meanwhile, the binding sites of ß-catenin were identified in the promoter region of SIX1 and it was also demonstrated that ß-catenin positively regulated SIX1 expression. SIX1 enhanced the promoter activity of key proteins in glucose metabolism, such as GLUT1 and LDHA. Results indicated that sf-RON regulated the cell proliferation and glucose metabolism of gastric cancer by participating in a sf-RON/ß-catenin/SIX1 signaling axis and had significant implications for choosing the therapeutic target of gastric cancer.

UQCRC1 downregulation is correlated with lymph node metastasis and poor prognosis in CRC.

BACKGROUND: Mitochondrial dysfunction is common in cancer. UQCRC1 is a nuclear-encoded protein localized to the inner mitochondrial membrane; however, little is known about it in colorectal cancer (CRC). The purpose of this study was to investigate the expression pattern and the possible clinical significance of UQCRC1 in CRC. METHODS: A total of 197 patients with CRC were enrolled in this study. Immunohistochemistry was used to evaluate the expression pattern of UQCRC1. The relationship between UQCRC1 and clinical characteristics, especially lymph node metastasis, was also assessed. In addition, we evaluated the significance of UQCRC1 in the prognosis for CRC patients. RESULTS: UQCRC1 was downregulated in 28.9% (57/197) of human CRCs. Downregulation of UQCRC1 was correlated with increased lymph node metastasis (p < 0.001) and decreased disease-free survival (DFS) and overall survival (OS). Multivariate analysis revealed that downregulation of UQCRC1 was an independent prognostic factor both for DFS (HR 3.009; 95% CI: 1.613-8.548, P = 0.009) and OS (HR 4.062; 95% CI: 2.835-8.910, P = 0.001). In addition, downregulation of UQCRC1 was correlated with increased VEGF-C expression (P = 0.002). CONCLUSION: UQCRC1 was downregulated in human CRC. Downregulation of UQCRC1 was correlated with increased lymph node metastasis and finally associated with decreased survival in CRC.

Advantage of Next-Generation Sequencing in Dynamic Monitoring of Circulating Tumor DNA over Droplet Digital PCR in Cetuximab Treated Colorectal Cancer Patients.

Epidermal growth factor receptor (EGFR) blockade resistance is common in the treatment of RAS wide type colorectal cancer (CRC). During the treatment of cetuximab, acquired resistant genomic alterations always occurs earlier than disease progression observed by medical images. Identification of genomic alterations dynamically might have certain clinical significance. Because of the limitation of repeated tissue biopsy, liquid biopsy is increasingly recognized. Droplet digital polymerase chain reaction (ddPCR) is the main detection methods for circulating tumor DNA (ctDNA), however, the application of next-generation sequencing (NGS) for ctDNA detection becomes more and more popular. Here we develop a NGS-based ctDNA assay and evaluated its sensitivity and specificity while using ddPCR as control. These two technologies were both used for genomic alteration detection for the peripheral blood samples from cetuximab-treated colorectal cancer patients dynamically. Fifteen patients were enrolled in this study, including eight males and seven females. The sensitivity and specificity of our NGS assay were 87.5% and 100% respectively, and liner regression analysis comparing variant allele frequency (VAF) revealed high concordance between NGS and ddPCR (R2 = 0.98). NGS actually found more mutation information than ddPCR such as the additional dynamic changes of TP53 which were observed in the disease progression patients. Moreover, the variant allele fraction of TP53 was also found by NGS to be changed along with the clinical efficacy evaluation dynamically during the whole treatment process. In conclusion, our newly developed NGS-based ctDNA assay shows similar performance with ddPCR but have more advantages of its high throughput of multigenetic detection for the dynamic monitoring during the treatment of cetuximab in metastasis CRC patients.

Hepatocyte growth factor-induced mesenchymal-epithelial transition factor activation leads to insulin-like growth factor 1 receptor inhibitor unresponsiveness in gastric cancer cells.

Insulin-like growth factor 1 receptor (IGF-1R) inhibitors have been developed as potential therapeutics for cancer treatment; however, the phase III trials have not produced promising overall survival rates. Therefore, understanding the mechanism underlying intrinsic resistance to IGF-1R-targeted agents is urgently required. A number of studies have revealed that activation of alternative receptor tyrosine kinases can mediate resistance to IGF-1R-targeted therapy. The present study investigated whether activated mesenchymal-epithelial transition factor (MET; also known as c-Met and hepatocyte growth factor receptor) confers resistance to an IGF-1R inhibitor (NVP-AEW541) of gastric cancer (GC) cells. NCI-N87 and MGC-803 cells were treated with varying concentrations and combinations of NVP-AEW541, hepatocyte growth factor (HGF) and MET small interfering (si)-RNA or crizotinib (a MET inhibitor). The effects of these agents on cell proliferation and pro-apoptotic events were assessed by Cell Counting Kit-8 assays and flow cytometry. Receptor activation and the downstream signaling pathway were examined using western blot analysis. Expression and/or activation of MET and IGF-1R in 156 GC specimens were evaluated by immunohistochemistry. The results demonstrated that NVP-AEW541 inhibited cell growth, with dephosphorylation of IGF-1R and protein kinase B (AKT), in NCI-N87 and MGC-803 cells. Application of HGF activated MET and the downstream AKT signaling pathways, decreased apoptotic events and restored cell proliferation, which were reversed by MET inhibition via crizotinib or siRNA knockdown. Furthermore, combination therapy of NVP-AEW541 and crizotinib exhibited an enhanced effectiveness in vitro. In addition, >40% of IGF-1R overexpressed GC specimens showed MET expression and activation. In conclusion, HGF-induced MET activation may represent a novel mechanism conferring unresponsiveness to IGF-1R-targeted agents in GC, and inhibition of MET may improve the efficacy of IGF-1R inhibitors.

Recent insights into biological functions of mammalian bombesin-like peptides and their receptors.

PURPOSE OF REVIEW: The current review highlights recent advances in physiological and pharmacological researches in biology of mammalian bombesin-like peptides (BLPs). RECENT FINDINGS: BLPs and their receptors were found to have regulatory roles in many biological processes in central nervous system. Two BLPs, neuromedin B and gastrin-releasing peptide (GRP), and their receptors are required for regulation of basal and induced sighing activity in rodents. This is the first study demonstrating central pathways involved in regulation of sighing activity. GRP receptor (GRPR) expressing neurons are excitatory glutamatergic interneurons located in the dorsal lamina without projections outside the spinal cord and mediate itch signals via vesicular glutamate transporter 2. Those neurons receive itch signals and make synapses with the parabrachial nucleus projecting spinal neurons to transmit itch signals to parabrachial nucleus. GRP expressing interneurons function in a proposed 'leaky gate model' to interpret the mechanism of both pain and itch transmission. In addition to recent advances of biology in nervous system, BLPs and their receptors were found to play potential regulatory roles in innate and adaptive immune responses and tissue development. SUMMARY: Several important biological roles of BLPs and their receptors in nervous system were identified. Together with researches regarding central roles of BLPs, studies revealing the regulatory roles of BLPs and their receptors in immunology and tissue development provide us with novel insights into understanding of the biology of BLPs and their receptors.

Expression of estrogen receptors and androgen receptor and their clinical significance in gastric cancer.

Despite the mounting studies exploring the role of estrogen receptor alpha (ERα), estrogen receptor beta (ERß) and androgen receptor (AR) in gastric cancer (GC), there remain controversies in those findings. The present study investigated the expression of ERα, ERß and AR in Chinese gastric cancer by immunohistochemistry, analyzed their clinical relevance in gastric cancer, and examined the potential mechanisms by which ERα and AR modulated GC progression. The positive rate of ERα, ERß and AR in GC tissues was 6% (9/150), 93.5% (143/153), and 42.4% (59/139), respectively. The expression of ERα was an independent unfavorable risk factor for overall survival (OS) (hazard ratio [HR] = 3.639, 95% confidence interval [CI] = 1.432-9.246, p = 0.007) for GC patients. Moreover, AR was borderline significantly associated with poor progress free survival (PFS) after adjustment with other variables (HR = 1.573, 95% CI = 0.955-2.592, p = 0.075). Knockdown of ERα inhibited the proliferation, migration and invasion of GC cells possibly via modulating the expression of p53, p21, p27, cyclin D1 and E-cadherin. Downregulation of AR suppressed the migration and invasion of GC cells and inhibited the epithelial-mesenchymal transition (EMT) associated pathways. CONCLUSION: The present study showed that positive ERα was associated with poor prognosis of Chinese GC patients. ERα might modulate the proliferation, migration and invasion via regulating the expression of p53, p21, p27, cyclin D1 and E-cadherin. ERα could be a valuable prognostic biomarker and promising therapeutic target for Chinese GC patients.

Overall survival of cancer patients with serum lactate dehydrogenase greater than 1000 IU/L.

High level of serum lactate dehydrogenase (LDH) is a well-known poor prognostic factor in patients with malignancies. However, there was no data on overall survival (OS) in cancer patients with serum LDH level > 1000 IU/L, and the prognostic value of the changes in LDH over time for OS had not been reported. Clinical data of 311 cancer patients with metastatic disease with serum LDH >1000 IU/L (four times upper limit of normal) admitted consecutively to a single center were reviewed in this retrospective study. LDH level ranged from 1002 to 8235 U/L with a mean of 1689 U/L. The median OS was 1.7 months (95 % CI: 1.4-2.0). About half of patients (n = 163, 52 %) died within 2 months with the median OS of 0.5 months (95 % CI: 0.3-0.7). Only 173 patients were indicated for salvage treatment. Fifty-one patients' serum LDH level decreased to normal at 2 months following chemotherapy; OS was significantly longer in these patients (22.6 months, 95 % CI: 10.9-34.3, p < 0.001) compared to those with persistently abnormal serum LDH at 2 months (4.0 months, 95 % CI: 3.4-4.6). The independent factors that increased the death risk were ECOG performance status 3-4 (HR: 2.05, 95 % CI: 1.42-2.97, p < 0.001), supportive care only (HR: 2.91, 95 % CI: 2.06-4.10, p < 0.001), and persistently abnormal serum LDH at 2 months (HR: 2.72, 95 % CI: 1.67-4.42, p < 0.001). In conclusion, serum LDH level > 1000 IU/L predicted a terminal stage in metastatic cancer patients. OS was significantly prolonged in patients indicated for effective palliative treatment and LDH level decreased to normal at 2 months.

Influences of ERCC1, ERCC2, XRCC1, GSTP1, GSTT1, and MTHFR polymorphisms on clinical outcomes in gastric cancer patients treated with EOF chemotherapy.

This study investigated the associations between genetic polymorphisms of six genes involved in DNA repair, detoxification pathways, and fluoropyrimidine metabolism and clinical outcomes in MGC patients receiving EOF treatment. This retrospective study included 108 Chinese MGC patients receiving EOF as first-line chemotherapy. Nine single nucleotide polymorphisms (SNPs) of six genes (ERCC1 rs2298881, ERCC2 rs13181 and rs1799793, XRCC1 rs25487 and rs25489, GSTP1 rs1695, GSTT1 rs2266637, and MTHFR rs1801133 and rs1801131) were genotyped, and the associations between each SNP and clinical outcome were analyzed. XRCC1 rs25487 A allele was significantly associated with progression disease (PD) to EOF (p = 0.002), and patients with AA genotype had significantly poorer progression-free survival (PFS) (p = 0.001) and overall survival (OS) (p = 0.041) compared with patients with the G allele (GG + GA). ERCC2 rs13181 G allele was significantly associated with PD (p = 0.026), and G carriers (GG + GT) tended to have poorer PFS (p = 0.092) than TT homozygotes. ERCC2 rs1799793 GA genotype was associated with unfavorable PFS (p = 0.034) and a tendency toward poorer OS (p = 0.090) compared with GG homozygotes. Patients were categorized as either good (0 risk factors) or poor risk (≥1 unfavorable SNPs) using a prognostic index based on XRCC1 rs25487 AA, ERCC2 rs13181 (GG + GT), and ERCC2 rs1799793 GA genotypes, with median OS and PFS of 534 days, 281 days (p = 0.009) and 206 days, and 123 days (p < 0.001), respectively. These results suggest that the prognostic index comprising XRCC1 rs25487, ERCC2 rs13181, and rs1799793 polymorphisms may be a useful predictor of clinical outcomes in MGC treated with EOF.

Neutropenia predicts better prognosis in patients with metastatic gastric cancer on a combined epirubicin, oxaliplatin and 5-fluorouracil regimen.

Chemotherapy-induced neutropenia (CIN) reportedly indicated better prognosis for some cancers. We retrospectively analyzed 150 evaluable metastatic gastric cancer (MGC) patients who had received first-line EOF5 (combination regimen of epirubicin, oxaliplatin and 5-day continuous infusion of 5-fluorouracil) treatment. We divided patients into three groups according to the worst grade of CIN: absent group (grade 0), moderate group (grade 1-2) and severe group (grade 3-4). Multivariate analyses of overall survival (OS) proved moderate and severe CIN were important prognostic factors whether regarding CIN as a time-varying covariate (TVC) or not. Compared with absent CIN, hazard ratio (HR) for moderate and severe CIN were 0.31 (95% confidential interval (CI): 0.17-0.55; P < 0.001) and 0.36 (95% CI: 0.20-0.64; P = 0.001) respectively with TVC; and were 0.31 (95% CI: 0.17-0.56; P < 0.001) and 0.34 (95% CI: 0.19-0.61; P < 0.001) respectively without TVC. In progression-free survival (PFS) analyses, moderate and severe CIN showed similar results. In the landmark group (n = 122 patients) analyses with TVC, moderate and severe CIN remained prognostic factors for PFS, while only moderate CIN was prognostic factor for OS. CIN predicted longer OS and PFS in MGC patients treated with first-line EOF5 chemotherapy.

Multiple receptor tyrosine kinase activation attenuates therapeutic efficacy of the fibroblast growth factor receptor 2 inhibitor AZD4547 in FGFR2 amplified gastric cancer.

Fibroblast growth factor receptor 2 (FGFR2)-targeted therapy has attracted considerable attention as novel anticancer agents in gastric cancer (GC). However, intrinsic or acquired drug resistance has emerged as a major challenge to their clinical use. In this study, we demonstrated that several receptor tyrosine kinase (RTK), including EGFR, HER3 and MET, activations contributed to AZD4547 (a selective FGFR2 inhibitor) hyposensitivity in FGFR2 amplified GC cells. The rescue effect was abrogated by inhibiting these RTKs with their targeted tyrosine kinase inhibitors (TKIs). In addition, synergy in growth inhibition was observed when the GC cells were treated with a combination of AZD4547 and cetuximab (an EGFR monoclonal antibody) both in vitro and in vivo. More importantly, tissue microarray analysis revealed that these resistance-conferring RTKs were highly expressed in FGFR2 positive GC patients. Taken together, these observations demonstrated RTKs including EGFR, HER3 and MET activations as novel mechanisms of hyposensitivity to AZD4547. It will be clinically valuable to investigate the involvement of RTK-mediated signaling in intrinsicor acquired resistance to FGFR2 TKIs in GC. A combination targeted therapeutic strategy may be recommended for treating FGFR2 amplified GC patients with these RTK activations.

Oxidative stress-related genetic polymorphisms are associated with the prognosis of metastatic gastric cancer patients treated with epirubicin, oxaliplatin and 5-fluorouracil combination chemotherapy.

BACKGROUND: Oxidative stress genes are related to cancer development and treatment response. In this study, we aimed to determine the predictive and prognostic roles of oxidative stress-related genetic polymorphisms in metastatic gastric cancer (MGC) patients treated with chemotherapy. METHODS: In this retrospective study, we genotyped nine oxidative stress-related single nucleotide polymorphisms (SNPs) in NQO1, SOD2, SOD3, PON1, GSTP1, GSTT1, and NOS3 (rs1800566, rs10517, rs4880, rs1799895, rs662, rs854560, rs1695, rs2266637, rs1799983, respectively) in 108 consecutive MGC patients treated with epirubicin, oxaliplatin, and 5-fluorouracil (EOF) regimen as the first-line chemotherapy and analyzed the association between the genotypes and the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS: We found that, in addition to a lower pathological grade (p = 0.017), NQO1 rs1800566 CT/TT genotype was an independent predictive factor of poor PFS (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.23-3.16; p = 0.005). PON1 rs662 AA/AG genotype was significantly associated with poor OS (HR = 1.95, 95% CI = 1.07-3.54; p = 0.029). No associations were detected between the nine SNPs and DCR. CONCLUSIONS: NQO1 rs1800566 is an independent predictive factor of PFS for MGC patients treated with EOF chemotherapy, and PON1 rs662 is a noteworthy prognostic factor of OS. Information on oxidative stress-related genetic variants may facilitate optimization of individualized chemotherapy in clinical practice.