Xiaotian Zhang

Change of Body Weight and Macrophage Inhibitory Cytokine-1 during Chemotherapy in Advanced Gastric Cancer: What Is Their Clinical Significance?

Background Weight loss in advanced gastric cancer (GC) has been widely acknowledged to be a predictor for poor survival. However, very few studies have investigated the weight loss that occurs during chemotherapy. Therefore, we focused on weight loss during chemotherapy in patients with advanced GC and investigated the concentrations of macrophage inhibitory cytokine-1 (MIC-1), which has been recognized as a probable etiological factor in anorexia and weight loss. Methods We analyzed 384 patients with inoperable locally advanced or metastatic GC receiving first-line chemotherapy. Patients were assigned to one of two groups on the basis of their weight change during chemotherapy: >3% weight loss and ≤3% weight loss. Serum MIC-1 and C-reactive protein (CRP) concentrations were also assessed in these patients. Results The >3% weight loss group had shorter overall survival (OS; 12.0 months vs. 17.5 months, Pu200a=u200a0.000) than the ≤3% weight loss group, and the survival rates improved if the weight loss was reversed during chemotherapy. Although the MIC-1 concentrations were not correlated with weight loss before (Pu200a=u200a0.156) or during chemotherapy (Pu200a=u200a0.164), it correlated significantly with the CRP concentration (Pu200a=u200a0.001). Furthermore, elevated MIC-1 concentrations before chemotherapy (Pu200a=u200a0.017) and increased MIC-1 concentrations during chemotherapy (Pu200a=u200a0.001) were both found to be predictors of poor OS. Conclusions Changes in the body weight during chemotherapy could influence the prognosis in patients with advanced GC, and the MIC-1 might be a potential predictive and prognostic biomarker in those patients.

PD-L1 expression is associated with massive lymphocyte infiltration and histology in gastric cancer

The mechanism of carcinogenesis of gastric cancer (GC) is still unclear now. This study aimed to explore the correlations among PD-L1, Epstein-Barr virus (EBV) infection, lymphocyte infiltration, HER2 expression, HER2 gene status, histology, and other clinicopathological factors in GC. A total of 44 GC patients with massive lymphocyte infiltration (GC-MLI) and 93 GC patients without massive lymphocyte infiltration were involved in this study. Immunohistochemical analysis was used to test the expression levels of PD-L1 and HER2. Fluorescence in situ hybridization was used on HER2-positive cases with a score of 2+ to test the HER2 gene status. EBV-encoded RNA was used to test for EBV infection. In univariate analysis, PD-L1 expression was significantly associated with GC-MLI (P<.001), lower age (P=.019), EBV infection (P<.001), lower HER2 expression (P=.011), and diffuse/mixed type of histology (P=.022). EBV-encoded RNA-positive cases were significantly associated with GC-MLI (P<.001), lower age (P=.016), diffuse/mixed type of histology (P=.011), and lower HER2 expression (P=.032). In the multivariate logistic regression model, GC-MLI and the diffuse/mixed type histology were identified as 2 independent factors that affected PD-L1 expression (P<.001). Furthermore, PD-L1-positive cases have worse overall survival than do PD-L1-negative cases (P=.011). These results suggest that massive lymphocyte infiltration and the diffuse/mixed type histology of GC should be taken into consideration to select the appropriate patients for PD-L1 inhibitory treatment in the future.

Combination of microtubule associated protein-tau and β-tubulin III predicts chemosensitivity of paclitaxel in patients with advanced gastric cancer.

AIMnTo investigate the role of microtubule associated protein-tau (MAP-tau) and β-tubulin III (TUBB3) in predicting the chemosensitivity of paclitaxel in patients with advanced gastric cancer (GC).nnnMETHODSnMAP-tau and TUBB3 expressions were detected using immunohistochemistry in 244 advanced GC patients prior to chemotherapy. The associations of MAP-tau and TUBB3 expressions with paclitaxel sensitivity were assessed using in vitro and in vivo xenograft analysis.nnnRESULTSnA total of 149 patients receiving paclitaxel plus capecitabine (cohort 1) and 95 patients receiving cisplatin plus capecitabine (cohort 2) were included in this study. In cohort 1, the clinical benefit rate (CBR), median progression-free survival (PFS) and overall survival (OS) were found to be significantly higher in patients with low levels of MAP-tau and TUBB3 expressions and were significantly higher than those in patients with high levels of MAP-tau and TUBB3 expressions (CBR: 72.2% versus 35.9%; PFS: 271 versus 102 days; OS: 394 versus 173 days; all P<0.05). This was not observed in cohort 2. In in vitro studies, the sensitivity of paclitaxel in human gastric cancer cells was inversely correlated with the expression levels of MAP-tau and TUBB3, as in in vivo animal xenografts.nnnCONCLUSIONSnThe combination of MAP-tau and TUBB3 was found to predict chemosensitivity to paclitaxel in gastric cancer in vitro and in vivo. This merits further study and may help guide individual therapy.

HER2 discordance between paired primary gastric cancer and metastasis: a meta-analysis

BACKGROUNDnA number of studies have examined human epidermal growth factor receptor 2 (HER2) status in primary gastric cancer (GC) and associated metastasis, some showed their great concordance in HER2 expression, but others demonstrated notable discordance. There is still little consensus on HER2 discordance, therefore, a systematic review and meta-analysis was conducted to assess the status on HER2 discordance between primary GC and its paired metastasis.nnnMETHODSnPubMed, EMBASE, ASCO and The Cochrane Library were searched for studies that explored the concordance between primary tumor and metastasis in patients with GC up to 10 March, 2014. Data of discordance of HER2 between primary GC and corresponding metastasis were extracted from the publications and random-effects models were used to estimate pooled discordance proportions.nnnRESULTSnEighteen articles including 1,867 patients were included for the meta-analysis in accordance with the selection criteria. Pooled discordance proportions were 7% [95% confidence interval (CI): 5-10%] for HER2 status. Pooled proportions of tumors shifting from positive to negative and from negative to positive were 17% (95% CI: 7-29%) and 4% (95% CI: 2-6%) respectively. No publication bias was found in the meta-analysis.nnnCONCLUSIONSnThe discordance of HER2 status is not rare in primary and metastatic GC through our meta-analysis. Prospective studies are needed to testify the clinical significance of the discordance of HER2 status.

Pretreatment lymphopenia is an easily detectable predictive and prognostic marker in patients with metastatic esophagus squamous cell carcinoma receiving first-line chemotherapy.

To explore the influence of pretreatment lymphopenia on the toxicity and efficacy of first‐line chemotherapy in patients with metastatic esophagus squamous cell carcinoma (ESCC). In total, 215 patients were included in this retrospective study. Correlations between pretreatment lymphopenia (lymphocyte count <1 × 109/L) and the occurrence of toxicity and the efficacy of first‐line palliative chemotherapy were investigated. Pretreatment lymphopenia was found in 19.1% of the patients. The overall response rate (ORR) was 35.5% (65 of 183 patients). Patients with pretreatment lymphopenia had a lower ORR to chemotherapy compared with those without lymphopenia (22.2% vs. 38.8%, respectively; P = 0.045). Furthermore, the patients with pretreatment lymphopenia have higher grade 3–4 hematological toxicity than that of patients without pretreatment lymphopenia (19 of 41 patients, 46.3% vs. 54 of 174 patients, 31.0%; P = 0.048). Pretreatment lymphopenia was not correlated with grade 3–4 nonhematological toxicity. Multivariate analysis showed that pretreatment lymphopenia is an independent prognostic factor. Patients with pretreatment lymphopenia had a significantly shorter overall survival time than those without lymphopenia (8.2 months vs. 12.7 months; P = 0.020). This study shows that pretreatment lymphopenia is a good prognostic factor as well as a predictive factor for tumor response and chemotherapy‐related hematological toxicity in metastatic ESCC.

Predictive value of serum HER2 ECD in patients with HER2-positive advanced gastric cancer treated with trastuzumab plus chemotherapy

The levels of serum HER2 extracellular domain (ECD) are highly correlated with tissue HER2 status in metastatic gastric cancer (AGC). We sought to explore whether serum HER2 ECD could predict the efficacy of trastuzumab-treated HER2-positive AGC. From 2011 to 2013, trastuzumab-treated AGC patients were enrolled. Serum HER2 ECD was centrally measured by chemiluminescence immunoassays (CLIA) method in available samples at baseline and after two cycles of trastuzumab combined with chemotherapy. The correlation between serum HER2 ECD and overall response rate (ORR) and progression-free survival (PFS) was analyzed. Sixty-five patients were analyzed with a median age of 58xa0years (range, 27–80xa0years). A significant difference of serum HER2 ECD levels was found between patients with HER2 IHC 3+ and those with HER2 IHC 2+ and FISH positive (pxa0=xa00.014). There was a significantly better ORR (80.00 vs. 50.00xa0%, pxa0=xa00.017) and PFS (median PFS, 268 vs. 139xa0days, pxa0=xa00.039) for patients with abnormal baseline serum HER2 ECD than for patients with normal serum HER2 ECD. Change in serum HER2 ECD during chemotherapy was significantly correlated with response to chemotherapy (79.17 vs. 51.52xa0%, pxa0=xa00.033) and PFS (median PFS, 303 vs. 147xa0days, pxa0=xa00.005) in patients with HER2-positive tumor tissue. Our results support the clinical utility of measuring serum HER2 ECD levels in patients with advanced gastric cancer. Baseline and early changes in serum HER2 ECD could be useful for monitoring clinical outcome in HER2-positive AGC patients receiving trastuzumab-combined chemotherapy.

Serum HER2 extracellular domain as a potential alternative for tissue HER2 status in metastatic gastric cancer patients

AIMnWe investigated whether serum concentrations of the HER2 extracellular domain (ECD) can be used as an alternative to test tissue HER2 status in metastatic gastric cancer.nnnMATERIALS & METHODSnA total of 133 cases of metastatic gastric cancer were included in present study. Serum HER2 ECD was measured by chemiluminescence immunoassay (CLIA). Receiver operating characteristic curve analysis was used to determine optimal serum HER2 ECD concentrations for differentiation between positive and negative HER2 status.nnnRESULTSnThe median level of serum HER2 ECD was 9.6 ng/ml in metastatic gastric cancer patients. There was a significant relationship between serum and tissue levels of HER2 protein (p < 0.001). Area under the curve for serum HER2 ECD was 0.771 (95% CI: 0.682-0.860).nnnCONCLUSIONnLevels of serum HER2 ECD are highly correlated with tissue HER2 status in metastatic gastric cancer. Serum HER2 ECD assay can be considered as a potential alternative for tissue HER2 status.

A phase II study of triweekly paclitaxel and capecitabine combination therapy in patients with fluoropyrimidine-platinum-resistant metastatic gastric adenocarcinoma

BACKGROUNDnAlthough randomized trials have shown a survival benefit of second-line chemotherapy (SLC) in metastatic gastric adenocarcinoma (MGA), no standard regimen has yet been established. Paclitaxel acts synergistically with capecitabine. In this phase II study, we evaluated the efficacy and safety of paclitaxel/capecitabine (PX) as an SLC regimen for patients with fluoropyrimidine-resistant MGA.nnnMATERIALS AND METHODSnPatients were eligible if the tumor progressed to fluoropyrimidine-based regimens or relapsed within 6 months after completion of therapy with adjuvant fluoropyrimidines. Treatment consisted of paclitaxel (80 mg/m 2 , days 1 and 8) and capecitabine (1000 mg/m 2 , bid, days 1-14), called PX, every 3 weeks. The primary endpoint was the objective response rate (ORR). Thirty-five patients were required according to the statistical design, and PX combination would be rejected if fewer than five patients responded.nnnRESULTSnFrom November 2004 to May 2007, 36 eligible patients were enrolled. Among them, 35 (97.2%) had previously received platinum/fluoropyrimidine as first-line therapy. Response was assessed in 35 patients; 10 partial responses were obtained, resulting in an ORR of 28.5%. The median progression-free survival was 5.0 months, and the median overall survival was 11.1 months. The most frequent grade 3/4 toxicity was neutropenia, observed in 11.1% of the patients.nnnCONCLUSIONSnPX regimen was clearly demonstrated to be active and safe for fluoropyrimidine-platinum-resistant MGA, and further evaluation in future phase III trials is warranted.

Irinotecan plus cisplatin followed by octreotide long-acting release maintenance treatment in advanced gastroenteropancreatic neuroendocrine carcinoma: IPO-NEC study

There have been very few prospective studies of first-line chemotherapy on advanced gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). This phase II study assessed the activity and safety of irinotecan plus cisplatin (IP) followed by octreotide long-acting release (LAR) maintenance treatment in advanced GEP-NEC. Forty patients were treated and eighteen patients (45.0%) had a partial response. The median progression-free survival (PFS) and overall survival (OS) were 5.7 months and 12.9 months, respectively. Because GEP-NECs are heterogeneous, a subgroup analysis was conducted by dividing all patients into a high proliferation neuroendocrine tumor (NET) group (well differentiated neuroendocrine neoplasms with a Ki-67 level between 20-60%) or a poorly differentiated NEC (PDNEC) group. Compared with the PDNEC group, the patients in high proliferation NET group had a lower response rate (0% versus 51.4%) but longer PFS (8.9 versus 5.7 months) and received more octreotide LAR treatment (median cycles, 7 versus 3). The most common toxicities included grade 3/4 leukopenia/neutropenia (60%), nausea/vomiting (17.5%) and diarrhea (12.5%). Therefore, IP is an active regimen in patients with advanced GEP-PDNEC and should probably not be given to patients with advanced high proliferative NET. The benefit of octreotide LAR maintenance therapy on high proliferation NETs requires further study.

Evolutionary Expression of HER2 Conferred by Chromosome Aneuploidy on Circulating Gastric Cancer Cells Contributes to Developing Targeted and Chemotherapeutic Resistance

Purpose: Previous human epidermal growth factor receptor-2 (HER2)-derived resistance studies were based on ex vivo models, which could not mirror evolutionary expression of HER2 during therapy. To investigate dynamic expression of HER2 and its contribution to developing therapeutic resistance conferred by chromosome aneuploidy, both the HER2 phenotype and chromosome 8 (Chr 8) aneuploidy on circulating tumor cells (CTC) were coexamined in advanced gastric cancer (AGC) patients. Experimental Design: A total of 115 AGC patients, including 56 of histopathologic HER2+ (hHER2+) subjects who received first-line HER2-targeted therapy plus chemotherapy, and 59 of hHER2− patients who received chemotherapy alone, were prospectively enrolled. Both HER2 phenotype and Chr8 aneuploidy of CTCs in patients were coexamined by HER2-iFISH during therapy. Results: A fluctuated positive HER2 phenotype on CTCs (cHER2+) was revealed, showing cHER2+ at different time intervals during treatment. Acquisition of the cHER2+ phenotype in 91.0% of hHER2+ and 76.2% hHER2− patients was demonstrated to correlate with development of resistance to trastuzumab-targeted therapy for hHER2+ patients and chemotherapy alone for hHER2− patients. Aneuploid Chr8 was demonstrated to participate in the acquisition of the cHER2+ phenotype, which provides a growth advantage to HER2+ CTCs against therapeutic pressure, leading to the development of therapeutic resistance. Conclusions: Compared with low positivity of conventional histopathologic hHER2 examination routinely performed once, significant higher positivity of cHER2+ on CTCs was observed. Continuously examining cHER2 shows unique advantages with respect to monitoring therapeutic resistance in real time in carcinoma patients. Moreover, contribution of chromosome aneuploidy to the phenotypic evolution of HER2 expression on CTCs may help elucidate underlying mechanisms of developing therapeutic resistance. Clin Cancer Res; 24(21); 5261–71. ©2018 AACR.