Purpose: Targeting human epidermal growth factor receptor 2 (HER2) therapy is currently considered as the standard treatment for HER2-positive (HER2 IntroductionPrevious studies have demonstrated that the human epidermal growth factor receptor 2 (HER2) signaling pathway is a critical driver of carcinogenesis and tumor progression in approximately 7% to 34% of total patients with gastric cancer (1-3). Targeting HER2 combined with chemotherapy has been the first-line treatment for HER2-positive (HER2 þ ) advanced gastric cancer (1, 4). However, only few patients with HER2 þ gastric cancer responded to the HER2-targeting agents. Recently, preliminary results of a phase III trials evaluating the efficacy of lapatinib, a dual tyrosine kinase inhibitor (TKI) targeting both HER2 and epithelial growth factor receptor (EGFR), in conjunction with cytotoxic chemotherapy for HER2 þ advanced or metastatic gastric cancer (LOGiC study) were released. Unfortunately, the addition of lapatinib to chemotherapy did not significantly improve OS, the primary endpoint, compared with chemotherapy alone. The median OS was 12.2 versus 10.5 months, respectively (HR, 0.91; 95% CI, 0.73-1.12; P ¼ 0.3492). The median PFS was 6.0 versus 5.4 months, response rate 53% versus 40% and duration of response 7.3 versus 5.6 months (5). Based on the data from LOGiC study, the observed unsatisfactory survival prolongation could be explained by the limited initial response to lapatinib for patients with HER2

Despite the mounting studies exploring the role of estrogen receptor alpha (ERα), estrogen receptor beta (ERβ) and androgen receptor (AR) in gastric cancer (GC), there remain controversies in those findings. The present study investigated the expression of ERα, ERβ 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, ERβ 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.ConclusionThe 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.

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.

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.