Zheling Chen

Potential biomarkers for anti-EGFR therapy in metastatic colorectal cancer.

Anti-epidermal growth factor receptor (EGFR) therapy has established efficacy in metastatic colorectal cancer, but a significant number of patients do not respond to such treatment. Recently, various biomarkers were reported to be useful in predicting resistance to anti-EGFR. All the potential biomarkers predicting resistance to anti-EGFR are reviewed herein from five aspects. First, upstream molecules, including epiregulin (EREG) and amphiregulin (AREG), might play different roles according to their abnormal levels in tumor tissue and serum. Second, the EGFR amplification and distinct polymorphisms may have roles in identifying patients for initial anti-EGFR mAbs therapy, while rare EGFR mutations have limited predictive values. Third, among the downstream molecularly related factors, rat sarcoma viral oncogene (Ras) has been identified as a successful predictor, while B-Raf proto-oncogene (BRAF) is considered as a prognostic factor rather than a predictor. Fourth, among the molecular bypass pathway components, phosphatidylinositol 3-kinase (PI3K) and phosphatase and tensin homolog (PTEN) may be potential biomarkers in the future, while activation of hepatocyte growth factor (HGF)/c-Met signaling confers resistance to anti-EGFR therapy. Fifth, many microRNAs and additional molecular biomarkers are promising in predicting the efficacy of anti-EGFR therapy. Applications of multiple biomarkers are more effective than the use of a single biomarker in selecting patients who might benefit from cetuximab- or panitumumab-based treatments. Comprehensive molecular analyses of the EGFR signaling pathways should be considered in the future. Subsequent prospective trials will be required to further confirm the clinical utility of these biomarkers.

Loss of PTEN expression in breast cancer: association with clinicopathological characteristics and prognosis

Various studies have evaluated the significance of PTEN (phosphatase and tensin homolog deleted from chromosome 10) expression in breast cancer, but their results remain controversial. We conducted a meta-analysis to evaluate the associations of PTEN expression with clinicopathological characteristics and prognosis in breast cancer. PubMed, Embase, Web of Science, and China National Knowledge Infrastructure were searched to identify relevant publications. The associations between PTEN expression and clinicopathological parameters, disease-free survival (DFS), and overall survival (OS) were then assessed via meta-analyses of odds ratio (ORs) and hazard ratio (HRs) with 95% confidence intervals (CIs). Based on 27 studies involving 10,231 patients, the pooled results revealed that PTEN loss was significantly more common in breast cancer than in normal tissues (OR = 12.15, 95% CI = 6.48–22.79, P < 0.00001) and that PTEN loss had clear associations with larger tumor size (> 2 cm, OR = 0.62, 95% CI = 0.48–0.82, P = 0.0006), lymph node metastasis(OR = 0.61, 95% CI = 0.45–0.82, P = 0.0001), later TNM stage(stage III–IV, OR = 0.55, 95% CI = 0.35–0.86, P = 0.009), poor differentiation(OR = 0.37, 95% CI = 0.24–0.59, P < 0.0001), and the highly aggressive triple-negative phenotype (OR = 1.62, 95% CI = 1.23–2.12, P = 0.0005). Moreover, patients with PTEN loss exhibited significantly worse DFS and OS(HR = 1.63, 95% CI = 1.04–2.22, P < 0.00001; HR = 1.41, 95% CI = 1.08–1.73, P < 0.0001; respectively). In conclusion, PTEN loss might predict more aggressive behavior and worse outcomes in patients with breast cancer.

Tumor vasculogenic mimicry formation as an unfavorable prognostic indicator in patients with breast cancer

Vasculogenic mimicry (VM), a newly defined pattern of tumor blood perfusion, describes the functional plasticity of aggressive tumor cells forming de novo vascular networks and is associated with the cancer progression and metastasis. However, the VM-positive rate and the impact of VM status on breast cancer patients’ clinicopathological parameters and prognosis remain unclear. Thus, we performed a meta-analysis by incorporating all available evidence to clarify these issues. Eight studies that involved 1,238 breast cancer patients were eligible for inclusion in our study. We found the VM-positive rate was 24% (pooled proportion was 0.24, 95% CI= 0.13–0.34), and VM was significantly associated with larger tumor size (>2 cm) (OR=0.49, 95% CI=0.26-0.90, P=0.02) and lymph node metastasis (OR=0.27, 95% CI=0.13-0.57, P=0.0005). A boardline correlation was also identified between VM and poorer differentiation (Grade II-III) (OR=0.07, 95% CI=0.00-1.24, P=0.07). Nevertheless, no statistically significant associations were observed between VM and hormone receptor and human epidermal growth factor receptor 2 status. Moreover, the results showed that breast cancer patients with VM-positive have a shorter overall survival than those with VM-negative (HR=0.23, 95% CI=0.08-0.38,P=0.003). In summary, VM was associated with more aggressive tumor phenotype and poor prognosis in patients with breast cancer. Developing strategies against the VM formation would be a promising therapeutic approach to breast cancer.

Invasive lobular carcinoma of the breast: A special histological type compared with invasive ductal carcinoma

The clinical outcomes and therapeutic strategies for infiltrating ductal carcinoma (IDC) and infiltrating lobular carcinoma (ILC) are not uniform. The primary objectives of this study were to identify the differences in the clinical characteristics and prognoses between ILC and IDC, and identify the high-risk population based on the hormone receptor status and metastasis sites. The Surveillance, Epidemiology, and End Results Program database was searched and patients diagnosed with ILC or IDC from 1990 to 2013 were identified. In total,796,335 patients were analyzed, including 85,048 withILC (10.7%) and 711,287 withIDC (89.3%). The ILC group was correlatedwith older age, larger tumor size, later stage, lower grade, metastasis disease(M1) disease, and greater counts ofpositive lymph nodesandestrogen-receptor-positive (ER)/progesterone receptor-positive (PR) positive nodes. The overall survival showed an early advantage for ILC but a worse outcome after 5 years. Regarding the disease-specific survival, the IDC cohort had advantages over the ILC group, both during the early years and long-term. In hormone status and metastasis site subgroup analyses, the ER+/PR+ subgroup had the best survival, while the ER+/PR- subgroup had the worst outcome, especially the ILC cohort. ILC and IDC had different metastasis patterns. The proportion of bone metastasis was higher in the ILC group (91.52%) than that in the IDC (76.04%), and the ILC group was more likely to have multiple metastasis sites. Survival analyses showed patients with ILC had a higher risk of liver metastasis (disease-specific survival[DSS]; P = 0.046), but had a better overall survival than the bone metastasis group (P<0.0001). We concluded that the long-term prognosis for ILC was poorer than that for IDC, and the ER+/PR- subgroup had the worst outcome. Therefore, the metastasis pattern and prognosis must be seriously evaluated, and a combination of endocrine therapy and chemotherapy should be considered.

Incidence and survival differences in esophageal cancer among ethnic groups in the United States

Objectives This study was performed to identify the differences in incidence, clinicopathological features, and survival in esophageal cancer among ethnic groups in the United States and to determine the reasons for the differences. Result A total of 49,766 patients were included. Black and Asian groups had a higher proportion of squamous cell carcinoma (ESCC) (85.5% and 75.4%, respectively) and mid-esophagus tumor (43.2% and 37.7% respectively) than the non-Hispanic white and Hispanic white groups. The incidences of ESCC in all ethnic groups declined since 1973, especially in black males. At the same time, incidences of esophageal adenocarcinoma (EAC) dramatically increased in white males since 1973. And incidences of ESCC and EAC were the lowest and stable in Asian female. Multivariable models showed that patients who were male, or black, or had larger tumors, or positive lymph nodes had an increased risk of death from esophageal cancer, while patients with ESCC or diagnosed after 2005 or treated with surgery had a lower likelihood of death. For ESCC, the black patients had the lowest DSS, while for EAC there were no significant differences in DSS among the ethnic/racial groups. Materials and Method From the Surveillance, Epidemiology, and End Results Program database, patients diagnosed with esophageal cancer from 1998-2013 were identified. Differences in incidences, clinicopathological features, treatments, and disease-specific survival (DSS) in four broad racial/ethnic groups were compared. Conclusion Histological type distribution between racial groups could be an important consideration in the incidence and the survival trend but other factors could also have an effect.

The efficiency and safety of trastuzumab and lapatinib added to neoadjuvant chemotherapy in Her2-positive breast cancer patients: a randomized meta-analysis

Background The addition of human epidermal growth factor receptor 2 (Her2) therapies to neoadjuvant chemotherapy (NAC) during treatment of Her2-positive breast cancer has been proposed as an effective way to improve the prognosis. However, the treatment outcomes of adding trastuzumab, lapatinib, or both to NAC were not unequivocal in randomized clinical trials. Based on these data, a meta-analysis was performed. Objective The main objective was to evaluate the efficiency and safety of trastuzumab and lapatinib added to NAC for treatment of Her2-positive breast cancer. Methods ClinicalTrials.gov and PubMed were searched for randomized clinical trials that compared trastuzumab, lapatinib, or both, added to NAC. The main endpoint was a pathologically complete response (pCR) rate, in breast only or in breast and lymph nodes. The drug safety and the influence of hormone-receptor status, comparing the clinical response and the rate of breast conservation, were evaluated. Results A total of eight publications were included in the primary analysis, designed as two or three subgroups. The cumulative cases were 2,349 and the analyses of all the clinical trials showed that the pCR rate was significantly higher in the group receiving trastuzumab than that in the group with lapatinib, either in breast only (P=0.001) or in breast and lymph nodes (P=0.0001). Similar results could be seen in comparisons of the combination versus trastuzumab group. Further studies of subgroups divided into hormone receptor-positive or-negative patients showed that the addition of trastuzumab or dual Her2-targeted therapy significantly improved the pCR rate in patients who were hormone-insensitive. Regarding the toxic effects, we found more grade 3 and 4 toxic effects, such as diarrhea, skin disorder, and hepatic biochemical changes in the lapatinib and combination groups. No temporally significant differences were found when the clinical response and the rate of breast conservation in the groups were analyzed. Conclusion The combination of trastuzumab and lapatinib was superior to single-agent treatment for improved pCR rate. However, combination treatment was not effective in improving the rate of breast conservation. Furthermore, a higher risk for toxicity was associated with combined administration.

Angiomotin Family Members: Oncogenes or Tumor Suppressors?

Angiomotin (Amot) family contains three members: Amot (p80 and p130 isoforms), Amot-like protein 1 (Amotl1), and Amot-like protein 2 (Amotl2). Amot proteins play an important role in tube formation and migration of endothelial cells and the regulation of tight junctions, polarity, and epithelial-mesenchymal transition in epithelial cells. Moreover, these proteins regulate the proliferation and migration of cancer cells. In most cancers, Amot family members promote the proliferation and invasion of cancer cells, including breast cancer, osteosarcoma, colon cancer, prostate cancer, head and neck squamous cell carcinoma, cervical cancer, liver cancer, and renal cell cancer. However, in glioblastoma, ovarian cancer, and lung cancer, Amot inhibits the growth of cancer cells. In addition, there are controversies on the regulation of Yes-associated protein (YAP) by Amot. Amot promotes either the internalization of YAP into the nucleus or the retention of YAP in the cytoplasm of different cell types. Moreover, Amot regulates the AMPK, mTOR, Wnt, and MAPK signaling pathways. However, it is unclear whether Amot is an oncogene or a tumor suppressor gene in different cellular processes. This review focuses on the multifunctional roles of Amot in cancers.

Clinicopathological features and survival of early stage breast cancer in northwest China: A population-based retrospective study of 1287 patients

Breast cancer (BC) displays different clinicopathological features and outcomes based on patient age, molecular subtype, and treatment. However, such features in BC patients in northwest China are unclear. This study investigated the clinicopathological features and overall survival (OS) of early stage BC patients using a population‐based study.

Tumor location as a novel high risk parameter for stage II colorectal cancers

Current studies do not accurately evaluate the influence of tumor location on survival of colorectal cancer patients. This study aimed to explore whether tumor location could be identified as another high-risk factor in stage II colorectal cancer by using data identified from the Surveillance, Epidemiology, and End Results database. All colorectal cancer patients between 2004 and 2008 were grouped into three according to tumor location. Of 33,789 patients diagnosed with stage II colorectal cancer, 46.8% were right colon cancer, 37.5% were left colon cancer and 15.7% were rectal cancer. The 5-year cancer specific survivals were examined. Right colon cancer was associated with the female sex, older age (> 50), and having over 12 lymph nodes resected. Conversely, rectal cancer was associated with the male sex, patients younger than 50 years of age and insufficient lymph node resection. The characteristics of left colon cancer were between them and associated with Asian or Pacific Islander populations, T4 stage, and Grade II patients. The prognostic differences between three groups were significant and retained after stratification by T stage, histological grade, number of regional nodes dissected, age at diagnose, race and sex. Furthermore, the significant difference of location was retained as an independent high-risk parameter. Thus, stage II colorectal cancers of different locations have different clinic-pathological features and cancer-specific survivals, and tumor location should be recognized as another high-risk parameter in stage II colorectal cancer.

Risk of subsequent primary malignancies among patients with prior colorectal cancer: a population-based cohort study

Background The site-distribution pattern and relative risk of subsequent primary malignancies (SPMs) in colorectal cancer (CRC) patients remains to be determined. Materials and methods A population-based cohort of 288,390 CRC patients diagnosed between 1973 and 2012 from the Surveillance, Epidemiology, and End Results database was retrospectively reviewed. Standardized incidence ratios were calculated to estimate the relative risk for SPMs. Results The overall risk of SPMs increased in CRC patients (standardized incidence ratio 1.02) in the first 5 years after CRC diagnosis compared with that in the general population, and was negatively related to age at diagnosis. Risk increased significantly for cancers of the small intestine, ureter, colorectum, renal pelvis, endocrine system, and stomach, and decreased significantly for cancers of the gallbladder, liver, myeloma, and brain, as well as lymphoma. Patients with different prior CRC subsites showed specific sites at high risk of SPM. Prior right-sided colon cancer was associated with cancers of the small intestine, ureter, renal pelvis, thyroid, stomach, pancreas, and breast and prior left-sided colon cancer associated with secondary CRC, whereas rectal cancer was associated with cancers of the vagina, urinary bladder, and lung. Conclusion Risk of SPMs increases in CRC survivors, especially in the first 5 years after prior diagnosis. Intensive surveillance should be advocated among young patients, with specific attention to the small intestine, colorectum, renal pelvis, and ureter. The common sites at high risk of SPM originate from the embryonic endoderm. Genetic susceptibility may act as the main mechanism underlying the risk of multiple cancers.