Clinicopathologic and Genomic Features in Triple-Negative Breast Cancer Between Special and No-Special Morphologic Pattern.

Background: Triple-negative breast cancer (TNBC) is refractory and heterogeneous, comprising various entities with divergent phenotype, biology, and clinical presentation. As an aggressive subtype, Chinese TNBC patients with special morphologic patterns (STs) were restricted to its incidence of 10-15% in total TNBC population. Methods: We recruited 89 patients with TNBC at Guangdong Provincial People's Hospital (GDPH) from October 2014 to May 2021, comprising 72 cases of invasive ductal carcinoma of no-special type (NSTs) and 17 cases of STs. The clinical data of these patients was collected and statistically analyzed. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matched blood samples were collected for targeted next-generation sequencing (NGS) with cancer-related, 520- or 33-gene assay. Immunohistochemical analysis of FFPE tissue sections was performed using anti-programmed cell death-ligand 1(PD-L1) and anti-androgen receptor antibodies. Results: Cases with NSTs presented with higher histologic grade and Ki-67 index rate than ST patients (NSTs to STs: grade I/II/III 1.4%, 16.7%,81.9% vs 0%, 29.4%, 58.8%; p<0.05; Ki-67 ≥30%: 83.3% vs. 58.8%, p<0.05), while androgen receptor (AR) and PD-L1 positive (combined positive score≥10) rates were lower than of STs cases (AR: 11.1% vs. 47.1%; PD-L1: 9.6% vs. 33.3%, p<0.05). The most commonly altered genes were TP53 (88.7%), PIK3CA (26.8%), MYC (18.3%) in NSTs, and TP53 (68.8%), PIK3CA (50%), JAK3 (18.8%), KMT2C (18.8%) in STs respectively. Compared with NSTs, PIK3CA and TP53 mutation frequency showed difference in STs (47.1% vs 19.4%, p=0.039; 64.7% vs 87.5%, p=0.035). Conclusions: In TNBC patients with STs, decrease in histologic grade and ki-67 index, as well as increase in PD-L1 and AR expression were observed when compared to those with NSTs, suggesting that TNBC patients with STs may better benefit from immune checkpoint inhibitors and/or AR inhibitors. Additionally, lower TP53 and higher PIK3CA mutation rates were also found in STs patients, providing genetic evidence for deciphering at least partly potential mechanism of action.

Tumor location of the central and nipple portion is associated with impaired survival for women with breast cancer.

BACKGROUND: Tumor location in the breast varies, with the highest frequency in the upper outer quadrant and lowest frequency in the lower inner quadrant. Nevertheless, tumors in the central and nipple portion (TCNP) are poorly studied types of breast cancer; therefore, we aimed to clarify the clinicopathological characteristics and prognostic features of TCNP. METHODS: Using the Surveillance, Epidemiology, and End Results database, we identifed 105,037 patients diagnosed with tumor in the breast peripheral quadrant (TBPQ) (n=97,046) or TCNP (n=7,991). The chi-squared test was used to compare categorical variables across TCNP and TBPQ. Cox proportional hazard models with hazard ratios were applied to estimate the factors associated with prognosis. RESULTS: The median follow-up was over 43 months. Compared with TBPQ, TCNP patients were signifcantly older (age ≥66 years: 40.4% vs 34.1%, P<0.001), with larger tumor sizes (>20 mm size: 46.9% vs 37.3%, P<0.001), higher proportions of TNM stage II-III (18.6% vs 9.9%, P<0.001), and more mastectomies (58.1% vs 37.8%, P<0.001). The breast cancer-specifc survival (BCSS)/overall survival (OS) rate was signifcantly worse for TCNP than for TBPQ. Multivariate Cox analysis showed a higher hazard ratios for TCNP over TBPQ (BCSS: hazard ratios =1.160, P=0.005, 95% CI: 1.046-1.287; OS: hazard ratios =1.301, P<0.001, 95% CI: 1.211-1.398). A subgroup analysis revealed inferior outcomes for TCNP in TNM stage II-III and breast subtype subgroup. Multivariate logistic regression indicated that TCNP was an independent contributing factor to LN metastasis. CONCLUSIONS: TCNP was associated with older age, larger tumor size, higher TNM stage, and lymph node metastasis. Compared with TBPQ, TCNP had adverse impacts on BCSS and OS.

GPC3 DNA vaccine elicits potent cellular antitumor immunity against HCC in mice.

BACKGROUND/AIMS: DNA-based tumor vaccine immunotherapy which elicits exclusively cellular immune response against cancer cells in an antigen-specific fashion has been documented to be an effective treatment for cancers in the past decade. Glypican 3 (GPC3) is especially overexpressed in hepatocellular carcinoma (HCC), but not in benign liver lesions and normal adult tissues, which makes it an ideal tumor antigen designed for HCC immunotherapy. METHODOLOGY: We constructed a GPC3 cDNA vaccine by using a recombinant plasmid encoding murine GPC3 cDNA for treatment of HCC in a C57BL/6 mouse model. The specificity and effectiveness of anti-tumor immunity were assessed in vitro and in vivo studies. RESULTS: In vitro studies showed that GPC3 DNA vaccine induced potent specific cytotoxic T lymphoctyes (CTLs) immune response against C57BL/6 homogenous HCC cell line Hepa 1-6 (GPC3+). However, there was no detectable immune response against GPC3-negative SP 2/0 cells and Sk-Hep-1 cells. In vivo study indicated that GPC3 DNA vaccine could significantly suppress homogenous tumor growth and prolong survival time of tumor bearing mice. CONCLUSIONS: This study demonstrated the first time that the GPC3 DNA vaccine could elicit specific and effective cellular antitumor immunity against GPC3 HCC. This may provide an alternative option for immunotherapy of HCC.

Prognostic significance of glypican-3 in hepatocellular carcinoma: a meta-analysis.

BACKGROUNDS: Glypican-3(GPC3) has been implicated in tumor development and progression for several years. However, the prognostic significance of GPC3 expression in patients with hepatocellular carcinoma (HCC) is controversial. We performed a meta-analysis of available studies to assess whether GPC3 can be used as a prognostic factor in patients with HCC. METHODS: We searched PubMed and Ovid EBM Reviews databases and evaluated the reference list of relevant articles for studies that assessed the prognostic relevance of GPC3 in patients with HCC. Meta-analysis was performed using hazard ratio (HR) or odds ratio (OR) and 95% confidence intervals (95% CIs) as effect measures. RESULTS: A meta-analysis of eight studies included 1070 patients was carried out to evaluate the association between GPC3 and overall survival (OS) and disease-free survival (DFS) in HCC patients. The relation between GPC3 and tumor pathological features was also assessed. Our analysis results indicated that high GPC3 expression predicted poor OS (HR: 1.96, 95% CI: 1.51-2.55) and DFS (HR: 1.99, 95% CI: 1.57-2.51) of patients with HCC. GPC3 overexpression was significantly associated with high tumor grade (OR: 3.30, 95% CI: 2.04-5.33), late TNM stage (OR: 2.26, 95% CI: 1.00-5.12), and the presence of vascular invasion (OR: 2.43, 95% CI: 1.23-4.82). CONCLUSIONS: GPC3 overexpression indicates a poor prognosis for patients with HCC, and it may also have predictive potential for HCC invasion and metastasis.

Prognostic significance of neutrophil-lymphocyte ratio in hepatocellular carcinoma: a meta-analysis.

BACKGROUNDS: Neutrophil-lymphocyte ratio (NLR) has recently been reported as a predictor of Hepatocellular carcinoma (HCC). However, its prognostic value in HCC still remains controversial. In this study, we aimed to evaluate the association between NLR and clinical outcome of HCC patients by performing meta-analysis. METHODS: A comprehensive literature search for relevant studies published up to August 2013 was performed by using PubMed, Ovid, the Cochrane Library and Web of Science databases. Meta-analysis was performed using hazard ratio (HR) or odds ratio (OR) and 95% confidence intervals (95% CIs) as effect measures. RESULTS: A total of 15 studies encompassing 3094 patients were included in this meta-analysis. Our pooled results showed that high NLR was associated with poor overall survival (OS) and disease free survival (DFS) in HCC initially treated by liver transplantation (HR = 3.42, 95% CI:2.41-4.85,P = 0.000; HR = 5.90, 95% CI:3.99-8.70,P = 0.000, respectively) and surgical resection (HR = 3.33, 95% CI:2.23-4.98, P = 0.000; HR = 2.10, 95% CI: 2.06-2.14, respectively). High NLR was also associated with poor OS in HCC treated by radiofrequency-ablation (HR = 1.28, 95%CI: 1.10-1.48, P = 0.000), TACE (HR = 2.52, 95% CI: 1.64-3.86, P = 0.000) and mixed treatment (HR = 1.85, 95% CI: 1.40-2.44, P = 0.000), respectively. In addition, high NLR was significantly correlated with the presence of vascular invasion (OR = 2.69, 95% CI: 2.01-3.59, P = 0.000), tumor multifocality (OR = 1.74, 95% CI: 1.30-2.34, P = 0.000) and higher incidence of AFP ≥ 400 ng/ml (OR = 1.46, 95% CI: 1.01-2.09, P = 0.04). CONCLUSION: Elevated NLR indicates a poor prognosis for patients with HCC. NLR may be a convenient, easily-obtained, low cost and reliable biomarker with prognostic potential for HCC.

Radiofrequency-assisted versus clamp-crush liver resection: a systematic review and meta-analysis.

BACKGROUND: Conflicting results were found between radiofrequency-assisted liver resection (RF-LR) and clamp-crush liver resection (CC-LR) during liver surgery. We conducted a systematic review and meta-analysis that included randomized controlled trials (RCTs) and non-RCTs to compare the effectiveness and safety of RF-LR versus CC-LR during liver surgery. METHODS: Articles comparing RF-LR and CC-LR that were published before December 2012 were retrieved and subjected to a systematic review and meta-analysis. Data synthesis and statistical analysis were carried out by Review Manager Version 5.2 software. RESULTS: In all, four RCTs and five nonrandomized studies evaluating 728 patients were included. Compared with CC-LR, the RF-LR group had significantly reduced total intraoperative blood loss (weighted mean difference [WMD] = -187 mL; 95% confidence interval [CI] = -312, -62; data on 628 patients), and blood loss during liver transection (WMD = -143.7 mL; 95% CI = -200, -87; data on 190 patients). However, RF-LR is associated with a higher rate of intra-abdominal abscess than the clamp-crushing method (odds ratio = 3.61; 95% CI = 1.26, 10.32; data on 366 patients). No significant difference was observed between both the groups for the incidence of both blood transfusion and bile leak. CONCLUSIONS: There is currently not sufficient evidence to support or refute the use of RF-LR in liver surgery. RF-LR has advantages in terms of reducing blood loss. However, RF-LR may increase the rates of both bile leak and abdominal abscess. So, the safety of RF-LR has not been established. Future well-designed RCTs are awaited to further investigate the efficacy and safety of RF devices in liver resection.

Glypican-3 is a potential prognostic biomarker for hepatocellular carcinoma after curative resection.

BACKGROUND: Glypican-3 (GPC3), an oncofetal protein, is overexpressed in hepatocellular carcinoma (HCC). The diagnostic efficacy of GPC3 for HCC has been evaluated intensively in recent years; however, the prognostic value of GPC3 for HCC has not been well clarified. The purpose of this study was to investigate the relationship between GPC3 and postoperative patient survival in a prospective database. METHODS: GPC3 protein was detected by immunohistochemistry. The relationship between GPC3 expression level and patients' clinicopathologic factors was analyzed. Kaplan-Meier survival analysis was used to calculate patients' survival and was compared by using the log rank test. The Cox regression model was used to identify the risk factors associated with prognosis. RESULTS: GPC3 was expressed in 84% of HCC tissues. GPC3 protein expression was correlated with the number of tumors (P = .015), serum alpha-fetoprotein (AFP) level (P = .011), and TNM stage (P = .006). High GPC3 expression was an independent risk factor for poor postoperative disease-free survival (hazard ratio [HR] = 0.469; 95% confidence interval [CI] 0.303-0.727; P = .001); and overall survival (HR = 0.435; 95% CI, 0.257-0.736; P = .002). Stratification analysis indicated that GPC3 had a good predictive value for tumor recurrence in patients with HCC who have normal serum AFP levels. Also, GPC3 expression status could predict the outcomes of patients with stage I disease. CONCLUSION: GPC3 is a potential and reliable biomarker for predicting tumor recurrence and overall survival in HCC patients after curative resection.