Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies.

Despite recent improvements in the comprehensive therapy of malignancy, metastatic colorectal cancer (mCRC) continues to have a poor prognosis. Notably, 5% of mCRC cases harbor Erb-B2 receptor tyrosine kinase 2 (ERBB2) alterations. ERBB2, commonly referred to as human epidermal growth factor receptor 2, is a member of the human epidermal growth factor receptor family of protein tyrosine kinases. In addition to being a recognized therapeutic target in the treatment of gastric and breast malignancies, it is considered crucial in the management of CRC. In this review, we describe the molecular biology of ERBB2 from the perspective of biomarkers for mCRC-targeted therapy, including receptor structures, signaling pathways, gene alterations, and their detection methods. We also discuss the relationship between ERBB2 aberrations and the underlying mechanisms of resistance to anti-EGFR therapy and immunotherapy tolerance in these patients with a focus on novel targeted therapeutics and ongoing clinical trials. This may aid the development of a new standard of care in patients with ERBB2-positive mCRC.

FBXW7 and Its Downstream NOTCH Pathway Could be Potential Indicators of Organ-Free Metastasis in Colorectal Cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths globally. Metastasis is associated with a poor prognosis, yet the underlying molecular mechanism(s) remained largely unknown. In this study, a total of 85 CRC patients were included and the primary tumor lesions were evaluated by next-generation sequencing using a targeted panel for genetic aberrations. Patients were sub-divided according to their metastasis pattern into the non-organ metastases (Non-OM) and organ metastases (OM) groups. By comparing the genetic differences between the two groups, we found that mutations in FBXW7 and alterations in its downstream NOTCH signaling pathway were more common in the Non-OM group. Moreover, correlation analysis suggested that FBXW7 mutations were independent of other somatic alterations. The negative associations of alterations in FBXW7 and its downstream NOTCH signaling pathway with CRC organ metastasis were validated in a cohort of 230 patients in the TCGA CRC dataset. Thus, we speculated that the genomic alterations of FBXW7/NOTCH axis might be an independent negative indicator of CRC organ metastases.

Depletion of DNA damage binding protein 2 sensitizes triple-negative breast cancer cells to poly ADP-ribose polymerase inhibition by destabilizing Rad51.

Poly ADP-ribose polymerase inhibitors (PARPi) have shown promising therapeutic efficacy in triple-negative breast cancer (TNBC) patients. However, resistance ultimately develops, preventing a curative effect from being attained. Extensive investigations have indicated the diversity in the mechanisms underlying the PARPi sensitivity of breast cancer. In this study, we found that DNA damage binding protein 2 (DDB2), a DNA damage-recognition factor, could protect TNBC cells from PARPi by regulating DNA double-strand break repair through the homologous recombination pathway, whereas the depletion of DDB2 sensitizes TNBC cells to PARPi. Furthermore, we found that DDB2 was able to stabilize Rad51 by physical association and disrupting its ubiquitination pathway-induced proteasomal degradation. These findings highlight an essential role of DDB2 in modulating homologous recombination pathway activity and suggest a promising therapeutic target for TNBC.

Breast-Conserving Surgery in Patients With Mammary Paget's Disease.

BACKGROUND: We aimed to analyze the association between Paget's disease (PD) and breast cancer (BC) subtypes and compare the effect of breast-conserving surgery (BCS) as a local treatment with mastectomy for PD. MATERIALS AND METHODS: Data of patients with histologic type International Classification of Diseases-0-3 8540-8543 who were treated from 1973 to 2014 were retrieved from the Surveillance, Epidemiology, and End Results database of the National Cancer Institute. A chi-square test was used to identify differences in categorical data among different groups. Overall survival (OS) was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, sequential landmark analysis, and propensity score-matched analysis. RESULTS: The study cohort included 5398 patients. Triple-negative BC accounted for the fewest patients with PD-only (1/22, 4.54%), Paget's disease-ductal carcinoma in situ (PD-DCIS) (3/48, 6.25%), and Paget's disease-invading ductal carcinoma (PD-IDC) (23/352, 6.53%). According to the results of the log-rank test and Cox analysis, the 10-year OS rates were similar for the BCS and mastectomy subgroups among patients with PD-DCIS or PD-IDC. Furthermore, there were no significant differences in survival benefits among the different surgeries after propensity score matching. Landmark analyses for OS of patients with PD-DCIS or PD-IDC surviving more than 1, 3, and 5 y showed no significant differences in survival. There were statistical differences in 10-year OS rates for patients with PD-DCIS or PD-IDC who underwent radiation therapy, or not, following BCS (both, P < 0.001). CONCLUSIONS: For patients with PD-DCIS or PD-IDC, breast conservation therapy with lumpectomy and radiation is an effective local treatment strategy, compared with mastectomy.

Effect of miR-146a-5p on proliferation and metastasis of triple-negative breast cancer via regulation of SOX5.

MicroRNA (miR)-146a-5p functions as a tumor suppressor in various types of cancer. However, the role of miR-146a-5p in the development of triple-negative breast cancer (TNBC) is unclear. The present study aimed to investigate the role of miR-146a-5p in TNBC. The expression level of miR-146a-5p in TNBC tissues and cell lines was initially detected using reverse transcription-quantitative polymerase chain reaction. To predict the target gene of miR-146a-5p, TargetScan software was used and a dual luciferase assay was performed to verify the prediction. Furthermore, in order to explore the role of miR-146a-5p in TNBC, miR-146a-5p was overexpressed in TNBC cells using miR-146a-5p mimics. An MTT assay was performed to detect cell proliferation, and a Transwell assay was conducted to determine cell migration and invasion. Furthermore, western blotting was performed to measure associated protein expression. It was revealed that miR-146a-5p was downregulated in TNBC tissues and cell lines. SOX5 was indicated to be a target gene of miR-146a-5p and was upregulated in TNBC cells. Additionally, miR-146a-5p could inhibit TNBC cell proliferation, migration and invasion, repress the expression of mesenchymal markers (N-cadherin, vimentin and fibronectin) and increase epithelial marker (E-cadherin) expression. Furthermore, SOX5 overexpression eliminated the effects of miR-146a-5p mimics on TNBC cells. In conclusion, the data of the present study indicated that miR-146a-5p inhibits the proliferation and metastasis of TNBC cells by regulating SOX5.

Association between molecular subtypes and lymph node status in invasive breast cancer.

BACKGROUND: The predictors for the involvement of lymph node (LN) have been widely studied. But the implication of the molecular type has not been well studied. Using the database of our institution, we investigated this relation. METHODS: Patients with T1 and T2 primary breast cancer without distant metastasis were included in our study from 2012 Jan to 2013 Dec. All patients undertook the resection of the primary and the axillary lymph nodes (ALNs). We collected the clinical data including age at diagnosis, the status of ER, PR and HER2, tumor size, nodal status, and histological type. The relationship between demographic, tumor characteristics and lymph node status was evaluated. RESULTS: 814 patients were included in our study. The number and the percentage (in parentheses) of each type of breast cancer is as follows: Luminal A 230 (28.3%), Luminal Her2- 284 (34.9%), Luminal Her2+ 104 (12.8%), HER2+ 72 (8.8%), TNBC 124 (15.2%). On univariate and multivariate analysis, tumor size and tumor subtype show statistical significance with LN involvement. Using TNBC as a reference, both Luminal B type (Luminal HER2-, Luminal HER2+) shows significant higher probability of LN involvement. CONCLUSIONS: LN involvement is an intrinsic characteristic for molecular subtype of breast cancer. Triple positive and triple negative breast cancer accounts the most and least possibility of LN involvement.

In vivo lymph node mapping by Cadmium Tellurium quantum dots in rats.

BACKGROUND: Intraoperative lymph node mapping (LNM) is highly significant for many surgeries in patients with cancer. Many types of tracers are currently used, but the ideal method has not yet been identified. We aimed to identify a stable lymphatic drainage pathway in an animal model and compared the effects of quantum dots (QD), a new fluorescent tracer, with those of methylene blue in intraoperative LNM. MATERIALS AND METHODS: Indian ink (0.2 mL) was subcutaneously injected into the plantar metatarsal regions of six Sprague-Dawley rats. After 2 wk of incubation and subsequent dissection, the potentially stained LNs were examined pathologically to identify the lymphatic drainage pathway. After applying anesthesia, 0.1 mL methylene blue (2%) and QD (1 mg/mL) were injected into the plantar metatarsal regions of six rats for intraoperative LNM. The QD group was observed with a near-infrared imaging system, and the methylene blue group was directly observed. Drainages were recorded at 5, 10, 30, 60, and 120 min and at 1 d. RESULTS: Two three-level drainage pathways, that is, a peripheral drainage (popliteal LNs, inguinal LNs, and axillary LNs) and a central drainage (popliteal lymph node [LN], iliac LN, and renal LN) pathways were identified. Both methylene blue and QD stained the sentinel lymph node (SLNs) quickly, but methylene blue was difficult to identify in the deep tissues and the LNs beyond the SLN. Furthermore, the blue-stained LNs remain dyed for only 2 h. In contrast, the QDs exhibited high target-to-background ratios in both the SLNs and the following LNs. Additionally, the fluorescence lasted from 5 min-1 d after injection. CONCLUSIONS: An ideal lymphatic drainage model was found. QDs are excellent tracers for intraoperative LNM compared with methylene blue. Near infrared fluorescent imaging is a promising LNM method for clinical practice.

Colonic J-pouch versus Baker type for rectal reconstruction after anterior resection of rectal cancer.

OBJECTIVE. There is no consensus regarding reconstruction type after anterior resection for rectal cancer. We conducted a meta-analysis of relevant randomized controlled trials (RCTs) to compare outcomes of colonic J-pouch (CJlP) and side-to-end anastomosis (STEA) after anterior resection of rectal cancer. METHODS. Electronic databases were searched in January 2013, with six RCTs selected for further analysis, for a total of 451 patients (229 CJP, 222STEA). Outcome measures included surgical, physiologic, and functional outcomes, as well as postoperative complications. The odds ratio (OR) was used in the statistical analysis; in other circumstances, qualitative descriptions were performed. RESULTS. As far as surgical outcomes and postoperative complications, there was no difference between groups. While functional outcomes were substantially impaired, this was similar between groups. CJP demonstrated better function in the early postoperative period. No difference was seen between groups with regards to physiologic outcome. CONCLUSION. CJP and STEA are comparable when choosing the type of reconstruction for restoration of bowel continuity in anterior resection for rectal cancer.

Synthesis of CdTe quantum dot-conjugated CC49 and their application for in vitro imaging of gastric adenocarcinoma cells.

The purpose of this experiment was to investigate the visible imaging of gastric adenocarcinoma cells in vitro by targeting tumor-associated glycoprotein 72 (TAG-72) with near-infrared quantum dots (QDs). QDs with an emission wavelength of about 550 to 780 nm were conjugated to CC49 monoclonal antibodies against TAG-72, resulting in a probe named as CC49-QDs. A gastric adenocarcinoma cell line (MGC80-3) expressing high levels of TAG-72 was cultured for fluorescence imaging, and a gastric epithelial cell line (GES-1) was used for the negative control group. Transmission electron microscopy indicated that the average diameter of CC49-QDs was 0.2 nm higher compared with that of the primary QDs. Also, fluorescence spectrum analysis indicated that the CC49-QDs did not have different optical properties compared to the primary QDs. Immunohistochemical examination and in vitro fluorescence imaging of the tumors showed that the CC49-QDs probe could bind TAG-72 expressed on MGC80-3 cells.