Extracapsular extension in the positive sentinel lymph node: a marker of poor prognosis in cT1-2N0 breast cancer patients?

Abstract

Objective

This study aims to evaluate whether extracapsular extension (ECE) in the sentinel lymph node (SLN) is associated with involvement of ≥ 4 lymph node metastases at completion axillary lymph node dissection (ALND) and the effect on 5-year disease-free survival (DFS) and 10-year overall survival (OS).

Summary background data

ECE in a SLN is usually a contraindication for omitting completion ALND in cT1-2N0 breast cancer patients treated with breast-conserving therapy and 1–2 positive SLN(s).

Methods

All cT1-2N0 breast cancer patients with 1–3 positive SLN(s) who underwent ALND between 2005 and 2008 were selected from the Netherlands Cancer Registry. Logistic regression analysis was used to determine the association between ECE and ≥ 4 lymph node metastases. Five-year DFS and 10-year OS were analyzed using Kaplan–Meier survival analysis. Cox regression analysis was performed to correct for other prognostic factors.

Results

A total of 3502 patients were included. Information on ECE was available for 2111 (60.3%) patients, consisting of 741 (35.1%) patients with and 1370 (64.9%) without ECE. The incidence of ≥ 4 lymph node metastases was 116 (15.7%) in the ECE group vs. 80 (5.8%) in the group without ECE (p < 0.001). Five-year DFS rate was 86.4% in the ECE group compared to 88.8% in the group without ECE (p = 0.085). 10-year OS rate was 78.6% compared to 83.0% (p = 0.018), respectively. Cox regression analysis showed that ECE was not an independent prognostic factor for both DFS and OS.

Conclusions

ECE was significantly associated with involvement of ≥ 4 lymph node metastases in the completion ALND group. ECE was not an independent prognostic factor for both DFS and OS.

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Epithelial-to-mesenchymal transition status of primary breast carcinomas and its correlation with metastatic behavior

Abstract

Background

Epithelial-to-mesenchymal transition (EMT) has been implicated as an important step in the development of distant metastases. We therefore wished to study EMT status of primary breast carcinomas from patients who during follow-up developed distant metastases.

Methods

mRNA expression profiles of primary breast carcinoma samples (n = 151) from patients who developed metastatic disease were analyzed and EMT status was designated using a previously described EMT-core signature. EMT status of the primary tumor was correlated to clinicopathological characteristics, molecular subtypes, metastasis pattern, chemotherapy response and survival outcomes. In addition, using immunohistochemistry, the expression levels of several proteins implicated in EMT were studied (CDH1, CDH2, NAT1, SNAI2, TWIST1, VIM, and ZEB1) compared with the designated EMT status and survival.

Results

Utilizing the 130-gene-EMT-core signature, 66.2% of the primary tumors in the current study was assessed as EMT-activated. In contrast to our expectations, analyses revealed that 84.6% of Luminal A tumors, 65.1% of Luminal B tumors, and 55.6% of HER2-like had an activated EMT status, compared to only 25% of the basal-type tumors (p < 0.001). EMT status was not correlated to the pattern of metastatic disease, metastasis-specific survival, and overall survival. Similarly, there was not a significant association between EMT status of the primary tumor and chemotherapy response in the metastatic setting. Immunostaining for NAT1 and TWIST1 correlated with the EMT status (p 0.003 and p 0.047, respectively). Multivariate analyses showed that NAT1 and TWIST1 staining was significantly associated with EMT status regardless of the estrogen receptor status of the tumors (p values: 0.020 and 0.027, respectively).

Conclusions

The EMT status of breast cancers, as defined by the presence of a core EMT gene expression signature is associated with non-basal-type tumors, but not with the pattern of distant metastasis. Of several potential immunohistochemical EMT markers, only NAT1 and TWIST1 expression levels were associated with the gene expression-based EMT status.

http://bit.ly/2F9Psvg

Clinical implications of germline mutations in breast cancer genes: RECQL

Abstract

Background

The identification of new hereditary breast cancer genes is an area of highly active research. In 2015, two independent studies provided initial evidence for a novel breast cancer susceptibility gene, RECQL, a DNA helicase which plays an important role in the DNA damage response. Several subsequent studies in independent patient cohorts have provided further data on RECQL variant frequency in additional populations, some of which have brought in to question the increased breast cancer risk associated with RECQL mutations.

Results

The initial reports present findings from whole exome sequencing of high-risk familial breast cancer cases in the French-Canadian, Polish and Han Chinese populations and estimate the carrier frequency of pathogenic RECQL mutations in high-risk breast cancer patients who have previously tested negative for BRCA1 and BRCA2 mutations to be approximately 1–2%. Proposed founder mutations were identified in French-Canadian and Polish populations. Functional studies support loss of function of the helicase activity of RECQL for some of the reported pathogenic mutations. An additional study in a cohort of Southern Chinese high-risk breast cancer patients estimated the frequency of pathogenic RECQL mutations to be 0.54%. A possible Chinese founder mutation was identified, but only a small number of controls were sequenced. Subsequent case–control studies screening for the Polish founder mutation in patients from Germany and Belarus did not find any evidence for increased breast cancer risk for this variant. An Australian case–control study also failed to identify an increased risk of breast cancer associated with RECQL loss of function variants.

Conclusions

RECQL plays an important role in DNA repair, and is a plausible candidate breast cancer susceptibility gene. Initial studies showed evidence of an association between variants in this gene and an increased breast cancer risk in three separate populations, and identified founder mutations with significantly increased odds ratios. However, several subsequent studies have failed to support the association. With the limited and conflicting evidence available, there remains debate as to whether there is an increased breast cancer risk in individuals carrying RECQL loss of function variants. Further studies are required to better quantify the risks associated with RECQL variants and the current evidence base is not sufficient to justify routine inclusion of RECQL on breast cancer gene panels in clinical use. Management of patients in whom RECQL variants have been identified should be based on clinician assessment, in the context of the family history. Further studies are required to better quantify the risks to RECQL mutation carriers and may also guide management and potential therapeutic targeting for patients.

http://bit.ly/2F5Qpol

Re: The relationship between patient and tumor characteristics, patterns of breast cancer care, and 5-year survival among elderly women with incident breast cancer. Breast Cancer Res Treat. Sep 2018;171(2):477-488

http://bit.ly/2F8qJXy

MicroRNA-663 antagonizes apoptosis antagonizing transcription factor to induce apoptosis in epithelial cells

Abstract

MicroRNAs are small functional RNAs that modulate various biological processes in cells by interfering with gene translation. We have previously demonstrated that certain miRNAs play a crucial role in the innate immune responses of human oral epithelial cells to Porphyromonas gingivalis. While addressing the mechanisms of P. gingivalis induced apoptosis in these cells, we discovered that certain miRNAs are upregulated upon stimulation with live bacteria. These upregulated miRNAs include hsa-miR-584, hsa-miR-572, hsa-miR-210, hsa-miR-492, hsa-miR-623 and hsa-miR-663. Further analysis revealed an unexpected role for hsa-miR-663 (miR-663). To further evaluate miR-663 function, we overexpressed miR-663 in epithelial cells which resulted in cellular apoptosis. The bioinformatics analysis of the miR-663 target prediction, revealed a strong binding affinity to a 3′ UTR region of Apoptosis Antagonizing Transcription Factor (AATF) mRNA. To demonstrate the binding of miR-663 to AATF mRNA, the putative miR-663 target site within the 3′-UTR region of AATF was cloned in luciferase vector and transfected to HEK293T cells. Luminescence data showed the downregulation of luciferase activity in cells that had the full length target region of the putative binding site, confirming that AATF is one of the targets for miR-663. This prompted us to further evaluate its role in a cancer cell line (MCF-7) to determine miR-663s' apoptotic function. The overexpression of miR-663 led to a significant increase in apoptosis of MCF-7 cells. Taken together, miR-663 may function as an 'apoptomiR' by inhibiting the anti-apoptotic gene AATF to induce apoptosis. These findings could have therapeutic implications for epithelial cell targeting in cancer therapy.

http://bit.ly/2F5wSVd

Survival Implications of De Novo Versus Recurrent Metastatic Non–Small Cell Lung Cancer

Objectives: Metastatic non–small cell lung cancer (NSCLC) has a poor prognosis. Most patients present with stage IV, and many patients treated curatively with stage I to III develop recurrent metastatic disease. It is unknown whether the natural history differs between patients with recurrent versus de novo metastatic NSCLC. We hypothesized that de novo metastatic status is associated with decreased overall survival compared with recurrent metastatic disease. Materials and Methods: A retrospective review was completed of all patients with NSCLC referred to BC Cancer from 2005 to 2012. Two cohorts were created; de novo metastatic disease and patients treated with curative intent (surgery or radiotherapy) that developed recurrent, metastatic disease. Information was collected on known prognostic and predictive factors. Overall survival was calculated from the date of diagnosis of metastatic disease. Results: A total of 9651 patients were evaluated, 5782 (60%) with de novo stage IV disease, and 3869 (40%) with stage I to III disease. Of the 1658 patients who received curative therapy for stage I to III disease, 757 (46%) developed metastases. Patients in the de novo cohort versus recurrent cohort were more likely male (52% vs. 48%), have poorer performance status (Eastern Cooperative Oncology Group≥2 50% vs. 44%), and receive no palliative systemic therapy (67% vs. 61%). The median overall survival in the de novo cohort was 4.7 versus 6.9 m in the recurrent cohort (P

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Epistemic Entitlements and the Practice of Computer Simulation

Abstract

What does it mean to trust the results of a computer simulation? This paper argues that trust in simulations should be grounded in empirical evidence, good engineering practice, and established theoretical principles. Without these constraints, computer simulation risks becoming little more than speculation. We argue against two prominent positions in the epistemology of computer simulation and defend a conservative view that emphasizes the difference between the norms governing scientific investigation and those governing ordinary epistemic practices.

http://bit.ly/2F82jhk