Etiology of hormone receptor positive breast cancer differs by levels of histologic grade and proliferation

Abstract

Limited epidemiological evidence suggests that the etiology of hormone receptor positive (HR+) breast cancer may differ by levels of histologic grade and proliferation. We pooled risk factor and pathology data on 5,905 HR+ breast cancer cases and 26,281 controls from 11 epidemiological studies. Proliferation was determined by centralized automated measures of KI67 in tissue microarrays. Odds ratios (OR), 95% confidence intervals (CI) and p-values for case-case and case-control comparisons for risk factors in relation to levels of grade and quartiles (Q1-Q4) of KI67 were estimated using polytomous logistic regression models. Case-case comparisons showed associations between nulliparity and high KI67 [OR (95% CI) for Q4 vs Q1 = 1.54 (1.22, 1.95)]; obesity and high grade [grade 3 vs 1 = 1.68 (1.31, 2.16)]; and current use of combined hormone therapy (HT) and low grade [grade 3 vs 1 = 0.27 (0.16, 0.44)] tumors. In case-control comparisons, nulliparity was associated with elevated risk of tumors with high but not low levels of proliferation [1.43 (1.14, 1.81) for KI67 Q4 vs 0.83 (0.60, 1.14) for KI67 Q1]; obesity among women ≥50 years with high but not low grade tumors [1.55 (1.17, 2.06) for grade 3 vs 0.88 (0.66, 1.16) for grade 1]; and HT with low but not high grade tumors [3.07 (2.22, 4.23) for grade 1 vs 0.85 (0.55, 1.30) for grade 3]. Menarcheal age and family history were similarly associated with HR+ tumors of different grade or KI67 levels. These findings provide insights into the etiologic heterogeneity of HR+ tumors. This article is protected by copyright. All rights reserved.

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Interaction analysis between germline susceptibility loci and somatic alterations in lung cancer

Abstract

Emerging evidence indicates that germline variations may interact with somatic events in carcinogenesis. However, the germline-somatic interaction in lung cancer remains largely unknown. We investigated whether lung cancer driver genes (CDGs) were more likely to locate within cancer susceptibility regions. Pathway analysis was performed to identify common pathways underlying CDGs and cancer susceptibility genes (CSGs). Next, we analyzed the associations between lung cancer risk SNPs and somatic alterations, including mutations and copy number alterations, in the level of genes, pathways, and overall burden of alterations. Enrichment analysis showed that lung CDGs are more likely to locate within cancer susceptibility regions (P = 8.40 × 10⁻³). Both of lung CSGs and CDGs showed significant enrichment in pathways such as cell cycle and p53 signaling pathway. Gene-based analysis showed that rs36600 (22q12.2) was associated with somatic mutations within ARID1A (OR = 2.45, 95%CI: 1.47-4.08, P = 5.78 × 10⁻⁴). Pathway-based analysis of somatic truncation mutations identified rs2395185 and rs3817963 at 6p22.1 were associated with cell cycle pathway (OR = 1.56, P = 3.61 × 10⁻⁴ for rs2395185; OR = 1.58, P = 4.15 × 10⁻⁴ for rs3817963), and rs3817963 was also associated with MAPK signaling pathway (OR = 1.54, P = 8.58 × 10⁻⁴). Further analysis associated rs2395185 at 6p22.1 (HLA class II genes) with increased APOBEC3A expression (P = 9.50 × 10⁻³) and elevated APOBEC mutagenesis (P = 3.58 × 10⁻³). These results indicate germline-somatic interactions in lung tumorigenesis, and help to uncover the molecular mechanisms underlying lung cancer risk SNPs. This article is protected by copyright. All rights reserved.

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A clinicopathological study and prognostic factor analysis of 177 salivary duct carcinoma patients from The Netherlands

Abstract

Salivary duct carcinoma (SDC) is a subtype of salivary gland cancer with a dismal prognosis and a need for better prognostication and novel treatments. The aim of this national cohort study was to investigate clinical outcome, prognostic factors, Androgen Receptor (AR) and Human Epidermal Growth Factor Receptor 2 (HER2) expression.

SDC patients diagnosed between 1990 – 2014 were identified by the Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands (PALGA). Subsequently, medical records were evaluated and pathological diagnoses reviewed. Data were analyzed for overall survival (OS), disease free survival (DFS), distant metastasis free survival (DMFS), and prognostic factors. AR was evaluated by immunohistochemistry (IHC), HER2 by IHC and fluorescent-in-situ-hybridization.

A total of 177 patients were included. The median age was 65 years, 75% were male. At diagnosis, 68% presented with lymph node metastases and 6% with distant metastases. Median OS, DFS and DMFS were 51, 23 and 26 months, respectively. In patients presenting without distant metastases, the absolute number of positive lymph nodes was associated with poor OS and DMFS in a multivariable analysis. AR and HER2 were positive in 161/168 (96%) and 44/153 (29%) tumors, respectively, and were not prognostic factors.

SDC has a dismal prognosis with primary lymph node involvement in the majority of patients. The absolute number of lymph node metastases was found to be the only prognostic factor for DMFS and OS. AR expression and, to a lesser extent, HER2 expression hold promise for systemic treatment in the metastatic and eventually adjuvant setting. This article is protected by copyright. All rights reserved.

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Comparison of propofol and desflurane for postanaesthetic morbidity in patients undergoing surgery for aneurysmal SAH: a randomized clinical trial

Abstract

Purpose

Surgery for aneurysmal clipping after subarachnoid haemorrhage (SAH) poses a unique anaesthetic challenge. However, data on the influence of anaesthetic agents in these patients are lacking. The study aims to evaluate the superiority of propofol over desflurane for postanaesthetic morbidity in patients undergoing surgery following aneurysmal SAH.

Methods

Seventy World Federation of Neurosurgeons Grade I and II patients were randomized into propofol (n = 35) and desflurane groups (n = 35). Anaesthesia was maintained with propofol/fentanyl in propofol group and desflurane/fentanyl in the desflurane group. Jugular venous oxygen saturation (SjVO₂) and brain relaxation were assessed intraoperatively. Time to eye opening, response to verbal commands, and extubation were noted from the time of discontinuing the anaesthetic agent. Duration of postoperative hospital stay and modified Rankin score (MRS) at discharge were subsequently compared.

Results

Median postoperative hospital stay was 9 (6, 14) days with use of propofol and 9 (7, 12) days in desflurane group (P = 0.671). 18 patients in the propofol group and 14 patients in the desflurane group had good outcome (modified Rankin score 0–1; P = 0.453). Both the anaesthetics were similar in terms of intraoperative haemodynamics, brain relaxation, time to eye opening, response to verbal commands, and extubation time (P > 0.05). Emergence hypertension was more in the desflurane group (P = 0.007). The intraoperative SjVO₂ values were significantly higher in the desflurane group (P < 0.05).

Conclusion

Propofol and desflurane are comparable in terms of postoperative morbidity in patients undergoing aneurysm neck clipping following SAH.

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Therapy-Educated Mesenchymal Stem Cells Enrich for Tumor-Initiating Cells

Stromal cells residing in the tumor microenvironment contribute to the development of therapy resistance. Here we show that chemotherapy-educated mesenchymal stem cells (MSC) promote therapy resistance via cross-talk with tumor-initiating cells (TIC), a resistant tumor cell subset that initiates tumorigenesis and metastasis. In response to gemcitabine chemotherapy, MSCs colonized pancreatic adenocarcinomas in large numbers and resided in close proximity to TICs. Furthermore, gemcitabine-educated MSCs promoted the enrichment of TICs in vitro and enhance tumor growth in vivo. These effects were dependent on the secretion of CXCL10 by gemcitabine-educated MSCs and subsequent activation of the CXCL10–CXCR3 axis in TICs. In an orthotopic pancreatic tumor model, targeting TICs using nanovesicles (called nanoghosts) derived from MSC membranes and loaded with a CXCR3 antagonist enhanced therapy outcome and delayed tumor regrowth when administered in combination with gemcitabine. Overall, our results establish a mechanism through which MSCs promote chemoresistance, and propose a novel drug delivery system to target TICs and overcome this resistance.Significance: These results establish a mechanism by which mesenchyme stem cells in the tumor microenvironment promote chemoresistance, and they propose a novel drug delivery system to overcome this challenge. Cancer Res; 78(5); 1253–65. ©2018 AACR.

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