A Case Report of Breast Cancer with Extensive Pulmonary Lymphovascular Tumor Emboli

We describe a patient with breast cancer who relapsed with an extensive pulmonary lymphovascular tumor embolism. A 38-year-old female, who previously received neoadjuvant chemotherapy and curative resection of breast cancer, underwent adjuvant chemotherapy and was referred to the emergency room because of sudden-onset pleuritic chest pain lasting for 10 days. Despite a trial of empirical antibiotics, the chest pain and the extent of consolidative lung lesion on chest radiographs rapidly aggravated. We performed an open lung biopsy to confirm the etiology. The histopathological review revealed a hemorrhagic infarction caused by lymphovascular tumor emboli from a metastatic breast carcinoma. Palliative first-line chemotherapy was administered, consisting of ixabepilone and capecitabine, and the lung lesion improved markedly

Genomic profile of metastatic breast cancer patient-derived xenografts established using percutaneous biopsy.

BACKGROUND: Metastatic breast cancer (mBC) is a complex and life-threatening disease and although it is difficult to cure, patients can benefit from sequential anticancer treatment, including endocrine therapy, targeted therapy and cytotoxic chemotherapy. The patient-derived xenograft (PDX) model is suggested as a practical tool to predict the clinical outcome of this disease as well as to screen novel drugs. This study aimed to establish PDX models in Korean patients and analyze their genomic profiles and utility for translational research. METHODS: Percutaneous core needle biopsy or punch biopsy samples were used for xenotransplantation. Whole exome sequencing and transcriptome analysis were performed to assess the genomic and RNA expression profiles, respectively. Copy number variation and mutational burden were analyzed and compared with other metastatic breast cancer genomic results. Mutational signatures were also analyzed. The antitumor effect of an ATR inhibitor was tested in the relevant PDX model. RESULTS: Of the 151 cases studied, 40 (26%) PDX models were established. Notably, the take rate of all subtypes, including the hormone receptor-positive (HR +) subtype, exceeded 20%. The PDX model had genomic fidelity and copy number variation that represented the pattern of its donor sample. TP53, PIK3CA, ESR1, and GATA3 mutations were frequently found in our samples, with TP53 being the most frequently mutated, and the somatic mutations in these genes strengthened their frequency in the PDX model. The ESR1 mutation, CCND1 amplification, and the APOBEC signature were significant features in our HR + HER2- PDX model. Fulvestrant in combination with palbociclib showed a partial response to the relevant patient\u27s tumor harboring the ESR1 mutation, and CCND1 amplification was found in the PDX model. AZD6738, an ATR inhibitor, delayed tumor growth in a relevant PDX model. CONCLUSIONS: Our PDX model was established using core needle biopsy samples from primary and metastatic tissues. Genomic profiles of the samples reflected their original tissue characteristics and could be used for the interpretation of clinical outcomes

Prognostic impact of AJCC response criteria for neoadjuvant chemotherapy in stage II/III breast cancer patients: breast cancer subtype analyses

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background Neoadjuvant chemotherapy (NAC) is a standard treatment for stage II/III breast cancer patients, and response to NAC is a useful prognostic marker. Since its introduction, 6–8 cycles of NAC has become the standard regimen to improve the outcome of these patients. The purpose of this study is to evaluate the prognostic impact of the American Joint Committee on Cancer (AJCC) response criteria and this tools usefulness in four different breast cancer subtypes. Methods We conducted a retrospective cohort study of clinical stage II/III breast cancer patients who received NAC of more than 6 cycles. Response after NAC and the clinicopathological factors were reviewed. AJCC response criteria for NAC were adopted from the AJCC Manual, 7th edition: complete response (CR), partial response (PR), and no response (NR). Results A total of 183 patients were enrolled; 22 (12.0 %), 123 (67.2 %), and 38 (20.8 %) patients showed CR, PR, and NR, respectively. The AJCC response was significantly associated with relapse-free survival (RFS) (P < 0.001), whereas pathologic CR (pCR), the current gold standard for response evaluation for NAC, was not (P = 0.140). AJCC response was a significant prognostic factor for RFS in all four breast cancer subtypes, namely luminal A (P = 0.006), luminal B (P = 0.001), HER-2 enriched (P = 0.039), and triple-negative breast cancer (P = 0.035). Conclusions The AJCC response criteria represent a simple and easily reproducible tool for response evaluation of NAC patients and a useful clinical prognostic marker for RFS. These criteria also have a prognostic impact in all four breast cancer subtypes, including luminal A in which pCR has a limited role

Epidermal growth factor receptor gene amplification predicts worse outcome in patients with surgically resected nonadenocarcinoma lung cancer

The epidermal growth factor receptor (EGFR) gene copy number was analyzed with fluorescent in situ hybridization (FISH) to examine the prognostic role in surgically resected nonadenocarcinoma of non-small-cell lung cancer (NA-NSCLC). Patients with EGFR gene amplification and high polysomy, who underwent curativeintent surgical resection, showed significantly shorter overall survival (hazard ratio, 1.36; 95% confidence interval, 1.040-1.782; P = .025). EGFR FISH evaluation of surgical tumor tissue, in addition to clinicopathologic factors, might better predict for the prognosis of early-stage or locally advanced NA-NSCLC patients. Purpose: The aim of the present study was to examine the prognostic role of amplification and increased expression of the epidermal growth factor receptor (EGFR) gene in surgically resected non-adenocarcinoma of non-small cell lung cancer (NA-NSCLC). Materials and Methods: The present retrospective study included 114 consecutive NA-NSCLC patients with available tumor tissue and survival data. EGFR gene copy number and protein expression were evaluated using fluorescent in situ hybridization (FISH) and immunohistochemistry in tissue microarray sections, respectively. Results: Among 114 patients, 99 (86.8%) had squamous cell carcinoma histologic features. EGFR gene amplification and high polysomy (EGFR FISH+) were observed in 7.9% and 31.6% of cases, respectively. Patients with EGFR FISH+ had significantly shorter overall survival (P = .011). A multivariate model confirmed that patients with EGFR FISH+ had a significantly greater risk of death than EGFR FISH- patients after adjusting for pathologic stage, presence of pleural invasion, venous invasion, and surgical margins (hazard ratio, 1.36; 95% CI, 1.040 to 1.782; P = .025). EGFR protein expression by immunohistochemistry was not associated with overall survival in the same group. Neither EGFR gene amplification nor EGFR immunohistochemistry expression was associated with relapse-free survival. Conclusion: An increased EGFR gene copy number in surgically resected NA-NSCLC was associated with worse survival. (C) 2018 Elsevier Inc. All rights reserved.N

Clinical implications of HER2 mRNA expression and intrinsic subtype in refractory HER2-positive metastatic breast cancer treated with pan-HER inhibitor, poziotinib

Introduction We explored clinical implication of intrinsic molecular subtype in human epidermal growth factor receptor 2 (HER2) + metastatic breast cancer (BC) with pan-HER inhibitor from a phase II clinical trial of poziotinib in refractory HER2+BC patients. Methods For this translational research correlated with phase II clinical trial, we performed an nCounter expression assay, using gene panel including 50 genes for PAM50 prediction and targeted deep sequencing. Results From 106 participants, we obtained 97 tumor tissues and analyzed gene expression in 91 of these samples. Of 91 HER2+BCs, 40 (44.0%) were HER2-enriched (E) intrinsic molecular subtype, 17 (18.7%) of Luminal A, 16 (17.6%) of Basal-like, 14 (15.4%) of Luminal B and 4 (4.4%) of Normal-like. HER2-E subtype was associated with hormone receptor negativity (odds ratio [OR] 2.93;p = 0.019), 3 + of HER2 immunohistochemistry(IHC) (OR 5.64;p = 0.001), high mRNA expression ofHER2(OR 14.43;p = 0.001) and copy number(CN) amplification ofHER2(OR 12.80;p = 0.005). In genetic alterations, alteration was more frequently observed in HER2-E subtype (OR 3.84;p = 0.022) but there was no association betweenPIK3CAalteration and HER2-E subtype (p = 0.655). In terms of drug efficacy, high mRNA expression ofHER2was the most powerful predictor of poziotinib response (median progression-free survival [PFS): 4.63 months [high] vs. 2.56 [low];p < .001). In a combination prediction model, median PFS of intrinsic subtypes except Her2-E with highHER2mRNA expression withoutPIK3CAgenetic alteration was 6.83 months and that of the remaining group was 1.74 months (p < .001). Conclusion HER2-E subtype was associated with hormone receptor status, HER2 IHC, CN and mRNA expression and TP53 mutation. In survival analysis, the information of level of HER2 mRNA expression, intrinsic molecular subtype and PI3K pathway alteration would be independent predictors to poziotinib treatment. ClinicalTrials.gov identifier: NCT02418689

Androgen receptor inhibitor enhances the antitumor effect of PARP inhibitor in breast cancer cells by modulating DNA damage response

The androgen receptor (AR) is expressed in 60%-70% of breast cancers regardless of estrogen receptor status, and has been proposed as a therapeutic target in breast cancers that retain AR. In this study, the authors aimed to investigate a new treatment strategy using a novel AR inhibitor AZD3514 in breast cancer. AZD3514 alone had a minimal antiproliferative effect on most breast cancer cell lines irrespective of AR expression level, but it downregulated the expressions of DNA damage response (DDR) molecules, including ATM and chk2, which resulted in the accumulation of damaged DNA in some breast cancer cells. Furthermore, AZD3514 enhanced cellular sensitivity to a PARP inhibitor olaparib by blocking the DDR pathway in breast cancer cells. Furthermore, the downregulation of NICX3.1 expression in MDA-MB-468 cells by AZD3514 occurred in parallel with the suppression of ATM-chk2 axis activation, and the suppression of NKX3.1 by AZD3514 was found to result from AZD3514-induced TOPORS upregulation and a resultant increase in NKX3.1 degradation. The study shows posttranslational regulation of NICX3.1 via TOPORS upregulation by AZD3514-induced ATM inactivation-increased olaparib sensitivity in AR-positive and TOPORS-expressing breast cancer cells, and suggests the antitumor effect of AZD3514/olaparib cotreatment is caused by compromised DDR activity in breast cancer cell lines and in a xenograft model. These results provide a rationale for future clinical trials of olaparib/AR inhibitor combination treatment in breast cancer. (C) 2018 AACR

Comparison and Contrast Analysis of Adsorption Geometries of Phenylalanine versus Tyrosine on Ge(100): Effect of Nucleophilic Group on the Surface

The discrepancy of geometric configuration between phenylalanine and tyrosine adsorbed on Ge(100) surfaces was investigated using scanning tunneling microscopy (STM) in conjunction with density functional theory (DFT) calculations and core-level photoemission spectroscopy (CLPES). The study focused on the role of nucleophilic group (hydroxyl group) on phenyl ring of tyrosine, and we elucidated the difference of the adsorption geometry between phenylalanine and tyrosine on Ge(100) surfaces. We first confirmed that the “O–H dissociated–N dative bonded structure” was the most favorable structure in both molecules at low coverage by results of CLPES and DFT calculations. Geometric differences for the adsorption configurations between phenylalanine and tyrosine were observed: the phenyl ring of phenylalanine was aligned axially with respect to the Ge(100) surface, whereas that of tyrosine was tilted, as determined by DFT calculations. In sequence, we found out the results of STM images to confirm DFT results. We determined the different geometric configurations are attributed to the nucleophilic hydroxyl group of tyrosine, which creates an uneven charge distribution