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The somatic activation of PI3K/AKT pathway mutations, PIK3CA and AKT1, and ESR1 mutations in plasma cell-free DNA (cfDNA) has been studied as a non-invasive procedure to quickly assess and monitor disease progression or therapeutic effect in breast cancer (BC) patients, but the clinical significance of these mutations in late treatment lines (TLs) remains unclear. The subjects of this study were a total of 251 plasma samples from 128 estrogen receptor-positive (ER+) BC patients. Of these plasma samples, 133 were from 73 primary BC (PBC) patients, and 118 plasma samples were from 68 metastatic BC (MBC) patients. We developed droplet digital PCR (ddPCR) assays to verify the clinical significance of PIK3CA, AKT1, and ESR1 mutations in these patients. cfDNA PIK3CA mutations were observed in 15.1% of the PBC patients, while a cfDNA AKT1 mutation was observed in 1.4% of patients, and cfDNA ESR1 mutations were observed in 2.7% of patients. Patients with detectable cfDNA PIK3CA mutations were not associated with clinical outcomes. According to the TL, the prevalence of the PIK3CA and ESR1 mutations in cfDNA were lower in early TLs compared with late TLs. In the early TL group, patients with cfDNA PIK3CA mutations had a shorter time to treatment failure (TTF) than patients without mutations (P = 0.035). However, there was no statistically significant difference between patients with or without cfDNA ESR1 mutations. However, in the late TL group, patients with cfDNA ESR1 mutations had a shorter TTF than patients without mutations (P = 0.048). However, there was no statistically significant difference between patients with or without cfDNA PIK3CA mutations. Since the prevalence of cfDNA AKT1 mutation is low in both PBC and MBC patients, the impact of AKT1 mutations on the prognosis remains unclear. We have demonstrated the difference in the clinical significance of the hotspot PIK3CA, AKT1, and ESR1 mutations in cfDNA for each TL in ER+ BC patients. [ABSTRACT FROM AUTHOR]

The characteristic adverse events of olaparib, a PARP inhibitor, are nausea, vomiting, and anemia, and interstitial pneumonia is rarely reported. We report a case of interstitial pneumonia following the treatment of a metastatic breast cancer with olaparib. The patient was a 34-year-old woman. In March 2018, she was diagnosed with stage Ⅳ breast cancer(multiple lung metastases). She was treated with epirubicin and cyclophosphamide followed by paclitaxel. In November 2018, brain and spinal cord metastases were detected, and she was treated with radiation. In December 2018, a BRCA1 deleterious mutation was confirmed, and treatment with olaparib was initiated. Six weeks later, olaparib was discontinued due to anemia; it also caused interstitial pneumonia. The interstitial pneumonia resolved following multidisciplinary treatment during hospitalization. Subsequently, she was treated with cyclophosphamide/methotrexate/fluorouracil. It is necessary to consider interstitial pneumonia as an adverse effect of olaparib.

Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) has been proposed as a surrogate endpoint for the prediction of long-term survival in breast cancer (BC); however, an increased pCR rate has not clearly correlated with improved survival. We hypothesized that some transcriptomic and functional pathway features correlate with survival after pCR in BC. We utilized 2 published NAC cohorts, 105 women with gene expression data before, "Baseline", and that changed during NAC, "Delta", and TCGA database with 1068 BC patients to investigate the relationship between the efficacy of NAC and survival utilizing differentially expressed-mRNAs, construction and analysis of the mRNA-hub gene network, and functional pathway analysis. In mRNA expression profiling, S100A8 was a gene involved in survival after pCR in Baseline and NDP was a gene involved in recurrence after pCR in Delta. In functional pathway analysis, we found multiple pathways involved in survival after pCR. In mRNA-hub gene analysis, HSP90AA1 , EEF1A1 , APP , and HSPA4 were related to recurrence in BC patients with pCR due to NAC. TP53 , EGFR , CTNNB1 , ERBB2 , and HSPB1 may play a significant role in survival for patients with pCR. Interestingly, high HSP90AA1 , HSPA4 , S100A8 , and TP53 , and low EEF1A1 , EGFR , and CTNNB1 expressing tumors have significantly worse overall survival in TCGA BC cohort. We demonstrated the genes and functional pathway features associated with pCR and survival utilizing the bioinformatics approach to public BC cohorts. Some genes involved in recurrence after pCR due to NAC also served as prognostic factors in primary BC., Competing Interests: None., (AJCR Copyright © 2020.)

Polo-like kinase 1 ( PLK1 ), the most investigated member of the PLK family, plays a pivotal role both in the p53-mediated regulation of DNA damage repair and in mitosis, especially in the G2/M phase. However, the evidence on the clinical and prognostic relevance of PLK1 is limited to triple negative subtype among breast cancer (BC). We hypothesized that high expression of PLK1 is associated with TP53 inactivation, DNA repair deficiency, and worse prognosis in ER positive in BC in a large-scale cohort should clarify its clinical relevance for each BC subtype. Total of 3173 BC cases; 1025 from TCGA cohort, 1904 from METABRIC, and 244 from neoadjuvant chemotherapy (NAC) cohort from Gene Expression Omnibus dataset, GSE32603, were analyzed. PLK1 expressions were significantly higher in high Nottingham Grade and triple negative BC. High expression of PLK1 was significantly associated with TP53 mutation, high expression of TP53 mRNA as well as protein, and it significantly correlated with the homologous recombination deficiency score. High PLK1 expression significantly enriched cell cycle related gene sets (G2/M check point, E2F targets), MTORC1 signaling, and MYC target gene sets in the Gene Set Enrichment Analysis. High expression of PLK1 was significantly associated with tumor infiltrating lymphocytes and tumor associated macrophages (high levels of CD8+ T cells, M0 and M1 macrophage, and low levels of M2 macrophage), and high immune cytolytic activity. While high expression of PLK1 did not associate with pathological complete response after NAC, it was associated with poor prognosis in the whole cohort and in the ER-positive/HER2-negative subtype of TCGA. High expression of PLK1 is significantly associated with TP53 mutations, DNA repair deficiency and worse prognosis in BC particularly in HR+HER2- subtype. Using bioinformatics methods with large cohorts., Competing Interests: None., (AJTR Copyright © 2019.)

Digital PCR (dPCR) enables the detection and characterization of fragmented DNA that is in low abundance in blood. Here, we describe the comparative analysis of mutations in tumor tissue DNA and plasma cell-free DNA (cfDNA) using a dPCR method. Tumor cells are captured by laser microdissection to obtain only cancerous cells from a small quantity of metastatic tissue samples and to exclude inflammatory and stromal cells. We extracted cfDNA from 500 μL of plasma, which is sufficient for target mutation analysis using dPCR. The dPCR assay for the detection of the specific region in the target gene consists of a pair of primers and two probes labeled with a fluorescent dye capable to recognize the presence or absence of a specific mutation. Using the dPCR method, we can identify only a few mutations in tissue that are present also in plasma.

Objective: The purpose of this study is to develop a computer training program of reading for the Japanese dyslexic children and to examine its short-term efficacy on their reading and writing abilities., Methods: Fifteen dyslexic children underwent two sets of training programs, one for single-hiragana and non-word reading, and the other for the reading of real words, in which each hiragana was followed by the correctly read sound. Subjects were required to use a given program for five minutes a day for three weeks, switching to the other program after a three-week interval. Four kinds of reading test and one writing test were done at the beginning and end of each program period., Results: The averages reading speeds increased, and the single-hiragana reading error average was lower after the training. Hiragana-writing errors also decreased, even though no writing procedure was involved in the programs., Conclusions: The results indicate the usefulness of these training programs as an early intervention of reading and writing for the Japanese dyslexic children.