Erratum: Association between metformin use after surgery for colorectal cancer and oncological outcomes: A nationwide register‐based study

http://bit.ly/2ScGIvb

1H NMR‐based metabolomics reveal overlapping discriminatory metabolites and metabolic pathway disturbances between colorectal tumor tissues and fecal samples

Previous studies have compared fecal metabolites from healthy and colorectal cancer (CRC) patients to predict the pro‐CRC signatures. However, the systemic mechanistic link between feces and colonic tissues of CRC patients is still limited. The current study was a paralleled investigation of colonic tumor tissues and their normal adjacent tissues alongside patient‐matched feces by using ¹H nuclear magnetic resonance spectroscopy combined with pattern recognition to investigate how fecal metabolic phenotypes are linked to the changes in colorectal tumor profiles. A set of overlapping discriminatory metabolites across feces and tumor tissues of CRC were identified, including elevated levels of lactate, glutamate, alanine, succinate and reduced amounts of butyrate. These changes could indicate the networks for metabolic pathway perturbations in CRC potentially involved in the disruptions of glucose and glycolytic metabolism, TCA cycle, glutaminolysis, and short chain fatty acids metabolism. Furthermore, changes in fecal acetate were positively correlated with alterations of glucose and myo‐inositol in colorectal tumor tissues, implying enhanced energy production for rapid cell proliferation. Compared to other fecal metabolites, acetate demonstrated the highest diagnostic performance for diagnosing CRC, with an AUC of 0.843 in the training set, and a good predictive ability in the validation set. Overall, these associations provide evidence of distinct metabolic signatures and metabolic pathway disturbances between the colonic tissues and feces within the same individual, and changes of fecal metabolic signature could reflect the CRC tissue microenvironment, highlighting the significance of the distinct fecal metabolic profiles as potential novel and non‐invasive relevant indicators for CRC detection.

This article is protected by copyright. All rights reserved.

http://bit.ly/2UFFENe

EGFR‐targeted therapy alters the tumor microenvironment in EGFR‐driven lung tumors: implications for combination therapies

Immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD‐1/PD‐L1) pathway have profoundly improved the clinical management of non‐small‐cell lung cancer (NSCLC). Nevertheless, the superiority of single‐agent PD‐1/PD‐L1 inhibitors in pre‐treated EGFR mutant patients has turned out to be moderate. One proposed mechanism for poor response to immune checkpoint inhibitors is an immunosuppressive tumor microenvironment. Therefore, we utilized two autochthonous EGFR‐driven lung tumor models to investigate dynamic microenvironmental responses to EGFR‐TKI treatment. We observed that at an early stage, sensitive EGFR‐TKIs caused obvious tumor shrinkage accompanied by increased cytotoxic CD8⁺ T cells and dendritic cells, eradication of Foxp3⁺ Tregs, and inhibition of M2‐like polarization of macrophages. However, the tumor microenvironmental changes that may be most beneficial for combination treatment with immune‐mediated anticancer approaches were only temporary and disappeared as treatment continued. Meanwhile, the level of myeloid‐derived suppressor cells (MDSCs), particularly mononuclear MDSCs, was consistently elevated throughout the treatment. Analysis of inflammatory factors in serum showed that EGFR‐TKIs increased the levels of IL‐10 and CCL‐2. Our study systematically analyzed dynamic changes in tumor microenvironments responding to EGFR‐TKIs in vivo. The results have implications for combination therapy using EGFR‐TKIs. The optimal sequence of the treatment and strategies that modulate the tumor microenvironment to a state that may favor antitumor immune responses need to be considered when designing clinical trials.

This article is protected by copyright. All rights reserved.

http://bit.ly/2Sc7Zhn

Immuno‐phenotypes of Pancreatic Ductal Adenocarcinoma: Meta‐analysis of transcriptional subtypes

Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas and has one of the highest mortality rates of any cancer type with a 5‐year survival rate of <5%. Recent studies of PDAC have provided several transcriptomic classifications based on separate analyses of individual patient cohorts. There is a need to provide a unified transcriptomic PDAC classification driven by therapeutically relevant biologic rationale to inform future treatment strategies. Here, we used an integrative meta‐analysis of 353 patients from four different studies to derive a PDAC classification based on immunologic parameters. This consensus clustering approach indicated transcriptomic signatures based on immune infiltrate classified as adaptive, innate and immune‐exclusion subtypes. This reveals the existence of microenvironmental interpatient heterogeneity within PDAC and could serve to drive novel therapeutic strategies in PDAC including immune modulation approaches to treating this disease.

This article is protected by copyright. All rights reserved.

http://bit.ly/2UEAIbi

Molecular Alterations and Poziotinib Efficacy, a pan‐HER inhibitor, in Human Epidermal Growth Factor Receptor 2 (HER2)‐positive breast cancers: Combined Exploratory Biomarker Analysis from a Phase II Clinical Trial of Poziotinib for Refractory HER2‐positive Breast Cancer Patients

We aimed to investigate the impact of genetic alterations on the efficacy of poziotinib in a phase II clinical trial of patients with heavily treated HER2‐positive metastatic breast cancer (BC). We performed targeted ultra‐deep sequencing with a customized cancer gene panel and RNA expression assay using BC specimens. Of 106 patients, biomarker data were available for 85. Copy number (CN) amplifications of HER2 were observed in 72 patients (85%), and CN>8 in 50 (59%). Single nucleotide variants (SNVs) of HER2 were found in 16 patients (19%). Genetic alterations of PIK3CA pathway were found in 40 patients (47%). Median progression free survival (PFS) of the biomarker analysis group was 3.61 months. In terms of PFS, HER2 with CN>8 prolonged (hazard ratio (HR) 0.61, 95% CI: 0.38, 0.97, p=0.037) and alteration of PIK3CA pathway shortened the duration of survival (HR 2.25, 95% CI: 1.39, 3.63, p=0.001). SNVs of HER2 increased survival duration, but the effect was not significant (HR: 0.58, 95% CI: 0.31, 1.08, p=0.085). In addition, SNVs in the ERBB3 cytoplasmic domain decreased poziotinib response (HR: 4.58, 95% CI: 2.02, 10.37, p <0.001). In multigene analysis, BC with HER2 CN>8 and intact PIK3CA pathway had significantly longer PFS compared to others (HR: 0.37, 95% CI: 0.21, 0.66, p=0.001), while SNVs in the ERBB3 cytoplasmic domain predicted poor prognosis (HR: 4.28, 95% CI: 1.71, 10.71, p <0.001). In conclusion, HER2 CN amplification, PIK3CA pathway alteration, and ERBB3 cytoplasmic mutation showed predictive roles on clinical outcomes of HER2‐positive MBC treated with poziotinib.

This article is protected by copyright. All rights reserved.

http://bit.ly/2Sc7X9f

Transcriptome analysis of Luminal Breast Cancer Reveals a Role for LOL in Tumor Progression and Tamoxifen Resistance

Luminal breast cancer (BC) has a sustained risk of late disease recurrence and death. Considerable numbers of patients suffer from anti‐endocrine therapy resistance. Here, we identified a novel lncRNA whose expression is high in breast cancer and especially higher in luminal breast cancer, dubbed LOL (lncRNA of luminal), that acts as a natural sponge for let‐7 microRNAs to regulate tumor growth and tamoxifen resistance. LOL overexpression in parental MCF‐7 cells exhibited a proliferative advantage in the addition of tamoxifen than negative control. Knocking down LOL in TamR MCF‐7 cells, recovered the sensitivity of cells to tamoxifen. Strikingly, we demonstrated that LOL is transcribed from a genomic locus of an enhancer to maintain its high expression in luminal BC and that it is extremely sensitive to enhancer‐regulating factors, such as ZMYND8 and BRD4. Estrogen deprivation or ERα signaling pathway blockage can further stimulate LOL expression, which can promote tumor progression. Clinical analysis of 374 luminal breast cancer samples indicated that LOL is an independent prognostic factor for poor survival in luminal BC. In conclusion, targeting LOL using preclinical/clinical drugs, such as BRD4 inhibitors, may represent a promising approach to inhibit luminal breast cancer progression and tamoxifen resistance.

This article is protected by copyright. All rights reserved.

http://bit.ly/2UIDxsc

Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China

To gain more information on the prevalence of germline mutations in BRCA1/2 and PALB2 genes in the Chinese population, and to explore the effects of the mutation status of these genes on clinical outcomes in patients with breast cancer, we performed a screening for BRCA1/2 and PALB2 mutations in a consecutive series of unselected breast cancer patients in the Chinese population. A total of 2769 cases were enrolled between June 1993 and September 2017. All of the exons and exon‐intron boundaries of the BRCA1/2 and PALB2 genes were screened with next‐generation sequencing. Of the 2769 breast cancer patients, BRCA1, BRCA2 and PALB2 mutations accounted for 2.7% (n=74), 2.7% (n=76), and 0.9% (n=24), respectively. The BRCA1 gene had the highest mutation frequency in patients with triple‐negative breast cancer (TNBC), which was 9.6% (n=42), while the BRCA2 gene had the highest mutation frequency in patients with Luminal, which was 3.2% (n=58). The disease‐free survival (DFS) of BRCA1 mutation carriers was significantly lower than that of non‐carriers (adjusted HR=2.20, 95% CI=1.15–4.18, p=0.017). The mutation status of the PALB2 gene was significantly associated with the decline in overall survival (OS) (adjusted HR=8.38, 95% CI=2.19–32.11, p=0.002). No significant difference was found between BRCA2 pathogenic mutation carriers and non‐carriers. These results demonstrate that BRCA1 mutation status may be associated with a worse disease progression in patients with breast cancer, and women who harbored a PALB2 mutation might be at a higher risk of death due to breast cancer compared with non‐carriers.

This article is protected by copyright. All rights reserved.

http://bit.ly/2SdQ8H3