What's new?

To assess how estrogen receptor (ER) status and age at diagnosis are related to long-term survival following diagnosis of breast cancer, authors conducted a large population-based study, which was over-sampled for young age at diagnosis, with a median follow-up of 15 years. They found that for women who survived >7 years, those with ER-negative disease were predicted to live longer, especially if diagnosed at a younger age.

What's new?

Gastric cancer is a heterogeneous disease from histologic and molecular viewpoints. Stratifying gastric cancer into Epstein–Barr virus-positive, microsatellite instability-associated and Lauren intestinal and diffuse/mixed subtypes demonstrates significant clinicopathological and prognostic discrimination, which is relevant to current genetic knowledge and clinical management. This combined molecular and histologic classification, correspondent to the molecular subtyping specified in the Cancer Genome Atlas study, is practically implementable with etiologic insight and therapeutic implications.

What's new?

Impaired metabolism may play an important role in the pathogenesis of lethal prostate cancer (LPC), but evidence remains scarce. This study examined the associations between serum metabolites and LPC risk years in advance of diagnosis using untargeted mass-spectrometry-based metabolomics. Increased oxidative stress-related thioproline and two other cysteine-related metabolites were prominently associated with lower LPC risk. By contrast, dipeptides including leucylglycine, and several gamma-glutamyl aminoacids, were related to elevated risk. This prospective molecular pattern points to a role for redox and peptide metabolism in LPC and provides potential leads regarding the molecular basis of its pathogenesis.

What's new?

In many cancers, evidence points to insulin-like growth factors and their associated binding proteins as a possible culprit. This study investigated how IGF and IGF binding proteins correlate with various other cancer-associated factors. The authors obtained data from 16,000 cancer-free males ranging in age from 22 to 89 years. Their analysis confirmed associations between circulating IGFs and IGFBPs and age, race/ethnicity and BMI. They also uncovered some new associations, including with height, drinking alcohol and smoking. IGFs and their binding proteins, they suggest, may be part of the mechanism by which these factors influence cancer risk.

What's new?

Previous epidemiological studies have examined whether hyperthyroidism and hypothyroidism affect breast cancer risk, but associations remain unclear. This large cohort study is the first study to demonstrate the association of serum thyroid hormone concentrations in both the abnormal and euthyroid range with breast cancer development. Abnormally high FT4 as well as higher FT4 within the euthyroid range were positively associated with breast cancer risk, while higher TSH concentration within the euthyroid range was negatively associated with breast cancer risk. The findings indicate that thyroid function within both the abnormal and euthyroid ranges may contribute to the development of breast cancer.

What's new?

Neutrophil-to-lymphocyte ratio (NLR) is associated with poor prognosis in patients with lung cancer, but the predictive role of NLR on the risk of developing lung cancer is unknown. Here, the authors investigated the association between NLR and lung cancer mortality in a large prospective cohort study of 527,124 cancer-free adults. The study reveals the association of elevated NLR with increased risk of lung cancer mortality, which was consistently observed in both never-smokers and low-risk individuals. NLR, a systemic inflammation marker, may thus play a role as an independent predictor of lung cancer mortality in never-smokers as well as low-risk populations.

What's new?

The CSF1-COL6A3 fusion gene has been detected in a third of tenosynovial giant cell tumor (TSGCT) cases, but additional signaling pathways or mutations may be involved. Here, RNA sequencing reveals several fusion transcripts involving CSF1, including novel CSF1-VCAM1, CSF1-FN1 and CSF1-CDH1 fusions, in 72% of TSGCT cases. All CSF1 fusion transcripts result in the deletion of CSF1 exon 9, a negative regulator of CSF1 expression. Moreover, novel CBL mutations are found in 35% of tumors, with or without the presence of CSF1 fusions. The data may contribute to the development of new targeted therapies and reveal the etiology of TSGCT.

What's new?

Signaling through the human epidermal growth factor receptor 2 (HER2) is associated with approximately 20% of breast cancers but the efficacy of anti-HER2 therapies is severely compromised by drug resistance. Here, the authors uncovered potential benefits of combining anti-HER2 treatments with inhibitors of histone deacetylases (HDACs). They found HER2 signaling silenced tumor suppressor gene expression by impairing the homeostasis of histone acetylation and manipulating the transcription factor Sp1. These findings offer a new explanation of HER2-driven carcinogenesis and point to potential benefits of combining HER2-targeting therapies with HDAC inhibitors.

What's new?

Multi-scale omics approaches provide a powerful tool to unravel cancer-related genes with the potential to serve as prognostic biomarkers and putative drug targets. This study shows that somatic mutations and epigenetic silencing of the ryanodine receptor 2 (RYR2) are frequent in head and neck cancer. Loss of RYR2 expression was found during transition from dysplastic lesions to invasive tumors. Detection of somatic mutations or promoter methylation might thus improve risk assessment of malignant conversion, which could enable timely and adequate treatment of premalignant lesions.

What's new?

Poland is a genetically homogeneous population similar to Iceland, currently designing national policies for genetic testing. To define the range of pathogenic mutations, the authors conducted a large analysis of breast cancer susceptibility genes, defining pathogenic mutations in 50.3% families with hereditary breast cancer. They identified 20 distinct founder mutations in six genes that were responsible for more than 80% of all detected mutations; these 20 mutations could be combined in a single genetic test of breast cancer susceptibility in Polish women.

What's new?

Women of African ancestry are more likely to be diagnosed with clinically aggressive breast cancer than women of European or Asian ancestry. Here, the authors examined associations between germline variants and mutational signatures in breast cancers across different ethnicities, especially in a unique sample set of indigenous African women. They identified four stable mutational signatures that explained the majority of tumor mutations, leading to a better understanding of the complex interplay between germline genetics and somatic mutations across different ethnicities.

What's new?

7-deoxynarciclasine (7-DONCS), an active compound isolated from the bulbs of Lycoris radiata (Amaryllidaceae), exhibits various biological effects including anti-cancer activities. The defined targets or molecular mechanisms underlying 7-DONCS-regulated tumorigenesis remain to be unveiled, however. This study elucidates that 7-DONCS induces apoptosis and autophagy in hepatocellular carcinoma (HCC) and inhibits epithelial-mesenchymal transition (EMT) by targeting Akt, which in turn prevents tumor growth. The findings indicate that 7-DONCS may serve as a potential inhibitor of Akt and a promising candidate for blocking tumorigenesis in HCC.

What's new?

Targeted radionuclide therapy (TRT) using radiolabeled peptides seeking gastrin-releasing peptide receptors (GRPRs) in tumors is a promising approach to treat disseminated prostate cancer. The possibility to improve the therapeutic index via combination therapies also warrants further investigation. Here, the authors developed and characterized a promising GRPR-targeting radioligand and demonstrated its therapeutic efficacy in prostate cancer xenografts. Moreover, this study using the anti-HER2 antibody trastuzumab presents the first in vivo proof-of-principle that the effects of anti-GRPR radiotherapy can be amplified by co-administration of anti-HER2 treatment leading to prolonged survival.

What's new?

An emerging therapy for metastatic breast cancer may extend survival over other chemotherapies. Eribulin mesylate (EM), a microtubule-dynamics inhibitor, was approved by the FDA in 2010 as a later-line therapy for metastatic breast cancer. Here, the authors evaluated EM effectiveness by analyzing data from 16,703 MBC patients. Treatment with EM as a third or fourth line therapy improved survival compared to other chemotherapy, but as a second line therapy, EM only benefited patients with HER2- disease. Since this trial was retrospective, not randomized, different proportions of patients in the two treatment groups received HER-targeting therapies, which may have influenced the result.

What's new?

Phase 2 clinical trials expose participants to unproven interventions. Human protection policies emphasize the importance of preceding trials with promise of efficacy and safety in preclinical studies. Here, the authors examine the extent to which phase 2 trials for novel anti-cancer drugs cite preclinical and clinical evidence matching the tested drug and indication. The results show that many early-phase cancer trial publications do not describe supporting preclinical studies. Preclinical efficacy evidence is sometimes lacking in publications even when clinical evidence is absent. Ethics committees and researchers should carefully consider whether proposed trials are supported by preclinical evidence.

What's new?

A drug that inhibits the JAK–STAT pathway may score a hit against K-RAS driven lung cancer. Here, the authors Investigated the JAK STAT pathway as a possible target in lung adenocarcinoma because of its role in inflammation-mediated tumorigenesis. First, they showed that JAK1 and JAK2 are both activated in lung adenocarcinoma patients with oncogenic mutations in K-RAS. Next, they treated the tumors with ruxolitinib, which inhibits JAK1/2. The drug successfully slowed tumor proliferation and progression in immunocompetent mouse models. Furthermore, treatment with ruxolitinib reduced the tumor-promoting factors present in the microenvironment.

What's new?

Adenocarcinomas that arise at the junction between the esophagus and the stomach are currently classified based on location. Here, the authors looked at patterns of gene expression of these cancers. They found that gastro-esophageal junction adenocarcinomas can be sorted into three biological subtypes, independent of location, based on gene expression. Group 1 cancers have boosted stomach-specific genes that combat the effects of acid reflux. Group 2 tumors express genes characteristic to the intestinal tract, and the genes active in Group 3 relate to inflammation. The differences in biological pathway expression means that these differences could be used to improve treatment.

What's new?

Long non-coding RNAs (lncRNAs) influence diverse cellular activities, including gene expression and the activity of adjacent genes. Hence, some lncRNAs are implicated in cancer. Here, the lncRNA TP73-AS1 was investigated for a possible functional role in medulloblastoma. TP73-AS1 was found to be overexpressed in medulloblastoma cells, with expression levels correlated to TP73-AS1 hypomethylation. Functionally, TP73-AS1 prevented cell death and promoted proliferation and tumorigenicity of medulloblastoma tumor cells in vitro and in vivo. Mice injected with TP73-AS1-knockdown medulloblastoma tumor cells exhibited reduced tumor growth and improved survival. The findings identify TP73-AS1 as a potential marker and therapeutic target in medulloblastoma.

What's new?

HER2-targeted therapies have proven effective against tumors positive for HER2 amplification, but there is an unmet clinical need for tumors that express HER2 in the absence of HER2 amplification. [fam-] trastuzumab deruxtecan (DS-8201a) is a novel antibody-drug conjugate composed of the anti-HER2 antibody and the topoisomerase I inhibitor. Here, DS-8201a showed efficacy on colorectal cancer (CRC) cell lines that express HER2 in the absence of HER2 amplification. Furthermore, [fam-] trastuzumab deruxtecan exhibited a bystander killing effect in co-culture models of HER2-expressing cells and HER2-negative cells. The results may offer a new treatment option against CRC according to HER2 expression levels.

What's new?

Aberrant methylation of the promoter region of various genes has long been recognized as a tumor-promoting factor. But what about intragenic DNA? In this genome-wide study, the authors found that intragenic DNA methylation of the ZMIZ1 gene can predict outcomes in multiple solid cancers, especially glioblastoma, astrocytoma, bladder cancer, and renal-cell carcinoma. Evidence from independent clinical cohorts, as well as from preclinical experiments, showed that intragenic ZMIZ1 methylation affects overall survival in cancer patients, and tumor-cell migration in vivo. These results indicate that ZMIZ1 may provide a useful prognostic biomarker for various cancers.

What's new?

Head and neck squamous cell carcinoma remains a deadly disease but new immunotherapeutic approaches are underexplored. Here the authors tested for antibody responses against human antigens to characterize the expression of such antigens in tumors positive or negative for human papillomavirus (HPV). Antibody responses were significantly different in prevalence and pattern based on HPV-status in a large patient cohort. The authors urge independent confirmation of their results but point out that multiplex serology of tumor antigens could be a promising strategy to identify immunotherapeutic targets based on HPV status.

What's new?

Although localized prostate cancer (PC) can be cured by radical prostatectomy (RP), both over- and under-treatment remain a major clinical problem as currently available routine prognostic tools cannot accurately distinguish aggressive from non-aggressive PCs at time of diagnosis. Here, the authors report a novel combined miRNA/methylation marker panel (miMe) for PC prognosis that was a significant independent predictor of post-operative PC outcome in three large RP cohorts. The results suggest that miMe may help guide personalized treatment decisions in the future, e.g. by identifying high-risk PC patients who might be candidates for intensified therapy.

What's new?

While genomic/transcriptomic data analysis has revolutionized cancer biology, this analysis is frequently only available late in the cancer history, often after years of therapy. Here the authors built a single sample genomic classifier to predict primary prostate cancer tumors with early small cell neuroendocrine differentiation. They show in three independent cohorts that small cell neuroendocrine tumors of the prostate are similar to small cell tumors of the lung and predict the specific prostate tumors to be responsive to inhibitors of poly ADP ribose polymerase and histone deacetylases, underscoring the use of these drugs in this subtype of prostate cancer.

What's new?

Alterations in histone modifications play a crucial role in the progression of various types of cancer. The histone methyltransferase SETDB1 is known to be involved in malignant melanoma. However, little is known about its effects or mechanisms of action in humans. In this study, the authors found that increased SETDB1 expression is linked to poor prognosis in melanoma patients, and that SETDB1 regulates expression of the oncogene THBS1. They also found that inhibiting SETDB1 leads to a strong reduction in melanoma-cell viability. This enzyme may thus offer a novel therapeutic target.