Effect of Estradiol as a Continuous Variable on Breast Cancer Survival by Menopausal Status: a Cohort Study in China

High levels of circulating estradiol (E2) are associated with increased risk of breast cancer, whereas its relationship with breast cancer prognosis is still unclear. We evaluated the effect of E2 concentration on survival endpoints among 8766 breast cancer cases diagnosed between 2005 and 2017 from the Tianjin Breast Cancer Cases Cohort. Levels of serum E2 were measured in pre-menopausal and post-menopausal women. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) between quartile of E2 levels and overall survival (OS) and progression-free survival (PFS) of breast cancer. The penalized spline was then used to test for non-linear relationships between E2 (continuous variable) and survival endpoints. 612 deaths and 982 progressions occurred over follow-up through 2017. Compared to women in the quartile 3, the highest quartile of E2 was associated with reduced risk of both PFS in pre-menopausal women (HR=1.79, 95% CI: 1.17-2.75, P=0.008) and OS in post-menopausal women (HR=1.35, 95% CI: 1.04-1.74, P=0.023). OS and PFS in pre-menopausal women exhibited a nonlinear relation (“L-shaped” and “U-shaped”, respectively) with E2 levels. However, there was a linear relationship in post-menopausal women. Moreover, patients with estrogen receptor-negative (ER-negative) breast cancer showed a “U-shaped” relationship with OS and PFS in pre-menopausal women. Pre-menopausal breast cancer patients have a plateau stage of prognosis at the intermediate concentrations of E2, whereas post-menopausal patients have no apparent threshold, and ER status may have an impact on this relationship.

Screening and Comprehensive Analysis of Cancer-Associated tRNA-Derived Fragments

tRNA-derived fragments (tRFs) constitute a novel class of small non-coding RNA cleaved from tRNAs. In recent years, researches have shown the regulatory roles of a few tRFs in cancers, illuminating a new direction for tRF-centric cancer researches. Nonetheless, more specific screening of tRFs related to oncogenesis pathways, cancer progression stages and cancer prognosis is continuously demanded to reveal the landscape of the cancer-associated tRFs. In this work, by combining the clinical information recorded in The Cancer Genome Atlas (TCGA) and the tRF expression profiles curated by MINTbase v2.0, we systematically screened 1,516 cancer-associated tRFs (ca-tRFs) across seven cancer types. The ca-tRF set collectively combined the differentially expressed tRFs between cancer samples and control samples, the tRFs significantly correlated with tumor stage and the tRFs significantly correlated with patient survival. By incorporating our previous tRF-target dataset, we found the ca-tRFs tend to target cancer-associated genes and onco-pathways like ATF6-mediated unfolded protein response, angiogenesis, cell cycle process regulation, focal adhesion, PI3K-Akt signaling pathway, cellular senescence and FoxO signaling pathway across multiple cancer types. And cell composition analysis implies that the expressions of ca-tRFs are more likely to be correlated with T-cell infiltration. We also found the ca-tRF expression pattern is informative to prognosis, suggesting plausible tRF-based cancer subtypes. Together, our systematic analysis demonstrates the potentially extensive involvements of tRFs in cancers, and provides a reasonable list of cancer-associated tRFs for further investigations.

The Role of Diet in Prognosis among Cancer Survivors: A Systematic Review and Meta-Analysis of Dietary Patterns and Diet Interventions

Cancer survival continues to improve in high-income countries, partly explained by advances in screening and treatment. Previous studies have mainly examined the relationship between individual dietary components and cancer prognosis in tumours with good therapeutic response (breast, colon and prostate cancers). The aim of this review is to assess qualitatively (and quantitatively where appropriate) the associations of dietary patterns and cancer prognosis from published prospective cohort studies, as well as the effect of diet interventions by means of randomised controlled trials (RCT). A systematic search was conducted in PubMed, and a total of 35 prospective cohort studies and 14 RCT published between 2011 and 2021 were selected. Better overall diet quality was associated with improved survival among breast and colorectal cancer survivors; adherence to the Mediterranean diet was associated to lower risk of mortality in colorectal and prostate cancer survivors. A meta-analysis using a random-effects model showed that higher versus lower diet quality was associated with a 23% reduction in overall mortality in breast cancer survivors. There was evidence that dietary interventions, generally combined with physical activity, improved overall quality of life, though most studies were in breast cancer survivors. Further cohort and intervention studies in other cancers are needed to make more specific recommendations.

Ki-67 and breast cancer prognosis: does it matter if Ki-67 level is examined using preoperative biopsy or postoperative specimen?

Purpose This study aimed to identify the association between Ki-67 level and the prognosis of patients with breast cancer, regardless of the timing of Ki-67 testing (using preoperative biopsy vs. postoperative specimen). Methods A total of 4177 patients underwent surgery between January 2008 and December 2016. Immunohistochemical Ki-67 levels, using either preoperative (1673) or postoperative (2831) specimens, were divided into four groups using cutoff points of 10%, 15%, and 20%. Results Groups with higher-Ki-67 levels, in both the pre- and postoperative periods, showed significantly larger tumor size, higher grade, more frequent hormone receptor-negativity and human epidermal growth factor receptor 2 overexpression, and active adjuvant treatments than groups with lower-Ki-67 levels. High-Ki-67 levels were also significantly associated with poor survival, irrespective of the timing of specimen examination. Conclusion Despite the problems associated with Ki-67, Ki-67 level is an important independent prognostic factor, regardless of the timing of Ki-67 testing, i.e., preoperative or postoperative testing.

MicroRNAs as biomarkers for prostate cancer prognosis: a systematic review and a systematic reanalysis of public data

Background Reliable prognostic biomarkers to distinguish indolent from aggressive prostate cancer (PCa) are lacking. Many studies investigated microRNAs (miRs) as PCa prognostic biomarkers, often reporting inconsistent findings. We present a systematic review of these; also systematic reanalysis of public miR-profile datasets to identify tissue-derived miRs prognostic of biochemical recurrence (BCR) in patients undergoing radical prostatectomy. Methods Independent PubMed searches were performed for relevant articles from January 2007 to December 2019. For the review, 128 studies were included. Pooled-hazard-ratios (HRs) for miRs in multiple studies were calculated using a random-effects model (REM). For the reanalysis, five studies were included and Cox proportional-hazard models, testing miR association with BCR, performed for miRs profiled in all. Results Systematic review identified 120 miRs as prognostic. Five (let-7b-5p, miR-145-5p, miR152-3p, miR-195-5p, miR-224-5p) were consistently associated with progression in multiple cohorts/studies. In the reanalysis, ten (let-7a-5p, miR-148a-3p, miR-203a-3p, miR-26b-5p, miR30a-3p, miR-30c-5p, miR-30e-3p, miR-374a-5p, miR-425-3p, miR-582-5p) were significantly prognostic of BCR. Of these, miR-148a-3p (HR = 0.80/95% CI = 0.68-0.94) and miR-582-5p (HR = 0.73/95% CI = 0.61-0.87) were also reported in prior publication(s) in the review. Conclusions Fifteen miRs were consistently associated with disease progression in multiple publications or datasets. Further research into their biological roles is warranted to support investigations into their performance as prognostic PCa biomarkers.

Machine Learning Algorithms as a Computer-Assisted Decision Tool for Oral Cancer Prognosis and Management Decisions: A Systematic Review

<b><i>Introduction:</i></b> Despite multiple prognostic indicators described for oral cavity squamous cell carcinoma (OCSCC), its management still continues to be a matter of debate. Machine learning is a subset of artificial intelligence that enables computers to learn from historical data, gather insights, and make predictions about new data using the model learned. Therefore, it can be a potential tool in the field of head and neck cancer. <b><i>Methods:</i></b> We conducted a systematic review. <b><i>Results:</i></b> A total of 81 manuscripts were revised, and 46 studies met the inclusion criteria. Of these, 38 were excluded for the following reasons: use of a classical statistical method (<i>N</i> = 16), nonspecific for OCSCC (<i>N</i> = 15), and not being related to OCSCC survival (<i>N</i> = 7). In total, 8 studies were included in the final analysis. <b><i>Conclusions:</i></b> ML has the potential to significantly advance research in the field of OCSCC. Advantages are related to the use and training of ML models because of their capability to continue training continuously when more data become available. Future ML research will allow us to improve and democratize the application of algorithms to improve the prediction of cancer prognosis and its management worldwide.

Altered Expression of TRIM Proteins-Inimical Outcome and Inimitable Oncogenic Function in Breast Cancer with Diverse Carcinogenic Hallmarks

Deregulation of ubiquitin-mediated degradation of oncogene products or tumor suppressors appears to be implicated in the genesis of carcinomas, according to new clinical findings. Conferring to recent research, some members of the tripartite motif (TRIM) proteins (a subfamily of the RING type E3 ubiquitin ligases) act as significant carcinogenesis regulators. Intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy, and carcinogenesis are all regulated by TRIM family proteins, the majority of which have E3 ubiquitin ligase activity. The expression of TRIMs in tumors is likely to be related to the formation and/or progression of the disease, and TRIM expression could be used to predict cancer prognosis. Breast cancer is the most common malignancy in women and also the leading cause of death. TRIM family proteins have unique, vital activities, and their dysregulation, such as TRIM 21, promotes breast cancer, according to growing evidence. Many TRIM proteins have been identified as important cancer biomarkers, with decreased or elevated levels of expression. TRIM29 functions as a hypoxia-induced tumor suppressor gene, revealing a new molecular mechanism for ATM-dependent breast cancer suppression. In breast cancer cells, the TRIM28-TWIST1-EMT axis exists, and TRIM28 enhances breast cancer metastasis by stabilizing TWIST1 and thereby increasing epithelial-to-mesenchymal transition. Interestingly, many TRIM proteins are involved in the control of p53, and many TRIM proteins are likewise regulated by p53, according to current research. Furthermore, TRIMs linked to specific tumors may aid in the creation of innovative TRIM-targeted cancer treatments. This review focuses on TRIM proteins that are involved in tumor development, progression, and clinical significance in breast cancer.

Relevance of gene mutations and methylation to the growth of pancreatic intraductal papillary mucinous neoplasms based on pyrosequencing

We aimed to assess some of the potential genetic pathways for cancer development from non-malignant intraductal papillary mucinous neoplasm (IPMN) by evaluating genetic mutations and methylation. In total, 46 dissected regions in 33 IPMN cases were analyzed and compared between malignant-potential and benign cases, or between malignant-potential and benign tissue dissected regions including low-grade IPMN dissected regions accompanied by malignant-potential regions. Several gene mutations, gene methylations, and proteins were assessed by pyrosequencing and immunohistochemical analysis. RASSF1A methylation was more frequent in malignant-potential dissected regions (p = 0.0329). LINE-1 methylation was inversely correlated with GNAS mutation (r = − 0.3739, p = 0.0105). In cases with malignant-potential dissected regions, GNAS mutation was associated with less frequent perivascular invasion (p = 0.0128), perineural invasion (p = 0.0377), and lymph node metastasis (p = 0.0377) but significantly longer overall survival, compared to malignant-potential cases without GNAS mutation (p = 0.0419). The presence of concordant KRAS and GNAS mutations in the malignant-potential and benign dissected regions were more frequent among branch-duct IPMN cases than among the other types (p = 0.0319). Methylation of RASSF1A, CDKN2A, and LINE-1 and GNAS mutation may be relevant to cancer development, IPMN subtypes, and cancer prognosis.

AKT Isoforms Interplay in High-Grade Serous Ovarian Cancer Prognosis and Characterization

High-grade serous ovarian cancer (HGSOC) is among the deadliest gynecological malignancies. The acquired resistance to platinum-based therapies and the intrinsic heterogeneity of the disease contribute to the low survival rate. To improve patients’ outcomes, new combinatorial approaches able to target different tumor vulnerabilities and enhance the efficacy of the current therapies are required. AKT inhibitors are promising antineoplastic agents able to act in synergy with PARP inhibitors, but the spectrum of patients who can benefit from this combination is unclear, since the role of the three different isoforms of AKT is still unknown. Here, we study the expression of AKT isoforms on a retrospective cohort of archive tissue by RT-droplet digital PCR (ddPCR) analyzing their association with the clinicopathological features of patients. Based on AKT1/AKT2 and AKT1/AKT3 ratios, we define four AKT classes which were related to patients’ survival, tumor morphology and BRCA1 expression. Moreover, our results show that high AKT3 expression levels were frequently associated with tumors having classic features, a low number of mitoses and the presence of psammoma bodies. Overall, our study obtains new insights on AKT isoforms and their associations with the clinicopathological features of HGSOC patients. These evidences could help to better define the subsets of patients who can benefit from AKT and PARP inhibitors therapy in future clinical trials.