Long-term survival of metastatic small intestine neuroendocrine tumors: a meta-analysis

This meta-analysis aims to evaluate long-term survival and prognostic factors in patients with metastatic small intestine neuroendocrine tumors (siNETs). Patients with siNETs usually present with advanced disease, limiting curative treatment options. Overall survival seems favorable compared to other cancers but differences in terminology, lack of consistent coding, conflicting results from smaller cohorts, and recent developments of new treatment options make (reliable) survival data difficult to achieve. Nevertheless, accurate survival data are essential for many facets of health care. A systematic literature search was performed, using MEDLINE® (PubMed), EMBASE®, Web of Science, and Cochrane Library up to June 30th, 2021. Studies were included if overall survival data in patients with metastatic siNETs were reported. The results were pooled in a random-effects meta-analysis and are reported as hazard ratios and 95% confidence intervals (CIs). Subgroup analyses and meta-regression were performed to assess the observed heterogeneity and the impact of important prognostic factors. After screening 9,065 abstracts there were 23 studies, published between 1995 and 2021, that met the inclusion criteria, with a total of 8,636 patients. The weighted five- and ten-year overall survival was 67% and 37% respectively. Meta-regression identified younger age and primary tumor resection to be associated with better prognosis. Subgroup analyses showed similar results. This study confirms that in an advanced, metastatic setting, the weighted five-year and 10-year overall survival reveal a favorable prognosis, improving over the last few decades. Meta-regression showed that age at diagnosis is an important prognostic factor.

Spironolactone is associated with reduced mitotane levels in adrenocortical carcinoma patients

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Mitotane, a derivative of the pesticide DDT, has been used successfully as first line chemotherapy since the 1960s, if maintained within a narrow therapeutic window. Spironolactone (SPL) is frequently used to treat glucocorticoid excess-associated adverse effects such as severe hypokalemia. Although data of a previous case report indicate a link, valid data regarding SPL use and mitotane plasma concentrations in a human cohort are lacking. This retrospective analysis includes data from 54 mitotane-receiving ACC patients (14 co-administered with SPL) treated between January 2005 and April 2020 (20 male, mean age 54.1 ± 2.2 yrs). All available mitotane concentrations, treatment doses, tumor stage and evidence of hormone activity were collected. Primary outcomes included mitotane levels and concentration/dose-ratios as well as time-in-range in patients with and without additional SPL treatment. The SPL group was characterized by higher glucocorticoid secretion. Other features such as tumor stage, size and anthropometrics were similar between groups. Interestingly, the SPL group had significantly lower mitotane levels despite higher doses. Mitotane time-in-range was significantly reduced in the SPL group, as was time-in-range to progression. These data provide first evidence in a human cohort for potential SPL-mitotane interactions (beyond mentioned case report), which affect dose response and may modulate treatment outcomes. This should caution clinicians to carefully adjust mitotane doses during SPL treatment in ACC patients or choose alternative therapeutic options.

TREM1 fosters an immunosuppressive tumor microenvironment in papillary thyroid cancer

The immunosuppressive microenvironment is associated with poor prognosis in papillary thyroid cancer (PTC); however, the molecular mechanisms involved are unknown. Among triggering receptor expressed on myeloid cell (TREM) family, we found that TREM1 expression in PTC was significantly higher than that in normal tissues. TREM1 overexpression was associated with BRAFV600E profiles and advanced tumor stages. Furthermore, TREM1 mRNA expression was negatively correlated with promoter methylation status. Specifically, hypomethylation of CpG site cg06196379 in the TREM1 promoter was related with poor patient disease free survival (DFS) and a high PTC recurrence rate. Mechanistically, TREM1 was mainly expressed in malignant epithelial cells but not macrophages in PTC by single-cell analysis. PTC tissues with high TREM1 levels had enhanced infiltration of regulatory T cells (Tregs) and decreased infiltration of CD8+ T cells. Our study confirms that hypomethylation-mediated overexpression of TREM1 in PTC cells promotes an immunosuppressive microenvironment by enhancing Treg infiltration. We recommend the future use of therapeutic strategy targeting TREM1 for the treatment of PTC.

The role of vitamin D in breast cancer risk and progression

The active form of vitamin D3, 1,25-dihydroxvitamin D3 [1,25(OH)2D3], is primarily known as a key regulator of calcium and phosphate homeostasis. It exerts its biological functions by binding to the vitamin D receptor (VDR), a transcription factor that regulates gene expression in vitamin D-target tissues such as intestine, kidney and bone. Yet, the VDR is expressed in many additional normal and cancerous tissues, where it moderates the antiproliferative, prodifferentiating and immune-modulating effects of 1,25(OH)2D3. Interestingly, several epidemiological studies show that low levels of 25(OH)D3, a biological marker for 1,25(OH)2D3 status, are associated with increased risk of breast cancer (BC) development. Mendelian randomization studies, however, did not find any relationship between single-nucleotide polymorphisms in genes associated with lower serum 25(OH)D3 and BC risk. Nevertheless, multiple in vitro and in vivo preclinical studies illustrate that 1,25(OH)2D3 or its less calcaemic structural analogues influence diverse cellular processes in BC such as proliferation, differentiation, apoptosis, autophagy and the epithelial-mesenchymal transition. Recent insights also demonstrate that 1,25(OH)2D3 treatment impacts on cell metabolism and on the cancer stem cell population. The presence of VDR in the majority of BCs, together with the various antitumoural effects of 1,25(OH)2D3, have supported the evaluation of the effects of vitamin D3 supplementation on BC development. However, most randomized controlled clinical trials do not demonstrate a clear decrease of BC incidence with vitamin D3 supplementation. However, 1,25(OH)2D3 or its analogues seem biologically more active, and may have more potential anticancer activity in BC upon combination with existing cancer therapies.

Serum markers, obesity and prostate cancer risk: results from the prostate cancer prevention trial

Molecular mechanisms linking obesity to prostate cancer involve steroid hormone and insulin/insulin-like growth factor-1 (IGF-1) pathways. We investigated the association of circulating serum markers (e.g., androgens and IGFs/IGFBPs) with BMI and in modifying the association of obesity with prostate cancer risk. Data and specimens for this nested case-control study are from the Prostate Cancer Prevention Trial, a randomized, placebo-controlled trial of finasteride for prostate cancer prevention. Presence or absence of cancer was determined by prostate biopsy. Serum samples were assayed for sex steroid hormone concentrations and IGF-1 axis analytes. Logistic regression estimated odds ratio and 95% confidence intervals (CIs) for risk of overall, low-grade (Gleason 2–6), and high-grade (Gleason 7–10) cancers. We found significant associations between BMI with serum steroids and IGFs/IGFBPs; the IGF-1 axis significantly associated with several serum steroids. Serum steroid levels did not affect the association of BMI with prostate cancer risk; however, IGFBP2 and IGFs modified the association of obesity with low- and high-grade disease. While serum steroids and IGFs/IGFBPs are associated with BMI, only the IGF-1 axis contributed to obesity-related prostate cancer risk. Understanding the biological mechanisms linking obesity to prostate cancer risk as it relates to circulating serum markers will aid in developing effective prostate cancer prevention strategies and treatments.

Prognostic stratification for patients with neuroendocrine tumours receiving 177Lu-Dotatate

177Lu-Dotatate is increasingly used in patients with advanced neuroendocrine tumour (NET). However, few prognostic markers are available to stratify progression-free survival (PFS) of patients received 177Lu-Dotatate. Clinicopathological data, including baseline circulating biomarkers of patients with advanced NET received 177Lu-Dotatate that were routinely collected were retrospectively analysed. Continuous variables were normalized by dividing them by their upper normal limits. The whole dataset was randomly divided into a training set and a validation set. Univariate and multivariate logistic regression analysis were used to identify independent markers and develop a scoring model to predict treatment failure at 1-year. In total, 195 patients were included. Elevated baseline chromogranin A (CgA), normal creatinine and previous chemotherapy were three risk factors independently associated with 1-year treatment failure. By combining these risk factors, a scoring model was developed which could accurately predict 1-year treatment failure both in the training set (area under curve, AUC, 0.813; 95% confidence interval, 95%CI, 0.731-0.895; P<0.001) and the validation set (ACU, 0.816; 95%CI, 0.644-0.968; P<0.001). After selecting a score of 29.7 as the cutoff value of the scoring model, patients could be stratified into two groups, low-risk and high-risk with significantly different 1-year treatment failure rate, PFS and overall survival (OS; P<0.001) both in training set and validation set. In conclusion, baseline CgA, creatinine level, and previous chemotherapy were independently associated with 1-year treatment failure of patients with advanced NET who received 177Lu-Dotatate and the scoring model and prognostic stratification based on these markers could accurately predict 1-year treatment failure, PFS and OS.

Pregnancy-associated breast cancer: the influence of gestational age

Whether PABC tumors arise before or during pregnancy and whether histopathology is affected by gestational age is currently unclear. The present study assesses the influence of gestational age and lactation on the histopathologic profile of PABC. We identified 744 patients with PABC (defined as breast cancer during pregnancy or 6-months following delivery). Histopathologic features were compared between pregnant and postpartum patients. Median age at diagnosis was 34.2 years and majority of cancers were diagnosed during pregnancy (71.3%). Within pregnant patients, tumors were significantly more often ER-negative in second and third trimesters (57.4%), as compared to first trimesters (41.9%) (p=0.036). Similarly, a PR-negative status was reported significantly less often within first trimesters (38.0%) compared to second and third trimesters (57.1%) (p=0.032). For HER2 status no significant differences were observed between gestational trimesters or lactating versus non-lactating patients. In postpartum patients, grade III tumors were found in over 80%, with high percentages of ER-negative tumors reaching 63% in those lactating versus 49% in non-lactating patients. This study demonstrates the varying histopathologic profile of PABC by gestational age and lactation status. Second and third trimester cancers display most typically the common ER/PR-negative phenotype, which is commonly reported in literature. The increased ER-negative status and percentage grade III tumors in lactating versus non-lactating patients also suggest presence of additional factors further diversify histology. This indicates the need for clear definitions of PABC and the role of potential subgroups, which may provide a stepping stone for further in-depth research into PABC-carcinogenesis.

Cancer-associated adipocytes release FUCA2 to promote aggressiveness in TNBC

Cancer-associated adipocytes (CAAs) have been suggested to promote tumor progression. Yet, the role of CAAs in triple-negative breast cancer (TNBC) is poorly investigated. We compared the expression of secretory protein-encoding genes in CAAs and control adipocytes. The effect of key secretory protein(s) on TNBC cell behaviors was explored. CAAs expressed and secreted FUCA2 at greater levels than control adipocytes. When FUCA2 activity was blocked with a neutralizing antibody, TNBC cell proliferation and migration induced by CAA conditioned medium was impaired. In contrast, supplement of exogenous FUCA2 protein reinforced the proliferation, colony formation, and migration of TNBC cells. In vivo studies confirmed that FUCA2 exposure enhanced tumorigenesis and metastasis of TNBC cells. Mechanistic investigation revealed that FUCA2 induced TNBC aggressiveness through TM9SF3-dependent signaling. Depletion of TM9SF3 blocked CAA- and FUCA2-induced TNBC cell proliferation and migration. Compared to adjacent breast tissues, TNBC tissues had increased expression of TM9SF3. Moreover, high TM9SF3 expression was associated with advanced TNM stage, lymph node metastasis, and shorter overall survival of TNBC patients. Altogether, CAAs secrete FUCA2 to promote TNBC growth and metastasis through interaction with TM9SF3. Inhibition of TM9SF3 may represent a potential therapeutic strategy in the treatment of TNBC.

Reduced MHC class II expression in medullary thyroid cancer identifies patients with poor prognosis

Increasing body of recent studies determining the expression of tumor-specific major histocompatibility complex (MHC) class II protein support its potential role in several malignancies but little is known in human medullary thyroid cancer (MTC). Here we report the expression of MHC-II and its clinicopathologic and prognostic relevance in MTC patients. Immunohistochemistry staining revealed a significant reduction in tumor cell specific MHC-II expression in a higher AJCC stage and its poor prognostic correlation with human MTC development. Further statistical analysis identified the low MHC-II expression as a significant and independent risk factor for MTC recurrence and patient survival. Moreover, in vitro studies showed that the MHC-II expression was remarkably increased by RET inhibitors, which were prescribed to treat advanced MTC. Similarly, inhibitors blocking the MAPK/ERK and AKT/mTOR pathways also augmented MHC-II expression, suggesting their implications in RET-MHC-II signaling axis. Importantly, in vitro assays manifested enhanced peripheral blood leukocytes-mediated cytotoxicity in MTC cells treated with RET inhibitors, which were partially alleviated by HLA knock-down. Together, our study demonstrates that low MHC-II expression levels may serve as a prognostic biomarker for aggressive diseases in MTC patients and indicates that RET activation may promote MTC immune escape through down-regulating MHC-II expression.