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James Yao, Abhishek Garg, David Chen, Jaume Capdevila, Paul Engstrom, Rodney Pommier, Eric Van Cutsem, Simron Singh, Nicola Fazio, Wei He, Markus Riester, Parul Patel, Maurizio Voi, Michael Morrissey, Marianne Pavel and Matthew Helmut Kulke

Neuroendocrine tumors (NETs) have historically been subcategorized according to histologic features and the site of anatomic origin. Here, we characterize the genomic alterations in patients enrolled in three phase 3 clinical trials of NET of different anatomic origins and assess the potential correlation with clinical outcomes. Whole-exome and targeted panel sequencing was used to characterize 225 NET samples collected in the RADIANT series of clinical trials. Genomic profiling of NET was analyzed along with nongenomic biomarker data on the tumor grade and circulating chromogranin A (CgA) and neuron-specific enolase (NSE) levels from these patients enrolled in clinical trials. Our results highlight recurrent large-scale chromosomal alterations as a common theme among NET. Although the specific pattern of chromosomal alterations differed between tumor subtypes, the evidence for generalized chromosomal instability (CIN) was observed across all primary sites of NET. In pancreatic NET, although the P value was not significant, higher CIN suggests a trend toward longer survival (HR, 0.55, P = 0.077), whereas in the gastrointestinal NET, lower CIN was associated with longer survival (HR, 0.44, P = 0.0006). Our multivariate analyses demonstrated that when combined with other clinical data among patients with progressive advanced NETs, chromosomal level alteration adds important prognostic information. Large-scale CIN is a common feature of NET, and specific patterns of chromosomal gain and loss appeared to have independent prognostic value in NET subtypes. However, whether CIN in general has clinical significance in NET requires validation in larger patient cohort and warrants further mechanistic studies.

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Young Shin Song, Seong-Keun Yoo, Hwan Hee Kim, Gyeongseo Jung, Ah-Reum Oh, Ji-Young Cha, Su-jin Kim, Sun Wook Cho, Kye Eun Lee, Jeong-Sun Seo and Young Joo Park

Synergistic effects of BRAFV600E and TERT promoter mutations on the poor clinical outcomes in papillary thyroid cancer (PTC) have been demonstrated. The potential mechanism of this phenomenon has been proposed: MAPK pathway activation by the BRAFV600E mutation may upregulate E-twenty six (ETS) transcription factors, increasing TERT expression by binding to the ETS-binding site generated by the TERT promoter mutation; however, it has not yet been fully proven. This article provides transcriptomic insights into the interaction between BRAFV600E and TERT promoter mutations mediated by ETS factors in PTC. RNA sequencing data on 266 PTCs from The Cancer Genome Atlas and 65 PTCs from our institute were analyzed for gene expression changes and related molecular pathways, and the results of transcriptomic analyses were validated by in vitro experiments. TERT mRNA expression was increased by the coexistence of BRAFV600E and TERT promoter mutations (fold change, 16.17; q-value = 7.35 × 10-12 vs. no mutation). In the ETS family of transcription factors, ETV1, ETV4, and ETV5 were upregulated by the BRAFV600E/MAPK pathway activation. These BRAFV600E-induced ETS factors selectively bound to the mutant TERT promoter. The molecular pathways activated by BRAFV600E were further augmented by adding the TERT promoter mutation, and the pathways related to immune responses or adhesion molecules were upregulated by TERT expression. The mechanism of the synergistic effect between BRAFV600E and TERT promoter mutations on cancer invasiveness and progression in PTC may be explained by increased TERT expression, which may result from the BRAF-induced upregulation of several ETS transcription factors.

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Jae Hyun Park and Jong Ho Yoon

The extent of thyroid surgery for patients with low- and intermediate-risk differentiated thyroid carcinoma (DTC), with a primary tumour <4 cm and no extrathyroidal extension (ETE) or lymph node (LN) metastases, has shifted in a more conservative direction. However, clinicopathological risk factors, including microscopic ETE, aggressive histology, vascular invasion in papillary thyroid carcinoma (PTC), and intermediate volume of LN metastases, can only be identified after completing thyroid lobectomy. It is controversial whether patients with these risk factors should immediately undergo complete thyroidectomy and/or radioactive iodine remnant ablation, or should be monitored without further treatments. Data are conflicting about the prognostic impact of these risk factors on clinical DTC outcomes. Notably, the recurrence rate in patients who underwent thyroid lobectomy is low and the few recurrences that develop during long-term follow-up can readily be detected by neck ultrasonography and treated by salvage surgery with no impact on survival. These findings suggest that a more conservative approach may be a preferred management strategy over immediate completion surgery, despite a slightly higher risk of structural recurrence. Regarding follow-up of post-lobectomy DTC patients, it is reasonable that an initial risk stratification system based on clinicohistological findings be used to guide the short-term follow-up prior to evaluating the response to initial therapy, and that the dynamic risk stratification system based on the response to initial therapy be used to guide long-term follow-up.

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Taymeyah Al-Toubah, Stefano Partelli, Mauro Cives, Valentina Andreasi, Franco Silvestris, Massimo Falconi, Daniel A Anaya and Jonathan Strosberg

New systemic treatments have improved the therapeutic landscape for patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). While drugs such as everolimus, sunitinib, temozolomide and 177Lutetium-dotatate are appropriate for patients with widespread disease progression, local treatment approaches may be more appropriate for patients with unifocal progression. Surgical resection, radiofrequency ablation (RFA), hepatic arterial embolization (HAE) or radiation, can control discrete sites of progression, allowing patients to continue their existing therapy and sparing them toxicities of a new systemic treatment. We identified 69 patients with metastatic GEP-NETs who underwent a local treatment for focal progression in the setting of widespread metastases. Twenty-six percent underwent resection, 27% RFA, 23% external beam radiation and 23% selective HAE. With a median follow-up of 25 months, 42 (61%) patients subsequently progressed to the point of requiring additional intervention (12 locoregional, 30 systemic) for disease control. Median time to new systemic treatment was 32 months (95% CI, 16.5–47.5 months). Median time to any additional intervention was 19 months (95% CI, 8.7–25.3 months). Control of local sites of progression enabled the majority of patients to remain on their existing systemic treatment and avoid potential toxicities associated with salvage systemic therapy.

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Phungern Khongthong, Antonia Roseweir and Joanne Edwards

Breast cancer is a heterogeneous disease, which over time acquires various adaptive changes leading to more aggressive biological characteristics and development of treatment resistance. Several mechanisms of resistance have been established, however, due to the complexity of estrogen receptor (ER) signalling and its crosstalk with other signalling networks, various areas still need to be investigated. This review focuses on the role of nuclear factor kappa B (NF-κB) as a key link between inflammation and cancer and addresses its emerging role as a key player in endocrine therapy resistance. Understanding the precise mechanism of NF-κB-driven endocrine therapy resistance provides a possible opportunity for therapeutic intervention.

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Kensey N Bergdorf, Donna C Ferguson, Mitra Mehrad, Kim Ely, Thomas Stricker and Vivian L Weiss

The prevalence of thyroid carcinoma is increasing and represents the most common endocrine malignancy, with papillary thyroid carcinoma (PTC) being the most frequent subtype. The genetic alterations identified in PTCs fail to distinguish tumors with different clinical behaviors, such as extra-thyroidal extension and lymph node metastasis. We hypothesize that the immune microenvironment may play a critical role in tumor invasion and metastasis. Computational immunogenomic analysis was performed on 568 PTC samples in The Cancer Genome Atlas using both CIBERSORT and TIMER deconvolution analytic tools for characterizing immune cell composition. Immune cell infiltrates were correlated with histologic type, mutational type, tumor pathologic T stage, and lymph node N stage. Dendritic cells (DCs) are highly associated with more locally advanced tumor T stage [T3/T4, Odds Ratio (OR)=2.6, Confidence Interval (CI)=1.4-4.5, p=5.4 x 10-4]. Increased dendritic cells (OR=3.4, CI=1.9-6.3, p=5.5 x 10-5) and neutrophils (OR=10.5, CI=2.7-44, p=8.7 x 10-4) significantly correlate with lymph node metastasis. In addition, dendritic cells positively correlate with tall cell morphology (OR=4.5, CI=1.6-13, p=4.9 x10-3) and neutrophils negatively correlate with follicular morphology (OR=1.3 x 10-3, CI=5.3 x 10-5-0.031, p=4.1 x 10-5). TIDE analysis indicates an immune-exclusive phenotype that may be mediated by increased galectin-3 found in PTCs. Thus, characterization of the PTC immune microenvironment using two computational platforms shows that specific immune cells correlate with mutational type, histologic type, local tumor extent, and lymph node metastasis. Immunologic evaluation of PTCs may provide a better indication of biologic behavior, resulting in the improved diagnosis and treatment of thyroid cancer.

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Kristen Wong, Francesca Di Cristofano, Michela Ranieri, Daniela De Martino and Antonio Di Cristofano

Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer. Despite its low incidence, it accounts for a disproportionate number of thyroid cancer-related deaths, because of its resistance to current therapeutic approaches. Novel actionable targets are urgently needed to prolong patient survival and increase their quality of life. Loss and mutation of the RB1 tumor suppressor are rare events in ATC, which suggests that therapies directed at inhibiting the cyclin D/CDK4complexes, responsible for RB phosphorylation and inactivation, might be effective in this tumor type. In fact, we found that the CDK4/6 inhibitor, palbociclib, strongly inhibits proliferation in all the RB1 wild-type ATC cell lines tested. Efficacy was also observed in vivo, in a xenograft model. However, ATC cells rapidly developed resistance to palbociclib. Resistance was associated with increased levels of cyclin D1 and D3. To counter cyclin D overexpression, we tested the effect of combining palbociclib with the PI3K/mTOR dual inhibitor, omipalisib. Combined treatment synergistically reduced cell proliferation, even in cell lines that do not carry PI3K-activating mutations. More importantly, low-dose combination was dramatically effective in inhibiting tumor growth in a xenograft model. Thus, combined PI3K/mTOR and CDK4/6 inhibition is a highly promising novel approach for the treatment of aggressive, therapy-resistant thyroid cancer.

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Miguel A Zaballos, Adrián Acuña-Ruiz, Marta Morante, Piero Crespo and Pilar Santisteban

Thyroid cancer is mostly an ERK-driven carcinoma, as up to 70% of thyroid carcinomas are caused by mutations that activate the RAS/ERK mitogenic signaling pathway. The incidence of thyroid cancer has been steadily increasing for the last four decades, yet there is still no effective treatment for advanced thyroid carcinomas. Current research efforts are focused on impairing ERK signaling with small molecule inhibitors, mainly at the level of BRAF and MEK. However, despite initial promising results in animal models, the clinical success of these inhibitors has been limited by the emergence of tumor resistance and relapse. The RAS/ERK pathway is an extremely complex signaling cascade with multiple points of control, offering many potential therapeutic targets: from the modulatory proteins regulating the activation state of RAS proteins, to the scaffolding proteins of the pathway that provide spatial specificity to the signals, and finally the negative feedbacks and phosphatases responsible for inactivating the pathway. The aim of this review is to give an overview of the biology of RAS/ERK regulators in human cancer highlighting relevant information on thyroid cancer and future areas of research.

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Robert Clarke, John J Tyson, Ming Tan, William T Baumann, Lu Jin, Jianhua Xuan and Yue Wang

Drawing on concepts from experimental biology, computer science, informatics, mathematics, and statistics, systems biologists integrate data across diverse platforms and scales of time and space to create computational and mathematical models of the integrative, holistic functions of living systems. Endocrine-related cancers are well suited to study from a systems perspective because of the signaling complexities arising from the roles of growth factors, hormones, and their receptors as critical regulators of cancer cell biology and from the interactions among cancer cells, normal cells, and signaling molecules in the tumor microenvironment. Moreover, growth factors, hormones, and their receptors are often effective targets for therapeutic intervention, such as estrogen biosynthesis, estrogen receptors, or HER2 in breast cancer, and androgen receptors in prostate cancer. Given the complexity underlying the molecular control networks in these cancers, a simple, intuitive understanding of how endocrine-related cancers respond to therapeutic protocols has proved incomplete and unsatisfactory. Systems biology offers an alternative paradigm for understanding these cancers and their treatment. To correctly interpret the results of systems-based studies requires some knowledge of how in silico models are built, and how they are used to describe a system and to predict the effects of perturbations on system function. In this review, we provide a general perspective on the field of cancer systems biology, and we explore some of the advantages, limitations, and pitfalls associated with using predictive multiscale modeling to study endocrine-related cancers.

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Weijun Wei, Heather Hardin and Quan-Yong Luo

Thyroid cancer is one of the most common endocrine malignancies. Although the prognosis for the majority of thyroid cancers is relatively good, patients with metastatic, radioiodine-refractory or anaplastic thyroid cancers have an unfavorable outcome. With the gradual understanding of the oncogenic events in thyroid cancers, molecularly targeted therapy using tyrosine kinase inhibitors (TKIs) is greatly changing the therapeutic landscape of radioiodine-refractory differentiated thyroid cancers (RR-DTCs), but intrinsic and acquired drug resistance, as well as adverse effects, may limit their clinical efficacy and use. In this setting, development of synergistic treatment options is of clinical significance, which may enhance the therapeutic effect of current TKIs and further overcome the resultant drug resistance. Autophagy is a critical cellular process involved not only in protecting cells and organisms from stressors but also in the maintenance and development of various kinds of cancers. Substantial studies have explored the complex role of autophagy in thyroid cancers. Specifically, autophagy plays important roles in mediating the drug resistance of small-molecular therapeutics, in regulating the dedifferentiation process of thyroid cancers and also in affecting the treatment outcome of radioiodine therapy. Exploring how autophagy intertwines in the development and dedifferentiation process of thyroid cancers is essential, which will enable a more profound understanding of the physiopathology of thyroid cancers. More importantly, these advances may fuel future development of autophagy-targeted therapeutic strategies for patients with thyroid cancers. Herein, we summarize the most recent evidence uncovering the role of autophagy in thyroid cancers and highlight future research perspectives in this regard.