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Bin Zhao, Hong Zhao and Jiaxin Zhao

The introduction of human epidermal growth factor receptor 2 (HER2)–targeted drugs into routine clinical practice has a dramatic effect on the outlook for patients with HER2-positive breast cancer (BC). However, the association between efficacy of HER2-targeted therapy and hormone receptor (HR) status is still unclear. Here we conducted a meta-analysis of randomized controlled trials (RCTs) to address this issue in both neoadjuvant and adjuvant settings. PubMed and EMBASE were searched from inception to October 2017 for studies involving trastuzumab, lapatinib, pertuzumab, trastuzumab emtansine and neratinib. Efficacy endpoints were pathological complete response (pCR) for neoadjuvant therapy and disease-free survival (DFS) for adjuvant therapy. In neoadjuvant setting, pCR was reported in 7 trials with 2868 subjects. Hormone receptor (HR)–negative women derived substantially greater benefit from HER2-targeted agents than did HR-positive patients (odds ratio (OR), 2.34; 95% confidence interval (CI), 1.99–2.75). Additionally, the impact of HR status on pCR was independent of anti-HER2 agents. In adjuvant setting, DFS was investigated in 7 studies with 12,768 patients. HR-positive patients benefit more from anti-HER2 treatment than did HR-negative subjects (OR, 0.81; 95% CI, 0.74–0.89). Moreover, patients who did not receive any endocrine or anti-HER2 neoadjuvant treatment showed similar outcome but with a smaller effect (OR, 0.88; 95% CI, 0.78–0.99). In summary, compared with HER2-positive/HR-negative subjects, HER2-positive/HR-positive patients achieved greater benefit from HER2-targeted treatment although the efficacy from neoadjuvant therapy was relatively poor.

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Ian S Fentiman

Male breast cancer (MBC) is a rare disease but, as a result of epidemiological collaborations, there is now greater clarity concerning endocrine risk factors. The significant rise in global age-standardised mean BMI in men is likely to lead to increases in incidence of maturity-onset diabetes and MBC. The metabolic changes accompanying obesity decrease androgens and sex hormone-binding globulin (SHBG), thereby increasing available oestrogens. The higher rates of MBC in North and Equatorial Africa are largely due to liver damage from endemic bilharziasis and hepatitis B causing elevated oestradiol (E2) levels from hepatic conversion of androgen. Klinefelter’s syndrome (XXY) is associated with a 50-fold increase in incidence of MBC compared with XY males, and this is the most pronounced evidence for testicular malfunction amplifying risk. Delay in presentation means that up to 40% of cases have stage III or stage IV disease at diagnosis. No randomised controlled trials have been reported on endocrine treatment of advanced disease or adjuvant/neoadjuvant therapy following or preceding surgery. Tamoxifen is the most effective endocrine therapy, but side effects can lead to non-compliance in a substantial number of men. Aromatase inhibitors are less effective because they do not inhibit testicular oestrogen production. There is an urgent need for collaborative trials to provide an evidence base for the most effective endocrine and least toxic therapies for men with breast cancer.

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Seong-Jang Kim, Sang-Woo Lee, Kyoungjune Pak and Sung-Ryul Shim

We aimed to explore the role of the diagnostic accuracy of F-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) for the detection of recurrent and/or metastatic diseases in differentiated thyroid cancer (DTC) patients with progressively and/or persistently elevated TgAb levels and negative radioactive iodine whole-body scan (RI-WBS) through a systematic review and meta-analysis. The MEDLINE, EMBASE and Cochrane Library database, from the earliest available date of indexing through June 30, 2017, were searched for studies evaluating the diagnostic performance of F-18 FDG PET/CT for the detection of recurrent and/or metastatic diseases in DTC patients with progressively and/or persistently elevated TgAb levels and negative RI-WBS. We determined the sensitivities and specificities across studies, calculated positive and negative likelihood ratios (LR+ and LR−). Across 9 studies (515 patients), the pooled sensitivity for F-18 FDG PET/CT was 0.84 (95% CI; 0.77–0.89) a pooled specificity of 0.78 (95% CI; 0.67–0.86). Likelihood ratio (LR) syntheses gave an overall positive likelihood ratio (LR+) of 3.8 (95% CI; 2.5–5.7) and negative likelihood ratio (LR−) of 0.21 (95% CI; 0.14–0.30). The pooled diagnostic odds ratio (DOR) was 18 (95% CI; 10–34). The area (AUC) under the hierarchical summary receiver-operating characteristic (HCROC) curve was 0.88 (95% CI: 0.85–0.90). F-18 FDG PET or PET/CT demonstrated moderate sensitivity and specificity for the detection of recurrent and/or metastatic diseases in DTC patients with progressively and/or persistently elevated TgAb levels and negative RI-WBS.

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Shani Avniel-Polak, Gil Leibowitz, Victoria Doviner, David J Gross and Simona Grozinsky-Glasberg

Patients with neuroendocrine neoplasms (NENs) often require systemic treatment, which is frequently limited by the emergence of drug resistance. mTOR inhibitors (mTORi), such as RAD001 (everolimus), have been shown to inhibit neoplasm progression. mTORi stimulates autophagy, a degradation pathway that might promote the survival of neoplasm cells that are exposed to anti-cancer therapy. Chloroquine (CQ), a well-known anti-malarial and anti-rheumatic drug, suppresses autophagy. Based on our previous results, we hypothesized that CQ may enhance the anti-tumorigenic effects of mTORi by inhibiting autophagy and we aimed to examine the anti-tumorigenic effect of CQ, alone or in combination with RAD001. We established a NEN subcutaneous xenograft mouse model and evaluated the effect of the drugs on tumor growth, mTOR pathway, autophagy and apoptosis. CQ alone and in combination with RAD001 significantly decreased neoplasm volume. Histopathological analysis revealed that the combination of CQ and RAD001 markedly inhibited mTOR activity and neoplasm cell growth, along with accumulation of autophagosomes and increased apoptosis. In conclusion, CQ enhances the anti-tumorigenic effect of RAD001 in vivo by inhibiting autophagy. Clinical trials addressing the effects of CQ therapy on neoplasm progression in patients with NENs, mainly in those treated with mTORi, are warranted.

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Huy Gia Vuong, Toru Odate, Hanh T T Ngo, Thong Quang Pham, Thao T K Tran, Kunio Mochizuki, Tadao Nakazawa, Ryohei Katoh and Tetsuo Kondo

There are ongoing debates with respect to the prognostic roles of molecular biomarkers in sporadic medullary thyroid carcinoma (MTC). In this study, we aimed at investigating the prognostic value of RET and RAS mutations – the two most common mutations in sporadic MTCs. A search was conducted in four electronic databases. Relevant data were extracted and pooled into odds ratios (OR), mean differences (MD) and corresponding 95% confidence intervals (CI) using the random-effect model. We used Egger’s regression test and visual of funnel plots to assess the publication bias. From 2581 studies, we included 23 studies with 964 MTCs for meta-analysis. Overall, the presence of RET mutation was associated with an elevated risk for lymph node metastasis (OR = 3.61; 95% CI = 2.33–5.60), distant metastasis (OR = 2.85; 95% CI = 1.64–4.94), advanced tumor stage (OR = 3.25; 95% CI = 2.02–5.25), tumor recurrence (OR = 3.01; 95% CI = 1.65–5.48) and patient mortality (OR = 2.43; 95% CI = 1.06–5.57). RAS mutation had no significant prognostic value in predicting tumor aggressiveness. To summarize, our results affirmed that RET mutation is a reliable molecular biomarker to identify a group of highly aggressive sporadic MTCs. It can help clinicians better assess patient prognosis and select appropriate treatment decisions.

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Sara Pusceddu, Francesco Barretta, Annalisa Trama, Laura Botta, Massimo Milione, Roberto Buzzoni, Filippo De Braud, Vincenzo Mazzaferro, Ugo Pastorino, Ettore Seregni, Luigi Mariani, Gemma Gatta, Maria Di Bartolomeo, Daniela Femia, Natalie Prinzi, Jorgelina Coppa, Francesco Panzuto, Lorenzo Antonuzzo, Emilio Bajetta, Maria Pia Brizzi, Davide Campana, Laura Catena, Harry Comber, Fiona Dwane, Nicola Fazio, Antongiulio Faggiano, Dario Giuffrida, Kris Henau, Toni Ibrahim, Riccardo Marconcini, Sara Massironi, Maja Primic Žakelj, Francesca Spada, Salvatore Tafuto, Elizabeth Van Eycken, Jan Maaten Van der Zwan, Tina Žagar, Luca Giacomelli, Rosalba Miceli and NEPscore Working Group

No validated prognostic tool is available for predicting overall survival (OS) of patients with well-differentiated neuroendocrine tumors (WDNETs). This study, conducted in three independent cohorts of patients from five different European countries, aimed to develop and validate a classification prognostic score for OS in patients with stage IV WDNETs. We retrospectively collected data on 1387 patients: (i) patients treated at the Istituto Nazionale Tumori (Milan, Italy; n = 515); (ii) European cohort of rare NET patients included in the European RARECAREnet database (n = 457); (iii) Italian multicentric cohort of pancreatic NET (pNETs) patients treated at 24 Italian institutions (n = 415). The score was developed using data from patients included in cohort (i) (training set); external validation was performed by applying the score to the data of the two independent cohorts (ii) and (iii) evaluating both calibration and discriminative ability (Harrell C statistic). We used data on age, primary tumor site, metastasis (synchronous vs metachronous), Ki-67, functional status and primary surgery to build the score, which was developed for classifying patients into three groups with differential 10-year OS: (I) favorable risk group: 10-year OS ≥70%; (II) intermediate risk group: 30% ≤ 10-year OS < 70%; (III) poor risk group: 10-year OS <30%. The Harrell C statistic was 0.661 in the training set, and 0.626 and 0.601 in the RARECAREnet and Italian multicentric validation sets, respectively. In conclusion, based on the analysis of three ‘field-practice’ cohorts collected in different settings, we defined and validated a prognostic score to classify patients into three groups with different long-term prognoses.

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B Cioni, W Zwart and A M Bergman

Androgen receptor (AR) signaling is vital for the normal development of the prostate and is critically involved in prostate cancer (PCa). AR is not only found in epithelial prostate cells but is also expressed in various cells in the PCa-associated stroma, which constitute the tumor microenvironment (TME). In the TME, AR is expressed in fibroblasts, macrophages, lymphocytes and neutrophils. AR expression in the TME was shown to be decreased in higher-grade and metastatic PCa, suggesting that stromal AR plays a protective role against PCa progression. With that, the functionality of AR in stromal cells appears to deviate from the receptor’s classical function as described in PCa cells. However, the biological action of AR in these cells and its effect on cancer progression remains to be fully understood. Here, we systematically review the pathological, genomic and biological literature on AR actions in various subsets of prostate stromal cells and aim to better understand the consequences of AR signaling in the TME in relation to PCa development and progression.

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Elke Tatjana Aristizabal Prada, Vera Heinzle, Thomas Knösel, Svenja Nölting, Gerald Spöttl, Julian Maurer, Christine Spitzweg, Martin Angele, Nina Schmidt, Felix Beuschlein, Günter K Stalla, Rainer Blaser, Klaus A Kuhn and Christoph J Auernhammer

Tropomyosin receptor kinase (Trk) inhibitors are investigated as a novel targeted therapy in various cancers. We investigated the in vitro effects of the pan-Trk inhibitor GNF-5837 in human neuroendocrine tumor (NET) cells. The human neuroendocrine pancreatic BON1, bronchopulmonary NCI-H727 and ileal GOT1 cell lines were treated with GNF-5837 alone and in combination with everolimus. Cell viability decreased in a time- and dose-dependent manner in GOT1 cells in response to GNF-5837 treatment, while treatment in BON1 and NCI-H727 cells showed no effect on cellular viability. Trk receptor expression determined GNF-5837 sensitivity. GNF-5837 caused downregulation of PI3K-Akt-mTOR signaling, Ras-Raf-MEK-ERK signaling, the cell cycle and increased apoptotic cell death. The combinational treatment of GNF-5837 with everolimus showed a significant enhancement in inhibition of cell viability vs single substance treatments, due to a cooperative PI3K-Akt-mTOR and Ras-Raf-MEK-ERK pathway downregulation, as well as an enhanced cell cycle component downregulation. Immunohistochemical staining for Trk receptors were performed using a tissue microarray containing 107 tumor samples of gastroenteropancreatic NETs. Immunohistochemical staining with TrkA receptor and pan-Trk receptor antibodies revealed a positive staining in pancreatic NETs in 24.2% (8/33) and 33.3% (11/33), respectively. We demonstrated that the pan-Trk inhibitor GNF-5837 has promising anti-tumoral properties in human NET cell lines expressing the TrkA receptor. Immunohistochemical or molecular screening for Trk expression particularly in pancreatic NETs might serve as predictive marker for molecular targeted therapy with Trk inhibitors.

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Minlu Zhang, Peng Peng, Kai Gu, Hui Cai, Guoyou Qin, Xiao Ou Shu and Pingping Bao

The impact of some prognostic factors on breast cancer survival has been shown to vary with time since diagnosis. However, this phenomenon has not been evaluated in Asians. In the present study, 4886 patients were recruited from the Shanghai Breast Cancer Survival Study, a longitudinal study of patients diagnosed during 2002–2006, with a median follow-up time of 11.2 years. Cox model incorporating time-by-covariate interactions was used to describe the time-varying effects of prognostic factors related to overall survival and disease-free survival. Age ≥65 years showed a progressively negative effect on breast cancer prognosis over time, whereas tumour size >2 cm had a lasting and constant impact. Age significantly modified the effects of the tumour grade, nodal status and oestrogen receptor (ER) status on breast cancer survival. The detrimental effect of poorly differentiated tumours was time limited and more obvious in patients aged 45–54 years. Having ≥4 positive lymph nodes had a persistent and negative impact on prognosis, although it attenuated in later years; the phenomenon was more prominent in the 55–64-year age group. ER-positive status was protective in the first 3 years after diagnosis but was related to a higher risk of recurrence in later years; the time-point when ER-positive status turned into a risk factor was earlier in younger patients. These results suggest that older age, positive lymph node status, larger tumour size and ER-positive status are responsible for late death or recurrence in Asian breast cancer survivors. Extended endocrine therapy should be given earlier in younger ER-positive patients.

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Yu-Tang Chin, Po-Li Wei, Yih Ho, André Wendindondé Nana, Chun A Changou, Yi-Ru Chen, Yu-Chen SH Yang, Meng-Ti Hsieh, Aleck Hercbergs, Paul J Davis, Ya-Jung Shih and Hung-Yun Lin

Thyroid hormone, l-thyroxine (T4), has been shown to promote ovarian cancer cell proliferation via a receptor on plasma membrane integrin αvβ3 and to induce the activation of ERK1/2 and expression of programmed death-ligand 1 (PD-L1) in cancer cells. In contrast, resveratrol binds to integrin αvβ3 at a discrete site and induces p53-dependent antiproliferation in malignant neoplastic cells. The mechanism of resveratrol action requires nuclear accumulation of inducible cyclooxygenase (COX)-2 and its complexation with phosphorylated ERK1/2. In this study, we examined the mechanism by which T4 impairs resveratrol-induced antiproliferation in human ovarian cancer cells and found that T4 inhibited resveratrol-induced nuclear accumulation of COX-2. Furthermore, T4 increased expression and cytoplasmic accumulation of PD-L1, which in turn acted to retain inducible COX-2 in the cytoplasm. Knockdown of PD-L1 by small hairpin RNA (shRNA) relieved the inhibitory effect of T4 on resveratrol-induced nuclear accumulation of COX-2- and COX-2/p53-dependent gene expression. Thus, T4 inhibits COX-2-dependent apoptosis in ovarian cancer cells by retaining inducible COX-2 with PD-L1 in the cytoplasm. These findings provide new insights into the antagonizing effect of T4 on resveratrol’s anticancer properties.