Summary Background The identification of circulating tumour cells correlate with poor prognosis in metastatic breast cancer, but there are few data describing the importance of circulating tumour ...cells in patients with non-metastatic disease. Our aim was to establish if circulating tumour cells predicted worse outcome in patients with non-metastatic breast cancer. Methods We prospectively collected data on circulating tumour cells at the time of definitive surgery from chemonaive patients with stage 1–3 breast cancer from February, 2005, to December, 2010. We deemed eligible all patients with operable breast cancer presenting at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients were ineligible if they had bilateral breast cancer or any other malignancy within 5 years of the diagnosis of the present cancer. We measured circulating tumour cells with the CellSearch System (Veridex, Raritan, NJ). We correlated findings of circulating tumour cells with standard tumour characteristics, including tumour size and grade; oestrogen and progesterone receptor and human epidural growth factor receptor 2 (HER2) status; and axillary lymph node status with χ2 or Fisher exact tests. We assessed outcomes at a median follow-up of 35 months. Log-rank test and Cox regression analysis was applied to establish the association of circulating tumour cells with progression-free and overall survival. Findings No patients reported adverse events or complications from blood collections. We identified one or more circulating tumour cells in 73 (24%) of 302 patients. Detection of one or more circulating tumour cells predicted both decreased progression-free survival (log-rank p=0·005; hazard ratio HR 4·62, 95% CI 1·79–11·9) and overall survival (log-rank p=0·01; HR 4·04, 1·28–12·8). Interpretation The presence of one or more circulating tumour cells predicted early recurrence and decreased overall survival in chemonaive patients with non-metastatic breast cancer. These results suggest that assessment of circulating tumour cells might provide important prognostic information in these patients. Funding Society of Surgical Oncology, Morgan Welch Inflammatory Breast Cancer Program, The University of Texas MD Anderson Cancer Center, and the State of Texas Rare and Aggressive Breast Cancer Research Program.
Summary Background Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the ...treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. Methods We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov , number NCT02314169. Results We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% 95% CI 15–33) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. Interpretation To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. Funding National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor.
Cancer stem cells (CSC) are purported to initiate and maintain tumor growth. Deregulation of normal stem cell signaling may lead to the generation of CSCs; however, the molecular determinants of this ...process remain poorly understood. Here we show that the transcriptional coactivator YAP1 is a major determinant of CSC properties in nontransformed cells and in esophageal cancer cells by direct upregulation of SOX9. YAP1 regulates the transcription of SOX9 through a conserved TEAD binding site in the SOX9 promoter. Expression of exogenous YAP1 in vitro or inhibition of its upstream negative regulators in vivo results in elevated SOX9 expression accompanied by the acquisition of CSC properties. Conversely, shRNA-mediated knockdown of YAP1 or SOX9 in transformed cells attenuates CSC phenotypes in vitro and tumorigenicity in vivo. The small-molecule inhibitor of YAP1, verteporfin, significantly blocks CSC properties in cells with high YAP1 and a high proportion of ALDH1(+). Our findings identify YAP1-driven SOX9 expression as a critical event in the acquisition of CSC properties, suggesting that YAP1 inhibition may offer an effective means of therapeutically targeting the CSC population.
SummaryBackgroundTaxane–platinum combinations have shown promising activity in metastatic castration-resistant prostate cancers in single-group clinical studies but not in randomised trials. Distinct ...biological subsets of the disease might derive the greatest benefit from the addition of platinum. We aimed to determine whether adding carboplatin to cabazitaxel would improve the outcomes of men with metastatic castration-resistant prostate cancer. MethodsWe did a phase 1–2, open label, randomised study at two centres in men with progressive metastatic castration-resistant prostate cancer. In phase 1, patients received intravenous cabazitaxel 20–25 mg/m 2 and intravenous carboplatin area under the curve (AUC) 3–4 mg/mL per min every 21 days. The maximum tolerated dose was defined as the highest dose cohort studied in which one of six or fewer patients experienced a dose-limiting toxicity. In phase 2, patients were randomly assigned (1:1) centrally by a computerised algorithm to intravenous cabazitaxel 25 mg/m 2 with or without intravenous carboplatin AUC 4 mg/mL per min. All patients received growth factor support and oral prednisone 10 mg daily. The primary endpoints were the maximum tolerated dose of the combination in phase 1 and investigator-assessed progression-free survival in phase 2. This trial is registered at ClinicalTrials.gov, number NCT01505868. FindingsBetween Aug 17, 2012, and May 11, 2015, nine patients completed phase 1 as planned, and 160 were randomly assigned to cabazitaxel (n=79) or cabazitaxel plus carboplatin (n=81) in phase 2. During phase I, grade 3 adverse events were anaemia (n=2), fatigue (n=1), thrombocytopenia (n=1), hypomagnesaemia (n=1), diarrhoea (n=1), hypokalaemia (n=1), anorexia (n=1), and dehydration (n=1), and no grade 4 adverse events occurred. No dose-limiting toxicities were observed, therefore, a maximum tolerated dose of cabazitaxel of 25 mg/m 2 and carboplatin of AUC 4 mg/mL per min was selected for phase 2. At a median follow-up of 31·0 months (IQR 20·5–37·1), the combination improved the median progression-free survival from 4·5 months (95% CI 3·5–5·7) to 7·3 months (95% CI 5·5–8·2; hazard ratio 0·69, 95% CI 0·50–0·95, p=0·018). In the phase 2 study, the most common grade 3–5 adverse events were fatigue (7 9% of 79 in the cabazitaxel group vs 16 20% of 81 in the combination group), anaemia (3 4% vs 19 23%), neutropenia (3 4% vs 13 16%), and thrombocytopenia (1 1% vs 11 14%). There were no treatment-related deaths. InterpretationCarboplatin added to cabazitaxel showed improved clinical efficacy compared with cabazitaxel alone for men with metastatic castration-resistant prostate cancer. Although adverse events were more common with the combination, the treatment was safe and generally well tolerated. Our data suggest that taxane–platinum combinations have a clinically beneficial role in advanced prostate cancer and a randomised phase 3 study is planned. FundingSanofi Genzyme, University of Texas MD Anderson Cancer Center Prostate Cancer Moon Shot Program, and Solon Scott III Prostate Cancer Research Fund.
Arsenic trioxide (As(2)O(3)) has shown considerable efficacy in treating hematological malignancies with induction of programmed cell death (PCD) type I, apoptosis. However, the mechanisms underlying ...the antitumor effect of As(2)O(3) on solid tumors are poorly defined. Previously, we reported that As(2)O(3) induced autophagic cell death (PCD type II) but not apoptosis in human malignant glioma cell lines. The purpose of this study was to elucidate the molecular pathway leading to autophagic cell death. In this study, we demonstrated that the cell death was accompanied by involvement of autophagy-specific marker, microtubule-associated protein light chain 3 (LC3), and damage of mitochondrial membrane integrity, but not by caspase activation. Analysis by cDNA microarray, RT-PCR, and Western blot showed that cell death members of Bcl-2 family, Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3) and its homologue BNIP3-like (BNIP3L), were upregulated in As(2)O(3)-induced autophagic cell death. Exogenous expression of BNIP3, but not BNIP3L, induced autophagic cell death in malignant glioma cells without As(2)O(3) treatment. When upregulation of BNIP3 induced by As(2)O(3) was suppressed by a dominant-negative effect of the transmembrane-deleted BNIP3 (BNIP3 Delta TM), autophagic cell death was inhibited. In contrast, BNIP3 transfection augmented As(2)O(3)-induced autophagic cell death. These results suggest that BNIP3 plays a central role in As(2)O(3)-induced autophagic cell death in malignant glioma cells. This study adds a new concept to characterize the pathways by which As(2)O(3) acts to induce autophagic cell death in malignant glioma cells.
The oncogenic miR-155 is upregulated in many human cancers, and its expression is increased in more aggressive and therapy-resistant tumors, but the molecular mechanisms underlying miR-155-induced ...therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors.
We performed
studies on cell lines to investigate the role of miR-155 in therapy resistance. To assess the effects of miR-155 inhibition on chemoresistance, we used an
orthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy. To analyze the association of miR-155 expression and the combination of miR-155 and
expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia, and acute lymphoblastic leukemia.
We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agents
, and that downregulation of miR-155 successfully resensitizes tumors to chemotherapy
We show that anti-miR-155-DOPC can be considered non-toxic
We further demonstrate that miR-155 and
are linked in a negative feedback mechanism and that a combination of high expression of miR-155 and low expression of
is significantly associated with shorter survival in lung cancer.
Our findings support the existence of an miR-155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcome drug resistance, an important cause of cancer-related death.
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Purpose: To investigate relationships among physical activity, changes in physical function, and health-related quality of life (HRQOL) among patients with pancreatic adenocarcinoma enrolled in a ...home-based exercise prehabilitation program. Methods: Patients with resectable pancreatic adenocarcinoma receiving preoperative chemotherapy and/or chemoradiation were enrolled on this prospective, single-arm trial and were advised to perform ≥60 minutes each of moderate-intensity aerobic exercise and strengthening exercise weekly. Activity was measured via self-report and accelerometers, including moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), and sedentary activity (SA). Physical function measures at baseline and restaging follow-up included 6-minute walk test (6MWT), 5 times sit-to-stand (5×STS), handgrip strength (HGS), 3-m walk for gait speed (GS), and the PROMIS Physical Function Short Form. HRQOL was measured via the FACT-Hep questionnaire. Results: Fifty participants with mean age 66 years (standard deviation = 8 years) were enrolled. The 6MWT, 5×STS, and GS significantly improved from baseline to restaging follow-up (P=.001, P=.049, and P=.009, respectively). Increases in self-reported aerobic exercise, weekly MVPA, and LPA were associated with improvement in 6MWT (β=.19, P=.048; β=.18, P=.03; and β=.08, P=.03, respectively) and self-reported physical functioning (β=.02, P=.03; β=.03, P=.005; and β=.01, P=.02, respectively). Increased weekly LPA was associated with increased HRQOL (β=.03, P=.02). Increased SA was associated with decreased HRQOL (β=-.02,P=.01). Conclusions: Patients with potentially resectable pancreatic cancer exhibit meaningful improvement in physical function with prehabilitation; physical activity was associated with improved physical function and HRQOL. These data highlight the importance of physical activity during treatment for pancreatic cancer.
Abstract Background Sunitinib is a standard-of-care treatment in advanced clear cell renal cell carcinoma (ccRCC). Retrospective and expanded access data suggest sunitinib has activity in advanced ...non–clear cell renal cell carcinoma (nccRCC). Objective To prospectively determine the clinical efficacy and safety of sunitinib in patients with advanced nccRCC. Design, setting, and participants This is a single-arm phase 2 trial with a two-stage design. Eligibility criteria included pathologically confirmed nccRCC or ccRCC with ≥20% sarcomatoid histology, performance status 0–2, measurable disease, a maximum of two prior systemic therapies, and no prior treatment with tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptors. Intervention Patients received sunitinib 50 mg daily on a 4-wk on, 2-wk off schedule. Outcome measurements and statistical analysis Primary end points were objective response rate (ORR) and progression-free survival (PFS). Secondary end points were safety and overall survival (OS). Results and limitations Fifty-seven patients were eligible (nccRCC histology: papillary, 27; chromophobe, 5; unclassified, 8; collecting duct or medullary carcinoma, 6; sarcomatoid, 7; and others, 4). Median PFS for 55 evaluable patients was 2.7 mo (95% confidence interval CI, 1.4–5.4). Two patients with chromophobe and one patient with unclassified histology had a confirmed partial response (5% ORR). Median PFS for patients with papillary histology was 1.6 mo (95% CI, 1.4–5.4). Median PFS for patients with chromophobe histology was 12.7 mo (95% CI, 8.5–NA). Median OS for all patients was 16.8 mo (95% CI, 10.7–26.3). Treatment-emergent adverse events were consistent with sunitinib’s mechanism of action. The nonrandomized design and small number of patients are limitations of this study. Conclusions The differential response of chromophobe histology to sunitinib suggests a therapeutically relevant biological heterogeneity exists within nccRCC. The low ORR and short PFS with sunitinib in the other nccRCC subtypes underscore the need to enroll patients with these diverse tumors in clinical trials.
MicroRNA (miRNA) expression profile can be used as prognostic marker for human cancers. We aim to explore the significance of miRNAs in colorectal cancer (CRC) metastasis.
We performed miRNA ...microarrays using primary CRC tissues from patients with and without metastasis, and validated selected candidates in 85 CRC samples by quantitative real-time PCR (qRT-PCR). We tested metastatic activity of selected miRNAs and identified miRNA targets by prediction algorithms, qRT-PCR, western blot and luciferase assays. Clinical outcomes were analysed in six sets of CRC cases (n=449), including The Cancer Genome Atlas (TCGA) consortium and correlated with miR-224 status. We used the Kaplan-Meier method and log-rank test to assess the difference in survival between patients with low or high levels of miR-224 expression.
MiR-224 expression increases consistently with tumour burden and microsatellite stable status, and miR-224 enhances CRC metastasis in vitro and in vivo. We identified SMAD4 as a miR-224 target and observed negative correlation (Spearman Rs=-0.44, p<0.0001) between SMAD4 and miR-224 expression in clinical samples. Patients with high miR-224 levels display shorter overall survival in multiple CRC cohorts (p=0.0259, 0.0137, 0.0207, 0.0181, 0.0331 and 0.0037, respectively), and shorter metastasis-free survival (HR 6.51, 95% CI 1.97 to 21.51, p=0.0008). In the TCGA set, combined analysis of miR-224 with SMAD4 expression enhanced correlation with survival (HR 4.12, 95% CI 1.1 to 15.41, p=0.0175).
MiR-224 promotes CRC metastasis, at least in part, through the regulation of SMAD4. MiR-224 expression in primary CRC, alone or combined with its targets, may have prognostic value for survival of patients with CRC.
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