News Article | May 15, 2017
Relapse is now the main cause of death for breast cancer patients. Researchers at EMBL have found that, in mice, the tumour cells that survive therapy and eventually cause a relapse have specific traits that distinguish them from healthy cells. In a study published today in the Journal of Clinical Investigation, the scientists revealed that two of these traits could be promising targets for treatments to reduce tumour recurrence in breast cancer patients. "Our results suggest that residual cells retain an "oncogenic memory" that could be exploited to develop drugs against breast cancer recurrence," says Martin Jechlinger, who led the research at EMBL. Thanks to improvements in primary care, more and more breast cancer patients survive the initial tumour. Although treatments like chemotherapy and mastectomies aim to eliminate all of a patient's tumour cells, breast cancer cells that survive these initial therapies often reinitiate growth, causing a relapse further down the line. These residual cells are difficult to identify and analyse because, until they relapse, they look and act as normal cells. This means breast cancer relapse has remained largely unexplored, and makes it difficult to predict if and when a patient will experience relapse. "We found that residual cells have molecular traits that clearly distinguish them from normal breast tissue, and seem to cause relapse," Jechlinger explains. "When we treated those features in mice, their tumours were less likely to recur." Jechlinger and colleagues found that, compared to healthy cells, residual cancer cells have altered lipid metabolism. This contributes to maintaining high levels of "reactive oxygen species" -- chemically reactive molecules that are known to damage DNA. The scientists think that this damage triggers the relapse. The team then compared the findings from the mouse model to samples from breast cancer patients, thanks to collaborators at the European Institute of Oncology in Milan, Italy, and the National Centre for Tumour Diseases in Heidelberg, Germany. The two sets of results were consistent, which suggests they could be useful to understand and treat breast cancer recurrence in humans. "Every patient is different and every story is unique, but our results suggest that lipid metabolism is an exciting therapeutic target to reduce breast cancer recurrence," says Kristina Havas, who carried out much of the research in Jechlinger's lab at EMBL. In this study, to isolate and characterize the cells which survived therapy, the researchers used organotypic structures, or organoids. Organoids are small clusters of cells cultured outside the body that accurately mimic some of the structure and function of real organs. Organoids can be used for drug testing, investigating personalised therapies and understanding organ development.
PubMed | University of Padua, European Institute of Oncology, Chioggia Hospital, Dolo Hospital and 2 more.
Type: Journal Article | Journal: Endoscopy international open | Year: 2015
Neoplastic lesions can be missed during colonoscopy, especially when cleansing is inadequate. Bowel preparation scales have significant limitations and no objective and standardized method currently exists to establish colon cleanliness during colonoscopy. The aims of our study are to create a software algorithm that is able to analyze bowel cleansing during colonoscopies and to compare it to a validate bowel preparation scale.A software application (the Clean Colon Software Program, CCSP) was developed. Fifty colonoscopies were carried out and video-recorded. Each video was divided into 3 segments: cecum-hepatic flexure (1st Segment), hepatic flexure-descending colon (2nd Segment) and rectosigmoid segment (3rd Segment). Each segment was recorded twice, both before and after careful cleansing of the intestinal wall. A score from 0 (dirty) to 3 (clean) was then assigned by CCSP. All the videos were also viewed by four endoscopists and colon cleansing was established using the Boston Bowel Preparation Scale. Interclass correlation coefficient was then calculated between the endoscopists and the software.The cleansing score of the prelavage colonoscopies was 1.560.52 and the postlavage one was 2,080,59 (P<0.001) showing an approximate 33.3% improvement in cleansing after lavage. Right colon segment prelavage (0.990.69) was dirtier than left colon segment prelavage (2.070.71). The overall interobserver agreement between the average cleansing score for the 4 endoscopists and the software pre-cleansing was 0.87 (95% CI, 0.84-0.90) and post-cleansing was 0.86 (95% CI, 0.83-0.89).The software is able to discriminate clean from non-clean colon tracts with high significance and is comparable to endoscopist evaluation.
PubMed | Humanitas Research Hospital, Foundation Medicine, European Institute of Oncology, Italian Institute of Technology and University of Milan
Type: Journal Article | Journal: Clinical chemistry | Year: 2016
The identification of circulating microRNAs (miRNAs) in the blood has been recently exploited for the development of minimally invasive tests for the early detection of cancer. Nevertheless, the clinical transferability of such tests is uncertain due to still-insufficient standardization and optimization of methods to detect circulating miRNAs in the clinical setting.We performed a series of tests to optimize the quantification of serum miRNAs that compose the miR-Test, a signature for lung cancer early detection, and systematically analyzed variables that could affect the performance of the test. We took advantage of a large-scale (>1000 samples) validation study of the miR-Test that we recently published, to evaluate, in clinical samples, the effects of analytical and preanalytical variables on the quantification of circulating miRNAs and the clinical output of the signature (risk score).We developed a streamlined and standardized pipeline for the processing of clinical serum samples that allows the isolation and analysis of circulating miRNAs by quantitative reverse-transcription PCR, with a throughput compatible with screening trials. The major source of analytical variation came from RNA isolation from serum, which could be corrected by use of external (spike-in) or endogenous miRNAs as a reference for normalization. We also introduced standard operating procedures and QC steps to check for unspecific fluctuations that arise from the lack of standardized criteria in the collection or handling of the samples (preanalytical factors).We propose our methodology as a reference for the development of clinical-grade blood tests on the basis of miRNA detection.
PubMed | University of Milan Bicocca, European Institute of Oncology and University of Milan
Type: Journal Article | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2016
Although tumor-infiltrating lymphocytes (TILs) have been associated with a favorable prognosis in triple-negative breast cancer (TNBC) patients, this marker is not currently considered robust enough for entering the clinical practice. In the present study, we assessed the clinical validity of the guidelines recently issued by the International TIL Working Group in a large retrospective series of well-annotated TNBC patients.TILs were evaluated in all the full-face H&E sections from 897 consecutive TNBC (i.e. tumors with <1% of ER and PgR immunoreactivity and absence of HER2 overexpression or amplification) patients diagnosed and treated at the European Institute of Oncology between 1995 and 2010 (median follow-up 8.2 years, range 6 months to 18 years). All mononuclear cells were evaluated in the stromal area within the borders of the invasive tumor, reported as a percentage value and treated as a continuous variable in survival analysis.The median percentage of TILs was 20%, and 21.9% of the cases had 50% (lymphocyte predominant breast cancer, LPBC) TILs. At univariable survival analysis, TILs were a significant predictor of better disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS) (P < 0.0001). Multivariable analysis confirmed that each 10% increase in TILs strongly predicted better survival, independent of patients age, lymph node status, tumor size, histological grade, peritumoral vascular invasion and Ki-67 labeling index. Patients with LPBC had a 10-year survival rate of 71%, 84% and 96% for DFS, DDFS and OS, respectively. Stratified analysis revealed a positive correlation between TILs and OS across all the subgroups analyzed.Our data support the analytical validity of the recently issued TILs evaluation guidelines in the clinical practice.
News Article | December 12, 2016
Patients with advanced non-small-cell lung cancer survive four months longer with fewer side effects on an immunotherapy drug called atezolizumab compared to chemotherapy, according to a phase 3 clinical trial published in The Lancet. The trial enrolled 1225 advanced non-small-cell lung cancer patients who have no more treatment options, but this study used an early analysis of the first 850 patients from the trial. Half of the group were given atezolizumab and the other half were given docetaxel chemotherapy, which is the standard treatment for advanced non-small-cell lung cancer. Patients given atezolizumab - a drug that blocks the programmed death ligand 1 (PD-L1) protein - survived for an average of 13.8 months, compared with 9.6 months for those on chemotherapy. As well as the benefits in survival, atezolizumab also had fewer side effects than chemotherapy with 14.8% (90 of 609) of those given the drug having grade three or four side effects compared with 42.7% (247 of 578) of those given chemotherapy. However, 46 (of 609, 7.6%) of the patients given atezolizumab still gave up treatment due to side effects, as well as 108 (of 578 patients, 18.7%) of those on chemotherapy. "Lung cancer is the most common cancer affecting 1.8 million people each year worldwide. It is also the leading cause of cancer death worldwide and survival remains stubbornly low. Recently, important advances in the treatment of the disease have come from immunotherapies that target the PD-L1 and PD-1 pathway," said Dr Achim Rittmeyer, lead author, University Goettingen, Germany. "Atezolizumab reinvigorates patients' immune systems against cancer, and our trial has shown that this has significant results for their survival."  In the trial the researchers also studied the amount of PD-L1 protein on the patients' cancer and immune cells and how long patients survived for on each treatment. They found that the drug worked best for patients with the highest levels of the PD-L1 protein on their cells - more than doubling survival compared with those given chemotherapy (20.5 months compared with 8.9 months overall survival) - but still increased survival for those with little to no levels of the protein by three and a half months (12.6 compared with 8.9 months overall survival). "This is the first phase 3 trial of a PD-L1-directed immunotherapy in lung cancer. The fact that it improves survival in patients with all categories of PD-L1 expression is highly encouraging and adds to the already known benefits of immunotherapy in lung cancer." said Dr David Gandara, senior author, UC Davis Comprehensive Cancer Center, USA.  Other immunotherapies for non-small-cell lung cancer, such as nivolumab and pembrolizumab, are designed to block PD-L1's counterpart, the programmed cell death protein 1 (PD-1) which is located on the immune cell surface. Normally the PD-L1 and PD-1 proteins signal to one another to activate the immune system to attack tumours. It's thought that the extra PD-L1 protein on some cancer cells' surfaces helps them hide from the immune system, meaning it cannot find and kill cancer cells as usual. But by blocking the extra PD-L1 protein, atezolizumab may unveil the cells to the immune system so they can be attacked and destroyed. The study is the first phase 3 trial of a PD-L1 inhibitor drug and has shown longer survival than trials of PD-1 inhibitors. The authors note that the trial was 'open label', meaning that patients and doctors knew whether or not they were being given immunotherapy. In addition, after the study treatment finished some (17%) of those given chemotherapy on the trial were prescribed another immunotherapy drug (mostly nivolumab) by their own doctor. This could have increased survival in the chemotherapy group, meaning that the difference between two groups may be greater than shown in this study. Writing in a linked Comment, Professor Elisabeth Quoix, Hôpitaux Universitaires de Strasbourg, France, said: "After decades of disappointments with non-specific vaccines or more recently tumor associated antigen specific vaccines, immunotherapy with antibodies that target the PD-L1 and PD-1 pathway have emerged as a major therapeutic breakthrough. This treatment improves the prognosis of patients with non-small-cell lung cancer that cannot benefit from targeted therapies... The time in which chemotherapy will no more be the mainstay of treatment of metastatic non-small-cell lung cancer is perhaps not so far away. Nevertheless... Several points need to be clarified, such as the optimum therapeutic schedule and the optimum duration of treatment, to limit treatment costs. Additionally combinations of different immunotherapies might be of interest." The study was funded by F. Hoffman-La Roche Ltd and Genentech Ltd.. It was conducted by scientists from Lungenfachklinik Immenhausen, Aix Marseille Universite, Sungkyunkwan University School of Medicine, Seconda Università degli Studi di Napoli, Asklepios Fachkliniken München-Gauting, Karmanos Cancer Institute/Wayne State University, Aichi Cancer Center Hospital, Institute M. Sklodowska-Curie, Hospital Regional Universitario Carlos Haya, AOU San Gerardo, Minnesota Oncology, Southern California Permanente Medical Group, PUCRS School of Medicine, University of California, Centro Internacional de Estudios Clinicos, European Institute of Oncology, Istanbul University Cerrahpasa Medical Faculty Hospital, Seoul National University Bundang Hospital, Genentech Inc. and UC Davis Comprehensive Cancer Center. A declaration of interests is available in the Article. [ 1] Quote direct from author and cannot be found in the text of the Article. IF YOU WISH TO PROVIDE A LINK FOR YOUR READERS, PLEASE USE THE FOLLOWING, WHICH WILL GO LIVE AT THE TIME THE EMBARGO LIFTS: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32517-X/fulltext
PubMed | European Institute of Oncology, Italian National Cancer Institute and University of Milan
Type: Journal Article | Journal: Future oncology (London, England) | Year: 2016
To shed light on the clinical role of HER2 status in serum as extracellular domain (ECD) and corresponding circulating tumor cells (CTCs) in metastatic breast cancer patients.68 patients were analyzed. Serum HER2 was determined by ADVIA Centaur() Serum HER2 test. CellSearch System was performed for CTC quantification.HER2 was overexpressed in 21 primary tumors. In total, 19 patients had ECD >15 ng/ml (the cut-off used), 48 patients had at least one CTC. ECD positivity was associated with CTC number (p = 0.01), HER2-positive CTC (p = 0.01) and the ratio HER2-positive CTC/total CTC (p = 0.02). ECD was not associated with survival.ECD in combination with HER2 CTC status would deserve further investigation in larger series for addressing its putative prognostic relevance.
PubMed | Instituto Nazionale Tumori Fondazione G Pascale, Regina Elena Cancer Institute, Scientific Institute of Romagna, Papa Giovanni XXIII Hospital and 7 more.
Type: Journal Article | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2016
Clinical responses to ipilimumab are variable in terms of onset, magnitude and duration. Upfront identification of patients who are more likely or unlikely to benefit from treatment is a major need.Prospectively collected data from 720 advanced melanoma patients treated with ipilimumab 3 mg/kg within the Italian expanded access program were analyzed. The derived neutrophil-to-lymphocyte ratio (dNLR) was calculated from baseline peripheral blood cell counts, and receiver operating characteristic curve was used to evaluate the best cutoff for this marker. Patients were stratified according to dichotomized baseline absolute neutrophil counts (ANC), dNLR and their combination. The prognostic values of ANC and dNLR for survival were assessed using multivariate Cox proportional hazard models. A subgroup analysis including LDH in the models was also carried out.The median follow-up was 16.5 months. The optimal cutoff for dNLR was 3. Baseline ANC and dNLR were significantly associated with the outcome of ipilimumab-treated melanoma patients, in terms of disease progression and death (P < 0.0001 for all). Furthermore, for each elevated variable, prognosis worsened. Patients with both ANC 7500 and dNLR 3 had a significantly and independently increased risk of death [hazard ratio(HR) = 5.76; 95% confidence interval (CI) 4.29-7.75] and of progression (HR = 4.10; 95% CI 3.08-5.46) compared with patients with both lower ANC and dNLR. Patients with one of the two factors elevated displayed an intermediate risk of progression and death. The 1- and 2-year survival rates were 2% and 0%, respectively, for patients with ANC 7500 and dNLR 3, and 43% and 24%, respectively, for patients with both lower ANC and dNLR.Although these findings need to be confirmed and validated, we suggest that a neutrophil-based index may help risk-group stratification and assist disease-management strategies. Furthermore, the potential predictive value of this index for response to ipilimumab should be investigated in randomized clinical trials.
PubMed | European Institute of Oncology, Italian Institute of Technology, Italian National Cancer Institute and University of Milan
Type: Journal Article | Journal: Molecular & cellular proteomics : MCP | Year: 2016
Histone post-translational modifications (hPTMs) generate a complex combinatorial code that has been implicated with various pathologies, including cancer. Dissecting such a code in physiological and diseased states may be exploited for epigenetic biomarker discovery, but hPTM analysis in clinical samples has been hindered by technical limitations. Here, we developed a method (PAThology tissue analysis of Histones by Mass Spectrometry - PAT-H-MS) that allows to perform a comprehensive, unbiased and quantitative MS-analysis of hPTM patterns on formalin-fixed paraffin-embedded (FFPE) samples. In pairwise comparisons, histone extracted from formalin-fixed paraffin-embedded tissues showed patterns similar to fresh frozen samples for 24 differentially modified peptides from histone H3. In addition, when coupled with a histone-focused version of the super-SILAC approach, this method allows the accurate quantification of modification changes among breast cancer patient samples. As an initial application of the PAThology tissue analysis of Histones by Mass Spectrometry method, we analyzed breast cancer samples, revealing significant changes in histone H3 methylation patterns among Luminal A-like and Triple Negative disease subtypes. These results pave the way for retrospective epigenetic studies that combine the power of MS-based hPTM analysis with the extensive clinical information associated with formalin-fixed paraffin-embedded archives.
PubMed | European Institute of Oncology
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016
2006 Background: QT interval prolongation associated with torsades de pointes (TdP) has been a common cause of withdrawal from the market for several promising drugs. We determined the degree of QT prolongation in patients treated within a phase I study with a thioxanthone derivative known to have arrhythmogenic potential.Clinical data and serial ECGs from 31 patients with advanced tumors who received 86 courses of investigational drug were prospectively reviewed. The drug has been administered intravenously over 24 hours every 3 weeks. Patients have been on a 24 hour Holter monitor until 24 hours after infusion was complete. Three baseline ECGs were done and compared to those every 6 hours during therapy and once 6 hours after the infusion was complete. ECGs were read at a central lab according to a standard protocol. All QT measurements were then corrected for heart rate (QTc) using Bazetts formula (QTc = QT interval divided by the square root of the R-R interval).Overall,843 ECG tracings were obtained, all evaluable for analysis. No basal ECG showed significant abnormalities. Prolonged QT intervals developed in 2 patients without clinical symptoms (1 patient had intervals 500 milliseconds).In both cases it was associated with the maximum concentration of the drug. Compared with baseline, the QTc interval was prolonged by 30 to 60 milliseconds in 20% of total tracings, and by more than 60 milliseconds in 2% of ECGs. In patients receiving multiple courses, QTc intervals returned to pretreatment levels before the second course.The assessment of QTc prolongation was a major effort in this study but produced an accurate information about such event. In phase I study such an effort is justified when arrhythmogenicity is suspected. The timing of collection of ECGs should be guided by the available preclinical information about the pharmacokinetic profile of the drug. Nevertheless uncertainty remains regarding the specific relationship between the degree of QT prolongation and the risk of life-threatening arrhythmias. The decision to use the drug ultimately has to be based on an estimation of the perceived risk relative to expected benefits for patients. No significant financial relationships to disclose.
PubMed | Erasmus Medical Center, Wren Laboratories, Yale University and European Institute of Oncology
Type: Journal Article | Journal: Seminars in nuclear medicine | Year: 2016
Peptide receptor radionuclide therapy (PRRT) has been utilized for more than two decades and has been accepted as an effective therapeutic modality in the treatment of inoperable or metastatic gastroenteropancreatic neuroendocrine neoplasms (NENs) or neuroendocrine tumors (NETs). The two most commonly used radiopeptides for PRRT, (90)Y-octreotide and (177)Lu-octreotate, produce disease-control rates of 68%-94%, with progression-free survival rates that compare favorably with chemotherapy, somatostatin analogues, and newer targeted therapies. In addition, biochemical and symptomatic responses are commonly observed. In general, PRRT is well tolerated with only low to moderate toxicity in most individuals. In line with the need to place PRRT in the therapeutic sequence of gastroenteropancreatic NENs, a recently sponsored phase III randomized trial in small intestine NENs treated with (177)Lu-octreotate vs high-dose octreotide long-acting release demonstrated that (177)Lu-octreotate significantly improved progression-free survival. Other strategies that are presently being developed include combinations with targeted therapies or chemotherapy, intra-arterial PRRT, and salvage treatments. Sophisticated molecular tools need to be incorporated into the management strategy to more effectively define therapeutic efficacy and for an early identification of adverse events. The strategy of randomized controlled trials is a key issue to standardize the treatment and establish the position of PRRT in the therapeutic algorithm of NENs.