bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of the colon cancer recurrence score with treatments received in patients with stage II colon cancer: The Clalit Health Services experience.
Authors: Brenner Baruch , Geva Ravit , Beny Alexander , Dror Ygael , Steiner Mariana , Hubert Ayala , Idelevich Efraim , Gluzman Alexander , Purim Ofer , Shacham-Shmueli Einat , Shulman Katerina , Soussan-Gutman Lior , Klang Shmuel , Merling Shahar , Liebermann Nicky
Published: March 2020

e22111

Background: The Oncotype DX Colon Cancer Recurrence Score (RS) is a validated prognosticator in stage II colon cancer following surgery. However, the impact of the RS on daily practice is still unclear. Clalit Health Services(CHS) has reimbursed Oncotype DX colon testing since 1/2011. This prospective study examined the use of the RS and its association with treatment decisions in this setting in Israel. Methods: Eligible patients had stage II colon cancer and testing reimbursed by CHS from 1/2011 to 5/2012. Patient/tumor data and treatment information were gathered prospectively. Data were analyzed using the Chi-squared test. Results: The study included 341 patients of whom 314 had confirmed stage II, T3N0 disease, and were included in the analysis. Median age was 68 years (range: 29-89); 18.2%, 68.5%, and 9.9% had grade 1, 2, and 3 tumors, respectively; 15.3% had colonic obstruction and 5.7% had lymphovascular invasion. Thirty-nine patients (12.4%) had mismatch repair (MMR)-deficient tumors and their samples were not tested further. Of the 275 tested patients, 160 (58.2%), 87 (31.6%), and 27 (9.8%) had low (<30), intermediate (30-40), and high (>40) RS, respectively (1 patient [0.4%] had no RS due to technical failure of the assay). The grade 3 group had a higher proportion of MMR-deficient tumors than the grade 2 and grade 1 groups (35.5%, 7.9% and 10.5%, respectively, P<.0001). In the MMR-proficient tumors, the proportions of low RS tumors according to grade were 60.8%, 58.1% and 70.0% for grades 1, 2 and 3, respectively (P=0.57). Chemotherapy was administered to 86/314 (27.4%) patients, including 3/39 (7.7%) in the MMR-deficient, 27/160 (16.9%) in the low, 39/87 (44.8%) in the intermediate, and 17/27 (63.0%) in the high RS groups. The most commonly used regimen was capecitabine monotherapy (61/86 treated patients, 70.9%). The differences in the proportions of patients receiving chemotherapy between the MMR-deficient, low, intermediate, and high RS groups were significant (P<.0001). Conclusions: Our findings suggest that the RS results and MMR-deficient status are significantly associated with treatment decisions in stage II colon cancer patients in Israel.
Chemotherapy selection by gene expression profiling (MAGE) in resistant/refractory (R/R) patients with solid tumors: A feasibility study.
Authors: Rebollo Joseba , Gonzalez-Manzano Ramon , Fernandez-Morejon Francisco J. , Rey Severino , Farre Jose , Sureda Manuel , Brugarolas Antonio
Published: March 2020

e22120

Background: Genomic-based profiling of tumors is a promising approach that allows the selection of the optimal chemotherapy regimen minimizing the possibility of futile therapies. Preliminary clinical results by our group showing a 23% response rate were presented at ASCO’12 (abstract 3,064). However, RNA isolation is a challenging technical step that requires a high quality specimen and takes 2-4 weeks interval to be finished. For this reason we analyzed the feasibility conditions in our series. Methods: Patients (pts) with R/R solid tumors had immediately frozen biopsies, underwent RNA isolation and quality validation after a pathologic confirmation of viable tumor in more than 30% of the sample. Results: From August 2010 to December 2012, 138 patients accepted the MAGE chemotherapy profiling. The median time from biopsy to MAGE analysis has been 4 weeks (ranging 2 to 6). In 17 (12%) pts the procedure was aborted for technical reasons. In these cases tumor samples were obtained from liver in 7 pts, local recurrence in 3 pts, soft tissues in 3 pts, peritoneum in 2 pts, and nodes in 2 pts. Reasons for canceling the assay were mainly a very low tumor cells rate (less than 30%) in 10 pts (fibrotic changes in 5 pts and predominance of necrosis in 5 pts), 2 pts with no tumor, 1 pt with a non-radiologically identifiable lesion, 1 pt with radiofrequency deterioration of the specimen and 3 pts with poor quality RNA. Among the remaining 121 pts who completed the procedure only 74 (61.2%) were treated according to the selected chemotherapy agents achieving a clinical benefit rate of 60%. The high attrition rate (38.8%) was due to poor clinical condition, refusal of recommendations and/or short life expectancy. Conclusions: MAGE-based chemotherapy profiling of tumors was feasible to guide antitumor therapy in selected patients. We recommend performing the study in untreated patients or earlier in the course of their disease (i.e. after failure to first line chemotherapy) in patients with a life expectancy of more than 3 months.
Integrin inhibition as a potential target for invasive meningiomas.
Authors: Mawrin Christian , Kirches Elmar , Wilisch-Neumann Anette
Published: March 2020

e22140

Background: Meningiomas are frequent intracranial tumors, which may show high rates of tumor recurrence after surgery. Additionally, a number of meningiomas show aggressive clinical behaviour with significant reduction of patient´s survival. In the present study, the impact of cilengitide, an integrin inhibitor, on migration, proliferation and radiosensitization of meningioma cells was evaluated. Methods: We analyzed integrin expression in tissue microarray samples and the anti-meningioma properties of cilengitide in vitro using different meningioma cell lines including pairs with knockdown of NF2, and tested the substance in subcutaneous and intracranial orthotopic nude mice models. Results: The predominantly expressed integrin in the tumor cells was αvβ5, while αvβ3 was mainly restricted to tumor blood vessels. One µM cilengitide was sufficient to significantly inhibit meningioma cell migration and invasion in vitro. On the other hand, even high doses of the drug resulted in only mildly reduced proliferation/survival of the cells, although the effects on cell survival were improved by irradiation. A daily dosage of up to 75 mg/kg did not affect tumor volumes in both mouse models. However, a combination of 75 mg/kg cilengitide daily and irradiation (2 x 5 Gy) led to a stronger reduction of MRI estimated tumor volumes in the intracranial model (67%, p<0.01), as compared to the corresponding reduction reached by irradiation alone (55%, p<0.05). Conclusions: These data show that the integrin inhibitor has mild cytostatic properties in meningioma cells, but strongly inhibits cell migration/invasion. In combination with radiotherapy it may help to further reduce meningioma tumor recurrence.
The cytotoxicity of select neutrophils in breast cancer patients and the role of chemokines in neutrophil cytotoxicity.
Authors: Comen Elizabeth Anne , Granot Zvika , Blum Brian , Coker Courtney , Shah Riddhi , Koh Eileen , Norton Larry , Benezra Robert
Published: March 2020

e22148

Background: Recent research in murine breast cancer models demonstrates that primary breast tumors can mobilize select neutrophils, which have the unique capacity to inhibit metastatic seeding in the lung through cell-kill mechanisms. (Granot Z et al. Cancer Cell. 2010). In both breast cancer patients and healthy women, we investigated whether neutrophils were cytotoxic to breast cancer cell lines. We also assessed whether serum chemokines were associated with neutrophil cytotoxicity. Methods: Neutrophils were purified from the blood of 59 randomly selected newly diagnosed pre-operative breast cancer patients without evidence of metastatic disease, 50 metastatic breast cancer patients, 15 DCIS patients, and 45 healthy female volunteers with no history of cancer. Cytotoxicity was evaluated by incubating neutrophils with luciferase labeled MDA-MB-231 cells. Luciferase activity was measured as a reflection of % cytotoxicity. Serum was also isolated from breast cancer patients and healthy volunteers. Millipore Milliplex Human Cytokine Plex Kit was used to assess the concentration of 42 different chemokines in each of the serum samples. Results: In comparison to healthy volunteers whose mean neutrophil cytotoxicity to MDA-MB-231 cells was 6.5%, pre-operative breast cancer patients demonstrated a mean neutrophil cytotoxicity of 13.4%, p<0.0001, metastatic patients mean neutrophil cytotoxicity was 19.4%, p <0.003 and DCIS patients had a mean neutrophil cytotoxicity of 11.7%. p <0.01. By Kruskal-Wallist test, the relative concentrations of three chemokines, Il.1a, MCP.1 and TNF-a, were found to have a statistically significant association with neutrophil cytotoxicity (p-value: 0.005, 0.002, 0.0005 respectively). Conclusions: Our work demonstrates the cytotoxic role of select neutrophils in the peripheral blood of breast cancer patients as contrasted with neutrophils from healthy women. We further demonstrate that select chemokines appear to be correlated with neutrophil cytotoxicity, in varying concentrations. Further studies are needed to evaluate the prognostic and therapeutic role of cytotoxic neutrophils as well as the role of chemokines in neutrophil cytotoxicity.
Imaging biomarker in phase I trials: DCE-US and early evaluation of antiangiogenic treatments.
Authors: Cohen Romain , Koscielny Serge , Soria Jean-Charles , Armand Jean-Pierre , Benatsou Baya , Lassau Nathalie
Published: March 2020

e22153

Background: The French prospective STIC study (Support for Innovative and Expensive Techniques) of dynamic contrast enhanced-ultrasonography (DCE-US) with quantification for evaluation of anti-angiogenic treatments showed that a decrease of 40% of AUC is predictive of response in 539 patients treated with approval drugs. The objective was to evaluate the decrease of AUC DCE-US at one month as a predictive imaging biomarker for time to progression (TTP) in phase I trials using anti-angiogenic agents. Methods: Patients included in phase I in our institution from 2007 and evaluated with DCE-US were retrospectively reviewed. Patients were evaluated at baseline and 1 month with the same standardized methodology: a bolus injection of contrast medium, 3 minutes of recorded raw linear data with 4 frames per second and the quantification using ESFUMB guidelines. All data were prospectively stored in a centralized database. TTP was calculated according to RECIST criteria and clinic. A decrease of more than 40% of AUC at one month was challenged to be predictive of TTP. Results: In the preliminary results concerning 26 patients, 6 had a decrease of more than 40% of AUC at one month with a median TTP of 5.5 months. The 20 others without a strong decrease of AUC had a TTP less than 2 months. The decrease of AUC was correlated to TTP (p=0.004). Eighty one supplementary phase I patients are under radiological blind review and will be included for presentation at ASCO. Conclusions: The decrease of more than 40% of AUC at one month could be a predictive biomarker of response to anti-angiogenic treatments in phase I. The final results will be presented with 107 patients. Considering the toxicity risk for the patients and the cost of anti-angiogenic drugs, such a simple and cheap imaging biomarker should be considered to maintain or not the treatment after US evaluation of the first cycle.
Challenges with the ODAC-proposed independent audit of site investigator assessments.
Authors: Bohnsack Oliver , Schmid Annette Maria , Chen Liddy , Chandler Barbara
Published: March 2020

e22161

Background: The ODAC (Oncologic Drug Advisory Committee) Meeting, July 24th, 2012, on “Evaluation of Radiologic Review of Progression-free Survival in Non-hematologic Malignancies” discussed the merits of implementing an audit process of the investigator assessments in certain oncology trials with PFS endpoint instead of a full Blinded Independent Central Review (BICR) of all cases. The discussion centered around two potential methods (Dodd et al., 2008, 2011 and Amit et al., 2011) – their methods aimed to reduce the risk of informative censoring based on site central discordance, streamline trial conduct and provide cost savings. Both methods provide novel and interesting approaches. However, based on logistical and especially statistical challenges we found that both proposed methods in their current form can not achieve either goal of reducing cost, complexity, time and data censoring challenges inherent in the BICR process. Methods: This paper criticially evaluate the proposed methods and challenge the proposed processes and provide detailed explanations to obstacles inherent logistically, timewise, statistically, operationally. Results: Both of the proposed methods increase the complexity of conducting Oncology trials. As such the study duration will not be shortened but rather extended in certain scenarios. The statistical consequences of a discrepancy rate between Local Evaluations (LE) and BICR are not fully foreseeable and not defined. Operationally, both sponsor and imaging CRO need to implement new and forego well established processes, increasing risk, complexity and the chance for errors. Conclusions: This paper gives examples why the proposed methods are not suitable in their current form to be implemented in Oncology trials and rather put sponsors and study data at risk.
Peripheral blood microRNAs expression profile: A fingerprint for metastatic prostate cancer.
Authors: Medina Villaamil Vanessa , Aparicio Guadalupe , Santamarina Cainzos Isabel , Gomez-Veiga Francisco , Valladares Ayerbes Manuel , Quindós Varela Maria , Antón Aparicio Luis M.
Published: March 2020

e22171

Background: We previously have studied differentially microRNA expression levels related to hormone refractory and sensitive prostate cancer cell lines (VCap and LNCap respectively). Now, we investigated circulating miRNAs differentially expressed between metastatic prostate adenocarcinomas (mPA) and healthy controls (HC) that may serve as novel diagnostic and/or prognosis markers. Methods: Using SYBR-green-based custom microRNA RT-qPCR arrays technology (Exiqon), we compared the expression levels of miRNAs in blood samples from 18 HC and 48 mPA. Results: Among a panel of 92 candidates we found 41 underexpressed (UE) and 8 overexpressed (OE) miRNAs. The level of significance was p<0.05. Conclusions: Among the UE miRNAs are miR-203 and 129 which regulate a cohort of metastatic genes. Among the OE is miR-200a, a member of miR-200 family which directly targeted β-catenin mRNA and miR-135b which induce invasion and distant metastasis. The knowledge of miRNAs involved in mPA progression could provide us a profile that could identify patients for adjuvant therapy or even propose new target drugs to avoid disease progression or treat mPA. Our group is actively involved in the study of selected OE miRNAs for their potential as circulating markers for mPA. [Table: see text]
A prospective registry study assessing decision impact and patient outcomes following gene-expression profiling for tumor-site origin.
Authors: Degtiar Irina , Pillai Raji , Colvin Gerald , Shtivelband Mikhail , Li Qianyi , Henner William David , Becker Shawn , Hornberger John C.
Published: March 2020

e22172

Background: A retrospective registry study has shown that gene-expression profiling (GEP) of the tissue of origin (Pathwork Tissue of Origin Test) of metastatic or poorly differentiated cancer changes the working diagnosis and management for the majority of patients. The FDA-cleared GEP test determines similarity of tumors of uncertain origin to gene expression patterns representing 60 morphologies in 15 cancer types. Inability to identify cancer primary sites presents challenges for patient treatment, outcomes, and prognosis. This study aims to prospectively assess impact of GEP on physician decisions and patient outcomes. Methods: A prospective, observational study is examining GEP’s impact on treatment changes and outcomes in adult patients with difficult-to-diagnose cancers. The study is assessing changes in diagnosis, management, oncologist confidence and perception of the test’s clinical utility, survival, therapy response, and other outcomes over 2 years of follow-up. Results before and after GEP are presented here for 18 patients. The study is designed to enroll 300 patients overall. Results: The primary working diagnosis changed for 37% of patients: 4 whose physicians obtained a working diagnosis while previously not having a tissue-specific diagnosis, and 3 for whom the primary diagnosis changed. After GEP, all patients had a working diagnosis. At least one aspect of management plans changed for 65% patients after GEP. Chemotherapy was ordered for 2 more patients and the regimen changed for 3 others; surgery was performed for 4 fewer, radiation for 1 fewer, and hospice for 2 more patients. After obtaining results from GEP, 58% of the treating oncologists “agreed” or “strongly agreed” that they were confident in both their diagnosis and treatment. Seventy-two percent believed that their changes in management would lead to improvement in at least one outcome (survival, response rate, time to relapse, quality of life, or patient anxiety). Conclusions: Current results of this prospective study are consistent with results of the prior retrospective study: GEP significantly changed and improved physician confidence in their diagnosis and treatment. Clinical trial information: NCT01649453.
Accuracy and clinical utility of in vitro cytometric profiling to personalize chemotherapy: Preliminary findings of a systematic review and meta-analysis.
Authors: Apfel Christian , Souza Kimberly , Hornuss Cyrill , Weisenthal Larry , Nagourney Robert Alan
Published: March 2020

e22188

Background: Cytometric analysis, or in-vitro functional profiling, has been developed as a method to predict tumor response to different drugs with the premise to personalize chemotherapy and improve patient outcomes. Methods: We performed a systematic review and a meta-analysis a) of correlative studies using cytometric profiling that reported diagnostic accuracy (sensitivity and specificity) and b) of effectiveness studies comparing patient outcomes when allocated to treatment guided by a cytometric assay versus population-based standard of care. We used Meta-DiSc software to find pooled sensitivity and specificity and analyze the summary receiver operating characteristic (sROC) curve and used Review Manager 5.1 to generate forest plots on overall tumor response (50% or greater decrease in tumor diameter) and on 1-year overall survival. Results: We included 28 mostly retrospective trials (n=664) reporting accuracy data and 15 prospective trials (n=1917) reporting therapeutic efficacy data. The accuracy of correlative study revealed an overall sensitivity of 0.922 (95% confidence interval 0.888 to 0.948), specificity of 0.724 (95% CI 0.669 to 0.774) and an area under the sROC curve of 0.893 (SE=0.023, p<0.001). Studies comparing the clinical utility revealed a two-fold overall tumor response for an assay-guided therapy versus standard of care therapy (odds ratio 2.04, 95% CI 1.62 to 2.57, p<0.001). Similarly, patients who received assay-guided therapy compared to those who received standard of care or physician’s choice had a significantly higher 1-year survival rate (OR 1.44, 95% CI 1.06 to 1.95, p=0.02). Conclusions: Despite various limitations of individual studies, the aggregate and fairly consistent evidence of these data suggests cytometric profiling to be accurate, to improve overall tumor response, and to increase 1-year patient survival. Given the enormous potential for our society, a well-designed and sufficiently-powered randomized controlled trial is urgently needed to validate these results.
Inhibition of the receptor tyrosine kinase ROR1 by anti-ROR1 monoclonal antibodies and siRNA induced apoptosis of melanoma cells.
Authors: Hojat Farsangi Mohammad , Ghaemimanesh Fatemeh , Daneshmanesh Amir Hossein , Bayat Ali-Ahmad , Mahmoudian Jafar , Jeddi-Tehrani Mahmood , Mellstedt Hakan
Published: March 2020

e22198

Background: The receptor tyrosine kinase ROR1 has important functions during normal embryogenesis. It is overexpressed and of importance for the survival of different malignancies, including lung adenocarcinoma, breast cancer and chronic lymphocytic leukemia (CLL). ROR1 inhibition in CLL cells and cell lines with high expression of ROR1 induced specific apoptosis of the cells. There is however little information on the expression and function of ROR1 in melanoma. Here, we investigated ROR1 expression, phosphorylation and the effects of anti-ROR1 monoclonal antibodies (mAbs) and ROR1 suppressing siRNA on seven melanoma cell lines. Methods: ROR1 expression and phosphorylation was analysed in a series of malignant melanoma cell lines using RT-PCR, immunocytochemistry, flow cytometry and western blot. Annexin V/PI staining, MTT assay, PARP and caspase 8 and 9 cleavage as well as MCL-1 protein were used for detection of apoptosis induced by anti-ROR1 mAbs. The cytotoxic effects of anti-ROR1 mAbs were evaluated in the absence or presence of complement (CDC) or immune effector cells (ADCC). Transfection of melanoma cell lines using ROR1 siRNA was used for gene silencing. Results: ROR1 was shown to be overexpressed to a varying degree at protein level. ROR1 was phosphorylated at tyrosine and serine residues. Three out of four anti-ROR1 mAbs (clones 3H9, 5F1 and 1A8) induced a significant direct apoptosis of the ESTDAB049, ESTDAB112, DFW and A375 cell lines as well as cell death in the presence of complement or immune effector cells. ESTDAB081 and 094 cell lines were resistant to direct apoptosis of the four anti-ROR1 mAbs alone compared to the other melanoma cell lines, but not to complement dependent cytotoxicity (CDC) and antibody dependent cell mediated cytotoxicity (ADCC). ROR1 siRNA transfection induced down-regulation of the ROR1 expression both at the mRNA and protein levels proceeded by a significant apoptosis of the melanoma cells. Conclusions: The results indicate that ROR1 may play an important role in the survival of melanoma cells. The surface expression of ROR1 on melanoma cells may support the notion that ROR1 might be a suitable targeted for mAb therapy.
Evaluation of dickkopf-1 (Dkk-1) expression in non-small cell lung, esophageal, and gastric cancer.
Authors: Park Haeseong , Poklepovic Andrew Stewart , Almenara Jorge , Sirard Cynthia , Qian Junqi , Powers Celeste N. , Grossman Steven R.
Published: March 2020

e22203

Background: Dkk-1 is an inhibitor of the canonical Wnt/β-catenin signaling pathway. Inhibition of Wnt pathway results in the stabilization of β-catenin, leading to target gene expression such as cyclin D1, c-myc, VEGF and other factors associated with cell growth. Elevated levels of serum Dkk-1 in a variety of tumor types are well established, and are hypothesized to have a negative prognostic value. Tumor tissue expression of Dkk-1 has not been systematically examined. We evaluated Dkk-1 expression in various tumors. Methods: Utilizing an anonymous banked tumor repository, we identified 119 patient samples (NSCLC (squamous, n=19; adenocarcinoma, n=47), esophageal (squamous, n=15; adenocarcinoma, n=17) and gastric (n=20)). Immunohistochemical (IHC) staining was performed using commercially available antibodies. One pathologist evaluated all slides using IHC staining quantification on a 4-point scale (0, 1+, 2+, 3+). Results: Dkk-1 expression is more pronounced in tumor tissues than peritumoral normal tissues of lung and esophagus. Unexpectedly, Dkk-1 expression is seen in two staining patterns, perinuclear and cytoplasmic that varied by primary location and histology. Conclusions: Elevated Dkk-1 expression is demonstrated in lung, esophageal and gastric cancer regardless of histology. All except squamous cell lung express perinuclear Dkk-1 more frequently than cytoplasmic pattern. Additional studies are needed to understand significance of these patterns and potentially define Dkk-1 as a novel therapeutic target in these malignancies. [Table: see text]
Period 2 (PER-2) biologic profile in advanced colorectal cancer (ACC) patients (pts).
Authors: Melucci Elisa , Torsello Angela , Ruzzo Annamaria , Sperduti Isabella , Giacomini Elisa , Zeuli Massimo , Gelibter Alain , Ferraresi Virginia , Diodoro Maria G. , Magnani Mauro , Mottolese Marcella , Cognetti Francesco , Garufi Carlo ,   AIRC Project 11770
Published: March 2020

e22206

Background: Circadian rhythms modulated by clock genes expression as the Period genes (PER-1, PER-2, PER-3) are involved in cancer growth. PER-2 loss in colorectal cancer cell lines and in animal models increases tumorigenesis by β-catenin and cyclin D activation (Wood P, Cancer Res 2008). PER-2 loss in ACC pts was linked to a worse prognosis (Iacobelli S, ASCO 2008). The aim of our study was to identify a PER-2 biological profile related to proliferative indexes and treatment activity. Moreover miRNA related to clock genes were studied as miR-219, target of CLOCK and B-MAL1, miR-206 which affect mammalian circadian clock, miR-132 acting at the SCN level. Methods: We retrospectively evaluated 59 ACC pts, treated with first line chronomodulated triplet combination (Irinotecan+Oxaliplatin+Folinic Acid+5-Fluorouracil) ± Cetuximab. Immunostaining for PER-2, EGFR, ERβ1, ERβ2, Cyclin D1, β-catenin, K-RAS and B-RAF mutations, miRNAs -206, -132, -192, -194, and -219 evaluated on FFPE tumor tissues and their expression levels by quantitative PCR were examined. Results: Clinical data: M/F 32/27; median age 57 y; liver involvment 53%; Cetuximab use: 38%; liver resection: 42%; response to first line chemotherapy: PR 61%, SD 25.4%, PD 10.2%; pts 2.4% not evaluable. Biological data: PER-2 negative (-) /positive (+) 44/56%; EGFR (+)/(-) 54/46%; KRAS wt/mut 75/25%; ERβ1 (-)/(+) 36/65%; ERβ2 (-)/(+) 39/61%; Cyclin D1 (-)/(+) 51/49%; β-catenin(-)/(+) 31/69%. PER-2(-) patients expressed more frequently EGFR (73%) (p>0.0001), ERβ1 (77%) (p=0.07), ERβ2 (88.5%) (p>0.0001), Cyclin D1 (69.2%) (p=0.06) and β-catenin (84.6%) (p=0.02). PER-2(-) was also associated to high miR-206, miR-192 and miR-219 expression. Explorative multiple correspondence analysis showed response to chemotherapy related to a profile including PER-2 (+), EGFR (-), ERβ1 (-), ERβ2 (-), β-catenin (-) and low expression of miR-206. Conclusions: Our data confirmed that: 1) PER-2 loss was associated to activation of cell proliferation confirming in vitro data; 2) PER-2 expression was linked to negative activation of cell proliferation, low miR-206 expression and response to chemotherapy.
Association of cyclin D2 downregulation with adverse prognostic factors and survival: Analysis of D-type cyclins, cyclin E1, p27, and ki-67 mRNA in breast carcinomas.
Authors: Brizova Helena , Mrhalova Marcela , Kodet Roman
Published: March 2020

e22208

Background: In a normal mammary gland D-type and E1 cyclins play a significant role in the cell cycle control. Not surprisingly, they are considered to have an oncogenic potential and belong among the most commonly overexpressed genes in breast cancer. Besides, cyclin D2 overexpression is associated with an inhibition of cyclin D1 phosphorylation and with an increase of the p27 inhibitor. Such a complex cell cycle regulation is realized at the quantitative level and results in the proliferation activity control. Therefore, we analyzed the molecules involved in the cell cycle regulation together with the proliferation marker Ki-67 at the quantitative level. Methods: We examined cyclin D1, D2, D3, E1, and p27 and Ki-67 mRNA level by qRT-PCR in 95 fresh frozen invasive ductal breast carcinomas and in 15 non-neoplastic breast tissues. In patients with the carcinoma we correlated the mRNA levels with the ERBB-2 positivity, estrogen and progesterone receptor status, proliferation rate, cyclin D1 protein expression, CCDN1 gene amplification, grade, lymph node status, tumor size and age at diagnosis. We looked for a correlation with overall survival and time to event in 70 patients with available long term follow-up data. Results: The only significant association found in this analysis related to cyclin D2. In comparison with non-neoplastic controls we observed cyclin D2 mRNA down-regulation in breast carcinomas and it was inversely correlated with a higher tumor grade and its greater size, which are considered as parameters related to a less favorable prognosis. Moreover, cyclin D2 mRNA down-regulation together with cyclin D1 and D3 up-regulation revealed a significant association with decreased overall survival and time to event in multivariate analysis. Conclusions: The data indicate that down-regulated cyclin D2 mRNA correlates with a greater malignant potential of breast carcinoma. Thus, establishing cyclin D2 mRNA level may be used as a prognostically relevant investigation and along with other prognostically related data it has a potential in helping to identify patients with an adverse prognosis. Support CZ.2.16/3.1.00/24022 and 00064203.
Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3).
Authors: Heinemann Volker , Fischer von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Vehling-Kaiser Ursula , Al-Batran Salah-Eddin , Heintges Tobias , Lerchenmueller Juergen , Kahl Christoph , Seipelt Gernot , Kullmann Frank , Stauch Martina , Scheithauer Werner , Hielscher Joerg , Scholz Michael , Mueller Sebastian , Schaefer Britta , Modest Dominik Paul , Jung Andreas , Stintzing Sebastian
Published: March 2020

LBA3506

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday June, 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Phase III trial of a 3-weekly versus 5-weekly schedule of S-1 plus cisplatin (SP) combination chemotherapy for first-line treatment of advanced gastric cancer (AGC): SOS study.
Authors: Ryu Min-Hee , Baba Eishi , Lee Kyung Hee , Boku Narikazu , Park Young Iee , Hyodo Ichinosuke , Nam Byung-Ho , Esaki Taito , Ryoo Baek-Yeol , Song Eun-Kee , Cho Sanghee , Lee Sung Sook , Kang Won Ki , Yang Sung Hyun , Zang Dae Young , Shin Dong Bok , Park Sook Ryun , Shinozaki Katsunori , Takano Toshimi , Kang Yoon-Koo ,   on behalf of SOS Investigators
Published: March 2020

LBA4024

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Duration of androgen deprivation therapy in high-risk prostate cancer: A randomized trial.
Authors: Nabid Abdenour , Carrier Nathalie , Martin André-Guy , Bahary Jean-Paul , Souhami Luis , Duclos Marie , Vincent Francois , Vass Sylvie , Bahoric Boris , Archambault Robert , Lemaire Céline
Published: March 2020

LBA4510

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Interim analysis of The Spanish Lung Cancer Group (SLCG) BRCA1-RAP80 Expression Customization (BREC) randomized phase III trial of customized therapy in advanced non-small-cell lung cancer (NSCLC) patients (p) (NCT00617656/GECP-BREC)
Authors: Moran Teresa , Cobo Manuel , Domine Manuel , Sanchez-Ronco Maria , Bover Isabel , Provencio Mariano , Massuti Bartomeu , Vergnenegre Alain , Lopez-Vivanco Guillermo , Robinet Gilles , Insa Amelia , Majem Margarita , De Las Penas Ramon , Sala María Ángeles , Isla Dolores , Baize Nathalie , Garde Javier , Chaib Imane , Camps Carlos , Rosell Rafael ,   Spanish Lung Cancer Group
Published: March 2020

LBA8002

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Nintedanib (BIBF 1120) plus docetaxel in NSCLC patients progressing after one prior chemotherapy regimen: Results of Lume-Lung 1, a randomized, double-blind, phase III trial.
Authors: Reck Martin , Kaiser Rolf , Mellemgaard Anders , Douillard Jean Yves , Orlov Sergey , Krzakowski Maciej Jerzy , Von Pawel Joachim , Gottfried Maya , Bondarenko Igor , Liao Meilin , Barrueco Jose , Gaschler-Markefski Birgit , Novello Silvia
Published: March 2020

LBA8011

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Alliance A091103: Multicenter phase II study of the angiopoietin-1 and -2 peptibody trebananib for the treatment of angiosarcoma.
Authors: D'Angelo Sandra P. , Mahoney Michelle R. , Van Tine Brian Andrew , Adkins Douglas , Grosse Perdekamp Maria T. , Condy Mercedes M. , Hartley Eliza , Antonescu Cristina R. , Schwartz Gary K. , Tap William D. ,   Alliance Clinical Trials in Oncology Group
Published: March 2020

TPS10592

Background: Angiosarcomas (ASs) are rare, aggressive, malignant endothelial cell tumors that constitute 1% to 2% of all soft tissue sarcomas with 5-year survival of 35%. Cytotoxic agents have demonstrated response rates of about 15%. Gene-array data from MSKCC has revealed up-regulation of endothelial associated genes, including active members of the angiopoietin system e.g., Tie2 and Angiopoietin 2 (Ang2). Trebananib (AMG386) is a novel agent that targets Ang1 and Ang2. We hypothesize that inhibition of angiopoietin 2 with trebananib will be an effective therapy in patients (pts) with AS. Methods: This CTEP sponsored, investigator initiated, multi-center phase II study uses trebananib, in pts with AS having metastatic/unresectable AS and conducted through the Alliance for Clinical Trials in Oncology (Alliance A091103). Pts must have adequate performance status, organ function, and measurable disease (RECIST v1.1). Patients are treated with trebananib 30mg/kg d1, 8, 15, and 22 every 28 days until either progressive disease or unacceptable toxicity. The primary endpoint is objective overall response rate (ORR) via RECIST v1.1. Secondary endpoints include the evaluation of progression-free survival (PFS) and overall survival (OS). Translational objectives include correlation of ORR, PFS and OS with i. baseline and post-treatment expression of Ang2 and Tie2 by immunohistochemistry (IHC), ii. serum levels of Ang1 and Ang2, iii. baseline and post-treatment phospho-receptor tyrosine kinase (p-RTK) status of Tie2, VEGFR-2, PI3K, MEK and MAPK, and iv. mutational status of VEGFR-2 and amplification of MYC/FLT4. A Simon Optimal two-stage phase II study design is used and one confirmed response in the first 12 pts expands enrollment to 25. Pre- and post-treatment biopsies will be performed in up to 10 pts treated at MSKCC. Enrollment began in July 2012. As of January 2013, 7 pts have been recruited. Clinicaltrials.gov#: NCT01623869. Funded by the Alliance Clinical Trials in Oncology. NIH Grant CA-25224. Clinical trial information: NCT01623869.
A randomized, phase II trial of AEZS-108 in chemotherapy refractory triple-negative (ER/PR/HER2-negative) LHRH-R positive metastatic breast cancer.
Authors: Buchholz Stefan , Engel Joerg , Schally Andrew V. , Seitz Stephan , Ortmann Olaf , Emons Guenter , Mahtani Reshma L. , Gluck Stefan , Vogel Charles L. , Montero Alberto J.
Published: March 2020

TPS11124

Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is clinically negative for expression of estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor-2 (HER2). It is characterized by its unique molecular profile, aggressive behavior, distinct patterns of metastasis, and lack of commercially available targeted therapies. Chemotherapy has been the mainstay of treatment for women with TNBC, but this current standard-of-care is suboptimal. AEZS-108 is an LHRH-cytotoxic hybrid drug whose rational design covalently couples the carrier D-Lys6-LHRH (an LHRH agonist) to the cytotoxic doxorubicin radical. Because LHRH receptors are expressed in a majority of TNBC, AEZS-108 represents a novel way to selectively deliver cytotoxic chemotherapy in patients with TNBC via a new therapeutic target. Methods: In this open label randomized two-arm multicenter phase II study, patients will be randomized in a 1:1 ratio into one of the two treatment arms: AEZS-108 (267 mg/m2 every 21 calendar days) [Arm A] or SSC (standard single agent cytotoxic chemotherapy [Arm B]) at discretion of treating oncologist cycled every 21 calendar days. Stratified randomization will be used with number of prior lines of therapies (1-2 vs. >2), ECOG performance status 0-1 vs. 2, and liver metastases (absent vs. present). Analysis of the main study endpoint, TTP, will follow a group sequential design with two interim analyses, including the final analysis. O’Brien Fleming stopping boundaries will be used. The primary endpoint is to evaluate the median time to progression (TTP) of AEZS-108 in patients with chemotherapy resistant advanced TNBC treated with AEZS-108 in relation to patients receiving standard single agent cytotoxic chemotherapy. Secondary endpoints include: overall response, clinical benefit, duration of response, overall survival, toxicity profile and quality of life (QoL). Clinical trial information: NCT01698281.
The ENCHANT-1 trial (NCT01677455): An open label multicenter phase II proof of concept study evaluating first-line ganetespib monotherapy in women with metastatic HER2-positive or triple-negative breast cancer (TNBC).
Authors: Awada Ahmad , Rodriguez Angel Augusto , Kong Anthony , Erban John Kalil , Cortes Javier , Mano Max S. , Perez Edith A. , El Hariry Iman , Vukovic Vojislav M. , Teofilovici Florentina , Yalcin Ilker , Bradley Robert , Cameron David A.
Published: March 2020

TPS1136

Background: Hsp90 is a molecular chaperone protein required for the stabilization and activation of many proteins, referred to as Hsp90 ‘clients’, including those commonly implicated in breast tumorigenesis such as HER2, EGFR, ER, PI3K, AKT, P53 and VEGFR. Ganetespib is a novel triazolone inhibitor of Hsp90 being studied in over 20 clinical trials, with over 700 patients treated to date. Ganetespib is ~50x more potent than 1st-generation Hsp90 inhibitors, and has been well tolerated in clinical trials with a favorable safety profile. Mild to moderate, transient diarrhea is the most common adverse event associated with ganetespib infusion and is manageable with appropriate supportive care. Ganetespib has shown activity in preclinical models of HER2+, ER+/PR+ and triple negative breast cancer (TNBC). In a phase I trial, ganetespib demonstrated single-agent clinical activity in HER2+ disease with an objective response rate (ORR) of 15% and a disease stabilization rate of 46% in heavily pretreated patients. This efficacy-screening study is designed to provide further evidence of ganetespib activity and identify potentially predictive biomarkers in metastatic breast cancer. Methods: The ENCHANT-1 trial is an international, first-line Phase II study in two cohorts of breast cancer patients: Cohort A, HER2 amplified (n=35), and Cohort B, TNBC (n=35). HER2+ patients must have received prior anti-HER2 therapy in the adjuvant setting. Patients are treated with ganetespib at 150 mg/m2 twice weekly on a three out of four-week regimen. Primary endpoint: ORR assessed using RECIST1.1 criteria. Key secondary endpoints include metabolic effects as assessed by PET/CT at week 3. Tumor genetic signature and proteomic profiling are performed on patient’s tumors in an effort to develop biomarkers of response. At the time of submission 6 patients have been enrolled into this study. Clinical trial information: NCT01677455.
Adjuvant phase III trial to compare intense dose-dense adjuvant treatment with EnPC to dose dense, tailored therapy with dtEC-dtD for patients with high-risk early breast cancer (GAIN-2).
Authors: Moebus Volker , Forstbauer Helmut , Wachsmann Grischa , Schneeweiss Andreas , Ober Angelika , von Abel Ekkehard , Krabisch Petra , Hoeffkes Heinz-Gert , Kast Karin , Christensen Bernd , Niedermeier Michael , Deryal Mustafa , Uleer Christoph , Fauster Yvonne , Goehler Thomas , Loibl Sibylle , Nekljudova Valentina , Von Minckwitz Gunter ,   German Breast Group
Published: March 2020

TPS1137

Background: Intense dose-dense (idd) chemotherapy (CT) significantly improves overall survival in breast cancer patients. Two preceding trials explored iddETC vs a dd combination of EC-TX (GAIN) and dtEC-dtD vs conventional dosed FEC-D (Panther). Nab-paclitaxel (nP) provides a better toxicity profile and higher efficacy compared to solvent based taxanes and might be preferred in an idd regimen. Methods: This is a multicenter, prospective, randomized, open-label phase III trial comparing iddEnPC or dtEC-dtD as adjuvant CT. Pts with uni- or bilateral primary high risk node-positive (N+) breast cancer (BC) and centrally confirmed ER/PR/HER2 and Ki-67 status can be included. Luminal A pts are only recruited with N+ ≥4. Randomization to iddEnPC or dtEC-dtD will be stratified by biological subtype defined by hormone receptor, HER2 and Ki-67. The iddEnPC arm will receive epirubicin (150mg/m2) q2w x3 followed by nP (260-330mg/m2, dose to be determined in run-in phase) q2w x3, followed by cyclophosphamide (2g/m2) q2w x3. The dtEC-dtD arm will receive EC (38-120/450-1200 mg/m2) q2w x4 followed after 1 wk rest by docetaxel (60-100mg/m2) q2w x4. GAIN-2 will compare toxicity and efficacy of an idd regimen (EnPC) vs a dd regimen with modification of single doses depending on individual hematological and non-hematological toxicities. Primary objective is invasive disease-free survival (IDFS). Secondary objectives are survival by other definitions, compliance, safety, side effects of taxanes and subgroup analyses (by 0-3, 4-9 or 10+ involved nodes and Ki-67). Efficacy analyses are planned 60 mths after end of accrual, safety interim analyses after 200 and 900 pts have completed CT. It was assumed that dtEC-dtD will achieve a 5-yr IDFS of 75% and ddEnPC will improve IDFS to 79% (HR 0.819) with a power of 80% (α=0.05, ß= 0.2).GAIN-2 is registered under NCT01690702 Results: 75pts were recruited since 1stOct 2012. Recruitment (in total 2886 pts) is planned for 36 mths in 80-100 sites in Germany. Run-in safety data to be presented. Conclusion: GAIN-2 will compare the efficacy of adjuvant iddEnPC and dtEC-dtD in pts with early N+ BC. Clinical trial information: NCT01690702.
MERiDiAN: A phase III, randomized, double-blind study of the efficacy, safety, and associated biomarkers of bevacizumab plus paclitaxel compared with paclitaxel plus placebo, as first-line treatment of patients with HER2-negative metastatic breast cancer.
Authors: Miles David , Faoro Leonardo , Wang Yan V. , O'Shaughnessy Joyce
Published: March 2020

TPS1142^

Background: Bevacizumab (BV), a humanized monoclonal antibody targeting the angiogenic VEGF, has demonstrated activity in patients with metastatic breast cancer (MBC). Plasma VEGF-A levels ([VEGF-A]p) appear to positively correlate with the effect of BV on progression-free survival (PFS) in MBC, metastatic pancreatic, and advanced gastric cancers. The MERiDiAN study will prospectively investigate (1) whether baseline [VEGF-A]ppredict treatment benefit with BV, (2) efficacy of BV with weekly paclitaxel (P), based on previously observed differences in the magnitude of benefit compared with BV + non-P chemotherapies. Methods: MERiDiAN is a global, randomized, double-blind, phase III study enrolling patients with HER2-negative MBC (first patient was enrolled in August 2012). The co-primary endpoints are PFS by investigator assessment in the intent-to-treat (ITT) population, and PFS in the subgroup with high baseline [VEGF-A]p. Secondary endpoints are overall survival (OS), 1-year survival, objective response rate and duration, and safety. Exploratory objectives include assessing the predictive or prognostic potential of blood, DNA and tumor tissue markers, and genetic variants involved in angiogenesis and tumorigenesis, with regard to BV efficacy and safety.Patients will be randomized 1:1 to either P 90 mg/m2 IV weekly (qw) for 3 weeks followed by a 1-week rest and BV 10 mg/kg every 2 weeks (q2w) until disease progression (PD); or P 90 mg/m2IV qw for 3 weeks followed by a 1-week rest and placebo 10 mg/kg q2w until PD. An interim analysis of OS will be performed at the time of the primary PFS analysis. Clinical Trial Registry Number NCT01663727. Clinical trial information: NCT01663727.
Randomized, placebo controlled, phase III trial of low-dose tamoxifen in women with intraepithelial neoplasia.
Authors: Puntoni Matteo , Bonanni Bernardo , D'Aiuto Giuseppe , Ponti Antonio , Paquola Maria Grazia , Cortesi Laura , D'Amico Cosimo , Gulisano Marcella , Cruciani Giorgio , Falcini Fabio , Giardina Giovanni , Cagossi Katia , Regolo Lea , Renne Mariuccia , Canavese Giuseppe , Branchi Daniela , Marra Domenico , Guerrieri-Gonzaga Aliana , Johansson Harriet Ann , De Censi Andrea
Published: March 2020

TPS1610

Background: Breast IntraEpithelial Neoplasia (IEN) is associated with a 8-10 fold increased risk of invasive disease, thus representing an important target for chemoprevention. The NSABP-P1 trial showed that tamoxifen (TAM) at 20 mg/day is associated with a 86% reduction of invasive breast cancer (BC) in women with previous atypical ductal hyperplasia (ADH) (RR=0.14, 95% IC, 0.03-0.47) and with a 56% risk reduction in women with previous LCIS (RR=0.44, 0.16-1.06). However, TAM broad use in chemoprevention has been significantly hampered by the increased risk of endometrial cancer and of venous thromboembolism (VTE). We recently showed that a dose of 5 mg/day does not increase endometrial proliferation, is associated with a decrease of the estrogenic activity of TAM on IGF-I, SHBG and antithrombin-III, and attains at the breast tissue level a concentration 10 times higher than that needed to inhibit cell growth in vitro. The CYP2D6 enzyme mediates oxidation of N-desmethyl tamoxifen to endoxifen, the most active metabolite of TAM. The SNP CYP2D6*4 (1846G>A) allele accounts for 75% of poor metabolizer phenotype which have been associated with a higher risk of a breast event compared to wildtype (Pharmacogenomics J. 2011;11:100-7). Methods: A randomized double-blind placebo-controlled phase III trial to assess the efficacy and safety of 5 mg/day TAM vs. placebo for 3 years in women with previous IEN (LIN 2-3 and ER+ or unknown DIN 1b-3). In Europe TAM is not registered in women with prior DCIS. 1400 women are needed to detect 50% reduction in the incidence of BC in the TAM arm (80% power, 1-sided 5% α error). Secondary endpoints are: incidence of other non-invasive breast disorders, endometrial cancer, clinical bone fractures, cardiovascular events, VTE events, and clinically manifest cataract. Pharmacogenetic endpoints includes the association between CYP2D6 genotype and modulation of biomarkers of TAM efficacy and safety (circulating IGF-I, hormones, mammographic density, endometrial thickness and hot flashes) and clinical events. As of February 5, 2013, 18 enrolment centers have been activated and n=338 women have been randomized. No suspected unexpected serious adverse reactions were registered. Clinical trial information: NCT01357772.