New Line Of Therapy Research Articles

A novel patient-aimed visual tool to aid in decision making in oncology.

21 Background: With up to 15% of Medicare patients receiving chemotherapy during the last two weeks of life, improving specialist-patient communication is a priority. The Help-Hurt Tool (2015) is a very simple patient-language visual aid for decision-making. It consists of two scales, a blue one labeled “from 1 to 5 how much could this therapy help me” and a red one with the same statement ending in “…hurt me”. The tool is held by the specialist and shown to the patient while arrows are moved to a particular point below each scale. That way, two values are given to the patient for the degree of benefit and of harm respectively expected from an offered treatment. Each number corresponds to an outcome in patient-language (i.e. a ‘help’ score of 2 is “small chance of making me feel better...” and of 4: “big chance of making me live at least a year longer”. A ‘hurt’ score of 2 is “likely non-dangerous side effects” and of 5: “likely life threatening therapy”). Methods: Feasibility study in an oncology clinic at an urban area in New York. Adult cancer patients without dementia whose disease had progressed through a previous treatment and were being offered a new line of therapy were enrolled. Results: Thirty encounters were enrolled. The tool was successfully used in 29 of them (96.7%); one patient was confused and could not follow at all. In more than 70% of encounters patients stated that the tool helped them understand their disease and treatments (‘helpful’: 32.3%, ‘very helpful’: 38.7%), and in 90% of encounters patients stated wanting to be approached with a tool like this again. Importantly in 60% of encounters patients were able to recall either the Help or Hurt score, and in 33.3% of encounters both values were perfectly recalled by patients. In 83.3% of encounters oncologists declared that the tool had a positive effect (‘helpful’ (40%) or ‘very helpful’ (43.3%)) in their interactions with the patient. Conclusions: This first-of-its-kind tool is promising for enhancing communication between specialists and patients at the time a therapy is being offered. Future steps for this tool would include a randomized trial to explore if its use can further affect outcomes like use of chemotherapy in the last two weeks of life, earlier hospice enrollment and quality of life, among others.

Mesenchymal stem cells: In vivo therapeutic application ameliorates carbon tetrachloride induced liver fibrosis in rats

BackgroundEgypt has the highest prevalence of hepatitis C virus in the world with infection rate up to 60%, for which liver fibrosis or hepatic carcinoma is the final outcome. Stem cell therapy provides a new hope for hepatic repair instead of traditional treatment, liver transplantation, as it is safer, gives long term engraftment and avoid expensive immunosuppressive drugs and unexpected hazardous effects. AimThis work aimed at determining the therapeutic potential of mesenchymal stem cells (MSC) in hepatic repair as a new line of therapy for liver fibrosis. Methods33 female albino rats were divided into three groups: Group I: 10 rats injected subcutaneously with olive oil, Group II: 13 rats injected with carbon tetrachloride (CCl4) and Group III: 10 rats injected with CCl4 then bone marrow derived MSC from male rats. Blood and liver tissue samples were taken from all rats for biochemical and histological study. ResultsLiver functions for group II rats showed significant deterioration in response to CCl4 in addition to significant histological changes in liver lobules and portal areas. Those parameters tend to be normal in MSC-treated group. Group III rats revealed normalized liver function and histological picture. Meanwhile, most of the pathological lesions were still detected in rats of second group. ConclusionUndifferentiated MSCs have the ability to ameliorate CCl4 induced liver injury in albino rats in terms of liver functions and histological features. So, stem cell therapy can be considered clinically to offer a hope for patients suffering from liver fibrosis.

Etanercept, a TNF-alpha blocker, may improve pregnancy rates after IVF in patients with advanced endometriosis: a pilot study

The elevation of peritoneal fluids’ TNF-α levels may play a role in the pathogenesis of infertility associated with endometriosis. The use of drugs such as etanercept, a TNF-α receptor immunoglobulin fusion protein which inhibits TNF-α activity, showed to reduce the severity of the disease, and the size of endometriotic foci in animal studies. TNF-a blockers were recommended as a possible new line of therapy for endometriosis.

Abstract P4-01-11: Circulating tumor cells (CTCs) detect HER2+ status and phenotypic heterogeneity in metastatic breast cancer (MBC)

Abstract Background Circulating tumor cells (CTCs) are epithelial cells that can be found circulating in the blood of MBC patients and may represent a heterogeneous population including epithelial cells and cancer stem cells (CSC) shed from the tumor. Their detection and enumeration has prognostic significance and can be used for longitudinal monitoring of response to treatment. Recent advances have allowed for the detection of HER2 protein expressing CTCs using the CellSearch™ platform. HER2 expression has been associated with CSCs phenotype in absence of gene amplification (Korkaya et al, Oncogene 2008) and particularly in Luminal B disease (Ithimakin et al, Cancer Res, 2014). We hypothesized that HER2+/CTCs are detectable in patients with MBC irrespective of their HER2 status and this information can be potentially be used for treatment selection. Targeting HER2+ CSCs may result in clinical benefit and improved outcome. Methods This is a prospective analysis of 40 patients with locally advanced or MBC whose blood was analyzed for the baseline detection of CTCs as part of their disease initial evaluation. Blood was drawn for CTC detection on eligible patients at initiation of a new line of therapy; CTCs monitoring was repeated at progression or change in therapy. The 7.5mL of whole blood was collected in a CellSave™ Preservative Tube, and CTC isolation, enumeration and characterization were performed using the FDA-approved CellSearch™ System (Janssen Diagnostics, USA). The CellSearch™ tumor phenotyping reagent HER-2/neu (Fluorescein-conjugated) was used to determine CTC with HER-2/neu expression using the CellTrack™ Analyzer II. Results Most patients in this study had metastatic disease (90%). According to disease subtype, 43% of patients were ER+/HER2- (Luminal A), 17% ER+/HER2+ (Luminal B), 20% ER-/HER2+ (HER2) and 20% ER-/HER2- (TNBC). Moreover, 55% had a clinical diagnosis of Inflammatory Breast Cancer (IBC). Twenty-two patients had CTCs detected (55%), the average number of CTCs was 8.6 (0-135) with a median follow up of two months. Of the patients who had CTCs detected and had HER2+ disease (IHC/FISH), 83% (5/6) had concordance in HER2+ CTCs. Interestingly, in the subset of patients who had HER2 negative disease (ICH/FISH) and had detectable CTCs, there was discordance in HER2 status: 44% (7/16) had HER2+ CTCs and all but one had Luminal A disease. Two patients have been started on HER2 targeted therapy based on finding HER2+ CTCs. One of these patients had 22 CTCs, 8 of which were HER2+, was initiated on HER-2 combined regimen and at a repeat evaluation in 3 months demonstrated 0 CTCs and clinical response. Conclusions CTCs offer a new and innovative approach to detect HER2+ cells in MBC. Tissue analysis with IHC and FISH has been the gold standard but these methods are unable to account for disease phenotyopic hetereogeity and identify patients who have CSCs (HER2+) and therefore would benefit from HER2 targeted therapy. This warrants further investigation in a prospective trial in Luminal disease to formally compare these methods and correlate the results with clinical outcomes. Citation Format: Laura Austin, Zhaomei Mu, Tiffany Avery, Rebecca Jaslow, Carmela Paolillo, Angela Toss, Paolo Fortuna, Ye Zhong, Hushan Yang, Massimo Cristofanilli. Circulating tumor cells (CTCs) detect HER2+ status and phenotypic heterogeneity in metastatic breast cancer (MBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-01-11.

Subcutaneous (SQ) Bortezomib (BTZ) in Patients (Pts) with Relapsed Mantle Cell Lymphoma (MCL): Retrospective, Observational Study of Treatment Patterns and Outcomes in US Community Oncology Practices

Subcutaneous (SQ) Bortezomib (BTZ) in Patients (Pts) with Relapsed Mantle Cell Lymphoma (MCL): Retrospective, Observational Study of Treatment Patterns and Outcomes in US Community Oncology Practices

Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans

AbstractChronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Having shown that germinal center (GC) formation and immunoglobulin deposition are required for multiorgan system cGVHD and associated bronchiolitis obliterans syndrome (BOS) in a murine model, we hypothesized that T follicular helper (Tfh) cells are necessary for cGVHD by supporting GC formation and maintenance. We show that increased frequency of Tfh cells correlated with increased GC B cells, cGVHD, and BOS. Although administering a highly depletionary anti-CD20 monoclonal antibody (mAb) to mice with established cGVHD resulted in peripheral B-cell depletion, B cells remained in the lung, and BOS was not reversed. BOS could be treated by eliminating production of interleukin-21 (IL-21) by donor T cells or IL-21 receptor (IL-21R) signaling of donor B cells. Development of BOS was dependent upon T cells expressing the chemokine receptor CXCR5 to facilitate T-cell trafficking to secondary lymphoid organ follicles. Blocking mAbs for IL-21/IL-21R, inducible T-cell costimulator (ICOS)/ICOS ligand, and CD40L/CD40 hindered GC formation and cGVHD. These data provide novel insights into cGVHD pathogenesis, indicate a role for Tfh cells in these processes, and suggest a new line of therapy using mAbs targeting Tfh cells to reverse cGVHD.

The use of large volume low pressure nasal saline with fluticasone propionate for the treatment of pediatric acute rhinosinusitis

ObjectivesFluticasone propionate and nasal saline irrigation have been used in the treatment of sinonasal diseases for a long time. Our study investigates the effect of the combination of large volume low pressure nasal saline irrigation and fluticasone propionate for the treatment of pediatric acute rhinosinusitis. MethodsNinety-one pediatric patients with acute rhinosinusitis were included in our study. The patients were randomized into two groups. The first group (n=45) was treated with standard therapy (antibiotherapy+nasal decongestant) for 2 weeks, the second group was treated with the large volume low pressure nasal saline+fluticasone propionate combination for 3 weeks. The clinical scores, radiologic evaluations (X-ray Waters view), peak nasal inspiratory flow (PNIF) measurements, total symptom scores and hematologic parameters (WBC, CRP, ESR) of the patients were evaluated and compared. ResultsThere were no significant differences in between the two groups regarding age, gender, height and weight. Even though the clinical scores of Group 2 improved more rapidly, there were no significant differences in between groups regarding clinical scores by the 21st day. There were no significant differences in post treatment radiologic evaluations (Waters graphy). Both groups had significant improvement of their post treatment PNIF values, yet the improvement was more marked in Group 2 than in Group 1. The rhinorrhea, nasal congestion, throat itching and cough symptoms improved more rapidly in Group 2 than in Group 1. Post-treatment nose itching and sneezing symptoms were significantly less in Group 2. The values of hematologic parameters were significantly reduced at the end of the 3rd week in both groups. ConclusionsOur study is a first in investigating the combined use of large volume low pressure nasal saline and fluticasone propionate in acute pediatric rhinosinusitis, and the results reveal that the combination therapy was effective. Low pressure large volume nasal saline+fluticasone propionate combination can be employed as a new line of therapy for the treatment of pediatric acute rhinosinusitis, either by itself or combined with standard therapy.

Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data

We aimed to assess the clinical validity of circulating tumour cell (CTC) quantification for prognostication of patients with metastatic breast cancer by undertaking a pooled analysis of individual patient data. We contacted 51 European centres and asked them to provide reported and unreported anonymised data for individual patients with metastatic breast cancer who participated in studies between January, 2003, and July, 2012. Eligible studies had participants starting a new line of therapy, data for progression-free survival or overall survival, or both, and CTC quantification by the CellSearch method at baseline (before start of new treatment). We used Cox regression models, stratified by study, to establish the association between CTC count and progression-free survival and overall survival. We used the landmark method to assess the prognostic value of CTC and serum marker changes during treatment. We assessed the added value of CTCs or serum markers to prognostic clinicopathological models in a resampling procedure using likelihood ratio (LR) χ(2) statistics. 17 centres provided data for 1944 eligible patients from 20 studies. 911 patients (46·9%) had a CTC count of 5 per 7·5 mL or higher at baseline, which was associated with decreased progression-free survival (hazard ratio [HR] 1·92, 95% CI 1·73-2·14, p<0·0001) and overall survival (HR 2·78, 95% CI 2·42-3·19, p<0·0001) compared with patients with a CTC count of less than 5 per 7·5 mL at baseline. Increased CTC counts 3-5 weeks after start of treatment, adjusted for CTC count at baseline, were associated with shortened progression-free survival (HR 1·85, 95% CI 1·48-2·32, p<0·0001) and overall survival (HR 2·26, 95% CI 1·68-3·03) as were increased CTC counts after 6-8 weeks (progression-free survival HR 2·20, 95% CI 1·66-2·90, p<0·0001; overall survival HR 2·91, 95% CI 2·01-4·23, p<0·0001). Survival prediction was significantly improved by addition of baseline CTC count to the clinicopathological models (progression-free survival LR 38·4, 95% CI 21·9-60·3, p<0·0001; overall survival LR 64·9, 95% CI 41·3-93·4, p<0·0001). This model was further improved by addition of CTC change at 3-5 weeks (progression-free survival LR 8·2, 95% CI 0·78-20·4, p=0·004; overall survival LR 11·5, 95% CI 2·6-25·1, p=0·0007) and at 6-8 weeks (progression-free survival LR 15·3, 95% CI 5·2-28·3; overall survival LR 14·6, 95% CI 4·0-30·6; both p<0·0001). Carcinoembryonic antigen and cancer antigen 15-3 concentrations at baseline and during therapy did not add significant information to the best baseline model. These data confirm the independent prognostic effect of CTC count on progression-free survival and overall survival. CTC count also improves the prognostication of metastatic breast cancer when added to full clinicopathological predictive models, whereas serum tumour markers do not. Janssen Diagnostics, the Nuovo-Soldati foundation for cancer research.

Abstract P6-10-03: Comparative efficacy of everolimus in combination with exemestane and chemotherapy for advanced breast cancer in terms of progression-free survival

Abstract Background: For hormone receptor-positive (HR+) advanced breast cancer (ABC), guidelines recommend endocrine therapy as the preferred option even in the presence of visceral disease. If there is evidence of endocrine resistance or rapidly progressive disease requiring a fast response then chemotherapy is recommended. The randomized controlled trial (RCT) BOLERO-2 demonstrated that everolimus plus exemestane (EVE+EXE) more than doubled median progression-free survival (PFS) compared with placebo+EXE while still maintaining quality of life in HR+/HER2- ABC patients who recurred or progressed during or after non-steroidal aromatase inhibitors (NSAIs). EVE+EXE offers a viable new line of therapy which can delay treatment with chemotherapy. Therefore, comparative evidence of EVE+EXE versus chemotherapies is relevant. In addition, such data will provide useful information for health technology assessment. Objective: 1) Assess the feasibility of network-meta-analysis (NMA) to compare the efficacy of EVE+EXE with chemotherapies in ABC in terms of PFS. 2) If feasible, to conduct the NMA. Methods: A systematic review of EMBASE, Medline, and Cochrane was performed to identify RCTs concerning the efficacy of everolimus, alternative hormonal therapies, and alternative chemotherapies for ABC in terms of PFS in order to facilitate an indirect comparison of everolimus versus chemotherapy. PFS data from published Kaplan-Meier curves for each treatment and RCT were synthesized and indirectly compared with random effects Bayesian Weibull network-meta-analysis (NMA) models. Analyses were performed assuming treatment effects as expressed with hazard ratios vary over time. Results: Based on a search of 6271 citations 24 RCTs were included. Differences across RCTs were identified in terms of age, post-menopausal status, receptor status, prior exposure to hormonal and chemotherapy, and types of hormonal therapies, visceral metastases, and performance status. Despite the limitations due to these differences, a NMA was performed to provide a broad estimate regarding comparative PFS for everolimus versus chemotherapy to inform current practice. Results of NMA in terms of mean PFS (i.e. area under the curve) up to 20 months are presented in Table 1. Sensitivity analyses will be performed to explore the impact of these differences on the robustness of the results. Table 1. Mean PFS until 20 months as obtained with NMATreatmentMean PFS time up to 20 months95% Credible Interval95% Credible IntervalEpirubicin6.162.5312.17Liposomal doxorubicin6.663.1212.00Paclitaxel7.103.7811.90Pegylated liposomal doxorubicin7.143.0913.56Doxorubicin7.353.9612.09Vinorelbine7.552.9914.28Docetaxel7.924.3712.45Capecitabine9.905.0316.67Nab paclitaxel10.105.4215.75Exemestane+ Everolimus12.216.2116.98 Conclusions: It is feasible to conduct NMA, however, differences in patient characteristics identified among studies are likely to have resulted in over or underestimation of the relative treatment effects. Based on the NMA, EVE+EXE is expected to be at least as efficacious as selected chemotherapies regarding PFS. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-10-03.

Abstract 9623: Stimulatory Effects of Cardiotrophin-1 on Atherosclerosis

Cardiotrophin-1 (CT-1), a cytokine belonging to the interleukin-6 superfamily, was recently shown to be expressed in the intima of early atherosclerotic lesions in the human carotid artery. CT-1 stimulates pro-atherogenic molecule expression in human vascular endothelial cells (EC) and monocyte migration. However, it has not been reported whether CT-1 accelerates atherosclerosis. This study was performed to examine the stimulatory effects of CT-1 on human macrophage foam cell formation, human EC proliferation, and the migration and proliferation of human vascular smooth muscle cells (VSMCs) in vitro, and on the development of atherosclerotic lesions in apolipoprotein E-deficient (ApoE-/-) mice in vivo. CT-1 was expressed at high levels in ECs and macrophages in both humans and ApoE-/- mice. CT-1 significantly enhanced oxidized low-density lipoprotein-induced foam cell formation associated with increased levels of CD36 and acyl-CoA:cholesterol acyltransferase-1 (ACAT1) expression in human monocyte-derived macrophages. CT-1 also significantly stimulated the migration and proliferation of human aortic VSMCs, but not EC proliferation. Four-week-infusion of CT-1 into ApoE-/- mice significantly accelerated the development of aortic atherosclerotic lesions with increased monocyte/macrophage infiltration and VSMC content in the aortic wall. Activation of inflammasome, such as apoptosis-associated speck-like protein containing a caspase recruitment domain, nuclear factor-κB, and cyclooxygenase-2, was observed in exudate peritoneal macrophages from ApoE-/- mice infused with CT-1. Infusion of anti-CT-1 neutralizing antibody alone into ApoE-/- mice significantly suppressed monocyte/macrophage infiltration in atherosclerotic lesions. These results indicate that CT-1 accelerates the development of atherosclerotic lesions by stimulating the inflammasome and foam cell formation associated with CD36 and ACAT1 up-regulation in macrophages and VSMC migration and proliferation, contributing to the occurrence of atherosclerotic vascular diseases. Blockade of cardiotrophin-1 is expected to emerge as a new line of therapy against atherosclerosis and its related diseases.

Oral multikinase inhibitor regorafenib for the treatment of patients with metastatic colorectal cancer

SUMMARY Regorafenib is an oral small molecule inhibitor of multiple kinases involved in pathogenic processes, such as oncogenesis, tumor angiogenesis and maintenance of the tumor microenvironment, whose efficacy has been recently demonstrated in the treatment of pretreated metastatic colorectal cancer patients. The introduction of regorafenib into clinical practice allows medical oncologists to offer a new line of therapy to patients who have already received all of the other available drugs. Nevertheless, some issues deserve to be further examined in order to improve our knowledge of this drug’s potentialities and to better integrate its use in the daily routine, including the evaluation of response beyond convential size-based response evaluation criteria in solid tumors, the identification of molecular predictors of benefit, and the investigation of the potential role of regorafenib in different settings and in combination with other agents.

Prognostic impact of changes in circulating tumor cells (CTC) in metastatic breast cancer (MBC).

11012 Background: To prospectively assess the prognostic value of CTC counts at baseline and after one cycle of therapy and their kinetics for response, progression-free (PFS), and overall survival (OS) in MBC. Methods: MBC patients underwent CTC enumeration (CellSearch, Veridex) at baseline (CTCBL), after one cycle of a new line of therapy (CTC1C), and at progression (CTCPD). CTC status was classified as negative (neg (−)) or positive (pos (+)) for &lt;5 and ≥5 CTC/7.5 ml peripheral blood, respectively. CTC kinetics (CTCKIN) from CTCBL to CTC1C were classified as favorable if CTCs remained neg (neg&gt;neg) or became neg (pos&gt;neg), or as unfavorable (neg&gt;pos or pos&gt;pos). Tumor response was assessed every 2–3 months using RECIST criteria. CTC status and kinetics were associated with outcome using log-rank and Fisher’s exact tests. Results: Of 326 patients enrolled (median age (range) at first diagnosis: 50 (23–81) years), 115/326 (35%) were CTCBL+, 51/162 (31%) were CTC1C+, and 39/108 (36%) were CTCPD+. Median follow-up was 15.9 months (mos). Median PFS and OS were significantly reduced in CTCBL+ compared to CTCBL− patients (PFS, 4.3 vs. 7.1 mos, p = .019; OS, 15.0 mos vs. not reached (nr), p &lt;.001) and for CTC1C+ compared to CTC1C− patients (p &lt;.001 for PFS and OS). CTCKIN were predictive of progressive disease as best response (neg&gt;neg, 33%; pos&gt;neg, 38%; pos&gt;pos, 60%; neg&gt;pos, 75%; p = .040). PFS and OS for patients with unfavorable CTCKIN were significantly shorter than for favorable CTCKIN (PFS, 3.7 vs. 6.8 mos, p &lt;.001; OS, 7.8 mos vs. nr, p &lt;.001). Conclusions: CTC at baseline, CTC after one cycle and CTC kinetics are highly predictive of outcome in MBC. Serial CTC enumeration could serve as a useful adjunct to standard diagnostic tests in tailoring therapy. Further details of CTCPD will be presented at the meeting. Clinical trial information: S-295/2009.

Downregulation of Androgen Receptor Transcription by Promoter G-Quadruplex Stabilization as a Potential Alternative Treatment for Castrate-Resistant Prostate Cancer

Androgen receptor (AR) signaling remains an important regulatory pathway in castrate-resistant prostate cancer, and its transcriptional downregulation could provide a new line of therapy. A number of small-molecule ligands have previously demonstrated the ability to stabilize G-quadruplex structures and affect gene transcription for those genes whose promoters contain a quadruplex-forming sequence. Herein, we report the probable formation of new G-quadruplex structure present in the AR promoter in a transcriptionally important location. NMR spectroscopy, circular dichroism, UV spectroscopy, and UV thermal melting experiments for this sequence are consistent with G-quadruplex formation. Fluorescence resonance energy transfer (FRET) melting studies have identified a novel compound, MM45, which appears to stabilize this G-quadruplex at submicromolar concentrations. The effects of MM45 have been investigated in prostate cancer cell lines where it has been shown to inhibit cell growth. A reporter assay intended to isolate the effect of MM45 on the G-quadruplex sequence showed dose-dependent transcriptional repression only when the AR promoter G-quadruplex sequence is present. Dose-dependent transcriptional repression of the AR by MM45 has been demonstrated at both a protein and mRNA level. This proof of concept study paves the route toward a potential alternative treatment pathway in castrate-resistant prostate cancer.

Potential New Indication for Ivabradine: Treatment of a Patient with Congenital Junctional Ectopic Tachycardia

Ivabradine is a new antiarrhythmic agent with direct inhibition of the pacemaker (If) current. It has been used extensively to decrease sinus rate in the treatment of cardiac failure, and also in a single case of atrial ectopic tachycardia in a child. Here we report the case of a 3-year-old girl with congenital junctional ectopic tachycardia (JET), resistant to conventional antiarrhythmic medications, who was successfully treated with ivabradine. We suggest that ivabradine can be an effective treatment for junctional automatic tachycardias and can be considered as a new line of therapy for this incessant form of tachycardia.

The prognostic impact of circulating tumor cells in subtypes of metastatic breast cancer

The detection of circulating tumor cells (CTCs) in the peripheral blood of metastatic breast cancer (MBC) patients is an independent marker of prognosis. This large prospective multicenter study aimed to assess the impact of CTCs on overall survival (OS) and progression free survival (PFS) in patients with predefined molecular subgroups of MBC. To this end, 468 MBC patients were divided into three subgroups based on immunohistochemical staining of the primary tumor: (1) hormone receptor-positive/HER2-negative (HorR+/HER2-), (2) HER2-positive (HER2+), and (3) HorR-negative/HER2-negative (HorR-/HER2-) patients. CTC status (<5 CTCs/7.5 ml blood (CTC-negative) vs. ≥5 CTCs/7.5 ml blood (CTC-positive)) was determined using the CellCearch(®) system before patients started a new line of therapy. At baseline, 205 (42 %) patients were CTC-positive. On multivariate analysis, CTC-positivity was an independent prognostic factor for shorter PFS and OS. In HorR+/HER2- patients, median PFS [95 % CI] of CTC-negative versus CTC-positive patients was 8.60 [5.93-11.27] versus 4.33 [3.29-5.38] months (p < 0.001), in HER2+ patients 7.60 [5.40-9.79] versus 6.60 [4.20-9.00] months (p = 0.477) and in HorR-/HER2- patients 5.83 [5.09-6.78] versus 3.05 [1.81-4.29] months (p < 0.001), respectively. Median OS [95 % CI] of CTC-negative versus CTC-positive patients was as follows: not reached by either in the HorR+/HER2- subgroup (p < 0.001), not reached versus 18.07 [11.10-25.05] months (p = 0.001) in the HER2+ subgroup, and not reached versus 8.57 [4.07-13.07] months in the HorR-/HER2- subgroup (p = 0.001). In conclusion, our results strongly confirm the independent prognostic value of CTC enumeration in MBC patients. In contrast to recent reports, there was no association between primary tumor-based molecular subgroups and the impact of CTC status on OS. Hence, CTC status may help to identify patients who require aggressive therapy, especially among those with triple-negative MBC.

Evaluation of regorafenib in colorectal cancer and GIST

Regorafenib is an orally administered multikinase inhibitor. It is administered on a continuous dosing schedule and shows non-specific binding to several intracellular kinases, with potent inhibitory activity against vascular endothelial growth factor receptors 1–3 (VEGFR1 [also known as FLT1], VEGFR2 [KDR], and VEGFR3 [FLT4]), PDGFRB, FGFR1, RAF, TIE2, and the mutant oncogenic kinases KIT, RET, and BRAF. 1 Wilhelm SM Dumas J Adnane L et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011; 129: 245-255 Crossref PubMed Scopus (921) Google Scholar Commonly reported (>10%) toxic effects include fatigue, hand-foot skin reaction, diarrhoea, anorexia, voice changes, hypertension, oral mucositis, rash, and weight loss. 2 Grothey A Van Cutsem E Sobrero A et al. for the CORRECT Study GroupRegorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2012; (published online Nov 22.)http://dx.doi.org/10.1016/S0140-6736(12)61900-X Google Scholar , 3 Demetri GD Reichardt P Kang Y-K et al. on behalf of all GRID study investigatorsEfficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2012; (published online Nov 22.)http://dx.doi.org/10.1016/S0140-6736(12)61857-1 Google Scholar Clinical trials are underway assessing regorafenib in the treatment of colorectal cancer, gastrointestinal stromal tumours (GIST), lung cancer, renal cell carcinoma, and hepatocellular carcinoma. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trialRegorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer which has progressed after all standard therapies. The present study provides evidence for a continuing role of targeted treatment after disease progression, with regorafenib offering a potential new line of therapy in this treatment-refractory population. Full-Text PDF Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trialThe results of this study show that oral regorafenib can provide a significant improvement in progression-free survival compared with placebo in patients with metastatic GIST after progression on standard treatments. As far as we are aware, this is the first clinical trial to show benefit from a kinase inhibitor in this highly refractory population of patients. Full-Text PDF

Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial

No treatment options are available for patients with metastatic colorectal cancer that progresses after all approved standard therapies, but many patients maintain a good performance status and could be candidates for further therapy. An international phase 3 trial was done to assess the multikinase inhibitor regorafenib in these patients. We did this trial at 114 centres in 16 countries. Patients with documented metastatic colorectal cancer and progression during or within 3 months after the last standard therapy were randomised (in a 2:1 ratio; by computer-generated randomisation list and interactive voice response system; preallocated block design (block size six); stratified by previous treatment with VEGF-targeting drugs, time from diagnosis of metastatic disease, and geographical region) to receive best supportive care plus oral regorafenib 160 mg or placebo once daily, for the first 3 weeks of each 4 week cycle. The primary endpoint was overall survival. The study sponsor, participants, and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01103323. Between April 30, 2010, and March 22, 2011, 1052 patients were screened, 760 patients were randomised to receive regorafenib (n=505) or placebo (n=255), and 753 patients initiated treatment (regorafenib n=500; placebo n=253; population for safety analyses). The primary endpoint of overall survival was met at a preplanned interim analysis; data cutoff was on July 21, 2011. Median overall survival was 6·4 months in the regorafenib group versus 5·0 months in the placebo group (hazard ratio 0·77; 95% CI 0·64-0·94; one-sided p=0·0052). Treatment-related adverse events occurred in 465 (93%) patients assigned regorafenib and in 154 (61%) of those assigned placebo. The most common adverse events of grade three or higher related to regorafenib were hand-foot skin reaction (83 patients, 17%), fatigue (48, 10%), diarrhoea (36, 7%), hypertension (36, 7%), and rash or desquamation (29, 6%). Regorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer which has progressed after all standard therapies. The present study provides evidence for a continuing role of targeted treatment after disease progression, with regorafenib offering a potential new line of therapy in this treatment-refractory population. Bayer HealthCare Pharmaceuticals.

Formulation and evaluation of a particulate oral breast cancer vaccine

Breast cancer being the most fatal form of cancer for female population, justifies exploration of immunotherapy as an alternative treatment. Here, we have formulated and evaluated an oral microparticulate breast cancer vaccine to provide a new line of therapy. The whole cell lysate of 4T07 murine breast cancer cells was incorporated in an aqueous polymer matrix and spray dried to formulate an enteric protected vaccine microparticle. These particles were characterized in vitro and then administered orally to female Balb/c mice in successive boosters. Serum antibody titers during the study were analyzed using enzyme‐linked immunosorbent assay. Postvaccination animals were challenged with live 4T07 cells, and tumor growth was monitored. Flow cytometry studies were performed to analyze the role of T cells. Results show that the vaccine microparticles were 1–4 µm in volume diameter and neutral in charge. The particles were protected enterically and had sustained‐release profile. Serum antibody titers of vaccinated animals increased significantly after boosters compared with controls (p < 0.05). Tumor challenge studies revealed that vaccinated animals developed significantly smaller tumors (p < 0.05). Significantly higher numbers of CD4+ cells occurred in vaccinated animals (p < 0.05). Thus, we conclude that the particulate oral breast cancer vaccine was effective in providing protective immune response in the murine model. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:3661–3671, 2012

Circulating tumor cells in metastatic breast cancer: Are they a strong and independent predictor of poor progression-free and overall survival?

1090 Background: Circulating tumor cells (CTCs) are detected in 30–60% of patients with metastatic breast cancer (MBC). The aim of this prospective multi-center study was to evaluate the impact of CTCs on progression free survival (PFS) and overall survival (OS) in a large cohort of 486 patients with progressive metastatic disease. Methods: CTC levels were determined for 486 patients at nine German University Breast Cancer Centers between 12/2007 and 06/2011. Samples of 7.5 ml blood were taken before initiation of a new line of therapy and CTCs were enumerated using the CellSearch System (Veridex LLC, Raritan, NJ, USA). CTC status (≥ 5 CTCs vs. &lt; 5 CTCs per 7.5 ml blood) was assessed as a prognostic factor for PFS and OS using univariate (log-rank test) and multivariate (Cox regression model) statistical methods. Results: CTCs were detected in 205/486 (42%) patients. The median CTC count was 2 (range 0–6380) per 7.5 ml blood. The presence of ≥ 5 CTCs/7.5 ml blood did not correlate with any of the established clinicopathological factors except estrogen receptor status (p = 0.038). PFS and OS were both significantly shorter in patients with ≥ 5 CTCs/7.5 ml than in those with &lt; 5 CTCs/7.5 ml blood. PFS was 5.0 [95% CI 4.1–5.8] months vs.7.6 [95% CI 5.9–9.3] months, p &lt; 0.001; and OS was 15.0 [95% CI 13.5–16.5] months vs. 18.3 [95% CI 17.4–19.2] months, p &lt; 0.001. In the multivariate analysis considering all clinicopathological factors and the CTC status, independent predictors of reduced OS and PFS were site of metastasis (visceral vs. bone), number of metastatic sites (multiple sites vs. one site), and CTC status. Conclusions: The presence of ≥ 5 CTCs/7.5 ml blood is a strong and independent predictor of poor PFS and OS in patients with MBC.

Clinical significance of circulating tumor cells in blood from patients with advanced or recurrent esophageal cancer.

19 Background: Circulating tumor cells (CTCs) measured by the CellSearch system in metastatic breast cancer have been reported to correlate with the response to chemotherapy. The purpose of this study was to clarify the clinicopathologic characteristics of CTCs in patients with advanced or recurrent esophageal cancer. Methods: CTCs from 35 patients with advanced or recurrent esophageal cancer were measured by this system before initiation of a new line of therapy and more than 3 weeks after initiation of therapy. Correlation between CTC counts and clinicopathologic variables was examined. Results: Of the 35 patients, 14 patients (40%) had recurrent esophageal cancer and 21 patients (60%) had primary advanced esophageal cancer. Their mean age was 65 years (range, 43 to 89 ). Of the 14 patients with recurrent esophageal cancer, measurable lesions included metastasis to lymph nodes, kidney metastasis, liver metastasis, and lung metastasis. With regard to their therapeutic effect, 1 patient (3%) obtained a complete response, 14 (40%) had a partial response, 9 (26%) had stable disease, 11 (31%) had progressive disease. Of the 15 patients with complete response and partial response, the number of CTCs diminished in 8 patients (53%). Of the 20 patients with stable disease and progressive disease, the number of CTCs increased in 16 patients (80%). The change in CTCs tended to correlate with disease progression and chemotherapeutic effect (P=0.07). The survival of patients with &gt;3 CTCs was shorter than that of patients with &lt;3 CTCs both before initiation of a new line of therapy (P=0.026) and more than 3 weeks after initiation of therapy (P=0.003). Conclusions: This study suggests that measurement of CTCs in advanced or recurrent esophageal cancer patients could be useful as a tool for predicting patients’ survival and monitoring response to cancer therapy.