bluuebunny/crossref_metadata_2025 huggingface dataset:
Immune gene expression in primary melanomas to predict lower risk of recurrence and death.
Authors: Sivendran Shanthi , Chang Rui R. , Harcharik Sara , Hall Lawrence , Bernardo Sebastian , Moskalenko Marina , Phelps Robert , Sivendran Meera , Cohain Ariella , DiFeo Analisa , Parides Michael , Lebwohl Mark , Friedlander Philip , Banchereau Jacques , Bhardwaj Nina , Oh William K. , Burakoff Steven J. , Palucka Karolina , Merad Miriam , Saenger Yvonne M.
Published: March 2020

3014

Background: Improved biomarkers are needed to define recurrence risk in patients with completely resected skin melanomas. Standard prognostic indicators used in staging, including depth, ulceration, and mitotic rate, while useful, often fail to accurately predict recurrence for individual patients. The immune system may prevent recurrence in this population, but no evidence-based immune biomarkers are in clinical use. Biomarker development has been hindered by clinical standards necessitating that the entire specimen be formalin fixed and paraffin embedded (FFPE) for morphology evaluation, a process damaging to RNA. Methods: To define a biomarker for melanoma recurrence, mRNA copy number of immune-related genes from FFPE melanoma was measured using NanoString, a hybridization assay suited for analysis of partially degraded RNA. Genes predictive of non-recurrence were defined using receiver operating characteristic (ROC) curves in a training cohort and then validated in an independent patient cohort. Results: A panel of 21 genes predictive of non-recurrence were defined using ROC curves in a training cohort (N=44). This result was validated in an independent patient cohort (N=37, AUC=0.794). Protein levels of the most differentially expressed gene, CD2, also associated with non-recurrence (p<0.001). The immune gene panel and CD2 staining associated with prolonged survival (p<0.001 and p=0.019, respectively). Conclusions: mRNA copy number of immune-related genes in primary FFPE melanomas predicts non-recurrence and prolonged survival. This data highlights the impact of immunosurveillance in primary human melanoma and the identified gene panel may be a useful tool for patient stratification for adjuvant immunotherapy studies.
Effect of oral cyclophosphamide on the immunogenicity of DPX-Survivac in ovarian cancer patients: Results of a phase I study.
Authors: Berinstein Neil Lorne , Oza Amit M. , Odunsi Kunle , Karkada Mohan , Villella Jeannine A , Nemunaitis John J. , Morse Michael , Pejovic Tanja , Bentley James , Nigam Rita , Weir Genevieve , MacDonald Lisa , Stanford Marianne , Burzykowski Tomasz , Mansour Marc
Published: March 2020

3030

Background: Survivin, a protein involved in regulation of apoptosis, is highly expressed in many tumor types and has reported prognostic value. DPX-Survivac is a cocktail of survivin HLA class I peptides (A1, A2, A3, A24 and B7) formulated in the novel adjuvanting vaccine platform DepoVax. A phase I study examined the safety and immune potency of DPX-Survivac in combination with cyclophosphamide in ovarian cancer patients. Methods: 18 of 19 advanced ovarian cancer patients treated with platinum chemotherapy and showing no disease progression completed their vaccine therapy. Cohort A (6 pts) received three 0.5 mL vaccine injections 3 weeks apart; cohorts B and C (6 pts each) received three 0.1 mL or 0.5 mL vaccine injections in combination with metronomic low dose oral cyclophosphamide. Adverse events were assessed using CTCAE v4.0. Blood was collected to study immune function (MDSCs, T regs and B cells) and vaccine-induced T cell immunity (ELISpot, tetramer analysis and multi-parametric intracellular cytokine staining). Repeated measures of immunity at baseline and after 1, 2 and 3 injections were analyzed using a general linear model. Results: DPX-Survivac was well tolerated with no significant systemic AEs. Local injection AEs occured in all patients. Grade 3 local reactions occured in 3 patients (1 pt in B and 2 pts in C). 11 of 12 patients receiving the combination therapy produced immune responses by at least 2 assays, generally established with one or two vaccinations and increased or maintained with boosters. A dose response was observed, with cohort C patients producing significantly higher magnitude responses (C vs B, P=.013). Low dose cyclophosphamide significantly enhanced the 0.5 ml dose (C vs A, P=.015). Notably, antigen specific CD8 T cells were detected ex vivoi n PBL’s using tetramers and further characterized as polyfunctional by multi-parametric ICS, suggesting a robust immune response. Conclusions: DPX-Survivac is well tolerated and immunogenic. Immune modulation with low dose oral cyclophosphamide can dramatically enhance the immunogenicity of this vaccine. The efficacy of the proposed DPX-Survivac vaccine therapy needs to be tested in a randomized phase II study. Clinical trial information: NCT01416038.
Up-regulation of stromal cell-derived factor by il-17 and il-18 via PI3K dependent pathway.
Authors: Ahn Inhye , Ju Ji Hyeon
Published: March 2020

3046

Background: Stromal cell-derived factor-1 (SDF-1) is a versatile chemotactic cytokine and a sole ligand of CXCR4. SDF-1-CXCR4 axis is the most commonly expressed pathway in cancer cells, and is also responsible for metastasis, homing of stem cell, HIV infection, and autoimmune diseases. Interleukin (IL)-17 plays a key role in the pathogenesis of inflammation by inducing SDF-1 to propagate inflammation and vascular endothelial growth factor to provoke angiogenesis. Recent studies revealed that IL-17 pathway is interwoven with multiple cytokines and downstream pathways. Members of the IL-1β family, including IL-18, have recently gained attention. By measuring SDF-1 production regulated by individual and simultaneous cytokine stimulations, two cytokines were explored to define their effects, their downstream signal transduction pathways, and the impact of their antibodies. Methods: Synovial tissue was obtained from patients with rheumatoid arthritis and their age- and sex-matched controls with osteoarthritis. Fibroblast-like synoviocytes (FLS) were isolated and stimulated with a combination of IL-17 and IL-18 and quantified SDF-1 production with ELISA and their transcripts with RT-PCR. Another subset of FLS were preconditioned with PI3K inhibitor, 100 nM wortmannin, and stimulated with either 5 ng/mL of IL-17, 10 ng/mL of IL-18, or combination of both cytokines. Mann-Whitney test was adopted for statistical analysis. Results: Both IL-17 and IL-18 increased SDF-1 level and its mRNA transcript, not only individually but also synergistically (p <0.05). In the group where PI3K inihibitor was applied, the individual and synergistic promotion of SDF-1 production by IL-17 and IL-18 were inhibited (p<0.05). Concomitant application of anti-IL-17 and anti-IL-18 led to further decline of SDF-1 production (p<0.01). Conclusions: This is the first report of PI3K-dependent synergism between IL-18 and IL-17, and adds a novel perspective of the role of IL-18 in immune regulation. The individual effects of these two cytokines, and their interaction through PI3K, suggest an interrelationship between the IL-1 family and IL-17.
An Fc-optimized NKG2D-Ig fusion protein for induction of NK cell reactivity against breast cancer.
Authors: Steinbacher Julia , Raab Stefanie , Grosse-Hovest Ludger , Schmiedel Benjamin Joachim , Steinle Alexander , Kanz Lothar , Salih Helmut Rainer
Published: March 2020

3054

Background: The anti-tumor activity and clinical success of the monoclonal antibody trastuzumab, approved for treatment of HER2/neu-overexpressing breast cancer, is at least partially mediated by induction of antibody dependent cellular cytotoxicity (ADCC). However, only about 20% of patients show HER2/neu overexpression, and trastuzumab treatment is associated with side effects. The ligands of the activating immunoreceptor NKG2D (NKG2DL) are widely expressed on malignant cells, but generally absent on healthy tissue. We aimed to take advantage of this tumor-restricted expression by using NKG2DL as target-antigens on breast cancer cells. To this end we generated NKG2D-Ig fusion proteins with modified Fc moieties and studied their ability to induce NK cell anti-tumor reactivity. Methods: The Fc parts within the constructs were modified by amino acid exchange as previously described (Lazar 2006; Armour 1999). Direct effects on tumor cell viability as well as induction of NK cell activation, degranulation, cytotoxicity and IFN-γ release in cultures with breast cancer cell lines expressing different HER2/neu levels were determined. Results: Compared to NKG2D-Fc containing a wildtype Fc part (NKG2D-Fc-WT) or trastuzumab, our mutants (S239D/I332E and E233P/L234V/L235A/ΔG236/A327G/A330S) displayed highly enhanced (NKG2D-Fc-ADCC) and abrogated (NKG2D-Fc-KO) affinity to the NK cell Fc receptor, respectively. In contrast to trastuzumab, no direct effect of the constructs on tumor cell viability was observed. In cultures of NK cells and breast cancer cells, NKG2D-Fc-KO significantly reduced NK reactivity due to blocking immunostimulatory NKG2D-NKG2DL interaction. NKG2D-Fc-WT substantially enhanced NK reactivity by induction of ADCC, while the effects of NKG2D-Fc-ADCC by far exceeded that of NKG2D-Fc-WT and, in case of HER2/neu-low targets also that of Herceptin. Conclusions: Fc-engineered NKG2D-Ig fusion protein effectively target breast cancer cells for NK anti-tumor reactivity. Due to the tumor-restricted expression of NKG2DL, NKG2D-Fc-ADCC may constitute an attractive means for immunotherapy especially of HER2/neu-low or -negative breast cancer.
A phase II study of NPC-1C: A novel therapeutic monoclonal antibody (mab) to treat pancreatic (P) and colorectal (CR) cancers.
Authors: Morse Michael , Patel Sandip Pravin , Beatson Melony A. , Arlen Philip M.
Published: March 2020

3070

Background: NPC-1C is a chimeric mab developed to treat P and CR cancers. This mab was selected from a panel of hybridomas derived from biologically screened, pooled human allogeneic colon cancer tissues. The NPC-1C target appears to be a variant of MUC5AC expressed specifically by human P and CR tumors with minimal cross-reactivity to normal GI mucosa. Methods: A phase IIa study with NPC-1C is enrolling patients (pts) with advanced P and CR cancer refractory to standard therapy. Primary objectives are to measure efficacy by analysis of CT scans pre- and post-therapy, clinical lab tests, and physical examinations. Secondary objectives are to determine safety, pharmacokinetics (PK), and select immune responses to the mab. Analyses of pts peripheral blood mononuclear cells (PBMCs) for antibody-dependent cell-mediated cytotoxicity (ADCC) and immune cytokine profiling utilizing the Milliplex MAP Human Cytokine/Chemokine Panel are planned to assess for immunologic outcome and correlation with clinical benefit. Results: Pts received 1.5 mg/kg IV of NPC-1C every two weeks. 10 subjects (8 colorectal, 2 pancreatic) have enrolled on study (2/10 non-evaluable). Treatment was well tolerated with grade 1 and 2 constitutional symptoms noted. Coombs positivity was reported in 4/8 pts shortly after the infusions, but only grade 1 hemolysis was reported (in 2/8 patients). There was 1 episode of each of the following grade 3 AE’s: weakness, increased bilirubin, and abdominal pain, possibly related to NPC-1C. 5 of 19 pts treated in this and the phase Ia study demonstrated stable disease (SD) on scans after completing the first course of treatment (4 doses). Conclusions: Preliminary results with NPC-1C show signs of clinical activity based on SD in heavily pretreated pts with P and CR cancer. Safety has been established at the 1.5 mg/kg dose. A new lot of NPC-1C, produced with improved sterility and purification procedures and demonstrating no red cell agglutination, has been manufactured under GMP conditions. We plan to introduce this new lot at the current 1.5 mg/kg dose level. If there are no dose limiting toxicities, we plan to dose escalate to a higher MTD at which we will re-evaluate clinical efficacy. Clinical trial information: NCT01040000.
A randomized phase II/III study of naptumomab estafenatox plus IFN-α versus IFN-α in advanced renal cell carcinoma.
Authors: Hawkins Robert E. , Gore Martin Eric , Shparyk Yaroslav , Bondar Vladimir , Gladkov Oleg , Ganev Tosho , Harza Mihai , Polenkov Serhii , Bondarenko Igor , Karlov Petr A , Karyakin Oleg , Khasanov Rustem , Hedlund Gunnar Eric , Forsberg Goran , Nordle Orjan , Eisen Tim
Published: March 2020

3073

Background: Naptumomab estafenatox/ANYARA (Nap) is a fusion protein of an antibody (5T4) and a superantigen (SEA/E-120). After phase I studies (Borghaei. J Clin Oncol. 2009, 27:4116) a prospective, randomized phase II/III trial of Nap + IFN-α (A) vs IFN-α (I) was conducted. Methods: Patients (pts) with RCC were randomized in an open label study to receive A or I. The primary endpoint was OS. Secondary endpoints were PFS, response rate and safety. Baseline (bl) plasma IL-6 was predictive of pazopanib (Tran. Lancet Oncol. 2012, 13:827) and MVA-5T4 vaccine (Harrop. Cancer Immunol Immunother. 2012, 61:2283) benefit in RCC pts. IL-6 and anti-SEA/E-120 antibodies (a-S) were analyzed. A subgroup SG1 had bl levels below median for IL-6 (<7 pg/ml) and a-S. Another subgroup SG2 had IL-6 below 13 pg/ml (Tran. Lancet Oncol. 2012, 13:827) and excluding upper quartile of a-S according to phase 1 levels (Borghaei. J Clin Oncol. 2009, 27:4116). Results: From 5/2007 to 10/2010 513 pts were treated (ITT) with a median follow-up time for censored pts of 43 months. Unexpectedly, pts in certain territories had increased bl a-S (median of 61 pmol/ml in Russia vs 34 in UK). The table summarizes efficacy results. The primary endpoint was not met. Multivariate analysis adjusted for risk scores and subsequent TKI usage verified Nap benefit in pts with low IL-6 and normal a-S. Nap was well tolerated. Pyrexia (A:46%/I:18%), nausea (21%/11%), back pain (18%/6%), vomiting (16%/7%) and chills (12%/4%) were more common after Nap. Conclusions: The study did not meet primary endpoint. In pts with low IL-6 and normal levels of a-S, addition of Nap to IFN-α improves OS and PFS. The results warrant further studies with Nap in sequence or combo with e.g. TKIs in this subgroup. More generally, as bl IL-6 appears to be prognostic and predictive of outcome on treatment with TKIs and immunotherapies this may be a stratification factor for RCC studies. Clinical trial information: NCT00420888. [Table: see text]
High hydrostatic pressure to induce immunogenic cell death in human tumor cells.
Authors: Truxova Iva , Fucikova Jitka , Moserova Irena , Partlova Simona , Bartunkova Jirina , Spisek Radek
Published: March 2020

3076

Background: Recent studies have identified molecular events characteristic of immunogenic cell death. These include surface exposure of calreticulin, HSP70 and HSP90, release of intranuclear HMGB1 and secretion of ATP from dying cells. Several chemotherapeutic agents, including anthracyclins, oxaliplatin and bortezomib, and hypericin-based photodynamic therapy have been described to induce the immunogenic cell death in human tumor cells. We investigated the potential of high hydrostatic pressure (HHP) to induce immunogenic cell death in human tumor cells. Methods: Prostate and ovarian cancer cell lines and primary tumor cells were treated by HHP and we analyzed the kinetics of the expression of immunogenic cell death markers. HHP killed tumor cells expressing immunogenic cell death markers were tested for their ability to activate dendritic cells (DCs), to induce tumor specific T cells and regulatory T cells. Results: HHP induced rapid expression of HSP70, HSP90 and calreticulin on the cell surface of all tested cell lines and primary tumor cells. HHP also induced release of HMGB1 and ATP from treated cells. The kinetics of expression was similar to doxorubicin, HHP, however, induced 1.5-2 fold higher expression of HSP70, HSP90 and calreticulin. The interaction of DCs with HHP-treated tumor cells led to the faster rate of phagocytosis, significant upregulation of CD83, CD86 and HLA-DR and release of IL-6, IL-12p70 and TNFα. The ability of HHP-killed tumor cells to promote DCs maturation was cell contact dependent. DCs pulsed with tumor cells killed by HHP induced high numbers of tumor-specific CD4+ and CD8+IFN-g-producing T cells even in the absence of additional maturation stimulus. DCs pulsed with HHP treated tumor cells also induced the lowest number of regulatory T cells among the tested conditions. Cells treated by HHP can by cryopreserved in liquid nitrogen and retain their immunogenic properties upon thawing thus allowing for their convenient use in the manufacturing of cancer immunotherapy products. Conclusions: High hydrostatic pressure is a reliable and very potent inducer of immunogenic cell death in the wide range of human tumor cell lines and primary tumor cells.
A phase I/II randomized trial using GM-CSF-producing and CD40L-expressing bystander cell line (GM.CD40L) vaccine in combination with CCL21 in stage IV lung adenocarcinoma: Preliminary results.
Authors: Gray Jhanelle Elaine , Chiappori Alberto , Williams Charles C. , Pinder Mary Colleen , Haura Eric B. , Kim Jongphil , Gonzalez Germaine , Noyes David , Antonia Scott J.
Published: March 2020

3091

Background: Our GM.CD40L vaccine (an allogeneic tumor cell-based vaccine generated from human bystander cell line) recruits and activates dendritic cells, which then migrate to regional lymph nodes, where T cell activation occurs, leading to systemic tumor cell killing. The CCL21 chemokine helps to recruit T cells and leads to enhanced T cell responses. The GM.CD40L.CCL21 combination has demonstrated additive effects in NSCLC mouse models. Methods: We initiated a phase I/II randomized study to evaluate GM.CD40L (Arm A) vs. GM.CD40L.CCL21 (Arm B) in patients with lung adenocarcinoma who had failed first-line therapy. Primary endpoints were safety and tolerability of Arm B in phase I and progression-free survival (PFS) in phase II; secondary endpoints included anti-tumor immune responses/T-cell responses by ELISpot assay on PBMC. Immune-related response criteria as determined by the investigator served to determine discontinuation from study treatment. Intradermal vaccines were administered every 14 days for 3 doses and then monthly X3. A two-stage minimax design was used. Results: In phase I, 3 patients received GM.CD40L.CCL21; no dose-limiting toxicities occurred. Between 4/2012 and 12/2012, Arm A enrolled 11 and Arm B enrolled 16 patients, including those in phase I (median age: 70/67.5 years, females: 45.5%/37.5%, PS1: 54.5%/75%, median prior regimens: 3/5 for Arm A vs. Arm B, respectively). Most common toxicities for Arm A vs. Arm B were injection site reaction (45.5%/43.8%), fatigue (9.1%/37.5%), anorexia (0%/12.5%), and pain in extremity (0%/12.5%). Median PFS for Arm A vs. B was 4.4 vs. 4.4 months (p=0.37). Of the 6 patients who remained on study post RECIST v1.1 progression, all demonstrated further progression on subsequent scans and were removed from the study. Of patients evaluable for efficacy, stable disease was 3/7 and progressive disease was 6/7 for Arm A vs. Arm B, respectively. Analyses of ELISpot assay on the PBMC are underway. Conclusions: GM.CD40L.CCL21 vaccine is well tolerated; thus far, median PFS results are similar to GM.CD40L vaccine. Updated results of the phase II trial will be presented. Clinical trial information: NCT01433172.
Booster inoculations of the AE37 peptide vaccine enhance immunological responses in a phase II study.
Authors: Anastasopoulou Eleftheria A , Pappou Efi , Tzonis Panagiotis , Ardavanis Alexandros , Ponniah Sathibalan , Baxevanis Constantin N. , Murray James L. , Papamichail Michael , Perez Sonia A. , Peoples George Earl , Mittendorf Elizabeth Ann
Published: March 2020

3095

Background: We are conducting a multicenter randomized phase II trial of AE37, the Ii-Key hybrid peptide of HER2 776-790 (AE36). The purpose of the study is to determine if the AE37 vaccine can prevent recurrence in disease-free conventionally treated node-positive (NP) and high-risk node-negative (NN) breast cancer patients at significant risk for recurrence. Since clinical efficacy is anticipated to occur as the result of long lasting memory immune responses induced by vaccination, repeated booster inoculations were scheduled as part of the trial. Here we present data on immune responses in patients who received boosters up to 24 months after completion of the primary vaccination series (PVS). Methods: The trial is enrolling NP or high-risk NN patients with any degree of HER2 expression (IHC 1-3+ or FISH > 1.2) rendered disease-free following standard of care therapy. The vaccine group (VG) received AE37+GM-CSF and control group (CG) GM-CSF alone in 6 monthly i.d. inoculations followed by boosters administered every 6 months x 4. Immunologic responses were assessed in vivo by dermal reactions at the inoculation site, and in vitro, against the AE36 peptide, with proliferation and IFN-γ ELISPOT assays. Results: 25 patients in the VG and 23 in the CG have completed their boosters. After the last booster (BRC24), 100%, 54% and 54% in the VG (vs. 9%, 18% and 27% in the CG) responded by dermal reaction, proliferation and IFN-γ ELISPOT, respectively. Mean dermal reactions (orthogonal mean in mm) in vaccinated patients was 25.9±3.13 at completion of the PVS (R6) and increased to 35.47±4.35 at BRC24 (p=0.01). VG patients increased their proliferation response (stimulation index, SI) to AE36 from 0.97±0.046 at baseline (R0) before vaccination to 2.27±0.57 at R6 (p=0.0003) which was maintained until BRC24 (SI 2.21±0,33, p<0.0001). The number of IFN-γ specific spots/106 PBMC increased from 26.88±12.36 at R0 to 40.35±17.02 (p=0.07) at R6, up to 62±16.82 (p=0.0076) at BRC24. Conclusions: Our data demonstrate that AE37 vaccine boosters enhance the immune responses against HER elicited during the PVS, thus sustaining long lasting immunity, a prerequisite for possible clinical efficacy which is currently being evaluated. Clinical trial information: NCT00524277.
Activity of PU-H71, a novel HSP90 inhibitor, and bortezomib in Ewing sarcoma preclinical models.
Authors: Ambati Srikanth R. , Caldas Lopes Eloisi , Kosugi Kohji , Mony Ullas , Zehir Ahmet , Moreira Andre L. , Meyers Paul A. , Chiosis Gabriela , Moore Malcolm A.S.
Published: March 2020

3101

Background: Heat shock protein (HSP) 90 regulates the disposition and activity of a large number of deregulated proteins in Ewing sarcoma. We have shown pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor developed at MSKCC, in Ewing sarcoma. Unfolded proteins as a result of HSP90 inhibition are degraded via the ubiquitin-proteasome pathway or the autophagy pathway. We investigated the effects of combined inhibition of HSP90 and the proteasome pathway. Methods: We studied the effects of PU-H71 and bortezomib alone and in combination on cell proliferation and viability in multiple Ewing cell lines, benign stromal cells and hematopoietic stem cells. We performed cell cycle analysis, clonogenic assay, immunoblot analysis, reverse phase protein array and in vivo experiments in NOD/SCID IL2R gamma null (NSG) mice using the A673 cell line transduced with GFP luciferase. Using A673 metastatic model in NSG mice, we investigated the disease burden when treated with PU-H71, bortezomib and in combination. Results: In vitro, PU-H71 and bortezomib treatment resulted in caspase mediated cell death in a dose-dependent and time-dependent manner. Using PU-H71 beads we showed that some of the critical proteins, including IGF1R, hTERT and EWS-FLI1, are stabilized by HSP90. Exposure to PU-H71 resulted in depletion of AKT, ERK, MYC, C-kit, IGF1R and EWS-FLI1. Combination index (CI)-Fa plots and normalized isobolograms indicated synergism between PU-H71 and bortezomib. We noted increased expression of cleaved PARP and cleaved caspase 3 when Ewing cell lines were exposed to a combination of PU-H71 and bortezomib. Based on PK studies we treated mice (4 groups) using vehicle, PU-H71 75mg/kg i.p three times/wk, bortezomib 0.8mg/kg i.v twice/wk or a combination of PU-H71 and bortezomib for 4 wk. Ewing xenografts were significantly inhibited when treated with combination of PU-H71 and bortezomib compared to vehicle or either drug alone. Conclusions: Both PU-H71 and bortezomib have single agent activity against Ewing sarcoma. However they exhibit synergism when combined in in vitro and in vivo models providing a strong rationale for clinical evaluation in Ewing sarcoma.
Effect of 3-5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: FACS randomized controlled trial.
Authors: Mant David , Perera Rafael , Gray Alastair , Rose Peter , Fuller Alice , Corkhill Andrea , George Steve , Little Louisa , Regan Scott , Mellor Jane , Pugh Sian Alexandra , Northover John , Weaver Andrew , Barsoum Gamal , Tan Li Tee , Mortensen Neil , Scholefield John , Wasan Harpreet , Ferry David , Primrose John Neil
Published: March 2020

3500

Background: Intensive long-term follow-up after surgery for colorectal cancer is common practice but neither the actual benefit nor the optimal methodology is known. Methods: Pragmatic factorial randomised controlled trial in 39 UK hospitals, comparing minimum follow-up (which included a single CT scan at 12-18 months) with 3-6 monthly blood carcinoembryonic antigen (CEA) testing and 6-12 monthly computerised tomography (CT) imaging of the chest, abdomen and pelvis following 1202 participants for 3-5 (mean 3.7) years. Results: The proportion of participants with recurrence treated surgically with curative intent was lower than predicted (6.0% overall) but was about 3x higher in the more intensive than minimum follow-up arms (p=0.019). The adjusted odds were 2.7 for CEA only (p=0.035) and 3.4 for CT only (p=0.007); the absolute differences in detection rate in the more intensive arms compared to minimum follow-up were 4.3-5.7% (5.8-8.0% per protocol). Combining CEA and CT provided no additional benefit (adjusted odds for CT+CEA arm = 2.9). The absolute difference in the proportion of participants with recurrence treated surgically with curative intent in the factorial comparison was 1.4% for CEA (p=0.28) and 2.8% for CT (p=0.04). There was no statistical difference in colorectal cancer deaths nor overall deaths in the minimum compared to the intensive follow-up arms. Conclusions: Both regular CEA measurement and CT scanning result in significantly higher rates of diagnosis of operable recurrent colorectal cancer compared to minimal follow up. There is no benefit in monitoring with both CEA and CT. To date no difference in the overall mortality has been demonstrated. CEA monitoring combined with a single CT scan at 12-18 months seems likely to be cost effective. Clinical trial information: 41458548.
Efficacy and safety according to age subgroups in AVEX, a randomized phase III trial of bevacizumab in combination with capecitabine for the first-line treatment of elderly patients with metastatic colorectal cancer.
Authors: Saunders Mark P. , Lang Istvan , Marcuello Eugenio , Lorusso Vito , Ocvirk Janja , Shin Dongbok , Jonker Derek J. , Osborne Stuart , Loeffler Markus , Waterkamp Daniel , Cunningham David
Published: March 2020

3521

Background: Elderly patients (pts) are underrepresented in clinical trials. The open-label phase III trial AVEX evaluated the benefit of adding bevacizumab (BEV) to capecitabine (cape) in elderly pts with previously untreated metastatic colorectal cancer (mCRC). This analysis explores clinical outcomes by age subgroup. Methods: In AVEX, 280 pts ≥70 y with mCRC for whom single-agent chemotherapy was deemed appropriate, were randomized to first-line cape (1000 mg/m2bid days 1–14) alone (n=140) or with BEV (7.5 mg/kg) q3w (n=140). The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), overall response rate, and safety. The study was powered to show a difference in PFS but not OS. A post hoc analysis was conducted to assess PFS, OS, and safety in pts 70–74 y, 75–79 y, and ≥80 y. Results: Median age was 76 y (range, 70–87). In the overall population, BEV + cape significantly prolonged PFS compared with cape (median 9.1 vs 5.1 mo; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.41–0.69; p<.001). Differences in OS did not reach statistical significance in the overall population (HR, 0.79; 95% CI, 0.57–1.09; p=.182). Treatment was well tolerated. Results according to age are shown (Table). Conclusions: The addition of BEV to cape was associated with significant improvements in PFS in the overall elderly mCRC population and within age subgroups. The safety profile of BEV + cape was consistent across age groups. Clinical trial information: NCT00484939. [Table: see text]
Prospective analysis of UGT1A1 genotyping for predicting toxicities in advanced colorectal cancer (aCRC) treated with irinotecan (IRI)-based regimens: Interim safety analysis of a Japanese observational study.
Authors: Ichikawa Wataru , Uehara Keisuke , Minamimura Keisuke , Tanaka Chihiro , Takii Yasumasa , Sadahiro Sotaro , Miyauchi Hideaki , Shinozaki Katsunori , Miyagaki Takuya , Otsuji Toshio , Kambara Takeshi , Morita Satoshi , Ando Yuichi , Okutani Yukihiro , Sugihara Masahiro , Sugiyama Toru , Ohashi Yasuo , Sakata Yuh
Published: March 2020

3535

Background: UGT1A1*6 and UGT1A1*28 are risk factors for severe IRI-related toxicities in Asians, but recommended IRI doses based on UGT1A1 genotypes and other risk factors are unclear. We conducted a prospective analysis to examine the correlation between UGT1A1 genotypes and the efficacy and safety of IRI-based regimens in Japanese aCRC patients (pts), (NCT 01039506). Methods: Pts who had histologically confirmed aCRC, PS of 0–2, received IRI-based regimens (FOLFIRI, IRI+S-1, IRI monotherapy), were UGT1A1 genotyped, and provided written informed consent were included. UGT1A1 polymorphisms were analyzed and categorized into 3 groups: wild (*1/*1), hetero (*1/*6, *1/*28), and homo (*6/*6, *6/*28, *28/*28). Detailed toxicities in the first 3 months of treatment were prospectively recorded. For interim safety analysis, incidences of grade 3–4 (severe) toxicities were compared among UGT1A1 genotypes and a logistic regression model was used to predict the risk of severe toxicities. Severe toxicities and associated risk factors were predicted using a nomogram and bootstrap validation was performed. Results: We enrolled 1376 pts between October 2009 and March 2012. At the time of abstract submission, toxicity data of 504 pts were available; 46% pts had wild, 44% hetero, and 11% homo polymorphisms. FOLFIRI was administered to 63% pts. Severe neutropenia developed during the first 3 months of treatment in 33% pts: 36% in hetero [OR, 1.5; 95% CI, 1.0–2.3], 47% in homo (OR, 2.3; 95% CI, 1.2–4.4), and 28% in wild. Severe diarrhea incidence was 5%, which did not correlate with UGT1A1 genotypes. Multiple logistic regression model included regimen, initial IRI dose, gender, age, UGT1A1 genotype, and PS as predictors of severe neutropenia in the first treatment cycle. The resulting nomogram demonstrated good accuracy in predicting severe neutropenia, with a bootstrap-corrected concordance index of 0.74. Conclusions: Considering UGT1A1 genotype along with other clinical factors is important for managing pts undergoing IRI-based regimens. Our presentation will provide analysis of data from more than 1000 pts. Clinical trial information: NCT01039506.
Using quantitative sensory testing as an early predictor of chronic oxaliplatin neuropathy in gastrointestinal cancer patients.
Authors: Reddy Sangeetha Meda , Kwon Nancy , Helenowski Irene B. , Harden Robert Norm , Paice Judith A. , Nimeiri Halla Sayed , Mulcahy Mary Frances , Benson Al B. , Vergo Maxwell Thomas
Published: March 2020

3540

Background: Acute oxaliplatin neurotoxicity has been shown to be predictive of chronic neuropathy, a devastating irreversible adverse effect of oxaliplatin. Our study was designed to test the utility of quantitative sensory testing (QST) to measure acute oxaliplatin neurotoxicity at early time points to identify those at risk for developing chronic neuropathy. Methods: Gastrointestinal cancer patients receiving 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy were evaluated over a 1 year period for development of acute and chronic oxaliplatin neurotoxicity: before starting FOLFOX, 1 hour into oxaliplatin infusion, before cycles 2, 4 and 12, and 1 year after start of treatment. Patients underwent QST to measure thermal and mechanical sensitivities, vibration detection, pain sensation, and fine motor skills. Chronic neuropathy was measured using National Cancer Institute Common Toxicity Criteria for Adverse Events version 4. Results: We conducted analysis of 18 patients that have reached the 1 year followup period. We found thermal QST measured during cycle 1 infusion, which is indicative of acute neurotoxicity, to be predictive of 1 year neuropathy. Decreased cold detection intrainfusion during cycle 1 relative to baseline scores yielded a significant correlation to chronic neuropathy scores (rs= -0.53, p=0.03) and predicted grade 2 or 3 neuropathy (p=0.048). Furthermore, decreased cold detection scores intrainfusion showed trend towards correlation to neuropathy scores (rs= -0.45, p=0.07) and prediction of grade 2 or 3 neuropathy (p=0.07). Additionally, patients with higher tolerance to cold and heat intrainfusion were at higher risk for grade 1 or higher neuropathy (p=0.057 for cold pain, p=0.03 for heat pain). We also found decreased mechanical detection scores using von frey filaments as early as cycle 2 were correlated to 1 year neuropathy scores (rs=0.52, p=0.03) and predicted development of grade 2 or 3 neuropathy (p=0.008). Conclusions: We can use QST to identify high risk patients that are likely to develop chronic neuropathy at 1 year, allowing for targeted use of preventive measures to decrease the incidence of this debilitating adverse effect.
Association between c-Met expression and tumor recurrence in colorectal cancer patients after liver resection.
Authors: Shoji Hirokazu , Yamada Yasuhide , Taniguchi Hirokazu , Okita Natsuko , Takashima Atsuo , Honma Yoshitaka , Iwasa Satoru , Kato Ken , Hamaguchi Tetsuya , Shimada Yasuhiro
Published: March 2020

3559

Background: c-Met is a receptor for hepatocyte growth factor that has been implicated in the pathogenesis and growth of a wide variety of human malignancies, including colorectal cancer (CRC). The aim of the present study was to clarify the correlation between c-Met protein expression in the primary lesion and relapse-free survival (RFS) in patients who had undergone curative hepatectomy for colorectal metastases. Methods: Between January 2004 and December 2009, formalin-fixed paraffin-embedded sections of surgical specimens from 108 CRC patients who had undergone hepatectomy were obtained at a single center. We performed immunohistochemical staining to detect c-Met expression. c-Met expression levels were scored dependent on staining intensity; 0, negative; 1, weak; 2, moderate; 3, strong. We defined scores 0 and 1 as c-Met-low, and scores 2 and 3 as c-Met-high. The Kaplan-Meier method and Cox proportional hazards model were used to investigate relationships between c-Met expression, patient characteristics, and RFS. Results: We identified 65 males and 43 females with a median age of 62 years. A total of 53% of patients underwent simultaneous resection of primary and metastatic liver lesions, and the others underwent metachronous resection. High levels of c-Met expression (c-Met-high) in the primary tumor were observed in 52% of patients. There were no differences in terms of size or number of metastatic liver lesions between the c-Met-low patients and the c-Met-high patients. RFS was significantly shorter in the c-Met-high patients (9.7 months) than that in the c-Met-low patients (21.1 months) in primary tumors (p=0.013). Multivariate analyses demonstrated that c-Met-high (hazards ratio [HR], 1.73; 95% confidence interval [95% CI], 1.08-2.79 for c-Met-high vs. c-Met-low) and hepatic resection for synchronous disease (HR, 2.17; 95% CI, 1.36-3.46 for synchronous vs. metachronous resection) were associated with worse RFS. Conclusions: High levels of c-Met expression in the primary tumor were associated with shorter RFS after hepatic metastasectomy.
Tumor perivascular PDGFBR as an independent prognostic factor in metastatic colorectal cancer.
Authors: Lindh Maja Bradic , Mezheyeuski Artur , Glimelius Bengt , Pfeiffer Per , Kure Elin , Ikdahl Tone , Skovlund Eva , Sorbye Halfdan , Tveit Kjell Magne , Pietras Kristian , Birgisson Helgi , Mulder Jan , Guren Tormod Kyrre , Ostman Arne
Published: March 2020

3571

Background: New vessel formation is an essential factor for tumor growth and metastasis. Tumor vessels show reduced and variable pericyte coverage. Several pericyte markers have been identified, including platelet-derived growth factor receptor beta (PDGFbR), smooth muscle α-actin (ASMA) and desmin. Variability in pericyte status and its prognostic significance remains largely uncharacterized in colorectal cancer (CRC). The aim of the present study was to perform a preliminary analysis of the variability in expression of the three pericyte markers and to investigate the potential prognostic significance of perivascular PDGFbR (PV-PDGFbR). Methods: A population-based cohort was used for double-staining, performed on 100 tumors with CD34 and above-named pericyte markers. For the rest of the study a metastatic CRC (mCRC) collection from the phase III NORDIC-VII study was used. Analyses were performed on a tissue microarray with tumor material from 328 out of the 566 patients in the intention to treat population. All tumors and corresponding normal tissue were scored by immunohistochemistry (IHC) with regard to PV-PDGFbR. 255 and 97 cases were analyzed by IHC with regard to perivascular ASMA and microvessel density (MVD), respectively. Results: Analyses of the double-staining revealed independent and variable expressions of all three pericyte markers. Analyses of the NORDIC-VII cohort revealed two prognostic groups with low and high PV-PDGFbR expression. Median OS was 14.3 mo for PV-PDGFbR-low tumors (N=22) vs. 22.9 mo for PV-PDGFbR-high (N=306) tumors (HR=1.95; 95% CI 1.20-3.16; log-rank p=0.007). Multivariate analysis, including WHO performance status, alkaline phosphatase level and BRAF mutation status confirmed PV-PDGFbR as an independent prognostic factor of OS (HR=1.75; 95% CI 1.07-2.84; p=0.025). PV-PDGFbR was not significantly linked to perivascular ASMA or MVD. PV-PDGFbR in normal tissue was not associated with survival. Conclusions: CRC display a previously un-recognized variability in pericyte characteristics. Low tumor PV-PDGFbR level is associated with worse prognosis in patients with mCRC, in a manner independent of performance status, alkaline phosphatase levels and BRAF status.
Primary tumor resection in metastatic colorectal cancer (mCRC): A prospective cohort study.
Authors: Wong Shu Fen , Field Kathryn M , Kosmider Suzanne , Tie Jeanne , Wong Hui-li , Tran Ben , Tacey Mark , Shapiro Jeremy , McKendrick Joseph , Gibbs Peter
Published: March 2020

3584

Background: The role of primary tumor resection in patients presenting with mCRC remains controversial. Previously reported survival benefits associated with primary tumor resection may not translate in the modern era of systemic therapies. We examined the impact of primary tumor resection on survival in a modern cohort of mCRC patients. Methods: Patients were identified using a clinician-designed mCRC registry involving 15 participating Australian sites from mid 2009. Patients were excluded if planned for curative metastasectomy or had incomplete data. Univariate logistic regression and multivariate cox regression was utilized to identify significant associations between resection, clinical variables and survival outcomes. Results: We identified 682 mCRC patients with median follow up 20 months. 40% (n = 275) had their primary in-situ. Rates of primary resection were higher for age > 70 years (OR 1.66 95% CI [1.22 – 2.26], p = 0.001) and Charlson score ≥3 (OR 1.50 [1.10 – 2.06], p = 0.011). Lower resection rates were observed for rectal v colon primary (OR 0.39 [0.28 – 0.55], p < 0.001), liver metastases (OR 0.59 [0.42 – 0.82], p = 0.002) and ECOG 2 - 4 (OR 0.64 [0.45 – 0.92], p = 0.015). There was a significant survival advantage for pts with primary tumor resection (median OS 21.3 vs 16.8 months; HR 0.63, p < 0.001), even when adjusting for known prognostic factors in a multivariate analysis (HR 0.56 [0.44 – 0.72], p < 0.001). Multivariate analyses also demonstrated that age > 70 years (HR 1.32 [1.03 – 1.71], p = 0.031) and ECOG ≥ 2 (HR 3.17 [2.43 – 4.15], p < 0.001) were significantly associated with poorer outcomes; whereas chemotherapy use (HR 0.61 [0.45 – 0.84], p = 0.002), bevacizumab use (HR 0.68 [0.52 – 0.89], p = 0.005) and rectal primary (HR 0.69 [0.53 – 0.91], p = 0.009) predicted improved survival. Conclusions: Our study suggests that primary tumor resection is associated with significant survival advantages for mCRC patients in the modern era of systemic therapies. The 40% of primary cancers in-situ is higher than previous mCRC studies and suggests a tendency for non-operative intervention in Australia. Further analysis aimed at examining the impact of other confounding variables such as tumor burden is ongoing and will be presented.
Peripheral blood monocytes as biomarkers for colorectal cancer.
Authors: Prenen Hans , Hamm Alexander , Wenes Mathias , Delamarre Estelle , D'Hoore Andre , Hendlisz Alain , Rothe Francoise , Sarmiento Roberta , Tejpar Sabine , Van Cutsem Eric , Schmidt Thomas , Gasparini Giampietro , Weitz Juergen , Mazzone Massimiliano
Published: March 2020

3588

Background: Peripheral blood monocytes (PBM) represent a reservoir of inflammatory cells that contribute to cancer progression. When recruited into tumors, monocytes give rise to either macrophages or dendritic cells. Tumor-derived soluble factors can influence the differentiation of tumor-associated macrophages (TAMs) and drive their phenotype to either tumoricidal (M1) or pro-tumorigenic macrophages (M2). We hypothesized that PBM might change their phenotype already when in circulation and can be used as potential markers for early diagnosis of colorectal cancer (CRC) and its progression to metastatic disease. Methods: Monocytes were isolated by using magnetic microbeads conjugated to antibodies against CD14. In a monocentric training set we included 55 (27 non metastatic (NM), 38 metastatic (M)) untreated CRC patients. The third group included age and gender matched healthy volunteers (HV). Following RNA extraction, gene expression profiles of PBM were investigated by high throughput screening using Illumina. Statistical analysis was done on the microarray expression data to delineate a disease specific signature. A cut off was set to select the genes showing a minimum fold change of 1,5. A validation study was performed in three additional major oncological centers throughout Europe. Results: There was a broad overlap in the gene signature of PBM from NM and M patients, indicating that this signature already exists in an early stage. Then we assessed the performance of the gene signature of cancer versus HV as diagnostic tool, in particular the sensitivity and specificity, which were remarkably high in the ROC analysis. Out of 40 differentially expressed genes, 21 genes were confirmed by qRT-PCR analysis on samples processed independently. In the validation study the number of genes was downsized to a 12 gene signature without loss of specificity and sensitivity. Conclusions: This first biomarker study of PBM in CRC suggests an ‘imprinting’ of PBM by the tumor in CRC patients. Since the imprinting profile might also be reversed, the PBM signature might not only be useful in CRC diagnosis, but also for the follow-up of treated CRC patients. Overall, our data offer new opportunities to develop a non-invasive test for CRC detection and monitoring.
Association of body mass index (BMI) with overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) who received targeted therapies (TT).
Authors: Patel Gargi Surendra , Ullah Shahid , Beeke Carol , Hakendorf Paul , Padbury Rob , Price Timothy Jay , Karapetis Christos Stelios
Published: March 2020

3592

Background: Preclinical data suggest that adiposity activates pro-inflammatory and insulin-dependent pathways which may lead to resistance to TT, e.g., bevacizumab (Bev) or cetuximab (Cet). Only two retrospective trials have studied the relationship between BMI and outcome for mCRC pts who received TT, with conflicting results. Our aim was to compare OS across BMI groups for mCRC pts treated with TT. Methods: Retrospective data, pertaining to clinical characteristics and outcome, were obtained from the South Australian Registry for mCRC from Feb 2006-Oct 2012. The BMI at first treatment was grouped as Normal (N) = 18.5- <25, Overweight (OW) = 25- <30, Obese I(Ob1) = 30- <35, Obese II (Ob2)≥35. Results: Of 1,174 pts, 39% were OW, 15% Ob1 and 7% Ob2. 352 pts received chemo+TT (Bev, Cet, panitumumab (Pan) and/or regorafenib) and 814 chemo alone. Baseline characteristics were similar across all BMI groups except for type of mCRC: N pts were more likely than obese pts to have synchronous CRC (77.9% vs 56-69.7% for obese). On adjustment for age, sex, synchronous disease, metastatic sites, number of lines of chemo and TT, median OS was longer for N versus OW or Ob1 pts with chemo+TT (35.4 vs 24.9 or 22.7 mons, Table) with no difference in OS for chemo alone. Only N gp pts had an improvement in OS on the addition of TT to chemo. On breakdown by type of TT, OW and Ob1 pts had a poorer outcome with Bev but not with EGFR TT. Conclusions: The BMI is an independent predictor for a poorer outcome for OW and OB1 pts with chemo+TT, specifically for pts receiving Bev. The OW and OB1 patients may be a target group for lifestyle and nutrition advice to improve OS with TT. Prospective studies are required to validate this finding. [Table: see text]