bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase Ib dose-escalation trial of the AKT inhibitor (AKTi) MK2206 in combination with paclitaxel (P) and trastuzumab (H) in patients (pts) with HER2-overexpressing (HER2+) cancer.
Authors: Chien Amy Jo , Truong Thach-Giao , Melisko Michelle E. , Moasser Mark M. , Kelley Robin Katie , Korn Michael , Ko Andrew H. , Pantoja Norma , Reinert Anne , Grabowsky Jennifer A. , Magbanua Mark Jesus M , Rugo Hope S. , Munster Pamela N.
Published: March 2020

2605

Background: AKT plays a key role in the survival, resistance, and overall aggressive pathogenesis of HER2+ malignancies, suggesting that AKTis may be of therapeutic value. MK2206 is a selective allosteric AKTi that has demonstrated synergy in combination with both H and P in preclinical studies. Methods: We conducted a phase 1b study of MK2206 in combination with weekly P 80 mg/m2 and H 2 mg/kg in pts with HER2+ solid tumors. MK2206 was given orally at a starting dose of 135 mg once a week (QW). Dose escalation was performed using a modified Ji method. The maximum tolerated dose (MTD) was defined as the dose level resulting in 3 or fewer dose limiting toxicities (DLTs) in 11 pts, then confirmed in 4 additional pts. Circulating tumor cells and PK samples were collected for all pts. Results: A total of 17 pts were enrolled, and 15 pts were evaluable for toxicity. All pts had HER2+ tumors (11 breast, 3 gastric, 1 esophageal). Based on interim toxicity data from other studies, the dose of MK2206 was not escalated beyond 135 mg QW. All 15 pts were treated at this dose level which was determined to be tolerable. Two DLTs were observed including grade 3 rash and grade 3 neutropenia resulting in a >7 day treatment delay. There were no severe adverse events (AEs) related to study treatment. Other grade 3/4 AEs were neutropenia (6 pts), febrile neutropenia (1 pt), peripheral neuropathy (1 pt), and depression (1 pt). The most common all-grade AEs include rash (13 pts), hyperglycemia (13 pts), neutropenia (13 pts), peripheral neuropathy (10 pts), diarrhea (9 pts), fatigue (9 pts), anorexia (9 pts), stomatitis (7 pts). Of the 14 pts evaluable for response, 9 pts (64%) had tumor response (2 CR, 7 PR), and 4 pts had SD. The median duration of response was 5.5 months. Pts were heavily pretreated (median lines of prior therapy 3, 11 prior taxane, 12 prior H). Conclusions: MK2206 at a dose of135 mg QW in combination with weekly P and H is safe and well-tolerated. 135 mg QW is the recommended phase 2 dose for this combination. Preliminary data indicate significant clinical activity in pts with HER2+ tumors despite extensive prior therapy. MK2206 is now being tested in the neoadjuvant ISPY2 trial. Clinical trial information: NCT01235897.
Use of tumor growth rate (TGR) to provide useful clinical information in phase I trials and reveal clear drug-specific profiles.
Authors: Ferte Charles , Fernandez Marianna , Hollebecque Antoine , Koscielny Serge , Levy Antonin , Bahleda Rastislav , Massard Christophe , Soria Jean-Charles
Published: March 2020

3010

Background: The evaluation of treatment response by RECIST does not take into account the tumor growth kinetics along the treatment sequence and may induce misleading information regarding the evaluation of the drug activity. TGR incorporates the time between the tumor evaluations and allows for a dynamic and quantitative evaluation of the tumor kinetics. How TGR is modified along the introduction of experimental therapeutics and is associated with outcome in phase I patients remains unknown. Methods: Medical records from all patients (n=304) prospectively treated at Institut Gustave Roussy in 19 phase I trials between 2009 and 2011 were analyzed. TGR was computed both during the pre-treatment period (REFERENCE) and between baseline and first evaluation (EXPERIMENTAL). TGR is defined as: log 10 (Vt/V0)/dt and is represented as a percentage increase of tumor volume per month for clinical relevance. The associations between TGR, RECIST, the most commonly used prognostic scores (ECOG, RMH score, PFS ratio) and the outcome (OS, PFS) were computed (multivariate analysis). The effect of treatment, prognostic scores, histology, and the number of previous treatment lines on TGR were assessed. Results: Overall, we observed a reduction of TGR between the REFERENCE vs. EXPERIMENTAL periods (11.5 vs. 1.5, P<.0001). Although most of the patients were classified as stable disease (57%) or progressive disease (28%) by RECIST at the first evaluation, 88% and 69% of them exhibited a decrease in TGR, respectively. TGR reveals clear drug specific profiles along the 19 experimental regimens tested, allowing for an early evaluation of the drug activity. The TGR decrease was associated with both PFS (P=.004) and OS (P=.001) and remained significant even after adjustment to the other prognostic scores for phase I patients. Conclusions: Adding TGR assessment in phase I patients is simple and provides clinically relevant information: (i) It allows for an early and precise assessment of the tumor growth, (ii) It reveals drug-specific profiles, suggesting its potential use for the early assessment of drug activity, (iii) TGR is independently associated with prognosis in phase I patients.
Ipilimumab in the real world: The U.K. expanded access programme (EAP) experience in advanced melanoma.
Authors: Ahmad Saif , Qian Wendi , Ellis Sarah Gabrielle , Khattak Muhammad Adnan , Gupta Avinash , Thillai Kiruthikah , Board Ruth E. , Nobes Jenny , Dalgleish Angus , Grumett Simon Aird , Maraveyas Anthony , Danson Sarah , Talbot Toby , Marples Maria , Plummer Ruth , Kumar Satish , Middleton Mark R. , Larkin James M. G. , Ottensmeier Christian , Corrie Philippa
Published: March 2020

3018

Background: Since publication of the registration trial in 2010 (Hodi et al, NEJM 2010;363:711-23), real world use of ipilimumab (Ipi) in previously treated advanced melanoma patients has extended beyond the specific trial entry criteria of ECOG PS 0-1. We undertook a review of UK patients (pts) treated in the international EAP prior to European licensing of Ipi in August 2011, to compare real world survival outcomes. Methods: UK clinicians registered in the EAP provided anonymised data using pre-specified variable fields for all pts. The EAP stipulated pts should have previously treated, unresectable stage III or IV metastatic melanoma and receive Ipi 3 mg/kg, 3 weekly IV, for up to 4 cycles. Response using RECIST criteria was assessed 12 weekly. Grade ≥3 adverse events (AEs) using CTCAE v3.0 were collected. Results: To date, information on 162 pts has been received from 16 UK sites. Primary sites were: 78% cutaneous, 4% ocular, 1% mucosal, 17% unknown. 78% pts had M1c disease, 14% had brain metastases. No prior therapies ranged from 0-4, 72% pts received 1 prior therapy. Median age was 60 years, men>women (1.6:1). ECOG PS was: 38% 0, 47% 1, 14% 2, 1% 3. BRAF status was known in 38% cases and WT in 75% of these. 19% pts were on steroids at baseline. No cycles delivered was 4 in 52%, 3 in 13%, 2 in 16%, 1 in 17% pts. Most frequent reason for stopping early was clinical evidence of disease progression (71%), death (16%) or unacceptable AE (12%). 32% pts experienced a grade ≥3 AE, the most common being diarrhoea (13%) and fatigue (8%). Complete and partial responses were reported in 1% and 21% of treated pts. At median follow-up of 17 months, median progression free survival and overall survival (OS) were 2.8 and 5.7 months, 1 year OS was 30%. Comparing outcomes of various pt subgroups, the strongest prognostic factor for OS was ECOG PS at the start of treatment (p<0.0001). For pts with PS 0 or 1, median OS was 8.8 months (compared with 10 months in the registration trial). More detailed safety and efficacy data on pt subgroups will be presented. Conclusions: This review, representing the largest Ipi EAP UK dataset, reports overall poorer survival outcomes than in the registration trial, but pts with similar characteristics to the trial population lived longer.
Clinical guideline on the prophylactic use of G-CSF on neutropenia by chemotherapy.
Authors: Rivera-Luna Roberto , Gonzalez-Garay Alejandro G , Velasco-Hidalgo Liliana , Mayorga-Butron Jose Luis
Published: March 2020

3050

Background: Febrile neutropenia (FN) is common in patients with chemotherapy. It requires conventional treatment, however, many studies have reported that G-CSF reduces the incidence of FN; the results were not clear and the physicians use it at their discretion. In this guideline we evaluated the efficacy and safety of the prophylactic use of G-CSF. Methods: We analyzed controlled trials (G-CSF, pegylated form or placebo) given to adult or pediatric patients with chemotherapy for leukemia (LEU), lymphoma and solid tumors (L&ST) or stem cell transplant (SCT), without infections and large radiation ports. Two independent reviewers applied CONSORT to determine the methodological quality; for ranking the evidence we used GRADE and the recommendations were developed by Delphi method. We developed subgroups according to age and type of intervention to analyze the outcomes (risk, duration, severity of FN and adverse events). We performed random-effects or fixed-effects meta-analysis methods according to their heterogeneity. Results: Of 1,776 studies,112 were included. For the risk of FN between C-GSF or pegylated form vs placebo found that G-CSF reduces the risk in adults with LEU (RR 0.89, 95% CI 0.81-0.98; p=0.024), L&ST (RR 0.758, 95% CI 0.68-0.84; p=0.000) and SCT (RR 0.85, 95% CI 0.74–0.97, p=0.017). The risk of developing severe neutropenia reduces in the adults with L&ST with the factor (RR 0.79, 95% CI 0.71-0.88; p=0.000) and pediatric patients with LEU (RR 0.789, 95% CI 0.71-0.88; p=0.000). While the duration of neutropenia in children with L&ST the time reduces with the factor (SMD -0.559; 95% CI -0.841 to -0.28; p=0.000). The G-CSF vs pegylated form, the evidence was inconclusive. Conclusions: When the risk and duration of neutropenia is present we suggest the use of G-CSF in adult and pediatric patients. For adults, we suggest the use of pegylated form, but for pediatric patients we do not have a specific suggestion because the evidence is nonexistent, so it is necessary to carry out clinical trials to obtain evidence.
Generation of tumor-specific cytotoxic T-lymphocytes from peripheral blood of colorectal cancer patients for adoptive immunotherapy.
Authors: Bregni Marco , Del Bue Serena , Galli Andrea , della Valle Alberto , Ferrante Pasquale , Carluccio Silvia
Published: March 2020

3056

Background: Adoptive T-cell transfer (ACT) using autologous TIL, grown ex vivo and then infused into the cancer patient after lymphoablative chemotherapy, has emerged as an effective treatment for patients with metastatic melanoma. However, this approach has been hampered by the difficulty of isolating TILs from tumors other than melanoma, and of amplifying a sufficient quantity of autologous tumor-reactive T cells. So we decided to adopt a recently described procedure for generating in vitro large numbers of anti-tumor HLA-restricted CTLs, by stimulating patient’s CD8-enriched peripheral blood mononuclear cells (PBMCs) with DCs pulsed with apoptotic solid tumor cells (TCs) as a source of tumor antigens. Methods: 61 patients affected by CRC were enrolled. Tumor biopsies were obtained at surgery, together with 100 ml of heparinized peripheral blood. Tumors were dissociated to a single-cell suspension and cultured in order to obtain tumor cell line from each patient. Dendritic cells (DCs) were generated from previously separated PBMCs, using a magnetic positive selection of CD14+ monocytes, cultured in presence of Interleukin-4 and recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). Anti-tumor cytotoxic T lymphocytes (CTLs) were elicited using DCs as antigen-presenting cells, autologous apoptotic tumor cells as source of antigens and T CD-8 lymphocytes enriched effectors, with weekly stimulation. To evaluate the cytotoxic activity of CTLs, interferon-γ (IFN-γ) secretion was assessed by ELISPOT. Results: Tumor cell lines and DCs were obtained from 19 out of 61 patients. ELISPOT was performed so far for 6 patients: strong IFN-γ secretion was detected at the third, fourth and fifth stimulations for one patient and at the second for another patient, whereas for three patients a weak secretion was detected during the second and the third stimulations. CTLs from one patient did not react to the stimulations. Conclusions: Generation of CTLs suitable for ACT immunotherapy is feasible from peripheral blood in patients with CRC.
A phase I study of ad.p53 DC vaccine in combination with indoximod in metastatic solid tumors.
Authors: Soliman Hatem Hussein , Minton Susan E. , Han Hyo S. , Ismail-Khan Roohi , Mahipal Amit , Janssen William , Streicher Howard , Vahanian Nicholas N. , Link Charles J. , Ramsey William Jay , Antonia Scott J. , Sullivan Daniel
Published: March 2020

3069

Background: Indeolamine 2,3 dioxygenase (IDO) is an inducible tryptophan-catabolizing enzyme that downregulates the immune system. Many tumor cell types overexpress IDO to avoid elimination by infiltrating cytotoxic T cells. 1-methyl-D-tryptophan (1-MT, indoximod) is an IDO pathway modulator. Published preclinical data suggested that blockade of IDO with indoximod enhances the immunologic response to dendritic cell (DC) vaccines. Ad.p53 is an adenovirus used for generating DC vaccines directed against p53 epitopes. Ad.p53 when given to previously treated SCLC patients significantly increased their response rate to subsequent chemotherapy. The primary goal in phase I is the MTD of indoximod +Ad.p53. Methods: This phase 1 study used a 3+3 design with 7 indoximod dose levels (DL) (100 mg, 200 mg, 400 mg, 800 mg QD then 800 mg, 1,200 mg, and 1,600 mg PO BID)+up to 6 fixed dose Ad.p53 DC vaccinations q2wks. Standard eligibility/exclusion criteria applied along with exclusion of patients previously treated with ipilimumab. Treatment will continue until disease progression or unacceptable toxicity. DLT rules are 1st cycle ≥G3 AE related to treatment. Results: Total patients accrued to phase I=32. Types treated were 22 breast, 3 colon, 2 gastric, 1 ovarian, 1 NSCLC, 1 oropharynx, 1 sarcoma. No. of patients treated at DL 1-7 were 3, 3, 4, 6, 6, 3, 6, respectively. Toxicities possibly related to therapy were G1-2 fatigue, nausea, constipation, diarrhea, photosensitivity, hyponatremia, hyperglycemia, AST elevation. The MAD was 1,600 mg BID of indoximod with no DLTs noted. All discontinuations were due to progression of disease. No objective responses to study therapy were noted, but 6/10 breast patients treated with carboplatin/gemcitabine or gemcitabine alone responded to salvage therapy. Conclusions: The combination of indoximod+Ad.p53DC vaccine was well tolerated.The RP2D of indoximod is 1,600 mg BID + Ad.p53DC vaccine. There may be a chemosensitizing effect of Ad.p53DC+indoximod with chemo. The phase II trial in metastatic breast is looking at the response rate of indoximod+Ad.p53DC vaccine followed by salvage carboplatin/gemcitabine in previously treated patients. NCT01042535 Clinical trial information: NCT01042535.
Effect of therapeutic targeting of EMP2 on breast and endometrial cancer stem cells.
Authors: Wadehra Madhuri , Kiyohara Meagan , Ashki Negin , Chan Ann
Published: March 2020

3080

Background: There is increasing evidence that tumor-initiating cancer stem cells (CSCs) contribute to tumor metastasis and therapeutic resistance. In breast and endometrial cancers, metastatic CSCs are defined as CD44+/CD24- and ALDH+, and in this study, we define another marker epithelial membrane protein-2 (EMP2) as a novel target for this population of cells. EMP2 is an oncogene whose expression has been shown to correlate with tumor progression and survival in a number of human cancers including triple-negative breast, ovarian, and endometrial tumors. Methods: A number of cancer cell lines were utilized both in vitro and in vivo to determine if EMP2 expression levels alter the number and expression of CSC markers. To translate this work, EMP2 and ALDH expression were correlated in primary human endometrial and breast cancers. To determine the therapeutic efficacy of our fully-human EMP2 IgG1 antibody, xenografts from breast or uterine cancer were treated, removed, and then reinjected into secondary mice. Results: In this study, we show new evidence that EMP2 is highly expressed in CSCs. High levels of EMP2 increase the tumor forming potential of both endometrial and breast cancer lines. In tumors created from these cells, high levels of ALDH+ expression were also observed. In contrast, reduction in EMP2 decreased CD44 expression and ALDH activity both in vitro and in vivo, with the net consequence of poorly vascularized and slow growing tumors. We have recently developed a novel monoclonal antibody to EMP2 and have started testing its therapeutic efficacy. In vitro treatment with EMP2 IgG1 reduced HIF-1a, CD44, and ALDH levels, ultimately leading to caspase mediated apoptosis. Treatment of breast cancer cells with EMP2 IgG1 reduced tumor load in both subcutaneous and metastatic models of breast and endometrial cancer resulting in a significant improvement in survival. Reinjection of these cells post treatment into secondary mice failed to efficiently form, and histological examination of the tumors revealed significant necrosis and elimination of ALDH+ CSCs. Conclusions: These results suggest that targeting EMP2 may reduce CSCs and represent an attractive target for further therapeutic development.
Evaluation of cyclophosphamide as an immune enhancer for the NY-ESO-1/ISCOMATRIX vaccine in patients with metastatic melanoma.
Authors: Klein Oliver , Davis Ian D. , McArthur Grant A. , Haydon Andrew Mark , Parente Phillip , Dimopoulos Nektaria , Jackson Heather , Maraskovsky Eugene , Hopkins Wendie , Stan Rodica , Chen Weisan , Cebon Jonathan S.
Published: March 2020

3093^

Background: We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine in patients with resected melanoma; however the same vaccine induced only a few vaccine antigen specific immune responses in patients with advanced disease. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with the immune-modulator cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine. Methods: LUD2002-013 was an open-label phase II study intended to evaluate the safety and immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine in patients with advanced melanoma. The first cohort of patients received vaccine alone; a second cohort with 19 patients was added after evaluation of responses in Cohort 1 and received vaccine in combination with low-dose cyclophosphamide. Patients received 3 injections of NY-ESO-1 ISCOMATRIX preceded, in Cohort 2, by cyclophosphamide at a dose of 300 mg/m2 every four weeks. Assessment of clinical and immunological responses was undertaken at week 11. Results: Fifteen patients of Cohort 2 completed at least one cycle of vaccination. No objective responses were observed with three patients having stable disease for more than three months. The inclusion of cyclophosphamide into the vaccination protocol did not lead to any significant toxicity. Seven of fourteen patients in Cohort 2 developed a vaccine induced NY-ESO-1 specific CD4 T cell response, a significant increase compared to cohort 1 (p=0.019). No differences were observed in the frequency of vaccine induced antibody or CD8 T cell responses. No change in the frequency of peripheral blood regulatory T cells or myeloid derived suppressor cells was detected. Conclusions: The administration of low dose cyclophosphamide has significantly increased the NY-ESO-1 specific CD4 T cell response of the NY-ESO-1/ISCOMATRIX vaccine in patients with metastatic melanoma. Given the emerging importance of CD4 T cells in tumour regression, the present findings warrant further clinical exploration of combining cyclophosphamide with vaccines and other immune-modulatory agents. Clinical trial information: NCT00518206.
Use of genetic variants in pericyte-driven tumor vessel maturation genes to predict treatment efficacy in mCRC patients treated with FOLFIRI/bevacizumab.
Authors: Volz Nico Benjamin , Zhang Wu , Yang Dongyun , Ning Yan , Stintzing Sebastian , Wakatsuki Takeru , El-Khoueiry Rita Elie , Li Joseph Ethan , Kardosh Adel , Loupakis Fotios , Marmorino Federica , Antoniotti Carlotta , Lenz Heinz-Josef
Published: March 2020

3566

Background: Angiogenesis is maintained by the presence of PDGFB (platelet derived growth factor beta) which binds to the receptor, PDGFRB on pericytes, signaling them to stabilize stalk cells adjacent to tip cells. PDGFB signaling by endothelial tip cells promotes proliferation, migration, and stabilization of pericytes which are closely associated with endothelial cells. VEGF driven angiogenesis in response to tumor hypoxia relies on several genes. Previously, studies showed RALBP1, RGS5, and CSPG4 greatly impact the structure of blood vessels during angiogenesis. Recognizing these genes are important in angiogenesis through pericytes, we investigated the correlation between polymorphisms in these genes and clinical outcomes in patients with mCRC treated with FOLFIRI/bevacizumab (BV). Methods: Genomic DNA was extracted from 455 patients’ blood or tissue treated with first-line BV + FOLFIRI and prospectively enrolled in a prospective pharmacogenomic translational study. Median follow up is 24 months and median PFS and OS were 10.5 and 29.9 months, respectively. Eight functionally significant SNPs; RGS5 (rs1056515, rs2661280), PDGFRB (rs2229562, rs2302271), CSPG4 (rs8023621, rs1127648), and RALBP1 (rs10989, rs329007) were analyzed by PCR-based direct sequencing. All candidate SNPs were analyzed for association with tumor response rate (RR), progression free survival (PFS), and overall survival (OS). Results: Four SNPs showed significant results in the univariate analysis of either OS or PFS. PDGFRB rs2302273 remained significant upon multivariate analysis. Univariate analysis of PDGFRB rs2302273 concluded patients with any T (CT/TT) allele were significantly associated with longer PFS compared to those with CC genotypes (median 10.2 vs 11.6 months, HR=0.78 [95%CI: 0.63-.98], p=0.031, log-rank test) which remained significant upon multivariate analysis (HR=0.73 [95% CI: 0.57-0.92], p=0.008, log-rank test). Conclusions: Our results show that the PDGFRB polymorphism rs2302273 may serve as a prognostic marker for the efficacy of FOLFIRI + BV treatment in patients with mCRC. Studies to confirm and update these preliminary findings are ongoing.
Primary tumor location and expression of mir-664 as a combined biomarker for bevacizumab effectiveness in metastatic colorectal cancer.
Authors: Boisen Mogens Karsboel , Dehlendorff Christian , Linnemann Dorte , Larsen Jim S. , Oesterlind Kell , Hansen Joergen , Nielsen Svend Erik , Pfeiffer Per , Tarpgaard Line Schmidt , Hollander Niels Henrik , Keldsen Nina , Hansen Torben , Jensen Brita Bjerregaard , Hoegdall Estrid Vilma Solyom , Jensen Benny Vittrup , Johansen Julia S.
Published: March 2020

3572

Background: We aimed to identify tissue microRNAs (miRs) that could predict outcome for patients with metastatic colorectal cancer (mCRC) treated with first line bevacizumab (BEV) and chemotherapy (CT) but not for patients treated with CT alone. Methods: Patients with mCRC treated with first line capecitabine and oxaliplatin (CT) with or without BEV at ten hospitals were identified and data was extracted retrospectively. Formalin-fixed paraffin-embedded tissue samples from primary tumors were collected and RNA was purified from 3 x 10 µm sections, without micro-dissection. miR expression was measured using Applied Biosystems TaqMan Custom LDA cards profiling 22 selected miRs in duplicate. The 22 miRs were selected from a previous discovery study profiling 754 miRs. miR expression was related to time to disease progression (TTP) and overall survival (OS) in multivariate analyses using Cox proportional hazards models with adjustment for age, prior adjuvant treatment, and no. of metastatic sites. We have previously found that patients with primary tumors originating in the sigmoid colon and rectum (S+R) experienced a better outcome than patients with other primary tumor locations (caecum to descending colon) when treated with BEV, so our analyses were stratified by primary tumor location. Results: miR expression was measured in samples from 399 patients: 155 samples from the original CT+BEV discovery study, 119 samples from a new CT+BEV cohort, and 125 samples from a CT alone cohort. Expression of miR-664 showed a significant positive association with increasing TTP, OS, and response rate (RR), but only in the cohort of patients with sigmoid colon- and rectal primary tumors treated with CT+BEV (n=183). Conclusions: We have identified a subgroup of patients with mCRC that are likely to benefit from BEV addition to first line CT using the combined information of location of the primary tumor and expression level of miR-664. [Table: see text]
Correlation of hypertension and proteinuria with outcomes in elderly bevacizumab (BEV)-treated patients with metastatic colorectal cancer (mCRC): Analysis of the BECOX and BECA studies.
Authors: Salud Salvia Antonieta , Feliu Jaime , Safont Maria Jose , García-Girón Carlos , Aparicio Jorge , Losa Ferran , Bosch Carlos , Escudero Pilar , Casado Enrique , Jorge Fernández Mónica , Bohn Sarmiento Uriel , Pérez-Carrión Ramon , Carmona Bayonas Alberto , Custodio Ana B. , Maurel Juan
Published: March 2020

3589

Background: Studies suggest a relationship between hypertension, which is common in older patients, and outcome in BEV-treated patients with mCRC. We performed a retrospective analysis of two studies – BECA [Feliu et al BJC 2010; EudraCT 2005-002808-42] and BECOX [NCT01067053] – to determine if hypertension and proteinuria predict outcome in elderly BEV-treated patients. Methods: Patients ≥70 years received capecitabine 1250 mg/m2 bid po on days 1–14 + BEV 7.5 mg/kg on day 1 every 21 days in the BECA study; BECOX patients received capecitabine 1000 mg/m2 bid po on days 1–14 with BEV 7.5 mg/kg and oxaliplatin 130 mg/m2 on day 1 (oxaliplatin discontinued after cycle 6). Primary endpoints were overall response rate (ORR) in BECA and time to progression (TTP) in BECOX. Correlations were investigated for hypertension and proteinuria with ORR, disease control rate (DCR), overall survival (OS) and TTP. Logistic regression was performed to identify factors associated with hypertension and proteinuria. Results: 127 patients were included (BECA n=59; BECOX n=68; 61% male, median age 76 years; ECOG PS 0/1/2 45%/52%/2%). During the study 16% of patients had hypertension and 61% had proteinuria as an adverse event. Hypertension correlated with DCR, OS and TTP but not ORR; proteinuria correlated with ORR and DCR (Table). Development of proteinuria or hypertension in the first 2 cycles did not correlate with efficacy. Risk factors associated with development of hypertension were female gender (odds ratio [OR] 0.241; p=0.011) and greater no. of BEV cycles (OR 1.112; p=0.002); factors associated with proteinuria were diabetes (OR 3.869; p=0.006) and greater no. of BEV cycles (OR 1.181; p<0.0001). Conclusions: This analysis of the BECOX and BECA studies suggests that hypertension and proteinuria are associated with outcome in BEV-treated elderly patients with mCRC. Clinical trial information: NCT01067053. [Table: see text]
Natural history and outcomes of synchronous and metachronous colorectal cancers (CRC): A population-based analysis.
Authors: Chu Jackson , Goktepe Ozge , Cheung Winson Y.
Published: March 2020

3593

Background: Early data suggest that synchronous and metachronous CRC portend a worse prognosis when compared to solitary CRC. Our aims were to 1) characterize the clinical features and treatment patterns of synchronous and metachronous CRC and 2) compare their survival outcomes with those of solitary CRC. Methods: All patients diagnosed with non-metastatic CRC between 1999 and 2008 and referred to any 1 of 5 regional cancer centers in British Columbia, Canada were reviewed. Synchronous and metachronous CRC were defined as multiple (2 or more) distinct tumors that were diagnosed within and beyond 6 months of the date of index CRC diagnosis, respectively, during the study period. Patients with liver metastases at initial diagnosis were excluded. Kaplan-Meier and Cox regression analyses were used to estimate survival among the different CRC groups. Results: A total of 6360 patients were identified: 6147 (96%) solitary, 178 (3%) synchronous and 35 (1%) metachronous tumors; median age was 68 years (IQR 59-76); 57% were men; and 75% were ECOG 0/1 at the time of index cancer diagnosis. Baseline demographic characteristics were comparable across patients (all p>0.05). Compared with solitary CRC, synchronous and metachronous CRC more commonly affected the colon rather than the rectum (84 vs 85 vs 59%, respectively, p<0.001), but presenting symptoms, treatment approaches, and use of chemotherapy, radiation and surgery were similar among the different tumor groups (all p>0.05). In terms of survival, no differences were observed in 3-year relapse free survival (66 vs 66 vs 56%, p=0.20), 5-year cancer specific survival (69 vs 69 vs 53%, p=0.34) and 5-year overall survival (62 vs 59 vs 49%, p=0.74) for solitary, synchronous and metachronous CRC, respectively. These findings persisted after controlling for known prognostic factors, such as age and ECOG. Conclusions: In this large population-based cohort, there were no differences in survival outcomes among solitary, synchronous and metachronous CRC. Patients who present with multiple tumors in the colon or the rectum should be managed similarly to those who present with an isolated tumor.
Discovering new targeted therapies for BRAF mutant-like colorectal cancers.
Authors: San Lucas F. Anthony , Kopetz Scott , Scheet Paul A. , Vilar Sanchez Eduardo
Published: March 2020

3623

Background: Approximately 10% of colorectal cancers (CRCs) harbor a BRAF mutation (BRAFm). Patients with BRAFm tumors have poor prognosis and are a therapeutic challenge. A BRAFm gene expression signature has been communicated (Popovici et al, JCO 2012), which can identify BRAFm tumors as well as BRAF wild-type tumors that display a similar expression pattern. Collectively, these tumors are termed BRAFm-like. Our goal was to validate this signature using next-generation sequencing and to discover novel therapies for BRAFm-like CRCs using a systems biology approach. Methods: We developed a semi-automated workflow that integrates publicly available tools named the Cancer In-silico Drug Discovery (CIDD). To validate the BRAFm-like signature, we used CIDD to analyze the CRC dataset from the The Cancer Genome Atlas Network (TCGA). Samples were stratified on BRAFm status using exome-sequencing, and expression profiles were inferred from RNA-sequencing. We matched expression profiles with drug-induced signatures inferred from the Connectivity Map (CMap) – a systems biology tool that contains expression data of cell lines treated with 1,500 compounds. CIDD statistically ranks candidate compounds and annotates them to pathways using public databases. Results: When applied to TCGA RNA-sequencing data, a classifier based on the BRAFm-like signature resulted in 93.3% sensitivity and 83.5% specificity for detecting BRAFm samples. When applied to Agilent gene expression data, this resulted in 80% sensitivity and 91.1% specificity. 41% of KRAS-mutated samples and 14% of double wild-type samples were predicted to be BRAFm-like. 100% of MSI-high and 18% of MSS samples were predicted to be BRAFm-like. Compounds near the top of our drug rankings include Gefitinib and MG-262 a proteasome inhibitor. Conclusions: We have validated the BRAFm-like signature using RNA-sequencing and Agilent expression data from the TCGA, and showed a high degree of robustness across technologies. We have identified EGFR and proteasome inhibitors as potential compounds to target BRAFm-like CRCs.
Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial.
Authors: Brose Marcia S. , Nutting Christopher , Jarzab Barbara , Elisei Rossella , Siena Salvatore , Bastholt Lars , de la Fouchardiere Christelle , Pacini Furio , Paschke Ralf , Shong Young Kee , Sherman Steven I. , Smit Johannes WA , Chung John Woojune , Siedentop Harald , Molnar Istvan , Schlumberger Martin
Published: March 2020

4

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 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 Sunday edition of ASCO Daily News.
Prognostic factors (PFs) of survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel (nab-P) plus gemcitabine (G) versus G alone in patients (pts) with metastatic pancreatic cancer (MPC).
Authors: Moore Malcolm J. , Von Hoff Daniel D. , Ervin Thomas J. , Arena Francis P. , Chiorean E. Gabriela , Infante Jeffrey R. , Hon Jeremy K. , Biakhov Mikhail Yu , Hingorani Sunil R. , Ganju Vinod , Weekes Colin D. , Scheithauer Werner , Ramanathan Ramesh K. , Tabernero Josep , Goldstein David , Wei Xinyu , Romano Alfredo
Published: March 2020

4059^

Background: In MPACT, pts who received nab-P + G vs G had improved overall survival (OS; median 8.5 vs 6.7 mo; HR 0.72; p= 0.000015). Here we assessed potential PFs of OS. Methods: 861 pts with MPC were randomized 1:1, stratified by region, presence of liver metastases, and Karnofsky performance status (KPS), to nab-P + G or G. OS was described in subgroups. A step-wise multivariate analysis (with significance level for entry of 0.20 and for stay of 0.10) was performed to evaluate the treatment effect and identify possible predictors of OS. Results: Pts with poorer PFs had a shorter median OS, consistent with the literature, and OS consistently favored nab-P + G in pts with these PFs (Table). Region of Eastern Europe, age ≥ 65 years, poorer KPS, presence of liver metastases, and number of metastatic sites all predicted OS (increased risk of death). The treatment effect remained significant (HR 0.72; 95% CI, 0.605 - 0.849; p < 0.0001, Cox proportional hazards [CPH] model). In another multivariate analysis in which baseline CA19-9 was added to the final model described above, the treatment effect HR was 0.67 (95% CI, 0.573 - 0.794; p < 0.0001, CPH model). Baseline CA19-9, a predictor of OS by univariate analysis, was not predictive after correction for the above factors. Conclusions: In MPACT, the most important predictors of OS were KPS, age, presence of liver metastases, number of metastatic sites, and region. After correcting for these factors, assignment to nab-P + G was an independent significant predictor of improved survival. Clinical trial information: NCT00844649. [Table: see text]
Variable penetrance of CDH1 mutation diffuse gastric cancer: A genomic analysis.
Authors: Kelsen David Paul , Schrader Kasmintan A. , Khanin Raya , Tang Laura H. , Salo-Mullen Erin E. , Offit Kenneth , Joseph Vijai , Viale Agnes , Mirander Markenya , Coit Daniel G. , Strong Vivian E. , Janjigian Yelena Yuriy , Ilson David H. , Shah Manish A.
Published: March 2020

4082

Background: CDH1 encodes E-cadherin; mutations (CDH1mut) increase the risk of diffuse gastric (DGC) and lobular breast cancers. Life-time risk of DGC is estimated at 80%. Current recommendations are prophylactic gastrectomy (PG) in CDH1mut carriers after age 20. Foci of DGC are found in some PG; others have none at PG, and some CDH1mut without PG never develop cancer. Identifying risk modifying alleles or other genomic events which increase the risk of DGC may improve understanding of DGC and may provide a biomarker for when to perform PG. Methods: For a Gastric Cancer Registry, we collected family pedigrees, germline DNA and FFPE tumor from CDH1mut DGC patients (pts) and their families. From 24 families, with 52 CDH1mut individuals, we identified 4 families in which a young CDH1mut pt developed advanced DGC while their CDH1mut parent and siblings had no clinical evidence of DGC. Several relatives had undergone PG with no DGC found. We hypothesize that there are risk modifying alleles and/or a “second hit” that causes variable penetrance and early onset of DGC in the young CDH1mut pts. Whole genome sequencing was performed on germ line DNA (Complete Genomics, Inc. Mountain View, CA); and whole exome sequencing on tumor specimens (MSKCC). Results: To date, 4 DGC pts and 8 relatives from 4 families have been studied. All 4 affected pts were women (ages 17, 25, 27, 42); their unaffected CDH1mut parents were 41, 51, 54, and 70 years old. The families are of Kenyan, Scandinavian, Italian, Eastern European, and Scottish origin. CDH1 mutations for the pts and their families were confirmed on WGS, and were as follows: 1451C>A(pro484his);c. 1792C>T (arg598ter);c. 1893dupA in exon 12;c. 1565+1G>A (IVS10+1G>A). Analysis of germline DNA for modifying alleles is being performed (Ingenuity Systems, Redwood, Ca.); whole exome sequencing of tumor to identify a possible "second hit" is underway. These data will be presented. Conclusions: Since at least some older pts with proven CDH-1mut do not develop DGC while their children do, CGH-1mut alone may not be sufficient to cause early onset DGC. We hope to identify the additional genomic events associated with early onset advanced DGC. Supported in part by grants from the Gerstner and DeGregorio Foundations.
Vascular endothelial growth factor expression in hepatitis C virus (HCV)-related advanced hepatocellular carcinoma (HCC) compared with hepatitis B virus (HBV)-related advanced HCC.
Authors: Shao Yu Yun , Hsieh Min-Shu , Huang Chung-Yi , Chang Yung-Ling , Hsu Chih-Hung , Cheng Ann-Lii
Published: March 2020

4115

Background: HCC with different etiologic factors may result in activation of different signaling pathways. This study aimed to clarify if HBV-related HCC (HBV-HCC) and HCV-related HCC (HCV-HCC) may have difference in the expression of key molecules that are relevant to contemporary molecular targeted therapy. Methods: We enrolled patients diagnosed with advanced HCC from 2001 to 2011 who had tumor tissues obtained upon the diagnosis of advanced HCC at our center. Tumor slides were immunohistochemically stained for phosphorylated extracellular signal-regulated kinases (p-ERK), Raf kinase inhibitory protein (RKIP), and vascular endothelial growth factor (VEGF). The expressions of p-ERK and RKIP were evaluated according to percentages of positive-staining cells and graded as: 0: 0; 1+: 1-10%; 2+: 11-50%; 3+: > 50%. Grades 0 and 1 were considered negative, and grades 2 and 3 positive. VEGF staining was evaluated as strong or weak according to staining intensity. The staining results of VEGF were further recorded as H scores, defined as intensity (0, 1, 2, or 3) × percentages of positive staining. Results: In total, 131 patients were enrolled in this study; 94 (72%) patients had HBV-HCC, and 37 (28%) patients had HCV-HCC. HBV-HCC and HCV-HCC had similar expression of p-ERK (positive: 45% vs. 51%, p = 0.491) and RKIP (positive: 83% vs. 84%, p = 0.912). HCV-HCC was more likely to have strong VEGF staining than HBV-HCC (95% vs. 72%, p = 0.005) and higher H scores for VEGF staining (289.5 vs. 248.8, p< 0.001). In multivariate analysis adjusting for age, sex, macrovascular invasion, extrahepatic metastasis, and α-fetoprotein level, HCV-HCC remained an independent factor associated with strong VEGF staining. VEGF staining intensity was not associated with age, sex, macrovascular invasion, extrahepatic metastasis, and α-fetoprotein level. Conclusions: HCV-HCC has stronger VEGF expression than HBV-HCC. (This study was supported by the grant of NSC101-2314-B-002-141, 100CAP1020-2, and NTUH.101-N1965.)
A multicenter phase II study of sorafenib, capecitabine, and oxaliplatin (SECOX) in patients with advanced hepatocellular carcinoma: Final results of Hong Kong-Singapore Hepatocellular Carcinoma Research Collaborative Group study.
Authors: Yau Thomas Cheung , Cheung Foon Yiu , Lee Francis , Choo Su Pin , Wong Hilda , Toh Han Chong , Leung A. K. , Chan Pierre , Yau T. K. , Wong Joyce , Tang Y. F. , Lau Sze Man June , Cheung Tan To , Fan Sheung Tat , Poon Ronnie Tung Ping
Published: March 2020

4117

Background: This is a single arm, multi-center, phase II study to assess the efficacy and tolerability of sorafenib, oxaliplatin and capecitabine combination for the treatment of advanced hepatocellular carcinoma (HCC) patients. Methods: Eligible patients received SECOX regime—sorafenib 400 mg bid (Day one-fourteen), oxaliplatin 85 mg/m2 (Day one) and capecitabine 1700 mg/m2(Day one-seven) every two weeks. Response assessment was based on RECIST 1.0 criteria. The primary endpoint was time-to-progression (TTP) and the secondary endpoints were tumor response rate (RR), progression-free survival (PFS), overall survival (OS) and tolerability. Results: A total of 51 patients were enrolled in the trial.The median age was 58 years (range, 28-81) and 84% of patients were chronic hepatitis B carriers. Ninety percent of recruited patients belonged to BCLC stage C disease and 41 (80%) patients had extra-hepatic metastasis. The best RR was 16% and they were all partial response. Another 62% of patients achieved stable disease for at least eight weeks. The median TTP was 5.29 months (95% CI 3.81-5.88 months), PFS 5.26 months (95% CI 3.75-5.88 months) and OS was 11.73 months (95% CI 8.87- 15.38 months). Diarrhea (75%), Hand-foot-skin reaction (73%) and transient liver function derangement were the most commonly encountered adverse events, with the majority of patients having grade one or two. No treatment-related death was reported. Conclusions: The SECOX regime indicates preliminary promising activity and safety in Asian population with advanced HCC. Our data support a randomized trial comparing SECOX versus sorafenib alone for treatment of advanced HCC. Clinical trial information: NCT00752063.
Impact of gender on survival of patients (pts) with hepatocellular carcinoma (HCC): A SEER analysis.
Authors: Yang Dongyun , Usher Josh , LoCoco Jordan , Pritesh Chaudhari , Lenz Heinz-Josef , El-Khoueiry Anthony B.
Published: March 2020

4128

Background: The incidence of HCC is significantly higher in males (M) than females (F). Preclinical models suggest a role for estrogen in attenuating progression of HCC by various mechanisms such Il-6 suppression or estrogen receptor α-mediated inhibition of NF-κB activity. We investigated the impact of age and gender on survival in patients with HCC using the SEER data. Methods: We identified all patients diagnosed with HCC (ICD-O-3 Site code C22.0 and Histology Code 8170-8175) from 1988 to 2009 from the SEER registry. Pts with information on gender, age, ethnic background, and staging were included in the analysis. Exclusion criteria included fibrolamellar histology, diagnosis at autopsy or by death certificate, and absence of survival data. Hazard ratios (HR) for survival were derived using Cox regression model adjusted for race, year of diagnosis, marital status, treatment, birthplace, differentiation and tumor size. Results: A total of 38,250 pts were identified; 76% males; 50% White, 12% African American, 21% Asian, 16% Hispanic, and 1% Native American. 45% had liver limited disease (44%M, 50%F), 37% had macrovascular invasion (37%M, 35%F), 18% had metastatic disease (19%M, 15%F). Treatment information was available for pts diagnosed after 1998 (n=32,938): 11% received liver directed therapy, 11% had surgical resection, and 7% underwent liver transplantation. Median age at diagnosis was 61 years for M versus 68 years for F. HR for OS of F versus M was 0.83 (95%CI:0.78-0.89) for pts < 55 years old. In contrast, the OS HR of F versus M was 0.95 (95%CI:0.92-0.98) for pts ≥ 55 years old and 0.98 (95%CI: 0.94-1.01) for pts ≥ 65 years old. The F vs. M (<55 yrs old) HR for OS by stage of disease was: liver limited disease: HR 0.90, CI: 0.81-1.01; macrovascular invasion: HR 0.81, CI: 0.73-0.89; metastatic disease, HR 0.80, CI: 0.70-0.92. Conclusions: Females under the age of 55 appear to have superior survival compared to males with HCC based on a SEER data analysis. This finding is in line with preclinical reports of estrogen attenuation of HCC development and progression.
sVEGFR2 and circulating tumor cells to predict for the efficacy of pazopanib in neuroendocrine tumors (NETs): PAZONET subgroup analysis.
Authors: Grande Enrique , Casanovas Oriol , Earl Julie , Castellano Daniel E. , Garcia-Carbonero Rocio , Teule Alex , Duran Ignacio , Fuster Jose , Sevilla Isabel , Escudero Pilar , Sastre Javier , García-Donas Jesús , Ortega Luis , Diez Juan Jose , Soria Rivas Ainara , Capdevila Jaume
Published: March 2020

4140

Background: The PAZONET trial (Grande et al, ESMO 2012) performed by the GETNE group analyzed the efficacy and safety of the use of pazopanib (800 mg/qd) in patients (pts) with progressive metastatic NETs that had been previously treated with other novel targeted agents. Here we report on the relationship between clinical outcome and circulating and tumor-related biomarkers. Methods: Kaplan-Meier analysis was used to correlate progression-free survival (PFS) with: blood circulating markers at baseline and after 12 weeks of treatment (VEGF-A and sVEGFR2 circulating plasma, Circulating Tumor Cells (CTC) and Circulating Endothelial Cells (CEC)), tumor functional status, Ki67, concomitant somatostatin analogues (SSA), chromogranin A (CgA) and primary tumor location. Results: 44 pts were enrolled, 42 were evaluable for response. sVEGFR2 decreased after 12 weeks of treatment (median decrease 20%, p<0.0001) and the duration of treatment with pazopanib was associated with a decrease in sVEGFR2 (p=0.0046). Pts with a decrease in sVEGFR2 of >20% and <=20% had a median progression-free survival (mPFS) of 12.6 and 9.1 months (mo) respectively (p=0.067). Pts with and without CTC at baseline had a mPFS of 5.8 and 9.1 mo respectively (p=0.12). VEGFA and CEC were not found to predict PFS. mPFS in the intention to treat population was 10.0 mo (95% CI 4.3-15.6). Significant differences in mPFS were found in concomitant SSA treatment (11.9 mo [10.6-13.2]) vs. pazopanib alone (4.8 mo [3.0-6.6]) (p=0.007); decrease of CgA (3.4 mo [0.0-6.8]) vs no decrease (11.2 mo [8.4-14.1]) (p=0.024) and pancreatic (12.8 mo [11.0-14.6]) vs gastrointestinal (10.0 mo [4.9-15.1]) vs other primary tumors (3.4 mo [0.0-7.0]). No differences in mPFS were seen in functioning (10.0 mo) and non-functioning tumors (9.3 mo) and Ki67 status (< 2% 10.0 mo, 3-10% 10.8 mo or >10% 4.1 mo). Conclusions: sVEGFR2 and baseline CTC are promising predictive biomarkers for pazopanib in NETs. The updated results confirm the efficacy of pazopanib as a sequencing treatment of pts with progressive NETs, particularly in those with pancreatic primary tumors. The combination of pazopanib and SSA seems to be synergistic. Clinical trial information: NCT01280201.