bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular pathways and gene ontology categories in association with response to combination chemotherapy plus bevacizumab in inflammatory and locally advanced breast cancer
Authors: Swain S. M. , Steinberg S. M. , Modrusan Z. , Smith V. , de Sauvage F. , Yang S. X. 
Published: March 2020

509 Background: Inflammatory breast cancer (IBC) is an extremely aggressive subtype of locally advanced breast cancer (LABC) accounting for 1% to 6% of all breast cancers. The overall response rate to a combined modality therapy is 61.4%-83.5% and 15-year overall survival is 20%. Identification of Gene Ontology (GO) category or molecular pathway signature to distinguish subsets of patients with distinct clinical outcomes is imperative. Methods: 20 patients with IBC and 1 with LABC received one cycle of bevacizumab at 15mg/kg followed by six cycles of doxorubicin at 50mg/m2 and docetaxel at 75mg/m2 plus bevacizumab before surgery. Response to combination chemotherapy plus bevacizumab was measured with radiologic imaging modalities. Gene expression profiles from 20 tumor biopsies at baseline (1 with PD had inadequate biopsy) were measured with Agilent Whole Human Genome arrays and utilized to correlate with clinical response. Results: 14 (67%) of 21 patients (95% CI, 43%-85.4%) had a clinical partial response (PR), 5 had stable disease (SD) and 2 had progressive disease (PD). Of 103 molecular pathways, those of the stathmin and breast cancer resistance to antimicrotubule agents, and BTG family proteins and cell cycle regulation were significantly associated with response (PR versus SD+PD; P = .002 and .003). Members of the stathmin pathway are cyclin B1, cell division cycle 2, stathmin 1 (kinase interacting with leukemia-associated gene), and mitogen-activated protein kinase 13; BTG family members are retinoblastoma 1, CCR4-NOT transcription complex, subunit 7, and B-cell translocation gene 1. Sixteen of 965 GO classes were differentially expressed between patients with PR and PD plus SD (P < .005). Those include GO categories of transcription factor complex (14 genes; P = .00009), extracellular matrix (69 genes; P = .0006), and protein kinase activity (90 genes; P = .002). Tumor differentiation, ER, HER2/neu, and p53 were not associated with clinical response. Conclusions: Two pathways that regulate microtubule stability and cell cycle, and 16 GO categories are significantly associated with the response to the combination chemotherapy of docetaxel-doxorubicin plus bevacizumab. No significant financial relationships to disclose.
Final results from phase II study of volociximab, an α5β1 anti-integrin antibody, in refractory or relapsed metastatic clear cell renal cell carcinoma (mCCRCC)
Authors: Yazji S. , Bukowski R. , Kondagunta V. , Figlin R. 
Published: March 2020

5094 Background: A critical survival step for proliferating endothelial cells is the ligation of fibronectin in the extracellular matrix to integrin a5β1. Voloxicimab, a chimeric monoclonal antibody, blocks fibronectin binding to a5β1, and induces apoptosis of proliferating endothelial cells. Voloxicimab activity is independent of growth factor stimulus, suggesting that a5β1 signalling occurs downstream of growth factor signalling, and is possibly a final common pathway for the development of neovasculature. Methods: This is a multicenter, open label, phase II study in mCCRCC. Patients (pts) received volociximab 10 mg/kg IV every 2 weeks until disease progression. Pts were evaluated for efficacy every 8 weeks using RECIST criteria. Results: A total of 40 pts were enrolled. All pts were evaluable for safety and efficacy. Median time since first diagnosis was 2.5 years. ECOG score was 0–1 in all pts. Prior nephrectomy occurred in 38 (95%) pts. Nineteen (47.5%) pts had ≥ 2 prior therapy. Twenty one (52.5 %) pts had prior anti agiogenic therapy. Other prior treatment included IL-2 in 15 (37.5%), interferon alpha in 7 (17.5 %), IL-2 + interferon in 2 (5%) pts. Most frequent side effects were fatigue in 27 (67.5%) pts, nausea 14 (35%) pts, dyspnoea 8 (20%) pts and arthralgia 7 (17.5%) pts, of which none were grade 3 or 4. Seven (17.5%) pts had SAEs. Stable disease (SD) was observed in 32 (80 %) pts including 1 confirmed PR. Duration of SD ranged from 2–22 months (mo). Fourteen (35%) pts had time to progression (TTP) between 5.8 to 22 mo: Four (10%) pts had TTP ≥ 14 mo (range 14- 22 mo), 8 (20%) pts had TTP ≥ 6 mo (range 6- 12 mo) and 2 (5%) pts had TTP = 5.8 mo. Median TTP was 4 mo. Median overall survival (OS) has not been reached after 22 mo. OS at 6 mo was 79% and 68% at 22 mo. Six (15%) pts died in the study, 5 (12.5%) pts due to progressive disease and 1 with arrhythmia (unrelated to volociximab). Conclusions: Volociximab is well tolerated at 10 mg/kg q2w. Stable disease is noted in 80 % of pts. Based on clinical activity, a randomized controlled trial is being planned. No significant financial relationships to disclose.
Sunitinib therapy for patients (pts) with metastatic renal cell carcinoma (mRCC): Updated results of two phase II trials and prognostic factor analysis for survival
Authors: Rosenberg J. E. , Motzer R. J. , Michaelson M. D. , Redman B. G. , Hudes G. R. , Bukowski R. M. , George D. J. , Kim S. T. , Baum C. M. , Wilding G. 
Published: March 2020

5095 Background: Two single-arm phase 2 trials reported a 42% objective response rate (ORR) with sunitinib as second-line therapy in mRCC pts (JAMA 2006;295:2516–24). Efficacy results were updated and an analysis of prognostic factors for survival was performed on pooled data. Methods: Eligibility criteria and treatment plan were nearly identical for both trials. Pts with mRCC who failed =1 prior cytokine-based therapy received sunitinib in repeated 6-week cycles of 50 mg/day orally for 4 weeks, followed by 2 weeks off treatment. Response was assessed by investigators according to RECIST. Pretreatment clinical and biochemical features were examined for prognostic factors by univariate and multivariate analysis (p<0.05 significance level was used in the backward stepwise selection procedure). Results: Updated efficacy data for 168 evaluable pts showed an ORR of 45% (95% CI: 39%, 54%), median progression-free survival (PFS) of 8.4 months (95% CI: 7.9, 10.7), and median overall survival (OS) of 22.3 months (95% CI: 14.8, 36.0). Twenty pts remain on treatment with sunitinib with the longest pt on the drug for >3.5 years with partial response for >3 years. The median duration of response was 11.6 months (95% CI: 9.9, 15.2), and included 1 pt with a complete response for >2 years. The proportion of pts alive at 2 years is 48%. Final prognostic factors for survival in the multivariate model were ECOG PS 0 vs. =1 (p=0.0034); time interval from diagnosis to sunitinib treatment =1 yr vs. <1 yr (p=0.0002); hemoglobin =13 vs. <13 g/dL for males and =11.5 vs. <11.5 g/dL for females (p=0.0002). Conclusions: Median survival is nearly 2 years, which compares favorably to the historical experience (12.7 months) in second-line therapy with other agents (JCO 2004;22:454–63). The influence of sunitinib therapy on patient survival is being investigated in a randomized phase 3 trial compared to interferon-a in first-line therapy for mRCC. Further study of prognostic factors to sunitinib therapy is warranted in the first-line setting. No significant financial relationships to disclose.
Down-regulation of HIF-1α expression by letrozole in ER+ve breast cancer patients
Authors: Generali D. G. , Berruti A. , Fox S. B. , Brizzi M. , Bonardi S. , Milani M. , Bersiga A. , Dionisio R. , Dogliotti L. , Bottini A. , Harris A. L. 
Published: March 2020

510 Introduction: Letrozole is a selective non steroidal aromatase inhibitor (AI) used for the treatment of estrogen positive (ER+ve) post-menopausal breast cancer (BC) women. HIF-1α, as marker of hypoxia, is involved in the selection of more aggressive phenotype being associated with both chemo and endocrine resistance Whether HIF-1α expression could be modulated by AI in BC is the subject of this investigation. Patients and Methods: 114 elderly women with T2–4 N0–1 and ER+ve BC were randomly assigned to 6 months of primary letrozole (2.5 mg/daily) (L) plus/minus oral “metronomic” cyclophosphamide (50 mg/daily) (LC). Tumor response was assessed clinically with a calliper. On TMAs HIF-1α was evaluated in tumor specimens collected before and after treatment. The intensity of the staining for TMAs marker was scored 0 (no staining), 1 (weak/moderate staining), 2 (strong staining) in nuclear intensity for HIF- 1α expression. Results: 107 patients had HIF-1a assessed at baseline, 80 patients had HIF-1α assessed both at baseline and after treatment. At baseline HIF-1α expression inversely correlated with tumor grade (p<0.01) and N positivity (p<0.01) while it did not correlate with stage, p53, bcl2, Ki67, progesterone ERa expression. HIF-1α expression was significantly reduced after treatment (p<0.004, Wilcoxon Rank sum test), with no difference between the arms. Reduction in HIF-1α did not showed any relationship with disease response. Conclusions: Letrozole was able to down-regulate HIF-1α expression and this may be a mechanism of its efficacy. These results should be taken into account when administering new target therapy able to modulate directly HIF-1α or indirectly via HIF- 1α related pathways in association with letrozole. No significant financial relationships to disclose.
Randomized prospective phase II trial of two schedules of sorafenib daily and interferon-α2a (IFN) in metastatic renal cell carcinoma (RAPSODY): GOIRC Study 0681
Authors: Bracarda S. , Porta C. , Boni C. , Santoro A. , Artioli F. , Di Bartolomeo C. , Contu A. , Gasparro D. , De Angelis V. , Caserta C. ,   GOIRC Study Group
Published: March 2020

5100 Background: Sorafenib is an oral multi-kinase inhibitor with a demonstrated efficacy in MRCC (Eisen, ASCO 2006). IFN is a pleiotropic molecule with an antiangiogenic activity probably dose and schedule-dependent (Folkman, 1992). Aim of this study was to evaluate the activity and safety of sorafenib combined with IFN in two different schedules. Methods: Eligible patients had metastatic renal cell carcinoma (MRCC) with a clear cell component = 50%, previous nephrectomy, ECOG Performance Status 0–2, no cerebral metastases or previous treatment, measurable disease; any Motzer’s score was allowed. Patients received oral sorafenib 400mg BID continuously plus sc IFN, 9 MU three times a week (arm-A) or 3 MU five times a week (arm-B), started 7 days after sorafenib to increase compliance. Planned sample size of this single-stage study was 100 cases to be enrolled over 18 months. Primary end points: Progression Free Survival (PFS) in the two arms and safety; secondary end-points: overall response (intention-to treat analysis) and overall survival. Results: Between January 2006 and January 2007 all the expected cases were enrolled into the study (median age 63 years, range 34–82; male/female: 71/29). Of 63 patients for whom a post baseline assessment was available (31 in arm A and 32 in arm B), 16 achieved a partial response (25.4%: 29% in arm A, 95% CI 13.2–44.9 and 22% in arm B, 95% CI 7.6–36.2), 26 had a stable disease (41.3%: 29% in arm A and 53% in arm B) and 21 progressed (33.3%: 42% in arm A and 25% in arm B). Due to the short follow-up period PFS data are not yet available. The most common grade 3/4 toxicities affecting more than 5% of the pts were equally distributed between arms except for fatigue and skin rash (respectively 19% and 8%, only arm A): hypophosphatemia (43%), hand-foot syndrome (22%), anorexia, stomatitis, hyperamylasemia (11% each), diarrhea (8%) and hyperlipasemia (5%). Conclusions: With an overall response rate of 25.4% and a tumor control rate (partial response + stable disease) of 66.7% (58.1% in arm A, 95% CI 40.7–75.5 and 75.0% in arm B, 95% CI 60.0–90.0; p = ns) sorafenib plus IFN can be considered a promising regimen in MRCC. Further investigations of the active and safe low-dose IFN combination arm are warranted. [Table: see text]
Randomized phase II study of docetaxel with or without DMXAA (AS1404) in hormone-refractory metastatic prostate cancer (HRMPC)
Authors: Pili R. , Rosenthal M. ,   AS1404–203 study group investigators
Published: March 2020

5115 Background: DMXAA (AS1404) is a small-molecule agent that disrupts tumor vasculature. Combination of DMXAA with taxanes produces synergistic inhibition of tumor growth in animal models. A randomized phase II study in non-small cell lung cancer reported a substantial survival benefit when DMXAA was added to paclitaxel-based chemotherapy. This randomized phase II study examined the effect of adding DMXAA to docetaxel in HRMPC. Methods: Patients had progressive metastatic, androgen-independent, histologically confirmed prostate adenocarcinoma previously untreated with cytotoxics. Patients were randomized 1:1 to receive docetaxel (75 mg/m2) ± DMXAA (1,200 mg/m2) every 21 days for up to 10 cycles. Efficacy endpoints were prostate-specific antigen (PSA) response rate, objective response rate, time to tumor progression, duration of response and disease stabilization, time to PSA progression, and median and 1-year survival. Results: 74 patients were randomized: 34 to DMXAA plus docetaxel (DMXAA arm) and 40 to docetaxel alone (control arm). Median baseline PSA values were 83 ng/ml (range 6–3574 ng/ml) in the DMXAA arm and 87 ng/ml (range 1–570 ng/ml) in the control arm. PSA response data are available from 64 patients (see table ). Latest safety data show a similar number of serious adverse events reported across the treatment groups with 15 and 19 in the DMXAA and control arms, respectively. Conclusions: Addition of DMXAA to standard-dose docetaxel was well tolerated and the combination produced a substantially higher PSA response rate than docetaxel alone. DMXAA demonstrates promising activity in this patient population. [Table: see text] [Table: see text]
A phase II trial of docetaxel and samarium in patients with bone metastases from castration-refractory prostate cancer (CRPC)
Authors: Laplanche A. , Beuzeboc P. , Lumbroso J. , Massard C. , Plantade A. , Escudier B. , Di Palma M. , Bouzy J. , Haddad V. , Fizazi K. 
Published: March 2020

5122 Background: Most patients (pts) with disseminated CRPC have bone metastases. Docetaxel is the current standard of care in CRPC. We assessed the association of docetaxel and samarium, a radio-pharmaceutical with a high affinity to bone, as consolidation treatment after docetaxel-estramustine. Methods: This is a prospective, bi-center phase II trial. Pts with bone metastases from CRPC received docetaxel 70 mg/m2 day 2 + estramustine 10 mg/Kg/day, day 1–5 (1 cycle/ 3 weeks). Pts with a response or stabilization after 4 cycles were given consolidation therapy: docetaxel 20 mg/m2/week × 6 weeks + samarium 37 MBq/Kg during week 1. Zoledronic acid was routinely used and was stopped 1 month before samarium infusion. A Simon design was used with a target of 39 pts receiving consolidation treatment. Response was defined according to the working group criteria (Bubley, J Clin Oncol 1999). The primary endpoint was progression-free survival (PFS). Results: From 01/04 to 12/05, 43 pts were included in the trial: 31 (72%), 11 (26%) and 1 (3%) achieved a PSA response, stabilization, and progression, respectively. After induction therapy, a pain response (defined as a decrease in pain intensity by at least 2/10 on a pain visual analog scale (VAS) in pts with a baseline pain level = 2/10) was achieved in 60% (18/30) and was confirmed in 69% (20/29) after consolidation therapy. Consolidation docetaxel-samarium was feasible with most pts experiencing a mild (grade 1–2) and rapidly reversible thrombocytopenia at week 5. The 7 months PSA-PFS rate was 48% (33–62%). While PSA relapse eventually occurred in all cases, this strategy resulted in an excellent long-term control of pain, with a median pain level on the VAS of 4/10, 1/10, and 0.5/10 at baseline, 12, and 18 months, respectively. With a median follow-up of 14 months, the median survival has not been reached and the 1-year survival rate is 71% (55–84%). Conclusions: Combining docetaxel and samarium is feasible and well-tolerated. It yields a major pain improvement that lasts long after consolidation therapy in pts with bone metastases from CRPC. Survival data are promising in this population of symptomatic metastatic CRPC. This approach should be tested in phase III trials. No significant financial relationships to disclose.
Suberoylanilide hydroxamic acid (vorinostat) post chemotherapy in hormone refractory prostate cancer (HRPC) patients (pts): A phase II trial by the Prostate Cancer Clinical Trials Consortium (NCI 6862)
Authors: Hussain M. , Dunn R. , Rathkopf D. , Stadler W. , Wilding G. , Smith D. C. , Bradley D. , Cooney K. A. , Zweibel J. , Scher H. 
Published: March 2020

5132 Background: Histone deacetylases (HDACs) are key regulators of histone acetylation status, which is critical to expression of genes implicated in the regulation of cell survival, proliferation, differentiation and apoptosis. Vorinostat is a potent oral HDAC inhibitor with anti-tumor activity in PC models and in phase I clinical trials. A phase II trial is assessing vorinostat in HRPC pts. Methods: Eligible pts had disease progression on 1 prior chemotherapy for HRPC, a PSA of ≥ 5ng/ml, and adequate organ function. Vorinostat was administered orally at 400 mg daily in 21-day cycles. Response was assessed every 12 weeks. The primary endpoint is proportion of pts without progression at 6 months by objective and biochemical measures. This study is designed to accrue 29 pts (80% power at the 5% significance level to distinguish between a rate of 10% vs 30%). If ≥ 7/29 pts are progression-free at 6 months, the drug will be recommended for further study. Secondary endpoints include safety, rate of PSA decline, objective response rate and overall survival. Correlative studies assessing the effect of vorinostat on serum levels of IL-6, soluble IL-6 receptor and gp130 levels were conducted. Results: To date 23/29 pts have been accrued. Median age is 68 years (range 54–77), 70% had performance status 1 and 78% are white. At registration disease progression was defined by: PSA in 83%, bone in 74% and soft tissue in 43%. Median number of cycles is 2 (range 1–6), 57% of pts required at least 1 dose reduction. At time of this report 39% of pts remain on therapy. 19 pts are toxicity evaluable. Most common treatment related adverse events (AEs) were: fatigue (74%), anorexia (63%), nausea (58%), diarrhea (32%), dehydration, taste alteration and vomiting (26% each). There was 1 grade (G) 4 thrombosis and 11 pts had G 3 AEs, the most common were: fatigue (32%) and nausea and anorexia (11% each). 3/9 response evaluable pts achieved stable disease. Conclusions: Vorinostat is feasible post chemotherapy in pts with HRPC, however it is associated with significant toxicities requiring dose reductions. Final efficacy, safety and correlative studies will be reported. Support: CTEP, N01-CM-62201, PC051375, PC 051382 No significant financial relationships to disclose.
Distinct patterns of PSA modulation by single-agent sunitinib before combination with docetaxel and prednisone in patients with metastatic castrate-resistant prostate cancer (CRPCa)
Authors: Zurita A. J. , Shore N. D. , Kozloff M. F. , Ryan C. W. , Beer T. M. , Maneval E. C. , Chen I. , Logothetis C. J. 
Published: March 2020

5134 Background: We are conducting a phase I study of the oral, multitargeted tyrosine kinase inhibitor sunitinib malate in patients with CRPCa as a single agent lead-in, followed by combination with docetaxel and prednisone, to determine the optimal dose, safety, efficacy and pharmacokinetic profile of the combination. The lead-in with sunitinib alone was included to evaluate whether PSA is modulated differently than with imatinib (Mathew et al. JCO 2004;22:3323–9), and if this is predictive of response and toxicity to the combination. In addition to blocking PDGF signaling (imatinib), sunitinib also blocks VEGF. Preliminary safety and efficacy were previously reported (ASCO Prostate Symposium 2007). Here we present PSA modulation results. Methods: All patients receive a lead-in of daily sunitinib 50 mg for 4 weeks (wks) on, 2 wks off, prior to starting combination therapy. To date, 3 successive cohorts have received 60 mg/m2 docetaxel every 3 wks combined with prednisone 5 mg bid and escalating sunitinib doses (12.5, 37.5 or 50 mg/d) on a 2/1 schedule (2 wks on, 1 wk off). An ongoing cohort is receiving 75 mg/m2 docetaxel + 37.5 mg/d sunitinib. Dose-limiting toxicities (DLTs) are evaluated over the first 3-wk cycle. Results: PSA results are available for 21 patients (pts) enrolled across the 4 cohorts (median age 68 yrs, PSA 42 ng/mL, Gleason score 8). Preliminary data showed 3 patterns of sunitinib-induced PSA modulation during the lead-in: PSA reduction (6 pts; mean decrease 37.8%; >50% in 2 pts), initial increase followed by drop during the off-sunitinib period (10 pts; mean decrease 32.5%), and PSA increase (5 pts; mean increase 61%). Conclusions: Single-agent sunitinib induces PSA decline in a subset of patients with CRPCa in contrast to that observed with agents targeting PDGF or VEGF alone. The predictive value of the “lead-in PSA kinetics” in determining later response to the sunitinib plus docetaxel and prednisone combination will require completion of the study. These data support the hypothesis that blocking VEGFR may alter the phenotype of CRPCa and be synergistic with blocking PDGFR. [Table: see text]
Elevated plasma TIMP-1 levels predict reduced survival in metastatic hormone-refractory prostate cancer patients
Authors: Oh W. K. , Leitzel K. , Kantoff P. W. , Regan M. M. , Hamer P. , Pierce K. , Brown-Shimer S. , Carney W. , Ali S. M. , Lipton A. 
Published: March 2020

5143 Background: Tissue inhibitor of metalloproteinase-1 (TIMP-1) has been shown to have parodoxical multifunctional roles in tumorigenesis: inhibition of the catalytic activity of MMPs, growth promotion, inhibition of apoptosis, and regulation of angiogenesis. Increased TIMP-1 has been associated with an unfavorable prognosis in many cancers including breast, colorectal, gastric, head and neck, lung cancer, and lymphomas. Methods: EDTA plasma TIMP-1 was determined from 60 hormone-refractory prostate cancer (HRCaP) patients using the TIMP-1 ELISA from Oncogene Science / Bayer HealthCare, Cambridge, MA. Patients were identified from an institutional database and had metastatic, HRCaP at the time of blood collection, which ranged from <1 month to 14 yrs. after the start of androgen-deprivation therapy (ADT); some patients had also received several chemotherapy regimens by the time of blood collection. Median follow-up was 17 mo. after blood collection and 27/60 patients had died. Overall survival was analyzed using Kaplan-Meier method and Cox modeling on tertiles of the TIMP-1 distribution. Results: The median EDTA plasma TIMP-1 level from the 60 HRCaP patients was 335 ng/ml (range 21 - 1391 ng/ml). Median survival since time of blood collection was 14 mo. Survival differed across TIMP-1 levels (P<0.01, logrank test), in particular the upper tertile of plasma TIMP-1 had a significantly reduced overall survival from the time of blood collection compared to the lowest tertile: A larger confirmatory study which will include a multivariate analysis of known prognostic factors is planned. Conclusions: Elevated plasma TIMP-1 tertile level predicted reduced survival in HRCaP patients. Soluble TIMP-1 deserves further study to determine its predictive and prognostic biomarker potential in a larger cohort of prostate cancer patients. [Table: see text] [Table: see text]