bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunoglobulin G fragment C receptor polymorphisms and response to trastuzumab-based treatment in patients with HER-2/neu-positive metastatic breast cancer
Authors: Musolino A. , Naldi N. , Bortesi B. , Capelletti M. , Pezzuolo D. , Missale G. , Laccabue D. , Camisa R. , Franciosi V. , Ardizzoni A. 
Published: March 2020

13090 Background: A potential mechanism of action of the humanized anti-HER-2/neu monoclonal antibody Trastuzumab involves antibody-dependent cellular cytotoxicity (ADCC) with the activation of immune effector cells via their immunoglobulin G fragment C receptors (FcγRs). Trastuzumab has been shown to engage both activation (FcγRIIIa; FcγRIIa) and inhibitory (FcγRIIb) antibody receptors on myeloid cells and several FcγR polymorphisms have been identified that may affect the antibody-dependent cytotoxicity of natural killer cells and macrophages. Methods: Forty consecutive HER-2/neu-positive (FISH+) metastatic breast cancer patients receiving a trastuzumab-based treatment (combined with paclitaxel for the majority) were examined for the FcγRIIIa 158 valine (V)/phenylalanine (F), FcγRIIa 131 histidine (H)/arginine (R), and FcγRIIb 232 isoleucine (I)/threonine (T) polymorphisms. A PCR-RFLP based assay using genomic DNA was performed for FcγRIIIa and FcγRIIa genotyping, while PCR-SSCP methods using complementary DNA were utilized for FcγRIIb. Patients’ peripheral blood mononuclear cells were drawn before treatment initiation and their trastuzumab-mediated killing function was measured by 51Cr release using a HER-2/neu-expressing human breast cancer cell line as a target. The results were then correlated with clinical outcome of these patients. Results: Median age was 60 years (range 26–83 years). Thirty-six (90%) patients received a trastuzumab-based treatment as first-line therapy. The overall clinical benefit rate (CR+PR+SD) was 65% (95% Confidence Interval: 62–71%), including 8 (20%) complete and 11 (27.5%) partial responses. Median survival was 22.3 mo with a median PFS of 7 mo. Trastuzumab-based treatment was well tolerated and no changes in cardiac function were observed. Conclusions: This study evaluates for the first time the potential role of FcγR polymorphisms in predicting response to trastuzumab-based treatment. Results according to this study purpose will be presented at the meeting. No significant financial relationships to disclose.
The mechanism of low molecular weight heparin (LMWH) inhibition of tumor growth
Authors: Smiley S. L. , Henry D. O. , Wong M. K. 
Published: March 2020

13093 Background: Clinical studies show that LMWHs improve survival in cancer patients. There is compelling and mounting evidence that non-anticoagulation factors are at play, and that these may be contributing in a major way to improved patient outcome. Methods and Results: Dalteparin, enoxaparin, and tinzaparin were tested for their in vivo ability to inhibit tumor lines engineered for aggressive angiogenesis-driven growth. Therapeutic daily doses of drug administered the day following tumor inoculation resulted in significant angiogenesis and tumor inhibition. We previously showed that LMWHs inhibit fibroblast growth factor (FGF) -induced mitogenesis of Tumor Derived Endothelial Cells (TDECs) in a time and concentration dependent manner in vitro. We now show that this endothelial inhibition occurs through LMWHs-mediated reduction of phosphorylation and down stream signaling through ERK. The potency of LMWH was significantly reduced when TDECs were pretreated with heparinase- suggesting that the molecular target for LMWH may be the cell surface, low affinity FGF receptor system. Both our in vivo and in vitro studies demonstrate that angiogenesis and tumor inhibition are greatest for dalteparin > tinzaparin > enoxaparin. Clues to the heparin-TDECs interaction comes from tracking the real-time movement of FGF using a highly fluorescent nanocrystal bead decorated on its surface with FGF. High resolution video-microscopy shows FGF binding onto TDEC surfaces, but once heparin enters the environment, FGF detaches from the TDECs and migrates to the heparin. This ultimately results in significant TDEC growth inhibition as compared to controls. Conclusion: LMWH treatment at pharmacologic doses significantly blunts tumor growth and angiogenesis. This inhibition resides in part via heparin’s ability to sequester FGF from the low affinity receptor system on tumor endothelial cells. No significant financial relationships to disclose.
Extended phase I study of AS1411 in renal and non-small cell lung cancers
Authors: Laber D. A. , Taft B. S. , Kloecker G. H. , Bates P. J. , Trent J. O. , Miller D. M. 
Published: March 2020

13098 Background: AS1411 is an oligonucleotide aptamer that binds to nucleolin, a protein expressed on the surface of tumor cells. A dose-escalating phase I trial in patients with various advanced cancers revealed no serious toxicities and consequently did not reach an MTD. There was evidence of activity, especially in renal cell carcinoma (RCC). This study has been reopened for further dose escalation to reach an optimal biological dose (OBD; unless an MTD is reached) in patients with RCC and non-small cell lung cancer (NSCLC). Methods: Patients had advanced RCC or NSCLC refractory to standard treatment. AS1411 was administered as a single continuous 7-day iv infusion, with the option of a second cycle. Patients were enrolled in cohorts of 3. If no serious toxicity was observed within 28 days, the dose was escalated to the next level. Toxicity was graded using the NCI CTCAE v3.0. The study plan was to enroll additional patients at the OBD such that a total of 12 RCC and 12 NSCLC patients received a 7-day infusion. Blood and urine samples were taken for pharmacokinetic analysis. Tumor responses were assessed every 28 days using the RECIST guidelines. Results: No serious adverse events have been observed up to a dose of 22mg/kg/day, which was associated with a mean peak plasma concentration of 1.5 μM. Response findings to date are as follows: of 5 RCC patients, 1 maintains a near-complete response 18 months after treatment, 3 have ongoing stable disease (SD; 1 at 3 months, 2 at 2 months) and a fourth had progressive disease (PD) at 2 months post-treatment; of 3 NSCLC patients, 1 has an ongoing SD and 2 had PDs at 1 month post-treatment. Recruitment and follow up continues. Conclusions: A 7-day infusion of AS1411 at 22mg/kg/day was not associated with any serious adverse events and achieved peak plasma concentrations in the range at which killing of various cancer cell lines is observed in vitro. A single further escalation is planned to reach a dose of 40mg/kg/day. Observation of additional cases of stable disease in RCC supports the previous observations of anti-cancer effects in this disease. [Table: see text]
Metronomic chemotherapy (MC) with irinotecan (CPT-11) in patients with diagnosis of metastatic colorectal cancer (MCRC): clinical and pharmacodynamic evaluation
Authors: Loupakis F. , Bocci G. , Allegrini G. , Cerri E. , Barletta M. T. , Masi G. , Fioravanti A. , Orlandi P. , Del Tacca M. , Falcone A. 
Published: March 2020

13111 Background: Preclinical studies have demonstrated that the frequent administration of low doses of cytotoxic drugs over prolonged periods of time (MC) reduces tumour cell growth through inhibition of angiogenesis. The antitumor effect of a MC with cyclophosphamide is due to an increase of thrombospondin-1 (TSP-1) plasma level, an endogenous inhibitor of angiogenesis. Methods: An exploratory study was conducted to assess the feasibility, the activity and the optimal metronomic dose of CPT-11 when administered as protracted continuous infusion (c.i.) in pretreated MCRC. A pharmacodynamic evaluation of anti- and pro-angiogenic factors, such as TSP-1 and vascular endothelial growth factor (VEGF), was performed. Weekly blood samples were taken. Three different CPT-11 dose levels have been evaluated: 1.4, 2.8 and 4.2 mg/sqm/day; 25%, 50% and 75% of the maximum CPT-11 tolerated dose in c.i. (5.6 mg/sqm/day), respectively. Results: Between Apr 04 and May 05 20 patients have been enrolled. Patients characteristics were: M/F = 11/9, median age = 71 years (range 51–79); PS 0/1/2 = 8/11/1; sites of metastasis: single/multiple = 7/13; median of previous lines of chemotherapy: 3 (range 1–5). No toxicities of grade >1 NCI scale have been observed. No objective responses were observed, but 4 patients (20%) had a stable disease with a median duration of 14 weeks (range 11–20). TSP-1 plasma levels significantly increased after one week and remained higher than the baseline for more than 8 weeks (120.1±10.3% vs. 100% of day 0). VEGF levels did not significantly change during the CPT-11 infusion. No statistical differences have been found for TSP-1 and VEGF concentrations among the three dose levels. Conclusions: CPT-11 metronomic chemotherapy is feasible. Plasma TSP-1 markedly increased during metronomic CPT-11 administration, suggesting a modulation of the angiogenic process in cancer patients. Supported by A.I.R.C. [Table: see text]
A phase I trial combining motexafin gadolinium (MGd) with docetaxel in the treatment of advanced solid tumors
Authors: Pandya K. J. , Phan S. 
Published: March 2020

13115 Background: MGd is a novel therapeutic agent that concentrates in tumors and generates reactive oxygen species. Pre-clinical models show that MGd enhances in tumors the cytotoxic activity of selected chemotherapies, including taxanes. This phase I trial studied the combination of MGd and docetaxel. Methods: Patients (pts) with advanced solid tumors, adequate bone marrow, hepatic and renal function were eligible. Cohorts of 3 pts were treated with MGd starting at 2.5 mg/kg followed 30 minutes later by docetaxel 75 mg/m2. Treatments were repeated q3wks. The primary objective was to determine the maximum tolerated dose (MTD) of MGd in combination with docetaxel on this schedule and to determine the dose limiting toxicities (DLT). The secondary objective was to evaluate the response rate. MGd dose was escalated in successive cohorts while docetaxel dose remained fixed. Results: Sixteen pts were entered (9 males, 7 females) at MGd dose of 2.5 to 10 mg/kg. The median age was 60.5 yrs (range 35 -75). ECOG PS0 (4), 1 (14). Diagnoses included prostate (1); ovarian (2); breast (2) and non-small cell lung (NSCLC) (11). Median number of prior chemotherapy regimens: 2 (range 1–14), 7 pts had previously received a taxane: paclitaxel 5, docetaxel 2. Reported toxicities (all grades) include urine discoloration from excretion of MGd (68%), fatigue (87%), diarrhea (81%) and nausea (56%), Grade 3 neutropenia (37.5%) febrile neutropenia (6%), neuropathy (foot drop) was seen in 1 patient, therefore additional pts were entered (4 registered, but 1 never treated) at 10 mg/kg dose. Recurrence of prior radiation esophagitis was seen in 1 pt therefore it was felt that DLT was reached and study was closed. Responses are as follows: PR by CT in 1 breast and 4 NSCLC, and by PSA in 1 prostate; SD by CT in 1 breast and 2 NSCLC. Conclusion: MGd 10 mg/kg in combination with docetaxel 75 mg/m2 is feasible and did not increase docetaxel toxicity while showing promising responses. Phase II study of this combination is underway in NSCLC. [Table: see text]
Targeting tumour markers: What makes therapy discriminating?
Authors: Johnson K. , Ward R. 
Published: March 2020

13129 Background: Therapy in inoperable non-small cell lung cancer has limited effectiveness. New therapy directed at tumour markers is attractive but limited by marker prevalence and intrinsic effectiveness. Prior work (Abstract 9639, 2005 PASCO) on 191 trials of first line therapy shows a “typical drug” needs at least a 35% difference in response rate, treatment versus control, to predict a survival gain. The current work describes the characteristics of targeted drugs likely to predict this gain at smaller differences, i.e., more discriminating drugs. We determine how much greater effects on response rate and survival, compared to the typical drug, need to be to predict this survival gain. Methods: By using 1.0, 1.1, 1.2, 2.0-fold increments in response rates over traditional therapy and the same increments for median survival up to that used for response, we defined 55 differently constructed targeted drugs. The drugs were all analysed at each of four marker prevalence rates, 5%, 20%, 50% and 100%, each analysis determining the response rate difference needed to predict a survival gain. For each analysis individual trial response rates were modified in one arm before applying linear regression. The response rate difference to predict a survival gain is the portion of the prediction band fully exceeding zero. Results: Improvements in discrimination were rare and highly sensitive to marker prevalence. Little improvement occurred for any drug with 5% or 20% prevalence, and if no survival improvement occurred, discrimination worsened (up to 90%). If both tumour response and survival were doubled, discrimination improved to 33%, 27%, 17%, and 7% for marker prevalence of 5%, 20%, 50%, or 100%, respectively. Modest changes (×1.4, ×1.6) in response and survival only improved discrimination with 100% prevalence. Clearly improved discrimination (to 20% or less) only occurred with at least ×1.8 increase in response and survival and 50% or more prevalence. Conclusions: The results show that targeting a marker only substantially improves discrimination if it doubles both tumour response rate and median overall survival and if marker prevalence is at least 50%. This approach may help rationalize aspects of drug development in oncology. No significant financial relationships to disclose.
A phase II trial of epigenetic therapy with hydralazine and magnesium valproate associated to doxorubicin and cyclophosphamide for locally advanced breast cancer
Authors: Arce-Salinas C. , Segura-Pacheco B. , Vela-Chavez T. , Bargallo-Rocha E. , Pérez-Cárdenas E. , Taja-Chayeb L. , Trejo-Becerril C. , Revilla-Vazquez A. , Dueñas-González A. 
Published: March 2020

13147 Background: DNA methylation and histone deacetylation are the most studied epigenetic alterations in cancer. Hydralazine and magnesium valproate are proven DNA methylation and histone deacetylase inhibitors respectively that in combination exert antitumor effects by their own and potentate the effect of chemotherapy. Methods: Open label two-stage design phase II trial to evaluate safety and efficacy of hydralazine and magnesium valproate plus chemotherapy in terms of pathologic complete response as neoadjuvant treatment. A total of 42 patients will be accrued. Untreated patients with histological confirmation of breast cancer in clinical stage IIb-IIIa, and hematological, renal and hepatic normal function are elegible. Patients with any collagen disease and any cardiovascular condition were excluded. Treatment consisted on four 21-day courses of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 plus epigenetic therapy starting 7 days before the first cycle of chemotherapy and continued until the end of chemotherapy. Oral hydralazine dosed according to acetylator phenotype and magnesium valproate at 30mg/Kg. After chemotherapy patients were evaluated with mammography and then submitted to surgical resection. Results: 17 patients in the first-stage have been accrued. Their characteristics are as follows: Median age 45-y (39–67), 67% were stage IIIa, median size of tumor was 5 cm (3–10 cm). All patients had clinically positive axillary nodes, with median size of 2 cm (1–5 cm), 80% were ductal carcinomas and 80% had either intermediate or high grade; 77% were ER-positive and 30% over-expressed HER2. Hematological toxicity was the most common side effect, neutropenia grade 3/4 was found in 35% of cases, anemia grade 3/4 was present in 15% of cases and most presented transient grade 2 depressed level of consciousness. Seven patients have completed planned treatment, clinical responses were CR 2, PR 4 and SD 1; in 1 of 7 a pathological complete response was seen. Conclusions: Epigenetic therapy with hydralazine and magnesium valproate associated to conventional chemotherapy is well tolerated. Its antitumor efficacy is pending to evaluate. No significant financial relationships to disclose.
Interim analysis of phase I trial of 17-DMAG
Authors: Cartwright E. P. , Kummar S. , Muir C. A. , Ivy P. , Conley B. A. , Scripture C. D. , Figg W. D. , Murgo A. J. , Doroshow J. H. , Gutierrez M. E. 
Published: March 2020

13148 Background: 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin (17-DMAG) binds specifically to heat-shock protein 90, leading to degradation of oncogene client proteins, inhibiting tumor growth. Based on in vitro/in vivo data, 17-DMAG has potent antitumor activity. Methods: 17-DMAG was administered by 1–2 hour infusion twice weekly for 4 weeks/cycle. Eligibility criteria included: solid tumor or lymphoma, ECOG ≤ 2 and adequate organ function. Exclusion criteria: brain metastases, pregnancy, prolonged QTc, or uncontrolled illness. Accelerated titration escalation design, one patient/cohort enters until a single patient experiences dose-limiting toxicity (DLT) or two patients exhibit grade ≥ 2 (G2) toxicity (except nausea / vomiting) during the first cycle. The maximum tolerable dose (MTD) is the dose level at which no more than 1/6 patients experience DLT and the dose below that at which at least 2/6 patients have DLT. Primary objectives: to determine the toxicity profile, and MTD of twice weekly 17-DMAG. Secondary endpoints: pharmacokinetics (PK) and pharmacodynamics of 17-DMAG. PK were determined by LC-MS on blood samples collected before and serially up to 48 hours after 17-DMAG infusion. Results: 6 patients (one patient per dose level) with the following diagnoses were accrued and treated: renal cell, pancreatic, medullary thyroid, NSCLC, and two colorectal cancers. The DLT and MTD have not yet been achieved. 17-DMAG toxicities have been acceptable, nausea/vomiting being the most common toxicity observed. Three patients developed G1 nausea, one patient had G3 nausea. Two patients had G2 vomiting. Other G1 toxicities included: diarrhea, weight loss, fatigue, elevated transaminases, hair loss, and leukocytopenia. PK results showed significant intra-patient variability as the dose was increased from 1–12 mg/m2 over 6 dose levels; the mean AUC increased from 370–970 ng*hr/mL, and the mean Cmax increased from 36–79 ng/mL. There was a 5-fold range in clearance (range: 6.5–33.1 L/h), but there was no association between dose and clearance. Following a single dose, the terminal phase half-life ranged from 16.4 - 24.3 hours. Conclusions: Since the DLT and MTD have not been reached, accrual will continue. No significant financial relationships to disclose.
Early prediction of response in patients with advanced/metastatic non-small cell lung cancer during chemotherapy with FDG-PET-CT
Authors: Lee D. , Kim S. , Kim H. , Choo J. , Song J. , Han J. , Kim H. , Lee J. 
Published: March 2020

13154 Background: To evaluate the use of 18-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) for prediction of response and survival early during the course of treatment in patients with advanced/metastatic NSCLC. Methods: Between May 2004 and November 2005, 31 patients (gender, 23M, 8F; stage, 2IIIB/29IV, histology, 6 squamous cell ca, 22 adenoca, 3 NOS; age median 57 (30–73 y)) with histopathologically proven NSCLC stage IIIB/IV were enrolled into this study. PET-CT was performed prior to and after one cycle of treatment. Early changes of primary tumor FDG-uptake measured by standardized uptake values (SUV) were correlated with best response to therapy as assessed by CT scan according to WHO response criteria. Results: Patients underwent standard treatment with gemcitabine/vinorelbine (15), gemcitabine/cisplatin (1) gemcitabine/vinorelbine/cisplatin (1), irinotecan/cisplatin (9) or gefitinib (5). In the 25 patients evaluable for response, other 6 patients ongoing, 9 patients achieved a partial response (36%), 5 showed stable diseases and 11 were progressive. Using a cut-off value of 20% reduction of FDG-uptake as a criterion for a response in PET-CT, subsequent best response was predicted with a sensitivity of 88.9% and a specificity of 87.5%. The positive predictive value of a metabolic response was 80.0% and the negative predictive value 93.3%, respectively. There was a significant correlation between the decrease of tumor metabolic activity and subsequent best response (p< 0.001). The median time to progression for PET-CT responder was 10.1 months when compared with that of non-responders with 2.6 months (log-rank p=0.009). Conclusions: Using FDG-PET best response to standard treatment and patient outcome can be predicted very early and therefore, the use of PET-CT may allow to reduce side effects and costs of ineffective therapy in non-responding patients No significant financial relationships to disclose.
Predictive markers for the treatment of colorectal cancer with cetuximab
Authors: Razis E. , Briasoulis E. , Kostopoulos I. , Bobos M. , Christodoulou C. , Papamichael D. , Rigatos S. K. , Papakostas P. , Kosmidis P. , Fountzilas G. 
Published: March 2020

13500 Background: Cetuximab is an anti-EGFR monoclonal antibody with activity in colorectal cancer. Patients most likely to benefit should be identified using molecular markers. Methods: A retrospective analysis was performed on patients treated with cetuximab who had paraffin embedded tissue available for testing. Tumor specimens were tested for EGFR (31G7, Zymed), PTEN (28H6, Novocastra) and pAkt 1/2/3 (Thr 308, Santa Cruz) expression by IHC. The EGFR gene status was investigated by FISH (Vysis). Results: Seventy-two patients were identified. EGFR expression was detected in 32/68 patients tested. PTEN was positive in all cases tested (64/64) and pAkt in 52 of 64 patients, in >70% of cells in 21/64 cases. Most patients were treated with cetuximab in various combinations, three patients received it as a single agent and 7 patients in more than one line of therapy. Median follow-up from diagnosis was 30.7 months and from Cetuximab initiation 6.9 months. Median survival from diagnosis has not been reached yet but from initiation of Cetuximab it is 13.6 months. 19 patients achieved a PR and 1 a CR. Most patients with PR were treated in first or second line however, 6 patients achieved a PR in 3rd line and 3 in subsequent lines. The patient with complete response, was treated in first line with CPT 11 and Cetuximab. TTP was 7.4 months for patients treated with Cetuximab in 1st line, 7.5 in 2nd line and 5.3 in 3rd line. Survival did not correlate significantly with any of the immunohistochemically assessed parameters. TTP correlated significantly with pAkt overexpression for patients treated in 3rd line (p=0.0065). The CR was seen in the only patient with EGFR amplification.The presence of skin toxicity did not correlate with response to therapy. Conclusions: Overexpression of pAkt may correlate with response to Cetuximab in colorectal cancer. No significant financial relationships to disclose.