bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene polimorphisms and biological factors as possible predictors for patients with pleural metastatic breast cancer
Authors: Montes-Worboys A. , Romero A. , Casas A. M. , Arellano E. , Juan J. M. , Moreno J. A. , Rodriguez Panadero F.
Published: March 2020

10671

Background: Pronosis of breast cancer varies widely in patients with similar clinical features. Therefore, we investigated other factors with possible prognostic value. The CYP17 gene has a polimorphism related to a increased susceptibility to breast cancer (single T; A1 allele to C; A2 allele). ( Mitrunen et al. Cancer Epidemiol Biomarkers Prev 2000,9;12;1343–8). On the other hand, it has been found in the MTHFR gene a common C-T substitution at nucleotide 677 that is associated with reduced enzyme activity and increased risk of breast cancer (Capmbell et al., Breast Cancer Research 2002;4,6:R14). Other genes such as GSTT1 and GSTM1 variant genotypes have a controversial association to breast cancer. We have analyzed the genotype and biological factors in a group of patients with pleural metastatic cancer of the breast and compared it to a control group of women with no cancer. Methods: Forty-six patients with breast cancer and forty women as controls were includes in the study. Age at diagnosis of the primary tumor, TNM staging, interval free of disease, estrogen and progesteron receptors, Ki67, p53 and Her-2neu expression were recorded, as well as survival from the time of diagnosis and polimorphism of CYP17, MTHFR, GSTT1 and GSTM1 genes. Results: Mean survival differed significantly between patients having pleural effusion as the first site of relapse as compared to those with other sites of relapse (28’9 vs 11’9 months, p = 0’004). A high Ki67 expression correlated best with longer survival after talc pleurodesis. We detected a high frequency in the CYP17 A2 variant genotype in patients with metastatic breast cancer compared to the control group. As for MTFHR gene, we found a high frequency for the T/T genotypes variant in breast cancer group. No significant differences between control and cancer group were found in either GSTT1 and GSTM1 gene variations. Conclusions: Genotype and biological factors, such as factors investigated in this study, play an important role as predictors for patients with pleural metastatic breast cancer.

No significant financial relationships to disclose.
The Head to Head trial: Letrozole vs anastrozole as adjuvant treatment of postmenopausal patients with node positive breast cancer
Authors: De Boer R. , Burris H. A. , Monnier A. , Mouridsen H. , O’Shaughnessy J. A. , McIntyre K. , Pritchard K. I. , Smith I. , Yardley D.
Published: March 2020

10672

Introduction: Aromatase Inhibitors (AIs) have demonstrated both efficacy and safety advantages over tamoxifen (T) in all treatment settings in breast cancer (BC) and are becoming the new standard of care as endocrine therapy for postmenopausal patients (PM) with BC. Rationale: Cumulative evidence suggests that all AIs may not be the same, raising the question of whether there is a superior AI, and whether any specific patient populations derive differing degrees of benefit from a particular AI. In the ATAC trial, evaluating anastrozole (A) in PM patients with early breast cancer (EBC), at 33 months median follow up the risk of recurrence in the hormone receptor positive (HR+) population was reduced by 22%.The BIG 1–98 Trial, evaluating letrozole (L) in PM women with EBC, showed a significant benefit in favor of L over T at a median follow up of 26 months, with a 19% reduction in the risk of recurrence; in subgroup analyses, L significantly decreased the risk of recurrence in LN+ patients and in patients who received adjuvant chemotherapy. This study is a head to head comparison of L and A in HR+, LN+ PM patients with EBC and aims to compare L vs A in the adjuvant treatment of these patients. Design and Methods: This is a Phase IIIb open-label, randomized, multicentre study including 4000 PM patients from up to 250 international sites. PM patients with HR+, LN+ BC who have recently undergone surgery for primary BC will be randomized to either receive L 2.5 mg or A 1 mg daily. Treatment will commence following completion of standard chemotherapy (if given) and concurrently with radiotherapy (if given)Patients will receive treatment until disease recurrence/relapse for up to 5 years. Patients will be stratified by number of LN and HER2 status. The primary objective is disease free survival at 5 years for L and A. Secondary objectives include safety, overall survival, time to distant metastases and time to contralateral breast cancer. Data analysis will be conducted by an independent group of investigators. Summary: Updated patient accrual figures, including any available early safety data, will be presented at the meeting.

No significant financial relationships to disclose.
Effect of microscopic residual tumor (MRT) at surgical margin of resection (SMR) in ductal carcinoma in-situ (DCIS) on survival of non-Hispanic white women in central Pennsylvania (PA)
Authors: Kumar P. , Ingle A. M. , Baney B. , Day K. , Dagen T. , Galley A. S. , Dixon R. H.
Published: March 2020

10706

Background: Few studies that have investigated the long-term effect of MRT in DCIS, have demonstrated conflicting results. Mount Nittany Medical Center (MNMC) is located in an agricultural, ethnically-homogenous (Non-Hispanic White) county in PA. To the best of our knowledge, there have been no similar studies conducted on such populations. Our study has investigated the effect of MRT at SMR on overall survival (OS) and event-free survival (EFS) of patients with DCIS. Methods: All women diagnosed with DCIS from 04/1992 to 06/2005 at MNMC were deemed eligible. Log-rank statistics and Cox proportional hazard models (CPHM) were used for obtaining survival rates. Results: Of the 266 eligible women analysis were performed on 167 women (age range 33–89 years; median 56 years) with complete data on diagnosis, surgical margins and treatment modalities. With median follow-up time of 4.6 years (range 0.03–11.6years), 148 (88.6%) patients had no residual tumor at SMR. 78 (46.7%) patients received radiation therapy (RT) ± hormonal therapy (HT), 42 (25.2%) received HT ± RT. The CPHM demonstrated no statistical significance of MRT on OS (hazard ratio 2.9, p = 0.19), and EFS (hazard ratio = 1.9, p = 0.43) after adjusting for treatment and age. Univariate 5-year OS rate in patients with no MRT was 93.9% (95% confidence interval (CI) 87.6% to 97.1%), versus 89.2% (95% CI 63.1% to 97.2%) in patients with MRT (p-value = 0.38). Five-year EFS was observed to be 92.6% (95% CI 85.6% to 96.3%) in patients with no MRT, versus 89.2% (95% CI 63.1% to 97.2%) in patients with MRT (p-value = 0.49). Conclusions: In our study, patients with DCIS who have MRT at surgical margin of resection have a 2.9 times the risk of death and 1.9 times the risk of recurrence as compared to patients with no MRT. However, this difference is statistically not significant over time.

No significant financial relationships to disclose.
Neoadjuvant dose-dense (DD) concurrent doxorubicin (A) and docetaxel (T) for stage III breast cancer (BC)
Authors: Abu-Khalaf M. , Kim R. , Cohenuram M. , Chung G. , Digiovanna M. , Haffty B. , Carter D. , Horvath L. , Tavassoli F. , Burtness B.
Published: March 2020

10721

Background: The addition of taxanes to anthracycline therapy results in improved disease-free survival (DFS) in the adjuvant setting, and increased pathologic complete response rates (pCR) in the neoadjuvant setting. DD chemotherapy improves DFS and overall survival (OS). We evaluated neoadjuvant DD concurrent AT. Methods: Eligible patients (pts) with stage III BC were treated with AT q 14 days at 1 of 3 dose levels; L1 = 60 mg/m2 for both drugs (4 pts), L2 = A 75 mg/m2 and T 60 mg/m2 (6 pts) or L3 = 75 mg/m2 for both drugs (7 pts) × 6 cycles with G-CSF. Dexrazoxane was given after a cumulative dose of 300 mg/m2 of A. Pts were stratified to post-operative moderate risk (ModR) (≥ partial response, ≤ 3 lymph nodes (LN)) and received adjuvant IV cyclophosphamide (C) 600 mg/m2, methotrexate 40 mg/m2, 5FU 600 mg/m2 IV q 21 d × 6 (CMF), or high risk (HiR) (≤ minor response +/or ≥ 4 LN) and received C 3 gm/m2 q 14 d x 3. Primary endpoints were clinical and pathologic response rates of neoadjuvant AT. Sample size was 42 pts to estimate pCR and provide 90% confidence the true incidence of severe toxicity is <10%. Results: 17 pts with stage III BC were enrolled between 2/1999 and 7/2001; accrual was halted after data on pre-operative trastuzumab were presented. Median age was 50 yrs [range: 34–69]. 3/17 pts (17.6%) had a pCR, and 3 pts had near pCR (residual foci ≤ 1mm), 4/17 (23.5%) had path (-) LN, 7/17 (41%) had a lumpectomy, 7/17 (41%) required dose reductions of AT due to grade 4 neutropenia (5 pts) and grade 3 neuropathy (2 pts). 3 pts required treatment cessation; 1 pt (L2) for prolonged neutropenic fever and 2 pts (L3) for decreased ejection fraction and for acute renal failure. 15 pts were ModR and received adjuvant CMF, 1/2 pts stratified to high dose C declined it and received CMF. Median follow-up is 63 months [range: 28–80] with 13/17 (76.5%) pts surviving, and 12/17 (70.5%) pts surviving and free of disease. Conclusion: Neoadjuvant DD AT every 2 weeks is well-tolerated, with promising activity and survival in locally advanced BC.

[Table: see text]
Study on the effects of c-erbB-2-specific antisense oligonucleotides on c-erbB-2 overexpressing breast cancer cells
Authors: Liu X. , Fan P. , Wu Z.
Published: March 2020

10724

Background: Overexpression of c-erbB2 oncoprotein was always correlated with bad prognostic. In this study, we will research on the effects of c-erbB-2-specific antisense oligonucleotides (ODNs) on c-erbB-2 expression, cell proliferation and apoptosis of c-erbB-2 over-expressing breast cancer TM40D cells, and to further study the effects of c-erbB-2-specific oligonucleotides on breast cancer xenografts in Balb/c mice. Methods: Balb/c mouse derived breast cancer cell line TM40D was incubated with liposome-mediated ODNs for 4 h and cultured for another 72 h, then the effects of ODNs on c-erbB-2 expression, cell proliferation and activation of apoptosis were examined by western blot, MTT assay and flow cytometry. Twenty-six mice with breast cancer xenografts were randomized into three groups—9 in control group, 9 in lipsome group and 8 in therapy group, which were injected hypodermically with 0.1 ml serum-free RPMI-1640 culture-medium, lipsome (10 ug/ml) solution, and the mixture of lipsome solution (10 ug/ml) and anti-sense ODN (1 uM) weekly for consecutive 6 weeks, respectively. After the therapy, the incidence of skin ulcer was recorded, the lumps were removed and weighted, and part of them were used for Flow Cytometry. Results: Western Blotting showed treatment of TM40D cells with c-erbB-2-specific antisense ODNs resulted in inhibition of c-erbB-2 expression. The effects of antisense ODNs on c-erbB-2 protein levels correlated with their effects on cell proliferation. MTT Assay showed antisense ODNs inhibited cell growth by about 50%. Flow cytometry analysis revealed that antisense ODNs increased cell apoptosis by38.5%, compared with cultured cells group 9.13% and liposome group 9.29%. The weight of lumps in the therapy group was significantly lower than that of in the other two groups. Flow Cytometry showed that in the therapy group the ratio of G0/G1 cells in cell cycles was 87.18%, which is higher compared with the other two and proliferation index was lower. Conclusions: Antisense ODNs reduced c-erbB-2 expression, inhibited cell proliferation and induced cell apoptosis. Anti-sense ODNs can inhibit the growth of c-erbB2-overexpressing breast cancer xenogarfts in Balb/c mice.

No significant financial relationships to disclose.
First line treatment of HER-2/neu positive advanced breast cancer patients with liposomal doxorubicin (Myocet), docetaxel and trastuzumab. A phase I-II study
Authors: Amadori D. , Gasparini G. , Vannozzi M. O. , Milandri C. , Serra P. , Di Costanzo F. , Di Blasio B. , Lunardi G.
Published: March 2020

10744

Background: Our preclinical data showed synergic effect of Adriamicyn followed by Taxotere in BC cell lines. The combination of anthracyclines, taxanes and trastuzumab could potentially obtain a high number of objective responses and a consistent impact on the time to progression and on the overall survival. The aim of this phase I-II study was to assess the maximum tolerated dose (MTD) of liposomal doxorubicin (Myocet-M) and Taxotere (T) in combination with Herceptin (H). A reduction of cardiotoxicity risk without reducing chemotherapy activity was supposed. Methods: Locally advanced or metastatic her-2/neu positive BC patients (pts) with LVEF ≥ 60% were enrolled in an open, single arm, non-randomized phase I-II escalation trial in 3 to 6 pts/cohorts. The treatment schedule was: M 50 mg/m2 (or 60, depending on dose level assignment) on day 1, T 30 mg/m2 on day 2 and 9, H 4 mg/kg on day 2 followed by weekly dose of 2 mg/kg, every three weeks. MTD dose was identified on the basis of DLT defined according to WHO grade classification of toxicity or specific conditions of LVEF decrease. A pharmacokinetic (PK) analysis of doxorubicin until 72 hours after M administration was planned. Results: Seven pts, median age 63 yrs, were enrolled. Four pts were allocated to dose level 50/30 (M/T) and other 3 pts to dose level 60/30. At the dose level 60/30 febrile neutropenia (DLT) occurred in 2 pts. Other 2 pts experienced febrile neutropenia (no DLT). One event of tachicardia (WHO grade 1) at maximum tolerated dose level was completely recovered without treatment. LVEF values were unmodified. Six patients were enrolled in the PK analysis. T pharmacokinetic data obtained on day 2 and on day 9 were not statistically different. Conclusions: The MTD was defined at M 50 mg/m2 in combination with T 30 mg/m2. The cardiac tolerability was good, with no significant change in LVEF values from baseline to the end of therapy. PK data indicated that the residual concentration of M found on day 2 was did not influence T pharmacokinetics, according to literature data. A phase II study is ongoing to assess activity and PK interactions between drugs. Till now 25 patients have been enrolled, the planned sample size is 45.

No significant financial relationships to disclose.
Safety of long-term administration of capecitabine in metastatic breast cancer patients
Authors: Lomas M. , Salvador J. , Ruiz M. , Bayo J. L.
Published: March 2020

10755

Background: To evaluate the effectiveness and tolerability of long -term treatment with capecitabine in metastatic breast cancer patients. Capecitabine (C) has been administered offering clinical benefit to women with metastatic breast cancer (MBC) (ORR: 42%). The aim of this trial was to evaluate the efficacy and tolerance of capecitbine in long-term treatment, administered as first, second and third line treatment in MBC. Methods: Patients ≥ 18 years old with MBC, ECOG performance status (PS) ≤2, HER-2 neu negative, non-chemotherapy naive were included in this prospective, multicentre, non-randomized. To date, twenty-two ambulatory patients were evaluable for toxicity and response. Median age 59.2 years (37–81). All of patients had previously received adjuvant treatment. Hormonal therapy were allowed as clinically required. They received three weekly cycles of oral capecitabine 1000–1250 mg/m2 twice daily, days 1–14, followed one week rest until progression or relapse. Results: The overall response rate (ORR) is including PR, CR, and EE 78%. The median treatment duration was 14 months, median range (3–32). Median progression-free and overall survival have not yet been reached. The most common grade ½ (NCIC CTC) treatment related adverse events were /23, hand foot syndrome 4/23, diarrea 1/23. Conclusions: These preliminary data confirm that the treatment with capecitabine (C) is an effective and well tolerated regiment in metastatic breast cancer patients.

No significant financial relationships to disclose.
Observations of differences in laterality imbalance of breast biopsies and breast disease between Caucasian and African American women
Authors: Jordan R. , Brzeski H. , London W. P. , Mural R. , Liebman M. N. , Hooke J. , Shriver C. D. , Hu H.
Published: March 2020

10781

Background: A number of published reports have indicated that the left breast is at greater risk of cancer than the right breast (laterality imbalance) in women of all ages. In addition, a woman’s left breast is usually larger than her right breast. In the Clinical Breast Care Project, more than 2400 subjects have been enrolled following HIPAA compliant, IRB approved protocols. Of these, 1200 have undergone a biopsy and completed demographic and pathological questionnaires. We investigated whether there is a laterality imbalance among the patients with respect to ethnicity, menopausal status or pathological diagnoses. Methods: Female patients with biopsies on only one breast whose pathological questionnaire was completed within 90 days of the demographical questionnaire were included in this analysis but patients who were surgically post-menopausal were excluded. Multiple biopsies on one breast for each woman were counted as one event. For statistical analysis, Pearson’s chi-square test in SPSS was used. Results: Of the 1200 patients, 708 (546 caucasian; CA and 172 African American; AA) satisfied the above criteria. Although the total number of biopsy events are essentially evenly distributed on either breast for either ethnicity, statistical analysis showed that post menopausal CA women have fewer biopsy events on the left breast (41%, n=264) than their pre-menopausal counterparts (52%, n = 282; p < 0.05); On the contrary, post-menopausal AA women have significantly more biopsy events on the left breast (62%, n=50) than their pre-menopausal counterparts (42%, n = 122; p = 0.02). Further analysis based on pathological diagnoses indicated that benign, pre-menopausal, AA patients have fewer events on the left breast (42%, n = 98) compared to CA (54%, n = 211; p < 0.05). Discussions: Despite the small sample size, the data nonetheless suggest that there are significant, menopausal status dependent, laterality imbalances of breast disease biopsy among CA and AA women. These differences await evaluation.

No significant financial relationships to disclose.
A novel low molecular weight inhibitor of focal adhesion kinase and insulin-like growth factor-1 receptor, TAE226, inhibits glioma growth
Authors: Rich J. N. , Shi Q. , Hjelmeland A. B. , Keir S. T. , Wickman S. , Wu G. , Jackson D. , Ohmori O. , Bigner D. D. , Friedman H. S.
Published: March 2020

11505

Background: Glioblastomas are highly lethal cancers that resist current therapies. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase overexpressed in glioblastoma patient specimens that may promote glioma growth and invasion by increasing cellular adhesion, migration, invasion, proliferation. TAE226 is a novel low molecular weight inhibitor of several kinases that demonstrates in vitro activity primarily against FAK with activity against insulin-like growth factor-1 receptor (IGF1R) at higher concentrations. Methods: As FAK and IGF1R are potential molecular targets in glioblastomas, we examined the efficacy of TAE226 against human glioma cell lines and xenografts. Results: TAE226 inhibited the activating phosphorylation of FAK at submicromolar concentrations with residue specific preference. Downstream effectors (Akt and ERK) were inhibited at slightly higher concentrations. TAE226 demonstrated a concentration-dependent decrease in cellular proliferation with an associated G2 cell cycle arrest in multiple glioma cell lines, whereas TAE226 potently induced apoptosis in a concentration-dependent manner in only one of four cell lines tested. TAE226 also induced a concentration-dependent decrease in cellular adhesion, migration, and invasion. In preliminary animal studies, a limited course of orally administered TAE226 (100 mg/kg qd 5 days on/2 days off/5 days) was well tolerated with minimal weight loss. TAE226 induced a modest growth delay of human glioma xenografts grown in a subcutaneous location in athymic mice (3 to 4 days delay, p < 0.001). In addition, mice bearing orthotopic intracranial human glioma xenografts demonstrated a modest increase in median survival (3.5 days, p = 0.078). Despite the modest degree of the tumor responses, these results are superior to other low molecular weight inhibitors, such as epidermal growth factor receptor (EGFR) inhibitors. As glioma xenografts often grow without invasion, these results may underestimate the efficacy of targeting FAK as FAK plays a major role in tumor invasion. Conclusion: TAE226 demonstrates modest activity as monotherapy against malignant gliomas and warrants further investigation, potentially in combination with other therapies.

[Table: see text]
Post-operative concomitant radiochemotherapy in the treatment of primitive CNS high grade gliomas. A retrospective analysis
Authors: Costa P. , Braga F. , Sottomayor C. , Honavar M. , Resende M. , Romaõ H. , Teixeira J.
Published: March 2020

11528

Background: The authors analyse retrospectively the impact on tumour control and toxicity of concomitant radiotherapy (RT) and Temozolomide (TMZ) in high grade gliomas (HGG) of the CNS, in patients treated in the Clínica de Radioterapia do Porto - Portugal. Methods: This cohort represents all patients with HGG treated between January 2002 and January 2006, with concomitant RT a median total dose of 60 Gy, 2 Gy per treatment given once daily 5-days/week and TMZ 75mg/m2 for 42 days, followed by adjuvant treatment with TMZ 5-days schedule every 28 days (150 mg/m2 for the first cycle increased to 200mg/m2). The cohort was retrospectively analyzed for gender distribution, age, extent of surgical resection, initial KPS, median overall survival (OS) and haematological toxicity. Results: 23 with HGG (6 females, 17 males) were treated with concomitant RT (44–72 Gy) and TMZ followed by adjuvant TMZ; median age was 58 (ranging from 17–72); median KPS was 80 (ranging from 40–90); 3 patients had complete resection, 17 partial resection and 3 biopsy. All patients except one, who had treatment interruption for thrombocytopenia, completed the concomitant phase of treatment; 19 patients continued to received adjuvant treatment with TMZ (median number of cycles was 5 (ranging from 1–20). Median OS (measured from the date of diagnosis to the date of death) was 20.4 month and 1 yr OS was 54%. During concomitant phase, one patient had grade 3–4 thrombocytopenia. During the adjuvant TMZ therapy 4 patients had grade 3–4 haematological toxicity (anaemia: 1; thrombocytopenia: 1; leucopoenia and thrombocytopenia: 2). Conclusions: The results of concomitant RT+TMZ followed by TMZ in these patients with HGG showed values in accordance with the latest data published on literature for this association. Differences observed might be due to the small sample size.RT+TMZ followed by adjuvant TMZ is a well tolerated treatment with better results in median OS comparatively with previous results of RT only treatment in HGG. Treatment related toxicity was within acceptable levels, and this approach became routine practice in this set of patients.

No significant financial relationships to disclose.
A pharmacokinetic study of Genetaxyl (G) together with cyclosporin A (CsA) administered orally in cancer patients
Authors: Liau C. , Lepper E. , Wang H. , Yang M. , Chiou T. , Chen P. , Chu Z. , Figg W. , Sparreboom A. , Chen J.
Published: March 2020

12002

Background: Oral administration of paclitaxel given with CsA has shown promising activity in Phase II trials, but the apparent bioavailability is low and dose-dependent due to the presence of high concentrations of Cremophor EL (CrEL). We hypothesized that the use of a novel oral paclitaxel formulation containing only 20% CrEL (Genetaxyl [G]; Genovate Biotechnology Ltd., Taiwan), given with CsA is associated with an improved pharmacokinetic (PK) profile. Methods: Cohorts of 6 patients with cancer were treated with oral G at a dose of 60, 120, or 180 mg/m2 and 10 mg/kg of oral CsA in cycle 1. In cycle 2, patients received IV G (175 mg/m2, 3-h infusion). Three additional patients received generic IV paclitaxel (GIP). Serial blood samples were analyzed by LC/MS/MS and equilibrium dialysis, to determine total and unbound paclitaxel PK. Results: The mean (± SD) total paclitaxel AUCs were 1299±189, 1682±636, and 2204±1407 ng.h/mL at the 3 consecutive dose levels, suggesting nonlinear PK. However, based on unbound AUC, the oral bioavailability was dose-independent (P=.62), with a mean value of 37.2±18.6% (n=15). As expected, the total paclitaxel AUC following IV G (9024±4648 ng·h/mL) was lower than that for IV GIP (13,732±3983 ng·h/mL), as a result of increased clearance (39.6 vs 18.3 L/h) and a larger volume of distribution (768 vs 268 L). Interestingly, the unbound paclitaxel AUC was similar between the two IV formulations (P=.25), as the ratio of unbound/total paclitaxel for G was 2.5 times higher than that for GIP (12.5 vs 4.9%). Toxicity profiles were mild, with only 2 patients experiencing ≥ Gr 3 myelosuppression following oral G at 180 mg/m2. Conclusions: The mean bioavailability of paclitaxel following oral Genetaxyl with CsA was about 37%, which is higher than that observed previously with paclitaxel (range, 21–31%). Further clinical exploration of oral Genetaxyl in taxane-sensitive diseases is warranted.

[Table: see text]
Phase I trial of bortezomib in combination with topotecan in advanced solid tumor malignancies
Authors: Morgan R. , Valdes-Albini F. , Synold T. , Somlo G. , Shibata S. , Chow W. A. , Lim D. , Koehler S. , Frankel P. , Doroshow J.
Published: March 2020

12004

Background: Bortezomib (B) and topotecan (T) have been shown in pre-clinical testing to be synergistic. Based on this data we have performed a phase I study to determine the maximally tolerated dose and toxicities (tox) of B and T delivered sequentially. Methods: 24 pts (KPS<ECOG 3) with advanced malignancies were treated with T (2.0, 2.5, 3.0 or 3.5 mg/m2 in sequential cohorts) IV on days 1 and 8 of each three week cycle. B 1.3 mg/m2 iv was administered six hours following T on days 1 and 8, and alone on days 4 and 12. Pts were treated in cohorts of 3, the MTD dose was expanded to include 10 additional pts for PK analysis. There was no limit on prior therapies. DLT was defined as any gr 3 or 4 non-hematologic toxicity not reversible in 48h or any gr 3 thrombocytopenia lasting >7 days or associated with bleeding or any gr 4. Results: Tumor types included: breast (4), ovary (5), lung (3), others (12). 24 pts were entered (11M 13F). The median age was 55 (range: 34–83). DLT was thrombocytopenia, observed in two pts at 3.5 mg/m2 and one pt at 3.0 mg/m2 (MTD). Other grade 3 or 4 tox included fatigue, lymphopenia, hypomagnesemia, and hypertriglyceridemia. Of the 24 enrolled pts, stable disease was observed in 4 (4 or 5 cycles), 9 progressed, 5 were inevaluable and 6 are too early. PK analysis is pending. Conclusions: T and B delivered sequentially are well tolerated on a weekly schedule. DLT is thrombocytopenia. PK will be presented.(Supported by NCI Grant CA33572).

[Table: see text]
Chemosensitisation by poly(ADP-ribose) polymerase-1 (PARP-1) inhitor 5-aminoisoquinoline (5-AIQ) on various melanoma cell lines
Authors: Radulovic S. , Bjelogrlic S. , Todorovic Z. , Prostran M.
Published: March 2020

12019

Background: PARP-1 facilitates DNA strand brakes repair and PARP inhibitors were investigated as enhancers of chemoradiotherapy. We investigated whether 5-AIQ potentates the effect of doxorubicin (DOXO), cisplatin (CDDP) and paclitaxel (Ptx) on human (slow-growing) FemX and murine (fast-growing) B16 melanoma cell lines. Methods: Twenty-four hours after cells were seeded in 96 well plates, cytotoxic drugs and 5-AIQ were added to cell medium. For evaluation of single-agent activity, drugs were applied in concentration ranges as follows: CDDP (0.3–30 μM), DOXO (0.1–3 μM), Ptx (1–100 ηM), 5-AIQ (1–100 μM). 5-AIQ (3μM) was combined with CDDP (0.1, 0.3, 1 μM), DOXO (10, 3, 100 ηM), or Ptx (1, 3, 10 ηM). Incubation lasted for 72 hrs when SRB assay was utilized to determine individual and combine activity (interactions calculated with isobole method). For cell cycle analysis B16 cells were seeded on 6 well plates and treated with each drug alone and combinations, using the same concentrations as those for investigation of combine cytotoxic activity. Cell cycle was determined after 72 hrs, on FACS Calibur with propidium iodide dye. Results: 5-AIQ induced minimal changes in cell viability and cell cycle progression on both cell lines, compared to non-treated control. CDDP revealed high activity against FemX (IC50 = 2.85 μM) and B16 cells (IC50 = 8.84 μM), and G0/G1 arrest. In B16 cells 5-AIQ multiply enhanced CDDP’s activity with strong synergistic interaction and cells slightly driven to S phase. Synergism was also detected on B16 cells treated with combination of DOXO (IC50 = 0.2 μM on B16 and 0.89 μM on FemX) and 5-AIQ when DOXO was applied in low concentrations (10 and 30 ηM), while 5-AIQ did not interfere with cell cycle changes. Cytotoxicity of Ptx (IC50 = 6.16 ηM on B16 and <1 ηM on FemX) was stimulated only at higher concentrations. 5-AIQ stimulated G0/G1 and S phase arrest on B16 cells with Ptx of 3 and 10 ηM, respectively. In FemX cells, most of the interactions of 5-AIQ with CDDP, DOXO, and Ptx revealed as antagonistic. Conclusions: PARP-1 inhibitor 5-AIQ enhances cytotoxic activity of both DNA damaging and agents with different mechanism of action, but the effect varies between cell lines with different proliferation rate.

No significant financial relationships to disclose.
A dose escalation trial of fixed dose gemcitabine and capecitabine
Authors: Morgan Meadows S. , Van Ummersen L. , Brandon H. , Oliver K. , Houston M. , Eickhoff J. , Wilding G.
Published: March 2020

12026

Background: Gemcitabine can be administered as a 30-minute infusion or a prolonged, fixed-dose infusion (FDR). FDR may have improved clinical activity. Gemcitabine and capecitabine have non-overlapping mechanism of activity. This phase I trial explored the combination of FDR gemcitabine plus capecitabine. Methods: Patients received gemcitabine (G) as a fixed dose on day (D) 1 and 8 and capecitabine orally D1–14 of a 21-day cycle. Capecitabine (C) dose was fixed at 500 mg/m2 twice daily (BID) with escalating doses of G, beginning at 400 mg/m2. The trial was a standard phase I trial with cohorts of three. Dose-limiting toxicity (DLT) was defined as febrile neutropenia, grade 3/4 neutropenia lasting > 7 days, grade 3/4 thrombocytopenia lasting > 7 days, grade ¾ nausea/vomiting despite maximal anti-emetic therapy, grade 3/4 diarrhea, or grade 3/4 hand-foot syndrome. Results: Nine patients have enrolled to date, receiving a total of 56 courses at dose level one (G 400 mg/m2, C 500 mg/m2 BID). Median age is 61 (range 47–61). Grade 3 neutropenia has been the predominate toxicity, occurring in 12.5% of courses. One patient with renal cell carcinoma had a partial response. Four additional patients had prolonged stable disease lasting 7–15 months. Prolonged stable disease was observed in two patients with cholangiocarcinoma, one patient with renal cell carcinoma and one patient with anal squamous cell carcinoma. Conclusions: This combination has manageable toxicity with some evidence of activity at G 400 mg/m2 and C 500 mg/m2 BID. Dose escalation continues.

No significant financial relationships to disclose.
A biodistribution of 5-fluorouracil co-administered with and without galactomannan derivative, in athymic mice implanted with COLO 205 human xenografts
Authors: Zomer E. , Klyosov A. , Platt D. , Stevens R.
Published: March 2020

12027

Background: The polysaccharide [(1–4)-linked β-D-mannopyranose]17- [(1–6)-linked-α-D-galactopyranose]10 (Davanat [D]), enhances activity of 5-Fluorouracil (5-FU) in 5-FU refractory murine colon tumor models. D binds to surface lectins and promotes transport of 5-FU into the tumor cells. Lectins are present in large amounts on the surface of metastatic tumor cells, and may mediate cell association, apoptosis and metastasis. Method: A preclinical biodistribution study was initiated to evaluate the intravenous (i.v.) administration of 5-FU (36 mg/kg/dose) in the absence and presence of D (60 mg/kg/dose) in female athymic mice with tumors. Forty mice either received 5-FU alone or with D on days 24–27 (Q1d × 4) after tumor implantation. On day 27, a (2-14C) labeled 5-FU was added to the regimen. After the injection, ten mice per time point (0.5, 1.5, 4 and 24 h) were bled, euthanized and then the plasma, tumor and tissues were assayed for radioactivity by a liquid scintillation analyzer. Objectives were to determine the biodistribution of 14C-5-FU in the absence and presence of D in plasma, tumor and tissues. Results: 14C-5-FU disappeared in a bi-phasic manner after i.v. injection both in the presence and absence of D. Addition of D increased the amount of 5-FU exposure as measured by area under the curve (AUC) from 1.5 to 24 hours post-dose. This finding confirms results from a Phase I study where administering escalating doses 30 to 280 mg/m2 D with fixed 500 mg/m2 5-FU also demonstrated an increase in 5-FU systemic exposure as the D dose increased to 280 mg/m2 Conclusions: In mice, 14C-5-FU dosed with D increased the overall exposure of 14C-5-FU during the 1.5 to 24 hr sampling time duration in plasma, tumor and kidneys, when compared to 14C-5-FU dosed alone. These results, and the results obtained from a Phase I study where D was co-administered with 5-, warrants further testing in a Phase II/III clinical trial.

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Gemcitabine (G) given as a prolonged infusion in patients (pts) with advanced solid tumors: A phase I study with intra-pt dose escalation (DE) and pharmacokinetic (PK) / pharmacodynamic (PD) analysis
Authors: Soulié P. , Luet D. , Dupuis S. , Boisdron-Celle M. , Guérin-Meyer V. , Abadie S. , Leproust B. , Maillart P. , Delva R. , Gamelin E.
Published: March 2020

12029

Background: Optimizing drug delivery based on pharmacokinetic data is an important research issue. Previous studies have demonstrated a pharmacological advantage for infusions of G with a fixed dose rate to maximize cellular accumulation of G active metabolite (GTP), despite high interindividual PK variability. Methods: To develop a PK-guided G dosing schedule, we conducted an intra-pt G DE trial to determine: (1) maximum tolerated dose level (MTD) and dose-limiting toxicity (DLT), (2) plasma G and peripheral mononuclear cell GTP post-infusion levels. G was administered over 150 min on day 1, 8 and 15, q4w. The initial dose level (DL) was 1000 mg/m2, escalated by 250 mg/m2 every cycle (cy) if no limiting toxicity occurred. Results: From 09/2003, 30 pts entered the study. Pts’ characteristics: 16 men/14 women; median age 66 years (49–81); tumor type: pancreas (10 pts), lung (7 pts), others (13 pts); prior chemotherapy (15 pts). A total of 109 cy were given (median: 3 cy/pt). Tolerance: Number of pts/DL: DL1 = 7 pts, DL2 = 5 pts, DL3 = 11 pts, DL4 = 5 pts, DL5 = 2 pts. Main reasons for stopping DE were: disease progression/early death (15 pts), DLT (4 pts), investigator’s decision (8 pts). DLT were: haematological (1 pt), asthenia (2 pts) and infection (1 pt). Most common grade (gr) 1–2/3–4 toxicities (% cy) included: nausea/vomiting (38%/2%), asthenia (56%/11%), neutropenia (29%/27%) and thrombocytopenia (42%/1%). Activity: 26 pts are evaluable (radiological assessment every 3 cycles) showing 5 partial response (2 unconfirmed), 7 stabilization and 14 progression. Conclusions: The main reason for DE failure was early progression, stressing the importance of an early individual dose adjustment. PK and PK/PD correlation analyses are ongoing to confirm our hypothesis.

No significant financial relationships to disclose.
Recombinant arginase as a novel anti-melanoma agent
Authors: Hsueh E. C. , Knebel S. , Collier I. , Kadze M. , Hsueh C. , Lo T. , Cheng P. , Leung T.
Published: March 2020

12032

Background: BCT-100 is a recombinant arginase comprised of 329 amino acid residues. Arginase converts arginine to urea and ornithine. Previous studies suggested that melanoma cells were auxotrophic for arginine due to absence of argininosuccinate synthetase (ASS) expression. Thus, we hypothesized that recombinant arginase, BCT-100, is cytotoxic to human melanoma cells and its cytotoxicity correlates with absence of ASS expression. Methods: BCT-100 pegylated recombinant human arginase was manufactured by large scale fermentation of a recombinant B. subtilis strain LLC101 encoded with a human arginase gene. Following fermentation, the recombinant protein was extracted, purified, pegylated, and ultra-dialyzed. Ten established human melanoma cell lines were used. Cells were grown to 90% confluence, harvested, and plated at 104 cells per well in a 96-well plate and co-cultured with increasing concentrations of pegylated BCT-100 for 72 hours. CellTiter 96 Aqueous Non-radioactive Cell Proliferation Assay (Promega, Madison, WI) was used to measure percent viability, with absorbances measured at 490 nm. Total cellular RNA was isolated from established melanoma cell lines converted to cDNA at a concentration of 5 ng/ul. Quantitative real time polymerase chain reaction was performed on a 7300 Real Time PCR System, using Gene Expression Assays for ASS and GAPDH (Applied Biosystems). 10,000 fold standard curves were generated for all samples using GAPDH expression. Results: All ten cell lines demonstrated decreased viability as concentrations of BCT-100 increased. Average IC50 value was 0.11 IU/ml. Eight of the 10 cells lines have IC50 values < 0.1 IU/ml. Of the 8 cell lines with IC50< 0.1 IU/ml, all of them have low or undetectable ASS expression using quantitative RT-PCR. Of the 2cell lines with IC50 > 0.1 IU/ml, ASS expression was detected in 1 of 2. Conclusions: Arginine depletion with recombinant arginase, BCT-100, was cytotoxic to melanoma cells in vitro. The cytotoxic effect of BCT-100 on melanoma cells correlated with expression of argininosuccinate synthetase. BCT-100 is a promising novel agent for treatment of melanoma. Further in vivo experiment with BCT-100 is ongoing.

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Prostate cancer: Autologous immunotherapy optimized by indoleamine-2,3-dioxygenase (IDO)-inhibitor as immune-tolerance breaker
Authors: Lasalvia-Prisco E. M. , Garcia-Giralt E. , Cucchi S. , Larrañaga J. , Wagner D.
Published: March 2020

12509

Background: In several peer review publications (Cancer Biol Ther 2003) our team has reported a procedure of cancer immunotherapy using an autologous thermostable hemoderivative vaccine (ATHV) with anti-progressive tumor effect in metastatic malignant disease from different primary tumors including prostate cancer. Last year (ASCO Meeting 2005) we have reported that the tolerance break for tumor associated antigens through the interference with CD4+CD25+ regulatory cells is a component of the mechanism of action of the ATHV antitumoral effect. Therefore, we have intended to optimize this autologous immunotherapy adding to the procedure different steps of immune-tolerance blockage selected due to their proven efficacy in pre-clinical models and their feasibility in the frame of ATHV technology. In this study we report the results in prostate cancer when the adjuvant step added was the translational knowledge the tolerance blockage by IDO-inhibition through 1-Methyl-Tryptophane or 1-MT (Munn DH et al J Exp Med 1999). Methods: Thirty metastasic prostate cancer patients, hormone and chemotherapy resistant, Performance Status ≤ 2 and PSA progressing serum level, were included in this institutional-IRB approved phase I/II trial. The patients were randomized in 3 groups submitted to 3 different treatments: I, only sympthomatic; II, the previously reported ATHV and III, ATHV + simultaneous s.c. 1-MT. Tumor size increase (tumor growth) measured according RECIST was registered in each case. Mean difference in the 3 groups was statistically assessed (Student’s t-test). Tryptophane to Kynurenine conversion was tested to assess IDO inhibition. Results: Tumor growth was significantly slower in Group II and III than in Group I (p<0.01 and p<0.005). Tumor growth was also significantly slower in Group III than in Group II (p<0.02). IDO-inhibition was confirmed only in Group III. No relevant toxicities were detected. Conclusions: These results support that additional tolerance break by IDO-inhibition optimizes the tumor growth inhibition through immunotherapy with an autologous thermostable hemoderivative vaccine.

No significant financial relationships to disclose.
Poly TLR agonist polyantigenic vaccine (Mycobacterium w) in palliative therapy of head and neck cancer
Authors: Dave R. I. , Tripathi U. , Shah S. , Patel K. M.
Published: March 2020

12512

Background: Poly TLR poly-antigenic vaccine containing Mycobacterium w (Mw) is found useful in the management of lung cancer and bladder cancer when used along with standard therapy1,2 but not in Head and Neck cancer3–4. This study was carried out to evaluate its efficacy as a single agent in advanced head & neck cancer. Methods: In a prospective study consecutive 75 symptomatic patients with advanced head & neck cancer (squamous cell) attending hospital for palliative care following failure of standard therapy were administered Mw once a week for 8 weeks. Results: Of 75 patients 43 were male & 32 females with 76% between the ages of 31 to 60). 18 had buccal mucosa tumor, 12 alveolar and 11 at base of the tongue. Partial response was seen in 27. It was associated with Pain relief (27/27), Healing of ulcer/fistula (4/5), improvement in dysphagia (7/15), improvement in voice(5/19). All 27 showed improvement in constitutional symptoms also. No systemic side effects were seen. Conclusions: Mw vaccine is useful in palliative care of head & neck cancer. Reference 1Sur PK, Dastidar AG. Role of mycobacterium w as adjuvant treatment of lung cancer. J Indian Med Assoc. 2003;101:118, 120. 2Chaudhuri P, Mukhopadhyay S. Bladder preserving approach for muscle invasive bladder cancer–role of mycobacterium w. J Indian Med Assoc. 2003;101:559–60 3M. C. Pant, R. Hadi, R. Prasad, D. Dalela, et al. Role of immuno-therapy as a adjuvant treatment in advance head & neck cancer, patient receiving chemo radiotherapy. Journal of Clinical Oncology 2005; 23, (16S Part 1): 190S 4S. K. Sarkar, C. Dasgupta. Role of Mycobacterium W as an adjuvant treatment of Head & Neck Cancer_A Randomised trial. Journal of Clinical Oncology 2005; 23, (16S Part 1): 521 s.

No significant financial relationships to disclose.
Effect of bevacizumab (BV) and chemotherapy (CT) on serum levels of vascular endothelial growth factor receptor-2 (sVEGFR-2) in patients with inflammatory and locally advanced breast cancer
Authors: Walshe J. M. , Denduluri N. , Berman A. W. , Nguyen D. , Yang S. Y. , Liewehr D. J. , Steinberg S. M. , De Sauvage F. , Chen H. , Swain S. M.
Published: March 2020

13003

Background: VEGFR-2 is a principal mediator of angiogenesis. The effects on sVEGFR-2 after anti-angiogenesis therapy are unknown. Methods: Twenty-one patients (pts) with breast cancer underwent neoadjuvant treatment with BV for 1 cycle (C1) followed by 6 cycles of BV, CT and filgrastim. Blood was collected at baseline (BL), post-cycles 1, 4 and 7. Objectives were to correlate sVEGFR-2 changes after treatment with response, assess wound healing complications, and evaluate for tumor VEGFR-2 mutations. sVEGFR-2 levels were measured by ELISA. Exons 17–26 were sequenced on tissue samples from 20 pts at BL and post C1 to evaluate for VEGFR-2 mutations. Statistical testing is non-parametric. All p-values are two-tailed, with a p < 0.01 interpreted as a statistically significant difference. Results: Thirteen pts had a partial response (PR), 1 unconfirmed PR, 5 stable disease (SD), and 2 progressive disease (PD). Median sVEGFR-2 levels increased by 16% from BL to post C1 (p = 0.0003) and decreased by 19% post C1 to post C4 (p = 0.048). sVEGFR-2 levels were not associated with clinical response. sVEGFR-2 levels at BL did not correlate with other BL parameters: Ki67, microvessel density, VEGF-A, pVEGFR-2, VEGFR-2 or TUNEL (apoptosis). A moderate-weak correlation was seen between post C1 levels of sVEGFR-2 and pVEGFR-2 (r = 0.43). A moderate inverse correlation was seen in the relative difference of sVEGFR-2 and TUNEL from BL to post C1 (r = −0.59). Comparing pts with (n = 5) and without (n = 16) wound healing problems, median sVEGFR-2 levels were 11322 ng/ml and 7524 ng/ml at BL (p = 0.019), 13928 ng/ml and 10148 ng/ml post C1 (p = 0.029), and 10965 ng/ml and 7932 ng/ml post C4 (p = 0.042). In 40 samples where tumor VEGFR-2 sequencing was obtained, no mutations were seen compared to the reference sequence. Conclusion: sVEGFR-2 levels rose significantly following BV alone but were not associated with response. There is a suggestion that sVEGFR-2 may correlate with activated VEGFR2 and a decrease in apoptosis. sVEGFR-2 levels were higher in pts with wound healing problems and may predict pts at higher risk of this complication. There were no mutations of VEGFR2.

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Comparing true tumor volume to unidimensional and bidimensional measurements in lung cancer—A better discriminator of response?
Authors: Schwartz L. H. , Zhao B. , Moskowitz C. , Michelle G. , Rizvi N. A. , Kris M. G.
Published: March 2020

13020

Background: Accurate evaluation of response is crucial to determine if a treatment is effective for a particular patient or if an experimental agent is effective against a specific tumor type. Current measurement techniques such as WHO and RECIST are limited by only identifying changes in size in the axial plane, and with one or two dimensions. We devised and tested a semi-automated algorithm to calculate tumor volume and other parameters on thin-section CT scans to assess response in patients with non-small cell lung cancer (NSCLC) treated with gefitinib in a clinical trial. Methods: CT scans of 15 measurable pre- and post-gefitinib-treated non-small-cell lung cancers in 15 patients were analyzed. A semi-automated three-dimensional segmentation algorithm was developed for lung cancer and applied to each tumor at baseline and follow-up. The computer automatically identified the boundaries of the tumors in three dimensions and the “true” volume and calculated the greatest diameter and the product of the greatest diameter and its perpendicular. Exact McNemar tests were used to analyze differences between RECIST, WHO and volumetric changes from baseline to follow up. Results: The computer accurately segmented 14 of 15 tumors. One paramediastinal tumor required manual separation from the mediastinum. Seventy-three percent (11/15) of patients had an absolute change of at least 20% in tumor volume, compared with 7% (1/15) and 27% (4/15) with similar changes in uni-dimensional (p < 0.01) and bi-dimensional (p = 0.04) tumor measurements, respectively. Forty-seven percent (7/15) of patients had an absolute change of at least 30% in tumor volume, but an absolute change of at least 30% was found in no patients by uni-dimensional measurement (p = 0.02) and in 13% of patients by bi-dimensional measurement (p = 0.06). Analysis of percentage change using an adjusted/scaled method will also be presented. Conclusions: By measuring tumor volume, greater numbers of patients were identified having absolute changes of at least 20% and 30% than by using RECIST or WHO. Therefore, volumetric changes may have the potential to be an earlier or better marker of regression or progression.

No significant financial relationships to disclose.