bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discordence of HER-2/neu overexpression and estrogen receptor between the primary breast cancer and axillary lymph node with metastasis
Authors: Shahid R. K. , Ahmad I. , Yadav S. , Sami A. , Haider K. , Rees H. , Ahmed S. 
Published: March 2020

20106 Background: Adjuvant hormonal therapy and trastuzumab are known to be associated with a significant reduction in cancer-related mortality in a subset of women with breast cancer. The treatment decision is usually based on immunohistochemistry (IHC) staining of the primary tumor. We reported here a case of discordance of HER-2/neu overexpression and estrogen receptor status between the primary breast cancer and axillary lymph node with metastasis. Methods: IHC and fluorescence in situ hybridization (FISH) analysis was perfromed for the assessment of HER-2/neu. E-cadherin staining was done on the primary tumor and lymph node with metastasis. Results: A 52 year old woman presented with right breast lump. The imaging studies showed a 5 × 5 cm speculated mass. No other abnormalities were noted. An excision biopsy revealed 3 cm moderately differentiated invasive lobular carcinoma. Subsequently a wider excision and axillary lymph node dissection was done. 2/20 lymph nodes were involved by the cancer. IHC was done in the primary tumor and the lymph node with metastasis. IHC of the primary tumor revealed less than 1% nuclei positive for estrogen receptor (ER), 0% nuclei positive for progesterone receptor (PR), and no HER-2/neu overexpression. IHC of the lymph nodes with metastasis revealed 80% nuclei positive for ER, less than 1% nuclei positive for PR, and equivocal HER-2/neu overexpression. FISH analysis for HER-2/neu gene was done on the primary tumor which revealed no amplification in the tumor nuclei (Her2/CEP17 ratio was 3.6/2.7 = 1.3) whereas FISH analysis on the lymph node section revealed amplification in tumor nuclei (Her2/CEP 17 ratio of 7.3/1.9 = 3.9). E-cadherin staining of the primary breast tumor as well as the lymph node with metastasis revealed no membrane staining of the malignant cells in either section. Conclusions: The unusual occurrence of a divergent IHC profile and FISH analysis results between the primary carcinoma and metastatic carcinoma may be due to a subselection of a malignant clone which were not represented in the section of primary tumor chosen for IHC. Future studies are required to determine the utility of IHC staining of metastatic cells involving the lymph nodes if primary tumor is negative for HER-2/neu & ER. No significant financial relationships to disclose.
Mystery of tumor specific immunity: LIGHT turns on silent tumor specific immunity
Authors: Cao L. T. 
Published: March 2020

20107 Background: More than 2000 tumor antigens have been identified so far. However, none of these tumor antigens are approved to be immunogenic. Genetic alteration which activates uncontrolled cell growth transforms normal cells to tumor cells. Tumor cells, therefore, do not carry any foreign antigens and thus tumor antigens are not immunogenic (unless in the presence of viral infection). The so-called tumor specific immunity is actually the host versus graft effect, not specific for tumors. Methods and Results: Using proper controlled tissue graft as control, our previous data indicated that the hosts could accept both the graft and the tumor. The immune system is silent to tumor antigens. By transfecting tumor cells with a modified LIGHT (Lymphotoxins, shows Inducible expression, and completes with herpes simplex virus Glycoprotein D for Herpes virus entry mediator, a receptor expressed by T lymphocytes) expressing vectors, Dr. Fu at the University of Chicago is able to eradicate tumors in his animal model. The expressed LIGHT on the tumor cell surface serves as tether for the naïve T cells and the stromal cells by binding to lymphotoxin-beta receptor on stromal cells and herpes virus entry mediator on T cells. The trio of tumor-LIGHT-stroma working like a foreign antigen attracts naïve T cells and increases the infiltration of naïve T cells within the tumors. The trio then co-activates naïve T cells to destroy tumors. The LIGHT mechanism may be similar to that in autoimmune phenomenon. Conclusion: Tumor specific immunity may be silent; however we can modify tumor antigens and activate silent immune system to destroy tumors. We currently have four immunotherapies against cancer. The LIGHT approach or in situ co-stimulation therapy, vaccine therapy, and ex vivo cell-transfer therapy are three active immunotherapies. The fourth one is a passive immunotherapy: the near-specific, personalized immunotherapy. No significant financial relationships to disclose.
Fraction of LOH on chromosome 17 and 18 (LOH-ratio) predicts colorectal cancer outcome
Authors: Kanazawa T. , Watanabe T. , Nagawa H. 
Published: March 2020

20114 Background: Identification of patients at high risk for recurrence remains a central issue in the treatment of colorectal cancer. Our goal was to identify predictive factors for recurrence in colorectal cancer patients. Methods: DNA from 84 colorectal cancers were analyzed for wide-ranging allelotyping. Using 27 microsatellite markers spanning every 10cM on chromosome 17 and 18, we defined the LOH-ratio as the proportion of markers which show LOH out of 27 markers. Tumors were grouped into two groups by the median value of LOH-ratio (0.19). Recurrence free survival was compared with Kaplan-Meier analysis and log rank statistic. The Cox proportional hazards regression model was used for both univariate and multivariate analysis of recurrence free survival. Results: Log rank statistic revealed that LOH-ratio, stage, lymph node metastasis significantly related to recurrence free survival. On univariate analysis, significant predictors of Recurrence free survival were LOH-ratio, lymph node metastasis, Dukes’ classification, and pathological type. On multivariate analysis, LOH-ratio (HR 3.1, p = 0.02) and lymph node metastasis (HR 5.2, p = 0.002) independently predicted for recurrence free survival. Conclusions: LOH-ratio and lymph node metastasis were the only independent predictors of recurrence free survival. Altogether with lymph node metastasis, LOH-ratio could help to improve postoperative surveillance and adjuvant therapy. No significant financial relationships to disclose.
A phase I trial of weekly combination KOS-862 (Epothilone D) and trastuzumab in HER-2 overexpressing malignancies
Authors: Cortes J. , Climent M. A. , Gomez P. , Ruiz A. , Calvo E. , Zhang X. , Perez E. S. , Demario M. , Baselga J. 
Published: March 2020

2028 Background: KOS-862 (Epothilone D) (K) has shown single agent activity against metastatic breast cancer (MBC) and NSCLC. Trastuzumab (H) is standard therapy for HER-2 overexpressing MBC. This phase IB trial determined the safety and PK profile of KOS-862 in a weekly schedule with H. Methods: Eligibility: pts with HER-2 overexpressing (IHC 3+ or FISH +) chemo-refractory tumors, ECOG ≤ 2, neuropathy ≤ gr 1, no CNS metastases, and no H ≤ 6 mo. prestudy. H given as a 4 mg/kg loading dose, then 2 mg/kg wkly. K given as a 90 min iv infusion wkly × 3 Q 4 wks after H. K dose escalation cohorts: 70, 85 & 100 mg/m2. H1 + H2 antagonists + corticosteroid prophylaxis given 30–60 min prior to K. DLT: gr 4 hematologic or gr 3 other toxicity, or toxicity requiring >4 wk treatment delay. Cycle 1 + 2 PK samples obtained for K + H. Results: 13 pts treated from 9/04 - 8/05. Median age 51 yrs (36–65). All pts had MBC. Prior H therapy n = 9, prior taxane n = 11. Enrollment: 70 mg/m2 (4), 85 mg/m2 (3), and 100 mg/m2 (6). Mean number cycles 3.9 (1–6). The 100 mg/m2 cohort was expanded to 6 pts per study design; no DLTs were noted. Toxicity: Principal neurotoxicities (gr 3 noted, if present): parasthesias (10 pts, 1 gr3), neuropathic pain (5 pts, 2 gr3), dizziness (4 pts), dysguesia (4 pts), ataxia (3 pts), transient confusion (3 pts), dysesthesias (2 pts), insomnia (2 pts). No gr 4 neurotoxicities reported. Non-neurologic toxicities were limited to gr 1/2 and included diarrhea, pyrexia, abdominal and back pain, arthralgias. PK (n = 13): KOS-862 CL 21 ± 10 L/hr, Vz 260 ± 110 L, T1/2 9.8 ± 3.9 hr. Seco-metabolite was 67% ± 35% of K. At 100 mg/m2 K dose (n = 6): Cmax 3.3 ± 1.1 μg/mL and AUCinf 11.0 ± 7.5 h*(g/mL). Neither K nor its seco-metabolite PK were affected by H. Responses: An 85 mg/m2 K pt (no prior H or taxane) had confirmed PR and a 100 mg/m2 K pt (prior taxane) had an unconfirmed PR. A 2nd 100 mg/m2 pt (no prior H or taxane, bone only disease) had > 90% CEA reduction. Conclusions: This phase I study demonstrates feasibility of full dose wkly KOS-862 coadministration with wkly H. Treatment-related toxicities were all gr 1 / 2, except for 3 cases gr 3 paresthesias and neuropathic pain. PK of K and its principal metabolite were not affected by H. Three clinical responses were observed; a phase II trial of this combination is ongoing in minimally-pretreated MBC. [Table: see text]
Phase 1 and pharmacokinetic study of weekly docosahexaenoic acid-paclitaxel (Taxoprexin) in resistant solid tumor malignancies
Authors: Fracasso P. M. , Govindan R. , Ellis M. J. , Tan B. R. , Linette G. P. , Picus J. , Goodner S. A. , Jones S. , Bellet R. E. , Burris H. A. 
Published: March 2020

2036 Background: Docosahexaenoic acid-paclitaxel (DHAP) is a covalent conjugate of paclitaxel and the essential fatty acid, docosahexaenoic acid. Preclinical studies have demonstrated increased activity relative to paclitaxel with the potential for an improved therapeutic ratio. We performed a phase 1 and pharmacokinetics (PK) study of DHAP in patients with resistant solid tumor malignancies. Methods: Patients were treated with DHAP administered by 2-hour intravenous infusion weekly for three out of four weeks. Dose escalation started at DHAP 200 mg/m2 and was increased by 100 mg/m2 per dose level ending at 600 mg/m2. Blood samples for PK of DHAP and paclitaxel derived from DHAP were collected in cycle 1 at 0 (prior to the start of the infusion), 2 (prior to the end of the infusion), 3, 4, 9, 26 hours and just prior to the next weekly treatment on days 8, 15 and 29. Results: Twenty-one patients enrolled and received 39 cycles of treatment (mean = 2). Three patients received DHAP at 200 mg/m2 (dose level 1), four at 300 mg/m2 (dose level 2), three at 400 mg/m2 (dose level 3) and 500 mg/m2 (dose level 4) each, and eight at 600 mg/m2 (dose level 5). In cycle 1, grade 2/3 neutropenia resulted in treatment delays for 8 patients, 6 of whom received treatment at dose level 4 and 5. Two of the 8 patients, treated with DHAP 600 mg/m2, went on to experience grade 4 neutropenia lasting < five days on later cycles. Only one patient had grade 2 sensory neuropathy, which occurred after 3 cycles of treatment. Preliminary PK analyses on all patients demonstrated that there is not a substantial accumulation of DHAP or paclitaxel with weekly treatment. Detailed PK analyses will be presented. Eighteen of the 21 patients were evaluable for response. Three patients, one each with esophageal and lung carcinoma and melanoma, had stable disease for 11, 16, and 17 weeks, respectively. Conclusions: DHAP administered weekly at 600 mg/m2 was well-tolerated and the maximum dose administered in this study. The slow release of paclitaxel from DHAP and the weekly schedule approximates continuous infusion paclitaxel which should be more active than every 3 week or weekly taxanes. Further studies with DHAP in non-small cell lung carcinoma and melanoma are on-going. [Table: see text]
Phase I dose-escalating study of bi-weekly pemetrexed (MTA) with fixed dose rate gemcitabine (gem) in patients with advanced cancer
Authors: Chen A. L. , Ryan T. , Muggia F. , Chachoua A. , Escalon J. , Moore S. , Haniff F. , Levinson B. , Nicol S. , Hochster H. 
Published: March 2020

2049 Background: Fixed dose rate (FDR) gem may optimize the documented benefit of gem in pancreatic, NSCL, head and neck, and breast cancers. Preclinical data of the combination of MTA and gem indicate synergy. We studied a bi-weekly combination of MTA and FDR gem to improve tolerance over the previous “Day 1, 8” regimen. Methods: MTA followed by FDR gem infusion was given every 14 days in a dose-escalation design below. Dose-limiting toxicities (DLT) is defined as: grade 4 neutropenia ≥ 5 days, febrile neutropenia, grade 4 thrombocytopenia, or grade 3–4 non-hematological toxicities in 1st cycle. 27 patients were enrolled with median age 59 (range 41–82), males/females 18/9, and ECOG PS 0/1 (5/22). All received Vitamin B12 (1 mg IM prior to study & q9 weeks) and folic acid (350–1000 mcg po qd) supplementation 1–2 weeks prior and during study plus dexamethasone 4 mg po BID day before, of, and after chemotherapy. Results: Dose level 7 has been reached and is being expanded with DLT in 1 patient. Toxicities per patient during all cycles include grade 3–4 neutropenia (8/27 patients), grade 3 anemia (3), brief febrile neutropenia (6), grade 3 rash (1 patient), grade 3 low back pain (1), grade 3 renal failure (1), grade 5 perforated duodenal stent (1). In 19 patients evaluable for response, there were 11 stable disease and 8 progression of disease. Conclusion: Recommended phase II dose for bi-weekly MTA with FDR gem is likely to be 800 mg/m2 and 1,200 mg/m2 × 120 minutes. This regimen allows full doses and dose intensity of both drugs to be administered on a simple schedule with excellent tolerance. A phase II study in biliary cancer is planned. This study is supported in part by Eli Lilly.a This toxicity was at baseline, therefore not drug related.b, c These toxicities were in one patient and were not drug related, rather related to the individual patient’s status going into therapy. [Table: see text] [Table: see text]
Pharmacogenomic analysis for individual response to CPT-11 in colorectal cancer: Prediction formula of tumor response using novel marker genes and genotypes associated with the toxicity
Authors: Narahara H. , Sugimoto N. , Tomita N. , Murata K. , Fukunaga M. , Ohue M. , Sakaeda T. , Ishida H. , Tanimoto K. , Nishiyama M. 
Published: March 2020

2060 Background: Despite recent encouraging data, the clinical efficacy and toxicity of CPT-11 in most colorectal cancer patients remain unpredictable. We conducted this prospective study to develop a prediction formula of efficacy using expression data of genes newly identified in vitro and to evaluate the clinical significance of several genetic polymorphisms known as potent predictors of toxicity. Methods: CPT-11 was intravenously administered on Days 1, 8, and 15, every 4 weeks in chemo-naive patients with stage IV colorectal cancer after palliative operation. Tumor samples were collected at surgery and PK analysis was done on day 1 of cycle 1. Tumor response and toxicity were evaluated by RECIST and CTCAE, respectively. Results: Forty seven pts were enrolled. All pts were assessed for tumor response, toxicity, gene expression, genotype, and PK. Partial response was obtained in 11 cases, and common grade 3/4 toxicities were neutropenia (15%), leucopenia (5%), and diarrhea (4%). Despite no correlation of UGT1A1*28 (hetero=5, homo=1) alone with the toxicities, there were associations between UGT1A1*28 or *7 (hetero=1) with UGT1A1 -64G>C (hetero=3) and G3/4 leucopenia (p=0.036). UGT1A1 1091C>T (hetero=3) was found to be associated with leucopenia (p=0.0009), neutropenia (p=0.012), and diarrhea (p=0.036). UGT1A1 1091C>T, ABCC2 -24C>T and 3972C>T were correlated with SN-38 AUC. We identified 7 novel potent marker genes including AMD1, CTSC, and EIF1AX for CPT-11 efficacy in vitro, through 2 different microarray analyses and subsequent real-time RT-PCR. We then successfully developed the best linear model, which converted the quantified expression data into objective tumor response, using 18 data sets of gene expression and clinical response. Utility-confirmation analyses using other clinical samples appeared to show that the formula could accurately predict tumor response (r=0.712, p=0.042). Conclusions: Polygenetic strategies using several known polymorphisms for toxicity and a prediction formula using 7 novel genes for efficacy would be of predictive value for individual response to CPT-11. No significant financial relationships to disclose.
Plasma levels of SN-38 after co-administration of gefitinib and oral irinotecan in young and old mice
Authors: Cook D. R. , Merz A. L. , Zirrolli J. A. , Basche M. , Gustafson D. L. 
Published: March 2020

2062 Background: Preclinical studies demonstrate that irinotecan, approved for I.V. administration, is most effective when administered at frequent, low doses. This administration schedule would be most practical if irinotecan were administered orally. However, the oral availability of irinotecan is limited. Gefitinib can alter the oral bioavailability of irinotecan through inhibition of gut transporters (ABCG2) that prevent intestinal absorption. Thus, we evaluated a potential method for giving irinotecan at low doses on a protracted schedule by administering orally with gefitinib. Additionally, we hypothesized that the pharmacokinetics of irinotecan may differ in older versus younger adult mice. Plasma levels of SN-38 were measured and compared in old and young Balb/c mice given oral irinotecan alone or with gefitinib. Methods: Adult (2 months old) and older, retired breeder (10 months old) Balb/c mice were orally administered irinotecan at 10 mg/kg, 20 mg/kg or 40 mg/kg either alone (control) or with 30 mg/kg PO gefitinib daily for 5 days. On the fifth day, the mice were sacrificed approximately 4–6 hours after administering drugs. Plasma was collected and SN-38 levels determined by HPLC. Results: Nearly all mice receiving irinotecan with gefitinib had a 3 fold or more increase in the level of SN-38 in the plasma as compared to the mice receiving irinotecan alone. The older mice had a more dramatic increase. Conclusions: The plasma levels of SN-38 were consistently elevated in mice treated with oral gefitinib and irinotecan when compared to mice treated with irinotecan only. The more pronounced increase in SN-38 levels seen in the older mice may be due to changes in drug elimination with aging. The results indicate that oral irinotecan can be given in the presence of gefitinib resulting in higher levels of SN-38 in the plasma of young and older mice. Combination treatment allows easier titration of irinotecan in protracted dosing protocols evaluating efficacy and toxicity in older mice, and ultimately, humans. [Table: see text] No significant financial relationships to disclose.
Autoresistance to ErbB2 kinase inhibitors: Elucidating mechanisms and identfying strategies to prevent its onset in breast cancer
Authors: Xia W. , Bacus S. , Hedge P. , Husain I. , Strum J. , Liu L. , Paulazzo G. , Harris J. , Trusk P. , Spector N. 
Published: March 2020

2075 Background: Clinical efficacy of ErbB1/ErbB2 kinase inhibitors is limited by the development of acquired autoresistance. Developing clinically relevant models to study the mechanism(s) of acquired autoresistance will identify therapeutic strategies to prevent its onset. Methods: BT474 cells, an ErbB2-overexpressing/ER+ breast cancer line sensitive to lapatinib-induced apoptosis were chronically exposed to lapatinib, simulating chronic administration of lapatinib in the clinic. Lapatinib-resistant cells (rBT474) and single cell clones were established. Baseline gene expression in parental BT474 and rBT474 cells was compared using Human Affymetrix oligonucleotide arrays. Sequential tumor biopsies were analyzed by quantitative IHC as part of a clinical trial using lapatinib monotherapy (1500mg/d) in patients with metastatic breast cancer. Results: Gene expression and protein analysis indicates that acquired resistance to lapatinib is mediated by increased estrogen receptor (ER) signaling rather than loss of ErbB2 expression or insensitivity of the ErbB2-MAPK-PI3K pathways to lapatinib. Activation of ER signaling results from de-repression of FOXO3a and transient up-regulation of caveolin-1, both facilitating ER transcriptional activity. Gene interference studies confirm that acquired resistance involves a switch in survival dependence and regulation of survivin from ErbB2 to ER. Since ErbB2 signaling is operative in rBT474 cells, treating parental BT474 cells with lapatinib plus (i) fulvestrant, or (ii) estrogen deprivation prevents the onset of acquired lapatinib resistance compared with either therapy alone. Importantly, increased ER signaling occurs in patients with ErbB2-overexpressing/ER+ breast cancers treated with lapatinib monotherapy, consistent with changes in cell lines. Conclusions: Chronic lapatinib monotherapy induces a shift in the dependence of cell survival from ErbB2 to ER. Combining lapatinib with selected anti-estrogens prevents its onset in cell lines and warrants clinical validation. Establishing models of acquired resistance simulating the clinic provides a tool to identify strategies to improve treatment options for patients with ErbB2-overexpressing breast cancers. [Table: see text]
Phase I dose-escalation study of ZK 304709, an oral multi-target tumor growth inhibitor (MTGI), administered for 14 days of a 28-day cycle
Authors: Ahmed S. , Molife R. , Shaw H. , Steward W. , Thomas A. , Barrett M. , Kowal K. , McCoy C. , De-Bono J. 
Published: March 2020

2076 Background: ZK 304709 is a novel oral MTGI that induces cell cycle arrest and inhibits tumour angiogenesis by selectively inhibiting Cyclin Dependent Kinases (CDKs) 1, 2, 4, 7 and 9,VEGF-R 1, 2 and 3, and PDGF-Rβ tyrosine kinases. Methods: Adult patients (pts) (WHO PS ≤2) with a histologically or cytologically confirmed solid tumor, resistant or refractory to conventional therapy, were eligible. ZK304709 was administered orally, once daily, at a 15 mg starting dose, on days 1–14 of a 28-day cycle, then escalated by 33–100% depending on incidence of drug-related toxicity ≥ grade (gr) 2 (CTC v2.0). At least 3 pts were treated at each dose level. The primary objective was to identify the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Secondary objectives were to determine the tolerability, pharmacokinetic (PK) profile, and preliminary efficacy. Results: Interim results were available for 24 pts (19 M/5 F; median age 56.5) at 5 dose levels (15–120 mg qd). Pts received a median of 2 cycles (range 0–10). Common drug related toxicities were nausea, vomiting, and fatigue. Two DLT were observed: dizziness and hypertension. However, the MTD has yet to be established. The PK profile for dose levels up to 90 mg demonstrated rapid absorption and a dose-dependent increase of exposure and Cmax. Disease stabilization for ≥4 cycles has been observed. Conclusions: ZK 304709 was rapidly absorbed and has been tolerated on this schedule at up to 120 mg qd. The MTD has not been reached and enrolment is ongoing. These preliminary data demonstrate that oral delivery on this schedule of an agent that inhibits both cell cycle and angiogenesis is feasible. [Table: see text]