bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of exemestane (E) in refractory ovarian cancer (ROC)
Authors: Verma S. , Alhayki M. , Le T. , Baines K. , Rambout L. , Hopkins L. , Fung Kee Fung M. 
Published: March 2020

5026 Background: Despite biologic rationale, endocrine therapeutic strategies have been under investigated in ovarian cancer. This is the first study to report the efficacy of an aromatase inhibitor, E, in patients (pts) with ROC. Methods: This was a pilot, phase II, single-centre, non-comparative, open-label study. Pts with ROC stage II - IV who had received no more than 2 lines of prior chemotherapy, had ECOG PS ≤ 2, and measurable disease or non-measurable disease with a CA 125 ≥ 30 U/mL and/or ascites were eligible. All pts must have received prior platinum and taxane chemotherapy. Treatment consisted of E 25mg p.o. daily until disease progression. The primary endpoint was objective response rate (ORR) and secondary endpoints were time to progression (TTP), duration of response (DR) and toxicity. Results: 24 pts have been enrolled to date. Only 2 pts who withdrew consent or never started E were excluded from this analysis. Subjects had stage III (77%) or IV (18%) ovarian cancer, the majority were grade 3,serous histology. 15 pts (68%) had 2 prior lines of therapy and 7 pts (32%) had only 1 prior line of therapy. Treatment was commenced in the majority immediately after progression on chemotherapy. There were no objective clinical responses; however 8/22 (36%) pts had stable disease (SD) >14 weeks (med. duration 23 wks). One pt remains with SD > 95 wks duration. The median TTP was 8.8 wks. Receptor status was available in 16/22 pts: ER+ (41%), PgR+ (32%), BCL-2+ (23%) and HER2+ (0%). Correlation of ORR/SD with receptors and CA 125 will be presented. Toxicity was evaluated in all pts who received at least one dose of E. Hyponatremia (gr 4), attributed to disease, was observed in 1 pt. All other toxicities were NCI CTC grade ≤ 2: fatigue (14%), hot flashes (9%), skin reaction (5%), and fluid retention (5%). Conclusions: In this highly refractory ROC pt population, E was associated with an impressive, clinically meaningful SD rate of 36%. As this potentially represents a less toxic, well-tolerated therapeutic option for women with ROC, further investigation is warranted. Supported by a grant from Pfizer Canada No significant financial relationships to disclose.
Phase I trial of intraperitoneal (IP) administration of a measles virus (MV) derivative expressing the human carcinoembryonic antigen (CEA) in ovarian cancer patients
Authors: Galanis E. , Hartmann L. C. , Cliby W. , Zollman P. J. , Peethambaram P. P. , Long H. J. , Kaur J. S. , Sloan J. A. , Peng K. W. , Russell S. J. 
Published: March 2020

5028 Background: Edmonston vaccine strains of MV have significant antitumor activity against ovarian cancer xenografts (Peng et al, Cancer Res, 2002). Oncolytic selectivity is due to overexpression of the MV CD46 receptor in ovarian cancer cells. Furthermore, engineering the virus to express the marker peptide CEA (MV-CEA) allows real time monitoring of viral gene expression/propagation in vivo. Methods: We are conducting a Phase I trial of MV-CEA in patients (pts) with recurrent, taxol and platinum refractory, ovarian or primary peritoneal carcinoma. Eligible pts should have protective anti-MV antibody (ab) titers and normal CEA levels. A standard phase I cohorts of three statistical design is employed. MV-CEA is administered IP via a port-a-cath, q 4 wks for up to 6 cycles. Results: To date, 12 pts have received viral doses from 103 to 106 TCID50. No dose-limiting toxicity has been observed. Most common toxicities included grade 1–2 nausea (4 pts); grade 1–2 fatigue (4 pts); grade 1 fever (3 pts); grade 1 abdominal pain (2 pts). One pt had grade 2–3 arthralgias in cycles 4–6. There was no treatment induced immunosuppression as assessed by DTH, CD4, CD8, immunoglobulin and complement levels, no significant increase in the titers of anti-MV abs in serum or ascites in response to treatment, and no development of anti-CEA abs. Viral genomes were detected in the peripheral blood mononuclear cells of 2 asymptomatic pts by QRT-PCR. No CEA elevation in the serum was observed in the dose range tested, and there was no viral shedding in urine or mouth gargle specimens. Testing of pt tumor samples for CD46 by IHC demonstrated overexpression of the target receptor in 7/8 pts. Best objective response was stable disease (2 - 9 mo duration) in 5 pts, while 3 pts had significant decrease in CA125 levels, of 44%, 72%, and 78%, respectively. Conclusions: In this first human application of an engineered oncolytic MV strain, we have observed excellent tolerance after repeat IP administration of the virus. Despite the low doses employed so far, there is early evidence of biologic activity. Dose escalation continues to the target dose of 109 TCID50. No significant financial relationships to disclose.
The outcome of patients with relapsed gestational trophoblastic neoplasm (GTN) after the completion of chemotherapy
Authors: Powles T. , Young A. , Short D. , Savage P. , Pappin C. , Schmid P. , Seckl M. 
Published: March 2020

5033 Background: Women requiring chemotherapy for GTN are stratified into low risk and high risk disease and treated accordingly. The vast majority of patients are cured with chemotherapy. Despite this a small number relapse after completing treatment. The prognostic factors predictive of outcome for these relapsed patients are unclear and are investigated here. Methods: Clinical data at presentation and at the time relapse on patients with relapsed GTN was collected from a prospective data base at the Charing Cross Hospital. This included stage of disease, time to relapse, treatment details and rate of HCG rise. Statistical analysis was performed using the Kaplan Meier method. Univariant and multivariant analysis was performed on the data. Results: Between 1980 and 2004 1708 patients were treated with chemotherapy for GTN. Sixty of these patents have relapsed. The median age of these 60 patients was 29 years (range 30–51) and the median follow up was 10 years. The overall 5 year survival for patients with relapsed GTN was 91% (84–99%). All deaths were tumour related. Patients who initially presented with low risk disease (n = 27) had an overall survival of 100% while those who presented with high risk disease had an overall survival of 91% (66–96%) (p < 0.05). Five patients progressed during treatment for relapsed disease, all of these patients died. Ten patients relapsed for a second time. All of these patients are currently alive and disease free with a median of 11 years of follow up. Significant prognostic factors included stage of disease at presentation, the presence of metastatic disease at relapse and the rate of rise of HCG at relapse. Conclusions: The outcome for patients with relapsed GTN is good especially those who relapse after initially having low risk disease. Failure to obtain a complete remission on 2nd line chemotherapy is a poor prognostic indicator. No significant financial relationships to disclose.
Biomarker discovery in endometrial carcinoma using novel proteomic methods
Authors: Borgia J. A. , Frankenberger C. , McCormack S. E. , Kaiser K. A. , Usha L. , Rotmensch J. , Coon J. S. 
Published: March 2020

5034 Background: A practical serum-based screening test for endometrial and ovarian carcinomas could greatly improve their early diagnosis, but developing such a test has proved elusive. Herein, we describe methods offering increased statistical power over conventional ‘batch’ analyses, via paired patient serum samples to identify biomarkers specific for uterine endometriod carcinomas (UEA). Methods: Paired serum samples (collected pre- and post- surgery) were prepared from patients undergoing UEA resection. A Ciphergen SELDI-TOF mass spectrometer was used to generate the patient serum proteomic profiles with data acquisition optimized to the 5,000–40,000 m/z (mass) range. Spectra quality was assessed using a specific function within the R-project statistical platform (v2.2.0), whereas data analyses were performed using Bioconductor, an extension of the R statistical platform; all in a blinded manner. Raw spectra were processed as follows: spectra pair normalization, baseline subtraction, and differential peak detection (with calibrated alignment). Aligned peaks were sorted into groups, based on tumor pathology and pre- vs. post-operative specimen type, and compared using a two tailed homoscedastic t-test in Microsoft Excel 2003. Results: Pre- and post-operative serum from 10 patients with UEA had their serum proteomic profiles evaluated for peaks lost after surgery. These values were then compared with a set of ‘normal’ samples (i.e. patients undergoing surgery for benign gynecologic disease). Even with our small sample size we identified 16 serum components that were significantly reduced or absent (p < 0.04) after tumor resection; 10 unique to UEA (p <0.04). From this group, species at m/z values of 4291.9, 4414.2, 5036.1, 9,615.0, and 25,508.8 seem most promising, based on their high level of significance (p < 0.02), for 10/10 patients. Conclusions: These results validate the power of our pre-and post-operative sample sets for the identification of new serum biomarker candidates for UEA. Work is in progress to increase the patient sample size, expand the study to patients with serous uterine and ovarian carcinomas, and identify the reported biomarker candidates via tandem mass spectrometry No significant financial relationships to disclose.
Relationship between CYP2D6 and estrogen receptor alpha polymorphisms on tamoxifen metabolism in adjuvant breast cancer treatment
Authors: Grabinski J. L. , Smith L. S. , Chisholm G. B. , Drengler R. , Rodriguez G. I. , Lang A. S. , Kalter S. P. , Garner A. M. , Fichtel L. M. , Pollock B. H. , Kuhn J. G. 
Published: March 2020

505 Background: Tamoxifen (TAM) and its metabolites display large inter-individual variation with profound implications for breast cancer outcomes. Tamoxifen is hydroxylated to the potent metabolites, 4-hydroxytamoxifen (4-OH TAM) and endoxifen, by various cytochrome P450 (CYP450) genes including CYP2C9 and CYP2D6. The SULT1A1 gene is involved in the conjugation of 4-OH TAM. Tamoxifen’s binding site is the estrogen receptor (ER). Methods: Clinical data and blood samples were collected for 301 patients (299 female, 2 male) receiving at least 8 weeks of adjuvant tamoxifen therapy. HPLC analysis assessed TAM, N-desmethyltamoxifen (N-DMT), and 4-OH TAM levels. Genotyping of the CYP2C9 (*2,*3), CYP2D6 (*2, *3, *4, *6, *7, *8, *14) and SULT1A1 (*2) genes was determined by Pyrosequencing. CYP2D6 genotypes were subdivided into poor (PM), intermediate (IM), and extensive (EM) metabolizers. Genotyping of ER alpha polymorphisms, Pvu II and Xba I, utilized a Taqman Allelic Discrimination Assay. The Wilcoxon Rank Sum test was used to test associations of genotype and quantitative metabolite levels, within genotype associations, and ethnicity. Results: The majority of our patients were Caucasian (68%) and Hispanic (26%). The mean (± SD) levels for TAM, 4-OH TAM and N-DMT were 111.7 (± 58.4 ng/ml), 2.2 (± 1.5 ng/ml) and 204.7 (± 104.1 ng/ml), respectively. The CYP2D6 genotype was statistically associated with 4-OH TAM levels (p=0.0002). Differences were detected between EM and PM (p=0.0001) and IM and PM (p=0.0029). ER alpha Pvu II genotypes were shown to influence TAM levels (p=0.02). Significant differences were identified between the PP and Pp genotypes (p=0.0064) and between PP and pp genotypes (p=0.03). Hispanics had significantly higher levels of TAM (p=0.02) and 4-OH TAM (p=0.007) than Caucasians. Conclusions: Genotype and ethnicity are significantly associated with levels of TAM and 4-OH TAM and may explain clinical variation in response to TAM treatment. No significant financial relationships to disclose.
A new prognostic index of advanced epithelial ovarian cancer (PIEPOC): A JMTO OC01–01 study
Authors: Teramukai S. , Ochiai K. , Tada H. , Fukushima M. 
Published: March 2020

5061 Background: The prognostic factors in patients with advanced epithelial ovarian cancer (EpOC) have been identified by many investigators. The purpose of this study was to construct a simple and powerful prognostic index (PI) of EpOC (PIEPOC) by using data from a long-term follow-up study. Methods: Data from 768 women with stage III or IV EpOC from 24 institutions in Japan who were treated between 1994 and 2000 were evaluated for clinical features predictive of overall survival. A PI to predict overall survival after initial surgery was developed using proportional hazards regression model. We selected the best classification in an attempt to separate the prognosis of patients. Results: Out of 768 patients, 408 patients were died and a median follow-up for 360 surviving patients was 4.2 years. We randomly selected 538 (70%) patients as a training sample set. The four prognostic factors that remained independently significant in the analysis of the training sample were age, performance status (PS), cell type, and size of residual disease. After combining levels of factors that appeared to have a similar effect on survival and checking additivity of effects by pooled interaction tests, a linear function based on estimated regression coefficients was as follows: 0.448 (if age 70 and above) + 0.539 (if PS 1 or 2) + 0.980 (if PS 3 or 4) + 0.488 (if mucinous or clear cell) + 0.943 (if residual size 0.1cm and above). From the weight of function, we derived a simplified PI (PIEPOC) = 1 (if age 70 and above) + 1 (if PS 1 or 2) + 2 (if PS 3 or 4) + 1 (if mucinous or clear cell) + 2 (if residual size 0.1 cm and above). The PIEPOC of patients were distributed between 0 and 6. Patients were classified into three risk groups, i.e., low (PI: 0–2), intermediate (PI: 3), and high (PI: 4–6). The PIEPOC was equally predictive in a randomly selected validation sample set (n = 230), identifying three groups (5-year survival: 0.67 in low, 0.43 in intermediate, 0.17 in high risk group, respectively). This predictability was reproducible in Stage IIIc or IV patients. Conclusions: Our PIEPOC is simple and easy to use to discriminate the risk groups among advanced EpOC. Thus PIEPOC should be useful for the selection of appropriate treatment options. No significant financial relationships to disclose.
Influence of platinum-based chemotherapy on disseminated tumor cells in patients with primary ovarian cancer
Authors: Wimberger P. , Kimmig R. , Schulte A. , Scheulen M. E. , Kasimir-Bauer S. 
Published: March 2020

5067 Background: Recent studies in patients (pts) with breast cancer have demonstrated the prognostic significance of disseminated tumor cells (DTC) in the bone marrow (BM) which even can survive high-dose chemotherapy. For ovarian cancer, the impact of chemotherapy on DTC is unknown. Here we evaluated whether first-line chemotherapy with carboplatinum and paclitaxel can eliminate DTC in BM and peripheral blood (PB) of pts with primary ovarian cancer (OC, FIGO IC-IIIC). Methods: PB of 28 pts with OC and bilateral BM aspirates of 18/28 pts were assessed for DTC before and after chemotherapy using density gradient centrifugation and an immunocytochemical cytokeratin (CK) assay with the anti-CK antibody A45-B/B3. Results: We identified CK+ cells in 7/28 blood samples (25%) before therapy with a mean number of 2 cells/20 ml (range 1–3). After chemotherapy, CK+ cells were detected in 3/28 blood samples (11%) with a mean number of 9 cells/20 ml (range 1–18). In 5 out of these 7 CK+ patients prior to therapy, no CK+ cells were found after therapy, a no change and a reduction of DTC could be demonstrated in one patient each. CK+ cells were found in 10/18 BM samples (56%) before therapy with a mean number of 2 cells/9x10E6 BM cells (range 1–7) and in 8/18 BM samples (44%) after therapy with a mean number of 10 cells/9x10E6 BM cells (range 2–35). After chemotherapy, no CK+ cells were found in 6 pts, no change in DTC counts was documented in 2 pts and a significant enhancement of DTC was shown in 6 pts, including 4 pts who had no CK+ cells before chemotherapy. Conclusions: DTC are frequently present in the BM and PB of pts with OC and are not always successfully eliminated after platinum-based chemotherapy. It has to be considered, whether these pts might profit from an additive immunotherapy as already shown by the intraperitoneal application of a trifunctional antibody targeting EpCAM, CD3 and accessory cells (Proc Am Assoc Cancer Res 46: 4260, 2005). No significant financial relationships to disclose.
Is the adjustment of serum creatinine level < 0.6 mg/dl to 0.6 mg/dl justified in estimates of carboplatin clearance calculated by the Jelliffe formula?
Authors: Nagao S. , Fujiwara K. , Kagawa R. , Kozuka Y. , Oda T. , Maehata K. , Ishikawa H. , Koike H. , Aotani E. , Kohno I. 
Published: March 2020

5072 Background: The Jelliffe formula (JF) does not include body surface area (BSA) or body weight to adjust the body size. We demonstrated that estimates of carboplatin clearance calculated by the JF tend to have greater positive bias compared to other formulae. The JF has been used to estimate carboplatin clearance in Gynecologin Oncology Group studies. In patients with serum creatinine level <0.6 mg/dl, it is adjusted to 0.6 mg/dl in estimates of carboplatin clearance (Adjusted-Jelliffe formula (AJF)). The purpose of this study is to evaluate whether this adjustment is suitable. Methods: Carboplatin clearance was estimated in 115 patients with serum creatinine <0.6 mg/dl who received carboplatin-based chemotherapy for gynecologic malignancies between January 1996 and August 2004. Creatinine clearance was estimated using the Cockroft-Gault formula (CGF), JF, and AJF. The median percent error (MPE) and the median absolute percent error (MAPE) were evaluated by comparing carboplatin clearance. The relationships between BSA and ratios of estimated carboplatin clearance (JF/CGF, AJF/CGF) were evaluated by using simple regression. Results: The estimated carboplatin clearances were: CGF, 126.7 ± 27.7; JF, 148.2 ± 20.5; AJF, 130.5 ± 14.3. Comparing the results of the CGF with the JF, AJF yielded MPEs of +20%, +6%, and MAPEs of 21%, 14%, respectively. There were the linear correlations between ratio of estimated carboplatin clearances and BSA (Y1 = −1.141X + 2.830, Y2 = -1.061 X + 2.581, Y1: ratio of carboplatin clearance (JF/CGF), Y2: ratio of carboplatin clearance (AJF/CGF), X: BSA). Conclusions: As expected, carboplatin clearance was decreased by adjusting serum creatinine to 0.6 mg/ml, but it did not adjust the bias by BSA. Estimates of carboplatin clearance calculated by the AJF tend to have greater negative bias, particularly when the BSA of the patient is large. No significant financial relationships to disclose.
ER+ PR- breast cancer defines a unique subtype of breast cancer that is driven by growth factor signaling and may be more likely to respond to EGFR targeted therapies
Authors: Finn R. S. , Dering J. , Ginther C. , Press M. , Forbes J. , Mackey J. , French T. , South M. , Rupin M. , Slamon D. J. 
Published: March 2020

514 Background: Hormonal based therapy has long been the mainstay for treatment of ER+ breast cancer. ER+ PR- disease is now known to exhibit different clinical behavior compared to ER+PR+ disease. Recent data indicate that ER+PR- disease is characterized by a lower response rate to estrogen deprivation, has a worse prognosis compared to ER+ PR+ disease, and may be dependent on other signaling pathways. To evaluate the role of the EGFR tyrosine kinase inhibitor gefitnib in the treatment of breast cancer, we conducted a pre-surgical study in women with operable disease. Methods: Frozen core biopsies were obtained at baseline. Patients then received a short-term exposure to gefitinib (at least 2 weeks) prior to definitive surgery when a frozen tumor specimen was obtained. Tissue integrity and composition was verified by H and E and RNA was isolated for microarray analysis. 59 women were enrolled in the study of which 43 were evaluable for molecular analysis. Baseline microarrays were performed on the initial biopsies to classify the ‘subtype‘ of breast cancer (e.g. basal, luminal, HER2 amplified). To analyze the genetic changes that occur in breast cancer tissue with exposure to gefitinib, a direct comparison of the baseline sample and post-treatment tumor was performed. In addition, ER and PR status were determined by immunohistochemistry and compared to the microarray findings. Changes in Ki67 and a set of cell cycle genes were used to define ‘molecular response” to gefitinib. Of the 43 samples evaluated by microarray, 11 patients were categorized as exhibiting molecular growth inhibition, 10 patients as molecular growth proliferation, and 22 did not have a significant change in Ki67 and the cell cycle gene set to assign a response. When grouped by subtype, ER+PR- and HER2 amplified tumors define a subgroup more likely to show molecular growth inhibition with gefitinib. Conversely, ER+PR+ tumors were more likely to show molecular growth proliferation. Conclusions: These results support the hypothesis that ER+PR- breast cancer is growth factor dependent and constitutes a unique subgroup of ER+ patients which may be more likely to benefit from EGFR inhibition. [Table: see text]
Epirubicin/paclitaxel (EP) vs. capecitabine/paclitaxel (XP) in first-line metastatic breast cancer (MBC): A prospective, randomized multicentre phase III study of the AGO breast cancer study group
Authors: Lueck H. , Minckwitz G. V. , Du Bois A. , Schrader I. , Huober J. , Heilmann V. , Beckmann M. , Stähle A. , Jackisch C. , Marth C. , Richter B. 
Published: March 2020

517 Background: Anthracyline-taxane combinations have the highest response rates in high risk MBC. Recently, anthracyclines and taxanes have become standards for adjuvant breast cancer chemotherapy. The addition of capecitabine to docetaxel improved overall survival in MBC. This regime was associated with a high rate of side effects (actually FN was not different from Taxotere mono - it was more the addition of cape AEs to Taxotere AEs). Earlier phase II studies with XP are able to show efficacy with better tolerability including less febrile neutropenia. Methods: Our aim was to show non-inferiority of XP to EP. The primary endpoint was progression-free survival (PFS). Secondary endpoints were toxicity and overall survival (OS).Patients (pts) were treated with 6x E 60 mg/m2 and P 175 mg/m2 d1 q21d, or with 6× X 2×1000 mg/m2 d1–14 q 21d and P 175 mg/m2 d1 q21d. Results: During a period of 2.5 y the planned 340 pts (170 in each arm) in 63 centres were recruited. The median number of cycles was 6 in both arms. The median PFS for EP was 11.8 months, and 12.3 for XP (p=ns). OS also was not different between the arms. The response rate (RECIST) was 41.0% (CR 6.6%, PR 34.4%) for EP and 41.5% (CR 8.5%, PR 33.1%) for XP. The main toxicity was myelosuppression (10% of cycles grade 3/4). Febrile neutropenia was seen in 5 cases in EP and in 1 case in XP. Skin toxicity grade 3 was observed in 5 of XP pts. Two patients stopped treatment for cardiological reasons in EP, and 4 patients for GI reasons in XP. Conclusions: This first analysis shows a comparable efficacy of the non-anthracycline regimen XP to the EP combination in first-line MBC. The toxicity is relatively low compared to other non-anthracycline containing combination therapies. XP is therefore an appropriate option for pts with anthracycline pretreated first line MBC. [Table: see text]