bluuebunny/crossref_metadata_2025_split huggingface dataset:
A large-scale multi-center independent validation study of a panel of seven biomarkers for the detection of ovarian cancer
Authors: Zhang Z. , Bast R. C. , Vergote I. , Høgdall C. , Ueland F. R. , Van der Zee A. , Wang Z. , Yip C. , Chan D. W. , Fung E. T. 
Published: March 2020

5057 Background: Previously we discovered seven serum biomarkers: ITIH4, transthyretin, ApoA1, CTAPIII, hepcidin, transferrin, and SAA, for the detection of ovarian cancer. They are fragments, cleavages, or PTMs of circulating proteins that are difficult to measure by conventional immunoassays. Using optimzed mass spectrometry assays, we evaluated these biomarkers in a large-scale multi-center study. Methods: A total of 607 serum samples from five sites were analyzed using SELDI TOF-MS protocols optimized for the seven biomarkers. They included 234 women with benign gynecologic diseases, and 373 patients with invasive epithelial ovarian cancer (101 early stage, 231 late stage, and 40 stage unknown). Among them, 165 benigns and 228 cancers had a CA125 available at time of analysis. The median and quartiles of CA125 for benign, early stage, and late or unknown stage were 26/11/57 IU, 80/22/434 IU, and 234/40/1114 IU, respectively. The biomarkers were assessed individually using the Mann-Whitney U Test. A linear composite index was derived in an unsupervised fashion using data from one site and then calculated for the remaining data using the fixed formula. ROC curve analyses were performed on data from individual sites and all sites combined. Results: All seven biomarkers individually demonstrated statistically significant differentiating power, and the majority had p-value<0.00001. AUCs of the composite index in ROC analyses for the six sites were 0.602, 0.566, 0.821, 0.813, and 0.592 in detecting cancer at all stages from benign. On the combined data, the differences in AUC between the index and CA125 were not statistically significant for the detection of cancer at all stages (AUC=0.706 vs. 0.725) or early stages only (AUC=0.534 vs. 0.653). However, the index did better at the high-sensitivity range. At a fixed sensitivity of 86%, the specificity of the index was 34% (77/226) compared to CA125 at 26% (42/163). For early stage cases, at a fixed sensitivity of 84%, the specificity of the index was 24% (55/226) compared to CA125 at 14%% (22/163). Conclusions: We validated seven previously discovered biomarkers, individually and in combination. Prospective studies and assay development are under way to further characterize their clinical utility. [Table: see text]
Advanced ovarian carcinoma: Which place for neoadjuvant chemotherapy?
Authors: Bousquet G. , Narducci F. , Lesoin A. , Taieb S. , Fournier C. , Querleu D. , Leblanc E. 
Published: March 2020

5071 Background: Most patients with ovarian carcinoma are diagnosed at an advanced stage. The ability to surgically resect tumor to microscopic residual disease remains a major prognostic factor. The use of a preoperative chemotherapy for patients with bulky disease is still debated. The objective of this study was to evaluate this therapeutic sequence. Methods: We retrospectively collected data from 207 stage III ovarian cancer patients between January 1998 and August 2004. 127 patients were considered as poor surgical candidates and received neoadjuvant chemotherapy. After 3 courses of a platinum-based chemotherapy, 51 patients who showed a good response by CA125 and CT scan underwent an interval debulking surgery (Group A). For the 43 patients with a partial response or stable disease, 3 other cycles of the same protocol were administered, followed by a secondary surgery (Group B). The remaining 33 patients progressed and had no surgery (GroupC). Results: Optimal tumor debulking (residuum <1 mm) was achieved in 90% and 81% of group A and B patients respectively. Node involvement was not different between the two groups (62%). After a median follow-up of 20.8 months, 98 patients had relapsed and 54 had died. Median OS was 42 months, 37.2 months and 14.4 months for group A, B and C respectively. Three-year OS was 76.7% for group A vs. 50.9% for group B (p = 0.11). Two-year disease free survival was not statistically different for groups A and B (17.3% and 18.5%). In the combined A and B sub-group, univariate analysis for OS showed non-optimal staging according to EORTC criteria (p = 0.005), post-surgical residuum (p = 0.02) and lack of lymphadenectomy (p = 0.01) as adverse prognostic factors. On multivariate analysis, only non-optimal staging remained significant. Conclusions: Neoadjuvant chemotherapy is feasible. We believe the difference in overall survival between groups A and B was likely due to a higher chemosensitivity for group A. Our results support the importance of an optimal surgical staging and the possible therapeutic role of routine lymphadenectomy. No significant financial relationships to disclose.
Phase I safety and immunogenicity study of NY-ESO-1b peptide and Montanide ISA-51 vaccination of patients with ovarian cancer (OC) in high risk first remission
Authors: Magid Diefenbach C. S. , Sabbatini P. , Aghajanian C. , Spriggs D. , Lee H. , Pezzulli S. , Jungbluth A. A. , Old L. J. , Gnjatic S. , Dupont J. 
Published: March 2020

5078 Background: The Cancer Testis (CT) antigen NY-ESO-1 is expressed in over 60% of advanced OC. NY-ESO-1 demonstrates strong immunogenicity and expression is restricted to gonadal tissues, making it an appealing immunologic target. Patients with high risk OC (suboptimal debulking, incomplete CA125 response at 3 cycles, or positive second look surgery) have a high recurrence rate, with median time to progression (TTP) of 10–12mos. Strategies to prolong remission are needed. Methods: After primary surgery and platinum based chemotherapy high risk HLA-A*0201 OC patients in first clinical remission received HLA-restricted NY-ESO-1b peptide (100 μg) and Montanide adjuvant (0.5mL) every 3 weeks for a total of 5 vaccinations. NY-ESO1 tumor expression was evaluated by immunohistochemistry (IHC). Toxicity using NCI-CTC v2 and immunogenicity: 1) NY-ESO-1 specific humoral immunity (ELISA); 2) NY-ESO-1 specific T-cell immunity (tetramer and ELISPOT); and 3) delayed type hypersensitivity (DTH) were assessed on weeks 0, 1, 4, 7, 10, 13, 16. Patients were monitored for progression of disease (POD). Results: Seventeen out of 46 (37%) screened patients were HLA-A*0201+. Eight of 10 enrolled patients have completed therapy, one patient is receiving treatment, and one patient was removed before initiation for POD. Treatment related adverse events (AEs) included: Grade 1 fatigue, anemia, pruritus, myalgias and hyperthyroidism and Grade 2 hypothyroidism. No Grade 3/4 AEs were seen. Five patients (50%) had NY-ESO-1+ tumor; 3 of 3 treated patients with NY-ESO1+ tumor demonstrated T cell immunity by positive tetramer (0.65%–9%) and ELISPOT (35–250 spots). Four of 5 (80%) treated patients with NY-ESO-1- tumor demonstrated T cell immunity by tetramer (1–12%) and/or ELISPOT (250–400 spots). There was no evidence of DTH reaction. With long-term followup 4 of 8 patients have recurred with median TTP of 8.5mos; 4 patients remain in complete remission at intervals of 9, 16, 22, and 37mos to date. Conclusion: Vaccination of high risk HLA A*0201+ OC patients with NY-ESO-1b and Montanide has manageable toxicity, and induces specific T cell immunity in patients with both NY-ESO-1 positive and negative tumors. Additional testing is warranted. No significant financial relationships to disclose.
Does the platinum-free interval predict the incidence or severity of hypersensitivity reactions to carboplatin? The experience from Women & Infants’ Hospital
Authors: Schwartz J. R. , Bradley A. , Bandera C. , Brard L. , Disilvestro P. , Legare R. , Moore R. , Tejada-Berges T. , Granai C. O. , Dizon D. S. 
Published: March 2020

5082 Background: Carboplatin (C) is a standard treatment for gynecologic cancers, but its use in recurrence is associated with an increased risk of hypersensitivity reactions (HSR) in those previously treated with C. However there is no way to predict those at risk for a C-HSR. We sought to evaluate whether the time between C was predictive of incidence and severity of HSRs. Methods: Patients treated with C between 1/1997 and 12/2005 were identified through our chemotherapy database. Records were reviewed for: dates and number of C regimens and cycles, age, drug allergies, cancer type, and date and symptoms of HSR. Severity was defined as mild if symptoms were rash, pruritis or severe for hypo/hypertension, vomiting, dyspnea, wheezing, chest pain, edema, rigors or generalized hives. Fisher’s exact test or Chi Square was used to compare categorized variables. Results: 126 patients were identified who had multiple C regimens. The median age was 60 (range, 40–90) and 89% were treated for ovarian cancer. 63 (50%) experienced C HSRs of which 36 (29%) were severe. The mean time between C regimens was 21 months for those with no HSRs and 24 months for those with HSRs (p = 0.1). The time between C regimens significantly predicted the incidence of HSRs (see table ). Of those receiving a 3rd regimen of C, 8/8 had a HSR and these were severe in seven (88%). Neither age nor presence of other drug allergies was associated with a risk of C HSR. Of interest, 60 patients received >8 (range 9–19) cycles with the first C regimen, and none of the patients reacted after cycle 8. Conclusions: A duration of greater than 12 months between C regimens is associated with an increased risk of both any- and severe- HSR. Our data also suggests that upfront treatment with C beyond eight cycles is not associated with an increased risk of HSR. Strategies for decreasing the risk of C HSR may be best focused on women receiving a repeat regimen after a platinum-free duration over 12 months or those receiving a 3rd regimen of C. [Table: see text] No significant financial relationships to disclose.
Identification of a basal-like subtype and comparative effect of epirubicin-based chemotherapy and sequential epirubicin followed by docetaxel chemotherapy in the PACS 01 breast cancer trial: 33 markers studied on tissue-microarrays (TMA)
Authors: Jacquemier J. , Penault-Llorca F. , Mnif H. , Charafe-Jauffret E. , Marque S. , Martin A. , Genève J. , Roché H. 
Published: March 2020

509 Background: Immunohistochemical profiling studies with TMA classified breast cancer by luminal, normal breast like, HER-2 overexpressing, and basal-like subtypes. The aim of this study was to evaluate the impact of these subclasses in terms of therapeutic benefit for patients (pts) with node positive operable breast cancer included in the phase III trial PACS01. Methods: Among the 1999 pts randomized, 1100 paraffin blocs were collected for TMA. Pts were treated with either arm A: 6 cycles of FEC100 (546 pts) or arm B: docetaxel 100 mg/m2 replaced FEC100 for the last 3 cycles (554 pts). The median follow up was 5 years. The 33 analysed markers explored different pathways: cellular differentiation (CK5/6,8/18,14, P-Cadherin, E-cadherin, α-catenin, β-catenin, AF6, MUC1, Cav1, moesin, Cd10, CD44), proliferation/apoptosis (AuroraA, Tacc2/3, Ki67, CyclinD1, Bcl2, p21, p27), ER related (ER, PR, Gata3), and oncogene/ antioncogene (P53, HER2, EGFR1, Pten, Cmet, Fhit, FGFR, Angiogenin, topoisomeraseIIα). All antibodies were evaluated in quick score. Results: In terms of metastases free survival (MFS) 16 markers harboured a statistical significant value under 20%. The hierarchical clustering for 80% of complete data, identify a cluster of pts (n=531) characterized by the positive expression of EGFR1, Moesin, Pcadherin, and p53, considered as basal-like subtype (BLST). This cluster presented a pejorative predictive value both in Log-rank test (LR) (p=0.002) and in Cox multivariate analysis (HR=0.65; p=0.009), confirmed in overall survival (OS) (LR p<0.0001; cox HR=0.46, p<0.001). BLST pts had a significantly better MFS (LR p=0.05) in the arm B, confirmed in OS (LR p=0.005), as for a more theoretical basal signature and ER negativity (LR MFS p=0.0033, OS p=0.0052; cox MFS HR=0.71 p=0.04, OS HR=0.51 p=0.003). For a second cluster considered as luminal subtype (ER positive and BLST parameters negatives) no difference was observed whatever the arm. Conclusions: The basal-like profile identified in this study is significantly associated to a worst prognostic, but also to a better response to sequential FEC/docetaxel chemotherapy. [Table: see text]
Phase I study of weekly topotecan and gefitinib in patients with platinum-resistant ovarian, peritoneal, or fallopian tube cancer
Authors: Slomovitz B. M. , Coleman R. L. , Levenback C. , Jung M. , Gershenson D. M. , Wolf J. 
Published: March 2020

5090 Background: To determine the dose limiting toxicity and the maximum tolerated dose (MTD) of weekly topotecan in combination with standard dose gefitinib in patients with relapsed, platinum-resistant, ovarian, peritoneal or fallopian tube cancers that are EGF-R positive (>/= 1+). Methods: Patients with measurable, recurrent or persistent cancer after treatment with a platinum and paclitaxel-containing regimen were eligible for this study. Initial treatment was gefitinib at a dose of 250 mg oral dose daily and topotecan at a dose of 2.0 mg/m2 on days 1, 8, and 15, with cycles repeated every 28 days. Dose escalations were planned for topotecan (Dose Levels 1–3: 2, 3, 4 mg/m2) until the MTD was reached. A conventional 3+3 algorithm was used. The 2mg/m2 dose of topotecan was chosen as a starting dose because there are reported responses to this level when it has been used as a single agent on this schedule. Results: Thirteen patients received a total of 45 cycles. Twelve patients were evaluated for toxicity and 11 patients for response. Median age range was 63 years. At the time of initial diagnosis, all twelve patients underwent tumor debulking surgery. One patient had one prior chemotherapy regimen, 6 patients had 2, 4 patients had 3 and 1 patient had more than 3 prior chemotherapy regimens. There were 3 patients treated at dose level 1, 3 patients at dose level 2 and 7 patients treated at dose level 3 (1 patient was inevaluable). One of 6 evaluable patients in the dose level 3 group had a grade 4 thrombocytopenia. Therefore, dose level 3 will used for the Phase II portion of the trial. There were no treatment related deaths. Of the 11 patients evaluated for response, there were 4 patients with stable disease (mean number of cycles 6.5, range 3–12) and 7 had progressive disease. Conclusions: Gefitinib with weekly topotecan infusion is a well-tolerated regimen and suitable for study in platinum-resistant or refractory ovarian or tubal cancers. The phase II component of this study is ongoing. No significant financial relationships to disclose.
A comparison of combination docetaxel/carboplatin versus sequential docetaxel then carboplatin in patients with recurrent platinum-sensitive ovarian cancer
Authors: Alvarez Secord A. , Havrilesky L. J. , Higgins R. V. , Nycum L. R. , Kohler M. F. , Puls L. E. , Holloway R. , Soper J. T. , Valea F. A. , Berchuck A. 
Published: March 2020

5092 Background: Combination paclitaxel and platinum-based chemotherapy has been shown to improve survival in patients with recurrent platinum-sensitive ovarian cancer. However, the incidence of neurotoxicity was significantly greater with combination therapy than with other platinum-based regimens. The aim of this study was to compare the efficacy and adverse event profile of combination versus sequential weekly docetaxel and carboplatin therapy in patients with recurrent platinum-sensitive ovarian cancer. Methods: Patients with recurrent platinum-sensitive ovarian, peritoneal, or tubal cancer were randomized to either weekly docetaxel 30 mg/m2/days 1 and 8 and carboplatin AUC 6/day 1 q 3 weeks (regimen A) or docetaxel 30 mg/m2/days 1 and 8, repeated every 3 weeks for 6 cycles followed by carboplatin AUC 6/day 1 every 3 weeks (regimen B) for 6 cycles or until disease progression. The primary endpoint was time to progression (TTP). Results: At the time of this analysis, 51 patients, with a median age of 65.1 years, had been enrolled. There were 25 randomized to regimen A and 26 to regimen B from January 2004 to April 2005. There were no differences between the groups with respect to age, performance status, prior consolidation therapy, or anatomic site of cancer. The study is still open to accrual and thus far the overall response rate was 51% (2 CR, 24 PR) with stable disease in 26%. Median TTP was 12.6 months. The incidence of grade 2 or 3 neurotoxicity and grade 3 or 4 neutropenia was higher with regimen A compared to regimen B (15% vs. 3%; 44% vs. 10%), respectively. Conclusions: Combination and sequential weekly docetaxel and carboplatin have significant activity in recurrent platinum-sensitive ovarian cancer. Both regimens have a low incidence of moderate to severe neurotoxicity relative to that observed in other studies that employed paclitaxel. [Table: see text]
Effect of anastrozole on bone mineral density: 5-year results from the ’Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial
Authors: Coleman R. E. 
Published: March 2020

511 Background: Since reporting the 1- and 2-year results from the ATAC trial bone sub-protocol, 68-month analysis results from the main ATAC trial have shown that, for postmenopausal women with invasive primary breast cancer, adjuvant treatment with anastrozole results in superior efficacy and tolerability compared with tamoxifen. Here we report 5-year bone mineral density (BMD) results from the monotherapy arms (anastrozole, n=81; tamoxifen, n=86) of the bone sub-protocol. Methods: Lumbar spine and total hip BMD were assessed by dual-energy X-ray absorptiometry at baseline and after 1, 2, and 5 years. Results: The median percentage changes in BMD at 1, 2, and 5 years, respectively, are shown in the table . Percentage changes in BMD from baseline to 5 years showed a statistically significant difference in favor of tamoxifen for both lumbar spine (treatment effect [percentage decrease of BMD on anastrozole relative to tamoxifen] −8.1; 95% confidence intervals [CI] −10.1, −6.1; p<0.0001) and total hip (treatment effect −7.4; 95% CI −9.6, −5.3; p<0.0001). For patients with data at baseline, 2, and 5 years, the rate of loss of lumbar spine BMD in the anastrozole group was significantly less from 2 to 5 years than from baseline to 2 years (mean difference in annual rate of change 0.0113, 95% CI 0.006, 0.017; p=0.0002), but there was no evidence of slowing down in the loss of total hip BMD. Five patients with osteopenia at baseline developed osteoporosis on treatment with anastrozole (4) or tamoxifen (1). No patients with normal BMD at baseline became osteoporotic at 5 years. Conclusions: Significant bone loss occurred throughout the 5 years in the anastrozole group, although there appeared to be a slowing down of the rate of bone loss in years 2–5. Although no patients with normal BMD at baseline had become osteoporotic at 5 years, regular monitoring of BMD and bone protection strategies are likely to be required in patients receiving anastrozole in the presence of pre-existing osteopenia. [Table: see text] [Table: see text]
Prognostic and predictive value of topoisomerase II alpha in a randomized trial comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTG MA.5)
Authors: O’Malley F. P. , Chia S. , Tu D. , Shepherd L. E. , Levine M. N. , Huntsman D. G. , Bramwell V. H. , Andrulis I. L. , Pritchard K. I. 
Published: March 2020

533 Background: It has been suggested that Topoisomerase II alpha (TOP2A) status rather than Her-2/neu status may predict response to anthracycline chemotherapy in breast cancer. Methods: In MA.5, 710 premenopausal women with node positive breast cancer were randomized to receive adjuvant CEF (epirubicin 60 mg/m2 & 5-FU 500 mg/m2 both IV, days 1 & 8, and cyclophosphamide 75 mg/m2 p.o. days 1 through 14); vs CMF (methotrexate 40 mg/m2 & 5-FU 600 mg/m2 both IV days 1 & 8 and cyclophosphamide 100 mg/m2 p.o. days 1 through 14), all for six 28-day cycles. Tissue microarrays (TMAs) were constructed from paraffin embedded specimens from 447 (63%) of these patients. TOP2A was measured by fluorescence-in-situ hybridization (FISH), classifying tumors into 3 groups by TOP2A/CEP 17 ratios: amplified (Amp) if ratio ≥2; deleted (Del) if ratio < 0.8; normal (N) if ratio 0.8 to 2. Cox models assessed interaction between treatment and TOP2A, adjusting for age, nodal status, ER, HER-2/neu status, grade, surgery and tumor size. Results: Thirty-one patients (6.9%) had tumours with Del TOP2A; 53 (11.9%) with Amp TOP2A; and 353 (81.2%) with N TOP2A. 5-year disease-free survival (DFS) was 48%, 51%, and 61% for patients with Del, Amp and N TOP2A respectively (p=0.22 adjusted global test). 5-year overall survival (OS) was 55%, 61% & 75% for patients with Del, Amp, and N TOP2A (p=0.67 adjusted global test). HRs for DFS and OS by treatment and TOP2A are presented in the table . Conclusions: TOP2A status was a significant predictive factor for benefit from CEF treatment for OS. Although there was a trend for TOP2A status predicting improved DFS with CEF, the test for interaction was not significant. In adjusted analysis TOP2A did not reach significance as a prognostic factor for DFS or OS. (This study was supported by the Canadian Breast Cancer Research Alliance (CBCRA), the National Cancer Institute of Canada (NCIC) and the Canadian Cancer Society.) [Table: see text] [Table: see text]
Improved prediction of disease-free survival in tamoxifen-treated patients using an expression signature of estrogen-regulated genes as compared to progesterone receptor
Authors: Creighton C. , Rae J. , Chinnaiyan A. , Lippman M. 
Published: March 2020

535 Background: Progesterone receptor (PR) is a direct downstream target of activated estrogen receptor (ER) and its expression is a marker of estrogen signaling within breast tumors. Studies suggest the absence of PR predicts the likelihood of distant recurrence in patients treated with hormonal therapies such as tamoxifen, but better clinical measures are needed. Methods: Through analysis of public mRNA expression profiling datasets, we identified 36 genes with the following expression patterns similar to PR: (1) induced by 17β-estradiol (E2) in estrogen receptor (ER)-positive breast cancer cell lines in vitro, (2) under-expressed in ER-negative compared to ER-positive breast tumors, and (3) correlated with PR expression in ER-positive tumors. The average expression of these 36 genes was used as a “risk index” for assessing disease-specific survival in two independent tumor profile datasets of 60 and 67 patients treated with tamoxifen (these data not having been used to initially select the 36 genes), with a high risk group in each dataset defined as those with the bottom 25% of risk index values. Results: The Kaplan-Meier estimates of the rates of distant recurrence at 10 years in the low-risk and high-risk groups were 24% and 64% in the one dataset and 32% and 72% in the other dataset. In both validation datasets, the rate in the low-risk group was significantly lower than that in the high-risk group (P=0.008 and P=0.006 by log-rank, respectively), whereas patient groups defined by histologically-assigned PR status did not show significant risk differences (P=0.70 and P=0.94, respectively). In a univariate Cox model, the risk index combined across both validation datasets provided significant predictive power (P=0.03). Conclusions: Through RT-PCR assay of a larger independent cohort of breast tumor samples, we are currently validating the prognostic value of individual genes within the 36-gene signature. No significant financial relationships to disclose.