bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicroRNAs that underlie response to salvage chemotherapy in ovarian cancer
Authors: Boren T. P. , Cui S. , Chan G. , Dressman H. , Lancaster J. M. 
Published: March 2020

10542 Background: MicroRNAs (miRNAs) are non-protein coding, endogenous, small RNAs that can bind complementary mRNA to modulate gene expression and protein translation. Recent studies indicate that miRNAs may be mechanistically involved in ovarian cancer chemosensitivity and may play an important role in the development of chemoresistance. The objective of the current study was to explore the role of miRNAs in the response of platinum-resistant recurrent or persistent ovarian cancer to salvage chemotherapy. Methods: MicroRNA was extracted from 16 ovarian cancer cell lines. All samples were hybridized to a miRNA array that contained Ambion and Invitrogen probe sets. In parallel, the 16 ovarian cancer cell lines were treated with Doxorubicin, Topotecan, Paclitaxel, Docetaxel, and Gemcitabine, and their response to treatment evaluated using proliferation assays. Logistic regression analysis was used to identify miRNAs associated with responsiveness to individual chemotherapeutic agents. Results: Linear regression analysis identified a total of 39 miRNAs significantly associated with salvage chemotherapy responsiveness. Sixteen miRNAs were associated with response to Doxorubicin, 18 associated with response to Topotecan, 2 associated with response to Docetaxel, 9 associated with response to Paclitaxel, and 11 associated with response to Gemcitabine (p<0.05). Ten miRNAs were associated with more than one chemotherapy (miR-126, miR-199a, miR-202 [Doxorubicin, Topotecan, Gemcitabine], miR-26a, miR-320 [Doxorubicin, Topotecan], miR-181b [Doxorubicin, Topotecan, Paclitaxel], 181a [Topotecan, Gemcitabine, Adriamycin, Paclitaxel], miR-99b [Doxorubicin, Paclitaxel, Docetaxel], miR-31 [Docetaxel, Paclitaxel], miR-339 [Doxorubicin, Gemcitabine]). Conclusion: We have identified miRNAs that may influence ovarian cancer responsiveness to salvage chemotherapy. Ten of the miRNAs were associated with chemosensitivity to more than one drug. These miRNAs may regulate common determinants of chemoresistance and may also serve as novel therapeutic targets for patients with chemoresistant ovarian cancer. Further studies are warranted to validate these results. No significant financial relationships to disclose.
Biomarker analysis by breast cancer phenotype in African-American versus Caucasian patients: Correlates with survival
Authors: Morris G. J. , Topham A. K. , Guiles F. , McCue P. , Schwartz G. F. , Park P. K. , Rosenberg A. L. , Brill K. , Rui H. , Mitchell E. P. 
Published: March 2020

10551 Background: Breast carcinomas in African-American (AA) patients (pts) have poorer prognosis and higher likelihood of aggressive basal phenotype (triple negative for ER, PR, HER2) than those in Caucasian (C) patients (Carey et al, JAMA 2006, 295(21):2492; Morris et al, Breast Cancer Res Treat 2006, abstr 3055). We have additionally examined biomarker expression by phenotype in AA pts in our registry to further explain more aggressive behavior in this population. Methods: Stage, grade, ER, PR, Ki-67, HER2, and p53 expressions were compiled for breast carcinomas in 2,230 AA and C pts diagnosed between 1995–2004. Immunohistochemical markers were assayed using antibodies to the above proteins on paraffin-embedded formalin-fixed tissue. Differences in expression were analyzed by Chi- squared and Wilcoxon tests, and survival by Kaplan-Meier estimates. Results: AA pts have higher propensity for basal phenotype breast cancers (20.8% vs 10.4%, p<0.001) and lower propensity for Luminal A/B (ER+/PR+-/HER2-) phenotype (44.2% vs. 54.1%, p<0.001) as compared with C pts. Higher ki-67 proliferation index was found in AA pts (86.4% vs 78.8% in basal, p=0.3423; 37.1% vs. 26.7% in Luminal A/B p=0.0233) as compared with C pts. p53-positivity was higher in AA and C pts in all cases (p=0.0158), higher in AA pts with basal phenotype (p=0.2597), but identical in AA and C pts with luminal phenotypes (p=0.881). Survival was similar in basal phenotypes between races in all cases stage for stage, and controlled for ki-67 and p53 status, with a trend toward poorer survival among luminal phenotypes between races. Conclusions: AA pts have higher propensity for basal phenotype breast cancers than C pts, with higher ki-67 expression in both basal and luminal phenotypes, and higher p53 expression in basal phenotype, but these do not correlate with significant differences in survival by phenotype between races. As neither ki-67 index nor p53 expression can therefore solely explain differences in survival rates seen between races, molecular array studies between races and matched by phenotype are proposed. [Table: see text]
Matrix metalloproteinase 2 (MMP2) polymorphism, Helicobacter pylori (HP) infection and esophageal adenocarcinoma (EA) risk
Authors: Liu G. , Fruh M. , Zhou W. , Zhai R. , Su L. , Heist R. S. , Wain J. C. , Lynch T. J. , Shepherd F. A. , Christiani D. C. 
Published: March 2020

10553 Background: Epidemiologic studies suggest that HP infection protects against EA risk, as HP-mediated chronic atrophic gastritis reduces acid reflux. Genetic variations may modify the host response to HP infection and alter this risk. MMP2 expression is commonly upregulated in HP infections. We hypothesize that a functional MMP2 promoter polymorphism (-C1306T) that abolishes a Sp1 binding site and decreases promoter activity will also reduce the protective effects of HP infections in EA risk. Methods: HP status was determined in 98 EA patients and 101 age and gender matched healthy controls, using a commercially available serum immunoblotting kit (Helicoblot 2.1, Genelabs Diagnostics) that measures ever, current, CagA+ and VacA+ HP infections. Genotyping was performed using TaqMan. Data were analyzed using unconditional logistic regression. Results: 39% of cases and 44% of controls (P=0.69) had MMP2 variants (T/T or C/T). 36% of cases and 42% of controls were ever HP infected (P= 0.35). In individuals carrying the MMP2 wild type (CC) genotype, ever HP infection was strongly protective against EA [Odds Ratio (OR) 0.32: 95% CI, 0.13–0.75; P=0.008]. In contrast, in individuals carrying the MMP2 variants that are associated with lower promoter activity, this protective effect was lost (OR 1.76; 95% CI, 0.06–5.2; P= 0.30). Similar results were found when evaluating the MMP2 and current, CagA or VacA infection. Statistical interactions between MMP2 genotype and ever HP infection (P=0.027) and between MMP2 genotype and VacA+ infection (P= 0.035) were significant. Conclusions: We are the first to report that host factors such as the MMP2 polymorphism modulate the role of HP infection in EA susceptibility. No significant financial relationships to disclose.
Absence of racial predilection for aggressive tumor phenotype among low socio-economic status women with breast cancer
Authors: Dookeran K. A. , Wang Y. , Gao X. , Ferrer K. , Sekosan M. , DeLaTorre R. , Radeke E. , McCaskill-Stevens W. , Zaren H. 
Published: March 2020

10554 Background: Survival disparity for African-American (AA) women with breast cancer has been associated with more frequent aggressive tumor phenotype, manifested as higher stage, high grade and negative estrogen/progesterone receptor (ER/PR) status. However, AAs more often have low socioeconomic status (SES), and other studies suggest that low SES, not simply race, is associated with these prognostic features. We hypothesized that low SES AAs and non-AAs with breast cancer would demonstrate similar aggressive tumor phenotype and prognosis. Methods: Variables were analyzed for 538 consecutive low SES women treated between 1/00–12/05. Comparison between racial groups was done with independent t-test & Chi-square test. Associations were examined with logistic-regression, and compared as odds ratios (OR) & 95% confidence intervals (CI). Survival was computed using Log-rank test & Kaplan-Meier method. Results: At median follow-up of 32 months, there were 335 AAs & 203 non-AAs. No significant differences occurred between racial groups for tumor size & grade, node status, stage, ER/PR status, and frequency of survival events. HER2+ status was more frequent in non-AAs (25.1% vs. 17.9% AAs; p=0.048). No significant differences occurred between races for treatment with surgery, chemo & endocrine therapy, however radiation was more common in non-AAs (73.4% vs. 62.2% AAs; p=0.012) but AAs were significantly older (p=0.0001) and had more comorbid disease (p=0.0001). See Table for prevalence of aggressive tumor features. Age-adjusted logistic-regression showed no racial predilection for negative ER/PR, high grade and higher stage, but AAs were less likely to be HER2+ (OR=0.644; 95% CI=0.415–1.00; p=0.05). Log-rank tests showed no differences between racial groups for age & stage-specific disease-free & overall survival. Conclusions: These results confirm that among similar low SES women with breast cancer, there is no racial predilection for aggressive tumor phenotype and poor prognosis. [Table: see text] No significant financial relationships to disclose.
Polymorphisms in angiogenesis related genes predict clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with first line 5-FU or capecitabine in combination with oxaliplatin and bevacizumab (FOLFOX/BV or XELOX/BV)
Authors: Shaye O. S. , Chang H. M. , Yang D. Y. , Shriki J. , Schultheis A. M. , Zhang W. , Lurje G. , Iqbal S. , Lenz H. J. , El- Khoueiry A. B. 
Published: March 2020

10576 Background: The inhibition of angiogenesis is central to the mechanism of action of BV, a monoclonal antibody to vascular endothelial growth factor (VEGF). We evaluated functionally significant polymorphisms of genes involved in the angiogenesis/VEGF pathway as potential molecular predictors of clinical outcome in pts with mCRC who received BV as part of their frontline therapy. These genes included: VEGF, VEGF receptor 2 (KDR), neuropilin 1 (NRP 1), Interleukin (IL) 6 and 8, IL receptor 1 and 2 (CXCR 1, CXCR 2) adrenomedullin (AM), leptin, fibroblast growth factor receptor 4 (FGFR4), tissue factor (TF), matrix metalloproteinases (MMP 2,7,9), epidermal growth factor receptor (EGFR), aryl hydrocarbon receptor nuclear translocator (ARNT), and nuclear factor kappa b (NFkb). Methods: PCR-RFLP assays were performed on genomic DNA extracted from the blood of 30 pts with mCRC treated with first-line FOLFOX/BV or XELOX/BV at USC. Results: the cohort consisted of 21 males and 9 females with a median age of 56 years (range: 29–81). 20 pts received XELOX/BV as part of an on-going phase II study, 10 pts received FOLFOX/BV. Radiologic response was evaluable in 27/30 pts: 2/27 (7%) complete response (CR), 14/27 (52%) partial response (PR), and 10/27 (37%) stable disease (SD) and 1/28 (4%) progressive disease. At a median follow-up of 19.4 months, 16/30 pts progressed with a median progression free survival (PFS) of 11.8 months. Pts homozygous A/A at the leptin 5'UTR region had a higher probability of response than pts with the G/A or G/G genotypes (p=0.03, Fisher's exact test). Pts with one or more G allele (G/G or A/G) at locus -181 in the promoter region of MMP7 had a higher probability of response than pts with the AA genotype (p=0.014, Fisher's exact test). There were statistically significant associations between genomic polymorphisms of KDR, CXCR2, MMP7 and PFS (<0.05, Log-rank test). Conclusions: This pilot study demonstrated, in a preliminary fashion, the potential predictive and prognostic value of several genomic polymorphisms in pts with mCRC treated with FOLFOX/BV or XELOX/BV. No significant financial relationships to disclose.
Biological mechanisms that trigger breast cancer (BC) tumor progression are molecular subtype dependent
Authors: Sotiriou C. , Desmedt C. , Haibe-Kains B. , Harris A. , Larsimont D. , Buyse M. , Wirapati P. , Delorenzi M. , Bontempi G. , Piccart M. 
Published: March 2020

10581 Background: We have recently developed several gene expression indices related to hallmarks of breast cancer involving various biological processes such as tumor invasion, impairment of immune response, sustained angiogenesis, evasion of apoptosis and self- sufficiency in growth signal, and investigated their impact on clinical outcome. Here, we aim to refine our biological understanding and the prognostic impact of these indices according to the previously described molecular subtypes based on the estrogen (ER) and ERBB2 receptors. Methods: Each of these indices were developed in a series of 581 BC samples and then computed on several publicly available microarray studies totaling over 2100 BC patients. Multivariate analyses were used to study the dependency patterns between these indices, the molecular subtypes and their impact on survival. Results: ER-/ERBB2- and ERBB2+ subgroups were significantly associated with high expression levels of the proliferation, tumor invasion, angiogenesis and immune response indices. Multivariate analysis showed that in the ER+/ERBB2- subgroup, only tumor size and the proliferation and tumor invasion indices were significantly associated with clinical outcome, with the proliferation index having the largest HR and most significant p-value (HR 3.25; CI 2.31–4.56; p=1.2 10-11). In contrast, in the ER-/ERBB2- subgroup, only tumor size (HR 2.08; CI 1.14–3.81; p=0.01) and immune response index (HR 0.66; CI 0.46–0.95; p=0.02) were associated with prognosis whereas in the ERBB2+ tumors only nodal status (HR 3.40; CI 0.96–12.10; p=0.05) and tumor invasion index (HR 3.03; CI 1.32–6.95; p=0.009) showed significant association with survival. Of interest, proliferation index lost its significance as almost all ER- /ERBB2- and ERBB2 + tumors showed high proliferation levels. Conclusions: Although proliferation seems to be the strongest parameter predicting clinical outcome in ER+/ERBB2- subtype, immune response and tumor invasion appear to be the main molecular mechanisms associated with prognosis in the ER-/ERBB2- and ERBB2+ subgroups respectively. Defining these clinico-genomic models in the specific molecular subgroups will be the key to success for personalized medicine. No significant financial relationships to disclose.
Activation of the PI3K/AKT signal transduction pathway is inversely associated with estrogen receptor levels and correlates with survival in hormone receptor-positive Her2/neu-negative breast cancer
Authors: Gonzalez-Angulo A. M. , Hennessy B. T. , Meric-Bernstam F. , Lu Y. , Symmans W. F. , Hortobagyi G. N. , Mills G. B. 
Published: March 2020

10588 Background: Hormone receptor-positive is the most common subtype of breast cancer. Despite the successes of antihormone therapy alone or combined with chemotherapy, a significant proportion of patients (30–40%) will have primary or acquired resistance to this treatment. There is a need to identify molecular markers to distinguish patients unlikely to benefit from therapy as well as novel targeted therapeutics that increase the response rate. Methods: We used a novel functional proteomics technology, reverse phase protein array (RPPA), to quantify expression and activation of 42 steroid and kinase signaling proteins in 64 hormone receptor-positive-Her2/neu-negative breast cancers from patients with stage I to III tumors managed with non-steroidal aromatase inhibitors ± chemotherapy. Unsupervised clustering analysis was used to molecularly group the tumors. Recurrence-free survival (RFS) was estimated with the Kaplan Meier product limit method and comparison was made using the Log-rank test. Correlation coefficients were used to look at the relationships between two variables. Results: Median age was 57 years (23–79). Sixteen patients (25%) had stage I tumors, 32 (50%) had stage II tumors and 16 (25%) had stage III tumors. There were two well-defined and distinct clusters of tumors: Group 1: ER high (n=25) and Group 2: PI3K/AKT activated (n=39). 3-year RFS estimates were 100% for group 1 and 59% for group 2 (p=0.04). There were thus clear inverse correlations between markers of activation of PI3K pathway and expression of ER (R for pAKT vs ER = -0.26, p=0.03). PIK3CA mutation was detected in 12/58 (21%) of hormone receptor-positive breast cancers and these tumors were found to have a proteomic signature distinct from PTEN loss with the former signature associated with a trend to improved RFS (p=0.06). Conclusion: Activation of the PI3K/AKT pathway in hormone receptor- positive-Her2/neu-negative breast cancer is inversely correlated with ER levels and associated with adverse outcome. At least in some cases, PI3K/AKT pathway activation, may be under the control of genomic aberrations. A validation set of 100 tumors treated with tamoxifen is on- going. No significant financial relationships to disclose.
β-catenin interacts with heat shock protein Hsp27 and heat shock transcription factor 1 and it is a useful prognostic marker in breast cancer patients
Authors: Gago F. E. , Fanelli M. A. , Montt-Guevara M. M. , Diblasi A. M. , Tello O. , Cuello-Carrión F. D. , Callegari E. , Ciocca D. R. 
Published: March 2020

10593 Background: We examined in breast cancer the possible interactions between heat shock proteins (Hsps) and the cadherin- catenin cell adhesion proteins, which have important roles in signaling pathways and tumor cell invasion. The cadherin-catenin proteins, like Hsps, have the capacity to bind other proteins. Moreover, there are common molecular pathways for the Hsp response and for the cadherin- catenin protein system. Methods: β-catenin was immunoprecipitated from breast cancer biopsies and the resulting product was probed with antibodies against Hsp members. LC-ESI-MSMS analysis was performed. Immunohistochemistry was used on paraffin sections. Statistical analyses were performed (Prism computer program): Kaplan-Meier, difference between curves evaluated with the log-rank test for censored survival or event observations, contingency tables analyzed by the Fisher`s exact test and Chi-square. Results: β- catenin interacted with Hsp27 and HSF1 (heat shock transcription factor 1), this is the first demonstration of these specific interactions, β- catenin did not interact with Hsp60, Hsp70, Hsp90, gp96 and CHOP. To confirm this finding, the 27 kDa band was excised and submitted to LC- ESI-MSMS, the band was identified as Hsp27. In addition, β-catenin interacted with P-cadherin and caveolin-1. In the co-localization studies, β- catenin was observed in the same tumor areas and cells that expressed Hsp27. This association was strong when β-catenin was expressed in the cytoplasm, not when β-catenin was expressed at the cell membrane. In addition, β-catenin co-localized with HSF1. Finally, the prognostic significance of cadherin-catenin proteins was examined in breast cancer patients (n=215, follow-up: >10 years). Conclusions: We found that cytoplasmic β-catenin interacted with Hsp27 and HSF1, and that the survival (disease free and overall) was significantly shorter for patients with P-cadherin + and cytoplasmic β-catenin + tumors. The interactions of β-catenin with Hsp27 and with HSF1 may explain some of the molecular pathways that influence tumor cell survival and the clinical significance in the prognosis of the breast cancer patients. No significant financial relationships to disclose.
Increased expression levels of human telomerase reverse transcriptase (hTERT) mRNA correlates with poor prognosis in resected non-small cell lung cancer (NSCLC) patients
Authors: Carrera S. , López-Vivanco G. , Calvo B. , Aresti U. , Jangi M. S. , Ferreiro J. , Martínez-Bueno A. , Rubio I. , Muñoz A. , Ancizar N. 
Published: March 2020

10594 Background: Telomerase adds hexameric TTAGGG nucleotide repeats onto the ends of chromosomal DNAs to compensate for losses of each cell replication. In several tumors, telomerase is expressed in a way that tumoral cell proliferates indefinitely. Correlation between telomerase level expression, clinico-pathological characteristics and survival of lung cancer is not well established in NSCLC. Methods: We studied 149 consecutive patients (140 men/9 women) with resected NSCLC: 37.6% adenocarcinoma, 59 % squamous cell, and 3.4% large cell carcinoma. Pathological stage: I (36.9%), II (32.3%) and III (30.8%). Reverse transcription-polymerase chain reaction (RT-PCR) analysis was used for the detection hTERT expression in lung cancer tissues immediately snap-frozen in liquid nitrogen at -80 °C. Results: Median and mean values of hTERT mRNA were 18.27 and 475.29 (SE 309.76). There were no significant differences on expression according to sex, histology, smoking history and pathological stage (ANOVA). Patients with highest values of hTERT mRNA expression (percentile 95, cut-off value >353) had worse median progression free survival (PFS) (p=0.024) and overall survival (OS) (p=0.020), using Kaplan-Meier method. Multivariate analysis by Cox regression yielded that hTERT level > 353 independently predicted a worse PFS (HR=0.39; 95% CI 0.17–0.93, p=0.034) and OS (HR=0.32; 95% CI 0.12–0.82, p=0.017). Conclusions: A high level of telomerase expression in tumoral tissue is strongly associated with increased risk of recurrence and mortality in resected NSCLC. The level of hTERT mRNA would predict the prognosis of lung cancer patients. No significant financial relationships to disclose.
Subgroup analysis of GEICAM 9906 trial comparing six cycles of FE90C (FEC) to four cycles of FE90C followed by 8 weekly paclitaxel administrations (FECP): Relevance of HER2 and hormonal status (HR)
Authors: Rodríguez-Lescure Á. , Martín M. , Ruiz A. , Alba E. , Calvo L. , García-Asenjo J. L. , Guitian M. , de la Cruz A. , Aranda I. , de Álava E. 
Published: March 2020

10598 Background: GEICAM 9906 interim analysis showed FECP improved disease-free survival (DFS) compared to FEC (SABCS 2005, abstract #39). As a secondary objective, predictive markers were centrally determined and DFS of subgroups analyzed. A prior report from CALGB 9344 trial suggested that patients (pt) with HER2+ tumors get the maximum benefit with adjuvant P (ASCO 2006, abstract #510). We aimed to confirm this finding in our dataset. Methods: 1248 node + pt received 6 q3wk cycles (cy) of FEC (600/90/600 mg/m2) or 4 cy of same FEC followed by 8 wk cy of P (100 mg/m2). Tumor paraffin-embedded blocks were prospectively collected from 889 pt (71%) for Tissue Microarrays. Statistical analysis used Kaplan-Meier estimates for DFS by treatment group at a median follow-up (FU) of 65 months (m). HER2 status was evaluated by FISH. HR status was determined by IHC, following Allred criteria. Results: At a median of 65 m FU, DFS for FECP remains better than FEC (79% vs. 72%; p=0.0042; HR= 0.71). HER2: DFS for HER2+ and HER2- pt were 66% vs. 78% (p=0.0008; HR= 0.60). HER2+ subgroup (n=177): DFS with FECP and FEC were 63% vs. 70% [p=0.5187, HR=1.18 (0.71–1.98)]. HER2- subgroup (n=712): FECP was significantly better than FEC [82% vs. 74%, p=0.0075; HR=0.65 (0.48–0.89)]. HR: DFS for HR+ and HR- pt were 80% vs. 68% (p<0.0001; HR= 0.52). HR+ subgroup (n=561): DFS with FECP and FEC were 82% vs. 79%, [p=0.2162; HR=0.79 (0.54–1.15)]. HR- subgroup (n=311): DFS was 72% vs. 65% [p=0.1633, HR=0.76 (0.51–1.12)]. DFS data in the four HER2/HR subgroups is summarized in the table . Conclusions: FECP is superior to FEC mostly in HER2-HR- (triple negative) tumors. Our subgroup analysis does not support the superiority of the paclitaxel-containing arm (FECP) in pt with HER2 positive tumors. [Table: see text] [Table: see text]