bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time dependence of prognostic values of gene-expression signatures for breast cancer
Authors: Lau K. F. 
Published: August 2020

11085 Background: Gene-expression signatures were shown to be prognostic and predictive for breast cancer but their performances over time have not been investigated. Methods: Recurrence score (RS) of oncotype, 70-gene profile (SGP) of Mammaprint, intrinsic subtype (IS) and wound signature (WS) were analyzed using a single dataset of 295 samples from Fan et al. (Fan et al. N Engl J of Med 2006; 355:560–9). Time-varying coefficient Cox models were used to estimate the time-dependent hazard ratios (HR) for relapse-free survival (RFS). Annualized RFS hazard rates were estimated using cubic splines. Concordance between RS and SGP was calculated for different intrinsic subtypes in all 295 samples and was evaluated in a subset of 173 ER+ samples not in the training set of SGP for unbiased comparison. Results: For the high risk groups of RS, SGP, IS and WS, hazard rates peaked around the 2nd year from surgery and decreased rapidly over time. For the low risk groups, hazard rates also peaked around the 2nd yr but remained fairly constant over time. Hazard ratios of high vs. low risk groups of RS at yr 2, 5 and 10 were 17.0 (8.4–34.0), 4.0 (2.0–8.0), 1.7 (0.83–3.4). For intermediate vs. low risk groups of RS, the corresponding HRs were 2.7 (1.1–7.0), 5.0 (1.1–7.4), 1.6 (0.63–4.2). Poor vs. good groups of SVP had HRs of 7.4 (4.5–12.1), 3.6 (2.2–5.9), 2.0 (1.2–3.3) at yr 2, 5, 10. HRs of Luminal B (LB), Basal-like (BL), HER2/ER- (HER2), Normal-like (NL) vs. Luminal A (LA) of Intrinsic Subtypes were 6.8 (4.0–11.5), 5.7 (3.2–10.0), 7.6 (4.0–14.1) and 1.7 (0.9–3.3) at yr 2. HRs at yr 5 were 4.0 (2.3–6.8), 0.7 (0.4–1.2), 1.1 (0.6–2.0) and 2.3 (1.2–4.4) respectively. For WS, HRs at yr 2, 5, 10 were 6.3 (3.3–11.9), 2.9 (1.6–5.6) and 2.2 (1.2–4.1) respectively. Concordance rates of RS and SVP were 1.0, 0.91, 0.86, 0.72 and 0.62 for BL, HER2, LB, LA, NL of Intrinsic Subtypes. In 173 ER+ samples not present in the SGP training set, concordance rate between RS and SVP was 0.77 (Cramer's V = 0.56); the same as in the whole set of 225 ER+ patients (Fan et al. N Engl J of Med 2006; 355:560–9). Conclusions: Prognostic values of gene-expression signatures decrease over time. They can best predict breast cancer relapse during the first 5 years. Concordance between RS and SPV is highest in the basal-like tumors and lowest in the Luminal B and Normal-like subtypes. No significant financial relationships to disclose.
Correlation of HuR cytoplasmic expression in pancreatic cancer and overall patient survival when treated with gemcitabine in the adjuvant setting
Authors: Brody J. , Dasgupta A. , Costantino C. L. , Kennedy E. , Yeo C. J. , Witkiewicz A. K. 
Published: August 2020

11097 Background:The Hu/ELAV mRNA binding protein HuR is normally localized to the nucleus and is activated upon stress. Previously, we observed that HuR expression is predominantly cytoplasmic in aggressive forms of pancreatic ductal adenocarcinomas (PDA). Additionally, we have shown that overexpression of HuR in pancreatic cancer cell lines renders them hypersensitive to gemcitabine (GEM). GEM is the standard first line therapy used against PDA. This study was designed to determine the relationship between endogenous HuR expression levels and patient outcome. Methods: We analyzed tissue from 29 resected PDA patients who did not receive neoadjuvant therapy. We determined the intensity of cytoplasmic HuR expression. All patients received adjuvant GEM, alone or in combination with radiation therapy or other chemotherapeutics. Correlation between HuR expression levels and overall survival was evaluated. Results: The median overall survival was 20.6 months, with 18 deaths observed. Median overall survival for low HuR expression was 15.3 months. Median overall survival for high HuR expression was not reached at a follow up of 40 months. A univariate Cox regression model gives a hazard ratio of low to high HuR of 3.36 (p=0.025) [95% CI 1.09–10.35]. Adjusting for age, sex, and radiation therapy in this patient group gives an adjusted hazard ratio of 5.04 (p = 0.03) [95% CI 1.15–22.02]. This indicates a 5-fold increase in risk of death in patients with low HuR levels compared to high HuR levels among patients receiving GEM. Conclusions: This is the first report of a correlation between levels of cytoplasmic HuR expression and overall survival in GEM treated patients. Together with our previously reported experimental data, HuR is regulating the key metabolic enzyme for GEM activation (deoxycytidine kinase). Therefore, HuR is a marker for therapeutic efficacy of GEM based regimens and is a candidate target for the optimization of GEM based treatment strategies. [Table: see text] No significant financial relationships to disclose.
P53 mutation and differential response to neoadjuvant chemotherapy in women with locally advanced breast cancer: Results from the I-SPY trial (CALGB 150007/1500012 and ACRIN 6657)
Authors: Pradhan S. M. , Carey L. , Edmiston S. , Hylton N. , Parrish E. , Moore D. , Conway K. 
Published: August 2020

11099 Background: Independent of other factors, p53 status may influence sensitivity to anthracycline (A)- and taxane (T)-based chemotherapy. We investigated p53 as a predictive marker of differential neoadjuvant chemoresponse by examining change in MRI longest diameter (LD) during sequential A- then T-based chemotherapy in a prospective clinical trial. Methods: 171 patients (pts) with newly diagnosed locally advanced breast cancer received neoadjuvant A- then T-based chemotherapy. LD were obtained pretherapy, between regimens, and posttherapy but prior to surgery. P53 mutation analysis was performed on pretherapy tissue using gene chip technology, SSCP, and sequencing. Subtypes were by IHC: LumA (ER/PR+/HER2-), LumB (ER/PR+/HER2+), Basal (triple negative), HER2 (HER2+/ER/PR-). Results: 99 pts had p53 mutant (M) tumors and 72 were wildtype (WT). M and WT did not differ by age, menopausal status, or HER2. M were significantly more common among basal (71%) and HER2 (59%) than Lum A (24%). Anthracycline response did not differ between WT and M within subtypes. Within HER2, Basal, and LumB, WT had higher taxane- and overall responses than M; within LumB these were statistically significant (p=0.03 and 0.05 respectively). Conclusions: P53 mutation status may affect chemosensitivity even within hormone receptor/HER2 subsets. In this dataset response to anthracycline appeared independent of p53 status within subtypes, while WT tumors responded better to taxanes and overall in LumB, with a similar trend among basal and HER2. Mutational subset and correlative analyses with gene expression, molecular subtyping, and IHC data are ongoing and will be presented. [Table: see text] No significant financial relationships to disclose.
CD24 expression and breast cancer stem cell phenotype
Authors: Rappa G. , Anzanello F. , Lorico A. 
Published: August 2020

11106 Background: Several studies suggest the existence of breast cancer-initiating cells (BCIC), responsible for tumor development and progression. Initial reports that only the CD44+CD24−/low subpopulation contains BCIC have been challenged by subsequent studies. We examined the relationship between CD24 and biological properties of breast cancer cells. Methods: MA-11 breast carcinoma cells, originating from bone marrow micrometastases, are CD44+ and have an heterogeneous expression of CD24 (214,000/cell; range 0–1,120,000). We have previously reported that upon in vitro culture as mammospheres under stem cell-like conditions, MA-11 cells acquired increased tumorigenicity and a CD44+CD24−/low phenotype. We have now investigated the relationship between CD24 expression and tumorigenicity in the MA-11 model. Results: Upon passage of MA-11 mammospheres in adherent culture, cells rapidly re-expressed CD 24. The rapid increase in CD24 was consistent with antigen up-regulation, not selection of CD24−/low cells. Exposure of adherent MA-11 cells to imatinib for 72h resulted in a reversible decrease in CD24 from 214,000 to 15,800/cell. CD44+CD24−/low cells, sorted by flow cytometry, generated CD44+CD24high, and CD44+CD24highgenerated CD44+CD24−/low. Immediately after sorting, >90% CD44+CD24−/low cells were in G0/G1. After 24–48 h in culture, cell cycle distribution, growth rate and invasiveness of the sorted cell populations were equivalent. Upon injection and s.c. growth, CD24 expression of CD44+CD24−/low populations and clones increased from 10,000 to 220,000/cell. Similarly, CD44+CD24−/low clones derived from human MCF-7 breast carcinoma cells formed tumors containing >99% CD44+CD24high cells. The average number of CD24 per cell was equivalent for tumors formed upon injection of CD44+CD24−/low, CD44+CD24+, mammosphere-derived cells or parental adherent MA-11 cells. The tumorigenic potentials of sorted CD44+CD24−/low, CD44+CD24−/lowsub-populations and clones in nu/nu mice were equivalent. Conclusions: CD44+CD24−/low breast cancer cells are not associated with increased tumorigenicity; the high CD24 level of mouse xenografts derived from both CD44+CD24−/low and CD44+CD24hi breast cancer cells suggests an important role for CD24 in tumor growth. No significant financial relationships to disclose.
Impact of molecular subtype on presenting characteristics of T1a,b tumors
Authors: Wiechmann L. , Jacks L. , Patil S. , Stempel M. , Morrow M. 
Published: August 2020

11111 Background: Gene expression profiling of breast cancers has identified molecular subtypes (Lum A and B, basal, HER2) which impact upon the risk of both local and distant recurrence. There is interest in the impact of molecular subtype on outcome in T1a,bN0M0 tumors, a group thought to have good prognosis and to be amenable to breast conservation. The purpose of this study was to determine if presenting features of T1a,b tumors differ among molecular subtypes. Methods: Subtypes were classified using IHC as Lum A (ER±PR pos, HER2 neg); Lum B: (ER±PR pos, HER2 pos); HER2: (ER+PR neg, HER2 pos); or Basal: ER, PR, and HER2 neg. Data was obtained from a registered database which included patients treated in our institution between 1/98 and 6/07. Of 7906 eligible patients, 6016 were classifiable into molecular subtypes and 1974 tumors (32.8%) measured 10 mm or less. The Chi square test and ANOVA were used for statistical analysis. Results: Data are shown in Table 1 . Patients overexpressing HER2 were significantly younger, had more nodal involvement, multicentric/multifocal (Multi) disease, extensive intraductal component (EIC), and lymphovascular invasion (LVI) (all p<0.0001). On multivariate analysis the HER2 subtype had an odds ratio of 2.5 for Multi versus Lum A/B, but HER 2 was not predictive of nodal status. Conclusions: Even in small breast cancers, presenting features vary with molecular subtype. Unlike Multi, the higher incidence of positive nodes in HER2 patients is explained by traditional prognostic features such as grade, age, and size rather than subtype, suggesting that evaluation of traditional prognostic factors remains valuable in the molecular era. [Table: see text] No significant financial relationships to disclose.
Methylation profile of human breast cancer: A possible biomarker for the detection of circulating tumor cells
Authors: Marzese D. M. , Gago F. E. , Vargas-Roig L. M. , Roqué M. 
Published: August 2020

11112 Background: Genetic and epigenetic events are complementary mechanisms involved in breast carcinogenesis. One of the most common epigenetic mechanisms by which genes are silenced is the aberrant methylation of their promoter CpG islands, i.e. hypermethylation in promoters of Tumor Suppressor Genes. The identification of circulating tumor cells (CTCs) in the blood of cancer patients, based on their aberrant methylation profile, appears as a potential tool for early detection and provides therefore the promise of a non-invasive and affordable cancer detection test. Methods: The methylation status of 26 cancer-related regions was studied, using Methyl Specific-Multiplex Ligation dependent Probe Amplification (MS-MLPA) assay in invasive breast tumors (n=24), axillary lymph nodes (n= 5), and normal breast tissue (n=2). A nested-Methyl Specific PCR (Nested-MSP) was designed for one of the methylated regions in the tumor suppressor gene rassf1A, to identify CTCs in peripheral blood samples. Blood samples from non tumor individuals were used as control. Results: We observed aberrant methylation of one or more of the 26 studied gene regions in all the breast cancer samples. The profiles were specific for each tumor. The more frequently aberrant methylated genes were: rassf1A promoter (62.5%), esr1 (54.17%), apc (54.17%) and rassf1A exon 1 (50%). Absence of aberrant methylation was confirmed in normal breast tissues. The specific methylation profile of tumors could be used to identify the metastasis origin in a patient with a left-sided breast tumor and bilateral tumor invasion of axillary lymph nodes. MS-MLPA revealed identical aberrant methylation patterns in both lymph nodes, revealing a left-sided origin of the right-sided lymph node. For the detection of CTCs in blood, a Nested-MSP on rassf1A was designed. This method allowed the detection of CTCs in the peripheral blood of a cancer patient by their aberrant rassf1A methylation. A healthy age-matched control blood sample revealed absence of CTCs. Conclusions: The identification of the methylation profile of the tumor by MS-MLPA allowed to establish the metastasis origin of invaded axillary lymph nodes and to detect CTCs in peripheral blood of a cancer patient. No significant financial relationships to disclose.
The individuality of tumor-stroma interaction in non-small cell lung cancer: Insights from functional and molecular analyses
Authors: Gottschling S. , Kuner R. , Granzow M. , Chang Xu E. , Muley T. , Hoffmann H. , Dienemann H. , Eckstein V. , Ho A. D. , Thomas M. , Meister M. 
Published: August 2020

11115 Background: Tumor-stroma interaction plays a significant role for malignant growth. Results from prostate and breast cancer rodent models show cancerogenic properties of tumor-associated and genetically altered stromal cells (SC) when combined with initiated or normal epithelium (Olumi et al., Cancer Res 1999, Kuperwasser et al., PNAS 2004). However, data on the mechanisms and sequels of tumor-stroma interaction in lung cancer are scanty. Methods: Here, we analyzed the functional and molecular sequels of cross-talk between the non-small cell lung cancer (NSCLC) cell lines A549, H23, and H1703 and primary stromal cells (SC) derived from matched normal lung tissue and tumors of newly diagnosed NSCLC patients. Tumor cells were kept in a non-contact co-culture system with SC and analyzed for alterations in proliferation, colony formation, migration, adhesion, invasion, chemosensitivity and gene expression by Affymetrix HG U133 Plus 2.0 arrays. Results: Exposure to SC altered cellular functions and gene expression profiles related to tumor growth, metastasis and response to therapy. Each cell line showed individual alterations that were hierarchically governed by the (1) type of tumor cell, (2) the SC donor and his histology (3) and the local origin of the SC (normal lung tissue vs. tumor-associated). Conclusions: This in vitro model demonstrates an individual pattern of tumor-stroma interaction in NSCLC that is determined by both, the properties of the tumor cells and those of the stromal environment. Thus, biomarker programs in NSCLC should also consider the stromal compartment. No significant financial relationships to disclose.
Weekly paclitaxel and capecitabine in HER2-negative metastatic breast cancer (MBC): A multicenter GINECO randomized phase II comparing two paclitaxel-capecitabine schedules
Authors: Lortholary A. , Hardy-Bessard A. C. , Bachelot T. , Dalivoust P. , de Rauglaudre G. , Alexandre J. , Bourgeois H. , Jaubert D. , Paraiso D. , Largillier R. 
Published: August 2020

1114 Background: Paclitaxel (Ta) and capecitabine (Xel) are synergistic in vitro. Compared to a continuous weekly Tax combined with a classical 14 days (d)/21 Xel administration (Elza-Brown et al., ASCO 2000), we have explored the combination of Xel 5d/week (wk) and weekly Ta 3 wk out 4 in the objective to increase the efficacy/toxicity ratio of the TaXel combination. Methods: Patients (pts) in first or second-line of MBC, previously treated with anthracyclins + docetaxel were randomized either to A: Ta (60 mg/m2/w) + Xel (2000 mg/m2/d x 14 d/21) or to B: Ta (80 mg/m2/w) + Xel (2000 mg/m2/d x 5 d/wk) 3wk out 4. Results: From January 2006 to January 2008, 130 pts were accrued (A 66, B 64). Pts characteristics were well balanced between the two arms including median age (58 yrs), histologic type and grade, hormone receptor-positive tumor (80%), previous treatment, visceral disease (72%), number of sites (>1; 63%), ECOG PS (0; 42%, 1; 58%). Pts received a median of 6 cycles (1–23) with a received/planned mean dose of 89.3% for Ta in both arms and of 74 and 76% for Xel respectively in arm A and B. Haematological toxicity (Tox) was low in both arms with neutropenia Gr 3 in only 8% of cycles, G-CSF support in 2% of cycles, and infection G3 in 5 pts. Alopecia G2 was less frequent in arm A (29 vs 60%). Other Tox were similar in both arms: [G2/3 (%) cutaneous (35/17), pain (36/9), fatigue (26/13), neuropathy (20/3), diarrhea (15/6), mucositis (8/2), vomiting (9/1)] but treatment interruption due to Tox was more frequent in A (A 19, B 7 pts) (p = 0.02). Response rate was 52% (B) versus 44% (A). A progression-free survival advantage was seen for B over A (366 vs 272 days, p = 0,15) including in the triple negative pt subset (n = 26 pts) (197 vs 150 days, p = 0.07). Conclusions: The intermittent regimen (3 wk out 4) of weekly paclitaxel and capecitabine 5 d/week is a well accepted, safe and effective TaXel schedule and might be a chemotherapy regimen of choice in MBC including triple negative patients. No significant financial relationships to disclose.
Phase II trial report of the new neoadjuvant chemotherapy with S-1 and docetaxel for advanced breast cancer
Authors: Okazaki K. , Kira M. , Yamai H. , Nakagawa Y. , Nagao T. , Kenzaki K. , Bando Y. , Morimoto T. , Kondo K. , Tangoku A. 
Published: August 2020

1121 Background: Primary chemotherapy with anthracycline and taxanes is a gold standard regimen which realize pathologically complete response in 20% of patients with advanced breast cancer. However, sequential administration of anthracycline and taxanes induces serious side effects. This regimen is therefore difficult to use for higj-risk patients. S-1 is a new oral anti-tumor drug, which is composed of 5-fluoro-1-(tetrahydro -2- furanyl)-2, 4(1H, 3H)-pyrimidinedione (Tegafur, FT), 5-chloro-2, 4- dihydroxypyridine (Gimeracil, CDHP) and potassium 1, 2, 3, 4-tetrahydro-2, 4-dioxo-1, 3, 5-triazine-6-carboxylate (potassium Oteracil, Oxo). Combined treatment with docetaxel and S-1 yielded significant response in patients with gastric cancer with minimal side effects due to biochemical modulation of both CDHP and Oxo. The purpose of this study was to evaluate the efficacy and toxicity of docetaxel in combination with S-1 for advanced breast cancer. Methods: Patients with advanced breast cancer (Stage IIA to IV) were treated with i.v. docetaxel (40mg/m2) on day 1 and oral S-1(80mg as FT/m2/day) on days 1 to 14 every 3 weeks for 8 courses. The clinical response was evaluated every 3 months with MMG, MRI, ultrasonography and CT scan based on RECIST criteria. The patients underwent surgery after completion of chemotherapy. Pathologic examination was performed with thin-sliced specimens. The specimens were also reserved for genetic analysis. Written informed consent was obtained from all patients or family members after the Ethics Committee of Tokushima University Hospital approved the study protocol. Results: Twenty-two patients completed the therapy and underwent surgery. Four cases (18.2%) of pathologic complete response (pCR) were recognized on pathologic examination. The response rate was 90.9% and 95.5% of the patients could preserved their breast. Bone marrow suppression was substantial, and low-grade anorexia, nausea, and peripheral neuropathy were observed. Conclusions: The new regimen of S-1 combined with docetaxel is expected to exhibit satisfactory efficacy in treating advanced breast cancer as primary chemotherapy. Genetic analysis will be performed to examine and to find biomarkers for measurement of the efficacy of this therapy. No significant financial relationships to disclose.
Effect of fulvestrant treatment on serum VEGF levels in hormone-sensitive metastatic breast cancer patients
Authors: Camerini A. , Garrone O. , Valsuani C. , Puccetti C. , Rondini M. , Donati S. , Siclari O. , Barni S. , Pronzato P. , Amoroso D. 
Published: August 2020

1124 Background: Fulvestrant (F) is a pure antiestrogen agent available for the hormonal treatment (HT) of post-menopausal ormone-sensitive advanced breast cancer (ABC). We previously reported (ASCO 2007 abs1085) a lipid lowering effect of F possibly related to an action on progesterone (P) receptor. Aim of the study is to analyze the effect of F treatment on serum VEGF levels that may represent an effect of P pathway alteration. Methods: 21 pts (median age 75 yrs [range 43–82]) with hormone-sensitive ABC were enrolled. All patients were heavily pretreated receiving a median of 2 [1–4] HT-lines and 2 [1–5] CT-lines before F. Last HT before F administration was exemestane in 8/21, letrozole in 9/21, anastrozole 3/21, and tamoxifene in 1/21. Treatment-related data, including response according to RECIST criteria and toxicity, were collected. Fulvestrant was administered as standard monthly 250 mg injection. Peripheral venous blood samples were collected before F administration, every 3 months, and at discontinuation time. VEGF levels were evaluated by ELISA and expressed as absolute absorbance values. Baseline values were always compared to the last available sample. Results: At report time pts received a median of 4 F injections (range 3–8). We observed a PR in 3/21, SD in 7/21, and PD in 11/21 pts with a clinical benefit of 45% and a median TTP of 4.5 [3–9] months. Serum VEGF levels significantly decreased during F treatment (156.8 ± 28.5 vs. 122.2 ± 14.5 A; p = 0.01). VEGF reduction was independent from clinical benefit (186.4 ± 44.6 vs. 131.1 ± 21.8 A, p = 0.04 in pts with CB and 158.9 ± 52.5 vs. 125.0 ± 27.9 A, p = 0.1 ns in pts without CB), type of last HT or treatment duration. Conclusions: We observed a reduction of serum VEGF levels associated with F treatment in our study population. Our data seem to strengthen the hypothesis of a possible effect of F on P pathway affecting both lipid metabolism and VEGF production regulation. No significant financial relationships to disclose.