bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of irinotecan plus capecitabine in patients with anthracycline and taxane pretreated metastatic breast cancer
Authors: Lee K. S. , Ro J. , Park I. H. , Kim E. A. , Nam B. 
Published: August 2020

1093 Background: Irinotecan (I) and capecitabine (X) have demonstrated single agent activity against breast cancer by different antitumor mechanism without cross-resistance. To assess the objective response rate (RR) of IX combination in metastatic breast cancer (MBC) patients (pts) was the primary end point. Methods: Anthracycline- and taxane-pretreated pts with measurable disease, age ≥ 18 years, adequate organ functions, and ECOG performance score (PS) 0–2 were eligible. Sample size of 36 was calculated with Simon's two stage minimax design. Pts received I 80 mg/m2 intravenously on days 1 and 8 and X 1,000 mg/m2 orally twice daily on days 1–14 of every 21-day cycle. Results: Between September 2006 and April 2008, 36 pts with median age of 50 years (range, 28–71) were enrolled. Median follow-up was 17 months (range, 8.3+ - 27.7+). Among 35 evaluable pts excluding 1-consent withdrawal, 86% received at least one prior chemotherapy for MBC; 20% had stage IV disease with 66% lung/37% liver metastases; 80% had PS 0–1; 77% had hormone receptor (HR) positive tumors, 20% triple negative disease and 3% HER-2 positive tumors. Overall RR was 60% (95% CI, 43.5–74.5) with median response duration of 6.3 months (range, 1.0+-17.1+); 2 CR (6%), 19 PR (54%), 8 SD (23%), and 6 PD (17%) with similar RR between HR+ (63%) versus triple negative disease (57%). Median survival was not reached with 76% estimated survival at 1-year, and median progression free survival (PFS) was 7.3 months (range, 0.7–21.1+). Pts received a median of 8 cycles of treatment (range, 1–26+). G1, G2, and G3 hand-foot syndrome were observed in 34%, 17%, and 0%, respectively. NCI grade ≥ 3 adverse events were: neutropenia (60%); asthenia, diarrhea, and vomiting (9%, each); transaminase elevation and febrile neutropenia (6%, each); abdominal pain, anorexia, fatigue, myalgia, and nausea (3%, each). Conclusions: I and X combination by this schedule and doses is highly efficacious in anthracyline- and taxane-pretreated MBC pts with manageable toxicities. Further investigation of this combination in phase III trials is warranted. No significant financial relationships to disclose.
Correlation of FcγR IIa-H131R and IIIa-V158F polymorphisms and clinical outcome of trastuzumab in both neoadjuvant and metastatic setting in patients with HER-2 positive breast cancer
Authors: Tamura K. , Shimizu C. , Koizumi F. , Kouno T. , Katsumata N. , Kinoshita T. , Aogi K. , Nishio K. , Ando M. , Fujiwara Y. 
Published: August 2020

1100 Background: The antibody dependent cell mediated cytotoxicity (ADCC) affects an efficacy of Immunoglobulin G1 antibody, including trastuzumab which is a humanized anti-HER-2 monoclonal antibody, through fragment C receptor (FcγR) polymorphisms. One report suggested that allotype of two kinds of FcγR single nucleotide polymorphisms (SNPs) are associated with clinical outcome of patients (pts) with metastatic breast cancer (BC) who received combination trastuzumab with taxane. Ethnic difference was reported in frequency of these SNPs between Western and Asian pts. The objective of this prospective study was to evaluate whether these SNPs are associated with pathological complete response (pCR) in neoadjuvant (N) setting with pts who received trastuzumab based chemotherapy, and objective response (OR) in metastatic (M) setting in pts who received single trastuzumab. Methods: Eligible criteria include HER-2 positive BC, chemotherapy-naïve, measurable disease, PS 0–2 and adequate organ functions. Pts in N setting received standard FEC (5-fluorouracil/epirubicin/cyclophosphamide q3w for 4cycles followed by weekly paclitaxel/trastuzumab for 12 weeks. Pts in M setting received single trastuzumab q1w until progression. 384 SNPs of different FcγR loci were assessed from genomic DNA extracted from peripheral blood by GOLDEGATE beads array (illumina Co.). Results: Nineteen operable and 36 metastatic HER-2 positive BC pts have been enrolled in each N and M setting, respectively. pCR in N setting was 26.3%, and OR in M setting was 22.2%. The frequencies of FcγRIIa131 genotypes were H/H 43%, H/R 49%, R/R 8%, and that of FcγRIIIa158 were V/V 43%, V/F 47%, F/F 10%, respectively. 131H/H genotype was significantly correlated with pCR (p = 0.0034) and OR (p = 0.037). 158V/V genotype had a tendency to be correlated with pCR (p = 0.067) and was significantly correlated with OR (p = 0.037). The median PFS was 8.9 months for pts with 131H/H and 3.8 months for R carriers (H/R or R/R). Conclusions: Our data for the first time suggest that these two SNPs predict pCR to trastuzumab based chemotherapy in N setting, and OR to single trastuzumab in M setting. No significant financial relationships to disclose.
Detection of MSC-like cells in soft tissue sarcoma cell lines and primary tumors
Authors: Wirths S. , Malenke E. , Wiesner T. , Buehring H. , Hartmann J. , Kopp H. G. 
Published: August 2020

11000 Background: Soft tissue sarcomas (STS) are a heterogeneous group of mesodermal tumors hypothetically originating from mesenchymal stem cells (MSC). While the expression profile of bone marrow derived MSCs and their in vitro differentiation potential have been examined extensively, knowledge regarding the in vivo counterparts of MSC is still evolving. We hypothesized that MSC-like cells within STS could represent sarcoma initiating cells. Methods: To target rare human cell populations including MSCs, an exclusive antibody panel was developed. The target antigens include platelet-derived growth factor receptor-β (CD140b), HER-2/erbB2 (CD340), TNFRSF16 (CD217), frizzled-4 (CD344), the recently described W8B2 antigen, as well as several surface antigens identified by novel antibodies. To define the expression pattern of MSC-markers in STS, both cell lines and primary tumor samples in suspension and in snap frozen sections were investigated. To reveal functional differences between identified rare tumor populations single cell proliferation kinetics were investigated after FACS-sorting. Results: All cell lines und primary tumor samples revealed expression of selected markers. Antigens identifying subpopulations within all sarcoma samples investigated, were selected for functional studies. These included frizzled-4, TNFRSF16, W5C5 and W8B2. Liposarcoma (SW872), leiomyosarcoma (SK-LMS) and fibrosarcoma (HT1080) cell lines enclosed subpopulations with differential expression of above markers and by FACS based limiting dilution it was demonstrated that only fractions of viable cells contained proliferative capacity. Cells lacking expression of CD271 had lower proliferative capacity compared to mock sorted HT1080 or SK-LMS, while CD271+ SW872 had significantly higher proliferation. The antigen defined by W5C5 identified cells with high proliferative capacity compared to control in SW872 and SK-LMS and its lack in HT1080 identified a subpopulation with largely reduced proliferation. Conclusions: Subpopulations within STS cell lines and primary sarcoma tissue express novel MSC-markers and display increased proliferative capacity, potentially reflecting the existence of sarcoma initiating cells. No significant financial relationships to disclose.
Construction of a five-marker protein-based model for stage-independent assessment of prognosis in breast cancer
Authors: Giltnane J. M. , Rapp J. , Moeder C. , Camp R. L. , Kluger H. , Molinaro A. , Rimm D. 
Published: August 2020

11013 Background: While the TNM method for assessment of stage in breast cancer is simple and robust, molecular methods for limited patient subsets are gaining popularity (i.e Oncotype Dx or Mammaprint). We hypothesized that multiplexed quantitative measurement of proteins known to be involved in breast cancer signaling pathways of growth, proliferation, survival, and metastasis can enhance clinical methods of predicting prognosis in all patients. Methods: We assessed the expression of twenty-three proteins (ER, PR, EGFR, HER2, HER3, HER4, ERK, PTEN, PI3Kp85α, PI3Kp110α, p27/Kip1,EIF4E, FOXO3,AKT1, AKT2, AKT3, MYC, cyclinD1, FOXO1, mTOR, p70S6Kb, NFkB and BCL2) in four subcellular compartments by automated quantitative analysis of protein expression (AQUA) on tissue microarrays of the archival Yale breast cancer cohort (n=676). To project future performance of these markers including clinicopathological parameters, we constructed univariate and multivariate logistic regression models using leave-one-out cross-validation and calculated prediction error (PE) estimates of each model's value to predict a binary endpoint of 10 year survival. In addition, we constructed univariate and multivariate Cox models of ten year disease specific survival (DSS). Results: By Cox univariate analysis, ER, PR, PTEN, and BCL2 were directly correlated with DSS, while FOXO1, HER2, HER3, and PI3Kp110α were inversely correlated with DSS. A five-variable logistic regression model of 10 year survival including nuclear AKT1, BCL2, nuclear FOXO1, cytoplasmic mTOR, and nuclear p70S6Kb (prediction error= .274) surpasses performance of TNM staging (PE=.367) and the Nottingham Prognostic Index (PE=.326). The same model is associated with 10-year DSS by Cox proportional hazard (p=<.00001) independent of TNM stage and NPI. Conclusions: Our protein-based, multiplexed approach to prognostic classification was superior to traditional methods (TNM or NPI) and single biomarkers in this retrospective cohort. Current outcomes are influenced by modern therapies, limiting the direct impact of this analysis. However, molecular profiling of primary tumor linked to outcome paves the way for the incorporation of new prognostic models into prospective studies. [Table: see text]
Use of microarray analysis of differentially expressed genes in luminal B subtype of breast cancers to evaluate NHERF1 as a marker of endocrine resistance
Authors: Rody A. , Karn T. , Solbach C. , Ruckhaeberle E. , Hanker L. , Ahr A. , Gaetje R. , Holtrich U. , Kaufmann M. 
Published: August 2020

11015 Background: In vitro and in vivo data demonstrate that the expression of estrogen receptor (ER) in breast cancer is mainly associated with low proliferation. Gene expression profiling has recently been used to identify a group of high proliferating estrogen receptor positive breast cancers (the luminal B subtype), which are associated with a prognosis that is even worse than that of high proliferating estrogen receptor negative tumors. The analysis of those tumors might provide valuable information about breast cancer biology and could be helpful for adjuvant or neoadjuvant treatment decisions.Methods and Results: We analyzed microarray data from breast cancer specimens to gain insight into genes which play a role in estrogen receptor signalling. Genes were identified showing strong expression in high proliferating ER-positive tumors but no expression in either Ki67-/ER+ or Ki67+/ER- samples. Among these genes the Na+/H+ exchanger regulatory factor NHERF1 was found. We assessed the clinical relevance of NHERF1 transcript levels using a total of 2469 breast cancers. Analysis indicates that enhanced NHERF1 expression is associated with metastatic progression and poor prognosis of breast cancer patients. We found no correlation between NHERF1 and the nodal status as well as age, but positive correlations for tumor size (P<0.001), grade (P<0.001) and erbb2 (P=0.033). Weak NHERF1 expression correlated with longer disease free survival (DFS) in grade 1 and 2 tumors, but not in grade 3 breast cancers. Since NHERF1 expression is strongly linked to the presence of ER, the predictive value for endocrine treatment was analyzed. For samples with weak or none NHERF1 expression a treatment benefit was observed (P=0.007). While untreated patients display a 10 yr DFS rate of 67.2 ± 3.8%, endocrine treatment resulted in 80.1 ± 4.0%. In contrast no differences in disease free survival were found for corresponding NHERF1 expressing breast cancers. Conclusions: Our data indicate that expression of NHERF1 defines a state of differentiation, where breast cancer cells are refractory to endocrine treatment. No significant financial relationships to disclose.
Role of FOXC1 in regulation of basal-like/triple-negative breast cancer
Authors: Ray P. S. , Wang J. , Qu Y. , Shin-Sim M. , Shamonki J. , Liu B. , Hoon D. S. , Giuliano A. E. , Cui X. 
Published: August 2020

11016 Background: Class identification studies have proposed 3 prognostically relevant molecular subtypes of breast cancer: luminal, HER2 and basal-like. The latter is associated with poor prognosis but its molecular basis is not clear. We hypothesized a direct correlation between FOXC1 expression and basal-like breast cancer. Methods: Expression of FOXC1, CK5, CK14, EGFR, c-Kit, αB-crystallin, ITGB4 and FOXC2 in basal-like breast cancer was examined using publicly available microarray datasets. A molecular signature of 40 genes sharing co-ordinate up or down regulation with FOXC1 was identified on one microarray (49 patients) and validated on 5 other microarrays (1,232 patients). The clinical significance of FOXC1 gene expression and the FOXC1 gene signature was evaluated using censored survival data. FOXC1 protein expression was assessed by immunohistochemistry (IHC) of a 96-sample breast cancer tissue microarray. Normal breast epithelial, luminal and basal breast cancer cells transfected with FOXC1 vectors were evaluated for cell proliferation, migration and invasion. Results: FOXC1 was found to be consistently and exclusively upregulated in basal-like triple negative breast cancer and was associated with poor overall survival (p<0.0001). The FOXC1 gene signature accurately predicted the basal-like phenotype. IHC analysis of FOXC1 protein expression in human breast cancers confirmed its potential to be used as a clinical biomarker of basal-like breast cancer. Normal breast epithelial cells and luminal breast cancer cells with low or no FOXC1 expression underwent epithelial-to-mesenchymal transition and displayed increased cellular proliferation, migration, invasion, and expression of basal cell markers when FOXC1 was overexpressed. In contrast, knockdown of FOXC1 by shRNA in basal-like breast cancer cells conferred luminal phenotype. Breast cancer progression-linked signaling pathways like NF-κB and p38MAPK were significantly stimulated in basal-like breast cancer as well as by in vitro FOXC1 overexpression. Conclusions: FOXC1 is a dominant determinant of the basal-like phenotype of breast cancer. We propose FOXC1 to be the single best molecular marker of and a potential therapeutic target for basal-like / triple negative breast cancer. No significant financial relationships to disclose.
CYFRA 21–1 (CYFRA) as a prognostic and predictive marker in advanced non-small cell lung cancer (NSCLC): CALGB 150304
Authors: Rosenblatt P. Y. , Edelman M. J. , Christenson R. H. , Hodgson L. , Wang X. , Kratzke R. , Vokes E. 
Published: August 2020

11020 Background: Cytokeratin 19 and its soluble fragment CYFRA have been studied as markers that may correlate with response to therapy and survival in NSCLC. As part of CALGB 30203, a randomized trial of carboplatin/gemcitabine with eicosanoid modulators (celecoxib, zileuton or both) in advanced NSCLC (Edelman JCO 2008), serum CYFRA levels were obtained prior to and during treatment. The objective of this study was to evaluate the possible correlation of CYFRA as a predictive and prognostic marker and to confirm a previous finding that a 27% reduction in CYFRA after one cycle (21 days) of treatment correlated with a longer survival (Vollmer Clin Ca Res, 2003). Methods: Paired specimens were available from 88 patients. CYFRA was measured at baseline and after cycles 1 and 2 using an electrochemoluminescent assay (Roche Diagnostics) on the ElecSys 2010 system as previously described. Using logarithm of the initial concentration and logarithm of the difference in concentrations, we analyzed these in relation to overall survival (OS) and failure free survival (FFS). Results: 1. Lower baseline CYFRA levels were associated with both longer overall survival and failure free survival (p = <0.0001 and p=0.0045). 2. Larger reductions in CYFRA levels correlated to longer overall survival and failure-free survival (p=0.0254 and p=0.0298). 3.We failed to replicate that a drop of >27% in CYFRA levels had statistical significance in overall or failure free survival (p=0.6489 and p=0.9636). Conclusions: CYFRA and change in CYFRA appear to be reliable markers in predicting the response to chemotherapy for nonsmall cell lung cancer; however, a precise threshold to mark response has yet to be determined. No significant financial relationships to disclose.
Clinicopathologic features of EML4-ALK mutant lung cancer
Authors: Shaw A. T. , Costa D. , Mino-Kenudson M. , Digumarthy S. , Yeap B. Y. , Admane S. , Rodig S. , Chirieac L. , Iafrate A. J. , Lynch T. J. 
Published: August 2020

11021 Background: EML4-ALK is a novel fusion oncogene in non-small cell lung cancer (NSCLC). The fusion results from a small inversion within chromosome 2p, leading to expression of a constitutively activated, chimeric tyrosine kinase. The clinicopathologic features of these patients have not been definitively established. Furthermore, the clinical outcome of these patients is unknown. Here we present the largest series of EML4-ALK mutants to date, and the first analysis of treatment response and survival in metastatic patients with and without EML4-ALK. Methods: Patients with NSCLC were selected for genetic screening based on 2 or more of the following characteristics: female gender, Asian ethnicity, never or light smoking history, and adenocarcinoma histology. The EML4-ALK inversion was identified using FISH and confirmed by IHC for ALK expression. EGFR mutation status was determined by direct sequencing of EGFR exons 18–21. Results: Of 141 patients screened, 18 (13%) were ALK mutant, 31 (22%) were EGFR mutant, and 92 (65%) were wild-type (WT) for both ALK and EGFR. The majority of tumors were adenocarcinomas, with ALK but not EGFR mutant tumors strongly associated with the signet ring cell subtype. Compared to the EGFR mutant and WT cohorts, patients with ALK mutant tumors were significantly younger (median age 52.5 vs 64 yrs, p=0.003), and more likely to be male (61% vs 30%, p=0.015). ALK mutants, like EGFR mutants, were also more likely to be light/never smokers compared with WT patients (100% vs 43%, p<0.001). Among patients with metastatic disease, there was a significant association between EML4-ALK and resistance to EGFR TKIs, with no responses by RECIST in the ALK cohort. ALK mutants and WT patients showed similar response rates to platinum-based chemotherapy (60% vs 65%, p=1), and had similar 1-yr survival rates (81% vs. 66%, p=0.43). Conclusions: EML4-ALK defines a new molecular subset of NSCLC with distinct clinical and pathologic characteristics. The frequency of EML4-ALK is particularly high in light/never smokers without EGFR mutation. These patients do not benefit from EGFR TKIs and should be treated with other standard agents or ALK targeted therapies. [Table: see text]
Combination effects of gefitinib plus cisplatin in non-small cell lung cancer (NSCLC): Why have phase III trials failed?
Authors: Tsai C. , Chen T. , Chang K. , Hsiao S. 
Published: August 2020

11022 Background: Four phase III large scale randomized controlled trials combining standard chemotherapeutics and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced NSCLC have failed to show benefit. The mechanism for the failure is still yet not clear. Methods: Seventeen NSCLC cell lines were tested; two had induced P-glycoprotein (Pgp) over-expression. Three of the 4 EGFR mutants exhibited activating mutations. All lines were simultaneously treated with gefitinib plus cisplatin (GC). Selected 4 lines were tested with paclitaxel plus cisplatin (PC) or gefitinib (PG) and three-drug combination (PCG). The MTT assay with application of classical isobole method and statistical analysis was used and dose-log response curves (DRCs) were examined for evaluating the possible resistance mechanisms. Results: We found that combined GC regimen had significant antagonism at the IC50 level (13/15 lines; mean CI=1.184±0.037, P=0.001). The mean CI values of PCG were higher than or comparable with those of PC or PG in either EGFR wild type or mutant cells. DRC analysis mainly showed non-saturable passive resistance, suggesting that gefitinib 0.001–0.3 μM could interfere with cisplatin cell entry in a dose dependent fashion when cisplatin concentrations over 1–3μM, thus leaded to antagonism. Giving gefitinib 24 hours after administration of cisplatin could abolish the antagonism. Conclusions: In NSCLC cells, combination of GC showed antagonistic interaction likely because gefitinib interfered with cisplatin cell entry. Three-drug combination PCG was not better than two-drug combination PC or PG in either EGFR wild type or mutant cells. Clinically, simultaneously combined EGFR TKI with platinum in NSCLC should be avoided regardless of EGFR mutation status. [Table: see text]
Effects of G-CSF on circulating tumor cells (CTC) and CA 27.29 in breast cancer patients
Authors: Hepp P. , Rack B. , Schneider A. , Rezai M. , Tesch H. , Beck T. , Söling U. , Lichtenegger W. , Beckmann M. W. , Janni W. 
Published: August 2020

11027 Background: Some recent publications indicated that the use of G-CSF could be connected to an increase in CTC as well as elevated levels of tumor markers such as CA 27.29. In the SUCCESS Trial CTC and CA27.29 are examined before and after adjuvant chemotherapy (CHT) in 3754 breast cancer patients (pts). Methods: The SUCCESS Trial is a phase III trial comparing FEC-Docetaxel vs. FEC-Doc-Gemcitabine regime and 2 vs. 5 years of treatment with zoledronate in patients with primary breast cancer (BC) (N+ or high risk). Blood samples are taken before and after CHT. CTC were assessed with the CellSearchSystem (Veridex, Warren, USA). After immunomagnetic enrichment with an anti-Epcam-antibody, cells were labeled with anti-cytokeratin (8,18,19) and anti-CD45 antibodies to distinguish epithelial cells and leukocytes. CA27.29 has been measured with ST AIA-PACK Ca27.29 reagent using MUC-1 for AIA-600II (Tosoh Bioscience, Tessenderlo, Belgium). The cutoff for CA27.29 is 32 U/ml and >1 cell for the CTC analysis. Patients were grouped to CTC/CA27.29 raise or no raise and 1 to 6 cycles with G-CSF or no G-CSF at all. Results: Data on 1510 pts are available for CTC analysis. 745 pts (49%) received at least one course of G-CSF. 117 pts (8%) showed an increase in CTC after CHT. In this group 52 (3%) pts received G-CSF and 65 (4%) did not. 693 pts with stable or decreased CTC received G-CSF (46%) and 700 did not (46%). There was no significant difference (p=0.29). The analysis of CA27.29 is based on the data of 2556 pts. 1252 pts (49%) received at least one course of G-CSF. 338 pts (13%) exceeded the threshold for CA27.29 only after CHT. In this group 209 pts (8%) received G-CSF and 129 (5%) did not. 1043 pts with stable or decreased CA27.29 received G-CSF (41%) and 1175 did not (46%). This difference was highly significant (p<0.0001). Conclusions: No evidence can be provided for a significant correlation between an increase in the number of CTC and the application of G-CSF over CHT. Nevertheless the results on CA27.29 showed a highly significant correlation between the administration of G-CSF and elevated CA27.29 levels directly after CHT. This could be a possible explanation for the often observed increase of tumor markers after CHT. [Table: see text]