bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein tyrosine kinase 6 (PTK6, BRK) amplification in HER2+ breast cancer as a mechanism of HER2 resistance.
Authors: Grushko Tatyana A. , Gomez-Vega Maria J. , Prat Aleix , Mueller Jeffrey , Coyle Mariann , Perou Charles M. , Guindalini Rodrigo Santa Cruz , Obeid Elias , Irie Hanna , Olopade Olufunmilayo I. 
Published: March 2020

11021 Background: PTK6 gene on chromosome 20q13 encodes the intracellular non-receptor tyrosine kinase. Studies in vivo and in vitro revealed a role for PTK6 in cell proliferation and survival, particularly in HER2+ breast cancer cells suggesting that PTK6 may associate with the HER2 pathway and confer resistance to HER2-targeted therapy. PTK6 protein is frequently overexpressed in breast cancer, however, the mechanism(s) underlying PTK6 overexpression and its role in cancer remains unclear. To address this problem, we analyzed the frequency of PTK6 gene copy number variation (CNV) and expression in association with breast cancer subtypes. Methods: Retrospectiveparaffinsamples of invasive tumor and normal epithelium, and matching DCIS and metastases were mounted on TMA. PTK6 CNV was determined using PTK6:CEP20 FISH assay. Tumor subtypes were defined using the five-marker IHC classifier. The correlation between PTK6 CNV and mRNA expression and association of both with the intrinsic PAM50 tumor subtype were studied using TCGA database (547 cases) and publicly available seven breast cancer data sets (1005 cases). Data were normalized, gene median centered and standardized for the purpose of the study. Results: By FISH, 20% of 41 invasive tumors carried PTK6 CNV: amplification (10%) and gene polysomy (10%). The proportion of PTK6 amplified cases differed by subtype, with the largest proportion in HER2-enriched (17%) and LumB (14%). Strikingly, amplified invasive cases also showed amplification in matching DCIS and metastases. Analysis of the public datasets confirmed the frequent PTK6 amplification in breast cancer. Both low and high levels of amplification were detected with the largest proportion in HER2+ tumors (HER2-enriched and LumB; p=2.05e-26). None of the basal-like tumors showed high levels of PTK6 amplification. A high correlation between PTK6 gene copies and mRNA expression was observed (p=1.13e-08). Conclusions: PTK6 gene is amplified early in breast cancer progression, particularly in HER2+ tumors. Further studies on PTK6 biology may help clinicians to understand its potential role in HER2 resistance. Supported by BREAST CANCER SPORE, NCI K12CA139160 and CTSA-ITM CS UL1 RR024999.
Trefoil factor 1 as a predictive factor of bone metastases in breast cancer.
Authors: Mercatali Laura , Kang Yibin , Zanoni Michele , Liverani Chiara , Carretta Elisa , Ricci Marianna , Riva Nada , Calpona Sebastiano , Bongiovanni Alberto , Zoli Wainer , Amadori Dino , Ibrahim Toni 
Published: March 2020

11022 Background: Patients with breast cancer frequently develop bone metastases, which are responsible for high morbidity and reduced quality of life. The early identification of patients with a high probability of relapsing in this site could be used to select candidates for tailored therapy with bone-specific drugs such as bisphosphonates or RANK-L inhibitors. We aimed to identify a pattern of tissue markers in primary breast cancer that could predict bone metastatization. Methods: Expression of different markers was retrospectively analyzed in frozen breast cancer tissue samples from 90 patients comprising 30 cases with no evidence of disease (NEDP), 30 with bone metastases (BMP) and 30 with visceral metastases (VMP). Eight transcripts were analyzed by Quantitative Real time PCR: trefoil factor 1(TFF1), bone sialoprotein (IBSP), heparanase (HPSE), secreted protein acidic and rich in cysteine (SPARC), connective tissue growth factoe (CTGF), B2 microglobulin (B2M) and receptor activator of Nf-kB (RANK). Immunohistochemistry of TFF1 was performed on a part of the case series. Results: Marker expression analysis in the 3 different subgroups showed at least twofold higher median values of all markers in NEDP and VMP subgroups than in BMP. In particular, TFF1, B2M and CXCR4 levels showed statistically significant values. Median TFF1 value in BMP patients was 430.64 compared to 115.83 and 32.79 in VMP and NEDP, respectively (p=0.0043). Considering markers as dichotomous variables, TFF1 expression in BMP reached 59% compared to 21% and 23 % in NEDP and VMP, respectively (p=0.0022). Univariate analysis confirmed that TFF1 predicted the relapse and also the site of relapse. Immunohistochemistry data on TFF1 revealed that this protein was expressed only by cancer cells. Furthermore, the accuracy of the marker did not change at RNA or protein level, thus excluding a post transcriptional control of the RNA. Conclusions: In this preliminary study we identified a gene expression pattern in primary breast cancer that can identify patients destined to relapse to the bone. In particular, TFF1 would seem to be a suitable marker for bone metastatization and a possible target for the development of new drugs.
Genetic and molecular biomarker characterization of KRAS mutant non-small cell lung carcinoma (NSCLC) tumors.
Authors: Liu Li , Liu Yuan , Santiago-Walker Ademi , Shi Hong , Zhang Vivian , Hughes Ashley , Arenas-Elliott Carmen P. , Roadcap Lori , Martin Anne-Marie , Gilmer Tona M. 
Published: March 2020

11026 Background: Preclinical studies demonstrated Brahma related gene 1 (BRG1) mutations or loss of expression, and mutations of LKB1 may be associated with lack of sensitivity for MEK inhibitor trametinib in a subset of KRAS mutant NSCLC lines. This study aimed to evaluate the frequency of KRAS, LKB1 and BRG1 mutations in NSCLC tumors; and determine whether KRAS mutations in corresponding plasma samples could be detected by evaluating circulating cell-free DNA (cfDNA). Methods: Human NSCLC FFPE tumor tissue and matched plasma samples were procured from Indivumed GmbH. KRAS mutation status of 101 NSCLC tumors and matched plasma were determined by direct sequencing of genomic DNA (gDNA) from tissue and/or BEAMing on tissue gDNA or plasma cfDNA. Genetic mutations of LKB1 and BRG1 were determined by direct sequencing. Additional mutations were determined using the Ion Torrent AmpliSeq Cancer Panel. BRG1 protein expression was evaluated by IHC. Results: By direct sequencing and BEAMing we found 27/101 (28.4%) NSCLC tissue and/or plasma samples harbored KRAS mutations: G12V (37.0%), G12C (29.6%), G12D (18.5%), G12S, G13C, G13D and Q61H (3.7% each). The KRAS mutation status concordance (mutant or wild-type) between tumor gDNA and plasma cfDNA was 79-81%. Among the KRAS mutant tumors, LKB1 and BRG1 mutations were detected in 10/26 (38%) and 1/26 (3.8%) tumors respectively by direct sequencing. By IHC, loss of BRG1 expression was detected in 1/21 KRAS mutant tumors. The mutation frequency and variants for KRAS and LKB1 in patient samples were comparable with KRAS mutant NSCLC cell lines and COSMIC database. However the frequency of BRG1 mutation and protein loss were much lower in patient tumors. In a subset of 15 KRAS mutant tumors, Ion Torrent confirmed KRAS and LKB1 mutations and provided additional mutations found in TP53, FGFR2, FGFR3, GNAS, KDR, KIT and MET. Conclusions: This study demonstrates that KRAS mutant NSCLC tissues have high frequency of LKB1 mutations along with other mutations. It also supports the feasibility of detection of KRAS mutations in cfDNA from blood of NSCLC patients using BEAMing technology, providing an alternative to invasive biopsy.
Phase I study (A8471004) in Asian patients of PF-03446962, a fully human mab against ALK-1 receptor involved in tumor angiogenesis: Safety, pharmacokinetics (PK), and pharmacodynamics (PD).
Authors: Lee Kyung-Hun , Doi Toshihiko , Kim Tae Min , Ohtsu Atsushi , Kim Tae Yong , Ikeda Masafumi , Yoh Kiyotaka , Gallo-Stampino Corrado , Hirohashi Tomoko , Suzuki Akiyuki , Yosuke Fujii , Bang Yung-Jue 
Published: March 2020

11031 Background: Activin receptor like kinase 1 (ALK-1) is a member of the TGF-βRI family selectively expressed in proliferating endothelial cells, and plays an important role in regulating tumor initiation and metastasis. PF-03446962 is a fully human IgG2 mAb anti ALK-1 evaluated within two phase 1 studies in Western and Asian pts. Herein we report the preliminary safety, PK and PD data of the Phase I study. Methods: Primary objective is to identify the maximum tolerated dose (MTD) in Asian cancer pts; secondary objectives include the safety profile, PK, antitumor activity, and potential PD markers in blood and tumor samples. PF-03446962 is administered IV on Day 1, 29 and then q 2 weeks. Results: Study A8471004 consists of two parts: a 3+3 dose escalation (Part 1) and a dose expansion (Part 2) at 2 dose levels. In Part 1, 16 pts have been enrolled at 3 dose levels (4 pts at 4.5 mg/kg, 3 pts at 7.0 mg/kg, and 9 pts at 10 mg/kg). No DLTs occurred in Part 1 and 10 mg/kg was confirmed as MTD in the Asian population. The observed AUC0-28day for the 4.5, 7 and 10 mg/kg doses, were 12960, 22190 and 28030 μg·h/mL and Cmax were 97.1, 131.5 and 179.8 μg/mL, respectively. Drug exposure (mean Cmax and AUC) increased in a nearly dose proportional manner in Asians. In Part 2, expansion cohorts at doses of 7.0 mg/kg (10pts) and 10.0 mg/kg (8pts) of pts previously treated with VEGF inhibitors (VEGFi) have been enrolled, and the most common drug related adverse events observed (>10%) being thrombocytopenia, pyrexia, epistaxis, and telangiectasia (an anti-ALK-1 mediated toxicity) similarly in the 2 dose levels. Telangiectasia was observed in 1 CRC and 3 HCC patients. 4 patients who progressed after VEGFi treatment (RCC, sarcoma, 2 HCC patients) presented a SD lasting for 290, 248, 247 and 208 days, respectively, suggesting the ALK-1 could serve as mechanism of escape for VEGF. Conclusions: PF-03446962 is a first in class mAb targeting ALK-1. Treatment with PF-03446962 is well tolerated in the Asian pts and preliminary observation of clinical activity supports ALK-1 as a viable target. Update of study results and potential PD effects obtained on blood and tumor samples will be presented. Clinical trial information: NCT01337050.
Association of downregulation of toll-like receptor 3 (TLR3) expression with aggressive breast cancer (BC).
Authors: Obeid Elias , Nanda Rita , Li Terri , Zhang Bifeng , Mueller Jeffrey , Olopade Olufunmilayo I. 
Published: March 2020

11035 Background: Inflammation in the tumor microenvironment plays a key role in human breast cancer. We previously showed that a high proportion of alternatively-activated, tumor-associated macrophages (M2) are associated with increased microvessel density (MVD) and worse outcomes in BC. The anti-tumor effect of TLR3 is well recognized. To our knowledge, there are no studies evaluating TLR3 expression and characteristics of inflammation in primary breast tumors. Methods: 48 breast tumors were obtained from the University of Chicago Breast Cancer SPORE tissue bank under IRB approved protocols. Tissue microarrays were constructed and molecular subtypes assigned based on immunohistochemical (IHC) staining into: luminal A, luminal B, HER2-like, and basal-like. Macrophage density was determined using double staining with CD68/CD163. MVD was measured by IHC using anti-CD34. Staining quantification was done by a pathologist. To evaluate the association between M2 macrophages, TLR3 and MVD, Spearman's rho correlation coefficients were calculated. Survival comparison analysis was done using Wilcoxon statistic. Results: Of the tumors studied, 46% were LumA, 38% basal-like, 4% HER2-like, 2% LumB. We found a significant association between high MVD and high M2 content in tumors (p<0.000). Tumors with high MVD exhibited shorter survival (Wilcoxon statistic 4.845, p=0.028). Spearman’s rho nonparametric correlations showed low TLR3 expression correlated with higher MVD (p=0.014), advanced pathologic tumor stage (p=0.046) and a trend for nodal disease (p=0.069). There was no statistically significant association between TLR3 expression and number of M2 macrophages (p=0.21). Conclusions: Neovascularization is promoted by tumor-associated macrophages and in turn poorer prognosis in BC. Our results suggest that reduced TLR3 expression is associated with more aggressive breast cancer. Future studies are needed to elucidate a mechanism by which TLR3 is downregulated in highly angiogenic BC. Thus, activation of TLR3 with TLR3-ligands such as poly (A:U) can potentially be coupled with anti-angiogenic therapies in patients with BC exhibiting low TLR3 expression and high MVD to improve treatment outcomes.
Correlation of Src activation with response to dasatinib, capecitabine, oxaliplatin, and bevacizumab in advanced solid tumors.
Authors: Strickler John H. , McCall Shannon , Nixon Andrew B. , Pang Herbert , Rushing Christel , Arrowood Christy , Haley Sherri , Meadows Kellen , Hurwitz Herbert 
Published: March 2020

11036 Background: Src inhibition may augment sensitivity to chemotherapy, but in unselected patients (pts) with advanced solid tumors, src inhibitors have shown limited clinical activity. Biomarkers to predict benefit from src inhibitors in advanced solid tumors are not yet known. Methods: 22 pts (dose escalation cohort= 12 pts; colorectal cancer [CRC] expansion cohort= 10 pts) were enrolled in a phase I study to determine the safety and tolerability of the src inhibitor dasatinib with capecitabine, oxaliplatin, and bevacizumab (J Clin Oncol 29: 2011 [suppl; abstr 3586]). Src activation (src-a) was assessed in tumors from 16 evaluable pts. Src-a was measured by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded tumor samples using an antibody that selectively recognizes the active conformation of src (clone 28). A GI pathologist who was blinded to pt outcomes graded membranous src-a using a standard semi-quantitative method. The endpoint of this exploratory analysis was objective response rate ([ORR]= PR+CR). 2-sided Fisher’s Exact test was used to evaluate the association between ORR and src-a. Results: Across all tumor types, 8 tumors had no/faint src-a (IHC=0/1); 8 tumors had moderate/strong src-a (IHC≥2). Benign colonic epithelium had no src-a (IHC=0). The ORR was 75% (6/8) for pts with moderate/strong src-a versus (vs) 0% (0/8) for pts with no/faint src-a (p =0.007). In the CRC expansion cohort, the ORR was 83% (5/6) for patients with moderate/strong src-a vs 0% (0/2) for pts with no/faint src-a (p=0.107); progression free survival range was 7.9-24.4 months for pts with moderate/strong src-a. Conclusions: In this small phase I study, src-a is associated with benefit from the combination of dasatinib and oxaliplatin-based chemotherapy. Further evaluation of dasatinib in patients whose tumors demonstrate high levels of src-a may be warranted. Clinical trial information: NCT00920868.
NOTCH1 as a potential prognostic biomarker for anti-VEGF therapy in patients with metastatic colorectal cancer.
Authors: Paiva Tadeu Ferreira , da Costa Alexandre Andre Balieiro Anastacio , Pinto Flavio Augusto Ismael , Jesus Victor Hugo Fonseca , Marques Raul A. , Peresi Patricia , Macedo Mariana Petaccia , Chinen Ludmilla T. D. , Rossi Benedito Mauro , Begnami Maria D. , Lima Vladmir C. 
Published: March 2020

11038 Background: There are no validated biomarkers for clinical response or survival benefit in patients treated with bevacizumab (Bv) in advanced metastatic colorectal cancer (mCRC). The aim of this study was to evaluate the predictive value of putative biomarkers in mCRC. Methods: One hundred and five mCRC patients who received Bv combined with FOLFOX or FOLFIRI were retrospectively evaluated for clinical and pathological characteristics. VEGFR1, VEGFR2, VEGFR3, PlGF, DLL4 and NOTCH1 expression were assessed by immunohistochemistry on formalin-fixed, paraffin-embedded neoplastic tissue of either primary or metastatic tissue in a tissue microarray. High levels of expression were defined as less than or equal to or more than the median. Survival curves were calculated by the Kaplan-Meier method and compared by the log-rank test. For multivariate analysis the Cox proportional hazards model was used. Results: Grade 1 or 2 (p=0.01), non-mucin-producing histology (p=0.04) and presence of liver metastasis (p=0.001) were associated with a higher response rate. There was no difference between the expression of markers and the response rate. ECOG 0 or 1 (p=0.002), grade 1 or 2 (p=0.02), liver metastasis (p=0.003), no lymph node metastasis (p=0.01) no peritoneal metastasis (p=0.02) and resection of metastasis (p<0.001) were correlated with higher progression-free survival (PFS). There was also a strong correlation between ECOG 0 or 1 (p=0.001), grade 1 or 2 (p=0.006), no lymph node metastasis (p=0.004), liver metastasis (p<0.001) and resection of metastasis (p<0.0001) with better overall survival. There was a trend between high expression of NOTCH1 (p=0.06) and worst PFS.High expression of VEGFR2 (p=0.07) was slightly associated with a better overall survival, while high expression of NOTCH1 was associated with a worse overall survival (p=0.01). Using multivariate analysis, NOTCH1 proved to be an independent variable for adverse overall survival (HR 2.01, IC 1.07 – 3.77, p=0.02). Conclusions: High NOTCH1 expression assessed by immunohistochemistry is capable of predicting poor survival in advanced colorectal cancer patients treated with bevacizumab.
Evaluation of prevalence, number, and temporal changes of circulating tumor cells as assessed after 2 and 5 years of follow-up in patients with early breast cancer in the SUCCESS A study.
Authors: Bauer Emanuel C. A. , Neugebauer Julia Katharina , Andergassen Ulrich , Jaeger Bernadette , Jueckstock Julia Kathrin , Fasching Peter A. , Haeberle Lothar , Friedl Thomas W. P. , Schrader Iris , Lorenz Andreas , Tesch Hans , Rezai Mahdi , Thurner-Herrmanns Elisabeth , Schneeweiss Andreas , Beckmann Matthias W. , Pantel Klaus , Janni Wolfgang , Rack Brigitte Kathrin 
Published: March 2020

11042 Background: Recent studies revealed that temporal changes in circulating tumor cells (CTC) prevalence assessed before and immediately after adjuvant chemotherapy (CT) might indicate treatment response in early breast cancer (EBC). However, there is limited knowledge on CTC status one or more years after chemotherapy treatment. Here we present descriptive data on CTC status prospectively evaluated 2 and 5 years after primary diagnosis in the German SUCCESS A study. Methods: The SUCCESS A trial is a large, randomized, open-label, 2x2 factorial design Phase III study comparing disease free survival (DFS) in patients with EBC treated with 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide (FEC) followed by either 3 cycles of Docetaxel (D) or 3 cycles of Gemcitabine-Docetaxel (DG), and comparing DFS in patients treated with 2 years or 5 years of Zoledronate. CTC status at various time points was assessed using the FDA-approved CellSearch System (Veridex, USA). Results: Data on CTC status both at 2 years and at 5 years after primary diagnosis were available for 983 (26.2%) out of 3754 randomized patients. After 2 and 5 years, CTCs were found in 132 (13.4%; median 1; range 1 – 99) and 88 (9.0%; median 1; range 1 – 60) patients, respectively. The majority of patients (n = 779; 79.2%) had no CTCs at any of the two time points. CTCs were found at 2 years but not at 5 years after primary diagnosis in 116 (11.8%) patients, at 5 years but not at 2 years of follow-up in 72 (7.3%) patients, and both at 2 and at 5 years of follow-up in 16 (1.6%) patients. Conclusions: CTCs in peripheral blood were detected in a subset of early breast cancer patients without relapse up to five years after primary diagnosis. These CTCs may indicate the presence of occult “dormant” micrometastases.
Metabolic characterization of inflammatory breast cancer (IBC) with baseline FDG-PET/CT: Relationship with histopathology, hormone receptor status, and pathologic response after neoadjuvant chemotherapy.
Authors: Youn Trisha , Jacene Heather A. , Dipiro Pamela , Tanaka Yoko , Bellon Jennifer Ruth , Nakhlis Faina , Hirshfield-Bartek Judith , Yeh Eren , Overmoyer Beth 
Published: March 2020

1105 Background: Higher metabolic activity on FDG-PET is associated with triple negative (TN) hormone receptor status and invasive ductal histopathology in non-IBC breast cancer. Pts with IBC and a complete pathologic response (pCR) in mastectomy tissue after neoadjuvant chemotherapy (NAC) have a better prognosis compared to pts with residual disease. The objectives were to characterize IBC on baseline FDG-PET with respect to hormone receptor status, tumor grade and to determine if baseline metabolic activity in primary or metastatic lymph nodes (LN) predicts pCR. Methods: This is an IRB-approved retrospective study of 28 pts. SUVmax of primary IBC tumor and local LN metastases were compared between (b/w) pts with pCR versus residual disease, b/w pts with different receptor status (ER, PR, HER2), and b/w pts with different grade tumors (1-3). Results: Baseline SUVmax was higher in 6 pts with TN tumors (median 12.4, range 5.4-29.3) compared with 22 pts with ER+ or PR+ or HER2+ tumors (5.0, 2.0-16.3, p=0.04). SUVmax in local LN metastases tended to be higher in TN tumors vs. others (11.2, 2.7-27.9 vs. 5.4, 2.0-15.5, p=0.06). SUVmax in primary IBC was not different based on tumor grade (p=0.26), but higher SUVmax was seen in metastatic LN in pts with grade 3 vs. 2 tumors (10.5, 2.0-27.9 vs. 4.7, 2.0-10.2, p=0.02). SUVmax of primary IBC tumor was not significantly different b/w pts with pCR (median 10.6, range 2-29.3) vs. residual disease (6.4, 2.5-13.6, p=0.36). No significant difference was seen b/w baseline SUVmax of locally metastatic LN between pts with pCR (9.0, 3.3-27.9) vs. residual disease (6.1, 2.0-16.2, p=0.13). Conclusions: Baseline metabolic activity of primary IBC tumor and locally metastatic LN did not predict pCR at mastectomy. Triple-negative receptor status is associated with higher SUVmax in primary tumor and marginally in metastatic LN suggesting a more aggressive nature. These findings are consistent with data in non-IBC breast cancer.