bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor markers of efficacy and resistance to cetuximab (C) treatment in metastatic colorectal cancer (mCRC): Results from CALGB 80203 (Alliance).
Authors: Hurwitz Herbert , Cushman Stephanie , Jiang Chen , Shterev Ivo , Mahoney Michelle R. , Niedzwiecki Donna , Mayer Robert J. , Venook Alan Paul , Owzar Kouros , Nixon Andrew B. ,   Alliance for Clinical Trials in Oncology
Published: March 2020

11011 Background: Beyond KRAS status, there are no validated markers for anti-EGFR therapy in mCRC. While expression of genes within the EGF signaling axis has been reported to correlate with benefit, most reports used data from non-randomized trials which cannot distinguish between general prognostic markers and markers that predict for benefit from C. CALGB 80203 was a 238-patient (pt), 4-arm, randomized phase II study of FOLFOX or FOLFIRI +/- C in mCRC pts. Formalin-fixed, paraffin-embedded (FFPE) tumor samples from CALGB 80203 were analyzed for gene expression of HER family ligands, receptors and regulators. Methods: FFPE tumor samples from consenting pts were analyzed for AREG, BTC, CD73, DUSP4, EGF, EGFR, EPGN, EREG, HB-EGF, HER2, HER3, HER4, PHLDA1 and TGFa by RT-qPCR. Interaction between baseline gene expression levels and treatment (C) with respect to progression-free survival (PFS) and overall survival (OS) was modeled using a multiplicative Cox proportional hazards model. Results: Baseline tumor tissue was available from 103 pts; 55% of tumors were KRAS wild type (WT). Two prognostic markers were identified; higher tumor mRNA levels of HER2 (HR=0.64, p=0.002) and EREG (HR=0.89, p=0.016) were associated with longer PFS across all pts. Potential predictive markers of benefit for C were identified. In KRAS WT tumors, lower HER3 expression was associated with longer OS from C treatment while higher HER3 expression was associated with shorter OS from C treatment (chemo + C: HR=1.15; chemo only: HR=0.48, interaction p=0.029). No association was observed for HER3 and outcome in KRAS mutant (MT) tumors. Interestingly, higher CD73 expression was associated with longer PFS in C-treated pts in both KRASWT (chemo + C: HR=0.91; chemo only: HR=1.57, interaction p=0.026) and MT tumors (chemo + C: HR=0.80; chemo only: HR=1.29, p=0.025). Conclusions: In one of the first reports using data from a randomized study, gene expression of HER3 and CD73 were identified as potential predictive markers for C. These data implicate not only HER axis signaling but also immune modulation as potential mechanisms of C action and sensitivity, and warrant confirmation in other large randomized trials.
Massively parallel sequencing (MPS) of circulating DNA in patients with metastatic colorectal cancer (mCRC): Prognostic significance and early changes during chemotherapy (CT).
Authors: Tie Jeanne , Kinde Isaac , Wong Hui-Li , McKendrick Joseph James , Gibbs Peter , Singh Madhu Sudan , Karapetis Christos Stelios , Desai Jayesh , Tran Ben , Roebert Justin Kelvin , Kinzler Kenneth W. , Vogelstein Bert 
Published: March 2020

11015 Background: Prognostic and predictive biomarkers in mCRC are urgently needed. Circulating tumor cells are a promising blood biomarker, but are detectable in only a minority of pts. Recently, analysis of circulating tumor DNA (ctDNA) has shown promise as a liquid biopsy, reflecting the evolving mutational status of the tumor. Here we explored baseline ctDNA as a prognostic marker, and early changes in ctDNA as a marker of CT response. Methods: Serial plasma samples and CEA were collected at baseline (D1), day 3 (D3) and cycle 2 day 1 (C2D1) from 40 mCRC pts receiving standard combination CT. Restaging scans performed at 8 weeks were centrally assessed using RECIST criteria. Samples were analyzed at Johns Hopkins Kimmel Cancer Center. Initially tumor tissue was analyzed for hotspot mutations in TP53, APC, KRAS, BRAF, PIK3CA and FBXW7. The same mutation was queried and quantified in plasma using a MPS platform (Safe-SeqS). Log-rank test was used to compare survival curves and Wilcoxon matched pairs test was used to compare paired plasma samples. Results: Preliminary data is available on 19 pts in this ongoing study. Using our initial panel at least 1 mutation was found in 16 of 19 (84.2%) tumors (7 KRAS, 3 TP53, 3 BRAF, 2 APC and 1 PIK3CA), with matching ctDNA found for each pt. For the remaining 3 cases a further panel of mutations is being analyzed. Median D1 cell free DNA (cfDNA) and ctDNA levels were 1.98 ng/ul (0.15 – 57.18) and 523 mutant fragments (frag)/ml (0.4 – 109,876), respectively. Pts with D1 cfDNA of ≥ 2.5 compared with < 2.5 had shorter median overall survival (OS; 6.9 v 12.2 months, p = 0.0086), with a trend for shorter progression-free survival (PFS; 3.6 v 8.2 months, p = 0.3477). A surge of ctDNA level from D1 to D3 was typically observed (median increase: 91.2 frag/ml, p = 0.0313), followed by a drop (median decrease from D1 to C2D1: 208.8 frag/ml, p = 0.0098). All pts with a decrease in ctDNA at C2D1 had a reduction in tumor size at 8 weeks. Conclusions: In all cases of mCRC where tumor mutation was identified, matching ctDNA was detected in plasma. Circulating DNA is a promising marker of prognosis. Early changes in DNA levels may be a useful marker of tumor response.
Study to explore the willingness of patients (pts) to undergo biopsy at the time of breast cancer (BC) recurrence.
Authors: Francl Mia Ivy , Sun Sophie , Villa Diego , Gelmon Karen A. , Lohrisch Caroline A. 
Published: March 2020

1102 Background: Physicians (MDs) may not request a biopsy (BX) when metastatic (M1) diagnosis is certain, however, there is increasing awareness of the value of tissue for cancer discovery. In addition, biomarkers can change from initial BC to M1 in 20%, affecting treatment. With ethics approval we investigated under what conditions BC pts would agree to a BX of recurrent cancer, to guide MD practice. Methods: Consenting English speaking pts with M1, or at least 3 months post adjuvant therapy, were asked to complete a survey (at home or with research assistant) about willingness to undergo BX at M1. Demographic and disease information was collected. The BX scenarios increased in inconvenience/discomfort and decreased in direct benefit to pt. Results: Among 204 participants, mean age was 60 (29-92), 71% were caucasian, 73% completed more than high school, 84% lived within 1 hour of the cancer centre. 87 (43%) pts had no relapse (M0) and 116 (57%) had M1 (including 20 [17%] with local relapse only, 21 [18%] de novo M1). 82 (71%) of M1 pts reported having had a BX for M1. When it required only image guidance and minimal discomfort (eg ultrasound guided liver BX), 86% of M1 pts would have a BX to join a trial and 81% would for pure research; 69% and 76% of M0 pts would have a BX to join a trial, or for research only, respectively. The Table shows the responses for the most invasive BX. Conclusions: Two thirds of BC pts would undergo the most invasive/inconvenient BX to join a trial, and half would for pure research. This demonstrates a large degree of altruism in this BC population. Willingness increased as direct benefit increased and the pain/inconvenience decreased. This data suggests MDs should not be hesitant to ask BC pts for a BX at M1. This study was limited to English speaking pts and most were well educated, thus it may not reflect all cultural attitudes toward BX. [Table: see text]
Nondisruptive mutations of TP53 and overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients (p).
Authors: Carcereny Costa Enric , Bertran-Alamillo Jordi , Molina-Vila Miguel Angel , Gervais Radj , Massuti Bartomeu , Bonanno Laura , Moran Teresa , Majem Margarita , Felip Enriqueta , Garcia-Campelo M. Rosario , Vergnenegre Alain , Viteri Ramirez Santiago , Gasco Amaya , Wannesson Luciano , Mayo-de las Casas Clara , Pujantell-Pastor Laia , Favaretto Adolfo G. , Karachaliou Niki , Rosell Rafael ,   Spanish Lung Cancer Group
Published: March 2020

11029 Background: The tumor suppressor TP53 is the most commonly mutated gene in lung cancer. Early-stage NSCLC p with TP53 mutations may have worse prognosis and be more radio/chemoresistant. However, few studies have addressed the issue of TP53 mutations in advanced NSCLC. We have retrospectively examined the influence of TP53 mutations on OS in 241 advanced NSCLC p. Methods: 99 EGFR-wild-type (wt), chemotherapy-treated p from 5 European hospitals and 142 EGFR-mutated (mut), erlotinib-treated p from two clinical studies were included. Exons 5, 6, 7 and 8 of TP53were analyzed by high resolution melting (HRM). All mutated samples were reconfirmed by sequencing. Mutations were classified as disruptive or non-disruptive based on their predicted effects on the function of the p53 protein. Results: TP53 mutations were detected in 31% of EGFR-wt and 24% of EGFR-mut p. OS results are available for 57 EGFR-wt p and 90 EGFR-mut p. Among EGFR-wt p, OS was 22 months (m) for p without TP53 mutations, 20m for p with disruptive TP53 mutations, and 9 m for p with non-disruptive TP53 mutations (P=0.09). Among EGFR-mut p, OS was 31 m for p without TP53 mutations, not reached for p with disruptive TP53 mutations, and 15 m for p with non-disruptive TP53 mutations (P=0.05). Complete OS results for all 241 p will be presented. Conclusions: Non-disruptive mutations in the TP53 gene are associated with shorter OS in advanced NSCLC p, both in EGFR-wt p treated with chemotherapy and in EGFR-mut p treated with erlotinib.These p could benefit from treatment to reactivate mutant p53.
Angiogenic marker associated with resistance to neoadjuvant chemoradiotherapy in rectal cancer.
Authors: Kim Hanjo , Lee Min Young , Ahn Tae Sung , Yun Jina , Kim Kyoungha , Kim Se Hyung , Kim Hyun Jung , Lee Sang Cheol , Bae Sang-Byung , Kim Chan Kyu , Lee Namsu , PARK Seong Kyu , Lee Kyu Taek , Won Jong-Ho , Hong Dae Sik , Park Hee Sook , Park Suk-Young , Lee Moon Soo , Baek Moo Jun 
Published: March 2020

11030 Background: The ability to achieve pathologic down staging after neoadjuvant chemoradiotherapy (CRT) is correlated with improved survival. However, there is no effective method of predicting which patients will response to neoadjuvant CRT. Neoadjuvant CRT can change the expression of angiogenic factors. However, little is known about its possible changes in response to preoperative CRT. We examined the expression of angiogenic factors in rectal cancer tissues before preoperative CRT and after surgery. Methods: Fifty five patients with locally advanced rectal cancer were studied. All patients were given preoperative CRT of 5040 cGy for 5-6 weeks with concurrent administration of 5-fluorouracil and leucovorin. Surgical resection was performed 6–8 weeks later in all patients. Immunohistochemical staining for angiogenenic markers (vascular endothelial growth factor [VEGF], placenta growth factor [PLGF], hypoxia inducible factor 1α [HIF 1α], stromal cell derived factor [SDF 1α]) were performed on specimens obtained before preoperative CRT and after surgery. A semiquantitative-immunohistochemical score established from the extension and intensity of the angiogenic factors was used for analysis. Results: The positive expression rate of VEGF, PLGF, SDF 1α, and HIF 1α was 56.4% (31/55), 65.5% (36/55), 70.9% (39/55), and 47.3% (26/55), respectively. The expression rate of VEGF, PLGF, SDF 1α, and HIF 1α was increased by 3.6% (2/55), 7.3% (4/55), 30.9% (17/55), and 1.8% (1/55) after neoadjuvant CRT, respectively. Expression of VEGF, PLGF, and HIF 1α protein was downregulated after neoadjuvant CRT in the rectal cancer tissues (P < 0.001, P = 0.001, P = 0.044, respectively). However, SDF 1α was upregulated after neoadjuvant CRT (P < 0.001). And also, upregulated expression of SDF 1α after neoadjuvant CRT was significantly associated with resistance to CRT (P = 0.035). However, SDF 1α showed no correlation with other clinical factors (age, sex, clinical stage). Conclusions: Expression of SDF-1α was increased in the rectal cancer tissue after neoadjuvant CRT, as well as has been associated with CRT resistance. Our data suggests that SDF 1α should be evaluated as new target for antiangiogenic therapy.
LAMC2 as a prognostic marker that promotes metastasis of lung adenocarcinoma through epithelial-mensenchymal transition (EMT).
Authors: Moon Yongwha , Park Kang-seo , Kim John , Sarfaraz Sami , Voeller Donna , Trung Pham , Wang Yisong , Giaccone Giuseppe 
Published: March 2020

11034 Background: Metastasis is the main cause of death in non-small cell lung cancer (NSCLC) patients. Genes responsible for NSCLC metastasis are unknown. LAMC2 is one of the 3 chains (α3, β3, γ2) of laminin 332, an important component of basement membranes, and LAMC2 involvement in metastasis is unclear. Methods: We have established a metastasis model in nude mice by repeated intracardiac injection of A549 lung adenocarcinoma cells. After 3-4 rounds of intracardiac injections, 100% metastasis penetrance was obtained. Microarray analysis was performed to identify genes differentially expressed between parental (A549P) and round-3 (A549R3) cells. In vitro migration/invasion and in vivo metastasis assays were performed in LAMC2-overexpressed A549P, LAMC2-knockdown A549R4, PC9, H358, and H322 cells. Public RNA microarray data of human NSCLC (GSE8894, GSE3141; n=249) and LAMC2 immunohistochemistry (IHC) of stage I NSCLC TMA samples (n=250) were analyzed to correlate LAMC2 and prognosis. Results: We identified LAMC2 as a putative metastasis marker of NSCLC through gene expression profiling of A549 cells enriched for metastasis in mice. Ectopic LAMC2 expression increased migration/invasion, whereas LAMC2 knockdown decreased migration/invasion in vitro. Conditioned media containing secreted LAMC2 promoted cell migration/invasion, which were blocked by LAMC2 knockdown or LAMC2 neutralizing antibody. Ectopic LAMC2 expression induced mesenchymal but decreased epithelial markers, indicating EMT, whereas LAMC2 knockdown elicited the opposite. A549R4 LAMC2 knockdown cells showed less metastatic activity than A549R4shRNA control cells in mice. In public microarray data high LAMC2 mRNA predicted high risk of recurrence (GSE8894, P=0.022; GSE3141, P=0.029) in adenocarcinoma (AC) but not squamous carcinoma (SC). Our IHC study showed that high LAMC2 predicted high risk of recurrence (hazard ratio =1.8; P=0.040) and death (hazard ratio=1.9; P=0.028) in AC but not SC by multivariate analysis. Conclusions: LAMC2 promotes metastasis through activation of EMT pathways, and is a potential prognostic marker and therapeutic target of metastasis in lung adenocarcinoma.
Fecal metabolome and microflora differences between colorectal cancer patients and healthy adults.
Authors: Weir Tiffany , Marschke Robert Frederick , Brown Regina J. , O'Malia Joanne , Dickson Erica , Bazan Marlon , Sheflin Amy , Heuberger Adam , Borresen Erica , Pettine Stefan , Ryan Elizabeth 
Published: March 2020

11050 Background: High throughput genomic technologies such as 454 pyrosequencing and metabolomics platforms are now available to explore the relationships between gastrointestinal microflora, metabolism and colorectal cancer (CRC). Recent efforts to characterize the colorectal cancer microbiome have led to the identification of numerous bacteria whose presence or absence is associated with diseased tissue. Methods: Stool samples were collected from 10 healthy adults and 11 colorectal cancer patients prior to surgery at the University of Colorado Health-Poudre Valley Hospital in Fort Collins, CO. Fecal samples were processed for isolation of microbial DNA and sequenced using the 454 pyrosequencing platform. Metabolites were extracted using acidified water for short chain fatty acids (SCFA) and 3:2:2 isopropanol:acetonitrile:water to obtain global metabolite profiles utilizing Gas Chromatography-Mass Spectrometry (GC-MS). Results: There were no significant differences in the overall microbial community structure associated with disease state, but several bacterial genera, particularly butyrate-producing species, were under-represented in the CRC samples, while a mucin-degrading species, Akkermansia muciniphila, was about 4-fold higher in CRC (p<0.01). Consequently, the chemoprotective SCFA, butyrate, was significantly lower in CRC samples than in those from healthy adults (p<0.0001) and GC-MS profiling revealed that there were higher levels of amino acids in stool samples from CRC patients and higher poly and monounsaturated fatty acids in stool from healthy adults (p<0.01). Conclusions: This systems biology approach may allow us to identify functional groups of gastrointestinal bacteria and their associated metabolites as novel therapeutic and chemopreventive targets. The Colorado Agricultural Experiment Station, Shipley Foundation and the NIH R03CA150070 supported this work.
Effect of BRM promoter variants on survival outcomes of stage III-IV non-small cell lung cancer (NSCLC) patients.
Authors: Cuffe Sinead , Cheng Lu , Azad Abul Kalam , Brhane Yonathan , Cheng Dangxiao , Chen Zhuo , Qiu Xin , Boyd Kevin , Emami Marjan , Leighl Natasha B. , Der Sandy , Xu Wei , Shepherd Frances A. , Tsao Ming Sound , Reisman David , Liu Geoffrey 
Published: March 2020

11057 Background: BRM, a key catalytic subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene in NSCLC. Loss of BRM expression occurs in 15% of NSCLC, and has been linked to adverse outcome. Recently, our group has shown that variants of two novel BRM promoter insertion polymorphisms (BRM-741, BRM-1321) lead to loss of BRM expression by recruiting histone deacetylases; individuals carrying homozygous variants for both polymorphisms have doubled NSCLC risk; pharmacological reversal of these epigenetic changes is a potentially viable therapeutic strategy. We thus evaluated the effect of BRM promoter variants on survival outcomes of advanced NSCLC patients, where initial clinical trials are likely to be focused. Methods: 564 stage III-IV NSCLC patients were genotyped for the BRM promoter variants using Taqman. Association of BRM variants and overall (OS) and progression-free survival (PFS) were assessed using Cox proportional hazard models adjusted for prognostic variables. Results: Among our patients, 73% were Caucasian, 52% male, median age 63yrs, 55% stage IV disease, and 67% adenocarcinoma. Median OS was 1.6yrs; median follow up, 3.6yrs. The frequency of homozygosity was BRM-741, 23%; BRM-1321, 21%; both, 12%. Homozygous variants of BRM-741 were strongly associated with worse OS (adjusted HR [aHR] 2.3 [p=2x10E-8]) and PFS (aHR 2.0 [p=2x10E-7]) compared to the wild types. Similar findings were observed for BRM-1321 homozygous variants (aHR for OS 1.8 [p=8x10E-5] and aHR for PFS 1.6 [p=2x10E-4]). Carrying homozygous variants of both BRM-741 and BRM-1321 was associated with substantially worse OS (aHR 2.3 [p=1x10E-5]) and PFS (aHR 2.2 [p=3x10E-6]), with similar associations seen among the stage III (aHR for OS 2.3 [p=6x10E-6]) and stage IV (aHR for OS 2.5 [p=5x10E-6]) patients. Conclusions: The same two homozygous BRM promoter variants that are associated with increased risk of NSCLC are also strongly associated with adverse OS and PFS in this cohort of stage III-IV NSCLC patients. Validation of results in a clinical trial dataset is underway, and will better elucidate the prognostic significance of these BRM promoter variants.
SPIO-enhanced MR imaging at 3T for the detection of metastases in sentinel nodes in patients with breast cancer.
Authors: Motomura Kazuyoshi , Takahashi Hiroyo , Nakayama Takahiro , Tamaki Yasuhiro , Nakanishi Katsuyuki 
Published: March 2020

1107 Background: We previously demonstrated the usefulness of SPIO-enhanced MR imaging at 1.5T for the detection of metastases in sentinel nodes localized by computed tomography lymphography (CT-LG) in patients with breast cancer (Ann Surg Oncol 2011, ASCO 2012). The aim of this study was to evaluate the accuracy of MR imaging at 3T with SPIO enhancement for the detection of metastases in sentinel nodes. Methods: This study included 60 patients with breast cancer and clinically negative nodes. Sentinel nodes identified by CT-LG were evaluated prospectively using SPIO-enhanced MR imaging at 3T. A node was considered non-metastatic if it showed a homogenous low signal intensity and metastatic if the entire node or a focal area did not show a low signal intensity on MR imaging. Sentinel nodes located by CT-LG were removed, and imaging results and histopathological findings were compared. Results: The mean patient age was 54.2 years (range, 33-78). Sentinel nodes were identified by CT-LG successfully in 59 (98.3%) of 60 patients. The mean number of sentinel nodes identified by CT-LG was 1.43 (range, 1-3). All 16 patients with positive sentinel nodes definitively diagnosed by pathology demonstrated metastases on SPIO-enhanced MR imaging. Five (31.3%) of them had micrometastases. Forty-one of 43 patients with negative sentinel nodes definitively diagnosed by pathology were non-metastatic on imaging studies. The sensitivity, specificity and accuracy of MR imaging for the diagnosis of sentinel node metastases were 100%, 95.3%, and 96.6%, respectively. No adverse events were associated with either CT or MR imaging. Conclusions: SPIO-enhanced MR imaging at 3T is useful for accurate diagnosis of sentinel node metastases, and therefore sentinel node biopsy may be avoided for most patients with breast cancer.
The predictive role of integrated BRCA1 and HERC2 mRNA expression in advanced non-small cell lung cancer (NSCLC) patients (p) treated with platinum-based first-line chemotherapy.
Authors: Bonanno Laura , Costa Carlota , Sanchez Jose Javier , Majem Margarita , Gimenez Capitan Ana , Rodriguez Ignacio , Vergnenegre Alain , Massuti Bartomeu , Favaretto Adolfo G. , Rugge Massimo , Pallares Cinta , Taron Miquel , Rosell Rafael 
Published: March 2020

11078 Background: The use of cis- or carboplatin is the backbone of first-line treatment for advanced NSCLC p, and currently no molecular markers of platinum sensitivity are used in routine clinical practice. Preclinical data and retrospective analyses have shown that high BRCA1 expression is associated with resistance to platinum. HERC2 is an E3 ubiquitin ligase promoting DNA repair by interacting with the E3 ubiquitin ligase RNF8 to facilitate the assembly of the RNF8-UBC13 complex, leading to the recruitment of BRCA1 and other DNA repair components responsible for double-strand break repair. Methods: We retrospectively analyzed 71 tumor samples from advanced NSCLC p treated with cis- or carboplatin plus gemcitabine or pemetrexed in the first-line setting. BRCA1 and HERC2 mRNA levels were determined by real-time PCR and categorized using medians as cut-off points. Results: Overall survival (OS) for all 71 p was 10.7 months (m), and progression free survival (PFS) was 7.2 m. Expression of both genes was successfully analyzed in 53 p (74. 6%). Neither gene as a single variable influenced outcome. However, the joint effect of BRCA1 and HERC2 was significant for predictive modeling. Among 30 p with low BRCA1 levels, OS was 15.3 m and PFS was 7.4 m in the 21 p with low HERC2 levels, compared to 7.4 m and 5.9 m, respectively, in the 9 p with high HERC2 levels (OS, P=0.008; PFS, P=0.01). The multivariate analyses identified the combination of low BRCA1 and low HERC2 expression as predictive of longer OS and PFS. In contrast, high levels of either gene were associated with an increased risk of death (HR=3.7, P=0.004) and of progression (HR=1.4, P=0.03). Conclusions: The integrated analysis of multiple DNA repair components can improve available predictive models in NSCLC. BRCA1 and HERC2 low expression levels can predict improved outcome to first-line platinum-based chemotherapy.