bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pilot trial of irinotecan, temozolomide and bevacizumab (ITB) for treatment of newly diagnosed patients with desmoplastic small round cell tumor (DSRCT).
Authors: Magnan Heather D. , Price Anita , Chou Alexander J. , Riedel Elyn , Wexler Leonard H. , Ambati Srikanth R. , Slotkin Emily Kanaya , Ulaner Gary , Modak Shakeel , La Quaglia Michael P. , Meyers Paul A. 
Published: September 2018

11050 Background: DSRCT is a rare tumor with a dismal prognosis in the setting of current treatment options. Preclinical data suggested that VEGF-dependent angiogenesis is important for DSRCT tumor biology and that targeting angiogenesis with bevacizumab in combination with irinotecan was more effective than treatment with irinotecan alone. This pilot study was designed to explore the safety and feasibility of adding ITB to the existing “P6- like” regimen used to treat DSRCT. Methods: Fifteen patients with newly diagnosed DSRCT were enrolled onto this single-institution study. They began treatment with 2 cycles of irinotecan (20 mg/m2/dose x 10 days) and temozolomide (100 mg/m2/dose x 5 days). Bevacizumab 10 mg/kg q2 weeks was added after sufficient time had passed from initial biopsy or surgery. Patients were then treated with cycles of alkylator based chemotherapy (3 cycles of cyclophosphamide, doxorubicin, vincristine and 3 cycles of ifosfamide, etoposide). An initial surgical resection was performed after cycle 5 and a second resection or second look surgery after cycle 8. Toxicity was graded according to CTCAE v.4.0. Secondary efficacy objectives were assessed using RECIST 1.1 criteria and the Kaplan Meir method. Results: 14 of 15 patients completed planned protocol therapy. One patient was taken off study due to complications associated with surgery after cycle 5 of chemotherapy. Stopping rules for unacceptable toxicity were not met. No patients experienced toxicity attributed to bevacizumab, and surgical morbidity was no greater than expected. Grade 3 diarrhea associated with irinotecan was experienced by 2 patients. Expected toxicities with “P6-like” cycles included grade 3/4 hematologic toxicity and admissions for febrile neutropenia in all patients. Response rate to the ITB cycles was 27% (95% CI 8-55%) and to the 5 pre-resection cycles was 73% (95% CI 45-92%). Median time to progression was 18.1 months. Overall survival at 1 year was 100% and 3 years 61% (95% CI 25-84%). Conclusions: The combination of ITB is active in patients with DSRCT, and it is feasible to combine these agents with standard chemotherapy without greater than expected toxicity. Clinical trial information: NCT01189643.
Genetic variations within the vitamin C transporter genes to predict outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI and bevacizumab: Data from FIRE-3 trial.
Authors: Berger Martin D. , Stintzing Sebastian , Yang Dongyun , Cao Shu , Miyamoto Yuji , Suenaga Mitsukuni , Soni Shivani , Gopez Roel , Melendez Elizabeth , Zhang Wu , Heinemann Volker , Lenz Heinz-Josef 
Published: September 2018

11507 Background: Vitamin C is involved in many critical metabolic processes. Beside its major role as an antioxidant and free radical scavenger vitamin C exerts a regulatory influence on angiogenesis. Additionally, epidemiologic studies show an association between vitamin C levels and incidence of cancer.We therefore hypothesize that variations in genes encoding for vitamin C transporter proteins may predict outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with FOLFIRI and bevacizumab (bev). Methods: Theimpact of 3 functional SNPs within the SVCT1, SVCT2 and Glut1 genes on outcome was evaluated in 292 pts with mCRC treated with first-line FOLFIRI/bev in the randomized phase III FIRE-3 trial. 294 pts receiving FOLFIRI and cetuximab (cet) (FIRE-3) served as a negative control. Genomic DNA was extracted from formalin fixed paraffin embedded tissue and SNPs were analyzed by PCR-based direct sequencing. Results: Baseline characteristics in the FOLFIRI/bev arm were as follows: female/male 99/193; median age = 65y andmedian PFS/OS = 10.1/24.2 months (mts). The SVCT1 rs11242462 SNP showed significant association with PFS. T allele carriers had a longer median PFS compared to those with a C/C genotype (10.7 vs 9.7 mts) in both univariate (HR 0.77, p = 0.046) and multivariate analysis (HR 0.73, p = 0.028). The effect on outcome was most significant among KRAS mutant pts. Here, T allele carriers showed a markedly prolonged PFS and OS compared to pts with a C/C genotype (12.5 vs 7.0 mts, HR 0.50, p = 0.018 and 32.8 vs 14.7 mts, HR 0.45, p = 0.009). These associations remained significant in multivariate analyses (p = 0.009 and p = 0.021, respectively). However, the favorable impact on outcome was not observed among T allele carriers treated with FOLFIRI/cet. Conclusions: Our results provide the first evidence that the SVCT1 polymorphism rs11242462 might serve as a predictive marker in pts with mCRC treated with FOLFIRI/bev in the first-line setting. Targeting vitamin C transporter proteins might be a promising approach to further improve treatment options against mCRC and to overcome resistance to anti-angiogenic therapy.
Evaluation of clinical outcomes by analysis of mutations in tumor tissue and circulating plasma DNA using next-generation sequencing (NGS) from STEAM, a prospective, randomized, multicenter study in metastatic colorectal cancer (mCRC).
Authors: Lee John J. , Palma John F. , Yao Lijing , Lovejoy Alexander F. , Yaung Stephanie , Zhang David , Wingate-Pearse Nasiema , Yau May , Williams Carolyn , Pimentel Monica , Munoz Abraham , Mayol Katrina , Mancao Christoph , Nicholas Alan , Sommer Nicolas , Bendell Johanna C. , Hurwitz Herbert , Rohr Ulrich Peter 
Published: September 2018

11510 Background: STEAM (NCT01765582) assessed the efficacy and safety of concurrent (c) and sequential (s) FOLFOXIRI-bevacizumab (BEV) vs FOLFOX-BEV for first-line treatment of mCRC. Methods: The AVENIO ctDNA Expanded Kit (Research Use Only) was used to assess somatic mutations in 77 cancer-related genes by NGS in tissue, and both pre- and post-induction plasma samples (n = 182, 150 and 118 respectively) from STEAM. Four mutation classes including single-nucleotide variants (SNVs), indels, copy number amplifications (CNAs) and fusions were identified. SNVs and indels were called in tissue and plasma at allele frequencies of 5% and 0.25% respectively. Results: Overall concordance of mutations in pre-induction plasma with tissue was 83%. Concordance for the seven most mutated genes ranged from 91.5%-100%. In pts with matched samples (n = 118), RAS WT pts showed significantly longer progression-free survival (PFS) in both cFOLFOXIRI-BEV (A) and sFOLFOXIRI-BEV (B) arms versus FOLFOX-BEV (C), using genotyping of either tissue or plasma. This was not seen in RAS MUT pts. In contrast, TP53 WT showed no significant treatment differences while TP53 MUT showed longer PFS for cFOLFOXIRI-BEV versus FOLFOX-BEV. A list of mutation frequencies for all samples, as well as hierarchical clustering analysis of tissue mutations will be presented. Conclusions: The AVENIO ctDNA Expanded Kit identified mutations in 77 cancer-related genes, in both plasma and tissue, with high overall concordance. Compared to FOLFOX-BEV, longer PFS was observed for c- or s- FOLFOXIRI-BEV in RAS WT pts and for cFOLFOXIRI-BEV in TP53 MUT pts, irrespective of sample type. These results are hypothesis generating and require further clinical validation. Clinical trial information: NCT01765582. [Table: see text]
Inter-tumor validation, through advanced MRI and circulating biomarkers, of plasma Tie2 as the vascular response biomarker for bevacizumab.
Authors: Jayson Gordon C. , Zhou Cong , Horsley Laura Hope , Marti Kalena , Shaw Danielle , Mescallado Nerissa , Clamp Andrew R. , Saunders Mark P. , Valle Juan W. , Backen Alison Catherine , Simpson Kathryn , Little Ross , Watson Yvonne , Cheung Susan , Roberts Caleb , Manoharan Prakash , Jackson Alan , O'Connor James , Parker Geoff J M , Dive Caroline 
Published: September 2018

11521 Background: VEGF inhibitor (VEGFi) use is compromised by lack of predictive/ response biomarkers. Previously, we identified plasma Tie2 (pTie2) as a vascular response biomarker (VRB) for bevacizumab (bev) in ovarian cancer (OC). Here, we applied dynamic contrast-enhanced MRI (DCE-MRI) and circulating biomarkers in colorectal cancer (CRC), to validate pTie2 as the first tumor VRB. Methods: Seventy patients were recruited, with untreated, mCRC and ≥1 lesion of 3-10cm diameter for DCE-MRI. Patients received bev 10mg/kg for 2 weeks to elicit a biomarker response and then FOLFOX6/bev until progressive disease (PD) Thirteen circulating and 6 imaging biomarkers were measured before and during treatment and at PD. Unsupervised correlation analysis identified bev-induced biomarker correlations. Biomarkers were evaluated by clustered parameter-time course studies to determine their epithelial or vascular origin. Clinical significance was determined by relating the biomarker data to tumor 3D volumetric change assessed by MRI and PFS. The emergent vascular biomarker signal was modelled with epithelial biomarkers to assess the independent contribution of the vascular compartment to PD. Results: Bev induced significant correlations between pTie2, Ang2 and Ktrans. Cluster analysis of Tie2 concentration-time course curves showed that pTie2 reflected tumor Ktransbut not CK18, an epithelial antigen, i.e. changes in pTie2 reflected tumor vascular biology Patients who had the greatest area under the pTie2-time curve had tumors with high Ktransand/or low pVEGFR2, pre-treatment. They also had the greatest reduction in tumor volume and longest PFS. Fusion of pTie2 and CK18 data significantly improved modelling of PD. Conclusions: Bev impacts tumor vasculature causing proportional changes in pTie2. Information from pTie2 adds clinical value to that derived from the epithelial compartment. Thus (i) pTie2 is the first vascular response biomarker for bev and probably all VEGFi and (ii) demonstration of separate vascular and epithelial compartments in ovarian and CRC validates the vascular compartment as a target. This work identifies the first assay that could optimise use of VEGFi. Clinical trial information: 2009-011377-33.
Early detection of competing resistance mutations using plasma next-generation sequencing (NGS) in patients (pts) with EGFR-mutant NSCLC treated with osimertinib.
Authors: Guibert Nicolas Marie , Paweletz Cloud , Hu Yuebi , Feeney Nora B. , Plagnol Vincent , Poole Valerie , Jones Greg , Oxnard Geoffrey R. 
Published: September 2018

11529 Background: In pts with EGFR+ NSCLC, genotyping of plasma cell-free DNA (cfDNA) has become a routine option for non-invasive detection of EGFRT790M. We hypothesized that serial NGS of cfDNA would allow early detection of co-existent resistance mutations during osimertinib treatment. Methods: Serial plasma samples were collected from pts with advanced EGFR+ NSCLC and T790M+ acquired resistance treated with osimertinib. Up to 4 specimens were analyzed, blinded to tumor genotype: baseline, initial 2 follow-ups, and progression. Plasma NGS was performed using enhanced tagged amplicon sequencing of hotspots and coding regions from 36 genes. Diagnostic accuracy was compared to tumor genotype (including NGS when available) and droplet digital PCR (ddPCR) of cfDNA. Results: 94 specimens from 26 pts underwent plasma NGS. Studying 26 baseline specimens, plasma NGS was more sensitive than ddPCR for known EGFR driver mutations (100% vs 88.5%). In 8 pts with pretreatment tumor NGS, 5 of 6 TP53 mutations were detected; one plasma positive/tissue negative result was seen across 36 genes, a PIK3CA mutation (0.6% AF) which was confirmed using ddPCR (99.6% specificity). Quantitative concordance of AF compared to ddPCR was high (R = 0.94). 21 pts had detectable EGFR driver mutations at resistance. Among 6 pts with maintained T790M, 4 acquired C797S and 2 of these additionally acquired low level KRAS mutations (G13D, Q61K). Among 15 pts with loss of T790M, 7 had competing non- EGFR alterations identified: MET amp, PIK3CA E545K, BRAF V600E (n = 2), HER2 amp, KRAS G12S, and FGFR1 amp. Resistance mutations detected at AF > 0.3% were confirmed with ddPCR. In 3 pts, a competing resistance mutation (1 KRAS, 2 BRAF) could be detected in plasma NGS pretreatment and reemerged as putative drivers at time of resistance. Conclusions: In this retrospective blinded validation, tagged amplicon-based plasma NGS was more sensitive than ddPCR with high specificity and quantitative concordance. In a subset of cases, serial plasma NGS can detect emergence of competing resistance mutations, creating an opportunity for the study of osimertinib-based targeted therapy combinations.
CCL5 expression and tumor infiltrating immune cells in triple negative breast cancer.
Authors: Araujo Jhajaira , Gomez Andrea C. , Salgado Roberto , Balko Justin M. , Aguilar Alfredo , Doimi Franco , Morante Zaida , Gomez Henry , Pinto Joseph A. 
Published: September 2018

11553 Background: CCL5 is a chemo-attractant of regulatory T cells, promoting tumor immune avoidance and related to a poor outcome in several malignancies; however, in triple negative breast cancer (TNBC), it is related to a better outcome. Our aim was to evaluate the correlation between CCL5 and tumor infiltrating immune cells and their prognosis value. Methods: We evaluated 72 TNBC patients with residual disease after neoadjuvant chemotherapy with matched data of tumor infiltrating lymphocytes (TILs) count and CCL5 expression (profiled with NanoString). CCL5 expression levels were log2 transformed and median centered. Correlation between TILs (log2 transformed) and CCL5 was evaluated with the Spearman’s rank test. Cox PH model was used to investigate the effect of CCL5 (median as cutoff) and TILs ( < 20% and ≥20%) in distant-recurrence free survival. We used the CIBERSORT platform to evaluate the immune cells composition according to the expression of CCL5 (higher vs. lower or equal than median) in 3 independent TNBC datasets (GSE25066, GSE58812 and GSE76124). Results: There was a significant correlation between TILs and residual tumor size (P = 0.017) and CCL5 (ρ = 0.347, P = 0.003). In univariate analysis, TILs (HR = 0.276, 95%IC: 0.128-0.593; P = 0.001) and CCL5 (HR = 0.401; 95%CI: 0.206-0.781; P = 0.007) were both associated with outcome. In a multivariate analysis with CCL5 expression and TILs count, TILs was the only significant marker with a P = 0.008 (HR = 0.336; 95%CI: 0.150-0.753), in contrast to CCL5 (HR = 0.573; 95%CI: 0.285-1.154; P = 0.124). CIBERSORT analysis suggested that high CCL5 expression is associated with recruitment of CD8 cells (13% v 6%, P < 0.001; 6% v 1%, P < 0.001 and 12% v 8%, P = 0.003), activated CD4 memory T cells (4% vs. 2%, P < 0.001; 5% vs. 0%, P < 0.001; 3% vs. 0%, P < 0.001) and Macrophages M1 (9% vs. 7%, P = 0.022; 13% vs. 8%, P = 0.005; 11% vs. 5%, P < 0.001) in GSE25066, GSE58812 and GSE76124 datasets, respectively. Conclusions: TILs was the stronger and more significant prognostic immunological marker, even than CCL5 expression. High CCL5 expression was associated with enrichment of CD8 cells, activated CD4 memory T cells and Macrophages M1. Role of these cells in TNBC should be explored more deeply.
Effect of chemoradiation for cervical cancer on transient decrease and variable expansion in T-cell infiltrate and diversity of T-cell repertoire.
Authors: Colbert Lauren Elizabeth , Dorta-Estremera Stephanie , Previs Rebecca A. , Eifel Patricia J. , Jhingran Anuja , Ramondetta Lois M. , Hahn Stephen M. , Welsh James William , Jazaeri Amir A. , Frumovitz Michael M. , Sastry Jagannadha , Klopp Ann 
Published: September 2018

11557 Background: The effect of fractionated radiation on intratumoral immune infiltrate is unclear. The purpose of this study was to characterize local immune changes and treatment response during chemoradiation (CRT). Methods: Cervical cancer patients underwent cisplatin based CRT over 5 weeks with brachytherapy. Cervical DNA swabs and cytology brushings were collected at baseline, one week, three weeks and five weeks. Deep T cell receptor β sequencing (TCR; Adaptive, Seattle WA) and multiparametric flow cytometry (MPFC) were performed for each time point. T cell density (TCD) and productive clonality (PC) were analyzed. Cells separated from the tumor brushings were stained and fixed with antibodies to T cell subsets with activation and suppressor markers including CD3, CD4, CD8, Ki67, PD-1, CTLA-4, and ICOS. Changes in T cell subsets were evaluated as percentage of live lymphocytes. Results: Eight patients were evaluated using MPFC. CD4 and CD8 percentages were lowest at one week and subsequently expanded. The percentage of proliferating CD4 (CD4+ Ki67+) was highest at week 5 (1.19%). There was no change in percentage of CD8+ cells expressing PD1, CTLA4 or ICOS over the course of treatment. TCR diversity was assessed for 9 patients. At baseline, week 1, week 3 and week 5, median TCD for all patients were 0.046 (IQR 0.008 to 0.097), 0.021 (IQR 0.005 to 0.043), 0.035 (IQR 0.015 to 0.083), and 0.033 (IQR 0.017 to 0.110). Median productive clonality at each point was 0.05 (IQR 0.06 to 0.02), 0.03 (IQR 0.06 to 0.02), 0.04 (IQR 0.05 to 0.02) and 0.03 (IQR 0.01 to 0.05). PC fold count increased (1.69, SD 1.3) for complete response (CR) patients and decreased 0.3 (SD 0.008) for patients with recurrent (REC) disease (p = 0.1). One TCR sequence was common in 4/9 patients at the end of treatment and six sequences were common in 3/9 patients. Conclusions: Chemoradiation induces a transient decline in tumor infiltrating CD8+ and CD4+ cells, followed by a variable expansion in T-cells at the end of treatment with an increase in proliferation phenotypes. TCR sequencing revealed increase in productive clonality during radiation for patients with a complete response to treatment.
The use of 18F-fluoroestradiol (FES) and 18F-fluorodeoxyglucose (FDG) PET in the evaluation of breast cancer heterogeneity.
Authors: Peterson Lanell M , Kurland Brenda F , Novakova Alena , Lee Jean H , Specht Jennifer M. , Muzi Mark , Romine Perrin , Wu Vicky , Mankoff David A. , Kinahan Paul , Linden Hannah M. 
Published: September 2018

11572 Background: 18F-Fluoroestradiol (FES) is an estrogen analogue that has been shown to be a promising biomarker in ER imaging of breast cancer. FES uptake correlates to ER expression, provides qualitative and quantitative assessment of multiple tumor sites simultaneously, and can predict response to endocrine therapies. Tumor heterogeneity is a known feature of metastatic breast cancer. Our work and others has shown that patients that have tumors with high FDG-PET SUV and low FES-PET SUV uptake have a poorer prognosis. Biopsies of metastatic disease may be done initially for diagnosis of metastatic disease, but are generally only performed in the setting of target identification for clinical trials. A change in ER or HER2 expression, however, can result in a change in therapy. FES-PET imaging offers a virtual biopsy and can reveal heterogeneity of the entire tumor burden. Methods: We reviewed our prior evaluations of tumor heterogeneity with FES-PET from 3 different studies. 46 breast cancer patients with metastatic disease (de novo or recurrent) who had biopsy proven ER+ primary breast cancer underwent FES-PET and FDG-PET imaging and a biopsy of a metastatic lesion prior to therapy initiation. ER and HER-2 expression was reviewed. Results: Of the 46 patients, 5 (11%) had ER- metastatic biopsies. One (2%) biopsy changed from ER+/HER-2 neg to ER-/HER-2+, and one (2%) biopsy changed from ER+/HER-2+ to ER+/HER-2-. All 5 patients (11%) with changes in ER/HER2 expression underwent a change in therapy due to the unexpected findings by metastatic biopsy. FDG findings helped to guide selection of biopsy sites. FES quantitative measures correlated with biopsy findings. Conclusions: Biopsy resulted in a change in therapy for > 10 % of patients enrolled in trials of FES imaging. Imaging can help identify heterogeneous tumor locations to assist identification of evolving tumor targets in breast cancer. In addition, FES imaging may reveal a change in tumor phenotype that can ultimately affect choice of therapy. Research Support: P01CA42045, R01CA72064
Persistence of AKT1 low quiescent cancer cells after neoadjuvant chemotherapy in triple negative breast cancer patients.
Authors: Kabraji Sheheryar Kairas , Sole Xavier , Huang Ying , Bango Clyde , Bowden Michaela , Bardia Aditya , Sgroi Dennis , Loda Massimo , Ramaswamy Sridhar 
Published: September 2018

11579 Background: The mechanisms that allow triple negative breast cancer (TNBC) tumors to survive neoadjuvant chemotherapy (NACT) are incompletely understood. Evidence suggests that proliferative heterogeneity may contribute to primary chemotherapy resistance in patients with localized triple negative breast cancer. However, the detailed characterization of a drug-resistant cancer cell state in residual TNBC tissue after NACT has remained elusive. AKT1lowquiescent cancer cells (QCCs) are a quiescent, epigenetically plastic, and chemotherapy resistant subpopulation initially identified in experimental cancer models. Here, we asked whether AKT1low QCCs actually exist in primary tumors from patients with TNBC and persist after treatment with NACT. Methods: We identified QCCs in primary and metastatic human breast tumors using automated, quantitative, immunofluorescence microscopy coupled with computational and statistical analysis. We obtained pre-treatment biopsy, post-treatment mastectomy, and metastatic specimens from a retrospective cohort of TNBC patients treated with neoadjuvant chemotherapy at Massachusetts General Hospital (n = 25). Using automated quantitative immunofluorescence microscopy, QCCs were identified as AKTlow / H3K9me2low / HES1high cancer cells using prespecified immunofluorescence intensity thresholds. QCCs were represented as 2D and 3D digital tumor maps and QCC percentage (QCC-P) and QCC cluster index (QCC-CI) were determined for each sample. Results: We found that QCCs exist as non-random and heterogeneously distributed clusters within primary tumors. In addition, these QCC clusters are enriched after treatment with multi-agent, multi-cycle, neoadjuvant chemotherapy in both residual primary tumors as well as nodal and distant metastases in patients with triple negative breast cancer. Conclusions: Together, these data qualify QCCs as a non-genetic mechanism of chemotherapy resistance in triple negative breast cancer patients that warrants further study.