bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACRIN 6698 trial: Quantitative diffusion-weighted MRI to predict pathologic response in neoadjuvant chemotherapy treatment of breast cancer.
Authors: Partridge Savannah C. , Zhang Zheng , Newitt David C , Gibbs Jessica E , Chenevert Thomas L , Rosen Mark Alan , Bolan Patrick J , Marques Helga , Esserman Laura , Hylton Nola M ,   ACRIN 6698 Trial and I-SPY 2 TRIAL Investigators Group
Published: September 2018

11520 Background: Diffusion-weighted (DW) MRI is a non-contrast technique that can reflect treatment-induced alterations in tumor microstructure and cellularity. ACRIN 6698 was performed as a sub-study of the I-SPY 2 TRIAL to evaluate quantitative DW MRI for early assessment of breast cancer response to neoadjuvant chemotherapy (NAC) in a multisite, multiplatform trial. Methods: The IRB-approved trial was performed at ten institutions. Of 406 enrolled breast cancer patients, 272 were randomized to treatment (12 weekly cycles paclitaxel+/-experimental agent, followed by AC) and underwent breast DW MRI at four time points: pre-NAC (T1), early-NAC after 3 cycles paclitaxel (T2), mid-NAC between paclitaxel and AC (T3) and post-NAC (T4). Tumor apparent diffusion coefficient (ADC) was measured at each time point and compared for patients with and without complete pathologic response (pCR) by Wilcoxon signed rank test. Exploratory analyses were performed across subtypes defined by hormone receptor (HR) and HER2 expression. Performance for predicting pCR was assessed by calculating the area under the ROC curve (AUC). Results: Of 272 treated patients, 227 comprised the final cohort (14 were excluded for missing MRI exams, 31 for poor image quality). Median patient age was 48 (range, 25-77) years, and 71/227 (31.3%) achieved pCR. Subtype groups were HR+/HER2+ (n = 38), HR+/HER2- (n = 95), HR-/HER2+ (n = 20), and HR-/HER2- (n = 74). For the full cohort (all subtypes and treatments), both ADC and change in ADC from T1 were significantly predictive of pCR at T3 (AUC = 0.63, 95% CI 0.55-0.71; AUC = 0.62, 95% CI 0.53-0.70, respectively), and also at T4. ADC measures were not predictive of pCR at either T1or T2. Stratifying by subtype showed change in ADC at T3 was more predictive in HR-/HER2+ (AUC = 0.86) and HR+/HER2- (AUC = 0.75) tumors than HR-/HER2- and HR+/HER2+ tumors (AUC = 0.59 and 0.56, respectively). Conclusions: DW MRI reflects cytotoxic effects of chemotherapy, and mid-treatment ADC was a predictive marker of pCR. The predictive value of ADC varied across biologic subtypes. Further work is needed to determine the comparative predictive value of ADC to other imaging metrics. Clinical trial information: NCT01564368.
Prospective characterization of circulating tumor cells using a nanotechnology-based capture system in oligometastatic patients undergoing definitive radiation therapy.
Authors: Lindsay Daniel Paul , Caster Joseph Michael , Wang Kyle , Myung Ja Hye , Chen Ronald C. , Chera Bhishamjit S. , Gupta Gaorav P. , Jones Ellen , Tepper Joel E. , Varia Mahesh A. , Zagar Timothy , Hong Seungpyo , Wang Andrew 
Published: September 2018

11533 Background: Circulating tumor cells (CTCs) can provide prognostic information in select patients with advanced cancers. We have developed a sensitive and specific CTC capture system (Oncosensor) which may predict clinical outcomes in patients undergoing definitive radiation for head and neck cancers. There is increasing interest in utilizing potentially curative metastasis-directed therapy for patients with oligometastatic solid-tumor malignancies. There is currently no biomarker to predict the success of this approach in most patients. The purpose of this prospective study is to investigate the potential utility of CTCs as a predictive biomarker for patients with oligometastatic cancer undergoing potentially curative therapy. Methods: Eligible patients had a metastatic solid-tumor malignancy with 3 or fewer metastases. All sites of disease were treated with definitive radiation or surgery. Concurrent chemotherapy was allowed. Peripheral blood (7 ml) was collected prior to starting, first week, mid-point, end RT, and every 4 to 12 weeks post RT. CTCs were quantified using the Oncosensor platform. We then assessed correlations between CTCs (baseline, end treatment, and changes during treatment) and clinical outcomes using multivariate analysis. Results: Baseline CTCs were detected in 20/20 enrolled patients with a mean baseline of 32/ml which decreased to a mean of 14/ml at the end of treatment. There was no association between pretreatment CTCs and clinical outcomes (p = 0.81). There was a significant association between post-RT CTCs and PFS (p = 0.039, HR 1.07 per CTC). Our data also suggest that post-treatment CTC monitoring may be able to detect early disease recurrence. Among the 4 patients with documented clinical failures and post-treatment CTC monitoring, all 4 had increases in CTCs with or prior to clinical or radiographic disease progression, with 1.6 to 7.3 fold increase at the time of progression compared to the prior time point. Conclusions: Our pilot data suggest CTCs may provide a predictive biomarker for patients with oligometastatic disease and could potentially provide a novel marker of disease recurrence.
Association of early reduction in circulating tumor DNA (ctDNA) with improved progression-free survival (PFS) and overall survival (OS) of patients (pts) with urothelial bladder cancer (UBC) treated with durvalumab (D).
Authors: Kuziora Michael , Higgs Brandon W. , Brohawn Philip Z. , Raja Rajiv , Bais Carlos , Ranade Koustubh 
Published: September 2018

11538 Background: Mutation variant allele frequencies (VAFs) in ctDNA indicate the frequency of cancer clones harboring the specific variant in the primary lesion and metastases, thus providing a surrogate for tumor burden. We previously reported that early reduction in VAF in ctDNA was associated with improved survival on durvalumab in NSCLC subjects. Here we replicated this association in UBC pts treated with durvalumab. Methods: CP1108/NCT01693562 was a nonrandomized phase 1/2 trial evaluating D in pts with advanced UBC or other solid tumors. By 24OCT2016, 103 UBC pts received 10 mg/kg Q2W of D with median 8.4 mos follow up. A panel of 70 genes was assayed for DNA variants using the Guardant360 cancer panel in plasma ctDNA from 33 UBC pts pre-treatment and 29 pts pre and 6 wks on-treatment. The mean VAF pre or on treatment of patient single nucleotide variants (SNVs) and insertion/deletions was correlated with clinical outcomes. Objective response rate (ORR) was calculated according to RECIST v1.1 and a Cox proportional hazard ratio (HR) was calculated adjusting for baseline ECOG, sex, age, and smoking status. Results: Complete and partial responders (CR/PRs) showed a significant decrease (Δ = -2.4%, p = 0.02) in ctDNA mean VAF post-treatment with D (i.e. reduction in tumor burden) compared to an increase in mean VAF (i.e. increase in tumor burden) in progressive disease (PD) pts (Δ = +2.7%, p = 0.31). This correlation was also observed in total mutation count in CR/PR (Δ = -4.6, p = 0.003) compared to PD pts (Δ = +2.8, p = 0.44). Pts with a decrease in ctDNA VAF at week 6 had longer median PFS (9.3 mos, 95%CI = [3.0, not reached(NR)] and OS (median NR, 95% CI = [20.3,NR]) compared to those with an increase in VAF (median PFS = 1.4 mos, 95%CI = [1.3,NR];HR = 0.29; p = 0.05 and median OS = 8.2 mos, 95% CI = [2.3,NR]; HR = 0.12; adjusted p = 0.04). DCR was 85%/14% for pts with a decrease/increase in VAF (p = 0.002). Conclusions: CtDNA VAFs were reduced in responders but not non-responders after six wks of D. A decrease in VAFs 6 wks following treatment with D correlated with longer PFS and OS, suggesting utility as an early indicator of clinical benefit. Clinical trial information: NCT01693562.
Evaluation of liquid biopsies for molecular profiling in untreated patients with stage III/IV non-small cell lung cancer (NSCLC).
Authors: Besse Benjamin , Remon Jordi , Lacroix Ludovic , Mezquita Laura , Jovelet Cecile , Howarth Karen , Plagnol Vincent , Morris Clive D. , Pannet Chloe , Nicotra Claudio , Green Emma , Soria Jean-Charles 
Published: September 2018

11540 Background: Molecular profiling is limited by tumour heterogeneity and access to sufficient tissue for comprehensive analysis. Circulating tumour DNA (ctDNA) can be used as a minimally-invasive liquid biopsy for mutation detection, quantification and monitoring for personalised treatment strategies. Methods: We recruited 110 patients into a prospectively-designed study for Stage III/IV NSCLC patients intended to initiate 1stline platinum-based chemotherapy. Blood collections (10ml K2-EDTA) were performed prior to treatment and analysed by InVision (enhanced tagged-amplicon sequencing) using a 34-gene panel. Tissue biopsies, when available, were analysed by NGS (Ion-Torrent, Sanger) for concordance analysis. To evaluate correlation with outcome, repeat blood collections were performed in selected patients. Results: 110 NSCLC pts were included (61% male, 14% never-smoker, and 70% adenocarcinoma). ctDNA profiling detected mutations in 83 pts (79%). TP53 (44%), KRAS (17%), STK11 (18%; 11/19 with KRAS/STK11) and EGFR (10%) were the commonest abnormalities detected. Additionally, MET (6%), ERBB2 (6%), PIKC3A (6%) and BRAF (4%) mutations and EGFR, MET, ERBB2 amplifications were detected in 2% of patients, respectively. 20% of the mutations detected in ctDNA were observed at < 0.5% allele fraction, with 6% between 0.03%-0.25% AF. Tissue was available in 44 pts; somatic mutations were detected in 73%. Tissue & liquid concordance was 92.3%. 10 pts (23%) reported as tissue negative had a positive liquid biopsy. 33 advanced NSCLC patients were evaluated for longitudinal serial ctDNA monitoring up to cycle 4 of chemotherapy; the ratio of mutated molecules between D1 and D42 was significantly correlated with change in RECIST 1.1 measurement at D42 (p-value = 0.002625 CI 95% 0.298, 0.875). Conclusions: ctDNA can be used as a ‘liquid biopsy’ for molecular profiling of NSCLC patients to detect clinically relevant and actionable mutations when tissue biopsy is unavailable. Liquid biopsies can be used longitudinally and may provide an early surrogate for response evaluation by radiographic RECIST.
Predictive impact of PD-L1-expressing circulating tumor cells in NSCLC patients treated with nivolumab.
Authors: Shibaki Ryota , Koh Yasuhiro , Akamatsu Hiroaki , Kurita Kazuki , Yagi Satomi , Kanai Kuninobu , Hayata Atsushi , Tokudome Nahomi , Higuchi Masayuki , Kanbara Hisashige , Akamatsu Keiichiro , Ueda Hiroki , Nakanishi Masanori , Yamamoto Nobuyuki 
Published: September 2018

11541 Background: PD-L1 expression on tumor tissue is associated with response to PD-1 blockade in NSCLC. Here, we conducted a serial evaluation of PD-1-expressing circulating tumor cells (CTCs) as a potential real-time diagnostic modality in NSCLC patients treated with nivolumab. Methods: Advanced NSCLC patients after failure of at least one prior chemotherapy regimen received nivolumab monotherapy (3mg/kg, q2W) until progressive disease (PD) or unacceptable toxicity. Peripheral whole blood (3 mL) was collected for CTC evaluation at baseline and at week 4. CTCs were detected using microcavity array system (Hitachi Chemical Co., Ltd, Chikusei, Japan). PD-L1 expression was immunohistochemically examined on both tumor tissues and CTCs. This study was registered at UMIN (ID: 000024414). Results: Thirty patients were registered in the study between January 2016 and September 2016 at Wakayama Medical University Hospital and 29 were included in the analysis. Demographics of the patients were as follows: median age 70 (range, 49 to 86); male 73 %; stage IV, 100 %; squamous/non-squamous, 27/73 %. At baseline, CTCs were detected in all patients (median, 15; range, 1 to 90) and PD-L1-expressing CTCs were detected in 87% of patients. Tumor proportion score (TPS) of PD-L1 expression on CTCs ranged from 6% to 100%, indicating intrapatient heterogeneity. Matched tumor tissues were available from 14 patients and 7 showed the PD-L1 TPS ≥ 50%. No positive correlation was observed on PD-L1 expression between tumor tissues and CTCs based on TPS (R2 = 0.0035). Overall response rate was 25% (7/29), and disease control rate was 54% (15/29). Total CTC count was significantly decreased after nivolumab treatment at week 4 (p < 0.05), but no significant change was observed in PD-L1 TPS on CTC. Patients harboring CTCs with PD-L1 TPS 50% or more at baseline were significantly more likely to achieve non-PD than those harboring CTCs with TPS less than 50% (p < 0.05). Conclusions: This is the first report on a serial monitoring of PD-L1 expression on CTCs in patients treated with nivolumab. PD-L1-expressing CTCs are suggested to hold potential for predicting clinical benefit. Clinical trial information: 000024414.
Assessing tumor heterogeneity using circulating tumor DNA to predict and monitor therapeutic response in metastatic breast cancer.
Authors: Ma Fei , Guan Yanfang , Yi Zongbi , Chang Lianpeng , Xia Xuefeng , Li Qiao , Chen Shanshan , Yi Xin , Yang Ling , Xu Binghe 
Published: September 2018

11543 Background: Within metastatic breast cancer (mBC), tumor heterogeneity limited efficacy and duration of response to treatment. In this study, circulating tumor DNA (ctDNA) was used to evaluate tumor heterogeneity as a prognostic factor and monitor therapeutic response in patients with mBC. Methods: We collected plasma samples from 37 HER2-positive mBC patients treated with pyrotinib. Target-capture deep sequencing was performed to detect somatic mutations in plasma ctDNA. Clonal population structures were identified based on variations from ctDNA using Bayesian cluster with PyClone. Molecular tumor burden index (mTBI) was calculated with the mean variant allele frequency of mutations in trunk clonal population. Results: Mutations in TP53 and genes of PI3K/Akt/mTOR pathway were associated with drug resistance for pyrotinib. The result showed that patients with resistant mutations occurring as a truncal event, who receiving monotherapy of pyrotinib, presented worse therapeutic effect (HR, 4.52; P = 0.03). The median PFS of patients with versus without resistant mutations in trunk clonal population was 7.8 weeks (95% CI 7.4 to 26.8 weeks) versus 31.6 weeks (95% CI 15.7 to 60 weeks), respectively. Patients with high heterogeneity (clonal population ≥3) had a significantly worse PFS (HR, 2.79; 95% CI 1.23 to 6.34; P = 0.014). The median PFS among patients with high versus low heterogeneity was 30.0 weeks (95% CI 13.9 to 53.5 weeks) versus 60.0 weeks (95% CI 31.4 to 84 weeks), respectively. Longitudinal monitoring of 21 patients during treatment showed positive correlation between mTBI in ctDNA and tumor size evaluated by CT imaging (P < 0.0001). Monitoring the mTBI in serial ctDNA increased sensitivity for prediction of progressive disease in 6 of 21 patients, with a mean time of 12.7 weeks earlier than using CT scan. ROC curve analysis showed an area under the curve value was 0.97 (p < 0.0001). Conclusions: Assessing tumor heterogeneity in ctDNA provides genetic predictors of treatment outcome. Molecular tumor burden in ctDNA is a potential indicator of therapeutic response. These observations might be supplements for the current therapeutic response evaluation.
Analysis of T-cell repertoires in early-stage breast carcinomas to evaluate tumor immunogenicity.
Authors: Carrasco Javier , Schröder David , Galant Christine , Berliere Martine , Canon Jean-Luc Re , Machiels Jean-Pascal H. , Delrée Paul , Hilbert Pascale , Duhoux Francois P. , Bar Isabelle , Coulie Pierre 
Published: September 2018

11554 Background: Breast carcinomas (BC) are often considered to be weakly immunogenic and thus poorly sensitive to immunotherapy. Methods: We analyzed the repertoire of tumor-infiltrating T cells (TILs) in 41 early BC by sequencing their T cell receptor β genes (TCRβ). Libraries were built using a digital sequencing approach, barcoding each sequenced molecule to improve accuracy and quantification. T cell repertoires were also obtained from paired blood samples allowing identification of T cell clones enriched in the tumors as compared to blood. For 5 patients, CD8+ TILs were cloned ex-vivo from a tumor sample and screened for recognition of autologous predicted neoepitopes. Results: T cell infiltration differed from one tumor to another. Its amount varied of more than 30 fold and its diversity ranged from < 100 to > 5000 different clonotypes. In 34% of the tumors, there was an important T cell infiltration and we detected several clonotypes with a ≥500 fold enrichment as compared to blood. In 22% of the tumors, an important T cell infiltration was observed but without significantly enriched clonotypes. In 43% of the tumors the T cell infiltration was very limited. For 5 tumors with a high T cell infiltration, we screened ex-vivo isolated CD8+ T cell clones for recognition of predicted neoepitopes. In 4 of these tumors, with no enriched clonotypes, no recognition was observed. In 1 of these tumors, with enriched clonotypes, 6 different CD8+ T cell clones recognized 4 predicted neoepitopes. Three of these clones were > 100 fold more frequent in the tumor as compared to blood. Conclusions: About 30% of early BC were infiltrated by T cell clonotypes significantly enriched relative to blood. In one of these tumors some of the most enriched clonotypes recognized neoepitopes, demonstrating that some primary BC are spontaneously immunogenic. About 20% of the tumors had an important T cell infiltration without enriched clonotypes. None of the TIL clones isolated from 4 such tumors recognized predicted neoepitopes. Our results suggest that the detection of intratumorally enriched T cell clonotypes could identify immunogenic tumors, which may be sensitive to treatment with immunostimulatory antibodies.
Characterisation of CCS1477: A novel small molecule inhibitor of p300/CBP for the treatment of castration resistant prostate cancer.
Authors: Pegg Neil , Brooks Nigel , Worthington Jenny , Young Barbara , Prosser Amy , Lane Jordan , Taddei David , Brown Richard , Harbottle Gareth , Shannon Jonathan , Paoletta Silvia , Knudsen Karen E. 
Published: September 2018

11590 Background: Targeted degradation of androgen receptor (AR) and AR variants (ARV) remains an attractive therapeutic opportunity for patients with castrate resistant prostate cancer (CRPC). E1A binding protein (p300) and CREB binding protein (CBP) are two closely related transcriptional activators of AR. We have developed CCS1477 which is a potent, selective and orally active small molecule inhibitor of the bromodomain of p300/CBP and investigated its role in regulating androgen receptor expression and function. Methods: Binding of CCS1477 to p300, CBP and BRD4, was measured in a surface plasmon resonance (SPR) assay. Potency and functional activity (proliferation and biomarker knockdown) was demonstrated in prostate cell lines in vitro (22Rv1, VCaP). Cross species in vivo pharmacokinetic (PK) properties were assessed, and in vivo efficacy, linked to inhibition of biomarkers, was determined in 22Rv1 and LNCaP xenograft models. Results: CCS1477 binds to p300 and CBP with high affinity (Kd = 1.3/1.7nM) and selectivity (Kd = 222nM; BRD4). It is a potent inhibitor of cell proliferation in prostate cell lines (IC50 = 96nM,22Rv1; 49nM,VCaP) with minimal effect in AR-ve lines. In 22Rv1 cells, p300/CBP inhibition down-regulates AR-FL, AR-V7 and c-Myc protein by Western, an effect not seen with the BET inhibitor, JQ1 at equivalent proliferation IC50s. Inhibition of p300/CBP also reduces c-Myc, KLK3 and TMPRSS2 gene expression (qPCR) in 22Rv1 cells in vitro. The in vivo PK properties of CCS1477 are consistent with qd or qod oral dosing in mouse. CCS1477 dosed at 10mg, 20mg/kg qd or 30mg/kg qod, caused complete tumour growth inhibition over 28 days in a 22RV1 xenograft model, including extended duration in the absence of the drug for a further 24 days. This was accompanied by complete inhibition of plasma PSA and significant knockdown of tumour AR-FL, AR-V7, and C-Myc protein as well as C-Myc and TMPRSS2 mRNA expression. Conclusions: Taken together these data support the clinical testing of CCS1477 in castrate resistant prostate cancer by down-regulation of AR, AR-SV and c-MYC expression and function.
A novel prognostic signature based on centrosome amplification-based genes to predict clinical outcomes in breast tumors.
Authors: Ogden Angela , Rida Padmashree C.G. , Aneja Ritu 
Published: September 2018

11604 Background: A majority of breast tumors exhibit centrosome amplification (CA), which imparts aggressive phenotypes like chromosomal instability and invasive behavior. Nevertheless, it is unclear whether CA is associated with poor clinical outcomes after adjusting for potentially confounding factors, like stage and age at diagnosis. Methods: We developed a twenty-gene signature, “CA20,” composed of genes related to centrosome structure and/or whose dysregulation induces CA and tested its prognostic value compared with that of CIN25, a chromosomal instability (CIN) signature, in combined multivariable Cox models using the METABRIC and TCGA microarray breast datasets. The n = 1,969 primary breast cancers of the METABRIC dataset were split randomly and approximately equally into training and validation sets, unlike the n = 524 primary invasive breast cancers of the TCGA dataset, which could not be split to preserve power ≈ 0.80, so bootstrapping was instead used. CA20 and CIN25 were dichotomized by average scores and optimal cutpoints based on the log-rank test. Results: In both discovery and validation METRABRIC sets, CA20 was a significant independent predictor of worse breast cancer-specific survival (HR = 2.9, p < 0.001 and 2.4, p < 0.001, respectively, using average scores as cutpoints; similar results obtained using optimal cutpoints) in multivariable Cox models, unlike CIN25. CA20 score was highly correlated with CIN25 score (ρ = 0.93, p < 10-6). In the TCGA dataset, high CA20 score was associated with 3.8- and 3.7-fold worse overall survival (bootstrap-p = 0.001 and 0.002, respectively, for average and optimal cutpoints) after adjusting for tumor stage and age at diagnosis, unlike CIN25. Also in the TCGA dataset, CA20 correlated very strongly with CIN25 (ρ = 0.95, p < 10-6). Finally, using the TCGA dataset, we identified processes and pathways enriched in the CA20-high group (q < 0.05) that may be potential therapeutic targets, such as DNA repair processes, the DNA integrity checkpoint, and regulation of microtubule dynamics. Conclusions: CA20 is a novel signature with robust prognostic value in breast cancer and identifies patients who might respond to centrosome declustering drugs.