bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying anti-EGFR (EGFRi) response subgroups using evidence of ctDNA selective pressure.
Authors: Parseghian Christine Megerdichian , Willis Jason , Morris Van K. , Raghav Kanwal Pratap Singh , Dasari Arvind , Raymond Victoria M. , Lanman Richard B. , Overman Michael J. , Kopetz Scott 
Published: May 2019

3587 Background: Metastatic colorectal cancers (mCRC) that respond to EGFRi display a robust circulating tumor DNA (ctDNA) signature that reflects selective pressure and clonal evolution. Conversely, non-responding tumors do not exhibit this signature. On this basis, we developed a novel method that defines EGFRi sensitivity with improved biological confidence with fewer patients (pts), and does not rely on clinical trial outcomes where responses may be confounded by concurrent chemotherapy. We used this method to further elucidate the association of several features that have been previously reported to be associated with EGFRi resistance, namely tumor sidedness, BRAF, PIK3CA, or ERBB2 ( HER2) MTs, and the absence of APC/ TP53MT. Methods: We analyzed 112 pts with baseline tissue based RASWT mCRC who had progressed following EGFRi, and with plasma samples available for ctDNA sequencing using a blood based NGS assay. Using our previously validated EGFRi exposure signature, we identified pts with evidence of selective pressure. Results: Post EGFRi ctDNA found 37% and 33% of pts with left sided and transverse tumors displayed evidence of selective pressure, respectively. 0 pts with right sided tumors displayed evidence of selective pressure; p= 0.01. Similarly, BRAFV600EMT displayed no evidence of selective pressure vs 30% of WT pts; in contrast, selective pressure was evident in pts with PIK3CAMT, ERBB2MT and pts with absence of APC/TP53MT (42% vs 28%, 67% vs 28%, 24% vs 43%, respectively for MT vs WT, p= NS for all). BRAF, PIK3CA, ERBB2, and APC/TP53 MT were present in 4/117, 12/108, 3/118 and 30/91 pts, respectively. ctDNA shedding was similar for all subgroups, as was time from previous EGFRi, indicating that these factors were not confounders. Conclusions: Consistent with prior large randomized studies, no pts with right sided tumors or BRAFMT had evidence of biologic benefit as assessed by presence of selective pressure. In contrast a number of pts with transverse tumors, ERBB2MT, PIK3CAMT or absence of APC/TP53MT had evidence of EGFR selective pressure, confirming that these are not absolute predictors of EGFR resistance and suggesting a subset of these pts were deriving benefit from EGFR inhibition. This biology based approach has the potential to more efficiently evaluate biomarkers of targeted therapy in the future without reliance on large randomized datasets.
Association of microRNA-21 with efficacy of cetuximab in RAS wild-type patients in the FIRE-3 study (AIO KRK-0306) and microRNA-21’s influence on gene expression in the EGFR signaling pathway.
Authors: Miller-Phillips Lisa , Heinemann Volker , Stahler Arndt , Fischer von Weikersthal Ludwig , Kaiser Florian , Al-Batran Salah-Eddin , Neureiter Daniel , Kahl Christoph , Kullmann Frank , Moehler Markus H. , Scheithauer Werner , Vazart Celine , Fontaine Karine , Held Swantje , Modest Dominik Paul , Neumann Jens , Jung Andreas , Kirchner Thomas , Stintzing Sebastian 
Published: May 2019

3593 Background: FIRE-3 compared first-line therapy with FOLFIRI plus cetuximab (cet) or bevacizumab (bev) in KRAS exon 2 wild-type (wt) patients with metastatic colorectal cancer. Recent analyses showed mircoRNA-21 (miR-21) expression level may be a predictive biomarker for anti-EGFR-therapy raising the question whether miR-21 influences gene expression in the EGFR signaling pathway. Methods: Reverse-transcription quantitative polymerase chain reaction assay identified quantitative miR-21 expression. Median expression was defined as a threshold value to discriminate FIRE-3 population into miR-21 low and high groups. Differential gene expression based on additional mRNA microarray data (Almac Inc, Xcel Array) was calculated by linear models adjusted for multiple testing followed by single sample gene set enrichment analysis (ssGSEA) to compare differentially enriched hallmarks of cancer gene sets. Overall response rate (ORR) was compared using Fisher´s exact test. Median progression-free (PFS) and overall survival (OS) were analyzed using Kaplan-Meier estimation and log-rank test. Results: 333 RAS wt patients provided material for miR-21 expression analysis. In these patients, low miR-21 expression was associated with higher ORR (80.0% vs. 57.9%; p = 0.005) and longer OS (35.8 months (mo) vs. 25.9 mo; p = 0.005) when cet vs bev was added to FOLFIRI. High miR-21 expression was associated with comparable ORR (74.6% vs. 64.0%; p = 0.21) and OS (24.5 mo vs. 23.8 mo; p = 0.4). There was no significant difference in PFS in either group. By comparing miR-21 low and high groups using normalized mRNA microarray data, 538 genes were found to be significantly differentially expressed in RAS wt patients after adjustment for multiple testing. Including data from the two groups into ssGSEA yielded 23 hallmark of cancer gene sets that were significantly differentially enriched; among them, KRAS-signaling showed higher enrichment in the miR-21 high group (adjusted p = 2.09 E-13). Conclusions: MiR-21 expression level might be a predictive biomarker for anti-EGFR-therapy by modulating KRAS signaling in FIRE-3 patients.
Prognostic stromal and immune response expression patterns in early-stage colorectal cancer predicted by genes intrinsically expressed by tumor epithelial cells.
Authors: Wirapati Pratyaksha , Qu Xueping , Huw Ling , Etlioglu Emre , Tejpar Sabine , Kabbarah Omar 
Published: May 2019

3601 Background: High stromal content (CMS4) and immune infiltration (CMS1) are important features of the tumor micro-environment (TME) in early stage colorectal cancer, with poor and good RFS prognosis, respectively. However, it remains unclear how these TME features are influenced by intrinsic tumor epithelial expression profiles. We examined how the former can be predicted by the latter, and assessed their respective prognostic contributions. Methods: Eighteen public gene-expression datasets (n=3511) were used for discovery, and an adjuvant trial dataset (PETACC3 n=688) was used for validation. Whole-transcriptome hierarchical clustering was applied to identify intrinsic versus extrinsic co-expression modules, corroborated by single-cell profiling data. The epithelial gene subset were used to predict previously assigned CMS labels, producing new CRC classifier that we refer to as epithelial-CMS (eCMS). Results: Despite lacking stromal and immune response genes, eCMS predicted CMS with an accuracy of 82% [CI 78-85%] in the test dataset. Not only were the RFS prognostic values retained (eCMS1 vs non-eCMS1: HR=0.59 [CI 0.35–0.95, p=0.029], and eCMS4 vs non-e-CMS4: HR=1.82 [CI 1.38–2.41, p=0.0003]), but they were also significantly improved when compared to the original CMS classification (CMS1 vs non-CMS1: HR=0.76 [CI 0.49–1.16, p=0.2] and CMS4 vs non-CMS4: HR=1.43 [CI 1.07–1.91, p=0.017]. In a multivariable regression comparison, eCMS was superior to CMS (p=0.001 vs p=0.36). Each eCMS group was associated with specific combinations of up- and down-regulation of CRC-relevant pathways, such as CDX2, map-kinase, mucin secretion, DNA damage repair and cell proliferation. Conclusions: Stromal and immune infiltration patterns in the TME are strongly associated with tumor epithelial expression profiles, as captured by eCMS. This finding sheds new light on the interplay between intrinsic molecular features of CRCs and their TME, and illuminates new paths for potential combination therapies.
A plasma-only integrated genomic and epigenomic circulating tumor DNA (ctDNA) assay to inform recurrence risk in colorectal cancer (CRC).
Authors: Parikh Aparna Raj , Van Seventer Emily E. , Boland Genevieve Marie , Hartwig Anna , Jaimovich Ariel , Raymond Victoria M. , Talasaz AmirAli , Corcoran Ryan Bruce 
Published: May 2019

3602 Background: ctDNA identifies patients (pts) at high risk for disease recurrence post CRC resection (post-op). Current ctDNA residual disease detection approaches assess only genomic alterations (alts) and rely on tissue sequencing to identify tumor-derived alts. We evaluated a plasma-only ctDNA assay to identify high risk pts. Methods: 72 CRC pts (surgery only = 42; adjuvant therapy (adj) = 30) had post-op and/or post-adj plasma samples (3-4mL). Extracted cfDNA (median 27 ng) was analyzed using a single-sample NGS test validated in early stage CRC that integrates assessment of genomic alts with epigenomic cancer signature (Guardant Health, CA). A variant classifier was applied to differentiate tumor-derived from non-tumor derived alts in a tumor tissue-uninformed approach. Results: In the surgery cohort, samples were collected a median of 31 days (d) post-op. 7/8 pts with post-op ctDNA detected (ctDNA+) recurred (PPV 88%; median time to recurrence (mTTR) 248d). The recurrence-free pt has < 180d follow-up. 7/34 pts without ctDNA detected (ctDNA-) recurred (NPV 79%; mTTR 333d). 1/1 Stage 0-II ctDNA+ pt recurred (PPV 100%; TTR 440d) while 1/20 ctDNA- recurred (NPV 95%; TTR 440d). 27 pts in the adj cohort had samples collected a median of 37d post-adj. 6/6 ctDNA+ pts recurred (PPV 100%, mTTR 239d). 4/21 ctDNA- pts recurred (NPV 81%, mTTR 466d). 2/2 ctDNA+ and 0/11 ctDNA- Stage III pts recurred (PPV, NPV 100%, mTTR 420d). All 3 post-op ctDNA+/post-adj ctDNA+ (ctDNA persistence) pts recurred. 1/2 post-op ctDNA+/post-adj ctDNA- (ctDNA clearance) pts is recurrence free (306d). 2 post-op ctDNA-/post-adj ctDNA+ pts recurred. In the entire cohort, ctDNA+ after standard therapy completion had a recurrence PPV 93%, NPV 80%, HR 11.29 (p < 0.0001). Conclusions: In post-op CRC, ctDNA detection utilizing a tumor-uninformed integrated genomic and epigenomic assay has high recurrence PPV and NPV following standard therapy completion. ctDNA identifies pts who may benefit from post-op adj therapy or additional/modified post-adj therapy. These findings demonstrate that ctDNA detection from a single post-op/post-adj plasma sample stratifies high/low risk pts and informs therapy decision making.
Voltage: Investigator-initiated clinical trial of nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable locally advanced rectal cancer.
Authors: Yoshino Takayuki , Bando Hideaki , Tsukada Yuichiro , Inamori Koji , Yuki Satoshi , Komatsu Yoshito , Homma Shigenori , Uemura Mamoru , Kato Takeshi , Kotani Daisuke , Fukuoka Shota , Sasaki Takeshi , Nishizawa Yuji , Nakamura Naoki , Wakabayashi Masashi , Kojima Motohiro , Togashi Yosuke , Sato Akihiro , Nishikawa Hiroyoshi , Ito Masaaki 
Published: May 2019

3606 Background: Chemoradiotherapy (CRT) with surgery (S) is standard for patients (pts) with locally-advanced rectal cancer (LARC), and nivolumab (nivo) is active in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). We studied nivo and radical S following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T3–4 NanyM0 LARC. Methods: Phase I included testing of a recommended phase II dosing schedule (RP2S). Efficacy and safety were studied in phase II pts and those given RP2S in phase I. In Cohort A-1, for microsatellite stable (MSS) LARC pts, the primary endpoint was centrally confirmed pathologic complete response (pCR) rate using AJCC tumor regression grading. The estimated required sample size assuming null and alternative hypotheses pCR = 10% and 30% was 37 pts, with a 1-sided alpha of 5% and power of 90%. Cohort A-2 was exploratory and included a maximum of 5 MSI-H pts. Results: Nivo 240 mg q2 weeks x 5 cycles, following CRT but pre-S, was the RP2S. From 1/17 to 6/18, 37 pts were enrolled in Cohort A-1. Eleven pts (30%; 90% CI 18-44%) showed pCR (AJCC grade (gr) 0). Including the 3 pts (8%) graded AJCC 1, 14 (38%) had major pathologic responses. In addition, clinical CR was observed in 1 pt (3%) refusing S after nivo. Both MSI-H LARC Cohort A-2 pts showed pCRs. Immune-related severe adverse events were observed in 2 pts (gr 3 myasthenia and gr 2 interstitial nephritis); both fully recovered and had S. No treatment-related deaths were observed. pCR rates of 60% (6/10) and 19% (5/27) (p = 0.038, Fisher exact test) were seen in pts with tumor cells with PD-L1 ≥1% and < 1% IHC staining, respectively, performed on biopsy samples taken pre-CRT. Rates of 62% (8/13) and 10% (1/10) (p = 0.029) were seen in 23 pts with samples analyzable by flow cytometry, according to CD8+ lymphocyte /regulatory T cell (CD8/Treg) ratios ≥2 and < 2, respectively. Conclusions: A promising pCR rate of 30%, with mild toxicity, was shown in MSS LARC pts treated with nivo plus radical S. PD-L1 expression and elevated CD8/Treg ratio may be better predictors of nivo benefit, warranting further study in a larger cohort. Clinical trial information: NCT02948348.
Effect of neoadjuvant treatment on locally advanced rectal mucinous adenocarcinoma or signet-ring cell carcinoma: A post-hoc analysis from 3 prospective studies.
Authors: Zhang Jianwei , Deng Yanhong , Cai Yue , Hu Huabin , Wu Zehua , Ling Jiayu 
Published: May 2019

3608 Background: Mucinous adenocarcinoma and signet-ring cell carcinoma were uncommon in locally advanced rectal cancer. And it has been reported that both mucinous adenocarcinoma and signet-ring cell carcinoma showed poor response to standard neoadjuvant chemoradiotherapy. Here, we tried to compare the efficacy of different neoadjuvant treatment regimen on locally advanced rectal mucinous adenocarcinoma or signet-ring cell carcinoma (M/S). Methods: We enrolled patients with locally advanced rectal cancer from 3 prospective clinical trials (NCT01211210, NCT02217020 and NCT02887313), including FOWARC study (N = 309), mFOLFOXIRI neoadjuvant chemotherapy trial (N = 103) and the total neoadjuvant treatment with FOLFOX and radiotherapy (N = 129). Among the 541 patients, 41 (7.6%) patients were M/S and 500 were non-M/S. Totally, 7 M/S patients and 84 non-M/S patients received 5FU concurrent with radiotherapy (Group A), 20 M/S patients and 208 non-M/S underwent FOLFOX concurrent with radiation or total neoadjuvant treatment (Group B), 11 M/S patients and 92 non-M/S patients underwent mFOLFOXIRI neoadjuvant chemotherapy alone (Group C). Other 3 M/S patients and 116 non-M/S patients received FOLFOX neoadjuvant chemotherapy alone (Group D). Results: Among M/S patients, only 4 (9.7%) achieved pathologic complete response (pCR), and 6 (14.6%) patients had tumor downstaging to ypstage 0-I. In group A, the pCR rate was 14.3% and 11.9% (p = 0.85), and the tumor downstaging rate was 14.3% and 36.9% (p = 0.22) in M/S and non-M/S patients, respectively. In group B, the pCR rate was 15.0% and 34.6% (p = 0.07), and the tumor downstaging rate was 25.0% and 60.1% (p = 0.002) in M/S and non-M/S patients, respectively. However, in group C and group D with chemotherapy alone as neoadjuvant treatment, no M/S patients showed pCR or tumor downstaging; while in non-M/S patients higher tumor downstaging rate was observed. Conclusions: M/S showed resistance to neoadjuvant chemotherapy along regimens. Even with chemoradiotherapy, M/S patients showed poorer response than that of non/M/S patients. Further study was warranted to explore the new regimen for M/S patients. [Table: see text]
Simultaneous versus staged resection for synchronous colorectal cancer liver metastases: A population-based cohort study.
Authors: Serrano Aybar Pablo Emilio , Bogach Jessica , Wang Julian , Parpia Sameer , Hallet Julie , Simunovic Marko 
Published: May 2019

3612 Background: Simultaneous resection of colorectal cancer primary and liver metastases is not performed routinely due to concerns about safety. We hypothesized that simultaneous resection has steadily increased overtime and that the outcomes are similar. Methods: Population-based cohort study of patients undergoing resection for synchronous (resection of the primary colorectal cancer and liver metastases within six months) liver metastases from 2006-2015 by linking administrative datasets in Ontario, Canada. Outcomes: post-operative complications, length of hospital stay, and overall survival. Survival for the staged group was measured from the last surgical resection to death and estimated using Kaplan Meier and compared with the log-rank test. Cox proportional hazard models were used to calculate risks for death. We aimed to identify practice patterns, outcomes of simultaneous vs. staged resections for these patients. Results: Of 2,738 patients undergoing colorectal and liver resection for colorectal cancer, 1,168 were synchronous, of which, 442 underwent simultaneous resection. Rate of synchronous disease presentation increased on average by 3% per year (p = 0.02). Median length of stay was shorter (8 vs. 11 days, p < 0.001); rate of major liver resections were lower (17% vs. 65%, p < 0.001), and 90-day post-operative mortality was higher (6% vs. 1%) for simultaneous resections. Major postoperative complications were higher in the simultaneous group (28% vs. 23%, p = 0.067), mostly due to a higher reoperation rate (6% vs. 3%, p = 0.034). Median overall survival was worse with simultaneous resection (40 months, 95%CI 35-46 vs. 78 months, 95%CI 59-86). Risks factors for worse survival were comorbidities, rurality, right-sided primary and simultaneous resection. There is selection bias that favours survival in the staged group, as patients must have survived the first operation and have stable disease in order to undergo the second operation. Conclusions: Simultaneous resection is associated with worse postoperative outcomes. Considering selection bias, randomized studies would be necessary to determine the role of simultaneous.
Pathway analysis of hypoxia-related factors in early colorectal cancer patients with poor prognosis.
Authors: Tan Yingxin , Rong Yuming , Yu Zhaoliang , Gao Feng , Chen Yufeng , Lin Xutao , Zou Yifeng , Chen Xi 
Published: May 2019

3613 Background: Colorectal cancer is one of the most common malignancies with a high mortality rate. Patients with stage I and stage II colorectal cancer have limited options for treatment. Hypoxia affects the activation and regulation of colorectal cancer cells and participates in its invasion and migration. However, there is lack of an accurate and non-invasive method for assessing tumor hypoxia. The aim of this study was developing and validating a hypoxia gene signature for predicting the outcome in stage I/II colorectal cancer patients. At the same time , we hypothesized that analysis of database of CIT microarray dataset could identify important biomarkers for stage I/II colorectal cancer patients. Methods: A total of 309 colorectal cancer patients of early stage with complete clinical information were enrolled for construction generation of hypoxia-related gene signature (HRGS) based on the CIT microarray dataset. 1877 colorectal cancer patients with complete prognostic information in 5 independent datasets were divided into a training cohort and two validation cohort (TCGA and meta-validation). Prognostic analysis was assessed in these cohort to evaluate the predictive value of HRGS. Results: A model of prognostic HRGS containing 14 hypoxia-related genes was developed. In training cohort and two validation cohorts, patients in hypoxia high-risk group satisfied by our HRGS had significant poor disease free survival compared with those in the in the low risk group (HR=4.35, 95% CI=2.30-8.23, P<0.001 in training cohort, HR=2.14, 95% CI=1.09-4.21, P=0.024 in TCGA cohort, HR=1.91, 95% CI=1.08-3.39, P=0.024 in meta-validation cohort). When compared with Oncotype DX, HRGS achieved an improved survival correlation in the training cohort (mean C-index, 0.80 vs 0.65, P<0.05) and the validation cohort (mean C-index, 0.70 vs 0.61 in the TCGA cohort, mean C-index, 0.68 vs 0.73 in the meta-validation cohort). Analysis of the data found that patients with low survival rates have significant relationships with genes regulated by the cell cycle pathway, such as mTROC1, E2F, G2-M, mitotic, oxidative phosphorylation, MYC, PI3K-AKT-mTOR (P<0.005). Conclusions: HRGS was a satisfactory prognostic prediction model for early stage colorectal patients. Hypoxia-related genes that regulate the cell cycle pathway were associated with prognosis in patients with stage I and stage II colorectal cancer. Further researches are needed to assess the clinical effectiveness of the system and the treatment options for biological targets.
ABC-06 | A randomised phase III, multi-centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy.
Authors: Lamarca Angela , Palmer Daniel H. , Wasan Harpreet Singh , Ross Paul J. , Ma Yuk Ting , Arora Arvind , Falk Stephen , Gillmore Roopinder , Wadsley Jonathan , Patel Kinnari , Anthoney Alan , Maraveyas Anthony , Waters Justin S. , Hobbs Claire , Barber Safia , Ryder David , Ramage John , Davies Linda M , Bridgewater John A. , Valle Juan W. ,   on behalf of the Advanced Biliary Cancer (ABC) Working Group
Published: May 2019

4003 Background: Level A evidence supports use of CisGem as first-line chemotherapy for ABC; no robust evidence is available for second-line chemotherapy. Methods: Pts diagnosed with ABC with disease progression after prior CisGem were randomised (1:1) to either ASC+mFOLFOX or ASC. Randomisation was stratified by serum albumin levels ( < 35 vs ≥35 g/L), platinum sensitivity (determined from first-line CisGem) and disease extent (locally advanced vs metastatic). Pts with ECOG PS0-1, adequate haematological, renal and liver function, and adequate biliary drainage were eligible. Primary end-point was overall survival (OS) (multivariable Cox regression adjusted for stratification factors); sample size: 162 pts delivering 148 events were required (80% power; 5% two-sided alpha) for a hypothesised hazard ratio (HR) of 0.63. Assumed median survival for ASC was 4 months. Results: 162 pts (81 in each arm) were randomised (27 March ‘14 - 04 Jan ‘18); median age 65 yrs (range 26-84); sex: 80 (49%) male, 82 (51%) female; primary site: intrahepatic 72 (44%), extrahepatic 45 (28%), gallbladder 34 (21%) and ampullary 11 (7%). Baseline characteristics were balanced between arms except platinum sensitivity (ASC+mFOLFOX 27 pts (33%); ASC 34 pts (42%)). After 150 OS events, the adjusted HR was 0.69 (95% CI 0.50-0.97; p = 0.031; ASC+mFOLFOX vs ASC). Median OS (months (m)), 6m and 12m OS-rate (%) were 6.2m, 50.6% and 25.9% for the ASC+mFOLFOX and 5.3m, 35.5%, 11.4% for the ASC arm, respectively. Grade 3/4 toxicities were reported in 48 (59%) and 32 (39%) pts in the ASC+mFOLFOX and ASC arm, respectively; these were balanced between arms except for fatigue and neutropenia (more frequent in ASC+mFOLFOX arm); data cleaning is ongoing. No chemotherapy-related deaths were reported. Conclusion: Survival with ASC was greater than assumed; ASC+mFOLFOX improved OS after progression to CisGem with a clinically meaningful increase in 6m and 12m OS rate. ASC+mFOLFOX should become standard of care in second-line for ABC. Clinical trial information: NCT01926236.