bluuebunny/crossref_metadata_2025_split huggingface dataset:
A tumor immune microenvironment-related lncRNA signature for the prognosis and immunotherapeutic sensitivity prediction in colorectal cancer.
Authors: Hu Chuling , Cai Du , Zhong Min-Er , Fan Dejun , Li Cheng-Hang , Lv Min-Yi , Huang Ze-Ping , Wang Wei , Wu Xiaojian , Gao Feng 
Published: June 2022

3543 Background: As important molecules in the CRC tumor microenvironment (TME), long non-coding RNAs (lncRNAs) regulate the functions of tumor infiltrating immune cells and sculpt the tumor immune microenvironment (TIME), resulting in difference in survival and response to immunotherapy among CRC patients. However, challenges remain in selecting TIME related lncRNAs (TIME-lncRNAs) of prognosis value and stratifying CRC patients for immunotherapy. Here, the aim of our study was to develop a CRC TIME-lncRNAs signature to provide survival and immunotherapy response predictions. Methods: Gene expression profiles and clinical information of CRC cases (n = 1807) were collected from 7 datasets and divided into training cohort (n = 519) and two testing cohorts (n = 595 and 693, respectively). Utilizing gene expression data of 97 immune cell lines and 61 CRC cell lines, differential expression analysis was used to identify TIME-lncRNAs. Univariate Cox regression and LASSO regression analysis were used to establish a TIME-lncRNAs signature to predict the prognosis of CRC patients. To further investigate the model, multivariate Cox regression, lncRNA-mRNA regulation analysis, gene enrichment analysis and immune infiltration analysis were carried out. The immunotherapy response predicting ability of the model was verified with an independent immunotherapy dataset. Results: Integrating the expression profiles of 10 TIME-lncRNAs, the model stratified CRC patients into low and high-score groups. Patients of the low score group had significantly prolonged survival in both training (hazard ratio (HR) = 2.63, 95% confidence interval (CI) = 1.9-3.63, P < 0.001) and testing cohorts (testing cohort 1: HR = 1.6, 95% CI = 1.19-2.16, P = 0.002; testing cohort 2: HR = 1.64, 95% CI = 1.19-2.26, P = 0.002), while higher tumor purity and less pro-tumor immune cells infiltration were also observed in the low score group. Further investigation showed that both genes differentially expressed between different groups and mRNAs regulated by 10 lncRNAs of the signature were enriched in immune-related and immunotherapy-related pathways. Multivariate Cox regression indicated that the TIME-lncRNAs signature was an independent prognosis factor. Validated with external immunotherapy dataset, the signature provided distinct predictions for patients’ responses to PD-L1 inhibitor therapy, suggesting cases of high score group could benefit more from immunotherapy. Conclusions: Based on the expression of 10 lncRNAs in the TIME, the signature makes predictions for patients’ survival and immunotherapy responses, which could help in stratifying CRC patients for immunotherapy at the bedside.
Pembrolizumab (pembro) plus binimetinib (bini) with or without chemotherapy (chemo) for metastatic colorectal cancer (mCRC): Results from KEYNOTE-651 cohorts A, C, and E.
Authors: Chen Eric Xueyu , Kavan Petr , Tehfe Mustapha , Kortmansky Jeremy S. , Sawyer Michael B. , Chiorean E. Gabriela , Lieu Christopher Hanyoung , Polite Blase N. , Wong Lucas , Fakih Marwan , Spencer Kristen Renee , Chaves Jorge , Li Chenxiang , Carpenter David , Leconte Pierre , Kim Richard D. 
Published: June 2022

3573 Background: Response to antiPD-1 monotherapy is poor in microsatellite stable (MSS)/mismatch-repair proficient (pMMR) mCRC; the combination of antiPD-1 pembro + anti-MEK bini, with or without chemo, may improve upon this limited response. KEYNOTE-651 (NCT03374254) is an open-label phase 1b multicenter trial of pembro + bini (cohort A) or pembro + bini + chemo (mFOLFOX7 in cohort C, FOLFIRI in cohort E) in MSS/pMMR mCRC. Preliminary results from the dose-finding phase at 2 dose levels (DL) of bini are presented. Methods: Patients (pts) had MSS/pMMR mCRC and must have been previously treated with fluoropyrimidine, irinotecan, and oxaliplatin in cohort A, or with fluoropyrimidine + oxaliplatin-based regimen in cohort E; pts were previously untreated in cohort C. Pts received pembro 200 mg Q3W + bini 30 mg BID (cohort A, DL1), pembro 200 mg Q3W+ bini 30 mg BID + mFOLFOX7 Q2W (cohort C, DL1) or pembro 200 mg Q3W + bini 30 mg BID + FOLFIRI Q2W (cohort E, DL1). Bini dose escalation to 45 mg BID (DL2) was planned in cohorts A, C, and E, with a target dose-limiting toxicity (DLT) of 30%. Primary end point was safety (DLT). Secondary end point was ORR. DCR, PFS, and OS were exploratory. ORR, DCR, and PFS were assessed by investigator per RECIST v1.1. Results: Median study follow-up at data cutoff (Oct 15, 2021) was 36 mo (range, 32-43) for cohort A, 17 mo (2-24) for cohort C, and 11 mo (2-25) for cohort E. In cohort A, 1/6 pts (17%) had DLT at DL1; no DLT occurred in 14 pts (0%) at DL2. In cohort A, gr 3/4 TRAEs occurred in 3/6 pts (50%) at DL1 and 8/14 pts (57%) at DL2. In cohort C, 3/9 evaluable pts (33%) had DLT at DL1; thus, bini dose was not escalated to DL2. In cohort C, gr 3/4 TRAEs occurred in 9/11 total pts (82%). In cohort E, 1/5 evaluable pts (20%) had DLT at DL1 and 5/10 evaluable pts (50%) had DLT at DL2. Enrollment was stopped in cohort E, DL2 and bini dose was de-escalated to DL1; 2/4 additional pts (50%) had DLT at DL1 (total 3/9 pts [33%] had DLT in cohort E, DL1). In cohort E, gr 3/4 TRAEs occurred in 5/9 pts (56%) at DL1 and 10/11 total pts (91%) at DL2. No gr 5 TRAEs occurred in any cohort. ORR was 0% in cohort A; limited efficacy was seen in cohorts C and E (Table). Conclusions: Bini could be safely combined with pembro in cohort A. However, with bini + pembro + chemo, the 45-mg dose of bini was not well tolerated and required dose reduction to 30 mg. Addition of bini to pembro + chemo did not improve efficacy; therefore, enrollment was prematurely closed in cohorts C and E. Efficacy by KRAS mutation status will be shown. Clinical trial information: NCT03374254. [Table: see text]
Post-treatment detection of circulating methylated BCAT1 and IKZF1 as prognostic indicators for recurrence in patients with colorectal cancer.
Authors: Young Graeme P. , Symonds Erin L. , Roy Amitesh Chandra , Cornthwaite Kathryn J , LaPointe Lawrence Charles , Pedersen Susanne Kartin 
Published: June 2022

3575 Background: Patient risk for recurrence after completion of initial treatment of colorectal cancer (CRC) is difficult to predict. Post-treatment circulating tumor DNA (ctDNA) analysis is a promising approach for stratifying such patients but the value of using tumor-uninformed biomarkers, such as methylated BCAT1 and IKZF1, is unknown. This study aimed to determine whether detection of circulating methylated BCAT1 and IKZF1 DNA following completed initial treatment with curative intent, identified patients at elevated risk of CRC recurrence. Methods: CRC stage I-III cases were eligible for study inclusion if a BCAT1/IKZF1 methylation test result was available at least 2 weeks after, but within 12mo, of completing initial treatment, and had had at least 2y follow-up unless recurrence was evident sooner (n = 142). Surveillance included regular clinical assessments and radiographic imaging. Level of methylation was reported as the total methylated BCAT1/ IKZF1 expressed as percent of cell-free DNA; levels ≥0.07% were considered positive. Primary outcome measure was recurrence-free survival. Mantel-Cox (logrank) method was used to assess the association between BCAT1/IKZF1 results and recurrence-free survival. Multivariable survival analysis by Cox proportional hazards modelling assessed the impact of covariates, including: BCAT1/IKZF1 result, age, gender, T-stage (T1-2 vs T3-4), N-stage (N0 vs N1-2), extra- and/or intra-mural vascular invasion (EMVI/IMVI) and nature of treatment. Time to recurrence was measured from the date of treatment completion to first evidence of recurrence and data were censored to last date of follow-up. Results: 33/142 (23.2%) cases had recurrence detected at a median 1.6y (IQR: 0.8-2.4). Follow-up time for those who remained recurrence free was 5.3y (IQR: 3.7-6.9). The time between completing treatment and BCAT1/IKZF1 testing was not different between these groups (median 2.4 vs 3.1mo, p = 0.530). 13 (9.2%) cases were positive for methylated BCAT1/IKZF1 after completing treatment and a positive result was associated with a significant risk of recurrence (hazard ratio [HR], 10.0 (95%CI 2.6-39.3), p < 0.001). In the multivariable survival analysis, only a positive BCAT1/IKZF1 methylation result following treatment (HR 2.6, 95%CI: 1.0-6.0, p = 0.041) and evidence of EMVI or IMVI (HR 2.3, 95%CI: 1.0-5.1, p = 0.044) were significant predictors of survival. Conclusions: This study shows that post-treatment BCAT1/IKZF1 methylation testing, which does not need personalization using tumor genotyping, is a promising independent prognostic indicator for CRC recurrence. Such cases are at high risk of recurrence compared to those who had no detectable ctDNA post treatment. These patients warrant enhanced and/or extended surveillance for recurrence. Clinical trial information: 12611000318987.
First-line (L1) therapy targeting EGFR in lung metastases (mets) of colorectal cancer (mCRC): An ARCAD pooled analysis.
Authors: Shmueli Einat Shacham , Raeisi Morteza , Chibaudel Benoist , Maughan Timothy S. , Douillard Jean-Yves , Van Cutsem Eric , Bokemeyer Carsten , Grothey Axel , Adams Richard , Zalcberg John Raymond , Yoshino Takayuki , Bachet Jean-Baptiste , Cohen Romain , Sharara Lama , Andre Thierry , Shi Qian , De Gramont Aimery 
Published: June 2022

3578 Background: Monoclonal antibodies (mab) targeting EGFR are recommended in L1 treatment (trt) for mCRC in patients (pts) with RAS wild-type (WT) tumor and primary left CRC. ARCAD database contains individual data of randomized trials that evaluated anti-EGFR mab plus chemotherapy (CT). In this analysis we aimed to evaluate anti-EGFR benefit in mCRC with lung mets, either as single site or multiple sites. Methods: Individual pts data from four trials (PRIME, CRYSTAL, COIN, OPUS) comparing CT +/- anti-EGFR were pooled. KRAS status was not required at inclusion to these studies. The primary endpoint, overall survival (OS), was estimated using Kaplan-Meier method, prognostic value of lung mets was evaluated by stratified Cox models in pts groups defined by KRAS status. The predictive value was evaluated by interaction test (Int) between trt and lung mets status in pts group defined by KRAS status and considered as significant with a P < 0.1. Results: 3681 pts with known KRAS status were included, 2171 WT and 1510 mutant (MT). Pts characteristics were well balanced. Significant median OS benefit of anti-EGFR was observed in the whole KRAS WT population and in the left colon and rectum subgroup but not in the right colon subgroup. In pts with KRAS WT single site mets, a non-significant benefit of anti-EGFR was observed only among pts without lung mets (N = 642). In pts with lung single site mets (N = 129), a significant benefit ( P= 0.018) in the KRAS MT population (N = 55) was observed, but Int was non-significant ( P =0.157). In pts with KRAS WT and multiple without lung mets sites (N = 673), no benefit of anti-EGFR was observed and Int was significant ( P= 0.054). Pts with KRAS MT multiple sites with (N = 656) or without (N = 397) lung mets, had no benefit of anti-EGFR. The same findings were found in the left primary pts and in the two fluoropyrimidine backbone. PFS analyses confirm the OS results. Conclusions: In this ARCAD analysis pts with lung mets as a single site appear to benefit from anti-EGFR L1 therapy in case of KRAS MT. This unexpected result based on a limited sample size cannot be explained on the knowledge of anti-EGFR therapy. Furthermore, pts with multiple mets sites have a benefit of anti-EGFR therapy only in the presence of lung mets even in KRAS WT left primary tumor. These findings need further confirmation and may initiate the search for a specific molecular phenotype associated with lung mets in CRC pts. [Table: see text]
Co-occurring alterations across molecular pathways in metastatic colorectal cancer (mCRC).
Authors: Liu Alex John , Walden Daniel , Mina Syeda , Langlais Blake , Drusbosky Leylah , Yang Dong , Starr Jason S. , Jones Jeremy Clifton , Bekaii-Saab Tanios S. , Ahn Daniel H. , Sonbol Mohamad B. 
Published: June 2022

3590 Background: Co-occurring alterations (COAs) in the HER2 and MAPK pathway are rare in mCRC. RAS, HER2 and BRAF alterations have been associated with resistance to EGFR inhibitor therapy (EGFR-mab). Typical co-occurring mutually exclusive gene mutations such as in KRAS and BRAF have been reported. This study aims to evaluate the prevalence of co-occurring alterations in the MAPK pathway or across MAPK/ HER2 and correlate to outcomes in patients with mCRC treated with EGFR-mab. Methods: This is a retrospective study of patients with mCRC within the Mayo Clinic database who have available blood-based NGS Guardant 360 data (September 2017-November 2021) and contained co-alterations in the MAPK pathway or across MAPK/ HER2. MSI-high cases were excluded. Typical-RAS was defined as alterations in codons 12, 13, 59, 61, 117, and 146 of KRAS, HRAS, and NRAS. Atypical-RAS alterations were considered mutations at other codons of these genes. Patient characteristics, specific mutations, and outcome data were assessed. Results: 692 patients (pts) with mCRC were identified and 66 (9.5%) of those had COAs detected. 59/66 pts had clinical data available. Median age was 52 years, 55.9% were male, and 61.0% had left-sided tumors. The frequency of detected alterations was: BRAF-V600E (7.3%), BRAF-non-V600E (7%), BRAF-amplification (3.04%), RAS-typical (39.5%), RAS-atypical (2.1%), HER2 amp (0.5%), HER2-mutation (1.2%) and PIK3CA (13%). COAs are described in the table. Twenty-three pts received EGFR-mab; COAs developed in 19 of them after progression on EGFR-mab. Four pts received EGFR-mab with documented COAs at baseline with none of them responding to treatment. Conclusions: COAs in MAPK and MAPK/ HER2 pathway are not uncommon in pts with mCRC emphasizing on the importance and feasibility of blood based NGS vs. selected gene testing. In pts with prior EGFR-mab treatment, COAs were detected after progression on treatment in the majority of pts, suggesting a mechanism of secondary treatment resistance. Further data including prospective validation is warranted. [Table: see text]
Effect of more versus less frequent abdominopelvic computed tomography follow-up testing on overall survival in patients with stage II or III colon cancer.
Authors: Jeongseok Jeon , Lee Da Bin , Beom Seung-Hoon , Shin Sang Joon , Ahn Joong Bae , Kim Han Sang 
Published: June 2022

3604 Background: Patients with colon cancer undergo an abdominopelvic computed tomography (AP-CT) scan surveillance every 6-12 months for five years after surgery. However, evidence of survival benefit from more intensive AP-CT patients in stage II and III colon cancer is still elusive. Methods: A total of 2,137 patients with stage II-III colon cancer who received curative aim surgery were analyzed in the Yonsei Cancer Registry Database between Jan 1, 2005, to Dec 31, 2015. The surveillance start date was defined as 90 days after curative resection or one day after adjuvant chemotherapy. All patients had at least one AP-CT for two years after the surveillance period. The average interval of AP-CT per patient was calculated as the postoperative surveillance duration divided by the number of AP-CT examinations. Patients who underwent AP-CT with an average interval of 6 months and 12 months were assigned to the high-frequent and low-frequent surveillance groups. Association of AP-CT frequency and demographic factors with overall survival (OS) were evaluated. Univariate and multivariate analyses were conducted. Results: Among 2,137 patients who underwent curative aim surgery, the median intervals of AP-CT scan were 6.1 months in high-frequent surveillance and 10.8 months in the less-frequent surveillance group, respectively. The 5-year overall survival (OS) was not significantly different in both groups; however, OS was significantly longer in the high-frequent surveillance group of patients who harvested lymph nodes less than 12 in curative resection ( P = 0.015) or measured postoperative serum carcinoembryonic antigen (CEA) level higher than 5 ng/ml ( P = 0.023). Of note, high-frequent surveillance group detected liver metastasis earlier (6.7 months) than the low-frequent group, leading to more curative aim metastasectomy (28.0% vs 4.3%, P = 0.020), and significantly longer 5-year OS (62.2% vs 34.8%, P = 0.017). Multivariate analysis showed that harvesting lymph nodes less than 12 (HR = 4.37, P = 0.004) and postoperative CEA level higher than 5 ng/ml (HR = 7.39, P < 0.001) were prognostic factors for overall survival. Conclusions: The average interval of AP-CT in patients with stage II-III colon cancer is not associated with improved OS. However, a high-frequent AP-CT enabled early detection of liver metastases, leading to the improved OS in high-risk patients, including the number of harvested lymph nodes less than 12 or postoperative CEA level is higher than 5 ng/ml. The risk-stratified approach is warranted to guide postoperative colon cancer surveillance.
A phase II trial of TGFβ type I receptor inhibitor, galunisertib, plus neoadjuvant chemoradiation in patients with locally advanced rectal cancer.
Authors: Young Kristina Hoot , Gunderson Andrew J , Gilchrist Miranda , Whiteford Mark , Kiely Maria X , Hayman Amanda , O'Brien David P , Ahmad Rehan , Manchio Jeffrey V , Brosnan Evelyn , Vaccaro Gina M. , Li Rui , Simon Miklos , McCormick Mary , Drokin Ashley , Cramer Julie , Urba Walter John , Gough Michael , Crittenden Marka R. , Yamazaki Tomoko 
Published: June 2022

3617 Background: Transforming growth factor beta (TGFβ) is an immunosuppressive cytokine upregulated in colorectal cancer. Preclinical data demonstrated improved response to chemoradiation with TGFβ blockade in colorectal adenocarcinoma. Here we report the results of our single arm Phase II study combining the TGFβ type I receptor kinase inhibitor, galunisertib, with neoadjuvant chemoradiation in patients with locally advanced rectal adenocarcinoma. Methods: Eligible patients had T3+ or N+ rectal adenocarcinoma planned for surgical resection. Enrolled patients completed a 14-day course of galunisertib, followed by chemoradiation with continuous infusion 5-fluorouracil or capecitabine with radiation to 50.4-54Gy in 28-30 fractions. On day 30, patients underwent another 14-day course of galunisertib concurrent with ongoing chemoradiation. Five to nine weeks after completing neoadjuvant therapy, patients underwent response assessment. Those with complete response by physical exam, proctoscopy, and MRI, could opt for non-operative management and proceed to mFOLFOX6. Those with less than a complete response underwent surgical resection. The primary endpoint was complete response rate (CR), which was a composite of pathologic complete responses in those patients who proceeded to surgery, and clinical complete responses maintained at 1 year after completion of therapy for those who chose non-operative management. Using a Simon Two-Stage approach with 90% power and α = 0.05, to detect a 20% improvement in complete response rate compared to historical control (15% vs 35%); we reject the null hypothesis if ≥10/38 patients have a CR. 38 patients were enrolled with 35 patients evaluable. Results: Median age was 51y, 68% of patients were male, 87% of patients were Stage III, 97% of patients were node-positive, and 97% were proficient in mismatch repair. 95% of patients completed study therapy. Toxicity attributed to galunisertib was Grade 1-2. 28 patients went to surgery, with a mean neoadjuvant rectal (NAR) score (NAR = 5pN-3(cT-pT)+12]2/9.61) of 11.29, and pCR in 7 patients. 7 patients underwent non-operative management, with 5 achieving cCR at 1 year. Therefore, complete responses were observed in 12 patients. Peripheral immune monitoring revealed percent change in CD3+CD4-CXCR3+ T cells and activated CD8EM T cells correlated with response to therapy. 2y PFS and OS were 81.5% and 97%. Conclusions: The addition of TGFβ inhibition to neoadjuvant chemoradiation in locally advanced rectal cancer markedly improved response to therapy, was well tolerated, and warrants further investigation. Clinical trial information: NCT02688712.
Circulating tumor DNA (ctDNA) as a minimal residual disease (MRD) assessment and recurrence risk in patients undergoing curative intent resection with or without adjuvant chemotherapy in colorectal cancer: A systematic review and meta-analysis.
Authors: Chidharla Anusha , Rapoport Eliot , Agarwal Kriti , Linares Brenda , Chakrabarti Sakti , Kasi Anup 
Published: June 2022

3623 Background: Minimal residual disease (MRD) assessment may effectively detect cure in patients with colorectal cancer (CRC). Emerging data have suggested that circulating tumor DNA (ctDNA) can be a reliable biomarker for MRD in patients. Recent studies have shown the ability to detect MRD using ctDNA assay to assess recurrence risk and patient selection for adjuvant chemotherapy. We performed a systematic review and metanalysis of post operative ctDNA in Stage I-IV (oligometastatic) CRC patients after curative intent resection with or without adjuvant chemotherapy. Methods: We searched PubMed/Medline, EMBASE, Web of Science, Cochrane Library, and Google from inception to February 3, 2022 using keywords related to colorectal cancer, ctDNA, and MRD. The search also includes paper and conference presentations. The search resulted in 427 studies after removing the duplicates. Data were extracted to perform a meta-analysis using RevMan 5.4. software. Subsequent subgroup analysis was performed for stages I-III and oligometastatic stage IV CRC patients. Results: After the initial abstract screening, 48 studies were identified. The final review led to the inclusion of 27 studies representing 3459 patients with evaluable ctDNA, with 623 having +ve post-surgery ctDNA levels. Seven studies had analyses of patients specifically with oligometastatic disease, the rest 20 studies subdivided within stages I-III. The pooled HR for RFS in post-surgical ctDNA +ve vs -ve patients in all stages was 7.16 (95% CI 6.12-8.36) p <0.00001. Subgroup analysis revealed pooled HR = 8.27 (95% CI 6.16-11.09) and 6.07 (95% CI 4.54-8.13) for stage I-III and IV CRC, respectively. Only 11 studies did analysis for post adjuvant chemotherapy patients based on ctDNA status. The pooled HR for RFS in post-adjuvant chemotherapy ctDNA +ve versus -ve patients in all stages was 12.40 (95% CI 9.24-16.64) p <0.00001. Subgroup analysis revealed pooled HR = 13.95 (95% CI 9.08-21.43) and 11.39 (95% CI 5.99-21.66) for stage I-III and IV CRC, respectively. Conclusions: This is the largest and most current meta-analysis done on ctDNA levels as MRD assessment in CRC. Our analysis emphasizes that post operative ctDNA is a strong prognostic marker of RFS. Based on our results ctDNA can be a significant and independent predictor of RFS. Several ctDNA-based randomized adjuvant trials are ongoing internationally to confirm the clinical utility of ctDNA in colorectal cancer. [Table: see text]