bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical impact of hemizygous deletion detection and panel-size in comprehensive genomic profiling.
Authors: Takahashi Kenta , Gen Yasuyuki , Tanimoto Kousuke , Kudo Atsushi , Oshima Noriko , Ban Daisuke , Takemoto Akira , Onishi Iichiro , Kumaki Yuichi , Yokobori Junko , Takamine Eriko , Kano Yoshihito , Miyake Satoshi , Miyasaka Naoyuki , Tanabe Minoru , Inazawa Johji , Ikeda Sadakatsu 
Published: May 2020

e15671 Background: Comprehensive genomic profiling (CGP) identified single nucleotide variants (SNVs), copy number alteration (CNA), indels, and rearrangements in cancer-related genes. Only limited CGP detects hemizygous deletion. Also panel size differs among CGPs. Clinical impact of hemizygous deletion and panel-size are not well characterized. Methods: Formalin-fixed paraffin-embedded tissues from 10 cancer patients were analyzed by two CGPs: 1) test A (ACT Onc+) that interrogates SNVs, indels, rearrangement, and CNA including amplification, hemizygous and homozygous deletions in 440 genes, 2) test B that interrogates SNV, indels, rearrangement and CNA including amplification and homozygous deletion in 114 genes, but hemizygous deletion only in limited genes. Result was discussed in molecular tumor board and actionable genes and candidate drug were determined. Primary objective was the number of actionable genomic alterations. Secondary objectives are the number of candidate drugs, SNVs, CAN, and rearrangement. When there was difference of results in two tests, other validation test, such as PCR-based copy number evaluation, was performed. The difference of two tests was statistically evaluated using student t-test. Results: Median age of patients was 56 (range 48 – 70), and 50% were male. Tumor types were neuroendocrine tumor (60%), ovarian cancer (30%) and pancreatic cancer (10%). In 10 patients, actionable genes were found as follows: 39 in test A and 9 in test B (P = 0.0056). Total 64 genomic alterations were found in test A compared 12 in test B. SNV was not statistically different among two tests (10 in test A, 6 in test B; P = 0.269). However, the number of CNA was different: 54 in test A and 6 in test B (P = 0.007). Among CNA, hemizygous alteration explained majority of the difference (30 in test A and 1 in test B, P = 0.059), followed by amplification (24 in test A and 5 in test B, P = 0.201). The number of drug candidates was 38 in test A and 11 in test B (P = 0.014). Conclusions: Detection of hemizygous deletion and larger panel size resulted in more actionable genes and drug candidates, which might impact clinical practice. Future study of clinical utility of hemizygous deletion and panel size is warranted.
Variety of clinical trial enrollment by actionable tumor suppressor genotype.
Authors: Avila Monica , Wathoo Chetna , Zeng Jia , Andersen Clark , Yuan Ying , Yap Timothy A , Rodon Ahnert Jordi , Meric-Bernstam Funda 
Published: May 2020

e15674 Background: In the last decade, genomics has been increasingly used for therapeutic management of cancer. In precision oncology, genes that can be directly or indirectly targeted with therapeutic agents are considered “actionable”. However, not all alterations affect gene function and alterations in tumor suppressor genes are especially challenging to interpret. The objective of this study was to determine frequency of trial enrollment in patients with “actionable” tumor suppressor alterations and determine whether this varied by genotype and tumor type. Methods: A single-institution retrospective review was performed on patients with metastatic, advanced, or recurrent solid tumors perceived to likely benefit from genomic profiling. Between 1/2015 and 1/2020, the top 5 tumor suppressor alterations CDKN2A, BRCA1/2, PTEN, ATM and NF1 were considered most common “actionable” tumor suppressor genes among patients reviewed by MD Anderson Precision Oncology Decision Support system. Once literature-based or inferred actionability of the tumor-suppressor alteration was determined, a clinical record review was performed to assess an institution-specific annotation detailing trial availability. This annotation matches somatic genomic alteration based on therapeutic significance and availability of matched investigative therapy based on available literature at the time. From here, patient demographics and trial enrollment was extracted from the electronic medical record. Results: 424 patients were categorized as having actionable alterations that had a trial available for enrollment based on genomic characteristics. Of these, 61 patients (14%) enrolled in a matched trial. Primary reasons for non-enrollment for a specific alteration were: enrollment in non-targeted therapeutic trial (39%), treatment with another stand of care therapy (32%), or enrollment in another genomically matched trial targeting another genomic alteration (14%). There was variability in enrollment by disease type approaching statistical significance (p = 0.073). CDKN2A alterations were the most common while BRCA1/2 had the highest rate of matched enrollment (39.5%). Conclusions: In this cohort of patients, the presence of an actionable tumor-suppressor alteration was associated with trial enrollment varying by genotype. Further work is needed to determine the impact of decision support on trial enrollment as well as strategies to increase actionability by building genomically-driven combination therapy trials.
Safety and efficacy of pembrolizumab monotherapy in patients with advanced colorectal MSI-h/dMMR cancers.
Authors: Michalaki Vasiliki , Polydorou Andreas , Dafnios Nikolaos , Theodosopoulos Theodosios , Vezakis Antonios , Iliakopoulos Konstantinos , Karandrea Despina , Papadimitriou Christos 
Published: May 2020

e16010 Background: Tumours that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) are likely to be immunogenic, triggering upregulation of immune checkpoint proteins. New therapeutic options are needed for patients with advanced colorectal cancer whose disease has progressed after 1 or more lines of therapy. We investigated the safety and efficacy of pembrolizumab, a monoclonal antibody to programmed cell death–1 protein (PD-1 in a cohort of colorectal MSI-H/dMMR cancers patients with previously treated with one line of therapy. Methods: Twenty two eligible patients with histologically/cytologically confirmed MSI-H/dMMR metastatic colorectal cancer who experienced failure with one line of prior therapy received pembrolizumab 200 mg every 3 weeks until disease progression or unacceptable toxicity The primary endpoint was objective response rate (ORR) per RECIST v1.1, as assessed by radiologic review and safety. Tumours were classified as MSI-H/dMMR when expression as detected by immunohistochemistry of at least one of four MMR proteins was absent, or when at least two allelic loci size shifts among the five analyzed microsatellite markers were detected by PCR. Results: Of 22 patients enrolled, median (range) age was 62 (39-78) years. Median follow-up was 15.6 months. The ORR was 36.8 % (95% CI, 29.3% to 42.8%). Median progression-free survival was5.3 months (95% CI, 2.9 to 5.9 months) and median overall survival was 21.5 months (95% CI, 12.8 months to not reached).Treatment-related adverse events occurred in 13 patients (59%). -Four patients (18%) had grade 3 to 5 treatment-related adverse events. There were no treatment-related fatal adverse events. Conclusions: Pembrolizumab monotherapy demonstrated durable clinical benefit and manageable safety in patients with metastatic MSI-H/dMMR colorectal cancer who had previously received 1 line of treatment. Further study of pembrolizumab for this group of patients is warranted.
Effect of TP53 mutation on antitumor immunity and responsiveness to immunotherapy in colorectal cancer.
Authors: Lu Zhihao , Shen Lin , Zhang Henghui , Jiao Xi , Wang Yujiao , Chen Huan , Han Wenbo , Liu Chang , Gong Jifang , Li Jian , Zhang Xiaotian , Wang Xicheng , Peng Zhi , QI Changsong , Wang Zhenghang , Li Yanyan 
Published: May 2020

e16014 Background: Although we have approved immune checkpoint inhibitors (ICIs) in microsatellite instability high (MSI-H) or mismatch-repair-deficient (dMMR) colorectal cancer (CRC), more than half of patients did not respond well to ICIs, emphasizing the need for effective biomarkers. Methods: Whole exome sequencing (WES) analysis was performed on a Chinese cohort of MSI-H/dMMR CRC patients (n = 16). We investigated the pertinence between clinic benefit and potential biomarkers, as TP53 mutation and tumor mutational burden (TMB). The open cohort of ICI-treated CRC patients from the Memorial Sloan Kettering cancer center (MSK ICI cohort) further validated the genomic correlation. Besides, we used the colorectal adenocarcinoma (COADREAD) cohort from The Cancer Genome Atlas (TCGA) dataset to explore the effect of TP53 mutation on the genomic and immunogenetic features. Results: In a Chinese cohort of MSI-H/dMMR CRCs receiving ICIs, we found that patients with TP53 mutation (6 out of 16) showed a remarkable lower durable clinic benefit (DCB) rate than TP53 wild-type subgroup (100% vs. 33%, P = 0.008). Moreover, TP53 wild-type patients were associated with prolonged progression-free survival (P = 0.02; HR, 0.11) and overall survival (P = 0.0037; HR, 0.04). However, TMB-high revealed no statistical significant predictive or prognostic value when using top 20%, 40% or 50% as the cutoff values in our cohort. Further, in order to confirm our observation, we analyzed the association of TP53 mutation with clinic outcome in the publicly available MSK ICI-treated CRC cohort. As expected, the TP53 wild-type patients had a better prognosis (P = 0.037; HR, 0.54) versus the TP53 mutant subgroup. Mechanically, we found that the retention of wild-type TP53 in the TCGA COADREAD cohort was associated with improvement of several steps in the cancer immunity cycle. More intriguingly, in the MSI-H subtype, the TP53 wild-type tumors showed enhanced recognition of cancer cells by T cells and a higher proportion of effector memory CD8+ T cells. Finally, TP53 wild-type tumors also showed reduced heterogeneity and decreased burden of copy number variation, but the correlation between TP53 wild-type tumors and TMB was limited due to MSI status. Conclusions: Our study highlights that TP53 mutations in CRC may indicate inhibition of the tumor microenvironment, particularly in MSI-H/dMMR CRCs. Therefore, the assessment of TP53 status may have important significance in predicting the effectiveness of ICIs in CRC patients and their MSI-H /dMMR subgroup.
Unraveling metabolism heterogeneity in colorectal cancer and its implications in pan-cancer cohort.
Authors: Wu Qijing , Huang Qiong , Sun Mengting , Liang Bishan , Hu Xingbin , Zeng Dongqiang , Wang Chunlin , Rong Xiaoxiang , Wu Zhenzhen , Li Shaowei , Wang Ling , Yao Zhiqi , Liu Yajing , Sun Fei , Liao Wangjun , Shi Min 
Published: May 2020

e16016 Background: Colorectal cancer (CRC) molecular subtype has been emphasized and links to biological and clinical behavior. However, comprehensive metabolism of CRC has not been characterized. Subtype-specific metabolic differences and immunometabolism phenotypes remain unclear. Therefore, this study performed metabolism clustering and explore its relation with immune phenotypes as well as prognosis predictive value. Methods: Transcriptome of TCGA CRC cohort was utilized to generate 113 KEGG metabolism pathway scores via GSVA algorithm. Consensus clustering were used to identify metabolism subtypes. Bioinformatic algorithms were applied in classification and survival analysis. Results: Energy metabolism-oriented subtype, featured by nitrogen metabolism and immune-inflamed, correlated with good prognosis (log rank P < 0.001). Pyrimidine synthesis activated most in nucleotide metabolism-oriented subtype, which was immune-deserted. Stroma metabolism-oriented subtype, characterized by glycosaminoglycan (GAG) biosynthesis and immune-suppressive phenotype, was an independent risk factor for overall survival (multivariate Cox: HR = 2.30 95% CI 1.23-4.28, P = 0.009). Clinical cohort from Nanfang Hospital composed of RNA-Seq data from 26 pre- and post-treatment samples in mCRC patients receiving mFOLFOX+Bevacizumab were classified. 22 were identified and 8 of them were pre-treatment, 4 of which were nucleotide subtype being 100% PR. The rest were stroma subtype with SD or PD, indicating drug resistance in stroma subtype. Interestingly, GAG chondroitin sulfate featured in stroma subtype outperformed other metabolisms in predicting negative prognosis (HR = 1.42 95% CI 1.18-1.71, P < 0.001). We then tested GAG metabolism in TCGA pan-cancer cohort. Chondroitin sulfate and heparan sulfate metabolism subtype correlated inversely with bladder (HR = 1.23 95% CI 1.06-1.43, P = 0.007) and breast cancer (HR = 1.27 95% CI 1.10-1.47, P = 0.001) patients’ survival, respectively. Keratan sulfate subtype predicted worse survival in glioblastoma, pancreatic and liver cancer (HR = 1.31 95% CI 1.09-1.57, P = 0.003; HR = 1.31 95% CI 1.06-1.61, P = 0.01; HR = 1.23 95% CI 1.04-1.46, P = 0.02). These indicated a pan-cancer relevant role of GAG disorder. Conclusions: CRC metabolism subtypes unraveled metabolism heterogeneity with prognosis value. CRC stroma subtype and other stroma-involved cancers share active GAG metabolism, which may lighten common targeting strategies in multiple stroma-accompanied cancers.
Mutational profiles and clinical outcomes in metastatic colorectal carcinoma patients with different metastases sites.
Authors: Zhang Xi , Jing Zhang , Li Yingmei , Chen Shifu 
Published: May 2020

e16020 Background: To compare the difference of genomic and survival of first metastases site between first metastases site of metastatic colorectal cancer (mCRC) in liver and other sites (bone, brain, lung, and so on). Methods: Genomic mutations and clinic data of 113,4 CRCs (consisting of 533 metastases) were collected from TCGA database. According to first site(s) of metastases, patients were categorized into group 1 (liver as first metastases site, n = 405) and group 2 (other organs as first metastases site, n = 128). OS curves were estimated with Kaplan-Meier method, p values were calculated by fisher exact test. Results: Mutation frequency in GNAS (2.34%), KRAS (37.78%), BRAF (16.41%) and proportion of MSI-high (8.5%) was significantly higher in group2. Compared with group2, group1 showed significantly higher mutation rate of APC (78.52%) and TP53 (77.28%). We assessed overall survival in the two groups. OS was significantly better for patients in group1 than in group2 (HR 0.57, 95% CI 0.41-0.79, p = 0.00075). Conclusions: According to the results of this study, mCRC patients showed different mutational signatures with respect to the site of first metastases, and presented higher OS rate in liver metastases group. Our findings provided new knowledge to understand the biological progress of different metastases and develop new prognostic markers for metastatic colorectal cancer.
FLT1 amplification predicts poor response in metastatic colorectal cancer patients treated with apatinib as 3rd line treatment.
Authors: Dong Ma , Yang Dongyang , Xu Fei , Lai Xiaorong , Han-Zhang Han , Chen Chunxiang , Shao Lin , Chen Shuyin , Zhang Lu 
Published: May 2020

e16033 Background: Apatinib, a selective vascular endothelial growth factor receptor-2 (VEGFR2) inhibitor, has demonstrated encouraging anticancer activity across a broad range of malignancies. Recent studies have shown efficacy of apatinib as a third-line treatment for patients with refractory colorectal cancer. In this study, we characterized the genomic profile and explored predictive and prognostic biomarkers in metastatic colorectal cancer (mCRC) patients treated with apatinib as the 3rd line treatment. Methods: We retrospectively recruited 19 mCRC patients, with a median age of 53, treated with apatinib as the third-line regimen. The cohort consisted of 10 female and 9 male patients with 13 and 6 patietns with left-seide and right-sided CRC, respectively. Tissue samples prior to apatinib treatment were profiled using a 520-cancer-related gene panel. Results: This cohort achieved an ORR of 16% (3/19) and DCR of 53% (10/19). The median PFS and OS were 5 and 8.7 months, respectively, comparable with published studies. The genomic profile of 19 patients showed that 57% of alterations were missense, and 18% and 12% were copy number variations (CNV) and frameshift, respectively. All 19 patients were microsatellite stable (MSS). Most frequently mutated genes were TP53 (95%), APC (53%) and KRAS (53%). Other commonly mutated genes included PI3KCA (26%), FAT3 (16%), LPR1B (16%), FLT1(16%), SAMD4 (16%), TCF7L2 (16%) and TCNNB1 (16%). Univariate Cox analysis revealed a shorter PFS in patients harboring FLT1 amplification (n = 3) versus those without (P = 0.0007). All 3 patients with FLT1 amplification had progressive diease as their best response, with an average PFS of 1.4 months. Furthermore, we also revealed that APC mutation was significantly associated with older age (P = 0.02) and lymph node metastasis (P = 0.01). Patients with pulmonary metastasis were more likely to have TP53 disruptive mutation (P = 0.02). Conclusions: Our study explored the potential predictive biomerkers for apatinib and revealed that FLT1 amplification might be a potential predictive biomarker for poor efficacy in mCRC patients treated with apatinib. FLT1 encodes VEGFR1, which could compete with VEGFR2 for binding with VEGF, potentially explaining the inferior response to apatinib observed in pateints harboring FLT1 amplification. Larger cohorts are needed to validate the finding.
Dehydration as a possible tool to slow down peritoneal metastases by changing the intraperitoneal environment.
Authors: Khosrawipour Tanja , Schubert Justyna , Siegert Thomas , Reinhard Sören , Migdal Pawel , Pieczka Marek , Bania Jacek , Pigazzi Alessio , Knoefel Wolfram Trudo , Khosrawipour Veria 
Published: May 2020

e16037 Background: Due to limited efficiency of current intravenous and intraperitoneal chemotherapeutic approaches, treating advanced peritoneal metastases (PM) remains an ongoing oncologic challenge. As the peritoneum is an optimal biological compartment for metastatic growth, stopping progressive tumor extension at more advanced stages is currently unachievable. With this study, we aim to investigate whether changing the intraperitoneal environment using dehydration might halt tumor progression. Methods: Commercially available human colon cancer cells (HT-29) were dehydrated for 15 minutes at 90% humidity and compared to cells treated with only oxaliplatin. Cell vitality was measured and structural cell changes following dehydration were analyzed via scanning electron microscopy. Additionally, staining with hematoxylin and eosin was performed on peritoneal tissue to assess dehydration effects using an ex vivo model. Finally, a mathematical model was established to measure dehydration of the abdominal compartment for feasibility evaluation. Results: Partial dehydration has a significant cytotoxic effect on colon cancer cells ( p< 0.05) even if only shortly applied. The addition of oxaliplatin treatment following dehydration results in highly reduced cell vitality ( p< 0.01). Sole dehydration vs. sole oxaliplatin application have similar effects. SEM revealed a cellular collapse of HT-29 cells caused by dehydration. Histopathological examination of peritoneal tissue demonstrated that the dehydration effect is superficial with penetration depths of < 200 µm. Conclusions: Our data indicate that dehydration is a potentially feasible technique with measurable cytotoxic effects on colorectal cancer cells. While changing the physiological milieu of the peritoneal cavity by means of dehydration could significantly reduce PM extent, the consequences of volume fluid loss must be equally considered. Thus, further studies are required to find a sustainable extent of dehydration while maintaining circulatory stability.
Anti-VEGF versus Anti-EGFR in the real world in metastatic colorectal cancer.
Authors: Namuche Fernando , Flores Claudio J. 
Published: May 2020

e16040 Background: The incidence of colorectal cancer (CRC) in Peru has increased in the last decades. But the use of monoclonal antibodies is restricted in our population because of insureance issues. Approximately 20% of patients with CRC already have metastases at diagnosis. There is a lack of data in the benefits of our population with the use of anti-VEGF and anti-EGFR that this study intents to fill. Methods: We retrospectively reviewed the electronic medical records of 58 patients with metastatic CRC, KRAS, NRAS and BRAF wild type from one specialized Peruvian cancer center between 2006 and 2017 Descriptive results for numeric variables were presented as means with standard deviation (SD) or medians with interquartile range (IQR), depending on their distributions; otherwise, we expressed the qualitative variables as numbers with percentages. The survival analysis was performed with Kaplan Meier method for PFS and OS, comparing the curves with Log Rank test. A multivariate analysis was performed using the Cox regression model with the statistically significant variables found in the univariate analysis. Results: There was 29 patients in the anti-EGFR arm, and 29 patients in the anti-VEGF arm. Patients that received first anti-EGFR and then anti-VEGF had better OS [HR, 0.87; 95% CI,0.019-0.811; p < 0.001] than patients that received first anti-VEGF and then anti-EGFR. Multpile Cox regressión analysis demonstrated that metastasectomy, debut with less thant 2 metastasis site, left side tumor, and histologic grade were associated with better OS. Conclusions: Patients with mCRC RAS and BRAF wild type that received anti-EGFR and then anti-VEGF had better OS than patients that received anti-VEGF and then anti-EGFR.
Role of palliative radiotherapy in patients with metastatic colorectal cancer: A propensity score matching analysis.
Authors: Lin Zhenyu , Ba Li , Ren Jinghua , Zhang Tao 
Published: May 2020

e16043 Background: To explore whether palliative radiotherapy can further improve overall survival (OS) of patients with metastatic colorectal cancer (mCRC) receiving systemic treatment and analyze its survival prognostic factors. Methods: The demographics, tumor characteristics, and survival outcomes of 484 mCRC patients who underwent systemic treatment with or without palliative radiotherapy from December 2014 to September 2019 were analyzed. A propensity-score model was used to compare the group of patients receiving systemic treatment plus palliative radiotherapy (PR) or simple systemic treatment (ST). Results: There were 334 ST patients and 154 PR patients in total, and 288 cases (144 cases/group) after paired matching. The OS (1 year, 2 years, 3 years) in PR group were 73.6%, 40.3%, 16.0% and, respectively, which were higher than those in ST group (61.1%, 22.9%, 6.9%). The median survival times were 50.8 months and 32.2 months, respectively (P = 0.003). Multivariate analysis showed that the site of primary tumor, patient surgery status, local treatment of metastasis as well as whether or not radiotherapy are independent prognostic factors of survival time. Conclusions: We definitely demonstrated that palliative radiotherapy on the basis of systemic chemotherapy is expected to increase OS in mCRC patients. Left colon, primary surgery, local treatment of metastasis and radiotherapy are the independent prognostic factors of mCRC.