bluuebunny/crossref_metadata_2025 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.
Preparing the peritoneal surface for intraperitoneal chemotherapy using high-intensity ultrasound (HIUS): Investigation of technical feasibility, safety and possible limitations.
Authors: Khosrawipour Veria , Frelkiewicz Piotr , Reinhard Sören , Nicpon Jakub , Khosrawipour Tanja , Lau Hien , Pieczka Marek , Pigazzi Alessio , Knoefel Wolfram Trudo , Mikolajczyk Agata
Published: May 2020

e16045

Background: The penetration of chemotherapeutic drugs into metastatic peritoneal nodules remains at levels well below 1 mm, thus significantly limiting the antitumor effect of intraperitoneal chemotherapy (IPC). Recently, high-Intensity ultrasound (HIUS) has been discovered as a potential tool to improve peritoneal diffusion rates. Despite promising preliminary data, basic aspects regarding its technical feasibility, safety and possible limitations remain unclear. This study aims to enhance our current understanding of HIUS and test its applicability using an ex-vivo swine model. Methods: Three postmortem swine were subject to laparotomy with consecutive lavage with 0.9%NaCl saline and HIUS application. For this purpose, a large HIUS radiating pen was introduced into the abdominal cavity and HIUS was applied on two of the four abdominal quadrants for 300 seconds each at an output power of 70 W, 50 % amplitude and 20 kHz frequency. Following the procedure, small intestinal tissue samples were removed for further analyses. Results: In all specimen, peritoneal and subperitoneal layers showed structural changes only visible on a microscopic level. The peritoneal layer was transformed into a mash-like structure while the subperitoneal layer (depth of 142 +/- 28 µm) exhibited microcavities and vascular detachment from surrounding tissues. No bowel rupture or vascular perforations were observed. Conclusions: Our data indicate that HIUS is a technically feasible add-on procedure for IPC with measurable microscopic changes on the peritoneal surface and no apparent bowel toxicity. Pretreatment of the abdominal cavity with HIUS could significantly improve IPC efficacy. Further studies are required to optimize and evaluate this novel approach.
Phase I results from a phase 1/2 multi-center study of nab-sirolimus combined with mFOLFOX6+bevacizumab (FB) as first-line (1L) therapy in patients (pts) with metastatic colorectal cancer (mCRC) with or without PTEN loss.
Authors: Sharma Sunil , Chiorean E. Gabriela , Alistar Angela Tatiana , Braiteh Fadi S. , Matrana Marc Ryan , Becerra Carlos Roberto , Grigorian Berta , Hou Shihe , Schmid Anita N. , Desai Neil
Published: May 2020

e16050

Background: The PI3K/mTOR pathway overactivation and loss of PTEN occur in 20-40% of mCRC pts. A recent phase 1/2 study in mCRC pts showed evidence that everolimus added to 1L SOC treatment improved outcomes, in particular in pts with PTEN loss (Gilcrease, 2019). This prospective, single-arm phase 1/2 study aims to identify the optimal dose and schedule of nab-sirolimus (ABI-009), an mTOR inhibitor, plus FB and evaluate the safety and preliminary efficacy of this regimen. Methods: Eligible pts have no prior therapy, ≥18 years old, ECOG performance status of 0-2. PTEN loss (by IHC) is evaluated for all pts. nab-Sirolimus IV starting dose and schedule was 30mg/m2 weekly for 3 weeks followed by a week of rest (on D1, 8, and 15 in a 28-day cycle, qw3/4) plus standard doses of FB on D1 and D15. Dose escalation to 45 and 60mg/m2 or de-escalation to 20 and 10mg/m2 followed the 3+3 design. Dose limiting toxicity (DLT) was assessed in cycle 1. Results: As of Jan 31, 2020, 24 pts were treated in the phase 1 study and 18 were evaluable for response. No DLTs were observed in the first 3 pts treated with nab-sirolimus at 30mg/m2 qw3/4; however, all 3 pts missed D8 doses (due to G2 thrombocytopenia and G3 neutropenia) and the cohort expanded to additional 3 pts for further observation. 5/6 pts missed D8 doses and a new dose cohort enrolled pts at 20mg/m2 qw3/4. No DLTs were observed and the cohort was expanded to 10 pts. A safety review of the first 18 pts observed that 9/18 pts missed doses on D8 and a new cohort was added to enroll pts at 20 mg/m2 q2w (D1 and D15, as for FB). This cohort enrolled 8 pts with no DLTs and represents the recommended-phase-2-dose (RP2D) and continues enrollment in phase 2. For all pts, 15/24 (63%) pts had G3-4 treatment-related adverse events (TRAEs); most common were neutropenia (6/24, 25%) and thrombocytopenia (4/24, 17%). At the RP2D 3/8 (38%) pts had G3-4 TRAEs (thrombocytopenia, weight loss, and hypertension, 1 pt each). Among 18 evaluable pts, best response was: 7/18 (39%) partial response, 10/18 (56%) stable disease, and 16/18 (89%) had tumor shrinkage. PTEN was assessed in 14 pts: 4/14 (29%) had PTEN loss, 2/4 (50%) PTEN loss pts responded, while 3/10 (30%) pts that were PTEN+ (WT) had a response. Conclusions: The RP2D of nab-sirolimus is 20mg/m2 q2w in combination with standard mFOLFOX+bevacizumab. The phase 2 portion of the study is ongoing. Clinical trial information: NCT03439462 .
Microsatellite instability and KRAS mutation in stage 4 CRC: Prevalence, geographic discrepancies and outcomes from the National Cancer Database.
Authors: Uhlig Johannes , Cecchini Michael , Stein Stacey , Lacy Jill , Kim Kevin
Published: May 2020

e16052

Background: To assess microsatellite instability (MSI) and KRAS mutation prevalence, discrepancies and their impact on outcome in AJCC stage IV colorectal adenocarcinoma (colorectal cancer; CRC). Methods: The 2010-2016 United States National Cancer Database was queried for stage IV CRC patients > 18yo and information on MSI and KRAS mutation. Microsatellite status was stratified as stable microsatellites (MSS, including low instability) and microsatellite instability high (MSI-H). KRAS status was stratified as mutation and wildtype. Prevalence and discrepancies were evaluated according to patient demographics, US geography and CRC factors. Overall survival (OS) was assessed using Cox proportional hazards models adjusting for age, gender, race, comorbidities, metastatic burden, CRC treatment, treatment center type, and year of CRC diagnosis. A priori, a statistical interaction test between microsatellite status, KRAS status and primary CRC site was planned. Results: Microsatellite/KRAS status was available for n = 10,844/n = 25,712 patients, respectively. OS was assessed in n = 5,904 patients with data on both microsatellite and KRAS status, and follow-up. Overall prevalence of MSI-H was 3.1% and KRAS mutation 42.4%. Microsatellite and KRAS status varied according to primary CR site, as presented in Table. Further variation was evident according to US-geography, with MSI-H rates ranging from 1.6% to 4.1%, and KRAS mutation rates ranging from 41.1% to 44%. On multivariable analyses, longer OS was observed in patients with KRAS wildtype versus mutation (HR = 0.91, 95% CI: 0.85-0.97 p = 0.004), MSS versus MSI-H (HR = 0.75, 95% CI: 0.62-0.9, p = 0.003), and left-sided versus right-sided CRC (HR = 0.65, 95% CI: 0.6-0.7, p < 0.001). The effect of KRAS mutation further varied with CRC site and microsatellite status (interaction p = 0.002). Conclusions: Depending on its primary site and US geography, stage IV CRC shows distinct mutational behavior. KRAS mutation, MSI-H, MSI-H and primary CRC sidedness independently affect overall survival and interact with distinct prognostic profiles. Generically classifying adenocarcinomas of different site as “CRC” might deprecate this diversity. [Table: see text]
Meta-analysis and systematic review of the cardiotoxicity of TAS-102.
Authors: Lopez Carlos Alberto , Azimi-Nekoo Elham , Chung Su Yun , Newman James , Shen Janice , Saif Wasif M.
Published: May 2020

e16053

Background: Fluoropyrimidines such as 5-FU and capecitabine are known to be cardiotoxic drugs. TAS-102 (trifluridine-tipiracil) is a novel oral fluoropyrimidine that was recently FDA approved to treat gastric and colon cancer. However, the incidence of cardiac related events of TAS-102 is not fully ascertained. We performed a meta-analysis and systematic review to determine the incidence of cardiotoxic events associated with TAS-102. Methods: We performed a literature search through PubMed, Embase, and Web of Science to identify any publications in any language up to December 31st, 2019 where TAS-102 (and equivalent terms such as “trifluridine-tipiracil” and “Lonsurf”) was used. These were then manually reviewed to identify any publications reporting cardiac events. Randomized controlled trials (RCTs) were included for meta-analysis to determine the incidence of cardiotoxic events, which were summarized as pooled odds ratios (OR) when compared to placebo. Non-randomized, non-controlled clinical trials (phase I and phase II studies) were included in the systematic review but excluded from the pooled OR calculation. Results: 869 publications were identified in the initial literature search, of which 17 trials (3 Phase III studies, 6 Phase II studies, and 8 phase I studies) met inclusion criteria. A total of 1,877 patients among 4 RCTs were included in the meta-analysis. Compared with placebo, TAS-102 did not increase the risk of myocardial infarction (OR 1.97 95% CI [0.22-17.89]), hypertension (OR 0.73 95% CI [0.37, 1.44]), palpitations (OR 1.51 95% CI [0.30, 7.56]), cardio-pulmonary arrest (OR 0.83 95% CI [0.11-6.32]), or syncope (OR 1.50 95% CI [0.06-37.14]). Among the 1,252 patients receiving TAS-102, the overall incidence of cardiovascular events was low, with hypertension being the most common side effect (21 events), followed by palpitations (6 events), cardiopulmonary arrest (2 events), and myocardial infarction (3 events), though there was no statistically significant increased risk compared to placebo. No deaths were reported. Conclusions: Unlike other fluoropyrimidines, TAS-102 appears to be a cardiogentle drug, with no increased risk of cardiac events compared to placebo. Since fluoropyrimidines remain the backbone of treatment for gastrointestinal malignancies, TAS-102 can offer an alternative to patients who developed cardiotoxicities from other agents. Prospective studies with consideration of cardiac risk factors are required.
Correlation between DIDO1 variation and MSI-status in colorectal cancer.
Authors: Zhang Xingwei , Cai Yonghua , Hou Yujie , Hu Huanxin , Chen Yaoxu , Huang Mengli , Kang Liang
Published: May 2020

e16054

Background: Several studies have displayed a sustained clinical response to immune checkpoint inhibitors with profound clinical improvement in patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC). MSI-H tumors may display higher numbers of TILs, many of which can be directed against tumor-related neoantigens. We set out to examine the underline mechanism in gene level to further explain the differences between MSI-H and MSS CRC. Methods: Whole exome sequencing(WES) was performed on 68 CRC patient.MSI status of these patients were determined using a targeted next generation sequencing panel covering 100 MSI loci. TCGA database was used to analyze WES data of 364 CRC patients with different MSI states, and immune signature was used to analyze the corresponding relationship of immune cell expression in different populations. Results: Of 56 MSS patients, 58.9% (33/56) had copy number variants (CNV) in DIDO1, and 1.8 (1/56) had single nucleotide variants(SNV) in DIDO1. Of 12 MSI-H patients, 33.3% (4/12) had SNV in DIDO1 gene, None had CNV in DIDO1. TCGA database showed that of 308 MSS patients, 8% (24/308) had CNV in DIDO1 and 3% (9/308) had SNV in DIDO1. Of 56 MSI-H patient, 39% (22/56) had SNV in DIDO1 and only one patent had both SNV and CNV in DIDO1. Gene variation of DIDO1 of 68 CRC patients showed a correlation with TCGA database. Gene variation of DIDO1 in MSI-H patients are mainly SNV, and the incidence of CNV is very small (4.3% of DIDO variation).While, gene variation of DIDO1 in MSS patients are mainly CNV, followed by SNV, indicating DIDO1 CNV are highly possible occurring in MSS patients. Furthermore we analyzed the relationship between the copy number of DIDO1 and immune signature through CRC TCGA database. The results showed increase of DIDO1 copy number was negatively correlated with the abundance of NK cells (P = 0.00048), T cells (P = 8.23×10-5) and macrophages (P = 1.75×10-8). Conclusions: Our results showed that different MSI status display unique patent of DIDO1 gene variation, which may be related to different immune micro environment among MSI-H/MSS patients.
Stage II high-risk colon cancer: A retrospective analysis of the benefit of chemotherapy in patient subgroups based on the risk factor.
Authors: Jacob Linu Abraham
Published: May 2020

e16068

Background: Adjuvant chemotherapy is routinely recommended for patients with high risk stage II colon cancer. However the risk conferred by each high risk feature (HRF) may be different. This study was done to analyze the magnitude of benefit of chemotherapy in individual HRF patient subgroups. Methods: Resected stage II colon cancer patients during the period January 2012 to March 2018 were retrospectively analyzed for risk features, chemotherapy treatment and survival. Statistical analysis was done with SPSS 16.0. Results: A total of 41 patients were identified as having pathological stage II colon cancer during the study period - 63.4% were males and 36.6%, females. 68.3% had left sided tumor while 31.7% had right sided tumor. 29.3% had none of the high risk features and received no adjuvant chemotherapy. 70.7% patients had at least one of the high risk features and received adjuvant chemotherapy with fluoropyrimidine ± oxaliplatin. 90.2%, 7.3% and 2.5% had stage IIA, IIB and IIC disease respectively. 36.6%, 43.9% and 19.5% had grade I, II and III tumors respectively. Lymphovascular invasion (LVI) and perineural invasion (PNI) were present in 14.6% and 19.5% patients respectively. 29.3% had inadequate lymph node dissection. 22.0% patients had elevated CEA prior to surgery and 4.9% patients had presented with intestinal obstruction. After a minimum follow up period of 20 months the median disease free survival (DFS) was 26 months for the entire cohort. Left sided tumors had significantly prolonged median DFS compared to the right sided tumors (31 vs 26 months; p = 0.05). Median DFS was 24 months for the high risk group compared to 33 months for the low risk group (p = 0.002). On subset analysis T4 HRF subgroup had superior DFS, while LVI HRF subgroup had inferior DFS both of which were statistically significant. Conclusions: Magnitude of chemotherapy benefit was highest in the T4 subgroup, while it was lowest in the LVI subgroup in resected stage II high risk colon cancer [Table: see text]
Age-dependent prognostic value of KRAS mutation in metastatic colon cancer.
Authors: Ozer Muhammet , Goksu Suleyman Yasin , Sanford Nina Niu , Aguilera Todd Anthony , Kainthla Radhika , Jones Amy Little , Sanjeevaiah Aravind , Beg Muhammad Shaalan , Kazmi Syed Mohammad Ali
Published: May 2020

e16085

Background: KRAS mutation is associated with poor prognosis in metastatic colon cancer (mCC). However, the age-dependent prognostic value of KRAS status is unknown. We aimed to confirm if the prognostic impact of KRAS is dependent on the age of diagnosis in mCC. Methods: We identified adult patients with mCC diagnosed between 2004 and 2016 using the NCDB. We compared patients with KRAS mutation and KRAS wild type, stratified according to age group < 50, 50-70, and ≥70. Categorical variables were compared using the chi-square test. We performed the Kaplan-Meier and Cox regression methods for survival analyses. We adjusted for patient and tumor characteristics (included KRAS status, MSI, 18q loss of heterozygosity, side of the primary tumor). Results: A Total of 19,875 patients had KRAS status reported; 43% had KRAS mutation, and 57% were KRAS wild type. Patients with KRAS mutation were more likely to be female, black, have elevated CEA, and have right-sided tumors (all p < .001). In the overall population, patients with KRAS mutation had significantly worse OS compared to patients with KRAS wild type (20 vs. 22 months, p < .001), and this difference was maintained after multivariable Cox regression analysis ( p < .001) (Table). Young patients ( < 50 years) with KRAS mutation had a worse prognosis than those with KRAS wild type in the tumor (23 vs. 29 months, p < .001). KRAS status did not maintain its prognostic value among older age (≥70 years) patients (14 vs. 14 months, p = NS). Conclusions: In this analysis of a national cancer registry, we confirmed that KRAS mutation was an independent poor prognostic factor for mCC. This effect persisted after adjusting for patient and tumor characteristics, including sidedness and MSI status. However, we identified that this prognostic value of KRAS mutation is significant in young mCC patients < 50 years, as compared to older patients. [Table: see text]
Incidence of and risk factors for hospitalizations from chemotherapy among patients with stage III and stage IV colorectal cancer.
Authors: Falconi April , Fishman Ezra , Barron John , Eleff Michael , Fisch Michael Jordan , Chi Winnie
Published: May 2020

e16090

Background: Despite the decreasing colorectal cancer (CRC) mortality rate over the past decade, complications from CRC treatment remain a challenge. Prior research has shown that a majority of patients with stage III CRC in the adjuvant setting experience hospitalizations due to chemotherapy-related toxicity. Minimal research, however, has examined risk factors of these events and the prevalence of hospitalization among stage IV CRC patients. Methods: We used claims data from a geographically-diverse private health insurer—including both commercially-insured and Medicare Advantage patients—to estimate and characterize risk factors of hospitalizations among Stage III or IV CRC patients. We compared sociodemographic, clinical, as well as provider characteristics and cancer treatment regimens between patients with and without hospitalizations from the initiation of chemotherapy to 60 days after the end of chemotherapy. Results: Incidence rates for hospitalization from chemotherapy were 49% and 70% for stage III and IV CRC patients, respectively. Although the oldest stage III CRC patients (age 75+) were the most likely to experience hospitalizations, the youngest age group (age 18-49) of stage IV patients experienced the highest incidence (74%) of hospitalizations (p < 0.05). Higher values of the Elixhauser comorbidity index was associated with a higher risk for hospitalizations among patients with stage III CRC (p < 0.001). Both stage III and stage IV patients with diabetes were more likely (p < 0.05) to have hospitalizations from chemotherapy (55% and 73%, respectively). Conclusions: Hospitalization from chemotherapy is very common among stage III and IV CRC patients. These data identify subgroups at higher risk. Study findings may inform choice of cancer treatment regimen and focus on key underlying medical needs
Sensitivity of colorectal or pancreatic cancers with high DDX5 and mutations in Kras and p53 genes to FL118 treatment.
Authors: Ling Xiang , Wu Wenjie , Liao Jianqun , Santha Sreevidya , Aljahdali Leman , Wang Jue , Fountzilas Christos , Iyer Renuka V. , Boland Patrick M , Li Fengzhi
Published: May 2020

e16102

Background: FL118 is a small molecule anticancer drug with novel mechanisms of action, although its chemical structure is similar to camptothecins. Currently, FL118 is completing its IND process to enter clinical trials for patients with advanced colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) cancers. Precision medicine is becoming a trend for modern cancer treatment. Thus, identification of drug efficacy-relevant biomarker(s) for patient selection is critical for enhancing patients’ response rates and avoiding unnecessary treatment in the clinic. Methods: Animal models of CRC and PDAC patient-derived xenograft (PDX) tumors were used to test FL118 efficacy; next generation sequencing (NGS) was used to determine PDX tumor molecular profiles; Western blots (WB) and real time RT-PCR were used to determine gene expression and/or apoptosis; Immunoprecipitation (IP) plus WB was used to determine protein phophorylation. Proteasome inhibitor was used to determine protein expression pathway. FL118 affinity purification was used to identify FL118 binding protein(s). Results: In association with WuXi Apptec, we have completed FL118 CMC and produced a clinical compatible product formulation. In this new product format, FL118 exhibits excess toxicity at a dose of ≥ 7.5 mg/kg via weekly x 4 schedules in mice. However, dosages of ≤ 6 mg/kg via the same schedule are tolerable. FL118 can eliminate the Kras/p53/APC triple-mutated SW620-established CRC tumors in a high percentage of mice at doses of 6 (maximum tolerated dose, MTD), 5, 4, 3, and 2 mg/kg. Tumor elimination under MTD is a typical characteristic of targeted drugs, which do not need MTD but only need the target to be saturated with drug for maximal efficacy. High expression of DDX5 (also called p68), a multifunctional oncogenic transcriptional co-activator and a DEAD-box RNA helicase, is associated with high FL118 efficacy in both CRC and PDAC PDX tumors. Mechanistically, FL118 binds to DDX5 to induce DDX5 tyrosine dephosphorylation and protein degradation without decreasing its mRNA. Tumors with Kras mutation (mKras) and/or TP53/p53 mutation (mp53) possess intrinsic resistance to multiple classic chemotherapeutic agents. However, PDAC PDX tumors with mp53 exhibit higher mKras expression and greater sensitivity to FL118 than tumors with wild type p53 and mKras. Conclusions: DDX5, mKras and mp53 appears to be favorable biomarkers for predicting FL118 high efficacy. However, further studies with a large cohort will be needed for confirmation.
Overlooking MMR deficiency in carriers of certain pathogenic variants by routine MSI and/or IHC testing in Lynch syndrome: Implications for a wider MMR deficiency testing.
Authors: Staninova Stojovska Marija , Kubelka Sabit Katerina , Jasar Dzengis , Jovanovic Rubens , Matevska Nadica , Angelovska Biljana , Mitrevski Nenad , Panovski Milco , Dimovski Aleksandar J
Published: May 2020

e16107

Background: DNA mismatch repair (MMR) deficiency occurs in both inherited/sporadic colorectal cancer (CRC) and endometrial cancer, but it may also be found in some other types of cancer. At present, MMR status testing in clinical practice is recommended for all CRC patients in order to identify those who should be offered genetic testing for the Lynch syndrome (LS), inform disease prognosis, and guide therapeutic management.There are two commonly accepted methods for MMR deficiency analysis, one based on the detection of microsatellite instability (MSI) by PCR and the other based on the detection of protein expression of the MMR genes using immunohistochemistry (IHC). The objective of this study was to evaluate the concordance between IHC and MSI in tumors from 18 LS patients with known pathogenic germline variants in MMR genes (MLH1, MSH2, PMS2 and MSH6). Methods: The MSI testing was performed using the five gene Bethesda panel (BAT25, BAT26, D2S123, D5S346, D17S250) while the IHC testing was done with the use of a standard 4 antibody panel (MLH1, MSH2, PMS2 and MSH6). Results: High concordance of the two methods was observed in 13/18 (72.2%) patients, mainly with disruptive mutations in the МLH1, MSH2 and PMS2 genes. Inconsistent results were obtained in 5/18 (28.8%) patients, of whom two had a positive result only with the use of the PCR method [carriers of MLH1 c.62C > T (p.Ala21Val) and c.244A > G (p.Thr82Ala) missense variants], other two had a positive result only with IHC [carriers of MSH6 c.3514dupA (p.Arg1172LysfsTer5) and c.2384T > C (p.Ile795Thr)] and one patient had normal results using both methods (carrier of MSH6 c.457+1G > T splice site mutation that results in exon 3 skipping). A positive predictive value of either MSI or IHC used as a single methods for screening was 83.3%, which indicates that a substantial number of cases with MMR tumors can be misdiagnosed by using only either one or the other of these two methods. Conclusions: These results have a potential implication not only for LS screening in CRC patients, but also for the detection of the MMR deficiency in patients with various tumors that might benefit from the checkpoint inhibitor immunotherapy. The use of extended MSI NGS panels might provide a higher sensitivity for the detection of MMR deficiency compared to the standard MSI or ICH testing.