bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of end-binding protein 1 (EB1), a potential response-predictive biomarker for lisavanbulin, in glioblastoma and various other solid tumor types.
Authors: Skowronska Magdalena , Tiu Crescens Diane , Tzankov Alexandar , König Fatima , Lewis Joanne , Vivanco Igor , Kleinschmidt Malte , Beebe Kirk , Anderson Stephanie , Bachmann Felix , Engelhardt Marc , Lane Heidi A , Kaindl Thomas , Stan Alexandru C , Plummer Elizabeth Ruth , Evans T.R. Jeffry , Zlobec Inti , Lopez Juanita Suzanne
Published: June 2021

3118

Background: EB1, a protein located on the plus-ends of microtubules is involved in microtubule function and has been associated with glioblastoma (GBM) stem-cell-ness and more aggressive disease. Lisavanbulin (BAL101553) is a prodrug of the lipophilic small molecule BAL27862, that promotes tumor cell death by modulating the spindle assembly checkpoint and has been shown in rodents to efficiently penetrate the brain. Data from GBM mouse models and recent phase 1 clinical data (Lopez et al. ESMO 2020) suggest that EB1 is a response-predictive marker for lisavanbulin in GBM. A phase 2 study is ongoing to confirm this hypothesis (NCT02490800). A proof-of-concept in GBM would support an expansion of EB1-directed lisavanbulin clinical development in non-GBM tumors, which requires prevalence estimates of EB1-positivity in non-GBM tumor types. Methods: Tissue samples from GBM and other tumor types were stained for EB1 using a CE-marked immunohistochemistry Clinical Trial Assay (Targos Molecular Pathology GmbH, Kassel Germany). EB1-positivity was assessed by a board-certified pathologist based on the percentage of tumor cells showing moderate or strong staining for EB1, using thresholds of ≥50%, ≥60% and ≥70% of tumor cells with EB1 positivity. Whole transcriptome sequencing (WTS) using RNAseq was performed in a subset of tissue samples to develop a potential RNA-based predictive response signature for lisavanbulin. Results: 73 GBM tissue samples and 333 tissue samples from 13 other cancer types were stained for EB1. The strongest overall signal for EB1-positivity was obtained for medulloblastoma, neuroblastoma and GBM. In addition, moderate or strong EB1-staining in ≥50% of tumor cells was observed in samples from colorectal cancer (CRC), non small-cell lung cancer (NSCLC), metastatic melanoma, small-cell lung cancer (SCLC) and triple-negative breast cancer (TNBC). An expanded staining campaign is ongoing in these cancer types. Initial results from the ongoing WTS analyses show marked differences in gene expression profiles between EB1-positive and -negative cases. Conclusions: Strong EB1-positivity is infrequent but occurs in a variety of tumor types, with the strongest signals in medulloblastoma, neuroblastoma and GBM. A phase 2 study is ongoing to assess prospectively whether EB1 is a response-predictive biomarker for lisavanbulin in GBM.[Table: see text]
The impact of clinical decision making in a molecular tumor board at a tertiary care center.
Authors: Sadaps Meena , Demski Kathryn , Ni Ying , Konig Vicky , Leach Brandie , Mazzei Emily , Funchain Pauline
Published: June 2021

3128

Background: Multidisciplinary molecular tumor boards were first established with the onset of precision oncology (PO), as many clinicians were unfamiliar with the interpretation and incorporation of the information into clinical practice. PO has since rapidly evolved and integrated itself into standard of care practices for most cancer patients, yet molecular tumor boards have not grown accordingly and in fact some have been discontinued. There remains a paucity of data in regards to the value and impact of molecular tumor board discussions themselves. We previously reported on our longitudinal experiences in PO ( Sadaps et al, 2018), focusing on the therapeutic impact of matched therapy. Here, we report on the utility of our molecular tumor board in clinical decision making. Methods: We conducted a retrospective review of patients seen at Cleveland Clinic with a solid tumor malignancy who had large panel, next-generation-sequencing (NGS) performed via any commercial platform from November 2019-January 2021. Cases were filtered through a local therapeutic algorithm and then reviewed individually. Initial review was performed by a core genomics committee comprised of 2 oncologists and 2 genetic counselors. Interesting and/or complex cases were flagged for discussion at our bimonthly molecular tumor board, which is regularly attended by medical oncologists, pathologists, genetic counselors, bioinformaticians, and patient care coordinators. Data analyzed included categorization of treatment recommendations and the percentage of cases for which initial recommendations were changed based on tumor board discussion. Results: Of 782 total cases, 575 (73.5%) had a clinically relevant genomics tumor board (GTB) recommendation as compared to 51.7% from our previously reported study. 16.7% of patients had on label recommendation(s) and 86.4% had off label/ clinical trial recommendation(s). 179 (22.9%) patients were recommended for genetic counseling (GC). During our bimonthly GTB, we discussed 173 (22.1%) of these cases. Of the discussed cases, the most common tumor types were hepatobiliary (18.5%), lower gastrointestinal (17.3%), and breast (16.2%). Topics of discussion at GTB included such things as pathologic/histologic/molecular testing, prioritization of available trials, appropriateness of an off label therapy, and need for a genetics consult. Discussion at GTB resulted in a change in treatment recommendation in 63 (36.4%) cases. Conclusions: Discussions from multidisciplinary molecular tumor board impacted treatment decisions for our patients. Referral to GC was also common and should be considered an integral part of somatic sequencing review. Molecular tumor boards remain a crucial platform for treatment guidance and clinical management, especially given the increase in “actionability” over the years due to newly discovered targets and targeted therapies in this rapidly evolving field.
Randomized study to investigate FOLFOXIRI plus either bevacizumab or cetuximab as first-line treatment of BRAF V600E-mutant mCRC: The phase-II FIRE-4.5 study (AIO KRK-0116).
Authors: Stintzing Sebastian , Heinrich Kathrin , Tougeron David , Modest Dominik Paul , Schwaner Ingo , Euker Jan , Pihusch Rudolf , Stauch Martina , Kaiser Florian , Kahl Christoph , Karthaus Meinolf , Mueller Christian , Burkart Christof , Reinacher-Schick Anke C. , Kasper Stefan , Fischer von Weikersthal Ludwig , Krammer-Steiner Beate , Prager Gerald W. , Taieb Julien , Heinemann Volker
Published: June 2021

3502

Background: FIRE-4.5 (AIO KRK-0116) compared FOLFOXIRI plus either cetuximab or bevacizumab in BRAF V600E-mutant metastatic colorectal cancer (mCRC) patients not treated for metastatic disease before. Methods: Within this 1:2 randomized, controlled, open-label phase-II study, patients received FOLFOXIRI every two weeks at the following schedule: irinotecan 150mg/m² (30-90min, day 1), folinic acid 400mg/m² (120min, day 1), oxaliplatin 85mg/m² (120 min, day 1), followed by 5-fluorouracil 3,000 mg/m², 48h. FOLFOXIRI was combined with either bevacizumab (arm A) at a dose of 5mg/kg body weight, every 2 weeks or cetuximab (arm B) at a loading dose of 400mg/m² and subsequent weekly doses of 250mg/m². FOLFOXIRI was applied for a maximum of 12 cycles before maintenance treatment was recommended. Primary endpoint was superiority of Arm B with respect to overall response rate (ORR) according to RECIST 1.1 criterions. Secondary endpoints included PFS, OS, and tolerability. Results: From November 2016 to December 2020 108 patients were randomized in 90 German and 10 French centers (35 arm A and 73 in arm B). No new or unexpected toxicities were observed. Primary endpoint was not met with an ORR of 66.7% and 52.0% (p =0.23) in the respective arms. Median PFS was significantly longer in arm A vs arm B (8.3 months vs 5.9 months; logrank p = 0.03; HR 1.8). While OS data is still immature, median OS time are comparable at the time of analysis. Patients with left-sided primary tumors had comparable results with either bevacizumab or cetuximab, whereas those with right-sided primary tumors showed a trend towards better efficacy of the bevacizumab combination. Updated results will be presented at the annual meeting. Conclusions: FIRE-4.5 is the first prospective and randomized study investigating efficacy of FOLFOXIRI combined with targeted therapy in the first-line treatment of BRAF V600E-mutant mCRC. FOLFOXIRI plus either bevacizumab or cetuximab have comparable efficacy with differential effects according to primary tumor sidedness supporting the heterogeneity of BRAF V600E-mutant subpopulation of mCRC. Clinical trial information: NCT04034459.
Microbiome signature, global methylation and immune landscape in early onset colorectal cancer.
Authors: Jin Ning , Mo Xiaokui , Hoyd Rebecca , Yilmaz Ayse Selen , Liu YunZhou , Jagjit Singh Malvenderjit , Muniak Mitchell , Hampel Heather , Spakowicz Daniel
Published: June 2021

3519

Background: The incidence of colorectal cancer (CRC) in young adults ( < 50 years old) has been rapidly increasing by 2% per year since early 1990. Approximately 20% of early-onset (EO) CRC cases are due to germline gene mutations. However, the etiology of sporadic EO CRC remains poorly understood. Research suggests that environmental factors such as the Western diet (high in fat and low in fiber) may be associated with an increased incidence of sporadic EO CRC. The gut microbiota decompose and ferment dietary fibers to produce microbial metabolites, which play pivotal roles in maintaining the integrity of intestinal epithelium as well as the immune cell homeostasis. Also, these microbial metabolites may influence the host epigenome by altering either the activity of epigenetic enzymes or by modifying the availability of cofactors needed for epigenetic modifications. The aim of our research is to associate intratumoral microbiota with methylation pattern and immune cell composition in EO CRC. Methods: A total of 358 CRC cases, including 54 cases of EO CRC (age < 50 years) and 304 cases of late onset (LO) CRC (age ≥ 50 years), with matched methylation array (Infinium HM450), RNA-sequencing (Illumina HiSeq) from colon adenocarcinomas (COAD) and rectal adenocarcinomas (READ), and clinicopathological information of each patient, were extracted from the Cancer Genome Atlas (TCGA). We characterized and compared the intra-tumoral microbiota composition, tumor-infiltrating lymphocytes (TILs), and methylation profile between EO and LO CRC. Results: We found that there is a distinct microbial distribution, gene expression and methylation pattern in the EO CRC when compared with LO CRC. Non-human sequences from several kingdoms including bacteria, fungi and viruses were found and the incidences were consistent with reported values by other methods, e.g. Fusobacterium incidence. The EO CRC cases showed global hypomethylation, even though hypermethylation pattern is expected in the young chronological age group (known as Horvath’s clock). Pathway overrepresentation analysis of differentially expressed genes showed significant activation of p53 and pentose phosphate pathways and de novo nucleotide synthesis in EO CRC. Integration across datasets showed positive correlations between microbes and inflammasome pathway, positive correlation with regulatory T cells (Tregs), and negative correlations with CD4 memory T cells. Conclusions: These data suggest a mechanism by which the colorectal cancer-associated microbiota may be associated with epigenetic regulation and host immune response.
Clinical utility of stool-based SDC2 methylation test for the detection and screening of colorectal cancer in a Chinese population.
Authors: Liu Yanmei , Yin Weiguo , Peng Lei , Wang Xianshu , Zou Hongzhi , Zhou Haibo
Published: June 2021

3525

Background: In 2020, colorectal cancer (CRC) ranks second in incidence and third in mortality among all types of cancers in China based on data from GLOBOCAN. Moreover, the rates of incidence and mortality have been continuously rising over the past several decades. In addition to conventional methods for detection and screening of CRC such as gFOBT, FIT, and colonoscopy, a stool-based methylation test of human SDC2 gene was recently approved by National Medical Product Association (NMPA) of China. We hereby report the performance of this newly approved test in a hospital-based cohort of more than 10,000 patients in the real world of daily clinical practice. Methods: The methylation target, human SDC2 gene, was extracted from stool and purified via sequence-specific capture technology. The isolated DNA was further treated with bisulfite before it was subsequently amplified by quantitative methylation-specific polymerase chain reaction (qMSP) to analyze the fecal level of SDC2 methylation. Subjects were further examined by colonoscopy or CT imaging. Pathological examination would also be performed in cases deemed necessary. Results: A total of 11,284 individuals were tested using the novel SDC2 methylation test. Among them, 858 and 10,426 were tested positive and negative, respectively. Follow-up visits, treatment, and medical information were complete for 429 positive and 780 negative patients who were included in this final analysis. Positive predictive value (PPV) of CRC and adenomas was 36.4% (156/429) and 24.5% (105/429), respectively. Stratified analysis implies that SDC2 methylation level in CRC was significantly higher than those in adenoma and normal groups. In CRC, no significant correlation was observed between SDC2 methylation and clinicopathological features including gender and grade of dysplasia. In < 65 and ≥ 65 age groups, the CRC detection rate in males was higher than that in females―almost two times higher in ≥ 65 age group. Conclusions: The stool-based SDC2 methylation test demonstrated high accuracy in the detection of CRC and advanced adenomas. It is a sensitive and valid modality expected to play a significant role to aid diagnosis and screening of CRC and precancerous lesions in order to reduce the morbidity and mortality of this malignant disease.
Automated computed tomography (CT)-derived skeletal muscle mass determination as a significant prognostic factor in colorectal cancer patients using deep neural network model.
Authors: Seo Dongjin , Kim Han Sang , Park Yu Rang
Published: June 2021

3534

Background: Although recent evidence suggests skeletal muscle depletion predicts the survival of patients with cancer, the retrieval and manual measurement of the computed tomography (CT) images hinder clinical application in routine clinical practice. The advent of recent deep learning applications enables highly accurate noninvasive longitudinal evaluation of skeletal muscle mass (SMM) changes. Here, we evaluated the prognostic impact of DNN-measured skeletal muscle changes in colorectal cancer (CRC) patients. Methods: A total of 6,196 newly diagnosed CRC patients were analyzed in the Yonsei Cancer Registry Database between Jan 1, 2010, and Sep 30, 2020. SMM is measured by the Skeletal muscle index (SMI). The formula used was: L3 skeletal muscle cross-sectional area (cm2)/height2 (m2). Patients’ SMI patterns were grouped by difference ratio of initial and last SMI. Patients were also classified by BMI pattern with the result of K-means clustering. Association of baseline SMI, baseline body mass index (BMI), SMI changes, BMI changes, and demographic factors with overall survival (OS) were evaluated. Univariate and multivariate analyses were conducted. Concordance (c) statistics were used to test the predictive accuracy of survival models. Results: Fully automated UNet architecture-based deep learning algorithms were applied for the third lumbar transverse CT detection, skeletal muscle segmentation, and skeletal muscle area quantification in CRC patients undergoing abdominal CT between at the time of diagnosis and one year after the diagnosis. Baseline BMI distribution was 28% obese, 26% overweight, 42% normal weight, and 4% underweight. Patients in all SMI categories varied widely in BMI. Changes in SMI were categorized into three groups: SMI increase (33%), steady (45%), and decrease (22%) group. Similarly, BMI changes were categorized into three groups: BMI increase (24%), BMI stable (57%), and BMI decrease (19%) group. Low baseline SMI, low baseline BMI, SMI decrease, and BMI decrease were independently prognostic of survival. Intriguingly, BMI and SMI changes had a different prognostic impact in men and women. For women, the SMI increase group (hazard ratio [HR], 0.4; 95% CI, 0.3-0.7; P= 0.001) was associated with longer OS, while the SMI decrease group (HR, 1.2; 95% CI, 0.6-2.2; P= 0.619) was not associated with shorter OS, both compared with SMI steady group. Conclusions: Automated CT-derived SMM depletion had a negative prognostic impact independent of BMI and age in CRC patients. A noninvasive automatic deep learning algorithm provides a unique opportunity to apply to routine clinical practice and understand how and when cachexia impacts cancer prognosis.
Are current family-history based colorectal cancer screening guidelines adequate for early detection and potential prevention of young-onset cases?
Authors: You Y. Nancy , Rodriguez-Bigas Miguel A. , Chang George J. , Bednarski Brian K. , Skibber John Michael , Mork Maureen E , Moskowitz Julie B , Nguyen Sa Thi , Thirumurthi Selvi , Lynch Patrick M. , Kopetz Scott , Vilar Sanchez Eduardo
Published: June 2021

3549

Background: Strategies to detect and prevent young-onset colorectal cancer (YOCRC, diagnosed under age 50) are critical. Established high-risk screening guidelines (SGs) aim to detect/prevent YOCRCs arising from hereditary syndromes. For non-hereditary YOCRCs, average-risk screening is being considered at an earlier age, but family history (FH)-based increased-risk screening has been poorly studied. We aimed to define the proportion of non-hereditary YOCRC with a FH, and to determine whether existing SGs could have detected/prevented these cases. Methods: 394 consecutive YOCRC patients presenting for surgical resection were reviewed for tumor MMR status, pedigree and genetic testing. Those with known/suspected hereditary syndrome (by phenotype, MMR status, and/or germline mutation) were excluded (N = 65). Pedigrees (N = 329) were analyzed for first- or second-degree relatives (FDR, SDR) with CRC and the ages of diagnosis. The gap between the recommended age for FH-based CRC screening and the age of YOCRC diagnosis was calculated. Results: 89 (27%) non-hereditary YOCRC patients had a FH of CRC. The median age of diagnosis was 45; the tumors were mostly from the distal colon (22%) and rectum (60%), and stage III (48%) and IV (27%). Twenty-one (24%) patients had 22 FDRs with CRCs diagnosed at age 64 (median); and 71 (80%) patients had 92 SDRs with CRCs diagnosed at age 65 (median). Thirteen (15%) had a FH of YOCRC. The existing SGs consider 39 patients (44%) at increased-risk, and the remaining, average-risk (Table). Screening would have begun prior to the YOCRC diagnoses in 28 (31% [or 46, 52%]) patients. But YOCRC diagnosis preceded the recommended screening age in the remaining 61(69% [or 43, 48%]) patients by a median of 5.3 [or 3.9] years (Table). Conclusions: FH is found in 27% of the non-hereditary YOCRC patients; 15% has a FH of YOCRC. In nearly half of the patients, YOCRC was diagnosed several years earlier than the recommended age for FH-based screening, even assuming perfect SG adoption and starting average risk screening at age 45. Refining existing FH-based SGs can potentially be impactful.[Table: see text]
Single-arm, phase 2 study of regorafenib plus nivolumab in patients with mismatch repair-proficient (pMMR)/microsatellite stable (MSS) colorectal cancer (CRC).
Authors: Fakih Marwan , Raghav Kanwal Pratap Singh , Chang David Z. , Bendell Johanna C. , Larson Timothy , Cohn Allen Lee , Huyck Timothy K. , Cosgrove David , Fiorillo Joseph A. , Garbo Lawrence E. , Ravimohan Shruthi , Potter Von , D'Adamo David , Sharma Neelesh , Wang Ying A. , Coppieters Sabine , Herpers Matthias , Soares Viana de Oliveira Carolina , Paulson Andrew Scott
Published: June 2021

3560

Background: The role of immunotherapy in the treatment of pMMR/MSS metastatic CRC is not established. A Japanese phase 1b trial in this setting showed the combination of regorafenib (multikinase inhibitor with immunomodulatory activity) plus nivolumab (anti PD-1) had encouraging activity and manageable safety (Fukuoka, 2020). This study further assessed the safety and efficacy of this combination. Methods: Patients (pts) from the US aged ≥18 years who progressed on/were intolerant to standard chemotherapy were enrolled. Regorafenib was given orally, once daily in 28-day (D) cycles (21D on/7D off) plus IV nivolumab 480 mg on D1. Regorafenib starting dose was 80 mg; if well tolerated, it could be escalated to 120 mg in Cycle 2. Primary endpoint was overall response rate (ORR; RECIST 1.1); secondary aims included disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and safety (NCI-CTCAE v5.0 grade). Biomarker analysis was exploratory. Results: 70 pts (59% male) started treatment. At baseline, median age was 57 years (range 34–85), ECOG PS 0/1 was 51%/49%, 67% had liver metastases (mets), and the primary tumor site was right-sided colon in 36% and rectum in 17%. Median number of cycles was 3.0 (range 1–13); 41% of pts escalated regorafenib to 120 mg. Five pts (7.1%) had a partial response (PR) lasting ≥16 weeks (wks) and 22 (31.4%) had stable disease (SD); pts without liver mets had a higher ORR (21.7%). In pts with tumor samples (n = 40), higher baseline expression (IHC) of cytotoxic T cells (CD3+/CD8+/GranzymeB+), Tregs (FoxP3+), and macrophages (CD68+) trended with clinical benefit (PR/SD ≥16 wks/PFS); pts with liver mets had lower expression. Lower plasma levels of biomarkers of vascular biology (e.g. VEGF-D, Ang-2, VWF) trended with longer PFS. Grade (Gr) 3 treatment-emergent adverse events (TEAEs) occurred in 53% of pts and Gr 4 in 10%. Three pts had a Gr 5 TEAE: n = 1 related to the combination (sepsis); n = 1 related to nivolumab only by investigator (sepsis); n = 1 unrelated to treatment (respiratory failure). Most common Gr 3/4 TEAEs: maculopapular rash (14%), fatigue (7%), pneumonia (6%), increased bilirubin (6%). Conclusions: Combination treatment with regorafenib (up to 120 mg/day) and nivolumab (480 mg every 28D) has manageable safety. Efficacy of this combination in the North American population did not emulate results in the Japanese population. Absence of liver mets and expression of specific biomarkers indicate a better response and may warrant further analysis. Clinical trial information: NCT04126733. [Table: see text]
Overall survival (OS) with encorafenib (enco) + cetuximab (cetux) in BEACON CRC: Effect of prior therapy for BRAF V600E-mutant metastatic colorectal cancer (mCRC).
Authors: Kopetz Scott , Aderka Dan , Grothey Axel , Van Cutsem Eric , Yaeger Rona , Wasan Harpreet Singh , Yoshino Takayuki , Desai Jayesh , Ciardiello Fortunato , Gollerkeri Ashwin , Golden Adele , Edwards Michelle L. , Tabernero Josep
Published: June 2021

3583

Background: Enco + cetux (doublet) has been approved in the US, EU, and Japan for the treatment of BRAF V600E-mutant mCRC after progression on 1–2 prior regimens. In the BEACON CRC study (NCT02928224), median OS (95% CI) with the doublet was 9.3 months (8.0–11.3) compared with 5.9 months (5.1–7.1) with cetux + irinotecan or FOLFIRI (control) in patients (pts) with BRAF V600E-mutant mCRC (HR 0.61 [95% CI: 0.5–0.8]). This post-hoc analysis investigates OS by prior therapies to the doublet treatment in pts with BRAF V600E-mutant mCRC from the BEACON CRC study. Methods: OS of pts treated with the doublet or control were compared according to prior treatment with bevacizumab, oxaliplatin, or FOLFOXIRI and duration of prior anticancer therapy (ACT). Results: The proportion of pts in the doublet and control arms who received prior bevacizumab were 64% and 55%, respectively. Of pts who had one prior therapy, 95% and 88% received prior oxaliplatin and 20% and 14% received prior FOLFOXIRI, respectively. OS by prior treatment in the doublet and control arms is shown in the table. In the doublet arm, pts who had bevacizumab < 4 months before start of study treatment had a median OS of 8.3 months (95% CI: 6.2–11.2); those who had bevacizumab ≥4 months prior had a median OS of 10.7 (95% CI: 7.5–17.7). Within each treatment arm, OS was similar regardless of prior treatment with oxaliplatin or FOLFOXIRI. The duration of prior ACT was similar across study arms, ranging from 5.6–5.8 months for the first line of ACT. Conclusions: In the BEACON CRC study, pts treated with the doublet for BRAF V600E-mutant mCRC demonstrated similar OS regardless of prior therapies or duration of prior therapy use. This exploratory post-hoc analysis provides data that reflect the prior treatment landscape clinicians may face when deciding subsequent treatment regimens for pts with BRAF V600E-mutant mCRC. Clinical trial information: NCT02928224. [Table: see text]
Association of plasma adiponectin with tumor infiltrating lymphocytes and survival in patients with stage III colon cancer (NCCTG N0147; Alliance).
Authors: Sinicrope Frank A. , Shi Qian , Smyrk Thomas C. , Goldberg Richard M. , Cohen Steven J. , Gill Sharlene , Kahlenberg Morton S. , Nair Suresh , Shields Anthony Frank , Jahagirdar Balkrishna N. , Jacobson Sawyer B. , Foster Nathan R. , Pollak Michael N. , Alberts Steven R
Published: June 2021

3591

Background: Adiponectin is a peptide hormone exclusively secreted by adipocytes that plays a role in immune regulation and in the host inflammatory response to cancer. We examined postsurgical adiponectin levels in relationship to tumor infiltrating lymphocytes (TILs), clinicopathological features, vitamin D status, and patient survival in participants in a phase 3 trial of adjuvant chemotherapy. Methods: Plasma adiponectin and 25-hydroxyvitamin D [25(OH)D] were analyzed by radioimmunoassay in 600 patients with stage III colon carcinoma who received adjuvant FOLFOX +/- cetuximab. TIL densities were determined at light microscopy in routine histopathological sections. The associations between adiponectin and 25(OH)D, TILs, other factors were evaluated by Fisher’s Exact, Chi-squared, t-test, and Kruskal-Wallis tests where appropriate. The association between adiponectin or 25(OH)D with disease-free survival (DFS), time to recurrence (TTR) and overall survival (OS) were evaluated by multivariable Cox regression, adjusting for body mass index (BMI), race, T, N stage, performance status, tumor location, TILs, BRAF/KRAS, and mismatch repair status. Results: A statistically significant and inverse association between adiponectin level and BMI was observed with lower levels found with obesity (BMI > 30 kg/m2) [p < 0.001]. The level of adiponectin was significantly lower in men vs women (p < 0.001), in blacks vs whites or Asians (p < 0.032), and in patients with fewer regional lymph node metastases (N1 vs N2 stage, p = 0.011). A significantly lower level of adiponectin was found in patients whose tumors had high vs low TIL densities (p = 0.040), but was unrelated to 25(OH)D. Insufficiency of 25(OH)D ( < 30 ng/ml) was detected in 291 (49%) of patients and was not associated with TILs. By multivariable analysis, adiponectin was not associated significantly with patient DFS (HRadj= 0.98, 95% CI 0.74-1.29, padj= 0.88) nor with OS nor time-to-recurrence (TTR). TIL densities were significantly prognostic, but 25(OH)D was not (DFS: HRadj= 1.12, 95% CI 0.85-1.47, padj= 0.44). No significant interaction was observed for adiponectin with TILs for the association with DFS. Conclusions: Lower adiponectin levels were associated with significantly increased TIL densities in colon cancers, indicating an enhanced anti-tumor immune response. In contrast to TILs, adiponectin was not independently associated with patient outcome. Nearly one-half of stage III patients were vitamin D insufficient, although 25(OH)D was not prognostic.
A novel clinical tool to estimate risk of false negative KRAS mutation in circulating tumor DNA testing.
Authors: Napolitano Stefania , Sun Ryan , Parikh Aparna Raj , Henry Jason , Parseghian Christine Megerdichian , Willis Jason , Raghav Kanwal Pratap Singh , Morris Van K. , Dasari Arvind , Overman Michael J. , Luthra Rajyalakshmi , Corcoran Ryan Bruce , Kopetz Scott
Published: June 2021

3594

Background: Recently, in metastatic colorectal cancer (mCRC), the detection of RAS mutations by circulating tumor (ct) DNA has recently emerged as a valid and non-invasive alternative approach, overall showing a high concordance with the standard tissue genotyping, giving information on response to EGFRi treatment and resistant mechanisms. However, RAS mutations may be missed due to low levels of any ctDNA in the blood (false-negative), and it has been difficult to distinguish this from patients without a RAS mutation in the tumor (true-negative). We propose a methodology that can be applied to multi-gene ctDNA testing panels to accurately distinguish true- and false-negative tests. Methods: 357 subjects with tissue and multi-panel ctDNA testing from MD Anderson (MDACC) were used as a training dataset and 295 subjects from Massachusetts General Hospital (MGH) dataset as the testing dataset. CtDNA panels contained between 65 and 70 genes, allowing evaluation of tumor ctDNA shedding from variant allele fraction (VAF) levels in the plasma from other genes (such as APC and TP53). Based on the relationship between KRAS and the VAFs of other gene, we established a Bayesian model providing a posterior probability of false negative in the ctDNA test, using thresholds of < 5% (low), 5-15% (medium), and > 15% (high). This model was validated on the MGH database. Results: Across both cohorts, 431 patients were ctDNA wild type for KRAS. Of those, 29 had tissue documenting a KRAS mutation for a false negative rate of 8%. The model provides the posterior probability that a KRAS mutation is indeed present in the tissue given the observed values of allele frequencies for other mutated genes in the plasma. In the validation cohort, a predicted low false negative had no false negatives (0/62, 95% CI 0%-5.8%), while a predicted medium false negative rate was associated with 3% false negative (1/32, 95% CI 0%-16%). In contrast, a high predicted false negative rate was associated with 5% false negative (5/100, 95% CI 1.6%-11%). The results demonstrate the ability of our tool to discriminate between subjects with true negative and false negatives, as a higher proportion of false negatives are observed at higher posterior probabilities. Conclusions: In conclusion, our approach provides increased confidence in KRAS ctDNA mutation testing in clinical practice, thereby facilitating the identification patients who will benefit from EGFR inhibition while reducing the risk of false negative tests. Extension of this methodology to NRAS and BRAF is possible, with clinical application enabled by a freely available online tool.
H101 treatment of hepatic metastasis of colorectal cancer with recombinant human adenovirus 5 injection: A phase I clinical trial-TROJAN 021.
Authors: He Yang , Chen Jianhua , Zhu Zhongzheng , Gao Song , Wang Hui , Mao Wei , Qian Hong , Liu Weixing , Guo Xianling , Qing Huanlong , Xu Qing
Published: June 2021

3605

Background: Recombinant human adenovirus serotype 5 injection (H101), obtained through genetic engineering to delete the E1B domain and part of the E3 domain and then selectively replicated in tumor cells, has been approved in 2005 for the local treatment of nasopharyngeal carcinoma and head and neck cancers. This trial aimed to evaluate the safety and the preliminary treatment efficacy of H101 combined with standard treatments in patients with liver metastases from colorectal cancer. Methods: In this phase 1, dose-escalation trial (ChiCTR1900027922), 17-75 years old colorectal cancer patients with unresectable liver metastases that failed to first-line therapy were included at The Tenth People's Hospital Affiliated to Tongji University between 2018.9 and 2020.12. All patients received H101 combined with standard therapy (bevacizumab + mFOLFOX6/FOLFIRI). Ultrasound-guided injection of H101 into the liver metastases was performed for all patients, with one of the following doses: 5×1011 vp/injection for the low, 1×1012 vp/injection for the moderate, 2×1012 vp/injection for the moderate-high, and 3×1012 vp/injection for the high dose groups. Intravenous infusion of bevacizumab (5 mg/kg) and administration of standard-dose mFOLFOX6 or FOLFIRI within 48 h after the intratumor injection was performed. The primary endpoint of the trial was the maximum tolerated dose (MTD). The secondary endpoints included safety, tumor responses, and tumor marker CEA. The adverse events (AEs) were monitored according to the NCI Common Terminology Criteria for Adverse Events (CTCAE, Version 3.0) and evaluated within 1 week after injection. Imaging examinations were performed for all patients to evaluate the tumor responses, according to the irRECIST. Results: Finally, 8 patients were included; the numbers of patients in the 4 groups were 1, 3, 3, and 1, respectively. MTD was not observed in this study. No grade >4 AEs were observed. The major AE included fatigue (5/8), fever (4/8), shiver (3/8), abdominal pain (3/8), and night sweat (3/8). The tumor responses included partial response in one patient (moderate dose group), stable disease in 6 patients (1, 1, 3, and 1 in the low, moderate, moderate-high, and high dose groups, respectively), and progressive disease in 1 patient (moderate group). No dose-effect response was found. The tumor marker CEA was reduced in 6 of the 8 patients, including 1 (1/1), 3 (3/3), 2 (2/3), and 0 patients in the low, moderate, moderate-high, and high-dose groups, respectively. Conclusions: The safety of H101 combined with standard therapy for liver metastases from colorectal cancer is acceptable, which also shows certain preliminary efficacy. The phase 2 trial is now ongoing. Clinical trial information: ChiCTR1900027922. [Table: see text]
Accurate early-stage colorectal cancer detection through analysis of cell-free circulating tumor DNA (ctDNA) methylation patterns.
Authors: Kinross James M. , Canal-Noguer Pol , Chersicola Marko , Knap Primož , Bitenc Marko , Perera-Lluna Alexandre , Roehrl Michael H. A. , Kruusmaa Kristi
Published: June 2021

3606

Background: Colorectal cancer (CRC) screening programs suffer from poor uptake and biomarkers have limited diagnostic accuracy. The measurement of the methylation status of tumor-derived cell-free DNA in plasma may address these challenges. We used a targeted methylation panel, tumor-derived signal deduction and machine learning algorithm to refine a blood test for the detection of early-stage CRC. Methods: This was a prospective, international multicenter observational cohort study. Plasma samples were collected either prior to a scheduled colonoscopy as part of standard colorectal cancer screening or prior to colonic surgery for primary CRC. Differentially methylated regions (DMRs) were initially selected by analyzing CRC and control tissue samples with whole genome bisulfite sequencing. A targeted sequencing assay was designed to capture these DMRs in plasma ctDNA. Individual sequencing reads were evaluated for cancer-specific methylation signal and scores calculated for each DMR in a sample. A panel of methylation scores originating from 203 DMRs was used in a prediction model building and validated in a test cohort of patients. Results: Calculated scores were used to train a machine learning model on 68 ctDNA samples from 18 early stage (I-II) and 16 late-stage (III-IV) CRC patients and 34 age, BMI, gender and country of origin matched neoplasia-free controls (median age 63 [50-74], mean BMI 27 [19.5-37], female 50%, Spanish and Ukrainian population, distal cancers 50%). This model was then applied to an independent set of subjects from Spanish, Ukraine and Germany, including 36 stage I-IV cancer patients (median age 61.5 [55-82], BMI 28 [16-39], female 47%, 42% of the tumors were distal) and 159 age and sex matched controls. 87 of the control patients had a negative colonoscopy finding (cNEG), 19 had hyperplastic polyps (HP), 37 had small non-advanced adenomas (NAA) and 16 were diagnosed with other benign gastrointestinal diseases (GID). The model correctly classified 92% (33/36) of CRC patients. Sensitivity per cancer stage ranged from 83% (5/6) for stage I, 92% (11/12) for stage II, 92% (12/13) for stage III to 100% (5/5) for stage IV. Specificity of the model was 97% (154/159), with 100% (37/37) NAA, 94% (15/16) GID, 95% (18/19) HP and 97% cNEG patients correctly identified. Lesion location, gender, BMI, age and country of origin were not significantly correlated to prediction outcome. Conclusions: Methylation sequencing data analyzed using read-wise scoring approach combined with a machine-learning algorithm is highly diagnostic for early-stage (I-II) CRCs (89% sensitivity at 97% specificity). This method could serve as the basis for a highly accurate and minimally invasive blood-based CRC screening test with significant implications for the clinical utility of ctDNA in early-stage cancer detection.
DNA and RNA sequencing analysis revealed alterations of ANK3, PKHD1 and olfactory transduction as potential biomarker of three-year survival in gastric cancer.
Authors: Wang Jian , Li Si , Xi Wenjing , Chen Dongsheng , Xiao Mingzhe
Published: June 2021

4034

Background: Gastric cancer is the third leading cause of cancer related death worldwide. Although targeted and immune therapy have brought new benefit for patients, it still faces challenges of limited effective group and survival. Here we investigate the association of overall survival with DNA and RNA alterations to explore potential biomarkers of prognosis in gastric cancer. Methods: Whole-exome sequencing, RNA sequencing and clinical data of 442 patients with stomach cancer were downloaded from TCGA. Clinical factors and mutational landscape (insertion/ deletion/ single nucleotide variant) were compared between group of OS3+ (overall survival > 3 years) and OS3- (OS < 3 years). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed based on differentially expressed RNAs between the two groups. Results: 415 of 442 patients with stage information were included. The corresponding rates of OS3+ for patients in stage of I/II/III/IV was 15.5% (9/58), 10.8% (9/58), 10.9% (9/58), 13.6% (9/58), respectively. When comparing the 49 patients with OS3+ to others with OS3-, no difference of stage or sex distribution was discovered, except that OS3+ group had lower median age at diagnosis than OS3- group (63 vs. 71 years, P = 0.029). Tumor mutation burden was comparable between groups. Mutational landscape showed that the two groups shared 70% of top 20 mutations. Among the 20 hot genes, mutations of ANK3(P = 0.006), PKHD1(P = 0.008) were more frequent in OS3+ group, Studies in breast and prostate cancer inferred that, ANK3 was involved in activity of androgen receptor signaling and cyclins, increased expression of ANK3 in cancer was probably associated with better survival. PKHD1 was involved in calcium ion binding and actin binding and was identified as a protective factor for colorectal cancer. OS3- group tend to have higher mutation frequency of HMCN1(P = 0.062). Previous reports showed that mutation of HMCN1 was enriched in peritoneal metastasis of gastric cancer, it might contribute to progression in gastric cancer. Enrichment analysis revealed difference between the two groups in olfactory transduction ( P < 0.01, KEGG analysis), neuroactive ligand-receptor interaction ( P < 0.05, KEGG analysis) and detection of chemical stimulus in sensory perception of smell ( P < 0.01, GO analysis). Numbers of discussions have inferred that genes involved in olfactory transduction may also participate in tumor cell proliferation, migration, and invasion. Conclusions: Patients with OS3+ was enriched with mutations of ANK3 and PKHD1 and present significant functional difference in olfactory transduction. These are potential biomarkers of better survival in gastric cancer. Further studies are needed to figure out their roles in tumor activity and provide insight for novel antitumor treatment development.
The prognosis of gastric adenocarcinoma depends on the crosstalk between immune profiles and tumor genomic alterations.
Authors: Wang Deqiang , Chen Xiaofeng , Xu Yaping , He Yuange , Li Lifeng , Shu Yongqian
Published: June 2021

4035

Background: Gastric adenocarcinoma (GAC) is with a complex microenvironment of tumor cells. A better understanding of the immune landscape of GACs may lead to the improved treatment strategies with ICIs. Methods: To determine whether the molecular characteristics can serve in prognostic stratification of GACs, tumor tissue and blood samples were collected from 231 GAC patients. The median follow-up time was 34 months. The TCR profile was determined by TCR-β CDR3 sequencing while mutation and gene expression profiles were determined by whole exon and whole transcriptome sequencing, respectively. Tumour-infiltrating immune cells were characterized using immunofluorescence (IF) staining. Results: The results showed the OS of patients with high levels of TCR clonality (TCR clonal expansion) was significantly improved compared with patients with low levels (HR = 1.80 and 2.22, p = 0.022 and 0.008, respectively) in the whole group and in the subgroup of patients with stages IB to III disease. Furthermore, low local clonality was an independent risk factor for OS (adjusted-HR = 1.68 and 1.95, p = 0.049 and 0.029, respectively). Thus, TCR clonal expansion in tumour tissue had a strong prognostic value for GAC patients, independent of clinicopathological factors. Based on whole exon and whole transcriptome sequencing, RNF43/FBXW7/ARID2 mutations and local TCR clonality jointly impacted prognosis (p < 0.001), and functional changes in corresponding Wnt pathway/Notch pathway/SWI/SNF complex characterized a GAC subset with enhanced tumour immunogenicity and TCR clonal expansion. TCR CDR3 sequence similarity comparisons yielded clusters of TCR clones of likely similar functions. The most expansive TCR clusters negatively correlated with the percentage of subclonal mutations (Pearson r = -0.8183, p < 0.001), indicating that tumors with less genomic heterogeneity might induce a greater immune response. By IF staining and mutual correlation analysis, only M1 macrophages showed a significant positive correlation with local TCR clonality for epithelia, stroma, and total cell counts. Tumors were categorized according to the density of M1 macrophages, M1 macrophage infiltrated subtype was associated with favorable OS (p = 0.040 and 0.043) and its combination with the local TCR clonality improved prognosis stratification (p < 0.001). Finally, the scoring by local TCR clonality, RNF43/FBXW7/ARID2 mutations and M1 infiltration determined the best prognosis (p < 0.001). Conclusions: TCR profiles were associated with genomic alterations and may serve as a prognostic biomarker for GACs. A multi-omic model including TCR profiles might produce an improved stratification for treatments and outcomes.
Subgroup analysis by Ki-67 and baseline CgA of the randomized, placebo-controlled phase 3 study of surufatinib in advanced well-differentiated pancreatic neuroendocrine tumors (SANET-p).
Authors: Yu Xianjun , Xu Jianming , Shen Lin , Bai Chunmei , Li Jie , Zhou Zhiwei , Li Zhiping , LI Enxiao , Yuan Xianglin , Chi Yihebali , Yin Yongmei , Lou Wenhui , Xu Nong , Bai Yuxian , Zhang Tao , Xiu Dianrong , Wang Xiuwen , Guan Sha , Xu Qian , Su Weiguo
Published: June 2021

4111

Background: In the phase 3 SANET-p trial (NCT02589821), surufatinib significantly increased progression-free survival (PFS) compared with placebo in patients with progressive, well-differentiated (grade 1 or 2), advanced pancreatic neuroendocrine tumors (NETs). Here we report the relationship of Ki-67 and baseline Chromogranin A (CgA) on efficacy outcomes. Methods: A total of 172 patients with advanced pancreatic NETs were randomized to surufatinib or placebo in a 2:1 ratio. Investigator-assessed PFS and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 were used for the analysis. The post-hoc subgroup analyses were performed on Ki-67 subcategory: < 5% (n = 40 vs 21), 5-10% (n = 57 vs 31), > 10% (n = 16 vs 7), and baseline CgA subcategory: ≤ 2 times of upper limit of normal (ULN) (n = 59 vs 31), > 2 × ULN (n = 44 vs 24). Results: In the intent-to-treat population, surufatinib was superior to placebo, median PFS (mPFS) of 10.9 vs 3.7 months (mo) ( p = 0.0011), with a stratified hazard ratio (HR) of 0.491 (95% confidence interval [CI]: 0.319, 0.755). mPFS was statistically significantly longer in the surufatinib arm versus that in the placebo arm in subgroups of Ki-67 5-10% (11.0 vs 3.7 mo, HR = 0.33, p= 0.0002), Ki-67 > 10% (11.1 vs 2.8 mo, HR = 0.04, p = 0.0003) and CgA > 2 × ULN (11.0 vs 3.7 mo, HR = 0.36, p = 0.0036). There was numerical PFS improvement with surufatinib compared to placebo in subgroup of Ki-67 < 5% (9.3 vs 5.6 mo, HR = 0.91, p = 0.8015) and CgA ≤ 2 × ULN (9.4 vs 3.7 mo, HR = 0.61, p = 0.0809). ORRs in the subgroups of Ki-67 < 5%, 5-10%, and > 10% with surufatinib were 15.8%, 24.0% and 12.5% respectively. There was only one partial response in the placebo arm (with Ki-67 < 5%). ORRs in the subgroups of CgA ≤ 2 × ULN and > 2 × ULN with surufatinib were 18.9% and 21.4%, while also only one partial response in the placebo arm with CgA ≤ 2 × ULN. Conclusions: Surufatinib showed statistically significant and clinically meaningful improvement in PFS compared to placebo in patients with advanced, progressive, well-differentiated pancreatic NETs. From this exploratory analysis, surufatinib demonstrated benefit irrespective of Ki-67 expression levels or baseline CgA. Clinical trial information: NCT02589821.