bluuebunny/crossref_metadata_2025 huggingface dataset:
Sociodemographic disparities in young adults with colorectal cancer (CRC): Analysis of 26,768 patients in the National Cancer Database (NCDB).
Authors: Matusz-Fisher Ashley , Trufan Sally Jeanne , Kadakia Kunal C. , Nazemzadeh Reza , Chai Seungjean , Salmon Stuart , Worrilow William Mills , Musselwhite Laura W. , Hill Joshua , Salo Jonathan C. , Kim Edward S. , Hwang Jimmy J. , Salem Mohamed E.
Published: February 2020

13

Background: The incidence of colorectal cancer (CRC) in young adults (YA) is rising. Impact of sociodemographic status on YA with CRC is not well described. Methods: Data obtained from the NCDB were used to examine the impact of sociodemographic status on clinicopathological features and outcomes of YA with CRC. Patients (pts) were categorized based on whether they lived in areas of low or high income and education. Logistic regression and chi-square were used to examine the differences between the groups. Results: In total, 26,768 YA (≤40 yrs) pts diagnosed with CRC between 2004 and 2016 were retrospectively studied. The majority of pts were male (51.6%), and 78.7% were white, 14.6% black, and 6.6% of other races. Of the entire cohort, 32.3% pts resided in the highest income areas (median ≥$68,000), whereas 18.4% were in the lowest ( < $38,000); 23% lived in areas that had the highest high school graduation rate ( > 93%), while 20% lived in areas of the lowest graduation rate ( < 79%); and 32.3% came from metropolitan areas, while 18.4% came from urban areas. Pts in the lowest compared to highest income and education areas were more likely to be black (OR: 6.4, 5.6-7.4), not have private insurance (OR: 6.3, 5.6-7.0), have T3/T4 stage (OR: 1.4, 1.3-1.6), have positive nodes (OR: 1.2, 1.1-1.3), be rehospitalized within 30 days (OR: 1.3, 1.1-1.6), or have a Charlson-Deyo score ≥ 1 (OR: 1.6, 1.4-1.9), and were less likely to have surgery (OR: 0.63, 0.6-0.7). After adjusting for race, insurance status, T/N stage, and Charlson-Deyo comorbidity scores, pts from lowest vs. highest income and education areas had a 24% increased risk of death (HRadj: 1.24, CI 1.1-1.44, p = 0.004), and pts from urban vs. metropolitan areas had a 10% increased risk of death (HRadj = 1.10 (1.01-1.20), P = 0.02). Pts with stage IV disease in the lowest vs. highest income populations had worse mOS (1.72 vs. 2.17 years, p < 0.001). Conclusions: YA with CRC in the lowest income and education population were more likely to have worse OS. Furthermore, regardless of income, pts in metropolitan areas seemed to have a lower risk of death likely due to greater access to care. More efforts are needed to eliminate disparities and achieve health equity.
Pertuzumab plus trastuzumab (P+T) in patients (Pts) with colorectal cancer (CRC) with ERBB2 amplification or overexpression: Results from the TAPUR Study.
Authors: Gupta Ranju , Garrett-Mayer Elizabeth , Halabi Susan , Mangat Pam K. , D'Andre Stacy D. , Meiri Eyal , Shrestha Sagun , Warren Sasha L. , Ranasinghe Shamika , Schilsky Richard L.
Published: February 2020

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Background: TAPUR is a phase II basket trial evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of CRC pts with ERBB2 overexpression or amplification treated with P+T are reported. Methods: Eligible pts had advanced CRC, no standard treatment (tx) options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts had ERBB2 overexpression or amplification, or certain ERBB2 mutations. Recommended dosing after initial dosing was P, 420 mg IV over 30-60 mins every 3 weeks (wks) and T, 6 mg/kg over 30-60 mins every 3 wks. Simon two-stage design was used to test a null rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16+ wks per RECIST (SD16+)), 18 more pts enrolled. If ≥7 of 28 pts have DC, the tx is worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-eight pts enrolled from November 2016 to September 2018 were evaluable for efficacy and safety. Demographics and outcomes are summarized in Table. All pts had ERBB2 amplification; 1 also had an ERBB2 mutation. 79% of pts had at least 3 prior txs. Four PR and 10 SD16+ were observed for DC and OR rates of 50% (90% CI, 36% to 60%) and 14% (95% CI, 4% to 33%), respectively. Two pts had at least one grade 3 AE or SAE at least possibly related to P+T including anemia, infusion reaction, and left ventricular dysfunction. Conclusions: The combination of P+T showed anti-tumor activity in heavily pre-treated CRC pts with ERBB2 amplification . Additional analyses by RAS mutation status are pending. Further study is warranted to confirm efficacy of P+T in this population. Clinical trial information: NCT02693535.

[Table: see text]
Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab: Results of the expansion part of a phase I study in patients with metastatic colorectal cancer.
Authors: Bordonaro Roberto , Calvo Aitana , Auriemma Alessandra , Hollebecque Antoine , Rubovszky Gabor , Saunders Mark P. , Papai Zsuzsanna , Prager Gerald W. , Stein Alexander , Andre Thierry , Argiles Guillem , Cubillo Antonio , Dahan Laetitia , Edeline Julien , Leger Catherine , Amellal Nadia , Cattan Valerie , Tabernero Josep
Published: February 2020

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Background: Trifluridine/tipiracil (FTD/TPI) is approved for use in patients (pts) with pretreated mCRC. In vivo studies have shown an increase in anti-tumor activity when combining FTD/TPI, oxaliplatin or bevacizumab, and an increase in tumor immunogenicity after treatment with FTD/TPI and oxaliplatin (Ghiringhelli, 2018). The recommended dose for expansion had been defined as FTD/TPI 35 mg/m² bid, days 1–5 q14, together with oxaliplatin 85 mg/m² (day 1). Methods: In addition to FTD/TPI and oxaliplatin, eligible pts received bevacizumab 5 mg/kg (Cohort A) or nivolumab 3 mg/kg (Cohort B) on day 1. Eligibility criteria included measurable disease, performance status (PS) 0-1, normal organ function, progression after > 1 prior anti-tumor therapy (excluding oxaliplatin), and confirmed MSS status (Cohort B). A Bayesian design was used for futility and efficacy assessments. Efficacy endpoints of objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and adverse events (AEs) were assessed for each cohort; biomarkers of immune function including PD-L1 expression for Cohort B. Results: A total of 37 and 17 pts were enrolled in Cohorts A and B respectively; with a median age of 64 years (range 33 to 83 years), 61% and 39% had an PS of 0 and 1. At baseline, no pt showed PD-L1 expression on tumor cells, and only 1 pt on immune cells (5% threshold). At data cutoff, 32 and 12 pts were evaluable for response in Cohorts A and B. In Cohort A, ORR was 13% (1 CR; 3 PR), and DCR was 91%. The mPFS was 6.9 months (95% IC, 4.3-9.3). In Cohort B, ORR was 8% (1 PR), DCR was 67%. The mPFS was 6.5 months (95% IC, 1.8-8.6). Overall, the most common treatment-related AEs (≥20% of pts) included neutropenia, nausea, diarrhoea, and fatigue; only 1 pt reported grade 3 febrile neutropenia; 5 pts discontinued due to AEs and no treatment-related death were reported. Conclusions: In this study, bevacizumab in addition to FTD/TPI and oxaliplatin showed antitumor activity. The cohort of nivolumab was prematurely discontinued due to lack of efficacy. Both cohorts showed an acceptable safety profile in pretreated mCRC pts. Clinical trial information: NCT02848443.
Complete neoadjuvant treatment for rectal cancer: A single institution experience.
Authors: Baekey John , Brunault Robert , Safran Howard , Breakstone Rimini , Vrees Matthew , DiPetrillo Thomas A. , Leonard Kara Lynne , Yu Esther , Almhanna Khaldoun
Published: February 2020

148

Background: Full dose adjuvant chemotherapy following preoperative chemoradiation and surgery is poorly tolerated in stage II and III rectal cancer. We reviewed our institution’s experience with complete neoadjuvant treatment for rectal cancer since publication of the BrUOG R-224 trial results. Methods: After obtaining IRB approval, Data on patients with stage II and III rectal cancer who underwent complete neoadjuvant therapy were collected.. Patients who were planned to receive 8 cycles of modified FOLFOX6, chemoradiation with capecitabine 825 mg/m2 twice daily and 50.4 Gy intensity-modulated radiation therapy, then surgery were included. Results: Thirty-five patients were treated with complete neoadjuvant therapy between January 2014 and December 2017. Median age was 58 years (27 to 75 y); 1 patient (3%) was clinical stage II and 34 (97%) stage III. Twenty-seven patients (77%) received all 8 cycles of mFOLFOX6, of whom 24 completed subsequent chemoradiation. Therefore 69% of patients completed therapy according to the BrUOG R-224 protocol. Pathologic complete response (ypT0N0) was observed in 9 patients (26%). Treatment related toxicities resulted in dose reductions or treatment interruption in 57% and 29% of patients receiving chemotherapy and chemoradiation respectively. Conclusions: Complete neoadjuvant therapy for clinical stage II to III rectal cancer is well-tolerated in routine practice and offers an alternative to preoperative chemoradiation, surgery, then adjuvant full dose chemotherapy.
Phase II study of lamivudine in p53 mutant metastatic colorectal cancer (mCRC).
Authors: Parikh Aparna Raj , Rajurkar Mihir , Van Seventer Emily E. , Gemma Angelo J. , Allen Jill N. , Blaszkowsky Lawrence Scott , Clark Jeffrey William , Goyal Lipika , Hong Theodore S. , Wo Jennifer Yon-Li , Corcoran Ryan Bruce , Solovyov Alexander , Greenbaum Benjamin , Szabolcs Annamaria , Tai Eric C. , Joseph Jasmin , Thapar Vishal , Zheng Hui , Ryan David P. , Ting David Tsai
Published: February 2020

149

Background: Non-coding repeat RNAs in cancers are pervasive and “mimic” viruses with activation of pattern recognition receptors and the innate immune response. Many repeat RNAs replicate in cancer genomes through a reverse transcriptional intermediate analogous to retroviruses. Nucleoside reverse transcriptase inhibitors (NRTIs) block this retroviral life cycle to increases repeat RNAs in p53 mutant colon cancer cell cancer lines. We initiated a Phase 2 study of lamivudine (3TC) in TP53 mutant mCRC. Methods: Two-stage design with target accrual of 20 patients (pts) in stage 1 and total of 32. Eligibility: pts with p53 mutant refractory mCRC with progression on or intolerance to 5FU, oxaliplatin and irinotecan and anti-EGFR if RAS WT. RNA sequencing was performed on pre-treatment (tx) and on tx biopsy to evaluate for repeat RNA expression and expression of other genes linked to 3TC response/resistance. Radiation was allowed. 9 pts were treated with 3TC 150 mg po bid for 28-day cycles, the maximum FDA approved dose of 3TC in HIV. Subsequent pts were treated at 600 mg po bid, previously tested in P1 trials. Tumor assessments were performed every 8 weeks until documented disease progression by RECIST 1.1 criteria or drug intolerance. Results: 29/32 pts have been treated. Median age: 60 yrs. (27-82) 18 males, 11 females. 2/ 9 (22%) pts on standard 3TC dosing had stable disease (SD) on single agent 3TC with a duration of tx of 169 and 167 days, respectively. Both pts had an initial drop in CEA upon initiation of 3TC. Of the next 20 pts on high dose 3TC, 19 were evaluable. 4 had SD, for 110, 159, 130 and 228+ days. 14 pts had tx-related adverse events (TRAE). 1 pt with a definite Grade 1 TRAE (fatigue). No pts with Grade ≥3 TRAEs. We obtained pre-tx fresh frozen biopsies on 24/29 pts. Of those with SD, 4 had biopsies and differential expression identified significantly higher HSATII repeat RNA in pts with SD compared to PD. There was an association of decreased epigenetic gene expression in HSATII repeat RNA high tumors. Conclusions: This proof-of-concept study demonstrates the safety and activity of single-agent 3TC. Repeat RNA levels appear to correlate with clinical benefit and can be measured in biopsies. Further combination studies and correlatives are planned. Clinical trial information: NCT03144804.
CCR5 Δ32 mutation and gene expression to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and MAVERICC phase III trials.
Authors: Lenz Annika , Zhang Wu , Xiao Yi , Millstein Joshua , Soni Shivani , Arai Hiroyuki , Wang Jingyuan , Parikh Aparna Raj , Mancao Christoph , Stintzing Sebastian , Heinemann Volker , Battaglin Francesca
Published: February 2020

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Background: Germline polymorphisms in CCR5 have been associated with treatment outcome in pts with mCRC receiving regorafenib and cetuximab-based treatment. CCR5 Δ32, a loss of function deletion, plays a key role in infectious diseases but data in CRC are scarce. We tested whether CCR Δ32 and CCR5 gene expression may be associated with outcome in mCRC pts receiving first-line treatment. Methods: The impact of CCR5 Δ32 was evaluated in 614 pts enrolled in the randomized FIRE-3 trial (FOLFIRI/cetuximab, cet, n = 313; FOLFIRI/bevacizumab, bev, n = 301). Gene expression was evaluated in 102 pts in the FOLFIRI/cet arm from FIRE-3 and 155 pts treated in the MAVERICC trial (FOLFIRI/bev, n = 76; FOLFOX6/bev, n = 79) from tumor tissue by HTG EdgeSeq Oncology Biomarker Panel and NanoString expression panel, respectively. The association between CCR5 Δ32 and clinical outcomes was evaluated using Cox regression and log-rank tests. Gene expression was dichotomized using an optimal cutoff and P-values computed using a permutation-based approach. Results: In FIRE-3, CCR5 Δ32 was significantly associated with worse PFS in patients with right-sided tumors (RT) receiving FOLFIRI/cet (n = 32; median PFS 3.41 vs 7.84 mo; HR 4.39, 95%CI 1.12-17.24; P= .022;). These associations were not observed in left-sided tumors or pts treated with bev. Lower levels of CCR5 expression trended to be associated with shorter PFS and OS in the same subgroup of RT treated in the cet arm ( P= .096 and P= .063 for PFS and OS, respectively). Lower CCR5 expression was associated with longer PFS in pts treated with FOLFIRI/bev in the MAVERICC trial, regardless of tumor side (mPFS 17.91 vs 11.04 mo; P= .03). A significant interaction between the impact of CCR5 expression levels on PFS and chemotherapy backbone was observed ( P= .019). Low CCR5 expression was associated with worse PFS in pts with RT treated with oxaliplatin (11.10 vs 13.80 mo; P= 0.023). Conclusions: Our results provide the first evidence that CCR5 Δ32 and CCR5 gene expression levels may predict outcomes in mCRC pts receiving first-line treatment with a differential effect depending on tumor location, biologic agent and chemotherapy backbone.
Plasma VEGF-D and PlGF levels according to prior use of biologics among metastatic colorectal cancer: Preliminary results from GI-SCREEN CRC-Ukit study.
Authors: Taniguchi Hiroya , Yuki Satoshi , Shiozawa Manabu , Masuishi Toshiki , Nishina Tomohiro , Kagawa Yoshinori , Takahashi Naoki , Yasui Hisateru , Denda Tadamichi , Sunakawa Yu , Yamazaki Kentaro , Esaki Taito , Kawakami Hisato , Kato Takeshi , Yoshida Kazuhiro , Takashima Atsuo , Ohmiya Hiroko , Nomura Shogo , Ohtsu Atsushi , Yoshino Takayuki
Published: February 2020

178

Background: Plasma vascular endothelial growth factor-D (VEGF-D) level is a potential predictor for ramucirumab efficacy in patients (pts) with metastatic colorectal cancer (mCRC), while a high VEGF-A and placental growth factor (PlGF) level in bevacizumab naïve pts receiving 2nd-line FOLFIRI plus aflibercept may suggest relatively higher activity. However, there are a few data associating 1st-line antiangiogenic treatments as well as anti-EGFR with angiogenic factors. Methods: This prospective longitudinal study aims to investigate an association between plasma angiogenesis-related mediators and clinical outcomes in mCRC. Serial plasma collections were done at time points of pre- and post-treatments of either 1st- or 2nd-line. Comprehensive measurements of 17 mediators were analyzed by the multiplex assay with Luminex technology. Here we report an association between levels of VEGF-D, PlGF and patient backgrounds. Results: From Sep 2017 to Aug 2019, 375 samples from 317 pts were enrolled in this analysis. Baseline characteristics were follows; 169 samples at pre-1st-line (pre-1L), 151 with prior bevacizumab treatment (post-bev) and 55 with prior anti-EGFR antibody (post-EGFR); median age, 66 years; male gender, 58%; RAS mutant, 46%; left-sided primary, 76%. In pre-1L, the median values of VEGF-D/ PlGF were 264/ 7.21 pg/mL without a clear association between the two in each patient (r = 0.094) and any baseline characteristics. Compared to pre-1L, the values of VEGF-D/ PlGF showed significantly higher in post-bev (median VEGF-D/ PlGF; 346/ 23.5 pg/mL, respectively). Moreover, there was no clear relationship between the two cytokines in each patient (r = 0.190). In 37 pts with serial blood collection, VEGF-D/ PlGF levels showed similar trends. In addition, VEGF-D/ PlGF levels in post-EGFR tended to be higher than those in pre-1L (median VEGF-D/ PlGF; 395/ 9.11 pg/mL, respectively). Conclusions: The VEGF-D/ PlGF may be separately induced by bev treatment as well as anti-EGFR therapy, suggesting the possibility of usefulness for selecting a better antiangiogenic inhibitor by measuring baseline VEGF-D/ PlGF. Clinical trial information: UMIN000028616.
Exosomal markers (CD63 and CD9) expression and their prognostic significance using immunohistochemistry in right-sided and left-sided colon cancer.
Authors: McCormick Ben , Prodduturvar Pranitha , Mneimneh Wadad , Dal Zotto Valeria , Grimm Leander , Rider Paul , Hunter John , Iliff Greire , Smith Clayton , Patel Girijesh Kumar , Singh Seema , Singh Ajay , Khushman Moh'd M.
Published: February 2020

182

Background: Exosomes play pivotal roles in cancer progression, metastasis and chemoresistance. CD63 and CD9 are widely accepted exosomal markers. Their pattern of expression and prognostic significance in patients with RSCC and LSCC is unknown. This study explored CD63 and CD9 expression and prognostic significance in patients with RSCC and LSCC using immunohistochemistry (IHC). Methods: Between 2015 and 2018, 63 patients underwent surgical resection of colon cancer for whom we had available tissues for CD63 and CD9 IHC staining. Two pathologists independently scored the CD63 and CD9 expression in the tumor and adjacent normal mucosa (ANM). Staining intensity was graded 1-3 and staining percentage was estimated in 10% increments. Mean Quick-score (Q-score) (intensity X percentage of staining) was calculated. Results: RSCC and LSCC represented 52% and 48% of the patients respectively. The ANM and Tumor CD63 Q-scores were 225 vs 191 (p = 0.009) in RSCC and 224 vs 154 (p = 0.0001) in LSCC, respectively. The ANM and Tumor CD9 Q-scores were 134 vs 152 (p = 0.142) in RSCC and 135 vs 154 (p = 0.137) in LSCC, respectively. In patients with RSCC and LSCC, the mean Tumor CD63 Q-score was 191 vs 154 (p = 0.024), while the mean ANM CD63 Q-score was 225 vs 224 (p = 0.920). The mean Tumor CD9 Q-score was 152 and 154 (p = 0.883), and the mean ANM CD9 Q-score was 134 vs 135 (p = 0.926). In our cohort, there was no difference in progression free survival (PFS) between patients with RSCC and LSCC (p = 0.2349). In all patients, there was no difference in PFS in patients with CD63 expression < 100 and ≥100 (p = 0.8284). Among patients with RSCC, there was a significantly lower PFS in patients with CD63 expression < 100 vs. ≥100 (p = 0.0259). However, among patients with LSCC, there was no difference in PFS in patients with CD63 expression < 100 vs. ≥100 (p = 0.3494). Conclusions: To our knowledge, this is the first study to show a difference in exosomal marker (CD63) expression pattern and its prognostic significance in patients with RSCC and LSCC. There was a significant positive correlation between progression free survival in patients with RSCC and higher exosomal expression.
Genetic variants in immunogenic cell death (ICD) relating genes to predict outcome in metastatic colorectal cancer (mCRC): Data from FIRE-3, TRIBE and MAVERICC trials.
Authors: Arai Hiroyuki , Xiao Yi , Loupakis Fotios , Stintzing Sebastian , Wang Jingyuan , Battaglin Francesca , Soni Shivani , Zhang Wu , Mancao Christoph , Salhia Bodour , Mumenthaler Shannon M , Weisenberger Daniel J , Liang Gangning , Cremolini Chiara , Heinemann Volker , Falcone Alfredo , Millstein Joshua , Lenz Heinz-Josef
Published: February 2020

187

Background: ICD is an immune response against dead-cell antigens from cancer cells treated with cytotoxic and/or targeted therapies. Oxaliplatin (OHP) and cetuximab (Cet) are distinct drugs to elicit ICD, while most other anticancer agents kill cancer cells in a nonimmunogenic manner. We hypothesized that genetic variants in ICD-related genes could predictive efficacy of OHP and/or Cet in mCRC. Methods: We analyzed data of mCRC patients enrolled in three 1st-line randomized trials [FIRE-3: FOLFIRI+Cet vs FOLFIRI+bevacizumab (Bev), TRIBE: FOLFOXIRI+Bev vs FOLFIRI+Bev and MAVERICC: FOLFOX+Bev vs FOLFIRI+Bev]. Genomic DNA from blood samples was genotyped through the OncoArray, a custom array manufactured by Illumina. Candidate 14 SNPs in five ICD-related genes ( CALR, HMGB1, ANXA1, LRP1 and P2RX7) were tested for association with progression-free survival (PFS) and overall survival (OS), using Cox proportional hazards model. We tested treatment-by-SNP interactions in the following cohorts: combined TRIBE and MAVERICC (OHP-containing treatment vs non-OHP-containing treatment), and FIRE-3 (FOLFIRI+Cet vs FOLFIRI+Bev). An interaction p-value (i p) < 0.05 was considered significant. Results: Totally, 890 patients’ SNPs were available (FIRE-3: n = 236, TRIBE: n = 324, and MAVERICC: n = 330). In the combined TRIBE and MAVERICC cohorts [the reference of hazard ratio (HR) is non-OHP-containing treatment], a significant interaction was observed in ANXA1 rs1050305 (A/A: HR 0.96, Any G: HR 2.62, i p < 0.01), LRP1 rs1466535 (G/G: HR 1.39, Any A: HR 0.91, i p = 0.02), P2RX7 rs2230911 (C/C: HR 0.98, Any G: HR 1.76, i p = 0.03) and P2RX7 rs208294 (C/C: HR 1.82, Any T: HR 0.93, i p < 0.01) on OS. For PFS, that was observed in CALR rs110222 (G/G: HR 1.30, Any A: HR 0.87, i p = 0.02), HMGB1 rs1045411 (C/C: HR 0.85, Any T: HR 1.30, i p = 0.04) and HMGB1 rs1360485 (T/T: HR 0.81, Any C: HR 1.40, i p < 0.01). However, in the FIRE-3 cohort, no significant interactions were observed in any SNPs. Conclusions: Our results showed for the first time that SNPs in ICD-related genes may predict efficacy of OHP-containing treatment in mCRC. But the predictive values for Cet efficacy was not evident.
Prognostic phenotypic subtypes to predict recurrence and response to adjuvant chemotherapy for colorectal cancer.
Authors: Roseweir Antonia K. , Park James Hugh , ten Hoorn Sanne , Powell Arfon GMT , Aherne Susan , Roxburgh Campbell SD , McMillan Donald C. , Horgan Paul G. , Ryan Elizabeth , Sheahan Keiran , Vermeulen Louis , Paul James , Graham Janet Shirley , Sansom Owen , Church David , Iveson Timothy , Edwards Joanne
Published: February 2020

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Background: Histological phenotypic subtypes have been proposed that stratify survival in a discovery cohort of patients with stage I-III colorectal cancer (CRC). However, clinical utility has not been validated nor associations with recurrence and chemotherapy assessed. Therefore, this study assessed prognostic value in patients with stage I-III CRC as well as predictive value for recurrence and chemotherapy response. Methods: Two independent stage I-III CRC patient cohorts were utilized to assess associations between phenotypic subtypes, survival, and recurrence. Stage II-III patients, from the SCOT adjuvant chemotherapy trial, were utilized to assess associations between phenotypic subtypes and adjuvant chemotherapy response. Log rank analysis compared immune and stromal subtypes. Results: In an 867-patient internal cohort, phenotypic subtype stratified patients by disease-free survival (DFS) (HR 2.18 95% CI 2.26-4.47, p < 0.001); independent of stage and location. The stromal subtype also predicted increased local and distant recurrence (p < 0.001). In a 146-patient external validation cohort, phenotypic subtype significantly stratified patients by DFS (HR 3.43 95% CI 1.60-7.35, p = 0.001). In 1343 SCOT trial patients, phenotypic subtype significantly stratified patients by DFS (HR 1.59 95% CI 1.13-2.25, p = 0.010). Furthermore, there was evidence that the effect of regimen depended on phenotypic subtype (p = 0.048), only significantly stratifying DFS in patients receiving FOLFOX (HR 3.73 95% CI 1.58-8.81, p = 0.003) but not CAPOX (HR 0.84 95% CI 0.56-1.26, p = 0.396) adjuvant chemotherapy. Interestingly, the immune subtype associated with improved DFS in patients receiving FOLFOX compared to CAPOX adjuvant chemotherapy (HR 3.40 95% CI 1.41-8.19, p = 0.006). Whereas patients with a stromal subtype trended towards improved DFS in patients receiving CAPOX compared to FOLFOX adjuvant chemotherapy (HR 0.72 95% CI 0.50-1.05 p = 0.088). Conclusions: Histological phenotypic subtypes are an effective independent prognostic classification for patients with stage I-III CRC that can predict response to FOLFOX adjuvant chemotherapy as well as the presence of local and distant recurrence.
Emergence of RAS mutations in patients with metastatic colorectal cancer receiving cetuximab-based treatment.
Authors: Wang Jaw-Yuan , Tsai Hsiang-Lin , Sung Yung-Chuan
Published: February 2020

208

Background: In management of patients with RAS wild-type mCRC, anti-EGFR therapies have demonstrated clinical benefit. However, the correlation between emergence of RAS mutations in circulating tumor DNA (ctDNA) and secondary resistance to anti-EGFR therapies requires further elucidation. In this study, we aim to examine evolutionary changes in RAS mutations through liquid biopsy in patients with mCRC during and after anti-EGFR therapy (NCT03401957). Methods: A total of 39 intention-to-treat (ITT) patients diagnosed with RAS wild-type mCRC, from Cathay General Hospital (CGH) and Kaohsiung Medical University Hospital (KMUH), were analyzed in this study. Of them, 24 were male and 15 were female, with median age of 55 years. Patients received cetuximab-based FOLFIRI or FOLFOX regimen as first-line treatment. Blood samples from enrolled patients were collected before and every 3 months during cetuximab-based treatment and also at disease progression. These blood samples were evaluated for RAS resistance mutations using MassARRAY platform. The primary endpoint is percentage of RAS mutations detected in ctDNA from patients during cetuximab treatment. The correlation between the tumor response of these patients and the emergence of RAS mutations in ctDNA is further analyzed. Results: Between January 2018 and July 2019, 3 (8.3%) of 36 per-protocol (PP) patients subsequently with newly detected ctDNA KRAS/NRAS mutations in their blood samples during the treatment period, and all of three patients developed progressive disease (PD). Of 36 PP patients, 19 (52.8%) patients had complete/partial response (CR/PR), 13 (36.1%) patients had stable disease (SD) and 4 (11.1%) patients had PD. The disease control rate was 88.9% in the present study. Three of 4 PD patients were detected with ctDNA KRAS/NRAS mutations in their blood sample, with time to onset of newly detected ctDNA RAS at 3 and 6 months posttreatment, respectively. Conclusions: In current study, the frequency of RAS mutations in blood samples during the treatment period was 8.3% and all of these 3 patients developed PD. The results of this study will offer substantial, valuable information for anti-EGFR therapeutic strategy in patients with mCRC.
Circular RNAs as biomarkers in liquid biopsy in colorectal cancer.
Authors: Valladares-Ayerbes Manuel , Garrigos Carmen , Taron Miquel , Figueroa Angélica , Aranda Enrique
Published: February 2020

230

Background: Circular RNAs (circRNAs) are emerging as essential regulators of cancer- related biological hallmarks, as cell proliferation, apoptosis, differentiation, immune regulation and angiogenesis. CircRNAs are abundant, conserved, and have a tissue‐specific expression pattern. These characteristics make them candidate to serve as biomarkers in liquid biopsy (LB) in cancer. The aim of this study is to analyse differential expression of circRNAs in the colorectal cancer (CRC) scenario. Methods: To comprehensively understand the expression patterns of circRNAs we characterized 13,617 circRNAs using a microarray [Arraystar v2 (8x15K)] in 10 human samples, five CRC cell lines, one colorectal human tumour, one normal colon healthy control, vs. Peripheral Human Blood Leukocytes (2 pools) and Human Bone Marrow. Differentially expressed circRNAs were identified using fold change (FC) cut-off or through Volcano Plot filtering respectively. CircRNAs having FC ▪2 and P-values ▪ 0.05 were selected. CircRNA/microRNA interaction was predicted with target prediction software. Results: Hierarchical clustering showed distinguishable circRNA expression profiling among 10 samples. These data indicated that circRNAs have a different expression pattern in colorectal tissues compared with that in blood and bone marrow tissues. The microarray data showed 2329 circRNAs differentially expressed (FC > 2.0, P < 0.05). Among them, 964 circRNAs were upregulated and 1365 were downregulated in colon tissues compared with blood and bone marrow. Using a stringent criterion (FC > 10, P≤ 0.01 and false discovery rate [FDR] < 0.05) we have identified 30 circRNA upregulated in colorectal cancer versus non tumour samples. CircRNA/microRNA interaction prediction analysis showed that most upregulated circRNAs contain miRNA Binding Sites (MREs) for cancer-related miRNA, including among others, miR-17, miR-103, miR-let-7g. Conclusions: Microarray analysis was used to comprehensively identify dysregulated circRNAs in CRC. We identify novel circRNAs could be valuable as blood-based CRC biomarkers.
Circulating tumor DNA (ctDNA) heterogeneity as first- and third-line treatment in patients (pts) with metastatic colorectal cancer (mCRC) treated with panitumumab.
Authors: Parseghian Christine Megerdichian , Beutner Karl , Boedigheimer Michael , Ruff Paul , Price Timothy Jay , Kim Tae Won , Fakih Marwan , Ang Agnes
Published: February 2020

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Background: RAS mutations are negative predictors of response to anti-EGFR therapies such as panitumumab in mCRC. Mutations at baseline (BL) and follow-up (FU) during randomized phase 3 studies of first line treatment (1L; study 20050203 [‘203]; panitumumab + fluorouracil, leucovorin and oxaliplatin [FOLFOX4] vs FOLFOX4) were compared with those in third line treatment (3L; study 20100007 [‘0007]; panitumumab + best supportive care [BSC] vs BSC) to assess tumor heterogeneity via ctDNA analysis. Methods: Biomarker analysis was conducted for pts with plasma samples at BL and FU. Samples were analyzed using the Plasma Select-R 63-gene panel (Personal Genome Diagnostics, Inc.), with a limit of detection of 0.1%. Mutations were defined at the amino acid level. The Cox hazard ratio (HR) by sum of RAS mutant allele frequency (MAF) was determined, as were event-free survival (EFS) and best response by RAS mutation status. Results: For all pts with available samples (‘203, n = 120; ‘0007, n = 90), fewer mutations and fewer mutations/gene were observed in the 1L vs 3L setting at BL ( KRAS 2 vs 3 maximum mutations/gene; EGFR 1 vs 4 maximum mutations/gene). In 3L the Cox HR increased continuously with RAS MAF; while this was not found in 1L. In the 1L setting, emergent RAS mutations were not predictive of EFS for FOLFOX4, but were predictive of shorter EFS for panitumumab + FOLFOX4. More panitumumab-treated pts in the 3L setting had detectable RAS mutations emerging from BL to FU (28.6%, 57.1%) vs pts treated in 1L (24.5%, 26.5%). For pts who achieved a partial response, more treated in 1L maintained a higher frequency of wild-type RAS from BL to FU (84.4%, 78.1%) vs pts treated in 3L (95.7%, 43.5%). Conclusions: The overall mutational landscape differs between the 1L vs 3L setting in anti-EGFR–treated mCRC pts. Panitumumab monotherapy in the 3L setting appears to induce greater RAS-specific selective pressure than panitumumab FOLFOX4 combination therapy in 1L, resulting in increased RAS mutations at FU in the 3L setting. The combination of panitumumab + FOLFOX in 1L is associated with delayed emergence of expansion of RAS mutations compared to later line single agent panitumumab.
Molecular profiling of early-stage colorectal cancer (CRC) using targeted next generation sequencing (NGS) to predict signatures of recurrence.
Authors: Burns Michael C. , Carroll Kristen , Jones Ryan , Kocherginsky Masha , Burdett Kirsten Bell , Yang Guang-Yu , Benson Al Bowen , Mahalingam Deva
Published: February 2020

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Background: While the 5-year recurrence rate in early stage CRC is low (12%) and there is currently limited role of adjuvant chemotherapy in such cases, a unique subset of patients (pts) will have late recurrences. To identify molecular signatures predictive of late recurrence after pts undergo intended curative resection, we employed a 22 targeted gene NGS panel in pts with early CRC. Association between mutation status and recurrence free survival (RFS) was analyzed. Methods: Pts with stage I-II CRC had their tumor prospectively sequenced between 09/2015-12/2018 by an ion torrent targeted 22 gene hotspot NGS panel, including KRAS, EGFR, BRAF, PIK3CA, AKT1, ERBB2/4, PTEN, NRAS, STK11, MAP2K1, ALK, DDR2, CTNNB1, MET, TP53, SMAD4, FBX7, NOTCH1, and FGFR1/2/3. Associations were analyzed with unadjusted p-values (p) and Benjamini & Hochberg adjusted (BHp) shown. Results: Clinical and pathologic data from 180 pts were analyzed: median age 66 (range 24-86), male (47%), stage I (41%), stage II (69%), left (54%) vs right (36%) sided primary tumors, and microsatellite stable (85%). 35 (19%) pts had adjuvant therapy (n = 21 rectal, n = 14 colon). Pathological mutations were found in 160 (89%) of pts, including TP53 (56%), KRAS (44%), PIK3CA (22%), BRAF (12%), SMAD4 (8%), MET (6%) and NRAS (3%). There was only 1 case of ERBB2 mutation. 33 pts (18%) had evidence of recurrence. 36 month RFS was 82%. Common sites of recurrence included liver (13 pts, 39%), lung (10 pts, 30%), and bone (2 pts, 6%). Alterations in MET cDNA and protein were associated with recurrence-free survival (RFS) (HR = 4.1; p =0.0026, BHp= 0.057). Interestingly, while TP53 mutations are typically associated with worse prognosis in metastatic colorectal cancers, it was not associated with RFS (HR = 0.8; p = 0.55, BHp= 0.98). There was also no association between the number of gene alterations and RFS (p = 0.45). Conclusions: These data highlight that targeted NGS tumor profiling of early stage CRC, including sequencing MET among other genes, may be utilized alongside known prognostic pathological factors to predict pts with a higher risk of recurrence and may facilitate tailored adjuvant chemotherapy to mitigate this risk.
Change of clinical features and outcomes of adolescents and young adults (AYA) with colorectal cancer over time: Pooled analysis of 26,768 patients in the National Cancer Database (NCDB).
Authors: Trufan Sally Jeanne , Worrilow William Mills , Kadakia Kunal C. , Nazemzadeh Reza , Musselwhite Laura W. , Chai Seungjean , Salmon Stuart , Hill Joshua , Salo Jonathan C. , Kim Edward S. , Hwang Jimmy J. , Salem Mohamed E.
Published: February 2020

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Background: The incidence of colorectal cancer (CRC) in younger patients (pts) is rising. The underlying etiology is unknown, and it is uncertain if disease biology and clinical features are changing over time. Methods: A retrospective study of pts data in the NCDB was performed to compare the clinicopathological features and outcomes of AYA with CRC over a 12-year period. Pts diagnosis period was dichotomized into older (2004 – 2009) and newer (2010 – 2015) eras. Uni- and multi-variable chi-square, logistic regression, and survival analyses were used for comparisons. Survival differences were assessed using Kaplan-Meier curves. Results: In total, 26,768 AYA (18-40yrs) with CRC were identified and included in the analysis: 45.8% (n = 12,268) from the older and 54.2% (n = 14,500) from the newer era. There were no differences between the 2 groups in gender distribution or levels of income and education. However, in the newer vs. older era, there was a greater proportion of non-white, non-black pts (7.2% vs. 6%; p = 0.0005) and pts diagnosed between the ages of 18-30 (21.1% vs. 18.8%; p < .0001). Pts in the newer era tended to have more comorbidities (8.6 vs 7.5%; p = 0.0012), left-sided tumors (77.5% vs. 76.1%; p = 0.04), and well-differentiated histology (12.0% vs. 8.3%; p < 0.0001). Newer era pts also had lower rates of metastatic disease at presentation (15.3% vs. 18.2%; p < 0.001%) and nodal involvement (54.9 vs. 58.4%; p < 0.001%). Median OS of pts with stage IV disease appears to have improved over time (24.1 vs. 22.5 mos; p = 0.014). After controlling for age, race, primary tumor site and grade, presence of comorbidities, and health insurance status, older era pts with stage IV CRC were at a 15.1% greater risk of all-cause death by year 5 compared to newer era pts (HRadj= 1.15 (1.07-1.24, p = 0.0001). Conclusions: Our data suggest that AYA with CRC in more recent years tend to present at a younger age and have a lower rate of metastatic disease. They also have improved survival. Further investigation of AYA disease etiology and biology are warranted. Continued efforts to increase awareness, promote early detection, and improve treatment options are essential.
Extensive peritoneal lavage after curative gastrectomy for gastric cancer study (EXPEL): An international multicenter randomized controlled trial.
Authors: So Jimmy Bok Yan , Ji Jiafu , Han Sang Uk , Terashima Masanori , Li Guoxin , Kim Hyung-Ho , Law Simon , Shabbir Asim , Song Kyo Young , Hyung Woo Jin , Kosai Nik Ritza , Kono Koji , Misawa Kazunari , Yabusaki Hiroshi , Kinoshita Takahiro , Lau Peng Choong , Kim Young Woo , Rao Jaideepraj , Tai Bee Choo , Yang Han-Kwang ,   EXPEL Study Group
Published: February 2020

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Background: Peritoneal recurrence of gastric cancer after curative surgical resection is common and portends a poor prognosis. Preliminary studies suggest extensive intraoperative peritoneal lavage (EIPL) may reduce the risk of peritoneal recurrence and improve survival. We sought to perform a randomized phase III study to definitively establish the role of performing EIPL after gastrectomy. Methods: This is a prospective, open-label, phase 3 multicentre randomised controlled trial involving 22 hospitals from Korea. China, Japan, Malaysia and Singapore. Patients aged between 21 to 80 years with cT3/4 stomach cancer undergoing curative resection were randomized to either surgery and EIPL (lavage with 10 litres of saline) or surgery alone. Comparison of DFS and OS were made via log-rank test. The cumulative incidence of peritoneal recurrence was compared using competing risks approach. All analyses were performed based on intention-to-treat. Results: Between March 2015 to August 2018, 800 patients were randomly assigned to surgery alone ( n= 402) or EIPL ( n= 398). Based on a median follow-up duration of 29 months, the 3-year cumulative incidence of all-cause mortality was 23.1% and 23.3% for EIPL and surgery alone respectively (hazard ratio [HR] = 1.09, 95% CI: 0.78 to 1.52, p = 0.615). Similarly, the 3-year cumulative incidence of recurrence were 28.0% and 25.9% respectively (HR = 1.01, 95% CI: 0.74 to 1.37, p = 0.947), and 7.9% and 6.6% respectively for peritoneal recurrence (Subdistribution HR = 1.33, 95% CI: 0.73 to 2.42, p = 0.347). Overall, the risk of adverse events was higher in EIPL as compared to surgery alone (relative risk = 1.58, 95% CI 1.07 to 2.33, p = 0.019). The most common adverse events were anastomotic leak, bleeding and intra-abdominal abscess. At the planned third interim analysis on 28 August 2019, the predictive probability of achieving even a 5% difference in 3-year OS in favour of EIPL at final analysis was < 0.4%. The trial was thus recommended to terminate on the basis of futility. Conclusions: EIPL does not show any survival benefit compared with surgery alone and is not recommended for patients undergoing curative gastrectomy for cancer. Clinical trial information: NCT02140034.
Evaluating maintenance therapies in advanced oesophago-gastric adenocarcinoma (OGA): Interim analysis and biomarker results from the PLATFORM study.
Authors: Cunningham David , Fong Caroline Yean Kit , Peckitt Clare , Anandappa Gayathri , Davidson Michael , Patel Bijal , Turner Andrea , Begum Ruwaida , Cafferkey Catherine , von Loga Katharina , Rebelatto Marlon , Petty Russell D. , Hewish Madeleine , Roques Tom , Coxon Fareeda Y. , Morgan Carys , Wadsley Jonathan , Waddell Tom , Starling Naureen , Chau Ian
Published: February 2020

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Background: Advanced OGA patients (pts) are treated with platinum-based 1st line chemotherapy but the role of maintenance therapy once disease control is obtained is unknown. Methods: PLATFORM is a prospective, open-label, adaptive phase II trial assessing maintenance therapy in OGA. HER2 negative pts with advanced OGA achieving response or stable disease on completion of 1st line platinum-based chemotherapy were initially randomised to surveillance (A1), capecitabine (A2) and durvalumab (A3). Rucaparib (A4) and capecitabine+ramucirumab (A5) were subsequently added as part of adaptive design. Primary endpoint is progression-free survival with target recruitment of 154pts/arm. A pre-planned futility interim analysis (IA) is triggered when 61 pts/arm are recruited and evaluable using 12-week progression-free rate (PFR). Individual arms will continue accrual if the upper limit of 1-sided 95% CI difference is > 0 when compared to A1. Biomarker analyses of A1 and A3 IA patients include: PDL1 as tumour and immune cell combined proportion (TIP), multiplex IHC of tumour infiltrating lymphocytes (TILs), TMB and MSI status by whole exome sequencing. Results: To date, 1053 pts have registered prior to or during 1st line therapy and 356 pts randomised. Primary attrition was due to disease progression. Baseline demographics in the IA population (arms A1 to A3, n = 183) were male (81%); median age 65 yrs; metastatic disease (92%); oesophageal (40%), OG junction (28%) and gastric (32%) primary. 12-week PFR were A1: 51% (95%CI: 38-64%); A2: 52% (95%CI: 40-65%); A3: 49% (95%CI: 36-62%). PFR differences to arm A1 were A2: 1.6% (95%CI: -13.2 to 16.5%); A3: -1.6% (95%CI: -16.5 to 13.3%). In A1, PFR was 53% vs 43% in PDL1 TIP < 10% and ≥10% respectively. In A3, PFR was 51% vs 100% in PDL1 TIP < 10% and ≥10% respectively. 3 pts in A3 had partial response; none were seen in A1 and A2. Density of TILs subsets, TMB and MSI data will be presented. Conclusions: PLATFORM IA did not indicate futility in maintenance capecitabine or durvalumab compared to surveillance in advanced OGA and will continue to target accrual. Incremental radiological responses were observed with maintenance durvalumab only. Clinical trial information: NCT02678182.
Comparing the accuracy of EUS and CT in staging of esophageal cancer.
Authors: Shim Hyun Ik , Lee Dong Ho , Cho Jae Ho , Shin Cheol Min , Yoon Hyuk , Park Young Soo , Kim Nayoung
Published: February 2020

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Background: Endoscopic ultrasound (EUS) is a suitable device for staging of esophageal cancers. However, chest computed tomography (CT) has traditionally been the standard diagnostic modality for malignancies. This study aimed was to compare the accuracies of EUS and chest CT in T and N staging of esophageal cancers. Methods: We retrospectively analyzed 149 patients who had undergone EUS examination and 275 patients who had undergone chest CT before cancer surgery. The inclusion criteria were: 1) patients diagnosed with esophageal cancer on biopsy, 2) patients who had undergone EUS examination or chest CT before cancer surgery, and 3) patients who underwent cancer surgery at the Seoul National University Bundang Hospital from May 2003 to December 2018. We determined the accuracy of T and N staging on EUS examination and chest CT with the biopsy specimens. Results: The overall accuracies of EUS examination and chest CT were 72.5% (108/149) and 68.7% (189/275), respectively, for T staging ( p = 0.487) and 64.4% (96/149) and 61.5% (169/275), respectively, for N staging, which was not statistically different ( p = 0.596). For the substaging, the accuracy of EUS examination was not statistically different than that of chest CT for the T, N stage. Conclusions: EUS examination is not superior to chest CT for diagnosing T stage in esophageal cancers, whereas chest CT is not superior to EUS examination for diagnosing N stage in esophageal cancers. EUS examination and chest CT are not satisfactory for diagnosing T, N stage in esophageal cancers. Futher study is needed for accurate T, N stage diagnosis in esophageal cancer.
Prediction of lymph node metastasis in early gastric cancer using artificial intelligence technology.
Authors: Irino Tomoyuki , Kawakubo Hirofumi , Matsuda Satoru , Mayanagi Shuhei , Nakamura Rieko , Wada Norihito , Kamiya Satoshi , Tanizawa Yutaka , Bando Etsuro , Terashima Masanori , Kitagawa Yuko
Published: February 2020

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Background: Early gastric cancer shows lymph node involvement in about 10-15% of patients. Despite the fact, we perform radical lymphadenectomy for all patients because predicting lymph node metastasis has yet to be successful. In this study, we hypothesize that image analysis using artificial intelligence (AI) technology may help solve the problem. Methods: We retrospectively collected 82 patients with clinical T1N0 and pathological node negative and 82 patients with clinical T1N0 and pathological node positives and then divided the 164 patients into a training:validation set in ratio of 9:1. Endoscopic images of the early tumors were analyzed by transfer learning using AlexNet, a deep neural network containing 5 convolutional layers and 3 fully-connected layers. The model was validated with newly-collected 40 images from 20 clinical T1N0 and pathological node negative and 20 patients with clinical T1N0 and pathological node positives as a test set. For comparison, three methods of prediction were implemented: prediction at random, by logistic regression, and by skilled endoscopists. Results: The AI predicted LNM with accuracy of 80.9% in the validation set and 66.9% in the test set. (48.3% for node negative cancers and 85.4% for node positive cancers) On the other hand, prediction at random, by logistic regression, and by 2 endoscopists resulted in 50.3%, 50.0%, and 47.5%, respectively. Conclusions: Although the accuracy still needs to be improved, image analysis using the AI technology resulted in the best prediction of lymph node metastasis, indicating that AI is a promising technology for the diagnosis of lymph node metastasis in early gastric cancer.