bluuebunny/crossref_metadata_2025 huggingface dataset:
Short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma.
Authors: Shamseddine Ali , Zeidan Youssef , Khalifeh Ibrahim Moustafa , Kattan Joseph Gergi , Turfa Rim , Mukherji Deborah , Temraz Sally Naji , Jamali Faek , Shaib Yasser Hani , Soweid Assaad , Deeba Samer , Kreidieh Malek , El Husseini Ziad zuheir , Charafeddine Maya , Al Darazi Monita , Geara Fady B.
Published: February 2020

139

Background: Total neoadjuvant treatment (TNT) for locally advanced rectal cancer is becoming an accepted approach over the last few years with increasing pathologic complete response (pCR) and compliance of patients for chemotherapy in comparison with the current standard of care i.e., fluoropyrimidine based chemoradiation followed by surgery and adjuvant chemotherapy. Sequential use checkpoint inhibitors after radiation therapy (RT) has demonstrated synergistic effect in vivo leading to decrease in size of irradiated and non-irradiated secondary tumors outside the radiation field (abscopal effect). Methods: This is an investigator initiated; open-label, single-arm multicenter phase II study, adopting Simon’s two-stage aiming at evaluating the pCR rate and safety of using short-course radiation therapy (25 Grays in 5 fractions), followed by 6 cycles of mFOLFOX-6 plus Avelumab (anti PDL1), then total mesorectal excision(TME) in patients with locally-advanced, potentially resectable rectal adenocarcinoma. Results: 13 out of 44 patients were accrued from 20, July till 28, Dec 2018 in the first stage of the study (30% from total sample size). They all met the inclusion criteria and received full protocol treatment. 12 out of the 13 completed TME. 1 of the 13 had progression of disease, so surgery was aborted and patient was dropped out the study. The sample consisted of 9 (69%) males and 4 (31%) females with median age of 62 (33.0, 73.0) years. The first interim analysis revealed 3 patients (25%) achieved pCR (tumor regression grade: TRG = 0) out of 12 as compared to the historical control group with pCR of 16%. For the rest of the patients, 3 (25%) had major pathologic response rate (pRR) with TRG = 1 (< 10% viable cells is tumor bed).In total, 6 out of 12 patients (50%) had major pathologic response rate. As for safety, no serious adverse events of grade 3 and 4 were reported. Conclusions: Based on the first interim analysis results, incorporation of Avelumab and short course radiotherapy is tolerable in patients with locally advanced rectal cancer treated with TNT. The study will resume recruitment to reach the target accrual. Clinical trial information: NCT03503630.
Analysis of hematologic adverse events (HeAEs) in trifluridine/tipiracil (FTD/TPI)-treated patients (pts) with or without renal/hepatic impairment (RI/HI): Pooled safety analyses from TAGS and RECOURSE.
Authors: George Ben , Van Cutsem Eric , Hochster Howard S. , Mayer Robert J. , Ohtsu Atsushi , Falcone Alfredo , Yoshino Takayuki , Doi Toshihiko , Ilson David H. , Arkenau Hendrik-Tobias , Benhadji Karim A. , Makris Lukas , Tabernero Josep , Shitara Kohei
Published: February 2020

145

Background: FTD/TPI has shown clinical benefit and consistent safety in pretreated pts with metastatic colorectal cancer (mCRC) and metastatic gastric or gastroesophageal junction cancer (mGC/GEJC) in the phase 3 RECOURSE and TAGS trials, respectively. HeAEs were the most frequent AEs with FTD/TPI treatment. Methods: Pts in this analysis received ≥1 FTD/TPI dose in the TAGS and RECOURSE trials. Subgroups included pts with normal renal function (nRF; CrCl ≥90 mL/min), mild RI (CrCl 60–89 mL/min), moderate (mod) RI (CrCl 30–59 mL/min), normal hepatic function (nHF) and mild HI (total bilirubin <1.5 X ULN, or AST >ULN). Results: FTD/TPI was administered to 868 pts in the overall pooled population (OPP; n=335, TAGS [mGC/GEJC]; n=533, RECOURSE [mCRC]); 52%, 36%, and 11% had nRF, mild and moderate RI, and 66% and 33% had nHF and mild HI, respectively. Frequencies of any-cause grade (gr) ≥3 HeAEs were similar across subgroups and the OPP, except for gr ≥3 anemia and gr ≥3 leukopenia, which were higher with mod RI (table). In the OPP, most gr 3/4 neutropenia events occurred within the first 2 cycles (median time to onset [mTTO], 49 d). Median time to resolution (mTTR) was 8 d. Gr 3/4 neutropenia TTO and TTR in most subgroups were consistent with the OPP, except with mod RI (mTTO, 29 d). HeAE management and correlative efficacy analyses will be presented. Conclusions: In this pooled analysis of pts with mCRC and mGC/GEJC, HeAEs with FTD/TPI in pts with mild to mod RI and mild HI were manageable and not largely different from those in the OPP. Clinical trial information: NCT02500043 and NCT01607957.

[Table: see text]
Stereotactic radiotherapy (SRT) in oligometastatic (OM) colorectal cancer (CRC): Can we improve systemic therapy (ST) free interval?
Authors: Palhares Daniel Moore Freitas , Reis Figueiredo Renata , Marchetti Katia Regina , Pereira Allan Andresson Lima , Alves Teixeira Marcela , Faria Luiza , Gumz Brenda Pires , Gadia Rafael , Fernandes Gustavo Dos Santos
Published: February 2020

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Background: Metastatic colorectal cancer is common disease that is treated mainly with systemic chemotherapy with or without target therapy combined with local therapies when feasible. Patients with OM-CRC may benefit from local treatments, classically surgery, but more recently SRT is also showing to be effective. We aimed to access the benefit of SRT in patients (pts) with OM-CRC that where not candidates for surgery. Methods: This retrospective study evaluated all the pts with CRC from a single institution that did SRT for OM-CRC. SRT was done with 3D or IMRT/VMAT planning and daily volumetric image. 1-10 fractions were delivered aiming to keep BED > 100Gy10. Dose was decreased as necessary to respect the constraints and minimize toxicity. Progression free survival (PFS) was analyzed from SRT to first progression or death, ST-free survival (STFS) from SRT to the beginning on next ST line or death. Results: We evaluated 32 consecutive pts from Sep/2014 to Jul/2019. Forty-six courses of SRT where performed. Mean age was 56 ± 13y, 60% female and 65% had colon cancer. 52% had metastatic disease after radical treatment. 63% were off ST by the time of the SRT. SRT treatment sites were lung and liver in 28%, bones and lymph nodes 13%, and CNS 11%. 72% of pts had only 1 treated lesion and 70% did 1 SRT course. Most commonly used regimens were 3 x 10-18Gy (35%), 4 x 10-12Gy (15%) and 5 x 7-10Gy (22%). 37% of treatments had BED≥100Gy10 and 78% were done with IMRT/VMAT. With a median follow-up of 16.1m (IQR 8.2-32.7), the median PFS was 5.4m (95% CI 4.1-11.0) and STFS was 12.7m (95% CI 0.8-24.5). Patients with multiple SRT courses had longer interval between disease progression and starting the next ST line (median 2.2 vs 12.4m). Pts that where on ST holidays before SRT had higher STFS (HR = 0.24 95% CI 0.1-0.6, p = 0.001) probably due to selection bias (lower disease volume). The 3y OS was 71%, median was not reached. Conclusions: Local treatment with SRT for OM-CRC showed to be feasible and safe with promising PFS and OS that deserves further investigation. The median STFS superior to a year suggests that SRT can influence OM-CRC treatment positively, possible impacting quality of life and even treatment costs.
A cost-effectiveness analysis of pretreatment DPYD and UGT1A1 screening in patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI+bevacizumab (FOLFIRI+Bev).
Authors: Rivers Zachary , Stenehjem David D. , Jacobson Pamala , Lou Emil , Nelson Andrew , Kuntz Karen M
Published: February 2020

168

Background: Variants in DPYD and UGT1A1 impact toxicities experienced by patients being treated with FOLFIRI+bev. Testing allows providers to preemptively adjust dosing, reducing the toxicity that patients experience. We assessed the cost-effectiveness of pre-treatment testing for variants in DPYD and UGT1A1 in patients with mCRC receiving FOLFIRI+bev. Methods: We developed a six-state Markov model to compare pre-treatment genetic testing to no testing. The genetic testing arm screened for UGT1A1 and DPYD using a multi-gene panel. Patients were dosed per proposed guidelines (Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group) and allowed dose reductions based on toxicity. In the no-test arm, patients received full doses of FOLFIRI+bev, and dose reductions based on toxicity. Costs included medications, clinic visits, and hospitalizations to treat the disease and adverse events, and were obtained from the literature, adjusted to 2019 $US. Quality-adjusted life years (QALYs) were used to assess effectiveness. We used a US health care system perspective with a 16 week horizon, the average length of time patients were exposed to FOLFIRI+bev in clinical trials. We conducted sensitivity analyses to determine the impact of uncertainty on outcomes. Results: Genetic testing cost $25,563, generating 0.21 QALYs. Standard of care cost $25,515, generating 0.20 QALYs. This resulted in an incremental cost-effectiveness ratio (ICER) of $4963 per QALY gained. Results were sensitive to costs of post-progression care, the probability of carrying UGT1A1 variants, and the impact of low-functioning DPYD variants on side effects. Conclusions: Pre-treatment testing for DPYD and UGT1A1 in patients receiving FOLFIRI+bev for mCRC is cost-effective, well below typical oncology ICERs of $50,000-100,000 per QALY. Further work is needed to characterize the impact of post-progression treatment and supportive care medications.
Biomarker analysis for UPCI 14-118: Phase II study of pembrolizumab in combination with azacitidine in patients with refractory metastatic colorectal cancer.
Authors: Kuang Chaoyuan , Park Yongseok , Bahary Nathan , Sun Weijing , Ohr James , Rhee John C. , Marks Stanley M. , Beasley H. Scott , Shuai Yongli , Lin Yan , Pai Reetesh K. , Krishnamurthy Anuradha , Zarour Hassane M. , Herman James , Chu Edward , Lee James J.
Published: February 2020

173

Background: DNA mismatch repair (MMR) proficient colorectal cancer (CRC) is resistant to immune checkpoint therapy compared to MMR deficient CRC. DNA hypomethylating agents may promote anti-tumor immune response by re-expression of cancer-testis antigen and reactivating immune genes suppressed by DNA methylation. This trial tested whether epigenetic modulation by concurrent treatment with azacitidine could enhance the anti-tumor activity of pembrolizumab in mCRC. Methods: Phase II trial was conducted to evaluate activity, safety, and tolerability of pembrolizumab in combination with azacitidine in patients with previously treated pMMR metastatic CRC. Patients received pembrolizumab 200 mg IV on day 1 and azacitidine 100 mg daily SQ injection on days 1-5 every 3 weeks. The primary endpoint of the study was ORR. Tumors were biopsied pre-treatment and on-treatment for biomarker studies. Results: 30 patients received at least one dose of therapy. One patient experienced a confirmed partial response, one experienced stable disease. ORR was 3% (1/30; 95% CI, 0.1-17%). Median PFS was 1.9 months, median OS was 6.3 months. Treatment was well tolerated with only one patient (3%) experiencing grade 3 adverse event. The patient with a PR had positive pre-treatment TILs, but no evaluable tumor from on-treatment biopsy. 2 of 6 patients who continued therapy despite PD on first restaging experienced temporary stabilization of disease later. 5 of 16 evaluable biopsy pairs demonstrated increased TILs on treatment compared to baseline; however, all of these patients experienced PD. 10 of 15 paired samples demonstrated decreased methylation of hypermethylated loci on-treatment. Clustering analysis demonstrated a correlation between pre-treatment methylation of immune activation genes with overall survival of the patients. Conclusions: Combining azacitidine and pembrolizumab is safe and tolerable for pMMR mCRC with only limited activity. DNA methylation and TIL changes are detectable after 3 cycles of therapy. DNA methylation of immune activation genes correlate with overall survival. RNA sequencing and peripheral immune cell flow cytometry are ongoing. Clinical trial information: NCT02260440.
Circulating miR-203 secreted from metastatic tissues could exacerbate myopenia in colorectal cancer patients.
Authors: Okugawa Yoshinaga , Toiyama Yuji , Hur Keun , Ide Shozo , Shimura Tadanobu , Fujikawa Hiroyuki , Yasuda Hiromi , Yokoe Takeshi , Hiro Junichiro , Ohi Masaki , Kusunoki Masato
Published: February 2020

181

Background: Sarcopenia is commonly observed in advanced cancer patients with distant metastases. In addition, biological functions of microRNAs (miRNAs) in cell-to-cell communication by incorporating into neighboring or distal cells has been gradually elucidated in various diseases, including sarcopenia, have been established. Methods: First, we quantified miR-203 expression, a key miRNA involved in cell-to-cell communication, by qRT-PCR and in situ hybridization in 58 pairs of primary CRC (pCRC) and corresponding matched liver metastasis (LM) tissues. We further evaluated miR-203 levels using pCRC tissues and matched preoperative serum to clarify its clinical significance in independent 183 CRC patients. Second, we assessed psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) using preoperative computed tomography imaging to clarify its clinical burden and correlations with miR-203 levels in CRC patients. Functional analysis of miR-203 overexpression was investigated in human skeletal muscle cells (SkMC), and cells were analyzed for proliferation and apoptosis. Expression of several, putative, miR-203-target genes was also validated in SkMC cells. Results: MiR-203 expression was significantly upregulated in LM compared with matched pCRC tissues. Serum miR-203 levels were significantly upregulated in a stage-dependent manner, and high miR-203 expression was associated with poor survival in patients with CRC in both patient cohorts. In contrast to IMAC, decreased PMI significantly correlated with well-established disease development factors, and decreased PMI was an independent prognostic factor for both overall survival, and disease-free survival in CRC patients. Although tissue miR-203 expression did not significantly correlate with the body composition status, serum miR-203 expression negatively correlated with preoperative PMI level. Overexpression of miR-203 inhibited cell proliferation and induced apoptosis via downregulation of BIRC5 (Survivin) expression in SkMC cell. Conclusions: Assessment of serum miR-203 could be used for risk assessment of metastasis-related myopenia in CRC.
The intersection of age and tumor biology with postoperative outcomes in patients after cytoreductive surgery and HIPEC.
Authors: Turgeon Michael K. , Gamboa Adriana C. , Lee Rachel M. , Zaidi Mohammad Yahya , Kimbrough Charles , Grotz Travis Edward , Fournier Keith F. , Dineen Sean Patrick , Veerapong Jula , Clarke Callisia , Mogal Harveshp , Patel Sameer H. , Lambert Laura A. , Ronnekleiv-Kelly Sean , Raoof Mustafa , Johnston Fabian McCartney , Staley Charles A. , Cloyd Jordan , Maithel Shishir K. , Winer Joshua H.
Published: February 2020

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Background: Patient age is often a significant factor in preoperative selection for major abdominal surgery. Its association with postoperative outcomes in patients undergoing cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC) remains ill-defined. Methods: The US HIPEC Collaborative database(2000-2017) was reviewed for patients who underwent a CCR0/1 CRS/HIPEC. Age was categorized into < 65 or >65yrs. Primary outcomes were postoperative major complications, readmission, 30-day mortality, and non-home discharge(NHD). Analysis was stratified by disease histology: non-invasive(appendiceal LAMN/HAMN), and invasive(appendiceal/colorectal adenocarcinoma). Results: Of 1090pts identified, 22% were >65yrs(n = 240), 59% were female(n = 646), 25% had non-invasive(n = 276) and 51% had invasive(n = 555) histology. Median PCI was 13(IQR7-20). Patients >65yrs had a higher rate of major complications(37vs26%, p = 0.02), readmission(28vs22%,p = 0.05), 30-day mortality(3vs1%,p = 0.02), and NHD(12vs5%,p < 0.01) compared to those < 65yrs. On multivariable analysis accounting for extent of disease as measured by PCI, for non-invasive histology, age >65yrs was an independent predictor for NHD(OR:2.54,95%CI:1.08-5.99,p = 0.03), but not major complications. For invasive histology, even when accounting for PCI, age >65yrs was an independent predictor for both NHD(OR:2.54,95%CI:1.08-5.98,p = 0.03) and major complications(OR:2.04,95%CI:1.16-3.59,p = 0.05). Age was not associated with hospital readmission or 30-day mortality for any histology. Conclusions: Regardless of histology, patients >65yrs are nearly at three-fold increased risk for non-home discharge after CRS/HIPEC. For invasive histology, age >65yrs is also associated with increased major complication rates, but the procedure seems to be better tolerated when performed for indolent biology. These data inform preoperative counseling and risk stratification. Early planning for discharge disposition in this high-risk population can potentially translate to cost savings.
Systemic impact on tumor growth after combined immuno-thermal ablation in a murine model of colorectal cancer.
Authors: Slovak Ryan J. , Park Hong-Jai , Kamp William M. , Ludwig Johannes M. , Kang Insoo , Kim Hyun S.
Published: February 2020

198

Background: Cryoablation exposes tumoral antigens capable of provoking an anti-cancer immune response. The addition of immunotherapy alongside cryoablation may synergistically promote a more robust systemic response. The purpose of this investigation was to study the growth of targeted and off-target tumors after combined cryoablation and dual immune checkpoint blockade (DICB). Methods: Sixty BALB/c mice were implanted with bilateral flank injections of 0.5 x 106 CT26.WT colorectal cancer cells (CRL- 2638; ATCC, Manassas, VA). Tumor volume was measured every other day via caliper (LxW2). Mice were randomly assigned to receive either sham injections (InVivoMAb IgG controls), dual anti-PD-1 and anti-CTLA-4 (DICB) (Clone J43 & Clone 9D9; BioXcell, West Lebanon, NH, USA), or DICB plus either partial or full cryoablation of a single targeted tumor. Treatment day 0 began once tumors reached a volume of ~300mm3. Injections of antibodies were given on treatment day 0, 3, and 5. Cryoablation was performed on treatment day 2. Full ablation was achieved via two 3-minute cycles at 100% power and partial ablation was defined as a single 3 minute cycle at 70% power ablation (Visual-ICE System, Galil Medical, St. Paul MN). Animals were sacrificed at 7 and 14 days after treatment. Results: There was an average of 177.15% ± 75.22 (SD) increase in tumor volume among control animals and 14.47% ± 9.69 decrease in animals treated solely with DICB. Mice that received full ablation demonstrated an average 72.39% ± 29.21 decreased volume in the target tumors and 48.94% ± 25.97 decrease in the off-target tumors. Partially ablated mice averaged 81.21% ± 16.43 decreased volume in the target tumors and 35.87% ± 16.95 decreased volume in the off-target tumors. The mean change in volume of every group was significantly less than that of the control (p < 0.05) and there was a significantly larger reduction in volume between both the full and the partial target tumors versus the DICB group (p < 0.05). Conclusions: The addition of cryoablation to DICB resulted in a significant reduction in volume of the targeted tumors. Additionally, this combination led to larger volume reductions in off-target tumors as compared to immunotherapy alone.
Gene polymorphisms of CCL3, CCL4, CCL5, and CCR5 network in metastatic colorectal cancer patients treated with regorafenib.
Authors: Suenaga Mitsukuni , Zhang Wu , Mashima Tetsuo , Schirripa Marta , Cao Shu , Okazaki Satoshi , Berger Martin D. , Miyamoto Yuji , Barzi Afsaneh , Lenz Heinz-Josef
Published: February 2020

199

Background: We previously reported that genetic variant in the CCL5/CCR5 pathway predict efficacy of regorafenib in metastatic colorectal cancer patients (mCRC). CCL5 rs2280789 G allele and CCL5 rs3817655 T allele were associated with longer overall survival (OS) and severe skin toxicity due to low VEGF-A production via endothelial progenitor cell (EPC). CCL4 rs1634517 G allele and CCL3 rs1130371 C allele correlated with longer Progression-free survival (PFS) and OS. We investigated the biological role of CCL4 and CCL3 gene polymorphisms. Methods: We analyzed genomic DNA extracted from 79 samples of a Japanese cohort receiving regorafenib. Single nucleotide polymorphisms (SNPs) of genes in CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Blood samples were obtained from 57 patients at baseline (BL), day 21 and progressive disease (PD), and serum CCR5, CCR5 ligands (CCL3, CCL4, CCL5) and VEGF-A levels were measured using ELISA. PFS and OS were analyzed using Kaplan-Meier curves and log-rank test. Results: Increased CCL3 levels at PD were associated with longer OS than decreased (12.6 vs 4.8 mos, P = 0.003). Patients with decreased CCL4 levels at day 21 had a trend toward longer PFS and tumor shrinkage. Positive correlation was observed between CCL3 and CCR5 throughout the treatment independent of other ligands (change at day 21: r = 0.426, P = 0.009). There was no significant correlation of CCL3 and CCL4 levels with VEGF-A levels. Patients with the G/G variant in CCL3 rs1130371 had increased CCL3, CCR5 and CCL5 levels at day 21 than any A allele. Similarly, patients with the C/C variant had increased CCL3, CCR5 and CCL5 levels at day 21 compared with those with any A allele. In contrast, both CCL5 rs2280789 G allele and CCL5 rs3817655 T allele were associated with increased CCL3 levels and decreased CCL4 levels at day 21 (P = 0.006, P = 0.043; P = 0.006, P = 0.043). Conclusions: Positive correlation of CCL3, CCR5 and CCL5 impact similarly on CCL3 and CCL4 SNPs, while different manner between CCL3 and CCL4 was found in CCL5 SNPs. This suggests an alternative mechanism of action in the network of CCR5 and the ligands except CCL5-VEGF-A signaling via EPC in mCRC patients receiving regorafenib.
Analysis of early tumor shrinkage (ETS) and depth of response (DpR) in metastatic colorectal cancer (mCRC) patients (pts) treated with second-line FOLFIRI plus panitumumab (Pani) or bevacizumab (Bev): Results from a randomized phase II WJOG6210G trial.
Authors: Izawa Naoki , Shitara Kohei , Masuishi Toshiki , Denda Tadamichi , Yamazaki Kentaro , Moriwaki Toshikazu , Okuda Hiroyuki , Kondoh Chihiro , Nishina Tomohiro , Makiyama Akitaka , Baba Hideo , Yamaguchi Hironori , Nakamura Masato , Tsuji Akihito , Esaki Taito , Miyata Yoshinori , Kotaka Masahito , Yamanaka Takeharu , Nakajima Takako Eguchi , Muro Kei
Published: February 2020

201

Background: The WJOG 6210G trial demonstrated a similar efficacy between Pani and Bev arms at 2nd-line setting in pts with KRAS exon2 wild-type mCRC (Shitara K, et al, Cancer Sci 2016). The exploratory analyses of clinical trials evaluating 1st-line chemotherapy for mCRC have shown significant associations of ETS and DpR with prognosis; however, there is few data in 2nd-line treatment. We investigated whether ETS and DpR are associated with clinical outcomes in mCRC pts treated with 2nd-line treatment using the data of WJOG 6210G trial. Methods: ETS was defined as tumor reduction of 20% at week 8 compared to baseline in the sum of longest diameters of target lesions according to the RECIST criteria. DpR was defined as the percentage of maximum tumor shrinkage of target lesions. Fisher’s exact test and t-test were used to compare ETS and DpR between Pani and Bev arms. A Cox regression model was used to evaluate associations between ETS and progression-free survival (PFS), and overall survival (OS). The association of DpR with PFS and OS was analyzed using Spearman’s rank correlation coefficient. Results: Eighty-seven pts were evaluable for ETS and DpR (Pani, n = 41; Bev, n = 46) among 121 pts enrolled in the WJOG6210G. Pts in the Pani arm had a higher ETS rate (39.0 % vs. 8.7 %, p < 0.001) and greater DpR [median: 23.7 % (range: -49.0 to 100) vs. 0 % (range: -40.7 to 61.5), p < 0.001] than pts in the Bev arm. Pts with ETS achieved longer PFS [median: 10.5 vs. 5.4 m, HR: 0.40 (95% CI: 0.20-0.80), p = 0.009] and OS [median: 22.3 vs. 14.5 m, HR: 0.49 (95% CI: 0.23-0.98), p = 0.044] than pts without ETS in the Pani arm. Similarly, the Bev arm pts with ETS had longer PFS [median: 17.1 vs. 5.6 m, HR: 0.078 (95% CI: 0.004-0.38), p = 0.0002] and OS [median: 30.9 vs. 13.2 m, HR: 0.35 (95% CI: 0.083-0.99), p = 0.048]. There were moderately linear correlations of DpR with PFS and OS in both Pani (PFS: r = 0.75, p < 0.001; OS: r = 0.60, p < 0.001) and Bev arms (PFS: r = 0.68, p < 0.001; OS: r = 0.44, p = 0.002). Conclusions: ETS and DpR were significantly associated with PFS and OS in mCRC pts treated with 2nd-line FOLFIRI in combination with Pani or Bev. Clinical trial information: UMIN000031621.
Prediction of hepatic metastasis and relapse: Concordance analysis among noninvasive liver fibrosis scores from colorectal cancers.
Authors: Cai Sanjun , Hu Xiang , Dai Weixing , Li Yaqi , Ma Xiaoji , Peng Junjie
Published: February 2020

202

Background: Liver fibrosis, resulted from several liver diseases, are increasing up to 25% in population globally. It remains undetermined how much of an impact liver fibrosis have on the development of hepatic metastasis and relapse in colorectal cancer (CRC). Hence the aim of this study was to clarify the role of liver fibrosis on hepatic metastasis and relapse in CRC undergoing curative therapy. Methods: We enrolled consecutive 1652 patients with radical surgery as the discovery cohort, and the validation set enrolled 432 CRC patients with hepatic metastasis treatment. To determine the degree of liver fibrosis, the NFS, FIB4 and APRI were applied. The influence of liver fibrosis on hepatic metastasis and relapse was assessed by survival analyses. Nomograms with fibrosis score incorporated was established to identify the incremental value for individualized relapse estimation, which was then assessed with respect to calibration, discrimination, and clinical usefulness. Results: The high liver fibrosis score patients had significantly worse outcomes than low score in 5-year hepatic metastasis (22.6 vs . 8.7%) in discovery cohort, and RFS (58.2 vs. 44.1%) in validation cohort. Multivariate analysis revealed liver fibrosis score as an independent prognostic factor. The distribution analysis also demonstrated higher liver fibrosis score a powerful prognostic factor for hepatic metastasis and relapse. Incorporating the liver fibrosis score into the nomogram resulted in better performance evaluated by C-index and AUC than TNM staging system and clinicopathologic nomograms. Importantly, in validation cohort, the discriminatory capacity of the fibrosis score incorporated was superior to that of the CRS score in predicting RFS, as demonstrated by the C-index and AUC. The concordance study showed well agreement among NFS, FIB4 and APRI in predicting DFS and RFS. Among these three noninvasive liver fibrosis scores, NFS score performed the best in predicting hepatic specific DFS and RFS. Conclusions: The liver fibrosis was a powerful predictor of hepatic specific DFS and RFS in CRC. Fibrosis niche may be a favorable microenvironment for metastatic formation in the liver.
Prospective study with circulating tumor cells as potential prognosis biomarker in metastatic colorectal cancer.
Authors: Souza E Silva Virgilio , Abdallah Emne Ali , Mello Celso Abdon Lopes de , Tariki Milena Shizue , Calsavara Vinicius Fernando , Chinen Ludmilla T.D.
Published: February 2020

203

Background: Colorectal cancer (CRC) is one of the most common cancer worldwide. Around 30% present metastatic disease at diagnosis and 50%–60% of patients develop metastasis. New prognostic markers are needed and circulating tumor cells (CTCs) are a promising tool. Methods: Prospective study conducted by blood collection from 75 patients (pts) with metastatic CRC (mCRC), twice, with 2 months interval, together with image exams for therapeutic response evaluation. CTCs were detected by ISET and identified by immunocytochemistry. Results: The mean age was 57.3 years old (24-81). RAS mutations in primary tumor was found in 38% (19/50) of patients (pts) and left colon topography in 41.3% (31/75). Comparing the baseline CTC level (CTC1) with the level at first follow-up (CTC 2), pts with CTC2 – CTC1 > 5.5 per ml demonstrated poor progression-free survival (PFS) (3.2 months) when compared to CTC 2 – CTC1 ≤ 5.5 (9.1 months) (p= 0.005). The median overall survival (OS) was 24.5 months for pts with CTC 1 > 1.5 per ml and 34.2 months for those with CTC1 ≤ 1.5 per (HR=1.89, 95% CI, 1.01 to 3.52; p= 0.041). Patients with RAS mutation (P= 0.001), primary tumor in the right colon (p= 0.014) and expression of Multidrug Resistance Protein 1 in CTCs (p= 0.044) had worse OS. By multivariable analyses, CTC 1 > 1.5/mL (p= 0.025) was an independent prognostic factor. Conclusions: This prospective study confirmed that counts of CTCs at baseline (CTC1) is an important prognostic marker for monitoring mCRC and correlates with other established prognostic factors. Clinical trial information: NCT02979470.
Validation of the Glasgow Microenvironment Score in patients with colon cancer: A pathology-based prognostic tool.
Authors: Alexander Peter G , Roseweir Antonia K. , Pennel Kathryn AF , Van Wyk Hester Catharina , Powell Arfon GMT , Roxburgh Campbell SD , Horgan Paul G. , Edwards Joanne , McMillan Donald C. , Park James Hugh
Published: February 2020

206

Background: The Glasgow Microenvironment Score (GMS), comprised of assessment of the tumour inflammatory cell infiltrate (using Klintrup-Mäkinen (KM) grade) and tumour-associated stroma (TSP), has been reported as a stage-independent prognostic score in patients with colorectal cancer. The present study aims to validate the GMS and examines its prognostic utility in the context of stage and MMR status. Methods: Patients who had undergone resection of stage I-III colon cancer were included ( n= 495). GMS was scored by combining KM and TSP as follows: high KM scores 0; low KM with low TSP scores 1; low KM and high TSP scores 2. Cancer specific (CSS) and overall survival (OS) were primary endpoints. Subgroup analysis was performed to assess the utility of GMS according to TNM, venous invasion and MMR status. Results: There were 30% of patients with GMS 0, 56% with GMS 1 and 14% with GMS 2. Five-year survival for GMS 0, 1 and 2 across the whole cohort were 89%, 74% and 66%, respectively. GMS was associated with age, mode of presentation, TNM, venous invasion and MMR status. On multivariate analysis, GMS was independently associated with CSS (HR 1.35, 95% CI: 1.02-1.79, p= 0.04) and OS (HR 1.23, 95% CI: 1.02-1.48, p= 0.03); this was independent of emergency presentation ( p< 0.01), T-stage ( p= 0.03) and N-stage ( p< 0.001) for CSS. Subgroup analysis found that GMS was able to stratify CSS regardless of node-negative or node-positive disease (both p< 0.01), venous invasion ( p< 0.05), elective presentation ( p< 0.01) and MMR-proficient tumours ( p< 0.001), although it was not able to stratify emergency presentation ( n= 154) or MMR-deficient disease ( n= 102) due to small sample size. Universally, the prognosis for GMS 0 was good, but was poor for GMS 2. The prognosis for GMS 1 varied depending on MMR and nodal status. Conclusions: This study validates the use of the GMS as an independent prognostic pathology-based tool for stratification of colon cancer. It could be readily applied to routine clinical practice and may be used to aid decision making regarding adjuvant treatments in colorectal cancer. It should be further validated in prospective randomised trials.
Assessing real-world biomarker testing rates in metastatic colon cancer.
Authors: Nakhoda Shazia , Deng Mengying , Iyer Pritish , Handorf Elizabeth A. , Jain Rishi , Meropol Neal J. , Dotan Efrat
Published: February 2020

209

Background: Despite national guideline recommendations for universal biomarker testing (KRAS, NRAS, BRAF, and mismatch repair/microsatellite instability [MMR/MSI]) in all patients with metastatic colorectal cancer (mCRC), little is known regarding adherence to these recommendations in the community. Methods: We evaluated 20,333 patients aged >18 years with mCRC diagnosed between 1/1/2013-12/27/18 from the nationwide de-identified Flatiron Health electronic health record-derived database. Changes in rates of biomarker testing based upon chart abstraction according to date of mCRC diagnosis were assessed in patients with ≥ 6 months of follow-up using Cochran-Armitage trend tests. We also assessed whether testing differed by patient characteristics using chi-square tests. Results: Biomarker testing rates increased between 2013 and 2018 (15.3 to 65.7% for NRAS, 23.9 to 56.6% for BRAF, and 34 to 76.6% for MMR, all p < 0.0001). There was no change in rate of KRAS testing (63.8 to 68.3% p= 0.1695) over this period of time. Univariate analysis showed that patients with, worse performance status, and Medicare/Medicaid insurance were less likely to be tested (for all variables, p <0.0001). There were no meaningful differences in testing rates by tumor sidedness, race, gender, or initial stage. Conclusions: In mCRC, adoption of guideline-driven recommendations for NRAS, BRAF and MMR/MSI testing increased significantly between 2013-2018. Adoption of BRAF and NRAS testing has neared the rate of KRAS testing. Interpretation of overall testing rates must recognize potential for missing biomarker test information for care not captured within the Flatiron network. Further study is required to characterize the magnitude of and reasons for absent biomarker testing among patients with metastatic colorectal cancer.
Rate of conversion from unresectable to resectable metastatic colorectal cancer (mCRC) in real-world patients (RWP) treated with FOLFIXIRI ± bevacizumab: A population-based retrospective cohort study.
Authors: Bhatti Tayyaba , Moser Michael , Tan Jon , Zaidi Adnan , Le Duc , Chalchal Haji I. , Shaw John , Kanthan Selliah , iqbal mussawar , Luo Yigang , Haider Kamal , Asif Tehmina , Dorie-Anna Dueck , Gill Dilip , Ginther Nathan , Ahmed Shahid
Published: February 2020

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Background: Recent evidence from randomized trials suggests that FOLFOXIRI (5FU, oxaliplatin, and irinotecan) ± bevacizumab is associated with higher response rates with a potential for conversion of unresectable to resectable disease in mCRC. Yet limited evidence is available about efficacy and safety of this regimen in RWP with mCRC. The current study aims to evaluate conversion rate and safety of FOLFOXIRI ± bevacizumab in RWP with unresectable mCRC. Methods: Each year about 175 patients are diagnosed with mCRC in Saskatchewan. Patients who were diagnosed with unresectable mCRC between Jan 2015 to Dec 2018 and received FOLFOXIRI ±bevacizumab were assessed. Kaplan Meier survival methods and log rank test were performed. Logistic regression analysis was performed to assess factors correlate with conversion. Results: 28 eligible patients with median age of 51 yrs (IQR:39-60) and M:F of 11:16 were identified. 42% patients had a comorbid illness, and 43% had WHO performance status of 0. 39% had rectal cancer, 46% had extrahepatic disease and 46% had bilobar liver metastases. 58% patients had a positive response to therapy, 60% had grade 3/4 toxicity & 32% required hospital admission. No treatment-related mortality was noted. 54% patients underwent metastasectomy (liver 73%, peritoneum and or ovaries 20%, lung 6%). 68% had primary tumor resection, 29% received rectal radiation, 21% had ablation and 18% had second surgery for recurrence. At 4 years 50% patients are alive. Median progression free survival of patients who underwent surgery is 18 (95%CI:11.3-24.7) vs. 11 months (4-18.1) without surgery (P = 0.28). Median overall survival of patients with surgery is 33 (17.5-48.5) vs. 16 months (8.3-23.7) without surgery (P = 0.03). Positive response to treatment is correlated with conversion (odd ratio 21.7, p = 0.002). Conclusions: In the real world setting younger patients with good performance status received FOLFIRINOX ± bevacizumab. Despite high rates of toxicity, more than half of patients were able to undergo surgery. A positive response to treatment significantly correlates with metastasectomy.
Differences in the immune microenvironment between early and late-onset colon and rectal cancer.
Authors: Gardner Ivy Hernandez , Siddharthan Ragavan , Watson Kate , Ruhl Rebecca , Anand Sudarshan , Tsikitis Vassiliki Liana
Published: February 2020

214

Background: Over the past 35 years, there has been a significant increase in the number of patients below the recommended initial screening age (50 years old) diagnosed with colorectal cancer (CRC). Early onset colorectal cancer is more likely to occur in non-white patients, be located in the rectum, be diagnosed at a more advanced stage, and have concerning pathological features. The immune microenvironment in CRC is a key player in disease progression, therapy response, and overall survival. However, the role of the immune microenvironment in early onset CRC, particularly in rectal cancer has not been investigated. This study aims to characterize the immune microenvironment of early onset ( 50 years old) and late onset ( 65 years old) colon and rectal cancer patients. Methods: We used Nanostring immune profiling to analyze FFPE surgical specimens and identified genes that were differentially expressed between early and late onset colon and rectal cancer groups. We validate our results with qPCR. The differentially expressed genes in the rectal cancer cohort were compared to our analysis of a publically available database (GSE8721) of gene expression profiles for 203 rectal cancer and 160 matched normal mucosa samples. Immunohistochemistry (IHC) was performed on FFPE colorectal specimens for CXCL3. Results: Using Nanostring, we identified two genes that were differentially expressed between early and late onset colon cancer (IFITM1, CXCL3) and two genes in the rectal cancer cohort (FLT3, SAA1). CXCL3 has increased expression in late onset colon cancer utilizing qPCR and IHC. High expression of CXCL3 in both IHC and qPCR is associated with improved disease free survival. Analysis of the GSE8721 database also showed that FLT3 and SAA1 were differentially expressed in early versus late onset rectal cancer. Using qPCR, FLT3 is increased in early onset rectal cancer specimens compare to late onset rectal cancer, early and late onset colon cancer, and normal colon. Conclusions: There are distinct differences in the immune microenvironment between early and late onset colon and rectal cancer that may hold the potential for targeted therapeutics.
ARID1A mutation to define an immunologically active subgroup in patients with microsatellite-stable colorectal cancer.
Authors: Mehrvarz Sarshekeh Amir , Roszik Jason , Manyam Ganiraju C. , Advani Shailesh M. , Willis Jason , Shen John Paul Y.C. , Morris Jeffrey , Davis Jennifer S. , Ajani Jaffer A. , Maru Dipen M. , Overman Michael J. , Kopetz Scott
Published: February 2020

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Background: AT-rich interactive domain 1A (ARID1A) is a chromatin regulator mutated in human cancers, frequently resulting in truncation and loss of expression of this protein. ARID1A recruits MSH2 during DNA replication to perform mismatch-repair. ARID1A deficiency has been shown to increase mutational load and immune activation in preclinical models (Shen J, Nat Med 2018) but its role in colorectal cancer (CRC) patients (pts) is being explored. Methods: The DNA sequencing and gene expression profiling of microsatellite-stable (MSS) CRC pts were extracted from TCGA and MD Anderson Cancer Center databases. The expression levels were normalized according to the mean values of each dataset. The mutational burden and expression signatures for IFN-γ and various immune markers were compared according to the ARID1A mutational status. Results: Among 417 pts with MSS CRC, 28 pts (6.7%) had a non-silent mutation in ARID1A. Out of the 58 genes most commonly mutated in CRC, non-silent mutation in ARID1A had the strongest association with the frame-shift mutation rate in MSS cases (8-fold increase, p< .001). ARID1A mutation had also a strong correlation with the IFN-γ expression signature in MSS CRC (Δz score +1.91, p< .001) . Compared with ARID1A wild-type pts, higher expression signatures for cytotoxic T cell function, NK cells, and immune checkpoints were observed in MSS ARID1A mutated cases. ARID1A mutant cases showed higher expressions of various immune checkpoint genes (CD274, CTLA4, HAVCR2, IDO1, LAG3, PDCD1, and PDCD1LG2) compared to wild-type cases (all p < .05). All findings were observed independently in both datasets. Conclusions: In MSS CRC, ARID1A mutation is associated with a high expression of IFN-γ pathway and immune signatures (such as cytotoxic T cell function and immune checkpoint markers). The immunogenicity of ARID1A mutant cases is likely due to the increased level of neoantigens resulting from the increased rate of frame-shift mutations. Tumors with ARID1A mutation may be more susceptible to immune therapy-based treatment strategies and should likely be recognized as a unique molecular subgroup in future immune therapy trials.
Feasibility and clinical impact of routine molecular testing of gastrointestinal (GI) cancers at a tertiary center with a multigene, next generation sequencing (NGS) panel.
Authors: Bregni Giacomo , Sticca Tiberio , Akin Telli Tugba , Camera Silvia , Craciun Ligia Ioana , Shaza Leila , Deleruelle Amélie , Anciaux Maëlle , Machiels Godelieve , Deleporte Amélie , Vandeputte Caroline , Demetter Pieter , Larsimont Denis , Hendlisz Alain , Sclafani Francesco
Published: February 2020

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Background: High-throughput technologies have been increasingly used in research. Nevertheless, limited data are available on the feasibility and clinical value of these technologies in routine practice. Methods: All consecutive GI cancer patients (pts) who were tested with the 48-gene Truseq Amplicon Cancer Panel (Illumina) as part of routine practice at our Institution were identified from a prospectively maintained pathology database. Feasibility, results and impact on management decisions were analysed. Associations were tested with Fisher’s test. Results: From Apr 2014 to Jun 2019, 314 pts were tested. Sequencing was successful in 290 cases (92.4%; 234 colorectal (CRC), 21 gastro-esophageal, 17 bilio-pancreatic, 9 GIST, 4 appendix, 3 small intestine, 2 hepatocellular). In successful and failed cases, respectively, analyses were attempted on core biopsy (37.0% vs 66.7%), surgery (62.6% vs 16.7%), and fine needle aspiration (0.4% vs 12.4%) tumour samples (p < 0.001). Median turnaround time (TAT) was 12.5 days, reducing from 13 days in 2014 to 10 days in 2019. The majority of successfully tested pts (85.6%) had stage IV disease. TP53 was the most frequent mutation (45.9%), followed by APC (42.1%), KRAS (39.7%), PIK3CA (12.1%), SMAD4 (7.6%), BRAF (6.2%), and NRAS (5.5%). All other mutations were found in < 5% of cases. Excluding RAS/BRAF and KIT/PDGFR mutations, sequencing results impacted on the management of 4 (1.4%) pts. In 199 stage IV CRC pts, KRAS mutations were associated with lung (p = 0.020) and bone metastases (mts) (p = 0.008), NRAS mutations with liver mts (p = 0.021), BRAF mutations with peritoneal mts (p = 0.001), and APC mutations with lymph node mts (p = 0.006). Assuming a median of 25 samples per run, the estimated cost of NGS analysis per pt was €186. Conclusions: Low failure rate, short TAT and fair costs support feasibility of multi-gene NGS in routine practice. The clinical impact of this technology, however, is still limited but it could raise with the identification of new biologically relevant genetic alterations and the increased availability of novel therapeutics.
Concordance between blood- and tumor-based detection of RAS mutations to guide therapy in metastatic colorectal cancer.
Authors: Brozos Elena , Lago Ramón , Covela Rúa Marta , Montes Ana Fernández , De la camara Juan , Candamio Folgar Sonia , Muinelo Laura , Vidal Yolanda , Vazquez Maria Francisca , López Rosa , Blanco Cristina , Ferreirós Isabel , Lopez Rafael
Published: February 2020

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Background: The study of RAS using circulating tumor DNA (ctDNA) provides a good alternative for the detection and monitoring of RAS mutations during therapy course. Liquid biopsy has the advantage of being less invasive than conventional tissue biopsy. Therefore, it is necessary to determine the degree of concordance of RAS status between plasma and tissue samples from mCRC patients. Methods: We conducted a study to evaluate RAS concordance in several hospitals in Galicia, Northwest of Spain. We analyzed samples from 380 patients with mCRC in Galicia. RAS genotyping in plasma was performed using OncoBEAM RAS CRC kit, Sysmex and compared with the PyroMark Q24 System, Qiagen for FFPE-tissue analysis. Clinical data were collected from electronical reports from each patient. We analyzed the clinical features that can be related with discordant cases. Results: The overall percent of agreement was 83%, with a positive concordance of 79% (143/180 patients) and a negative concordance of 87% (116/132 patients). Taking into account the clinical features of the patients, those with only liver metastasis showed a higher level of concordance (88,8%) and the highest level was in the group of patients that presented liver metastasis and another location (91,3%). On the other hand, patients with only peritoneal disease showed the lowest level of agreement (68,2%), and the absence of liver metastasis was a significant factor of discordance of RAS (71% vs 28%, p<0.0001). Conclusions: The high overall concordance between plasma and tissue RAS mutation support the liquid biopsy technology as an alternative to tissue testing for RAS characterization in mCRC patients, especially in patients with liver metastasis and less in those with peritoneal disease. These results reinforce the use of liquid biopsy as a non-invasive tool for guiding targeted therapy in our patients.

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