bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcome of preoperative concurrent radiation and infusional gemcitabine in locally advanced rectal cancer, a phase 2 trial.
Authors: Bazarbashi Shouki , Gad Ahmed Mostafa , Badran Ahmed Ali , Elshenawy Mahmoud , Aljubran Ali H , Al Zahrani Ahmad , Al Manae Hadeel , Alsuhaibani Abdullah , Elashwah Ahmed , Neimatallah Mohammed , Abdul Jabbar Alaa , Ashari Luai , Al Homoud Samar , Ghebeh Hazem , Alsanea Nasser , Mohiuddin Mohammed
Published: January 2022

94

Background: The achievement of a pathological complete response with preoperative concurrent chemoradiotherapy in locally advanced rectal cancer has been found to correlate with a reduced incidence of local and distant recurrences. With the radiosensetizing properties of gemcitabine, we tested the efficacy and toxicity of preoperative concurrent infusional gemcitabine and radiotherapy in locally advanced rectal cancer. Methods: This was a phase II, single-arm, single-institution trial. Eligibility included a diagnosis of rectal adenocarcinoma with stage T2–4 and/or nodal involvement by MRI and endoscopic rectal ultrasound, age ≥ 18 years and no prior chemotherapy or radiotherapy. Patients received preoperative radiation at a dose of 50.4–54 Gy over 28 days with concurrent infusional gemcitabine administered at a dose of 100 mg/m2 over the course of 24 hours weekly for 6 weeks. The primary endpoint was a pathological complete response (pCR). The trial was registered at clinicaltrials.gov (NCT02919878). Results: Forty patients were enrolled in the study. All of the patients completed the planned therapy, except for one patient who died at the end of his concurrent chemoradiation. Eight patients did not undergo surgery, with 1 patient dying (mentioned above), 2 patients progressing to nonresectable disease and 5 patients withdrawing consent. Six patients progressed prior to or had metastases identified at surgery, with 2 patients having unresectable metastases, 3 patients having resectable liver metastases and 1 patient having a peritoneal metastasis (not resected). Serious adverse events were reported in 8 patients (20%). The most common grade 3–4 toxicities in the preoperative period included lymphopenia (50%), neutropenia (41%), anemia (15%), diarrhea (12%), abdominal pain (12%) and proctitis (8%). Out of the 32 patients who underwent surgery, 7 patients achieved pCR at a rate of 20%. With a median follow-up of 30 months, 4 additional patients relapsed (all of these patients had distant metastases, with one subsequently having a local recurrence). The 3-year event-free and overall survival rates were 70% and 85%, respectively. Conclusions: Concurrent preoperative chemoradiotherapy using infusional gemcitabine for locally advanced rectal cancer achieved an encouraging local control. Distant metastasis remains not decreased. Further investigations of a preoperative regimen containing gemcitabine is warranted. Clinical trial information: NCT02919878.
Phase II study of durvalumab following neoadjuvant chemoRT in operable rectal cancer: NSABP FR-2.
Authors: George Thomas J. , Yothers Greg , Jacobs Samuel A. , Finley Gene Grant , Wade James Lloyd , Rocha Lima Caio Max Sao Pedro , Rose Jeffrey Scott , Pahuja Shalu , Krishnamurthy Anuradha , Krauss John C. , Deutsch Melvin , Fabregas Jesus C. , Lee James J. , Allegra Carmen Joseph , Wolmark Norman
Published: January 2022

99

Background: Although immunotherapy shows no benefit in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve the likelihood of anti-tumor activity with checkpoint inhibitor use. Using a “window-of-opportunity” study design, this prospective phase II trial will determine the safety and activity of this approach with the anti-PD-L1 agent durvalumab (MEDI4736). Methods: Stage II/III patients (pts) with MSS rectal cancer undergoing standard NCCN guideline-compliant neoadjuvant chemoradiotherapy (CRT) followed by definitive surgery were eligible. Treatment included durvalumab (750mg IV infusion once every 2 wks) for 4 total doses beginning within 3-7 days after CRT completion followed by surgery within 8-12 wks of the final CRT dose. Primary end point (EP): Improvement in modified neoadjuvant rectal cancer (mNAR) score (goal 10.6) compared to historical controls (15.6) targeting a 20% DFS RR reduction and 3-4% absolute OS improvement. Secondary EPs: toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, and exploratory assessments of tumor-infiltrating lymphocytes, tumor Immunoscore, circulating immunologic profiles, and molecular predictors of response. We test H0: mNAR ≥15.6 vs HA: mNAR <15.6 at alpha 0.10 one-sided with statistical significance defined as p<0.1. Results: From May 2018 to October 2020, 45 pts were enrolled with 40 pts evaluable for mNAR. Mean mNAR was 12.03 (80% CI: 9.29-14.97) (p=0.06 one-sided). pCR=22.2%; cCR=31.1%; R0 resection=81.0%, and sphincter preservation=71.4%. Side effects were consistent with both CRT and durvalumab safety profile. Most common grade 3 AEs included diarrhea, lymphopenia, and back pain. There was one grade 4 AE (elevated amylase/lipase) and no grade 5 AEs. Remaining secondary and correlative immunologic end points are still being assessed. Conclusions: Durvalumab immediately following CRT prior to surgery for definitive management of rectal cancer was safe and without unexpected short-term toxicities. The primary end point of mean mNAR score was significantly less than our historical control, warranting further investigation. Correlative analyses for immunologic markers of response including PD-(L)1 expression and Immunoscore are ongoing. NCT 03102047. Support: AstraZeneca-Medimmune, NSABP Foundation. Clinical trial information: NCT03102047.
A nomogram for predicting cancer specific survival (CSS) in patients with pathological T3N0M0 (pT3N0M0) rectal cancer.
Authors: Liu Shuang , Xi ShaoYan , Wu Xiao-Jun , Cai Peiqiang , Ding Pei-Rong , Chen Gong , Pan Zhi-Zhong , Gao Yuan-Hong , Xiao Weiwei
Published: January 2022

113

Background: Preoperative chemoradiotherapy followed by total mesorectal excision (TME) surgery has been widely adopted as the standard treatment for stage II-III rectal cancers. However, the role of adjuvant chemotherapy in pathological T3N0M0 (pT3N0M0) patients remains controversial. A reliable prognostic model is needed to discriminate the high-risk patients from the low-risk patients, and optimize adjuvant chemotherapy treatment decisions by predicting the likelihood of adjuvant chemotherapy benefit for the target population. Methods: We gathered and analyzed 276 patients in Sun Yat-Sen University Cancer Center from March 2005 to December 2011. All patients underwent total mesorectal excision, without preoperative therapy, and were pathologically proven pT3N0M0 rectal cancer. LASSO regression model was used for variable selection and risk factor prediction. Multivariable cox regression was used to develop the predicting model. Optimum cut-off values were determined using X-Tile plot analysis. The 10-fold cross validation was adopted to validate the model. The performance of the nomogram was evaluated with its calibration, discrimination and clinical usefulness. Results: A total of 188 patients (68.1%) had adjuvant chemotherapy and no patients had adjuvant radiotherapy. Age, carbohydrate antigen 19-9 [CA199], monocyte percentage [MONO%], lymph node dissection numbers [LNDs] and nerve invasion were identified as significantly associated variables that could be combined for an accurate prediction risk of CSS for pT3N0M0 patients. The model adjusted for CSS showed good discrimination with a C-index of 0.723 (95% CI = 0.652 to 0.794). The calibration curves showed that the nomogram adjusted for CSS was able to predict 3-, 5-, and 10-year CSS accurately. The corresponding predicted probability was used to stratify high and low-risk patients. Adjuvant chemotherapy improved survival rate in the low-risk patients (HR = 0.338, 95% CI: 0.135 to 0.848, P = 0.021), while it did not exhibit a significant benefit in the high-risk patients. Conclusions: The nomogram effectively predicts CSS in patients with pT3N0M0 rectal cancer, which can be conveniently used in clinical practice. Adjuvant chemotherapy may improve overall survival in the low-risk patients. But the benefit of adjuvant chemotherapy was not seen in the high-risk patients.
Radioembolization with chemotherapy for liver-dominant colorectal cancer: Analysis of patient subgroups in the EPOCH trial.
Authors: Harris William Proctor , Mulcahy Mary Frances , Salem Riad ,   On behalf of the EPOCH Trial Investigators
Published: January 2022

115

Background: The EPOCH trial evaluated potential benefit of second-line transarterial radioembolization (TARE) plus chemotherapy compared to chemotherapy alone in patients with liver-dominant metastatic colorectal disease (mCRC). Presented here are additional results from EPOCH of depth and duration of response (DoR), and progression-free survival (PFS) and hepatic progression-free survival (hPFS) subgroup analyses. Methods: EPOCH was a 1:1 randomized, open-label, global, multicenter phase 3 trial of second-line chemotherapy for liver-dominant mCRC comparing outcomes from chemotherapy with or without unilobar or same-day bilobar TARE treatment using glass microspheres. Primary study endpoints were PFS and hPFS. Pre-specified subgroup analyses of PFS and hPFS were performed. PFS, hPFS, DoR for patients with objective response, and depth of response (percent change from baseline to nadir in sum of longest diameters of target lesions) were based on blinded, independent central review using RECIST 1.1. The use of TheraSphere in the trial in the USA was under Investigational Device Exemption from FDA. Results: Both primary endpoints of PFS (HR = 0.69, 95% CI: 0.54, 0.88; 1-sided p=0.0013) and hPFS (HR = 0.59, 95% CI: 0.46, 0.77; 1-sided p<0.0001) were met in the EPOCH study. Median DoR in the 73 responders of the TARE arm was numerically longer, with 7.2 months by Kaplan-Meier analysis; in the 45 responders of the chemotherapy only arm, 6.6 months (HR = 0.79, 95% CI: 0.48, 1.30; 1-sided p = 0.178). Mean depth of response across all patients in the TARE arm with data available (N=196) was -25.6%, compared to -13.0% in the chemotherapy only arm (N=182; mean difference -12.6 percentage points; 95% CI: -18.9, -6.3; 1-sided p = 0.0001). Key subgroups of interest which showed improved PFS and/or hPFS in the TARE arm (ie, 95% CI for the HR entirely below 1) are as follows: Conclusions: These data suggest that liver-dominant mCRC patients in this trial benefitted in second-line treatment from a combination of TARE plus chemotherapy based upon improved PFS and hPFS over the full set of patients and in a number of subgroups. The addition of TARE to chemotherapy improves depth of response compared to chemotherapy alone. Clinical trial information: NCT01483027. [Table: see text]
Maintenance therapy following an anti-EGFR-based induction regimen in metastatic colorectal cancer (mCRC): A network meta-analysis of clinical trials.
Authors: Lopes da Silva Laércio , Nazareth Aguiar Pedro , D'Alpino Renata , Dienstmann Rodrigo
Published: January 2022

128

Background: A fluoropyrimidine with or without bevacizumab is often used in clinical practice as maintenance therapy after a first-line chemotherapy + bevacizumab induction in mCRC. However, the role of maintenance following an anti-EGFR-based induction and the optimal regimen are not well established. Methods: We searched PubMed and conferences’ proceedings for clinical trials assessing maintenance therapy after first-line treatment for RAS WT mCRC. Two independent reviewers excluded single-arm studies and retrospective reports from trials that were not designed to assess maintenance therapy. We used the method of Guyot et. al. to obtain the individual patient data, followed by a Cox procedure to derive the survival hazard ratios (HR) from studies that did not report that value. Safety analysis included grade 3-4 asthenia, neuropathy, neutropenia, rash, and diarrhea. We performed a random-effects bayesian network metanalysis using the package “GeMTC R Package” to compare all treatment strategies included (anti-EGFR, anti-EGFR + chemotherapy [CT], CT alone, and observation). The risk of bias was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions. Results: The systematic review retrieved 145 studies from which 142 were excluded. Two additional studies were found in the Conferences’ Proceedings review. Consequently, 5 studies were included in this NMA. In terms of Progression-Free Survival (PFS), there was a benefit of anti-EGFR and anti-EGFR+CT versus CT alone (HR 0.63 [95%CrI 0.31-1.30] and 0.72 [95%CrI 0.41-1.30], respectively). The rank probability of anti-EGFR being the best option considering PFS was 61%. In terms of Overall Survival (OS), the benefit of anti-EGFR and anti-EGFR+CT versus CT alone was statistically weak (HR 0.92 [95%CrI 0.54-1.50] and 0.84 [95%CrI 0.57-1.20], respectively). The rank probability of anti-EGFR+CT be the best option in terms of OS was 51%. Comparing anti-EGFR versus anti-EGFR+CT resulted in no statistically significant difference. Anti-EGFR-containing regimens increased the rate of rash and diarrhea compared to CT alone (RR 11.23 and 1.23, respectively). The risk of bias was average low, except for the unclear risk of selection bias linked to unpublished studies. Conclusions: Anti-EGFR±CT maintenance therapy improves PFS and OS compared to CT alone or observation in RAS WT mCRC, with manageable safety profile.
TACH101, a first-in-class pan-inhibitor of KDM4 for treatment of gastrointestinal cancers.
Authors: Perabo Frank , Chandhasin Chandtip , Yoo Sanghee , Dang Van , Del Rosario Joselyn , Chen Young K , Stafford Jeffrey , Quake Stephen , Clarke Michael F.
Published: January 2022

132

Background: TACH101 is a novel, potent small molecule inhibitor of KDM4, a novel epigenetic target for cancer therapy. KDM4 is a family of histone lysine demethylases that, when overexpressed, drives key processes linked to cancer. Validation of KDM4 as a driver gene was confirmed across gastrointestinal tumor types including esophageal, colon and gastric cancers, and is associated with formation of aggressive tumors. Methods: TACH101 was evaluated in in vitro and in vivo studies including cell inhibition assays, patient-derived xenograft (PDX) and organoid models, and bioinformatics analyses studies. Results: In vitro, TACH101 treatment potently inhibited cell proliferation in cell lines and organoid models representing esophageal, CRC, and gastric cancers. TACH101 induced apoptosis in human CRC (HT-29) and esophageal (KYSE-150) cancer cell lines (EC50s 0.033 - 0.092 µM). Further evaluation using a panel of > 300 cell lines from different tumor types showed potent activity of TACH101 against gastric cancer and CRC. In gastric cancer, 2D cell viability inhibition assays conducted on a panel of 11 gastric cancer cell lines showed 9/11 (82%) were sensitive to TACH101 treatment (IC50 0.004 - 0.072 µM); in PDX models, 4/5 (80%) were sensitive to TACH101 treatment (IC50 0.007 - 0.039 µM). In CRC, bioinformatics analysis indicated increased TACH101 sensitivity in cell lines with MSI-H status (IC50 1-150 nM). Sensitivity of MSI-H CRC to TACH101 was further confirmed in a panel of 14 CRC PDX models and 7 CRC organoid models in culture-based viability inhibition assays. In PDX models, 5/5 (100%) characterized as MSI were sensitive to TACH101 treatment (IC50 0.001 - 0.014 µM), whereas 4/8 (50%) characterized as MSS were sensitive to TACH101 (IC50 0.003 - 0.270 µM). In patient derived CRC organoid models, 3/3 (100%) characterized as MSI were sensitive to TACH101 treatment (IC50 0.022 - 0.149 µM) whereas 0/3 (0%) characterized as MSS were sensitive (IC50 > 10 µM). In vivo, TACH101 triggered effective tumor control (≥70%) in xenograft models of CRC (SU60), esophageal (KYSE-150) and gastric (GXA-3036) cancers. Pharmacologic studies showed TACH101 demonstrated favorable cell permeability, good oral bioavailability, and high metabolic stability. Conclusions: Preclinical work on TACH101 KDM4 inhibitor demonstrates compelling data and applicability as a potential therapy for gastrointestinal cancers. Preparations to advance TACH101 into clinical trials are underway.
Ensemble voting decreases false positives in AI second-observer reads for detecting colorectal cancer.
Authors: Salinel Brandon , Grudza Matthew , Zeien Sarah , Murphy Matthew , Adkins Jake , Jensen Corey , Bay Curt , Kodibagkar Vikram , Koo Phillip , Dragovich Tomislav , Choti Michael A. , Kundranda Madappa N. , Wang Hongzhi , Syeda-Mahmood Tanveer , Chang John ,   2022 GI-ASCO
Published: January 2022

141

Background: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths, and survival can be improved if early, suspect imaging features on CT of the abdomen and pelvis (CTAP) can be routinely identified. At present, up to 40% of these features are undiagnosed on routine CTAP, but this can be improved with a second observer. In this study, we developed a deep ensemble learning method for detecting CRC on CTAP to determine if increasing agreement between ensemble models can decrease the false positives detected by artificial intelligence (AI) second-observer. Methods: 2D U-Net convolutional neural network (CNN) containing 31 million trainable parameters was trained with 58 CRC CT images from Banner MD Anderson (AZ) and MD Anderson Cancer Center (TX) (51 used for training and 7 for validation) and 59 normal CT scans from Banner MD Anderson Cancer Center. 20 of the 25 CRC cases from public domain data (The Cancer Genome Atlas) were used to evaluate the performance of the models. The CRC was segmented using ITK-SNAP open-source software (v. 3.8). To apply the deep ensemble approach, five CNN models were trained independently with random initialization using the same U-Net architect and the same training data. Given a testing CT scan, each of the five trained CNN models was applied to produce tumor segmentation for the testing CT scan. The tumor segmentation results produced by the trained CNN models were then fused using a simple majority voting rule to produce consensus tumor segmentation results. The segmentation was analyzed by the percentage of correct detection, the number of false positives per case, and the Dice similarity coefficient (DSC). If parts of the CRC were flagged by AI, then it was considered correct. A detection was considered false positive if the marked lesion did not overlap with any CRC; contiguous false positives across different slices of CT image were considered a single false positive. DSC measures the quality of the segmentation by measuring the overlap between the ground-truth and AI detected lesion. Results: Our results showed that increasing the agreement between the 5 models dramatically decreases the number of false positives per CT at the expense of slight decrease in accuracy and DSC. This is described in the table. Conclusions: Our results show that AI-based second observer can potentially detect CRC on routine CTAP. Although the initial result yields high false positives per case, ensemble voting is an effective method for decreasing the false positives with a slight decrease in accuracy. This technique can be further improved for eventual clinical application.[Table: see text]
Tumor microbiome variation in young versus average onset colorectal cancer.
Authors: Barot Shimoli V , Sangwan Naseer , Nair Kanika G. , Schmit Stephanie , Xiang Shao , Kamath Suneel Deepak , Liska David , Khorana Alok A.
Published: January 2022

144

Background: The incidence of young onset colorectal cancer (yoCRC) is rising at alarming rates. The gut microbiome may be a factor accounting for the increase. We analyzed differences in the intratumoral microbiome of yoCRC vs average onset CRC (aoCRC) and its clinical impact. Methods: We identified 314 histologically confirmed cases of stage I-IV CRC that underwent surgical resection at our institution from 2000-2020, diagnosed <50 years of age for yoCRC and >60 years for aoCRC, who consented to a prospective biorepository. 36 cases were excluded due to nonmalignant, non-adenocarcinoma or metastatic site specimens. Fresh frozen tissue from the primary tumor with paired adjacent nonmalignant tissue specimens were analyzed. 16S rDNA was isolated and sequence reads were assigned to genus level amplicon sequence variants in DADA2 and analyzed for alpha and beta diversity using Phyloseq. Statistical tests included analysis of variance (ANOVA), permutational multivariate analysis (PERMANOVA), linear regression, and Wilcoxon test. Differential abundance and correlation analysis were adjusted for sex and ethnicity as confounding factors. Correlation analysis was adjusted with Benjamini Hochberg correction. Clinical differences were analyzed using Fisher's exact test. Results: Of the cohort of 278 patients, 137 had yoCRC (median age 43 years, range 16-49) and 141 had aoCRC (median age 73 years, range 61-95). yoCRC patients were more likely to have stage III or IV disease at presentation (29% vs 14%, p =0.002; 29% vs 18%, p =0.024 respectively), left sided tumors (74% vs 58%, p =0.003) and receive neoadjuvant therapy (29% vs 15%, p =0.004). yoCRC had significantly higher tumor microbial alpha diversity than aoCRC ( p <2.22e−16, Wilcoxon rank-sum test). Beta diversity analysis demonstrated significantly different diversity of genera between the groups (R2=0.12, p =0.001, PERMANOVA). The prevalent taxa identified in both groups were Lactobacillus, Bacillus and Listeria. Differential abundance analysis (ANOVA, p <0.05) revealed a significant variation of intratumoral microbiome (Table). Correlation analysis revealed an association of longer overall survival (OS) with the presence of Akkermansia in yoCRC (R2 =0.36, p <0.001), but not in aoCRC. Conclusions: We found significant differences between the intratumoral microbiome of yoCRC and aoCRC. In particular, Akkermansia, considered a healthy gut microbe, was found in greater relative abundance in yoCRC and correlated with improved OS. Further studies are warranted to understand the nature of association of these microbes with the development of and outcomes in yoCRC. [Table: see text]
Analysis of tumor-associated macrophages' heterogeneity in colorectal cancer patients using single-cell RNA-seq data.
Authors: Nussbaum Yulia Innokenteva , Manjunath Yariswamy , Kaifi Jussuf T. , Warren Wesley , Mitchem Jonathan B.
Published: January 2022

146

Background: Colorectal cancer (CRC) is one of the deadliest malignancies worldwide. Though immune checkpoint inhibition has proven effective for a number of other tumors, it offers benefits in only a small group of CRC. In general, heterogenous cell groups in the tumor microenvironment (TME) are considered as the major barrier for unveiling the causes of low immune response. Therefore, deconvolution of cellular components in highly heterogeneous microenvironments is crucial for understanding those mechanisms. Single cell sequencing technology revolutionized TME research enabling profiling cells in high resolution. Methods: We have analyzed scRNA-seq data from 23 CRC patients with pre-treatment primary tumors using Seurat V3 pipeline. To investigate intercellular ligand-receptor interactions, we used CellPhoneDB and CellChat methods. The results of two independent analyses showed 4 CRC samples with no SPP1-CD44 interaction. It is known, that OPN which is the protein encoded by SPP1 gene, binds to CD44 and can cause cell survival, proliferation, and angiogenesis. Interestingly, analysis of the cellular composition of all 23 samples did not reveal differences in SPP1+ macrophages’ content for those 4 “no SPP1-CD44” samples. To investigate the mechanisms that could cause differences in SPP1-CD44 expression across the samples, we analyzed developmental trajectories of single cells using Slingshot trajectory inference method. Results: Ligand-receptor interactions analysis revealed 4 CRC samples that lacked SPP1-CD44 interaction that is known to be responsible for tumor progression in CRC. But the proportion of SPP1+ cells was not significantly different in those 4 samples compared to other samples. Trajectory inference analysis showed that the cells from “no SPP1-CD44” samples had high expression of anti-inflammatory macrophage markers in the end of the trajectory. While cells from “high SPP1-CD44” samples had high expression of pro-inflammatory macrophage markers at the same point. Conclusions: Based on our data-driven study, we suggest that SPP1+ macrophages’ heterogeneity may affect SPP1-CD44 interaction. Thus, targeting SPP1+ macrophages that have anti-inflammatory phenotype can potentially interrupt SPP1-CD44 interaction and therefore reduce tumor progression and immune suppression.
Comprehensive landscape of BRAF variant classes, clonalities, and comutations in metastatic colorectal cancer using ctDNA profiling.
Authors: Johnson Benny , Yang Dong , Dada Hiba I. , Drusbosky Leylah , Kopetz Scott
Published: January 2022

152

Background: Although BRAF V600E accounts for the majority of the BRAF mutations in mCRC, non-V600 BRAF variants have been shown in recent years to represent a distinct molecular subtype of mCRC. This study provides a comprehensive profile of BRAF V600 and non-V600 variants, their clonalities and co-mutations in mCRC using a large genomic database of circulating tumor DNA (ctDNA). Methods: A systematic analysis of Guardant360 results was performed among ctDNA samples of mCRC patients from September 2014 to May 2021. A variant was defined as clonal if the mutant allele frequency (MAF) was greater than 50% of the highest somatic MAF in the sample; otherwise it was defined as subclonal. A previously validated anti-EGFR exposure score was applied to predict prior anti-EGFR therapies. Co-mutation analysis was conducted with BRAF, KRAS, NRAS, NF1, ERBB2, PIK3CA and SMAD4. Results: 1,733 out of 14,742 mCRC patients had at least one BRAF variant, including 6.5% of patients with BRAF V600 variants, 1.1% with class II variants, 1.9% with class III variants, and 3.2% with unclassified variants. 431 unique BRAF variants were identified in a total of 1,905 BRAF variants. 70.7% of BRAF V600 variants were clonal while most (56.0%-78.8%) class II, III and unclassified BRAF variants were subclonal (Table). Patients with non- BRAF V600 variants tend to be younger and male. The prevalence of BRAF class II and III variants were higher (2.1% and 3.7%) in patients with predicted prior anti-EGFR exposure compared with patients predicted to have no prior exposure (0.8% and 1.4%). BRAF variants of all classes are more likely to be subclonal in patients predicted to have anti-EGFR exposure than those predicted nonexposed ( p <0.05 in all classes, Fisher’s exact test). Among patients with non- BRAF V600 variants, a greater fraction of co-occurring KRAS and NRAS mutations were detected in those predicted to have prior anti-EGFR exposure. In the patients without predicted EGFR exposure, BRAF class II and III variants showed a higher rate of co-occurring KRAS mutations (25.6% and 21.5%) and co-occurring NRAS mutations (5.8% and 2.7%) compared with BRAF V600 variants (2.4% for KRAS and 0.1% for NRAS); however, co-occurring KRAS G12C was only noted in one patient with a BRAF class II variant. The analysis of outcome data by variant class will be presented at the meeting. Conclusions: We noted significant differences between BRAF V600 and class II/III variants using a large genomic database. Within BRAF class II and III variants, the enrichment in patients with predicted anti-EGFR exposure and the high fraction of co-mutations in KRAS/ NRAS suggest a unique therapeutic need for these patients.[Table: see text]
Genomic landscape of ERBB2/3 alterations in colorectal cancer: Comutations, immuno-oncology biomarkers, and consensus molecular subtype.
Authors: Tie Jeanne , El-Refai Sherif Mohamed , Yoshino Takayuki , Siena Salvatore , Lonardi Sara , Sartore-Bianchi Andrea , Nakamura Yoshiaki , Bando Hideaki , Fujisawa Takao , Lok Sheau Wen , Wong Hui-Li , Kadakia Kunal C. , Mauer Elizabeth , Salem Mohamed E.
Published: January 2022

176

Background: ERBB2 is a rapidly emerging therapeutic target for a subset of colorectal cancer (CRC) harboring oncogenic alterations in this gene. Oncogenic ERBB3 mutations have been reported in various cancers including CRC, but little is known about its functional impact. Optimal targeting of this pathway requires understanding of the genomic context in which somatic ERBB2/3 alterations ( ERBB2/3-alt) occur in a real-world CRC population. Methods: We analyzed 7,688 de-identified records from CRC patients that underwent next generation sequencing with the Tempus|xT assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq). We assessed the prevalence and association of ERBB2/3-alt with demographics, co-occurring alterations, immuno-oncology biomarkers (microsatellite instability [MSI], tumor mutational burden [TMB], PD-L1 expression), and consensus molecular subtype (CMS, available for the subgroup with primary biopsies and RNA data [n = 2,686]). Results: Overall, 5% (376/7688) of tumors harbored an ERBB2 or ERBB3-alt. 1.9% (n = 143) ERBB2-amplified, 1.3% (n = 97) ERBB2-mutated, 0.9% (n = 72) ERBB3-mutated, < 1% other combinations (excluded from analyses). There were no significant differences in baseline demographics (e.g., age of onset, race and gender) between groups. Patients with ERBB2/3-alt were more likely to be MSI-high and TMB-high (Table). There was a trend towards higher prevalence of positive PD-L1 in ERBB3-alt vs ERBB3-WT tumors. We observed significant differences in co-occurring alterations among ERBB2/3-alt and WT groups (Table). CMS classification did not identify significant differences by ERBB2-alt or ERBB3-alt; ERBB2-alt compared to WT (CMS1: 8.6% vs 13%; CMS2: 24% vs 26%; CMS3: 20% vs 17%; CMS4: 30% vs 34%; p = 0.12) and ERBB3-alt compared to WT (CMS1: 24% vs 13%; CMS2: 12% vs 26%; CMS3: 16% vs 17%; CMS4: 40% vs 34%; p = 0.3). Conclusions: ERBB2/3 mutated CRC are more frequently MSI-H, TMB-high and KRAS mutated than ERBB2/3-WT tumors. Correlation of ERBB2/3 alterations with other genomic alterations including BRAF, TP53, CDK12, PIK3CA, and TOP2A will help advance the clinical development of HER2-targeted therapies.[Table: see text]
Clinical implication of KRAS mutation variants in patients with resected colon cancer.
Authors: Baek Jin Ho , Kang Byung Woog , Choi Gyu Seog , Kim Jong Gwang
Published: January 2022

179

Background: This study evaluated the clinical implication of KRAS mutation variants in patients with resected colon cancer (CC). Methods: We retrospectively reviewed 482 patients diagnosed with CC and underwent curative surgical resection at Kyungpook National University Chilgok Hospital. The inclusion criteria were: pathologically diagnosed with primary CC; stage I–III CC according to the 7th edition of American Joint Committee on Cancer staging system; and with available test results for KRAS mutation status. In total, 345 patients met these criteria and were included in this study. Results: Among the 345 patients, 140 (40.6%) exhibited KRAS mutations, with their incidences as follows: 90/140 (64.3%) in Exon 2 Codon 12, 37/140 (26.4%) in Exon 2 Codon 13, 1/140 (0.1%) in Exon 3 Codon 59, 7/140 (5.0%) in Exon 3 Codon 61, and 5/140 (3.6%) in Exon 4 Codon 146. KRAS mutation status was not a significant prognostic factor for disease-free survival (DFS) or overall survival (OS). Although, there were no significant differences in survival between patients with Exon 2 Codon 12 and Exon 2 Codon 13 mutations, poorer DFS ( p = 0.085) and OS ( p = 0.005) were seen in those with Exon 3 Codon 61 mutation than in others. Conclusions: KRAS mutation status was not correlated with survival, but Exon 3 Codon 61 mutation might be a poor prognostic factor in resected CC patients.
Efficacy of regorafenib and 5-fluorouracil-based rechallenge treatment in the third-line treatment of metastatic colorectal cancer: A Turkish oncology group study.
Authors: Şenocak Taşçi Elif , Oyan Basak , Sonmez Ozlem , Mutlu Arda Ulaş , Atcı Muhammed Mustafa , Oner Irem , Yesil Cinkir Havva , Karakurt Eryılmaz Melek , Yazdan Balçık Onur , Paksoy Nail , Kivrak Salim Derya , Özen Mirac , Ozcelik Melike , Arican Ali , Inal Ali , Akagunduz Baran , Aydın Dinçer , Ozer Leyla , Turhal Nazim Serdar , Gulmez Ahmet
Published: January 2022

202

Background: The optimal treatment for metastatic colorectal cancer (mCRC) after the second line is still controversial. Regorafenib (Reg) revealed promising results by improving overall survival compared to best supportive care. However, in real-world practice rechallenge chemotherapy (CTr) is often preferred even though supporting evidence is not enough. We aim to compare the efficacy of regorafenib and 5-fluorouracil-based (5-FU) rechallenge treatment in the third line setting of mCRC. Methods: In this retrospective multi-institutional trial, mCRC patients from 21 centers in Turkey progressing after 2 lines of chemotherapy between 2012-2020 were analyzed. Patients who were treated with Reg or rechallenge therapy in the third-line setting were eligible. Rechallenge chemotherapy was identified as the re-use of the 5-FU based regimen which was administered in one of the previous treatment lines. Overall survival (OS), objective response rate (ORR), progression free survival (PFS) and toxicity were analyzed. Chi-square, Kaplan-Meier method and Cox regression analysis were used for analysis. Results: The clinical data of 441 mCRC patients were analyzed. Of these, 284 received regorafenib while 156 received rechallenge chemotherapy. The mean age was 57 and 56% was male. Median OS since the diagnosis was better with CTr than with Reg (48 months (95% CI, 43.4–52.6) vs. 39 months (95% CI, 35.4–42.5), p<0.001). Median OS after the third-line treatment was 12.0 (95% CI, 9.9–14) and 9.0 months (95% CI, 7.5–10.4) for CTr and Reg groups, respectively (p<0.001). PFS was 6 months for patients receiving CTr and 4 months for those treated with Reg (p = 0.139). ORR was significantly higher in CTr group than Reg (p<0.001). BRAF status, MSI status and treatment type (CTr vs. Reg) are factors found associated with OS in Cox regression analysis (p<0.001, p=0.021 and p<0.001, respectively). Adverse effects were seen in 82% and 68.2% of patients receiving Reg and CTr, respectively. Discontinuation of treatment due to adverse effects was higher in patients treated with Reg (10% vs. 2.5%). Conclusions: Our analysis revealed that rechallenge is an appreciated option, in both efficacy and toxicity, when the limited treatment options for mCRC is considered. Although regorafenib treatment contributes to survival, CTr shows better disease control. Our study has the highest number of patients in the literature. Still, prospective studies are mandatory for validation of CTr in the third-line treatment of mCRC.
Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in patients (pts) with localized microsatellite instability-high (MSI)/mismatch repair deficient (dMMR) oeso-gastric adenocarcinoma (OGA): The GERCOR NEONIPIGA phase II study.
Authors: Andre Thierry , Tougeron David , Piessen Guillaume , De La Fouchardiere Christelle , Louvet Christophe , Adenis Antoine , Jary Marine , Tournigand Christophe , Aparicio Thomas , Desrame Jérôme , Lièvre Astrid , Garcia-Larnicol Marie-Line , Pudlarz Thomas , Henriques Julie , Cohen Romain , Lefevre Jérémie , Svrcek Magali
Published: January 2022

244

Background: In pts with resectable gastric adenocarcinoma or OGA, radical surgery is the only curative option and perioperative chemotherapy seems worthless for those with MSI/dMMR tumors. Methods: We conducted phase II study evaluating the efficacy of neo-adjuvant nivolumab and ipilimumab followed by adjuvant nivolumab in pts with resectable MSI/dMMR, T2-T4 NxM0 tumors. Treatment consisted of nivolumab 240 mg every 2 weeks (6 infusions) and ipilimumab 1 mg/kg every 6 weeks (2 infusions), followed by radical surgery 5 weeks (±1 week) after last injection of nivolumab. Pts with Becker tumor regression grade (TRG) < 3 were treated with adjuvant nivolumab 480 mg every 4 weeks (9 infusions). The primary objective was pathological complete response (pCR) rate. Results: From 10/2019 to 06/2021, a total of 32 pts were enrolled (all had dMMR±MSI-H status; 16 with gastric cancer and 16 with OGA). The median age was 65.5 years (range, 40-80). Initial stage was: usT3Nx = 22, usT2Nx = 4, and usTxNx = 6 (not evaluable by ultrasound endoscopy). At data lock, 32 pts had terminated neo-adjuvant period and 27 (84%) completed all 6 neo-adjuvant cycles. 8 pts (32%) experienced G3/4 adverse events (AEs) during neo-adjuvant treatment. 29 pts underwent surgery; 2 refused surgery and had complete endoscopic response with tumor-free biopsies, 1 had surgery not performed in relation with a metastatic progression. The median delay between last injection and surgery was 35 days (extreme, 25-170). Overall surgical morbidity (54%, n = 14) was related to: anastomotic leakage = 4, pancreatitis = 2, pneumonia = 2, and other = 6. The incidence of post-operative mortality was 3.8% (n = 1) due to cardiovascular AE at post-operative day 3. All the 29 pts who underwent surgery had R0 resection: 17 (59%) had pCR (i.e., TRG 1a as per Becker grade, ypT0N0) and 4 (14%) had TRG 1b as per Beker grade (< 10% residual tumor per tumor bed). 1 pt had TRG 2 (10-50% of residual tumor) and 7 pts had TRG 3 (˃50% of residual tumor) as per Becker grade, per local pathological assessment (central pathological review is awaited). With a median follow-up of 10.9 months, 1 pt had metastatic relapse, 1 pt died without relapse and 30 pts were recurrence/progression-free. Conclusions: Neo-adjuvant therapy with nivolumab and ipilimumab is feasible and is associated with a high pCR rate in pts with MSI/dMMR resectable OGA. Data will be updated for the congress. Clinical trial information: NCT04006262.
Changing epidemiology of esophageal cancer: A population-based study over 43 years (1975–2018).
Authors: Bien Jeffrey , Nguyen Theresa Hoang-Anh , Aljehani Mayada , Lee Jerry S.H. , Wang David H. , Lin Albert Y.
Published: January 2022

247

Background: Esophageal cancer (EC) is the seventh most common cancer worldwide. Previous studies have indicated that the incidence of squamous cell carcinoma of the esophagus (SCE) in the US has declined since the 1970s. In comparison, the incidence of adenocarcinoma of the esophagus (ACE) has sharply risen in the US since the 1970s. This study aimed to examine temporal trends in incidence rates of EC, ACE, and SCE that include recent decades. Methods: Data were derived from the Surveillance, Epidemiology, and End Results (SEER) of the National Cancer Institute - a population-based cancer database. Using SEER*Stat, we calculated the age-adjusted incidence rates (AAIR) for EC, ACE, and SCE in both SEER 9 (for longest follow-up time) and SEER 21 (the largest cohort covering 36.7% of the US population). Temporal incidence trends were examined using Joinpoint analyses to estimate the annual percent change (APC). Subgroup analyses were performed for sex, age, and race/ethnicity. Results: See Table. When stratified by age, age <64 years had a significant decrease in incidence with an APC of -1.1 (2007-2018), while the incidence plateaued in the remaining age groups. The rise in incidence was highest among non-Hispanic whites (NHW) from 2000-2004 (APC 4.0), especially NHW males (APC 3.0); however, the incidence plateaued in all race/ethnicity groups after 2006. Conclusions: The AAIR of EC as a whole has been decreasing since 2004. The AAIR of ACE has, for the first time, plateaued in the most recent decade (2006-2018), after having risen for three preceding decades (1975-2006); we find this effect is mainly driven by the AAIR from NHW males, age <64 years. The incidence of SCE has continued to decline since 1975. Future studies should further explore the underlying etiology of these patterns.[Table: see text]
Efficacy and safety of neoadjuvant chemotherapy for locally advanced gastric cancer in elderly patients: A phase II trial (KSCC1801).
Authors: Uehara Hideo , Ota Mitsuhiko , Matsuda Yoshiko , Tsutsumi Satoshi , Kusumoto Tetsuya , Yasui Hisateru , Ubukata Yasunari , Yamaguchi Shohei , Orita Hiroyuki , Horie Yoshiki , Kakizoe Saburo , Shimokawa Mototsugu , Oki Eiji , Kakeji Yoshihiro , Saeki Hiroshi , Mori Masaki
Published: January 2022

254

Background: Gastrectomy with D2 dissection and adjuvant chemotherapy is currently the standard treatment for locally advanced gastric cancer (LAGC) in Asian countries. However, administering chemotherapy with sufficient intensity after gastrectomy is often challenging. Thus, several trials have been undertaken to demonstrate the efficacy of neoadjuvant chemotherapy (NAC). NAC-SOX regimen for LAGC has been already shown to reduce distant micro-metastasis and to improve the R0 resection rate by tumor shrinkage in Asian trials. However, there have been few studies of the feasibility of NAC-SOX for elderly patients with LAGC. KSCC1801 is a phase II study to evaluate the safety and efficacy of NAC-SOX in elderly patients aged 70 years or over with LAGC. Methods: Patients received three cycles of SOX as neoadjuvant chemotherapy followed by gastrectomy with D2 dissection. Oxaliplatin was administered intravenously (130 mg/m2) on day 1, and S-1 was administered orally (80- 120 mg/day) for 14 days followed by 7-day rest period. The primary endpoint was the dose intensity (DI). A sample size of 25 was set according to a one-sided significance level of 0.025 and a power of 80% on the basis of a one-sample t-test and assuming a null hypothesis of a 75% DI and an alternative hypothesis of an 85% DI with an estimated standard deviation of 14%. The secondary endpoints were safety, R0 resection rate, response rate, overall survival, and relapse-free survival. Results: Twenty-six patients were enrolled in this study. The median age was 74.5 years. The median DI in NAC-SOX was 97.2% for S-1 and 98.3% for oxaliplatin. Three cycles of NAC could be performed in 25 patients (96.2%), of whom 23 (88.5%) underwent gastrectomy with D2 dissection. The R0 resection rate was 92.3% and the pathological response rate (≥grade 1b) was 62.5% [95% confidence interval: 40.6 - 81.2]. The major adverse events (≥grade 3) were neutropenia (20.0%), thrombocytopenia (11.5%), anorexia (11.5%), nausea (7.7%) and hyponatremia (7.7%). Postoperative complications of abdominal infection, elevated blood amylase, and bacteremia occurred in one patient each. One treatment-related death occurred, probably due to severe diarrhea and dehydration. Conclusions: NAC-SOX was feasible and promising even in elderly patients. Systemic management and more careful monitoring of adverse events are necessary for elderly patients. Clinical trial information: jRCTs071180001.
Risk factors for short-term interval readmission after radical gastrectomy for gastric cancer: The merits of the home-health-care support over the readmission in gastric cancer.
Authors: Jeon Chul Hyo , Song Kyo Young
Published: January 2022

263

Background: Readmission that occurs within a short period after discharge of initial gastrectomy for gastric cancer may affect the patient's prognosis and adversely affect the overall treatment courses. Among the possible related factors, the Influence between postoperative home-health-care support and readmission has been studied in various diseases, but the relationship with gastric cancer patients was limited. The purpose of the study was to investigate the risk factors associated with readmission after gastrectomy and home-health-care support on readmission. Methods: A total of 2,605 patients who underwent curative gastrectomy with lymphadenectomy between 2013 and 2020 were retrospectively reviewed. Chi-squared tests were performed to evaluate for potential risk factors for readmissions. A multivariate regression analysis was performed to identify independent predictors, including home-health-care support. Results: Among 2,605 undergoing gastrectomy, 134 (5.18%) had suffered unplanned readmission within postoperative 60-days (0̃50days). There was no significant annual difference in the postoperative length of hospital stay and the proportions of the home-health-care support during the study period, but the readmission rate decreased significantly by 0.646% annually from 7.88% in 2013 to 1.22% in 2020 (P = 0.023). The readmission group had a higher Eastern Cooperative Oncology Group (ECOG) score, a significantly higher rate of open and total gastrectomy, and a higher rate of postoperative complications and severe postoperative complications (C-D grade≥3a). Multivariable analysis demonstrated that the occurrence of severe postoperative complications (odds ratio (OR) 9.306, p < 0.001) and the presence of home-health-care support (OR 1.725, p = 0.009) were independently associated with readmission. However, age, sex, ECOG, preoperative body mass index, preoperative comorbidity including cardiovascular comorbidity, surgery-related factors, and the disease severity had no significant effect on readmission. Among the significant factors, home-health-care support showed the effect of reducing the time span between the index discharge and readmission (p = 0.049) and the length of the second hospitalization (p = 0.029). Conclusions: Readmission after radical gastrectomy is affected by various factors. Among them, home-health-care support has the merits of reducing the length of hospital stay for readmission by identifying patients in need of hospitalization at an early stage through direct face-to-face contact with the patient. It is necessary to establish an appropriate strategy to improve the quality of postoperative courses for high-risk patients of readmission.