bluuebunny/crossref_metadata_2025 huggingface dataset:
Metagenomic analysis of the fecal microbiome in patients with colorectal cancer compared to healthy controls as a function of age.
Authors: Kharofa Jordan , Apewokin Senu , Alenghat Theresa , Ollberding Nicholas
Published: June 2022

3532

Background: Colorectal cancer (CRC) incidence is increasing in young patients ( < 50 years old) without a clear etiology. Emerging data has implicated the fecal microbiome in CRC carcinogenesis. However, its impact on young onset CRC (YO-CRC) is poorly defined. Colibactin producing E. Coli and fadA producing Fusobacterium nucleatum can drive CRC carcinogenesis, however their effects across the age spectrum are unknown. Methods: We performed a meta-analysis of fecal metagenomics sequencing from n = 692 patients with CRC and n = 602 healthy controls from eleven studies to evaluate species and known microbial derived factors (colibactin and FadA) associated with CRC as a function of age. Generalized linear mixed effects regression was used to model the predicted prevalence of gene families and taxa as a non-linear function of age. Two-stage individual patient data meta-analysis (IPDMA) with adjustment for gender, CRC status, and body mass index was also used to estimate summary odds ratios for colibactin, F. nucleatum, and E. Coli. Interaction ORs were obtained to assess the difference in the effect of each gene or taxa on CRC case status in YO-CRC. Shannon Diversity index and metabolic pathway differences in the fecal metagenome for YO-CRC patients were assessed using phyloseq and MetaCyc respectively using an IPDMA approach. Results: Summary odds ratios (OR) for CRC were increased relative to controls with the presence of colibactin (OR 1.92 95%CI 1.08-3.38), fadA (OR 4.57 95%CI 1.63-12.85), and F. nucleatum (OR 6.93 95%CI 3.01-15.96) in models of all patients adjusted for age, gender, and body mass index. The OR for CRC for the presence of E.coli was 2.02 (0.92-4.45). An increase in the prevalence of F. nucleatum (OR = 1.40 [1.18; 1.65] and Escherichia coli (OR = 1.14 [1.02; 1.28]) per 10-year increase in age was observed in models including samples from both CRC and healthy controls. No difference was observed for Shannon Diversity (OR 1.36 95%CI 0.68-2.72) or MetaCyc pathways in YO-CRC patients. Species relative abundance was differentially enriched in YO-CRC relative to old CRC patients and controls for five species- Intestinimonas butyriciproducens, Holdemania filiformis, Firimicutues bacterium CAG 83, Bilophilia wadsworthia, and Alistipes putredinis. Conclusions: Strong associations with CRC status were observed for colibactin, fadA, and F. nucleatum with increased F. nucleatum in older patients. Several species were enriched in YO-CRC patients including B. wadsworthia which can produce carcinogenic sulfur metabolites and is increased with adherence to a sulfur microbial diet-low in vegetables and legumes. A sulfur microbial diet has also been associated with higher incidence of YO-CRC in population studies (Nguyen Gastroenterology 2021). Additional study is warranted to understand causal mechanisms of enriched species observed in YO-CRC patients.
Clinical outcomes of immune checkpoint inhibitor (ICI) therapy among Veterans Affairs patients with colorectal cancer and discordant dMMR/MSI-H status.
Authors: Isaacs James , Guo Aixia , Vashistha Vishal , Katsoulakis Evangelia , Boswell Elizabeth , Strickler John H , Ahmed Sara , Kelley Michael J.
Published: June 2022

3534

Background: Clinical trials have demonstrated improvements in survival with immune checkpoint inhibitors (ICIs) for advanced colorectal cancer patients with MSI-H/dMMR detected using PCR-based assays (PCR) or immunohistochemistry (IHC), respectively. MSI-H can also be assessed by next-generation sequencing (NGS). Evaluation of real-world outcomes among MSI-H patients by NGS treated with ICIs are warranted, particularly when results are discordant between these tests. Methods: The VA National Precision Oncology Program Database was accessed to select veterans with colorectal cancer and an MSI-H biomarker by NGS. Baseline patient variables, disease characteristics, and duration of ICI treatment were obtained from the VA’s Corporate Data Warehouse. Concordance between NGS and IHC or PCR testing was computed, and the response rate and duration of ICI treatment in patients with discordant test results were recorded from chart review. Results: Among 1,276 colorectal cancer patients, 71 (5.6%) were found to have MSI-H by NGS. Of these, 22 (30.1%) received ICI. Among 49 patients who did not receive ICI, 36 had stage I-III disease, 5 had limited performance status, 5 were actively being treated with chemotherapy and 3 had completely resected stage IV disease. Of the 71 patients, 29 had dMMR IHC testing, 8 had MSI-H PCR testing, 1 had both IHC and PCR testing, and 34 patients had only NGS testing. No PCR tests were discordant with NGS but 8 of 29 IHC tests were discordant. Among these 8 patients with discordant IHC MMR and MSI-H by NGS, 5 received pembrolizumab. There were 3 partial responses, 1 stable disease and 1 progressive disease. Durable responses were seen with 3 of 5 patients remaining on therapy without progression at the time of this analysis at a median follow up of 8.5 months. Conclusions: In a cohort of NGS MSI-H colorectal cancer patients, there was a high rate of discordant IHC results. Clinical benefit is seen in patients treated with ICI with discordant testing results, suggesting that NGS testing identifies patients with false negative dMMR IHC testing in the real-world clinical setting.
Consensus molecular subtypes (CMS) as prognostic and predictive biomarkers of panitumumab (Pmab), fluorouracil and folinic acid (FU/FA) or FU/FA maintenance therapy following Pmab-FOLFOX induction in RAS wildtype metastatic colorectal cancer (mCRC): PANAMA trial (AIO-KRK-0212).
Authors: Hoppe Beeke , Modest Dominik Paul , Keilholz Luisa , Na Il-Kang , Karthaus Meinolf , Fruehauf Stefan , Graeven Ullrich , Von Weikersthal Ludwig Fischer , Goekkurt Eray , Reinacher-Schick Anke C. , Kasper Stefan , Kind Andreas Jay , Kurreck Annika , Held Swantje , Heinemann Volker , Horst David , Jarosch Armin , Stintzing Sebastian , Trarbach Tanja , Stahler Arndt
Published: June 2022

3537

Background: Consensus molecular subtypes (CMS1-4) of colorectal cancer were evaluated as prognostic and predictive biomarkers in the PANAMA trial. PANAMA compared maintenance therapy with panitumumab (Pmab) and fluorouracil/folinic acid (FU/FA) vs. FU/FA alone after Pmab-FOLFOX induction therapy in RAS wildtype mCRC. Methods: Gene expression was measured after mRNA isolation in 179 of 248 patients of the full analysis set. The analysis was conducted using a customized Nanostring PanCancer Progression Panel. The original CMS classifier was re-derived for Nanostring data using a multinomial regression analysis.Median progression-free (PFS) and overall survival (OS) since start of maintenance were estimated by Kaplan-Meier-method and Cox-regression, using the log rank test. Objective response rates (ORR) of maintenance therapy were compared by Chi-square-test. Results: Prevalence of CMS was: CMS1, n = 15 (8.4 %); CMS2, n = 82 (45.8 %); CMS3, n = 20 (11.2 %) and CMS4, n = 62 (34.6 %). A prognostic impact of CMS regardless of treatment was not evident for PFS (p = 0.245) and OS (p = 0.169), but for ORR (p = 0.022), with CMS1 and CMS3 being associated with unfavourable efficacy during maintenance therapy. Potential predictive effects of CMS were observed in patients with CMS2 and CMS4 tumours. In CMS2 and CMS4 tumours, ORR was significantly higher when treated with Pmab-FU/FA in maintenance therapy (CMS2: 56.5% vs 30.6%, p = 0.026; CMS4: 55.6% vs. 28.6%, p = 0.040). In patients with CMS2 mCRC, this translated into a significant effect on PFS (Hazard ratio: 0.61 (95% CI 0.38 – 0.99) p = 0.046 (Table). Conclusions: CMS have limited prognostic impact for pmab-based maintenance therapy. However, CMS2 and CMS4 are positively associated with Pmab efficacy during maintenance therapy in the PANAMA trial. Further trials are necessary to confirm these results. [Table: see text]
Discovering colorectal cancer biomarkers with individual fragments analysis of cell-free DNA using attention-based deep multi-instance learning.
Authors: Lee Eunsaem , Shin Seungho , Park Seungtae , Yu Seunghyeon , Jo Shin-Sang , Jeon Hee Joon , Yoon Na Ri , Kim Jinho , Park Donghyun , Hwang Hyung Ju
Published: June 2022

3539

Background: Cell-free DNA(cfDNA) are DNA fragments circulating in blood stream. Among these fragments, there are tumor-derived DNA(ctDNA) fragments which can be a significant biomarker for cancer diagnostics. Recently, there are evidences that reveals methylation patterns of ctDNAs facilitate statistical models to diagnose cancers with plausible accuracy than mutation patterns. Despite of such promising facts, an early detection of cancers with methylation patterns of ctDNAs is still statistically difficult since proportion of ctDNAs to cfDNAs is marginal. As a result, it is difficult to set differential threshold on ctDNA proportion to successfully classify early cancer patients. For such a reason, we develop a high-throughput classifier whose classification resolution is per-fragment unlike per-batch approach in existing models. Methods: Targeted methylation sequencing was performed with DNA extracted from plasma cfDNA of 141 colon adenocarcinoma (COAD) patients and 200 healthy individuals. To extract DNA fragment-level methylation status, we profiled the methylation status using Bismark software and home-built python scripts were used to recover methylation status of DNA fragments. We implement an attention based multi-instance learning model which is permutation-invariant with fragments to analyze the impact of individual fragments on COAD prediction. Our models were trained using k-fold cross-validation and to assess generalization performance. Results: We first trained on local differentially methylated regions (DMRs) that contain 80 to 200 CpG sites using our deep learning model. With a single local region, we achieved a mean sensitivity of 87.2% (mean 95% CI 75.8–93.2%) at 97.7% (mean 95% CI 88.3–99.1%) specificity. By analyzing attention weights, we scored on each fragment according to the model contribution to predicting cancers. To find biomarkers, we added up scores according to methylation of each CpG site. Top 10 high scored CpG sites were validated with tissue sample DNA and almost all of them are overlapped with the 10 CpG sites with the highest statistical differences between cancer and normal tissue in the region. For the global region analysis, we combined local DMRs to confirm collaboration between distant regions and other chromosomes in the colorectal cancer prediction. We achieved a mean sensitivity of 93.4% (95% CI 80.1–98.1%) at 98.3% (95% CI 90.4–99.3%) specificity for the global region prediction. Conclusions: Our study shows a potential of targeted sequencing cell-free DNA as a cancer biomarker. An attention based deep learning model allowed for the analysis of individual fragments and showed the potential for biomarker discovery. The model uses only cell-free DNA and excludes tissue sample DNA, which makes our model less sensitive to the tumor heterogeneity.
A tumor immune microenvironment-related lncRNA signature for the prognosis and immunotherapeutic sensitivity prediction in colorectal cancer.
Authors: Hu Chuling , Cai Du , Zhong Min-Er , Fan Dejun , Li Cheng-Hang , Lv Min-Yi , Huang Ze-Ping , Wang Wei , Wu Xiaojian , Gao Feng
Published: June 2022

3543

Background: As important molecules in the CRC tumor microenvironment (TME), long non-coding RNAs (lncRNAs) regulate the functions of tumor infiltrating immune cells and sculpt the tumor immune microenvironment (TIME), resulting in difference in survival and response to immunotherapy among CRC patients. However, challenges remain in selecting TIME related lncRNAs (TIME-lncRNAs) of prognosis value and stratifying CRC patients for immunotherapy. Here, the aim of our study was to develop a CRC TIME-lncRNAs signature to provide survival and immunotherapy response predictions. Methods: Gene expression profiles and clinical information of CRC cases (n = 1807) were collected from 7 datasets and divided into training cohort (n = 519) and two testing cohorts (n = 595 and 693, respectively). Utilizing gene expression data of 97 immune cell lines and 61 CRC cell lines, differential expression analysis was used to identify TIME-lncRNAs. Univariate Cox regression and LASSO regression analysis were used to establish a TIME-lncRNAs signature to predict the prognosis of CRC patients. To further investigate the model, multivariate Cox regression, lncRNA-mRNA regulation analysis, gene enrichment analysis and immune infiltration analysis were carried out. The immunotherapy response predicting ability of the model was verified with an independent immunotherapy dataset. Results: Integrating the expression profiles of 10 TIME-lncRNAs, the model stratified CRC patients into low and high-score groups. Patients of the low score group had significantly prolonged survival in both training (hazard ratio (HR) = 2.63, 95% confidence interval (CI) = 1.9-3.63, P < 0.001) and testing cohorts (testing cohort 1: HR = 1.6, 95% CI = 1.19-2.16, P = 0.002; testing cohort 2: HR = 1.64, 95% CI = 1.19-2.26, P = 0.002), while higher tumor purity and less pro-tumor immune cells infiltration were also observed in the low score group. Further investigation showed that both genes differentially expressed between different groups and mRNAs regulated by 10 lncRNAs of the signature were enriched in immune-related and immunotherapy-related pathways. Multivariate Cox regression indicated that the TIME-lncRNAs signature was an independent prognosis factor. Validated with external immunotherapy dataset, the signature provided distinct predictions for patients’ responses to PD-L1 inhibitor therapy, suggesting cases of high score group could benefit more from immunotherapy. Conclusions: Based on the expression of 10 lncRNAs in the TIME, the signature makes predictions for patients’ survival and immunotherapy responses, which could help in stratifying CRC patients for immunotherapy at the bedside.
Pembrolizumab (pembro) plus binimetinib (bini) with or without chemotherapy (chemo) for metastatic colorectal cancer (mCRC): Results from KEYNOTE-651 cohorts A, C, and E.
Authors: Chen Eric Xueyu , Kavan Petr , Tehfe Mustapha , Kortmansky Jeremy S. , Sawyer Michael B. , Chiorean E. Gabriela , Lieu Christopher Hanyoung , Polite Blase N. , Wong Lucas , Fakih Marwan , Spencer Kristen Renee , Chaves Jorge , Li Chenxiang , Carpenter David , Leconte Pierre , Kim Richard D.
Published: June 2022

3573

Background: Response to antiPD-1 monotherapy is poor in microsatellite stable (MSS)/mismatch-repair proficient (pMMR) mCRC; the combination of antiPD-1 pembro + anti-MEK bini, with or without chemo, may improve upon this limited response. KEYNOTE-651 (NCT03374254) is an open-label phase 1b multicenter trial of pembro + bini (cohort A) or pembro + bini + chemo (mFOLFOX7 in cohort C, FOLFIRI in cohort E) in MSS/pMMR mCRC. Preliminary results from the dose-finding phase at 2 dose levels (DL) of bini are presented. Methods: Patients (pts) had MSS/pMMR mCRC and must have been previously treated with fluoropyrimidine, irinotecan, and oxaliplatin in cohort A, or with fluoropyrimidine + oxaliplatin-based regimen in cohort E; pts were previously untreated in cohort C. Pts received pembro 200 mg Q3W + bini 30 mg BID (cohort A, DL1), pembro 200 mg Q3W+ bini 30 mg BID + mFOLFOX7 Q2W (cohort C, DL1) or pembro 200 mg Q3W + bini 30 mg BID + FOLFIRI Q2W (cohort E, DL1). Bini dose escalation to 45 mg BID (DL2) was planned in cohorts A, C, and E, with a target dose-limiting toxicity (DLT) of 30%. Primary end point was safety (DLT). Secondary end point was ORR. DCR, PFS, and OS were exploratory. ORR, DCR, and PFS were assessed by investigator per RECIST v1.1. Results: Median study follow-up at data cutoff (Oct 15, 2021) was 36 mo (range, 32-43) for cohort A, 17 mo (2-24) for cohort C, and 11 mo (2-25) for cohort E. In cohort A, 1/6 pts (17%) had DLT at DL1; no DLT occurred in 14 pts (0%) at DL2. In cohort A, gr 3/4 TRAEs occurred in 3/6 pts (50%) at DL1 and 8/14 pts (57%) at DL2. In cohort C, 3/9 evaluable pts (33%) had DLT at DL1; thus, bini dose was not escalated to DL2. In cohort C, gr 3/4 TRAEs occurred in 9/11 total pts (82%). In cohort E, 1/5 evaluable pts (20%) had DLT at DL1 and 5/10 evaluable pts (50%) had DLT at DL2. Enrollment was stopped in cohort E, DL2 and bini dose was de-escalated to DL1; 2/4 additional pts (50%) had DLT at DL1 (total 3/9 pts [33%] had DLT in cohort E, DL1). In cohort E, gr 3/4 TRAEs occurred in 5/9 pts (56%) at DL1 and 10/11 total pts (91%) at DL2. No gr 5 TRAEs occurred in any cohort. ORR was 0% in cohort A; limited efficacy was seen in cohorts C and E (Table). Conclusions: Bini could be safely combined with pembro in cohort A. However, with bini + pembro + chemo, the 45-mg dose of bini was not well tolerated and required dose reduction to 30 mg. Addition of bini to pembro + chemo did not improve efficacy; therefore, enrollment was prematurely closed in cohorts C and E. Efficacy by KRAS mutation status will be shown. Clinical trial information: NCT03374254. [Table: see text]
Post-treatment detection of circulating methylated BCAT1 and IKZF1 as prognostic indicators for recurrence in patients with colorectal cancer.
Authors: Young Graeme P. , Symonds Erin L. , Roy Amitesh Chandra , Cornthwaite Kathryn J , LaPointe Lawrence Charles , Pedersen Susanne Kartin
Published: June 2022

3575

Background: Patient risk for recurrence after completion of initial treatment of colorectal cancer (CRC) is difficult to predict. Post-treatment circulating tumor DNA (ctDNA) analysis is a promising approach for stratifying such patients but the value of using tumor-uninformed biomarkers, such as methylated BCAT1 and IKZF1, is unknown. This study aimed to determine whether detection of circulating methylated BCAT1 and IKZF1 DNA following completed initial treatment with curative intent, identified patients at elevated risk of CRC recurrence. Methods: CRC stage I-III cases were eligible for study inclusion if a BCAT1/IKZF1 methylation test result was available at least 2 weeks after, but within 12mo, of completing initial treatment, and had had at least 2y follow-up unless recurrence was evident sooner (n = 142). Surveillance included regular clinical assessments and radiographic imaging. Level of methylation was reported as the total methylated BCAT1/ IKZF1 expressed as percent of cell-free DNA; levels ≥0.07% were considered positive. Primary outcome measure was recurrence-free survival. Mantel-Cox (logrank) method was used to assess the association between BCAT1/IKZF1 results and recurrence-free survival. Multivariable survival analysis by Cox proportional hazards modelling assessed the impact of covariates, including: BCAT1/IKZF1 result, age, gender, T-stage (T1-2 vs T3-4), N-stage (N0 vs N1-2), extra- and/or intra-mural vascular invasion (EMVI/IMVI) and nature of treatment. Time to recurrence was measured from the date of treatment completion to first evidence of recurrence and data were censored to last date of follow-up. Results: 33/142 (23.2%) cases had recurrence detected at a median 1.6y (IQR: 0.8-2.4). Follow-up time for those who remained recurrence free was 5.3y (IQR: 3.7-6.9). The time between completing treatment and BCAT1/IKZF1 testing was not different between these groups (median 2.4 vs 3.1mo, p = 0.530). 13 (9.2%) cases were positive for methylated BCAT1/IKZF1 after completing treatment and a positive result was associated with a significant risk of recurrence (hazard ratio [HR], 10.0 (95%CI 2.6-39.3), p < 0.001). In the multivariable survival analysis, only a positive BCAT1/IKZF1 methylation result following treatment (HR 2.6, 95%CI: 1.0-6.0, p = 0.041) and evidence of EMVI or IMVI (HR 2.3, 95%CI: 1.0-5.1, p = 0.044) were significant predictors of survival. Conclusions: This study shows that post-treatment BCAT1/IKZF1 methylation testing, which does not need personalization using tumor genotyping, is a promising independent prognostic indicator for CRC recurrence. Such cases are at high risk of recurrence compared to those who had no detectable ctDNA post treatment. These patients warrant enhanced and/or extended surveillance for recurrence. Clinical trial information: 12611000318987.
First-line (L1) therapy targeting EGFR in lung metastases (mets) of colorectal cancer (mCRC): An ARCAD pooled analysis.
Authors: Shmueli Einat Shacham , Raeisi Morteza , Chibaudel Benoist , Maughan Timothy S. , Douillard Jean-Yves , Van Cutsem Eric , Bokemeyer Carsten , Grothey Axel , Adams Richard , Zalcberg John Raymond , Yoshino Takayuki , Bachet Jean-Baptiste , Cohen Romain , Sharara Lama , Andre Thierry , Shi Qian , De Gramont Aimery
Published: June 2022

3578

Background: Monoclonal antibodies (mab) targeting EGFR are recommended in L1 treatment (trt) for mCRC in patients (pts) with RAS wild-type (WT) tumor and primary left CRC. ARCAD database contains individual data of randomized trials that evaluated anti-EGFR mab plus chemotherapy (CT). In this analysis we aimed to evaluate anti-EGFR benefit in mCRC with lung mets, either as single site or multiple sites. Methods: Individual pts data from four trials (PRIME, CRYSTAL, COIN, OPUS) comparing CT +/- anti-EGFR were pooled. KRAS status was not required at inclusion to these studies. The primary endpoint, overall survival (OS), was estimated using Kaplan-Meier method, prognostic value of lung mets was evaluated by stratified Cox models in pts groups defined by KRAS status. The predictive value was evaluated by interaction test (Int) between trt and lung mets status in pts group defined by KRAS status and considered as significant with a P < 0.1. Results: 3681 pts with known KRAS status were included, 2171 WT and 1510 mutant (MT). Pts characteristics were well balanced. Significant median OS benefit of anti-EGFR was observed in the whole KRAS WT population and in the left colon and rectum subgroup but not in the right colon subgroup. In pts with KRAS WT single site mets, a non-significant benefit of anti-EGFR was observed only among pts without lung mets (N = 642). In pts with lung single site mets (N = 129), a significant benefit ( P= 0.018) in the KRAS MT population (N = 55) was observed, but Int was non-significant ( P =0.157). In pts with KRAS WT and multiple without lung mets sites (N = 673), no benefit of anti-EGFR was observed and Int was significant ( P= 0.054). Pts with KRAS MT multiple sites with (N = 656) or without (N = 397) lung mets, had no benefit of anti-EGFR. The same findings were found in the left primary pts and in the two fluoropyrimidine backbone. PFS analyses confirm the OS results. Conclusions: In this ARCAD analysis pts with lung mets as a single site appear to benefit from anti-EGFR L1 therapy in case of KRAS MT. This unexpected result based on a limited sample size cannot be explained on the knowledge of anti-EGFR therapy. Furthermore, pts with multiple mets sites have a benefit of anti-EGFR therapy only in the presence of lung mets even in KRAS WT left primary tumor. These findings need further confirmation and may initiate the search for a specific molecular phenotype associated with lung mets in CRC pts. [Table: see text]
Co-occurring alterations across molecular pathways in metastatic colorectal cancer (mCRC).
Authors: Liu Alex John , Walden Daniel , Mina Syeda , Langlais Blake , Drusbosky Leylah , Yang Dong , Starr Jason S. , Jones Jeremy Clifton , Bekaii-Saab Tanios S. , Ahn Daniel H. , Sonbol Mohamad B.
Published: June 2022

3590

Background: Co-occurring alterations (COAs) in the HER2 and MAPK pathway are rare in mCRC. RAS, HER2 and BRAF alterations have been associated with resistance to EGFR inhibitor therapy (EGFR-mab). Typical co-occurring mutually exclusive gene mutations such as in KRAS and BRAF have been reported. This study aims to evaluate the prevalence of co-occurring alterations in the MAPK pathway or across MAPK/ HER2 and correlate to outcomes in patients with mCRC treated with EGFR-mab. Methods: This is a retrospective study of patients with mCRC within the Mayo Clinic database who have available blood-based NGS Guardant 360 data (September 2017-November 2021) and contained co-alterations in the MAPK pathway or across MAPK/ HER2. MSI-high cases were excluded. Typical-RAS was defined as alterations in codons 12, 13, 59, 61, 117, and 146 of KRAS, HRAS, and NRAS. Atypical-RAS alterations were considered mutations at other codons of these genes. Patient characteristics, specific mutations, and outcome data were assessed. Results: 692 patients (pts) with mCRC were identified and 66 (9.5%) of those had COAs detected. 59/66 pts had clinical data available. Median age was 52 years, 55.9% were male, and 61.0% had left-sided tumors. The frequency of detected alterations was: BRAF-V600E (7.3%), BRAF-non-V600E (7%), BRAF-amplification (3.04%), RAS-typical (39.5%), RAS-atypical (2.1%), HER2 amp (0.5%), HER2-mutation (1.2%) and PIK3CA (13%). COAs are described in the table. Twenty-three pts received EGFR-mab; COAs developed in 19 of them after progression on EGFR-mab. Four pts received EGFR-mab with documented COAs at baseline with none of them responding to treatment. Conclusions: COAs in MAPK and MAPK/ HER2 pathway are not uncommon in pts with mCRC emphasizing on the importance and feasibility of blood based NGS vs. selected gene testing. In pts with prior EGFR-mab treatment, COAs were detected after progression on treatment in the majority of pts, suggesting a mechanism of secondary treatment resistance. Further data including prospective validation is warranted. [Table: see text]
Effect of more versus less frequent abdominopelvic computed tomography follow-up testing on overall survival in patients with stage II or III colon cancer.
Authors: Jeongseok Jeon , Lee Da Bin , Beom Seung-Hoon , Shin Sang Joon , Ahn Joong Bae , Kim Han Sang
Published: June 2022

3604

Background: Patients with colon cancer undergo an abdominopelvic computed tomography (AP-CT) scan surveillance every 6-12 months for five years after surgery. However, evidence of survival benefit from more intensive AP-CT patients in stage II and III colon cancer is still elusive. Methods: A total of 2,137 patients with stage II-III colon cancer who received curative aim surgery were analyzed in the Yonsei Cancer Registry Database between Jan 1, 2005, to Dec 31, 2015. The surveillance start date was defined as 90 days after curative resection or one day after adjuvant chemotherapy. All patients had at least one AP-CT for two years after the surveillance period. The average interval of AP-CT per patient was calculated as the postoperative surveillance duration divided by the number of AP-CT examinations. Patients who underwent AP-CT with an average interval of 6 months and 12 months were assigned to the high-frequent and low-frequent surveillance groups. Association of AP-CT frequency and demographic factors with overall survival (OS) were evaluated. Univariate and multivariate analyses were conducted. Results: Among 2,137 patients who underwent curative aim surgery, the median intervals of AP-CT scan were 6.1 months in high-frequent surveillance and 10.8 months in the less-frequent surveillance group, respectively. The 5-year overall survival (OS) was not significantly different in both groups; however, OS was significantly longer in the high-frequent surveillance group of patients who harvested lymph nodes less than 12 in curative resection ( P = 0.015) or measured postoperative serum carcinoembryonic antigen (CEA) level higher than 5 ng/ml ( P = 0.023). Of note, high-frequent surveillance group detected liver metastasis earlier (6.7 months) than the low-frequent group, leading to more curative aim metastasectomy (28.0% vs 4.3%, P = 0.020), and significantly longer 5-year OS (62.2% vs 34.8%, P = 0.017). Multivariate analysis showed that harvesting lymph nodes less than 12 (HR = 4.37, P = 0.004) and postoperative CEA level higher than 5 ng/ml (HR = 7.39, P < 0.001) were prognostic factors for overall survival. Conclusions: The average interval of AP-CT in patients with stage II-III colon cancer is not associated with improved OS. However, a high-frequent AP-CT enabled early detection of liver metastases, leading to the improved OS in high-risk patients, including the number of harvested lymph nodes less than 12 or postoperative CEA level is higher than 5 ng/ml. The risk-stratified approach is warranted to guide postoperative colon cancer surveillance.
A phase II trial of TGFβ type I receptor inhibitor, galunisertib, plus neoadjuvant chemoradiation in patients with locally advanced rectal cancer.
Authors: Young Kristina Hoot , Gunderson Andrew J , Gilchrist Miranda , Whiteford Mark , Kiely Maria X , Hayman Amanda , O'Brien David P , Ahmad Rehan , Manchio Jeffrey V , Brosnan Evelyn , Vaccaro Gina M. , Li Rui , Simon Miklos , McCormick Mary , Drokin Ashley , Cramer Julie , Urba Walter John , Gough Michael , Crittenden Marka R. , Yamazaki Tomoko
Published: June 2022

3617

Background: Transforming growth factor beta (TGFβ) is an immunosuppressive cytokine upregulated in colorectal cancer. Preclinical data demonstrated improved response to chemoradiation with TGFβ blockade in colorectal adenocarcinoma. Here we report the results of our single arm Phase II study combining the TGFβ type I receptor kinase inhibitor, galunisertib, with neoadjuvant chemoradiation in patients with locally advanced rectal adenocarcinoma. Methods: Eligible patients had T3+ or N+ rectal adenocarcinoma planned for surgical resection. Enrolled patients completed a 14-day course of galunisertib, followed by chemoradiation with continuous infusion 5-fluorouracil or capecitabine with radiation to 50.4-54Gy in 28-30 fractions. On day 30, patients underwent another 14-day course of galunisertib concurrent with ongoing chemoradiation. Five to nine weeks after completing neoadjuvant therapy, patients underwent response assessment. Those with complete response by physical exam, proctoscopy, and MRI, could opt for non-operative management and proceed to mFOLFOX6. Those with less than a complete response underwent surgical resection. The primary endpoint was complete response rate (CR), which was a composite of pathologic complete responses in those patients who proceeded to surgery, and clinical complete responses maintained at 1 year after completion of therapy for those who chose non-operative management. Using a Simon Two-Stage approach with 90% power and α = 0.05, to detect a 20% improvement in complete response rate compared to historical control (15% vs 35%); we reject the null hypothesis if ≥10/38 patients have a CR. 38 patients were enrolled with 35 patients evaluable. Results: Median age was 51y, 68% of patients were male, 87% of patients were Stage III, 97% of patients were node-positive, and 97% were proficient in mismatch repair. 95% of patients completed study therapy. Toxicity attributed to galunisertib was Grade 1-2. 28 patients went to surgery, with a mean neoadjuvant rectal (NAR) score (NAR = 5pN-3(cT-pT)+12]2/9.61) of 11.29, and pCR in 7 patients. 7 patients underwent non-operative management, with 5 achieving cCR at 1 year. Therefore, complete responses were observed in 12 patients. Peripheral immune monitoring revealed percent change in CD3+CD4-CXCR3+ T cells and activated CD8EM T cells correlated with response to therapy. 2y PFS and OS were 81.5% and 97%. Conclusions: The addition of TGFβ inhibition to neoadjuvant chemoradiation in locally advanced rectal cancer markedly improved response to therapy, was well tolerated, and warrants further investigation. Clinical trial information: NCT02688712.
Circulating tumor DNA (ctDNA) as a minimal residual disease (MRD) assessment and recurrence risk in patients undergoing curative intent resection with or without adjuvant chemotherapy in colorectal cancer: A systematic review and meta-analysis.
Authors: Chidharla Anusha , Rapoport Eliot , Agarwal Kriti , Linares Brenda , Chakrabarti Sakti , Kasi Anup
Published: June 2022

3623

Background: Minimal residual disease (MRD) assessment may effectively detect cure in patients with colorectal cancer (CRC). Emerging data have suggested that circulating tumor DNA (ctDNA) can be a reliable biomarker for MRD in patients. Recent studies have shown the ability to detect MRD using ctDNA assay to assess recurrence risk and patient selection for adjuvant chemotherapy. We performed a systematic review and metanalysis of post operative ctDNA in Stage I-IV (oligometastatic) CRC patients after curative intent resection with or without adjuvant chemotherapy. Methods: We searched PubMed/Medline, EMBASE, Web of Science, Cochrane Library, and Google from inception to February 3, 2022 using keywords related to colorectal cancer, ctDNA, and MRD. The search also includes paper and conference presentations. The search resulted in 427 studies after removing the duplicates. Data were extracted to perform a meta-analysis using RevMan 5.4. software. Subsequent subgroup analysis was performed for stages I-III and oligometastatic stage IV CRC patients. Results: After the initial abstract screening, 48 studies were identified. The final review led to the inclusion of 27 studies representing 3459 patients with evaluable ctDNA, with 623 having +ve post-surgery ctDNA levels. Seven studies had analyses of patients specifically with oligometastatic disease, the rest 20 studies subdivided within stages I-III. The pooled HR for RFS in post-surgical ctDNA +ve vs -ve patients in all stages was 7.16 (95% CI 6.12-8.36) p <0.00001. Subgroup analysis revealed pooled HR = 8.27 (95% CI 6.16-11.09) and 6.07 (95% CI 4.54-8.13) for stage I-III and IV CRC, respectively. Only 11 studies did analysis for post adjuvant chemotherapy patients based on ctDNA status. The pooled HR for RFS in post-adjuvant chemotherapy ctDNA +ve versus -ve patients in all stages was 12.40 (95% CI 9.24-16.64) p <0.00001. Subgroup analysis revealed pooled HR = 13.95 (95% CI 9.08-21.43) and 11.39 (95% CI 5.99-21.66) for stage I-III and IV CRC, respectively. Conclusions: This is the largest and most current meta-analysis done on ctDNA levels as MRD assessment in CRC. Our analysis emphasizes that post operative ctDNA is a strong prognostic marker of RFS. Based on our results ctDNA can be a significant and independent predictor of RFS. Several ctDNA-based randomized adjuvant trials are ongoing internationally to confirm the clinical utility of ctDNA in colorectal cancer. [Table: see text]
Outcomes of appendiceal cancer treated at a state peritonectomy service.
Authors: Strach Madeleine Cornelia , Ansari Nabila , Koh Cherry , Solomon Michael , Horvath Lisa , Mahon Kate
Published: June 2022

3629

Background: Appendiceal cancers (AC) are rare with varied prognosis. Nomenclature refined by the WHO 2019 classification is: appendiceal mucinous neoplasms (AMNs), adenocarcinomas (AA) including mucinous (MAC), not otherwise specified (ANOS), signet ring (SRC) and goblet cell (GCA), and neuroendocrine tumours (NET). Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS+HIPEC) is the definitive treatment. The role of chemotherapy remains unclear with conflicting outcomes and there is need to delineate the optimal regimen in different disease settings. The aim of this study was to evaluate AC treatment and clinical outcomes by the WHO 2019 classification and analyse the impact of perioperative chemotherapy. Methods: We reviewed prospective data from the database at an Australian state peritonectomy service, Apr 2017-Dec 2021. Variables included demographics, tumour characteristics, treatment details and survival outcomes. Analysis was by the Kaplan-Meier method using the log-rank test for statistical comparison (SPSSv27). Results: 115 patients (of 207 referred) with confirmed AC proceeded to CRS. Histopathology comprised 49 AMNs (43%), 62 (63%) AA, 3 SRCs and 1 NET. The mean age was 56y (21-78), 53% female. 94% had CRS+HIPEC (Mitomycin 85%). 70% had cytoreductive score 0. The median peritoneal cancer index was 23 (0-39). 20 (17%) had localised (M0) disease, 10 acellular mucin (M1a) and 85 (74%) metastases (M1b/c). 71% were lymph node negative (N0). 40% had chemotherapy (oxaliplatin/5-fluorouracil 57%). 8 of 15 who had molecular testing had a KRAS mutation. Median follow-up was 26m (1.9-167). The table shows univariate survival analysis. Conclusions: This is the first study evaluating outcomes of perioperative chemotherapy for AC in a cohort of patients since the WHO 2019 classification. MAC have worse survival compared to ANOS, but similar to GCAs. Peritoneal acellular mucin has a similarly improved prognosis to patients with no peritoneal disease compared to those with cellular disease. Chemotherapy demonstrated worse survival compared to no chemotherapy, also seen in the literature and likely influenced by selection of more aggressive disease. There is a need to develop biomarkers and better treatments to improve the survival of these patients. Further multivariate analysis for prognostic and predictive factors is planned.[Table: see text]
NET-02: A multicenter, randomized, phase II trial of liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients (pts) with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC).
Authors: McNamara Mairead Geraldine , Swain Jayne , Craig Zoe , Sharma Rohini , Faluyi Olusola Olusesan , Wadsley Jonathan , Morgan Carys , Wall Lucy R. , Chau Ian , Reed Nick , Sarker Debashis , Margetts Jane , Krell Daniel , Cave Judith , Sharmila Sothi , Anthoney Alan , Patel Alkesh , Lamarca Angela , Hubner Richard A , Valle Juan W.
Published: June 2022

4005

Background: The prognosis for pts with PD-EP-NEC is poor. A recognised first-line (1L) treatment for advanced disease is etoposide/platinum-based chemotherapy; there is no standard second-line (2L) treatment (area of unmet need). Methods: This was a multi-centre, randomised (1:1), phase II trial of IV nal-IRI (70mg/m2 free base)/5-FU (2400 mg/m2)/folinic acid, Q14 days (ARM A), or IV docetaxel (75mg/m2), Q21 days (ARM B), as 2L therapy in a planned 102 pts with progressive PD-EP-NEC, aimed at selecting a treatment for continuation to a phase III trial. Pts with histologically-confirmed PD-EP-NEC (Ki-67>20%; Grade 3, WHO 2019), who had prior 1L platinum-based chemotherapy and radiological disease progression or discontinuation of 1L therapy due to intolerance, with an ECOG performance status ≤2 were eligible. Randomisation was stratified by Ki-67, ECOG PS, presence of liver metastases, and response to previous platinum-based therapy. Primary endpoint was 6 month (mo) progression-free survival (PFS) rate; 80% power to demonstrate the one-sided 95% confidence interval (CI) of the 6 mo PFS rate excluded 15%, if the true rate was at least 30%, where 30% was the required level of efficacy; a rate of <15% would give grounds for rejection. Intention was to show that the regimens were sufficiently active, but not to assess superiority of one regimen over the other. Secondary endpoints included objective response rate (ORR), PFS, overall survival (OS), and toxicity. Based on futility analysis, the DSMB recommended closure of recruitment in Dec 21. Results: Of 58 patients in 15 UK centres (Nov 18-Dec 21), 29 in ARM A, 29 in ARM B, 57% were male, median age (range): 63.5 years (22-85), 90% ECOG PS 0/1, 10% PS 2, 90% Ki-67≥55%, 33%/38%/29% small/large cell/unknown morphology, primary site: 69% gastrointestinal, 12% unknown, 9% genitourinary, 5% head & neck, 3% gynae, 2% breast, 60% had liver mets, 91%/7%/2% were resistant/sensitive/intolerant to 1L platinum-based treatment. At a median follow up of 6.6 mo, the primary end-point of 6-mo PFS rate was met in ARM A; ORR, median PFS and OS are also presented (Table). Adverse events ≥ grade 3 occurred in 51.7% and 55.2% in ARM A and B and there were 1 and 6 discontinuations due to toxicity in ARM A and B, respectively. Data cleaning is on-going. Conclusions: nal-IRI/5-FU, but not docetaxel, met the primary endpoint (exceeding the threshold for efficacy), with manageable toxicity, and warrants evaluation in a phase III trial. Clinical trial information: 03837977. [Table: see text]
Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): Expanded efficacy and safety analyses from CheckMate 648.
Authors: Chau Ian , Ajani Jaffer A. , Doki Yuichiro , Xu Jianming , Wyrwicz Lucjan , Motoyama Satoru , Ogata Takashi , Kawakami Hisato , Hsu Chih-Hung , Adenis Antoine , El Hajbi Farid , Di Bartolomeo Maria , Braghiroli Maria Ignez Freitas Melro , Holtved Eva , Blum Murphy Mariela A. , Abdullaev Sandzhar , Soleymani Samira , Lei Ming , Kato Ken , Kitagawa Yuko
Published: June 2022

4035

Background: NIVO + chemo and NIVO + IPI demonstrated significant overall survival (OS) benefit vs chemo in previously untreated patients (pts) with advanced ESCC in the phase 3 CheckMate 648 study. We report expanded results from the primary analysis with 13-month (mo) minimum follow-up. Methods: Pts with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR) in pts with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Secondary endpoints planned for hierarchical testing included OS, PFS, and objective response rate (ORR) per BICR in all randomized pts. Duration of response (DOR) per BICR and PFS2 per investigator (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death) were exploratory endpoints. Results: Among all pts randomized to NIVO + chemo (n = 321), NIVO + IPI (n = 325), or chemo (n = 324), PFS2 favored NIVO + chemo (HR 0.64, 95% CI 0.54–0.77) and NIVO + IPI (HR 0.74, 95% CI 0.62–0.88) vs chemo. ORR (95% CI) was 47% (42–53), 28% (23–33), and 27% (22–32), respectively. More responders with NIVO + chemo or NIVO + IPI vs chemo had prolonged DOR (≥12 mo; 39%, 48%, and 23%, respectively). Efficacy data by tumor cell PD-L1 and PD-L1 combined positive score will be presented. Grade 3/4 treatment-related adverse events with potential immunologic etiology (select TRAEs) occurred in ≤ 6% of pts with NIVO + chemo and NIVO + IPI, and non-endocrine select TRAEs resolved in 57%–95% of pts across organ categories (Table). Conclusions: NIVO + chemo and NIVO + IPI demonstrated favorable PFS2 and a higher proportion of pts with prolonged DOR vs chemo, as well as acceptable safety profiles. These results provide further support for each regimen as a new potential 1L standard of care in advanced ESCC. Clinical trial information: NCT03143153. [Table: see text]
Phase II trial of perioperative chemotherapy of esophageal cancer: PIECE trial.
Authors: Nomura Motoo , Goto Masahiro , Watanabe Masayuki , Hato Shinji , Kato Ken , Baba Eishi , Matsubara Hisahiro , Mukaida Hidenori , Yoshii Takako , Tsuda Masahiro , Tsubosa Yasuhiro , Kitagawa Yuko , Hideki Ishikawa , Muto Manabu
Published: June 2022

4038

Background: Neoadjuvant chemotherapy followed by surgery (NAC-S) is the standard therapy for locally advanced esophageal squamous cell cancer (ESCC) in Japan. The aim of this phase II trial was to assess the efficacy and safety of the addition of adjuvant S-1 after R0 resection in patients treated with NAC-S. Methods: Key eligibility criteria were as follows: ESCC of clinical stage IB-III (without T4 disease); aged 20 to 75 years; ECOG performance status 0 or 1; and performed neoadjuvant chemotherapy (5-FU + cisplatin). All patients registered before surgery. Patients received adjuvant therapy with 4 cycles of S-1 (80 mg/m2/day) that is administered orally for 4 weeks of a 6-weeks cycle. The primary endpoint was three-year relapse free survival (RFS). Results: A total of 52 patients were enrolled between January 2016 and January 2019. Two patients (one with small cell carcinoma and the other with synchronous malignancy) were excluded from analysis. Five patients were diagnosed as R1 or R2. Seven patients did not receive adjuvant S-1 due to adverse events of surgery in 5 patients, refusal to adjuvant S-1 in a patient, and forgot to start in a patient. Thirty-eight patients received adjuvant S-1, with 32 patients completing 4 cycles. The median relative dose intensity of adjuvant S-1 was 85.8%. Median follow-up time among survivors after surgery was 4.5 years (range 0.2-5.6). Three-year RFS in intention to treat population was 72.3% (90% confidence interval [CI] 59.9-81.5), suggesting that the primary endpoint was met, and 3-year overall survival was 85.0% (90% CI 73.9-91.6). Grade 3 or higher adverse event with an incidence 10% of greater were neutropenia (13.2%), anorexia (13.2%), and diarrhea (10.5%). There was no treatment-related death. Conclusions: Adjuvant S-1 showed promising efficacy with manageable safety profile for patients with resectable ESCC after NAC-S, and warrants further evaluation in larger studies. Clinical trial information: UMIN000020204.
The adjudication rates between readers in Blinded Independent Central Review (BICR) of advanced esophageal cancer trials with or without immune checkpoint initiators as first-line therapy.
Authors: Liu Yan , Wang Yi , Iannessi Antoine
Published: June 2022

4039

Background: It is challenging to use RECIST 1.1 for the response assessment in esophageal cancer, because it excludes certain examines such as the use of barium meal and endoscopy. In some esophageal trials, the study protocols also recommend not selecting the primary tumor as a target lesion, because esophageal lesion could be infiltrative in a cavity organ and difficult to measure reliable especially after treatment. Moreover, it can even be more difficult for independent central readers, as they are often blinded to patient clinical symptoms and outcomes. The aim of this study is to analyze a pool of advanced esophageal cancer trials which used RECIST 1.1, and to document the proportion of reader discrepancies, reader performance through monitoring procedures, and to provide suggestions for the reduction of read inconsistency. This study provides benchmarks of reader adjudication rate in novel esophageal cancer therapeutic trials with or without immune checkpoint inhibitors, which will help to trigger corrective actions, such as reader initial training and follow up re-training. Methods: We analyzed 4 esophageal cancer BICR trials that included 1,875 patients (8,501 time-points) involving 14 radiologists. We analyzed the adjudication rate of each trial as well as testing inter-trial differences. The analysis of adjudication allowed to compute trial and reader adjudication rate, readers endorsement rate, root causes of adjudications. Results: Trials had an average adjudication rate of 45.28% [42.60%-47.99%], while readers endorsement rates ranged [23.1%-81.6%]. The differences of target lesion selection (34.4%) and lesion measurement (40.3%) are the two main reasons that led to discordance per adjudicators’ assessment. The difference of new lesion determination and identification of non-target lesion progression contributed 17.8% and 7.5% of the discordance reasons, respectively. Conclusions: We provided benchmark performances for monitoring reader performance in trials with double reads. The discordances of baseline lesion selection and lesion measurement in follow up visits are the main reasons triggering adjudications in esophageal cancer central reading. Appropriate reader training and monitoring are solutions which can not only mitigate a large portion of the commonly encountered reading errors and help to reach more consensus on lesion selection and measurement between readers.