bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterizing the genomic landscape of POLE/POLD1-mutated colorectal adenocarcinoma.
Authors: Coston Tucker , Mauer Elizabeth , Jones Jeremy Clifton , Hubbard Joleen M. , Bekaii-Saab Tanios S. , Stoppler Melissa Conrad , Starr Jason S.
Published: January 2023

199

Background: The progression of neoplasia in colorectal cancer (CRC) has been well characterized, with the evolution typically involving mutations in APC, KRAS, and p53, among others. POLE/POLD1 genes encode for proteins essential in enzymatic DNA polymerase function, yet POLE/POLD1 mutations in tumors are poorly characterized. Pathogenic mutations in POLE/POLD1 lead to decreased fidelity of DNA replication, resulting in a high tumor mutational burden (TMB-H) independent of deficient mismatch repair (dMMR) and high microsatellite instability (MSI-H). Studies have shown associations between this hypermutated phenotype and susceptibility to immune checkpoint inhibition, which may be attributable to neoantigen creation. As such, these tumors are a clinically relevant phenotype requiring further investigation. Here, we characterized POLE/POLD1 alterations in a large, real-world cohort of patients with CRC. Methods: We retrospectively analyzed de-identified records of 9,136 primary CRC patients profiled with the Tempus xT assay. The assay includes DNA-seq of 595-648 genes at 500x to evaluate single-nucleotide variants, insertions/deletions, and copy number changes. Immunological markers analyzed included tumor mutational burden (TMB), MSI, and dMMR. MSI-H was determined by the assay through assessment of 239 loci. dMMR was determined by immunohistochemistry. Results: A total of 217 patient tumors harbored somatic POLE/POLD1 mutations (n = 203 POLE, n = 13 POLD1, and n = 1 POLE and POLD1; none germline), with no differences noted in baseline demographics including gender and age. Among the POLE/POLD1-mutant cohort, POLE copy number losses accounted for most mutations (n = 127, 59%), with short variants and copy number amplifications accounting for 35% (n = 76). The remainder of tumors exhibited POLD1 copy number changes (n = 14), including one with both POLE and POLD1 copy number loss. POLE/POLD1-mutated tumors presented with a lower frequency of MSI-H compared to wild-type (1.8% vs 6.1%, P= 0.018). Conversely, there was a higher frequency of TMB-high cases ( > 10 mut/Mb) for POLE/POLD1-mutated compared to wild-type tumors (22% vs 9.9%, P< 0.001). Differences between POLE/POLD1-mutated and wild-type tumors were also observed among many co-mutated genes, including APC (80% vs 65%, P< 0.001), ALK (31% vs 11%, P< 0.001), ATM (12% vs 3.6%, P< 0.001), BRCA2 (12% vs. 3.2%), and RET (24% vs 8.9%, P< 0.001). Conclusions: Patients with POLE/POLD1 mutations exhibited significant differences across immunological markers and molecular co-alterations. POLE/POLD1 mutations in CRC have been previously described to present with a hypermutated phenotype; however, 78% of tumors exhibited low TMB despite POLE/POLD1 mutations. Thus, these results have identified POLE/POLD1-mutated tumors as a unique genomic subpopulation, and further studies are needed to better characterize POLE/POLD1 mutations in CRC.
Disparate outcomes for Black patients following neoadjuvant chemoradiation for rectal cancer are multifactorial in origin.
Authors: Shulman Rebecca Maria , Lynch Shannon M. , Deng Mengying , Handorf Elizabeth A. , Meyer Joshua E. , Arora Sanjeevani
Published: January 2023

21

Background: Studies have shown that Black patients receiving chemoradiation (CRT) for locally advanced rectal cancer (LARC) have achieved clinical outcomes less satisfactory than those achieved by other racial groups, but the source of this disparity is poorly understood. This study investigated the demographic, geographic, socioeconomic, and clinical factors that underlie this disparity. Methods: We interrogated the National Cancer Database from 2004-2017 to identify patients with T3-T4 or N > 0 LARC treated with CRT prior to surgery. Response to CRT was determined by the rates of pathologic complete response (pCR) and tumor downstaging after treatment. Univariate analysis (UVA) was performed with chi-square and Fisher’s exact tests. Multivariate analysis (MVA) was then used to identify independent factors associated with improved pCR. Results: A total of 37,783 patient records were reviewed for the study (7.8% Black, 86.0% White, 6.1% Other). Black patients were younger (p < 0.0001), more often female (p < 0.0001), and more likely to live in metropolitan areas (p < 0.0001). LARC in Black patients was diagnosed at a higher clinical stage (p = 0.0007) and was more often treated with abdominoperineal resection in preference to low anterior resection (p < 0.0001). Black patients were more often uninsured or covered by Medicaid (p < 0.0001) and less often covered by commercial insurance (p < .0001). UVA demonstrated that Black patients achieved pCR and tumor downstaging at lower rates than White patients (11.6% vs 14.5%; 46.9% vs 51.8%, both p < 0.0001). On MVA, Black race (OR 0.8015, 95%CI 0.7101-0.9047), a rural location (OR 0.8211, 95% CI 0.7082-0.952), absence of commercial medical insurance (Medicaid OR 0.8394 95% CI 0.7456-0.9449; Medicare OR 0.8989 95% CI 0.8226-0.9823; No Insurance OR 0.6107 95% CI 0.5103-0.7309), and higher tumor grade and stage remained independent risk factors for a lower pCR. Additional significant unfavorable prognostic factors for pCR included younger age, male sex, lower hospital treatment volume, and higher tumor grade or stage. Similarly, Black race, lower hospital treatment volume, absence of commercial medical insurance, and higher grade or stage were significant unfavorable prognostic factors for downstaging. Neither lower income nor fewer years of education was associated with pCR or tumor downstaging. Conclusions: The results confirm a lower rate of response to CRT in Black patients with LARC. The identification of race as an independent risk factor after adjustment for sociodemographic, geographic, and clinical factors suggests that other unknown variables–including genetic differences unaddressed in this study–must be pursued comprehensively in future studies. The more advanced stage of rectal cancers in Black patients suggests that critical evaluation of current cancer screening methods may play a role in this effort.
Mutation status of full RAS and BRAF in 169 Moroccan patients with colorectal cancer.
Authors: El zaitouni Sara , Laraqui Abdelilah , Ghaouti Meriem , Benzekri Asmae , Kettani Fouad , El Annaz Hicham , Abi Rachid , Tagajdid Mohamed Rida , El Kochri Safae , Lahlou Idriss Amine , Ameziane El Hassani Rabii , Ennibi Khalid
Published: January 2023

216

Background: Morocco has the highest cancer mortality rate in MENA Countries. Colorectal cancer (CRC) is classified as the first digestive cancer and remains a burden in Morocco. According to the data on GLOBOCAN 2020, there were 4324 new CRC patients and 2374 deaths, accounting for 7.3% and 2.8% of all cancers, respectively. Our study aimed to investigate the frequency of the full RAS ( KRAS, NRAS) and BRAF genes in CRC patients from Morocco and their possible associations with clinico-pathological features. Methods: Archived FFPE of 169 CRC patients were screened for KRAS, NRAS and BRAF mutations by Idylla technology. Results: Full RAS mutations were identified in 46.1% (42% in KRAS, 4.1% in NRAS). In KRAS gene, exon 2 mutations accounted for 84.5% (69% in codon 12, 15.5 % in codon 13). Within codon 12, KRAS G12D and G12C were more frequently detected (29.5% and 16.9%, respectively). Detection of KRAS mutations, and particularly G12D and G12C subtypes, are of large significance for CRC patients, have possible therapeutic implications. Within codon 13, the most frequently observed mutation was G13D (15.5 %). Outside exon 2, the mutation rate was 35.1% (8.4% in exon 3 and 26.7% in exon 4). Concurrent KRAS mutations were identified in 8 cases, which suggests that multiple mutations can occur in the same or different codons. In NRAS gene, the mutation rates of exon 2 and 3 were 71.4% and 57.1% respectively. G13V and Q61K were the most common mutations, accounting for 28.6 % of each. Concurrent KRAS mutations were identified in 2 cases. Of the 169 samples, mutations in the BRAF gene at V600E were detected in 3.5%. Combined mutational analysis of KRAS, NRAS and BRAF was able to identify 49.6% of patients with CRC as likely non-responders to anti-EGFR therapy. There was an association between KRAS mutations and age, which were higher in the age group>50 years old (p=0.022). Tumors in the left colon (36.61%) are more likely to harbor mutations in KRAS than the rectum (19.7%) in both sexes. The adenocarcinoma well-differentiated was the most frequent for patients with KRAS mutations (54.9%). No significant clinicopathologic correlations with NRAS and BRAF mutations were identified. Conclusions: Beside established anti-CRC treatment, better understanding of the causality of CRC can be established by combining epidemiology and genetic/epigenetic on CRC etiology in Morocco. This approach may be able to significantly reduce the burden of disease in the country. Moreover, the Moroccan government should develop policy on CRC prevention and public health programs which may serve as a feasible setting to increase public awareness on lifestyle risk factors.
Impact of RAS and BRAF heterogeneity on the efficacy of EGFR blockade in patients with metastatic colorectal cancer.
Authors: Yamada Takeshi , Matsuhashi Nobuhisa , Takahashi Takao , Hirata Keiji , Nagasaka Takeshi , Nakamura Yuki , Sakamoto Kazuhiro , Koda Keiji , Hiramatsu Kazuhiro , Matsuoka Hiroshi , Kuramochi Hidekazu , Ishida Hideyuki , Kataoka Kozo , Yokomizo Hajime , Kagawa Yoshinori , Suenaga Mitsukuni , Ohta Ryo , Matsuda Akihisa , Yoshida Hiroshi
Published: January 2023

219

Background: Epidermal growth factor receptor (EGFR) blockade can effectively shrink tumors in metastatic colorectal cancer (CRC) patients without RAS nor BRAF mutations. However, some patients without RAS nor BRAF mutations in their primary tumors have them in metastatic tumors (heterogeneity). Circulating tumor DNA (ctDNA) can reflect these mutations in metastatic tumors. Here, we evaluated the efficacy of EGFR blockade in patients who had no RAS nor BRAF mutations in their primary tumors, but who had them in ctDNA. Methods: We prospectively enrolled 100 patients with confirmed metastatic CRC without RAS nor BRAF mutations in their primary tumors. Patients were treated with first-line systemic chemotherapy that included EGFR blockade. We obtained ctDNA from each patient before they started chemotherapy, and at the time they acquired resistance. We detected RAS, BRAF (V600E), and PIK3CA mutations using digital polymerase chain reaction. Results: In the ctDNA obtained before starting chemotherapy, RAS, BRAF, and PIK3CA mutations were detected in 10, 4, and 2 of the 100 patients, respectively. No patients had both RAS and BRAF mutations in their ctDNA; however, one patient had both BRAF and PIK3CA mutations. Eighty-nine patients had measurable tumor lesions. Of those, 3 experienced a complete response (CR), 72 had a partial response (PR), 12 had stable disease (SD), and 2 had progressive disease (PD). Of 14 patients who had measurable tumors and RAS or BRAF mutations in the ctDNA, 11 (79%) had a PR and 3 (21%) had SD. Of 75 patients who had measurable tumors and no RAS or BRAF mutations in the ctDNA, 3 (4%) experienced a CR, 61 (81%) had PR, 9 (12%) had SD, and 2 (3%) had PD. Patients with RAS or BRAF mutations and patients with neither mutation had response rates of 79% and 85%, respectively. There was no significant difference. Conclusions: As we previously reported, incidence of RAS and BRAF heterogeneity were 10% and 4%, respectively. Heterogeneity of RAS and BRAF mutations had no effect on the response rate of EGFR blockade as first line chemotherapy. Other possible causes of resistance could be MET or HER-2 amplification, PIK3CA mutation, or ALK fusion. The effect of heterogeneity on the duration of response is of great interest; however, one-third of patients are still undergoing treatment with EGFR blockade. Clinical trial information: 000031177 .
Unique microbial biomarkers identified in Nigerian patients with colorectal cancer.
Authors: Abate Miseker , Alatise Olusegun Isaac , Omisore Adeleye Dorcas , Komolafe Akinwunmi O. , Omoyiola Oluwatosin Zainab , Abdulkareem Fatimah Biade , Olatoke Samuel Adegboyega , Adeyeye Ademola Adetoyese , Agodirin Sulaiman Olayide , Lawal AbdulRazzaq Oluwagbemiga , Olasehinde Olalekan , Osinowo Adedapo Olumide , Owoade Israel Adeyemi , Njokanma Iloba Gabriel , Oludara Mobolaji A , Kingham T. Peter , Weiser Martin R. , Vanderbilt Chad
Published: January 2023

222

Background: The microbiome is an important biomarker associated with the pathogenesis and progression of disease in colorectal cancer (CRC). Genetic, dietary and environmental factors have been implicated in CRC microbial dysbiosis, however geographical distinctions in the microbiome of CRC are largely unknown. In this study, we characterize distinctions in the microbial diversity and microbial enrichment of CRC specimen obtained from a Nigerian and U.S. population. Methods: A validated microbiome bioinformatics pipeline that is generalizable across multiple next generation sequencing platforms was utilized. Microbial profiles for alpha diversity and enrichment were generated for two large, geographically distinct cohorts: (1) U.S. (n=498) and (2) Nigerian (n=65) cohorts. CRC specimen from Nigeria were compared to CRC specimen from the U.S. using the same microbial bioinformatics pipeline and methodology for analysis. Microbial differences stratified based on CRC microsatellite-instability (MSI) status were identified. Results: 9 unique microbial species were significantly enriched in the CRC specimen from the Nigerian cohort when compared to the US cohort. Subset analysis based on MSI status revealed enrichment of Faecalibacterium and Veillonella in the Nigerian cohort for both MSI and microsatellite stable (MSS) CRC (Table). Prevotella was significantly enriched in MSS CRC in the Nigerian cohort (OR=53.35, CI=10.34,275.37, p<0.001). There were no significant differences in alpha diversity between the Nigerian and U.S. cohorts (p>0.05). Conclusions: Several unique species with taxonomic diversity are enriched in Nigerian CRC and can be independently validated based on stratification by MSI status. Given the varied accessibility of diagnostic and therapeutic tools for CRC in these distinct geographical settings, understanding unique microbial biomarkers will provide the landscape to explore key microbial targets for therapy specific to this population.[Table: see text]
Immunohistochemical assessment of COX2, P53, and beta-catenin expression to predict metachronous lesion development following polypectomy.
Authors: Johnstone Mark Scott , Al-Badran Sara SF , Stoops Reiss , Hay Jennifer , Jawny Jakub , Lynch Gerard , McSorley Stephen T , Edwards Joanne
Published: January 2023

234

Background: Following colorectal polypectomy, 20-50% develop metachronous polyps, and some have increased colorectal cancer (CRC) risk. Surveillance colonoscopy is recommended to high-risk patients, based on index polyp number, histology and size. We aimed to assess if COX2, p53 and beta-catenin expression could predict metachronous polyp/ CRC risk. Methods: Tissue microarrays (TMA’s) were constructed for 339 patients from the INCISE study, a retrospective analysis of all patients undergoing screening polypectomy (Apr’09-Dec’16) followed by surveillance (6months-6years) in Glasgow, UK. Epithelial COX2, p53 and beta-catenin expression were assessed for each patient’s most advanced index polyp using immunohistochemistry, quantified by QuPath software. Kaplan-Meier analysis, log-rank tests and univariate/ multivariate cox regression assessed the association between marker expression and time to metachronous polyp/ CRC detection. Results: Low nuclear p53 expression was associated with shorter time to metachronous polyp/ CRC detection (p=0.024). Low nuclear (p=0.012) and membranous (p=0.046) beta-catenin expression was associated with shorter time to metachronous polyp/ CRC detection. There was no association between cytoplasmic COX2 expression and time to metachronous polyp/ CRC detection overall (p=0.309), but high cytoplasmic COX2 expression was associated with shorter time to detection of advanced metachronous lesions (advanced colorectal polyps/ CRC) (p=0.011). A combined score using the two most powerful biomarkers (nuclear p53 and nuclear beta-catenin – both high/ one low/ both low) was also associated with shorter time to metachronous polyp/ CRC detection (p=0.011). Univariate and multivariate cox regression are shown. Conclusions: Index polyp number and combined nuclear p53/beta-catenin expression independently predicted time to metachronous polyp/ CRC detection. [Table: see text]
The role of gene expression of CDC37 in colorectal cancer (CRC).
Authors: Arai Hiroyuki , Baca Yasmine , Battaglin Francesca , Algaze Sandy , Jayachandran Priya , Soni Shivani , Wu Zhang , Lo Jae Ho , Sohal Davendra P.S. , Goldberg Richard M. , Hall Michael J. , Scott Aaron James , Hwang Jimmy J. , Lou Emil , Weinberg Benjamin Adam , Marshall John , Goel Sanjay , Xiu Joanne , Lenz Heinz-Josef
Published: January 2023

237

Background: CDC37-HSP90 axis is an essential chaperoning system for stabilization of kinases. CDC37 determines selectivity of client kinases recognized by HSP90. We previously showed patients with CDC37-dependent ( CDC37 high expression) colorectal cancer (CRC) derived more benefit from regorafenib and bevacizumab both of which target HSP90 client kinases or signaling pathway, but not from cetuximab which targets HSP90 non-client kinase. However, molecular characteristics and interaction with relevant signaling pathways in CDC37-dependent CRC are largely unknown. Methods: We retrospectively reviewed CRC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix AZ). Next-generation sequencing of DNA and RNA (whole-transcriptome sequencing) and immunohistochemistry were performed. Molecular profiles between top quartile transcripts per million for CDC37 expression (Q4, CDC37-high: n = 5056) and bottom quartile (Q1, CDC37-low: n = 5056) were compared for gene mutations, microsatellite instability (MSI) status, PD-L1 expression, co-expression of HSP90 genes ( HSP90AA1 and HSP90AB1), MAPK pathway activity score (MPAS), T-cell inflamed signature, and cell infiltration in the tumor microenvironment (TME) assessed by QuantiSEQ. Gene set enrichment analysis (GSEA) was performed between CDC37-high (Q4) and CDC37-low (Q1) tumors. Results: KRAS mutations trended higher in CDC37-high tumors compared to CDC37-low tumors (49.5% vs 47.1%) while APC (76.9% vs 72.3%), TP53 (75.5% vs 71.8%) and TCF7L2 (5.0% vs 3.5%) mutations were significantly higher in CDC37-high tumors compared to CDC37-low tumors (q < 0.05). No significance in expression quartiles were observed for dMMR/MSI-H or PD-L1 expression. HSP90AA1 and HSP90AB1 expression levels were significantly higher in CDC37-high tumors (2.9-fold and 2.6-fold in median, respectively; both q< 0.05). Both MPAS and T-cell inflamed signatures were significantly higher in CDC37-high tumors ( q< 0.05). Infiltration of NK cells, Tregs, neutrophils, M1 macrophages, and B-cells were greater in CDC37-high tumors (q < 0.05). GSEA showed several signaling pathways, such as KRAS, TGF-beta, hypoxia, WNT-beta catenin, and PI3K-AKT-MTOR, were enriched in CDC37-high tumors. Conclusions: Highly CDC37-expressed (CDC37-dependent) CRC was associated with aberrant TME where abundance of immune cell infiltrate and broad activation of kinase-related signaling pathways were evident. Our results support the kinase-stabilizing function of CDC37 in CRC. Further investigations combined with survival data are warranted to address the prognostic and predictive values of CDC37 expression in targeted therapies of CRC.
Deep learning–assisted colonoscopy images for prediction of mismatch repair deficiency in colorectal cancer.
Authors: Hu Jiancong , Hu Huabin , Cai Yue , Chen Xijie , Liao James , Han Ming , Shi Lishuo , Chen Junguo , Liu Wei , Su Mingli , Wang Chao , Huang Yan , He Xiaosheng , Lan Ping , Deng Yanhong
Published: January 2023

24

Background: Deficient mismatch repair (or microsatellite instability) is a major predictive biomarker for the efficacy of immune checkpoint inhibitors of colorectal cancer. However, routine testing is time-consuming and incur substantial costs. We developed and validated a deep learning-based classifiers (MMR-Scopy) to detect mismatch repair-deficient status from routine colonoscopy images. Methods: We retrospectively obtained the colonoscopy images from the imaging database at Endoscopic Center of the Sixth Affiliated Hospital of Sun Yat-sen University. Colorectal cancer images from patients that had undergone colonoscopy procedures, surgery and the mismatch repair immunohistochemistry test were eligible for this study. Colonoscopy images from a prospective trial (Neoadjuvant PD-1 blockade by toripalimab with or without celecoxib in mismatch repair-deficient or microsatellite instability-high locally advanced colorectal cancer, PICC) were used to test MMR-Scopy. The primary outcome was dMMR status. The primary performance metrics were accuracy, negative predictive value (NPV), and area under the receiver operating characteristic curve (AUROC). Results: A total of 5226 eligible images from 892 tumors from the consecutive patients were utilized to develop and validate the deep learning model. 2105 CRC images from 306 tumors were randomly selected to form model development dataset with a class-balanced approach. 3121 images of 488 pMMR tumors and 98 dMMR tumors were used to form the independent dataset. The MMR-Scopy model achieved an AUROC of 0.948 (95% CI 0.919- 0.977) on the test dataset. On the independent validation dataset, the AUROC was 0.807 (0.760- 0.854), and the NPV in was 94.2% (95% CI 0.918-0.967). On the PICC dataset, the model identified 29 tumors among the 33 dMMR tumors (87.88%). Conclusions: MMR-Scopy achieved a high NPV in detecting dMMR colorectal cancers. This model might serve as an automatic screening tool, one that might potentially assist doctors in determining a new treatment strategy. [Table: see text]
Twitterchats as a means to educate patients with CRC and caregivers and stimulate collaborations.
Authors: George Manju , Parikh Aparna Raj , Loree Jonathan M. , Sanford Nina Niu , Jethwa Krishan
Published: January 2023

255

Background: During the COVID-19 pandemic, Twitter has been instrumental in accelerating knowledge dissemination and forging collaborations within the medical community and amongst patient advocates. Tweetchats within Twitter are scheduled conversations on a specific topic. In oncology, Tweetchats have been used by cancer advocates to spread awareness and for patient and caregiver education. A colorectal cancer (CRC) specific tweetchat did not previously exist. This abstract describes the creation, and experiences with a CRC specific tweetchat. Methods: The #CRCTrialsChat tweetchat was created by a patient advocate for colorectal cancer patients, caregivers and clinicians to meet and exchange clinical trial-related information. Two gastrointestinal (GI) medical oncologists and two radiation oncologists were enlisted as moderators. The topic for each session is chosen by the patient advocate, who creates an outline and divides the content, which is designed to last a one hour session. The idea is to create engaging, technical, but easy to understand content. Each moderator then works on the answers to their assigned section, which is edited to fit tweet character limit. Sessions may also have guest moderators with expertise on a specific topic. Through tweeting, moderators answer specific questions that come up during the session and later. Results: To date, we have had four sessions covering the following topics: Clinical trial basics, CRC Updates from ASCO22, ClinicalTrialFinders and BRAF-mutated tumors. The content created has been simple and engaging, the format has functioned smoothly, and the reach of #CRCTrialsChat has been steadily increasing. After the most recent session on BRAF in September 2022, the @CRCTrialsChat has 281 followers, 17K impressions and 14.6K profile visits, a reflection of its excellent content. From a clinician perspective, this is a great format to interact with colleagues, discuss enrolling trials and also become familiar with using Twitter. Conclusions: A CRC clinical trial focused tweetchat is an engaging way to deliver trial-related content to an audience of clinicians, patients and caregivers. The current format appears to be an effective way to create and disseminate information. Future sessions will focus on ctDNA, molecular markers such as KRAS and HER2, and rectal cancer trials. Our hope is that #CRCTrialsChat will stimulate continued patient and clinician engagement, increase awareness of clinical trials, enhance trial participation and initiate patient-centric research and collaborations.
Nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 3-year follow-up from CheckMate 649.
Authors: Janjigian Yelena Y. , Shitara Kohei , Moehler Markus H. , Garrido Marcelo , Gallardo Carlos , Shen Lin , Yamaguchi Kensei , Wyrwicz Lucjan , Skoczylas Tomasz , Campos Bragagnoli Arinilda Silva , Liu Tianshu , Tehfe Mustapha , Elimova Elena , Bruges Maya Ricardo Elias , Cleary James M. , Karamouzis Michalis , Soleymani Samira , Lei Ming , Amaya-Chanaga Carlos , Ajani Jaffer A.
Published: January 2023

291

Background: NIVO + chemo demonstrated superior overall survival (OS) and clinically meaningful progression-free survival (PFS) benefit vs chemo and an acceptable safety profile in previously untreated patients (pts) with advanced GC/GEJC/EAC, leading to approvals in multiple countries including the US. NIVO + chemo continued to demonstrate clinically meaningful improvement in efficacy after 2 years of follow-up. We present efficacy and safety analyses from NIVO + chemo vs chemo from the 3-year follow-up of CheckMate 649. Methods: Adults with previously untreated, unresectable advanced, or metastatic GC/GEJC/EAC were enrolled, regardless of programmed death ligand 1 (PD-L1) expression. Pts with known HER2-positive status were excluded. Randomized pts received NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 581 pts were concurrently randomized to NIVO + chemo or chemo. With 36-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts. The objective response rate (ORR) per BICR in pts with PD-L1 CPS ≥ 5 who had measurable lesions at baseline was 60% (95% CI 55–65) with NIVO + chemo vs 45% (95% CI 40–50) with chemo; in all randomized pts, ORR per BICR was 58% (95% CI 54–62) with NIVO + chemo vs 46% (95% CI 42–50) with chemo. Responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5 (median [m] duration of response [mDOR] 9.6 mo [95% CI 8.2–12.4] vs 7.0 mo [95% CI 5.6–7.9], respectively) and in all randomized pts (mDOR 8.5 mo [95% CI 7.7–9.9] vs 6.9 mo [95% CI 5.8–7.2], respectively). OS benefit with NIVO + chemo was observed across most prespecified subgroups. No new safety signals were identified. A summary of treatment-related adverse events (TRAEs) is shown here. Conclusions: After 3 years of follow-up, NIVO + chemo continued to demonstrate clinically meaningful long-term survival benefit with an acceptable safety profile, further supporting its use as a standard 1L treatment in previously untreated pts with advanced GC/GEJC/EAC. Clinical trial information: NCT02872116 . [Table: see text]
Risk of gastric cancer development according to the combination of anti–Helicobacter pylori antibody titer and degree of atrophic gastritis.
Authors: Lim Joo Hyun , Cho Soo Jeong
Published: January 2023

297

Background: Helicobacter pylori is known as the main risk factor for gastric cancer. It is also well known that gastric atrophy which is the result of long-term H. pylori infection induces spontaneous regression of H. pylori infection and such atrophic status with negative H. pylori infection is related with high risk of gastric cancer, as in so called “ABC method”. However the implication of anti- H. pylori antibody titer is not well investigated. This study was designed to identify the risk for gastric cancer according to the combination of level of anti- H. pylori antibody titer and gastric atrophy. Methods: Those who had health checkups including upper endoscopy and serum anti- H. pylori antibody test between 2003 and 2018 were enrolled. Among them, those who had positive results for anti- H. pylori antibody were included in this study and those who had followed up for less than 1 year were excluded. Kimura-Takemoto classification C3 or more was defined as gastric atrophy. Individuals were classified into 4 groups: low B (low titer without atrophy), high B (high titer without atrophy), high C (high titer with atrophy), and low C (low titer with atrophy). Their risks for gastric cancer were compared under adjustment with other risk factors. Results: During median 5.7 years of follow-up, among 28,311 subjects, 231 developed new gastric cancer. Among them, 159 were intestinal type, 68 were diffuse type, and 4 were type-unknown. For intestinal type gastric cancer, high C group and low C group showed significantly high risk compared with low B group (high C: aHR 10.516; 95% CI, 6.485-17.054) (low C: aHR 11.191; 95% CI, 7.096-17.649). However, for diffuse type gastric cancer, high B group showed higher risk compared with low B group (aHR, 1.713; 95% CI, 1.021-2.875). When those two factors were taken separately, grade of atrophy was related with the risk for intestinal type gastric cancer (aHR, 2.047; 95% CI, 1.862-2.251), while the level of anti- H. pylori antibody titer was related with the risk for diffuse type gastric cancer (aHR, 1.158; 95% CI, 1.041-1.288). Conclusions: Among those with current H. pylori infection, high anti- H. pylori antibody titer is related with diffuse type gastric cancer. The risk was prominent especially among those without atrophy. Therefore, those with high level of anti- H. pylori antibody titer need to be considered as high risk group even without atrophy and should be considered as good candidates for H. pylori eradication and intensive screening.
Disparities and outcomes in young adults admitted for gastric cancer in the US.
Authors: Litvin Rafaella , Deenadayalan Vaishali , Ibrahim Muhammad Bilal , Ishaya Michelle
Published: January 2023

298

Background: Although global incidence of gastric cancer has been decreasing over the past decades, an upward trend has been reported in younger patients and certain ethnic groups over the past few years. The reason for this epidemiological trend is not fully understood, but differences in presentation and prognosis suggest that gastric cancer in the young might represent a different clinical entity. Here, we seek to identify differences in demographic characteristics and outcomes between young adults and older patients admitted for gastric cancer. Methods: Using the National Inpatient Sample (NIS) database, we identified all adult patients admitted primarily for gastric cancer from 2016 to 2019. We analyzed demographic characteristics of young adults (defined as those aged between 20 and 49-years-old) and older patients (aged 50 and above) as well as differences in in-hospital mortality, total hospital charges, and length of stay. Multivariate logistic regression analysis was conducted to adjust for confounders. Results: During the period studied, 77,720 patients were admitted with gastric cancer, of which 9,650 (12.4%) were young adults and 68,115 (87.6%) were old individuals. Young adults were more likely to be female (42.4 vs. 35.6%, p < 0.01). Hispanics comprised 30.9% of admissions for gastric cancer of young adults (vs. 15% in older adults p-value <0.01). Young adults were also over 3 times more likely to be uninsured than older individuals (9.6 vs. 2.6%, p-value <0.01) and more likely to be cared for in urban (98.2 vs. 96.2%, p < 0.01) and teaching (85.4 vs. 80.8%, p < 0.01) hospitals. Young adults had longer lengths of stay and lower hospital charges (see table). No difference was found in mortality, despite a lower comorbidity burden in young adults based on the Charlson Comorbidity Index, possibly due to young adults being candidates for more aggressive therapy and having more aggressive disease. Conclusions: The higher incidence of gastric cancer in Hispanic and uninsured young adults poses a complex public health issue, especially in the context of recent research suggesting more aggressive disease in this population. The reported findings likely reflect both a shift in the U.S. population over the years as well as a rising incidence among Hispanic young adults. It is important to increase awareness of these epidemiological disparities. Further research is needed to determine whether establishing screening programs for gastric cancer in certain populations might be beneficial in the U.S. [Table: see text]
Comparison of survival between de novo stage IV and recurrent stage IV gastric cancer.
Authors: Ji Jun Ho , Lee Danbi , Lee Yong-Pyo , Huh Seok Jae , Go Se-Il , Kim Jung Hoon , Oh Sung Yong , Kang Jung Hun , Kim Kwang Min
Published: January 2023

304

Background: The characteristics and prognosis of de novo metastatic gastric cancer and recurrent metastatic gastric cancer have not yet been elucidated. Here, we compare prognosis and characteristics of patients with de novo versus recurrent gastric cancer. Methods: This retrospective study included 301 advanced pathologically confirmed gastric cancer patients who received palliative chemotherapy between 2012 and 2022. The de novo cohort was included of patients who presented with distant metastasis at diagnosis and recurrent metastatic cohort was composed of patients with metastasis after curative gastrectomy. We analyzed prognostic association by Cox regression and compared survival time of both cohorts using the Kaplan-meire method. Results: A total of 167 de novo and 112 recurrent patients were included. There were no differences noted among the patients with de novo disease and recurrent metastatic disease with respect to age, sex, ECOG, primary cancer location and pathologic features. Patients in the recurrent group versus de novo group were longer duration of chemotherapy (1.16 ± 1.18 years versus 0.85 ± 0.84, P = 0.01) and lower mean body mass index. (20.22 ± 2.78 versus 21.93 ± 3.38, p < 0.001) The median overall survival in the de novo group was 11.6 versus s 14.4 months in the recurrent group. ( P = 0.02) In a multivariate analysis, the age of 70 years or older at the time of stage 4 diagnosis was independently associated with shorter survival. Conclusions: De novo and recurrent metastatic gastric cancer characterize distinguished subpopulations. And advanced gastric cancer with distant recurrence has significantly better survival versus those with de novo cohort. This differences between de novo and recurrent gastric cancer could facilitate discussions about patient selection of clinical trial and help with advanced personalized treatment. [Table: see text]
Real-world outcomes of patients with advanced gastric cancer treated with FOLFIRI.
Authors: Fawaz Ali , Tilley Derek , Karachiwala Hatim
Published: January 2023

307

Background: Doublet chemotherapy regimens such as 5-fluorouracil and irinotecan (FOLFIRI) appear to be viable first-line treatment options in advanced gastric cancer (AGC). A phase III French intergroup study demonstrated a longer time to treatment failure, improved toxicity profile, and no difference in median OS when using FOLFIRI, compared to epirubicin, cisplatin, and capecitabine (ECX). Purpose: To investigate the real-world efficacy of FOLFIRI in AGC. Methods: Patients diagnosed with AGC in Alberta, Canada from 2012-2020 were identified by the Alberta Cancer Registry. Data points that could not be obtained automatically were obtained by retrospective chart review. Survival was compared by Log-Rank analysis or Cox Regression. Factors associated with FOLFIRI use were determined using logistical regression. Results: A total of 285 patients were analyzed. Eighty-four (29%) patients received FOLFIRI as first-line therapy, 69 received ECX (24%), 82 received CX (29%), 31 received EOX (11%), and 19 received FOLFOX (7%). Thirty-six (12.6%) received a subsequent line of therapy, most commonly FOLFIRI (52.8%). Age, sex, topography (cardia v. non-cardia), or morphology (adenocarcinoma v. signet ring cell v. NOS) did not influence the use of FOLFIRI in the first-line setting. Median overall survival with FOLFIRI was 5.8m vs. 7.4m (p = 0.12) when compared to the patients receiving all other regimens. Conclusions: FOLFIRI had comparable efficacy to other first-line regimens in patients with AGC.
A single center survival analysis of patients with colorectal cancer who underwent next generation sequencing.
Authors: Krzywon Lucyna , Lazaris Anthoula , Gomez Andrea , Kalil Jennifer , Zlotnik Oran , Metrakos Peter
Published: January 2023

31

Background: Colorectal cancer (CRC) remains a lethal diagnosis with an overall 5-year survival rate of 5-10% for patients with unresectable metastatic disease. The advent of next generation sequencing allows tailored systemic therapy to specific mutations with the goal of improving patient survival. McGill University Health Center instituted next generation sequencing in 2019. Our study aims to evaluate survival outcomes in patients who underwent NGS testing. Methods: A retrospective collection of data on all patients with CRC who were presented at both lower gastroenterology and hepatobiliary tumor boards from January 2019 through July 2022 ( n= 498). Survival and was compared between patients who were found to have genetic alterations identified using the Illumina Miseo platform. Statistical Analysis was performed with GraphPad Prism. Results: A total of 321 (64%) patients had NGS performed on either their primary tumor or a metastasis. A total of 229 (71%) CRC patients had genetic alterations identified on NGS. The most commonly mutated genes were KRAS (41%), APC (17%), PIK3CA (16%) and BRAF (8%). There was no significant difference in median overall survival between patients who had an identified genetic alteration and patients who did not (p = 0.8). Patients with metastatic disease and synchronous presentation had higher rates of genetic alterations (69% and 70%, respectively). Conclusions: This study provides real world data for a single institution initiating Next generation sequencing in colorectal cancer patients. Next Generation testing is an advantageous tool which can help stratify patients into tailored treatment regiments which will lead to improved patient outcomes.
Impact of malnutrition on postoperative outcomes of patients undergoing gastrectomy for gastric cancer: A nationwide analysis between 2012 and 2017.
Authors: Katiyar Vatsala , Vohra Ishaan , Gopakumar Harishankar , Sharma Vivek R.
Published: January 2023

315

Background: Gastrectomy offers a curative treatment option for non-metastatic gastric cancers (GC). Unfortunately, cancer associated malnutrition is a common and potentially actionable problem in GC patients. In this nationwide study, we analyzed the impact of malnutrition on outcomes of patients undergoing gastrectomy for GC. Methods: The Nationwide inpatient Sample database (NIS) was used to identify patients who underwent gastrectomy for gastric cancer from 2012-2017 using ICD 9 and ICD 10 codes. The population was then divided into patients with or without PEM (Protein energy malnutrition) to compare their outcomes. Univariate and Multivariable logistic and linear regression models were used to analyze mortality and healthcare resource utilization. Results: Of the 6,620 patients identified, 4,607 (69.6%) patients were ≥ 60 years old and 3,972 (60%) were males. Majority were White (49.1%) followed by Asians (20.3%). 2,052 (31%) patients were malnourished. Patients with PEM had higher rates of sepsis [adjusted Odds ratio (aOR) 3.6(2.4-5.4), p =0.000], shock [aOR 2.9(1.9-4.5), p =0.000], acute kidney injury [aOR 2.1(1.5-2.9), P<0.001], ICU admissions [ aOR 1.9(1.3-2.9), p =0.001], and higher post operative mortality [aOR 2.5 (1.5-4.3), p =0.001]. Mean Length of stay was longer in PEM patients as compared to non-PEM patients (16.2 vs 9.4 days). On survival analysis, overall survival (OS) was significantly worse for patients with PEM undergoing gastrectomy [HR adj: 1.14 (p=0.04)]. A comparison of these outcomes has been detailed in the table. Conclusions: In this analysis, we highlight the importance of nutrition for gastric cancer patients undergoing gastrectomy. Ensuring adequate nutritional status prior to surgery can improve patient outcomes and decrease health care costs.[Table: see text]
Optimal interval of surveillance gastroscopy after endoscopic resection for gastric neoplasia: A multicenter cohort study.
Authors: Kim Byung-Wook , Choe Younghee , Kim Tae Ho , Chung Jun-Won , Kim Joon Sung
Published: January 2023

316

Background: Due to the possibility of metachronous recurrence of gastric neoplasia, surveillance gastroscopy is mandatory after endoscopic resection (ER) for gastric neoplasia. However, there is no consensus on the surveillance gastroscopy interval. This study aimed to find an optimal interval of surveillance gastroscopy and to investigate the risk factors for metachronous gastric neoplasia (MGN). Methods: Medical records were reviewed retrospectively in patients who underwent ER for gastric neoplasia in 3 teaching hospitals from June 2012 to July 2022. Patients were divided into 2 groups; annual surveillance vs. biannual surveillance. The incidence of MGN was identified, and the risk factors for MGN were investigated. Results: Among the 1,533 patients, 677 patients were included (annual surveillance 302, biannual surveillance 375). The median follow-up for all patients was 22 (range, 12‒91) months. MGN was observed in 61 patients and metachronous gastric cancer (MGC) in 26 patients, both of which were not significantly different between the annual and biannual surveillance groups (annual vs. biannual: 26/302 vs. 32/273, P=0.989 in MGN; 13/302 vs. 13/373, P=0.582 in MGC). All the lesions were removed by ER successfully. In a multivariate analysis, severe atrophic gastritis on endoscopy was an independent risk factor for MGC (odds ratio 3.8, 95% confidence interval 1.4‒10.1; P=0.008). H. pylori infection was not a significant risk factor in this study. Conclusions: Meticulous observation is necessary for patients with severe atrophic gastritis during follow-up gastroscopy after ER for gastric neoplasia. Annual surveillance gastroscopy might be enough after ER for gastric neoplasia.
Comparison of efficacy and safety of salvage-line nivolumab monotherapy between 240 and 480 mg for advanced esophageal squamous cell carcinoma.
Authors: Murashima Yuko , Yamamoto Shun , Hirose Toshiharu , Kadono Toru , Ikeda Go , Ohara Akihiro , Itoyama Mai , Yokoyama Kazuki , Honma Yoshitaka , Ishiyama Koshiro , Oguma Junya , Daiko Hiroyuki , Kato Ken
Published: January 2023

317

Background: Nivolumab monotherapy was established as the standard second-line treatment of advanced esophageal squamous cell carcinoma (ESCC) based on the results of the ATTRACTION-3 trial. Initially, fixed dosing of 240 mg every two weeks (240) was used according to the results of the ATTRACTION-3 trial in Feb 2020. After that, fixed dosing of 480 mg every four weeks (480) was available in clinical practice according to pharmacokinetic data on advanced melanoma in Sep 2020. However, there were little data on the efficacy and safety of these dosing for advanced ESCC patients. Methods: We retrospectively reviewed data from ESCC patients who received nivolumab monotherapy for second or later-line at our institution. We evaluated progression-free survival (PFS), objective response rate (ORR), and the incidence rate of adverse events (AEs) compared between 240 and 480. Cox proportional regression model, Fisher’s exact tests, and t-tests were used for analysis. Results: We identified 117 patients as the subject of this study. Patients characteristics in 2nd line were as followed (240 vs 480); the median age (range): 68(46-85) vs 68.5(51-84) years old, PS (0/1/2): 34/61/5% vs 54/42/4%, taxane refractory cases: 18.6 vs 53.8%. In 3rd or later line; the median age (range): 63.5(47-85) vs 58(46-80) years old, PS (0/1/2): 28/60/12% vs 14/86/0%, taxane refractory cases: 72 vs 71.4%. The ORR were 11.9 vs 24.0% in 2nd line (p=0.19), and 0 vs 14.3% in 3rd or later line (p=0.22). The median PFS was 1.7 vs 4.1 months in 2nd line (HR = 0.60; [95% CI: 0.35-1.01; p = 0.056]), and 1.4 vs 1.8 months in 3rd or later line (HR = 0.58; [95% CI: 0.23-1.46; p = 0.25]). The all-grade AEs in 58.3 vs 69.7 were observed; rash 16.7 vs 6.1%, diarrhea 9.5 vs 6.1%, adrenal insufficiency 3.6 vs 6.1%, and interstitial pneumonia 3.6 vs 15.2%. There were no treatment-related deaths. Conclusions: In this study, fixed dosing of nivolumab in 240mg and 480mg showed comparable outcomes on efficacy and safety.