tbuckley/cabot-search huggingface dataset:
Identification of dMMR in metastatic colorectal and non-colorectal cancers in a private Mexican institution.
Authors: Georgina Filio, Rita Dorantes-Heredia, Daniel Motola, Mariam Escamilla-López, Eduardo Tellez-Bernal, Emilio Conde-Flores, Daniel Escalera, Emilio Medina-Ceballos, Paulina Jimenez-Aguilar, Jose Manuel Ruiz-Morales, Elena Dorokhova, Lucia Flores
Journal: Journal of Clinical Oncology (2024)

177 Background: DNA mismatch repair is a process in which normal cells maintain their original genomic information avoiding errors in mismatched nucleotides or base modifications from recombination processes. The failure of this process could drive carcinogenesis due to increased mutation rate as well as high microsatellite instability. It is estimated that the global average prevalence of dMMR/MSI-H across tumor types and stages is approximately 16%, with higher rates reported for early stages. However, the prevalence for colorectal (CRC) and non-colorectal cancers for this biomarker in Mexico has not been reported. Objective:To explore the prevalence of dMMR in metastatic CRC (mCRC) and non-CRC (gastric, esophageal, and endometrial cancer) from a private Mexican institution. Methods: In this retrospective study, the dMMR status of 215 samples were analyzed from a primary database of stored biopsies from patients diagnosed with metastatic CRC, gastric, esophageal, or endometrial cancers between January 2017 and December 2020. 65 records had information about MMR status. Samples were analyzed using a commercial kit to detect dMMR (BioSb). Prevalence of dMMR was stratified by age and gender and expressed as frequencies. Statistical analysis was conducted in SPSS. Results: dMMR was found in 18.5% (N=27) endometrial cancer cases, 12.7% (N=150) of CRC cases, and 8.3% (N=24) of gastric cancer cases. However, it was not detected in any cases of esophageal cancer (N=14). In CRC, we found a higher percentage of incidence in men than in women, 15.6% (n = 14/90) vs. 8.3% (n = 5/60) respectively. By age groups, the highest total percentage (20%) was observed among those 41-50 years old. The age group with the lowest dMMR rate was 31- 40 yo, with 7.7%. All cases of CRC patients over 91 yo (n=3), were pMMR. Conclusions: Even though this data is not representative for the entire Mexican population, it provides preliminary prevalence dMMR estimates for some key cancers. Additional research is needed to give the limited sample sizes available for non-CRC.
Correlation of exploration of immune profile and genomic with microsatellite stable/tumor mutational burden-low colorectal cancer.
Authors: Hassan Mohammed Abushukair, Azhar Saeed, Ibrahim Halil Sahin, Anwaar Saeed
Journal: Journal of Clinical Oncology (2024)

213 Background: Microsatellite stable/tumor mutational burden-low (MSS/TMB-L) tumors, represent the majority of colorectal cancer (CRC) patients and derive limited benefit from immune checkpoint inhibitors (ICI). Given the vast heterogeneity of this population, some patients may be candidates for ICI. Herein, we study the tumor immune microenvironment (TIME) and genomic correlates associated with favorable immune response in MSS/ TMB-L CRC patients. Methods: Using The Cancer Genomic Atlas Colorectal Adenocarcinoma (TCGA-COAD) cohort (n = 594), MSS patients (MSI Mantis score &lt; 0.4) with TMB-L (&lt;10 mutations/megabase) were identified. The CIBERSORT algorithm was used to calculate the fraction of 22 immune cells using RNA-seq data. Relevant immune expression signatures from the CRI iAtlas were used to assess TIME profiles. An antitumor immune activity (AIA) score was constructed using CD8+ T cells, T regulatory cells, and M1 &amp; M2 macrophage fractions. Enriched mutations in MSS/ TMB-L patients with favorable antitumor immune scores were identified and used to stratify patients into favorable and unfavorable immune profiles (FIP &amp; UIP). Comparisons were made using the Mann-Whitney U T-test and Fisher’s exact test. Results: We identified 430 (72.4%) MSS/TMB-L patients among the TCGA-COAD cohort. The AIA score ranged from – 0.44 to 0.62 (higher scores denote favorable AIA activity). The majority of patients (77%) had scores &lt; 0. Top enriched mutated genes associated with higher scores included HMX2, BBS12, IFNLR1, SLC30A2, WDR48, ZNF329, H4C11, PARD3B, ENAM, ASCC1, CCDC88B, CMKLR1, IL21, KLHL11, and OTOP2. Patients harboring a mutation in one or more of these 15 genes were categorized in the FIP group (n=50, 11.6%) and patients with no mutations were categorized in the UIP group (n=360, 88.4%). The FIP group had significantly (p &lt; 0.05) higher levels of TMB, CD8+ T cells, activated NK cells, M1 macrophages, immunogenic SNV mutations, and cytotoxic activity while patients with UIP had higher levels (p &lt; 0.05) of M2 macrophages, neutrophils, and a trend for higher regulatory T cells and TH17 cells. Gene set enrichment analysis showed upregulation of T cell proliferation, interferon signaling, and Fanconi anemia pathway in FIP. Compared to UIP, FIP patients had a trend for better disease-specific survival after adjustment for CC subtype (colon vs. rectum) and age (HR: 0.26, 95% CI: 0.06-1.09, p = 0.066). Conclusions: Findings from this analysis highlight a subset of MSS/TMB-L CRC patients, with features of favorable anti-tumor immune response and unique mutation profile, that might derive benefit from immunotherapy. Further investigation is underway to further explore the genomic correlates in this subset of patients.
Clinical outcomes of early gastric cancer resected by endoscopic submucosal dissection at young age.
Authors: Jong-Jae Park, Moon Kyung Joo, Jun Hee Kim, Chan Mi Kwon, Ji Min Kang, Min Hyung Kang, Si Eun Lee, Sunsuk Kim, Won Shik Kim, Seung Han Kim, Beom Jae Lee, Hoon Jai Chun
Journal: Journal of Clinical Oncology (2024)

314 Background: A small portion of patients are diagnosed as early gastric cancer (EGC) and undergo endoscopic submucosal dissection (ESD) at young age, however, their clinical outcomes are rarely known. We investigated clinical characteristics and outcomes of patients who underwent ESD for treatment of EGC at age under 50. Methods: We enrolled patients who were diagnosed as EGC and underwent ESD during 2006 and 2020. We divided them either for young age (YA) group if age ≤ 50 years and other age (OA) group if &gt; 50 years. Results: We enrolled 1,349 patients (YA group: 105 patients [7.8%], OA group: 1244 [92.2%]). Compared with OA group, YA group contained more female patients (36.2 vs. 26.5%, P= 0.033), their tumor was located at middle third (41.0 vs. 29.6%, P= 0.006) and was depressed (40.0 vs. 28.8%, P= 0.001), and had more undifferentiated (30.5 vs. 12.1%, P&lt; 0.001) and diffuse type (22.9 vs. 7.3%, P&lt; 0.001) histology. However, synchronous tumor was less frequent in YA group (2.9 vs. 12.4%, P= 0.001). When we sorted 884 patients who achieved curative resection and were followed-up longer than 12 months, Kaplan-Meier analysis showed that metachronous neoplasm (dysplasia or cancer) and metachronous cancer were significantly less in YA group than OA group ( P= 0.003 and 0.013, respectively), however, local recurrence was not significantly different between two groups. Conclusions: ESD is a favorable and effective therapeutic modality for EGC patients who are aged under 50, once curative resection is achieved.
Moving towards a personalised understanding of the nutritional impact of self-expanding metallic stents (SEMS) in gastro-oesophageal cancer: A retrospective case note review of a tertiary referral oncology centre.
Authors: Aimee Cunningham, Taibah Alattal, Lindsey Foulkes, Alexandra R Lewis, Alison Catherine Backen, Fiona Williamson, Esther McQueenie, Vikki Owen-Holt, Kate Williams, Richard Hubner, Tom Waddell, Sara Valpione, Hans-Ulrich Laasch, Wasat Mansoor, Jamie Weaver
Journal: Journal of Clinical Oncology (2024)

301 Background: Dysphagia is a common life-impacting complication for patients with gastro-oesophageal (O-G) cancer. Options to alleviate dysphagia include insertion of SEMS or percutaneous endoscopic gastrostomy (PEG). SEMS improve quality of life by enabling a person to eat a varied diet, but are associated with complications including pain and need for reintervention. Although studies have shown SEMS improve dysphagia, consequent longitudinal impact on nutritional status has not been evaluated. There is a need to better characterise risks and benefits of SEMS to allow a personalised approach to both insertion and follow-up. Methods: We identified patients with a confirmed diagnosis of O-G cancer, who underwent SEMS insertion at The Christie NHS Foundation Trust in 2021 and 2022. Data was retrospectively collected about patient and stent characteristics, and patient outcomes to quantify benefits and risks of SEMS. Results: 112 patients had 127 SEMS inserted at The Christie. Patients’ International Dysphagia Diet Standardisation Initiative (IDDSI) score significantly improved after SEMS insertion (N=120); prior to SEMS 62% were only managing liquids and purees (IDDSI 3 and 4) and 24% were not able to eat enterally. Post SEMS, 76% tolerated textured foods (IDDSI 5 and above) and only 21.5% were limited to liquids/purees. We observed a significant reduction in the rate of weight loss (% body weight/10 days) following SEMS insertion (-0.010 ± 0.009 vs. -0.001 ± 0.010, P &lt; 0.001). 12% of patients experienced grade 3 SEMS-related toxicity or stent failure within 30 days, and 20% developed significant pain within 24 hours of SEMS insertion. Conclusions: SEMS provide meaningful nutritional benefit in the majority of patients with O-G cancer, as weight loss is significantly slowed following insertion. However, we identified two groups of patients who did not benefit from SEMS; those who continued to lose weight and those who had stent failure. We did not find predictive factors for stent failure from multivariate analysis of baseline demographics or stent characteristics. Therefore, more detailed analysis of tumour factors, imaging findings and SEMS location from a larger cohort of patients may be required to identify patients who are unlikely to benefit from SEMS, and alternative interventions such as PEG feeding could be considered.
Comprehensive clinico-molecular profile and efficacy of anti-HER2 therapy for <i>HER2</i>-amplified biliary tract cancer.
Authors: Kanae Inoue, Yoshiaki Nakamura, Bennett Caughey, Binbin Zheng-Lin, Makoto Ueno, Masayuki Furukawa, Yasuyuki Kawamoto, Shinji Itoh, Kumiko Umemoto, Kentaro Sudo, Taroh Satoh, Nobumasa Mizuno, Takeshi Kajiwara, Takao Fujisawa, Hideaki Bando, Takayuki Yoshino, John H Strickler, Tanios S. Bekaii-Saab, Chigusa Morizane, Masafumi Ikeda
Journal: Journal of Clinical Oncology (2024)

544 Background: Biliary tract cancer (BTC) is an aggressive malignancy with poor prognosis and limited treatment options. The prevalence of HER2 amplification in BTC has been reported to be 5-20%, and clinical trials suggested the clinical benefit of HER2-targeted treatment in this disease subpopulation. In a global collaboration, we investigated the comprehensive clinico-molecular characterization as well as the efficacy of anti-HER2 therapy in HER2-amplified BTC. Methods: Patients with advanced BTC who received systemic therapy were included from the GOZILA and MONSTAR studies in Japan and from the COLOMATE trial in the US. Genomic alterations were detected by tissue next-generation sequencing (NGS), including FoundationOne CDx and TempuslxT, and plasma circulating tumor DNA NGS including Guardant360 and FoundationOne Liquid CDx. The clinico-molecular characteristics were evaluated in an exploratory cohort comprised of patients from Japan, whereas the efficacy of anti-HER2 therapy was assessed in a biomarker selected cohort with patients from both Japan and the US. Results: Of 439 patients included in the exploratory cohort, 43 (10%) had HER2 amplification. BTC with primary tumor location in the gallbladder accounted for 58% of primary sites of patients with HER2 amplification. TP53 mutation (84% vs 61%, p=0.003) and BRAF amplification (9% vs 2%, p=0.030) were significantly more frequent in patients with HER2 amplification compared to those without, and no KRAS mutation co-occurred with HER2 amplification. There was no significant difference in overall survival (OS) between patients with and without HER2 amplification (17.7 months [M] vs 16.9 M, hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.65-1.40, p=0.799). Of 58 patients with HER2-amplified BTC included in the biomarker selected cohort (43 Japan, 15 US), 27 (47%) received anti-HER2 therapy. The median OS of patients treated with anti-HER2 therapy was significantly longer than that of patients who did not receive anti-HER2 therapy (24.3 M vs. 12.1 M, HR 0.43, 95% CI 0.23-0.82, p=0.011). Multivariate analysis also identified anti-HER2 therapy as an independent prognostic factor for OS (HR 0.42, 95% CI 0.20-0.85, p=0.015). Conclusions: HER2 amplifications were found in 10% of advanced BTC and did not represent an independent predictive factor for OS. Of clinical significance, patients with HER2-amplified BTC derive a significant benefit from anti-HER2 therapy.
Genomic and immune landscape of biliary tract cancers with <i>ARID1A</i>, <i>PBRM1</i>, and <i>BAP1</i> alterations.
Authors: Gentry Teng King, Rachel Berg, Binyam Yilma, Melissa Conrad Stoppler, Ronan Wenhan Hsieh, Rachael A Safyan, David Bing Zhen, Andrew L. Coveler, Stacey A. Cohen, Veena Shankaran, E. Gabriela Chiorean, William Proctor Harris
Journal: Journal of Clinical Oncology (2024)

557 Background: Alterations in ARID1A, PBRM1 and BAP1 subunits of the SWI/SNF complex are common in biliary tract cancers (BTCs) and have been implicated in tumor microenvironment (TME) immunomodulation. However, there is heterogeneity in outcomes, with PBRM1 and BAP1 conferring improved survival vs worse survival with ARID1A. We explored relationships between ARID1A, PBRM1 and BAP1 alterations with putative immunotherapy biomarkers and genomic co-alterations. Methods: We examined BTC patients in the Tempus database with ARID1A, PBRM1 and BAP1 alterations. Co-alterations were identified through next-generation sequencing (NGS) using the Tempus xT assay, a targeted, tumor-normal-matched DNA panel that detects SNVs, indels, and CNVs in 648 genes, as well as chromosomal rearrangements in 22 genes with high sensitivity and specificity. Samples additionally underwent whole transcriptome RNA-seq via the Tempus xR assay (Tempus Labs, Chicago, IL). Immune biomarkers explored include MSI-H, PD-L1, Tumor Mutation Burden (TMB), and immune cell infiltration by RNA sequencing. Parameters were analyzed between two groups: BTC with ARID1A, vs BTC with PBRM1 and/or BAP1 alterations. Results: 696 BTC patients with ARID1A, PBRM1 and BAP1 alterations were included. Overall, there was low frequency of MSI-H (3.2%), PD-L1-positivity (5.7%) and TMB &gt;10 mt/Mb (4.7%). Among the two groups, there was a higher proportion of MSI-H patients in ARID1A BTC vs PBRM1 and/or BAP1 BTC (4.9% vs 1.4%, p=0.01). Macrophages were the predominant immune cell (46%), followed by CD4+ T-cells (23%) and NK cells (12%). CD8+ T cells were the least encountered (5%). B-Cells were seen more in ARID1A vs PBRM1 and/or BAP1 (9% vs 6%, p &lt;0.001) while macrophages were more frequent in PBRM1 and/or BAP1 vs ARID1A (49% vs 44%, P &lt;0.001). Co-alterations in SMAD4, TP53, ARID2 and KRAS were more frequent in ARID1A BTC while IDH2 and NRAS were more common in PBRM1 and/or BAP1. Within the PBRM1 subgroup, TP53 was most frequently encountered (33%), while CDKN2A alterations were most frequently encountered in BAP1 BTC (35%) (Table 1). Conclusions: This is the largest known data set exploring the genomic and immune landscape of BTC with ARID1A, PBRM1 and BAP1 alterations. Macrophages were the dominant immune cell TME and may be a target of interest. Co-alteration profile is distinct between ARID1A- vs PBRM1- and/or BAP1-altered BTC.[Table: see text]
A phase II trial of TAS-102 in patients with colorectal cancer with ctDNA-defined minimal residual disease post-adjuvant therapy: Results from the MD Anderson INTERCEPT Program.
Authors: Andrew Jared Pellatt, Alisha Heather Bent, Christine Megerdichian Parseghian, Benny Johnson, Ryan W Huey, Kanwal Pratap Singh Raghav, Van K. Morris, Michael J. Overman, Maria Pia Morelli, Jason Willis, Phat Le, John Paul Y.C. Shen, Michael Sangmin Lee, Kristin Alfaro, Kathryn Aziz, Robert J. Kell, Ryan Sun, Scott Kopetz, Arvind Dasari
Journal: Journal of Clinical Oncology (2024)

136 Background: Circulating tumor DNA (ctDNA) has emerged as a novel marker with high specificity and positive predictive value for identifying radiographically occult microscopic or minimal residual disease (MRD) in colorectal cancer (CRC) patients (pts). An additional widely acknowledged unmet need is the development of therapeutic strategies to eradicate MRD and increase the cure rate of the disease. Ongoing trials are evaluating MRD as a biomarker for determining the intensity of post-operative adjuvant therapy. However, the feasibility and efficacy of therapy in pts who are MRD+ during surveillance (after all curative intent treatments including adjuvant chemotherapy) is unknown. Methods: In this proof-of-concept phase II study, pts with stages II-IV CRC noted to be MRD+ during surveillance (ctDNA+ but no radiographic evidence of disease on imaging in last 30 days) received 6 months (m) of TAS-102. Pts were identified through the MD Anderson INTERCEPT program that integrates MRD testing with a tissue informed assay (Signatera) into standard of care for CRC pts. The primary endpoint was 6-m ctDNA clearance and secondary objectives included 3-m ctDNA clearance, and disease-free survival (DFS). Assuming H0 = 5% spontaneous, HA = 30% ctDNA clearance with TAS 102 &amp; 1-sided α = 0.05, 15 patients are required for β = 85%. Results: Between 7/22/22 and 9/7/23,15 pts with MRD were enrolled. Baseline characteristics included a median age of 62 years (range: 37-73), Caucasian (77%), male (77%), resected Stage IV (92%) and median ctDNA level of 1.55 MTM/ml (range 0.04-28.72). At data cutoff, 11 pts had 3-m ctDNA levels and 10 had a decrease in their ctDNA level (91%) including 5 with undetectable levels (45%). At 6-m, 60% of patients had ctDNA levels at or below prior levels; three maintained undetectable ctDNA at 6-m: of those, two pts had subsequent radiographic progression following therapy completion. Median DFS was 9.4-m in the full cohort. Conclusions: We demonstrate the feasibility of identifying and enrolling MRD+ pts through screening during surveillance onto therapeutic trials and show the ability of an experimental therapy to convert patients to MRD negative status, a necessary but not sufficient step for disease eradication. Preliminary results suggest that treatment with TAS-102 is effective in inducing ctDNA clearance in the short term in most pts, but with no evidence of persistent clearance. Updated results including 6-m ctDNA levels and survival data will be presented. Clinical trial information: NCT05343013 .
Applying the fragility index to randomized controlled trials evaluating total neoadjuvant therapy for rectal cancer.
Authors: Tyler McKechnie, Kelly Brennan, Cagla Eskicioglu, Ameer Farooq, Sunil Patel
Journal: Journal of Clinical Oncology (2024)

32 Background: A relatively novel summary measure that is not commonly reported in randomized controlled trials (RCTs) is the fragility index (FI). FI describes the number of additional events required for an outcome to lose statistical significance. It has been applied to a number of medical subspecialities such as critical care, orthopedic surgery and colorectal surgery. Recently, there has been significant interest in, and adoption of, total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC). A number of RCTs have assessed TNT, but the robustness of these practice changing RCTs has never been evaluated. As such, we designed the present study to assess the robustness of the RCTs evaluating TNT for LARC using the FI. Methods: Relevant articles were identified through a recently published review article by Johnson et al. in the Canadian Journal of Surgery, that narratively reviewed all of the previously published RCTs evaluating TNT for LARC. We manually searched Google Scholar and PubMed to identify any other relevant RCTs. Outcomes within these RCTs that were either dichotomous outcomes or time to event outcomes were eligible for inclusion if the reported effect size had an associated p-value of less than 0.05. The main outcome was the FI for each statistically significant outcome. Walsh et al.’s method of calculating FI was utilized. A RCTs results were considered fragile if the FI was less than the loss to follow up for a given outcome. Correlations between FI and research characteristics were assessed using the Spearman’s rank correlation coefficients. Results: Ten RCTs were identified with 25 outcomes having statistically significant differences between groups (p-values &lt; 0.05). Eleven outcomes were time-to-event outcomes, while the remainder were dichotomous outcomes. About half (n=13) were oncologic outcomes (i.e., survival, recurrence), while the rest (n=12) were short- and long-term complications. The median FI was 2 (interquartile range [IQR] 1-16). The number of patients lost to follow-up exceeded the FI in 17 outcomes (68.0%) and thus these results were considered “fragile”. Lower FI was associated with high risk of bias (rho=-0.5594) and higher loss to follow-up (i.e., greater than 5% vs. less than 5%) (rho=-0.4394), while higher FI was associated with large sample size (i.e., greater than 500 patients vs. less than 500 patients) (rho=0.5120). Conclusions: The robustness of outcomes from trials assessing TNT for LARC was found to be questionable. Most of these outcomes were fragile, as determined by the FI. In most cases, two or less additional events would have resulted in a loss of statistical significance of the reported results. Those using the results of these studies, including clinicians and health policy experts, should apply caution when interpreting these types of trials.