tbuckley/cabot-search huggingface dataset:
Comprehensive analysis of differentially methylated regions in colorectal cancer (CRC).
Authors: Omid Solari, Tudor Constantin, Yuqian Jiang, Wengching Chan, Ilker Tunc, Preethi Srinivasan, Misagh Kordi, Marianne Santaguida, Breeana L. Mitchell, Alexey Aleshin, Ryan Swenerton, Joshua Babiarz, Trupti Kawli, Johannes G. Reiter
Journal: Journal of Clinical Oncology (2024)

73 Background: Epigenetic alterations have been shown to govern many disease states, including cancer. A key epigenetic mark is the DNA methylation of CpGs. Large studies, like The Cancer Genome Atlas, have shown that DNA methylation can differentiate between cancer status and type. Here, differentially methylated genomic patterns were defined between patients with CRC and healthy individuals by utilizing patterns of co-methylation of adjacent CpG loci. Methods: Deep, whole genome bisulfite sequencing (WGBS) was conducted on DNA samples from 100 healthy individuals (median effective coverage of 352x±38x) and from 75 patients with CRC (median effective coverage of 48x±18x). The two cohorts were chosen to be balanced in terms of age (CRC: 58±11 years; healthy: 57±8 years) and to represent major ethnicities in the USA, and the CRC cohort was chosen to represent all stages, histologies and morphologies, and microsatellite instability (MSI, 23%). A novel machine learning model was developed to discover differentially methylated regions between the healthy and CRC cohorts as well as between subpopulations within the CRC cohort, including age, sex, stage, histology, and MSI vs microsatellite stability (MSS). Results: In total, we discovered 132,911 differentially methylated regions between healthy and CRC cohorts, spanning more than 1.14 million CpGs. 76% of all discovered regions were hypermethylated (70% CpG islands, 1.3% CpG shelves, 21% CpG shores) and the rest were hypomethylated (7.3% CpG islands, 8.6% CpG shelves, 25% CpG shores). We also discovered 220 hypermethylated regions that were differentially methylated between CRC MSI samples and CRC MSS samples and healthy cfDNA samples. Furthermore, we discovered subtype-specific differentially methylated regions, such as 62 hyper-methylated regions that were differentially methylated between mucinous adenocarcinoma samples and the rest of the cohort. Conclusions: Based on deep WGBS data from heterogeneous cohorts, representative of the US population eligible for CRC screening, we identified many differentially methylated regions as strong biomarker candidates for the early detection of cancer. Compared to recurrently mutated driver genes in CRC, we find that differential methylation profiles of CRC samples are generally much more homogenous and are therefore ideal biomarkers for targeted sequencing panels with the purpose of early cancer detection. Further, analysis of these patterns based on clinicopathologic factors enabled discovery of subtype specific markers, which can be incorporated to ensure equivalent performance for underrepresented subtypes or subpopulations.
The interim analysis of a single-arm, open-label, phase II study investigating ALLEN regimen (durvalumab plus albumin paclitaxel and lenvatinib) in patients with unresectable biliary tract cancers (BTCs).
Authors: Zhifang Li, Meixia Chen, Qianyi Ming, Yan Zhang, Kaichao Feng, Qian Mei, Yang Liu, Weidong Han
Journal: Journal of Clinical Oncology (2024)

504 Background: BTCs are a heterogeneous group of malignancies with a poor prognosis. Despite the improved outcome achieved by the addition of the anti-PD-L1 antibody durvalumab to standard chemotherapy, the benefits were modest and cannot satisfy the clinical demands adequately. This study aimed to evaluate the efficacy and safety of the combination therapy of Albumin paclitaxel, Durvalumab and Lenvatinib (ALLEN regimen) in unresectable BTCs. Methods: This single-arm, single-center, open-label, phase I/Ⅱ study enrolled patients with locally advanced or metastatic BTCs. Eligible patients with ECOG score 0-2 were treated with ALLEN regimen. Durvalumab (1000mg IV, q3w) in combination with albumin paclitaxel (180-220 mg/m 2 IV q3w) and lenvatinib (8mg PO QD) were given regularly until disease progression. The primary endpoint was objective response rate (ORR) evaluated by investigators according to RECIST 1.1. The secondary endpoints were disease control rate (DCR), progression-free survival (PFS) and treatment-related adverse events (TRAEs). Results: From September 2021 to September 2023, fourteen patients were enrolled including three patients who were failed to prior anti-PD-1 antibody treatment. The median follow-up was 6.8 months (95% CI 1.9, 10.9). The median age of the patients was 59.0 years, and male patients accounted for 35.7%. The ORR and DCR were 35.7% and 100%, respectively. The median PFS was 7.3 months (95% CI 4.9, 8.2). TRAEs of any grade occurred in 13 (92.9%) patients without grade 3 or higher. The most common TRAEs were alopecia (13/14, 92.9%), peripheral sensory neuropathy (10/14, 71.4%), decreased appetite and nausea (9/14, 64.3%), hypertension (6/14, 42.9%), rash (5/14, 35.7%), diarrhoea (4/14, 28.6%), and asthenia (4/14, 28.6%). Conclusions: The ALLEN regimen demonstrated encouraging anti-tumor activity with a tolerable safety profile in unresectable BTCs. The preliminary results were promising, which deserved further investigation in a larger population. Clinical trial information: NCT05327582 .
Efficacy of biomarker-matched therapy in clinical trials for advanced gastrointestinal cancers: A pooled analysis of SCRUM-Japan studies.
Authors: Tadayoshi Hashimoto, Takao Fujisawa, Nozomu Machida, Akitaka Makiyama, Shogen Boku, Shigenori Kadowaki, Naoki Takahashi, Eiji Oki, Chigusa Morizane, Yu Sunakawa, Yoshito Komatsu, Naohiro Okano, Taito Esaki, Takashi Ohta, Takeshi Kato, Hiroshi Ozaki, Naoko Iida, Yoshiaki Nakamura, Hideaki Bando, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2024)

753 Background: We conduct the SCRUM-Japan MONSTAR-SCREEN, a nationwide molecular profiling project to facilitate the enrollment of patients with advanced solid tumors into matched clinical trials based on identified biomarkers. Here, we investigated clinical outcomes of patients with gastrointestinal cancers in this project. Methods: The SCRUM-Japan GI-SCREEN was launched for gastrointestinal cancers in 2015, followed by GOZILA, MONSTAR-SCREEN-1, and MONSTAR-SCREEN-2 for advanced solid tumors. The used profiling assay for genomic alterations was Oncomine Comprehensive Assay for tumor tissue in GI-SCREEN, Guardant360 for plasma in GOZILA, FoundationOne CDx for tissue and FoundationOne Liquid CDx for plasma in MONSTAR-SCREEN-1, and CARIS MI Profile for tissue in MONSTAR-SCREEN-2. Patients were treated in clinical trials or practice based on identified biomarkers. We analyzed data from patients with gastrointestinal cancers in this project. Results: Of 11,408 patients enrolled in our project as of May 22, 2023, 555 (5.0%) were enrolled in matched clinical trials based on identified biomarkers. The major cancer types that had matched clinical trials included colorectal (63.2%), biliary tract (12.4%), gastric (n=9.2%), esophageal (n=6.5%), and pancreatic cancer (n=4.7%). The objective response rate (ORR), median progression-free survival, and median overall survival (OS) for patients in matched trials were 27.8% (95% CI, 24.0% to 31.9%), 3.0 months (95% CI, 2.8 to 3.7 months), and 14.4 months (95% CI, 13.0 to 16.1). The major treatment lines in which investigational drugs were administered were third (24.6%) and fourth (16.0%) line. Evaluating by each drug target given to at least 20 patients, therapies targeting HER2 had the highest ORR of 46%, followed by PD-1/PD-L1 (33%), BRAF (30%), and MEK (28%). Antibody-drug conjugates demonstrated the highest ORR with 48.8%, followed by monoclonal antibodies at 37.7% and small molecule inhibitors at 23.0%. Overall, patients who received matched therapy in clinical trials or practice had significantly longer OS than those who did not (hazard ratio, 0.76; 95% CI 0.69 to 0.84; P &lt;0.01). Conclusions: Our nationwide molecular profiling project has facilitated the enrollment of patients with advanced gastrointestinal cancers in clinical trials. Furthermore, it demonstrated a survival benefit by providing patients matching targeted therapy.
Lifestyle factors, viral hepatitis, and hepatocellular carcinoma in Uganda.
Authors: Redeat Assefa, Jim Aizire, Sara Nsibirwa, Ponsiano Ocama, Gregory Kirk
Journal: Journal of Clinical Oncology (2024)

571 Background: The effect of lifestyle factors, namely alcohol use, cigarette smoking, and other forms of tobacco use on hepatocellular carcinoma (HCC) remains unclear. We assessed the independent associations of lifestyle factors with HCC among individuals with and without viral hepatitis. Methods: In a hospital-based case-control study recruiting from Mulago and Lacor hospitals in Uganda from March 2015 to August 2021, HCC cases were confirmed by clinical and ultrasound criteria, with biochemical and pathology confirmation on a subset. Controls were frequency matched by age and sex and from the same hospitals. Demographic, clinical and lifestyle data were collected using standardized instruments. Alcohol content of local drinks was standardized, and intensity categorized as light, moderate, or heavy based on CDC definitions. We analyzed alcohol (use status (current, former, never), duration (years), frequency (drinks/week)), cigarette smoking (status (current, former, never), cumulative (pack‐years), duration (years), intensity (cigarettes/day), and time since cessation), other tobacco use (tobacco chewing and pipe-smoking), and viral hepatitis (HBV surface antigen (HBsAg) and HCV antibody (HCVAb)). We used logistic regression models (Stata 18.0) to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CIs) controlling for age, sex, family history of HCC, socioeconomic status, and Schistosomiasis (urine Circulating Cathodic Antigen (CCA)). Stratified analyses were performed separately by HBV and HCV status. Results: Among 596 HCC cases and 1,277 controls, the median age (IQR) was 43 (32-56) and 45 (31-54) years, 410 (68.8%) and 832 (65.0%) were males, 460 (24.6%) and 442 (23.7%) current or former alcohol users, 96 (5.1%) and 251 (13.4%) current or former cigarette smokers, and 177 (9.45%) and other tobacco users, respectively. Other tobacco users were more likely to be heavy (⩾10 pack-years) cigarette smokers (aOR=5.10; 95% CI: 2.41-10.79), heavy (&gt;14 drinks/week for males and &gt;7 drinks/week for females) alcohol drinkers (aOR=5.25; 95% CI: 2.84-9.68), farmers (aOR=1.61; 95% CI: 1.01-2.57) and lower socioeconomic status (aOR=3.23; 95% CI: 1.76-5.94). HCC risk was associated with HBV (aOR=18.66; 95% CI: 12.96-27.88), HCV (aOR= 4.03; 95% CI:2.31-7.02), and other tobacco use (aOR=1.86; 95%CI: 1.13-3.08). The observed HCC risk with other tobacco use, and the null associations with heavy alcohol use (aOR= 0.89; 95% CI: 0.60-1.31) and heavy cigarette smoking (aOR=0.74, 95% CI:0.34-1.60), were homogenous by HCV status (positive versus negative), and similarly by HBV status. Conclusions: Viral hepatitis (HBV and HCV), and lifestyle factors (tobacco chewing and pipe-smoking) were strongly associated with HCC. Further research should explore the role of tobacco chewing and pipe-smoking in HCC risk in Uganda and similar settings in Sub-Saharan Africa.
Phase 1 trial of navitoclax and sorafenib in patients with refractory solid tumors with a hepatocellular carcinoma expansion cohort.
Authors: Oluwadunni Eunice Emiloju, Jun Yin, Emily Koubek, Joel M. Reid, Mitesh Borad, Yanyan Lou, Mahesh Seetharam, Martin Joseph Edelman, Yixing Jiang, Ahmed Omar Kaseb, James Posey, S. Lindsey Davis, Gregory J Gores, Lewis R. Roberts, Naoko Takebe, Andrea Elisabeth Wahner Hendrickson, Scott H. Kaufmann, Joleen Hubbard, Brian Addis Costello
Journal: Journal of Clinical Oncology (2024)

507 Background: Navitoclax (ABT-263) is an oral Bcl-2 homology-3 mimetic that binds with high affinity to pro-survival Bcl-2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor inhibits tumor angiogenesis and also promotes apoptosis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. Methods: In this phase 1 pharmacokinetic and pharmacodynamic study (NCT01364051), we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). The study agents were provided by the Cancer Therapy Evaluation Program at National Cancer Institute under CRADA. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. The maximum tolerated dose (MTD) was determined using the continual reassessment method. Results: Ten patients were enrolled in the dose escalation cohort and 15 patients with HCC were enrolled in the expansion cohort. Two dose levels were tested, dose level 1 (navitoclax 150 mg daily plus sorafenib 400 mg twice daily) and dose level 2 (navitoclax 200 mg daily plus sorafenib 400 mg twice daily). At dose level 1, one dose limiting toxicity (DLT) [grade 3 aspartate aminotransferase elevation] was observed among 6 patients treated at this dose level. In a cohort of 3 patients treated at dose level 2, two DLTs were observed (grade 3 hypertension, and grade 3 rash), hence dose level 1 was identified as the MTD. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities (Table). Patients received a median of 2 cycles (range 1-36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, 5 had progressive disease and 4 with unavailable data. There were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Conclusions: Navitoclax plus sorafenib resulted in manageable, but not ideal toxicities for continuous oral administration which precluded dose escalation. The lack of clinical benefit in the HCC expansion cohort does not support further development of this combination for the treatment of advanced HCC. Clinical trial information: NCT01364051 . [Table: see text]
Impact of baseline liver function on survival outcomes in patients with unresectable hepatocellular carcinoma (uHCC) treated with camrelizumab + rivoceranib vs sorafenib: A post hoc analysis of study CARES-310.
Authors: Arndt Vogel, Ann-Lii Cheng, Wei Shi, Seong Jang, Laura Alexander, Xianzhang Meng, Natalia Raphael, Stephen Lam Chan
Journal: Journal of Clinical Oncology (2024)

509 Background: CARES-310 study (NCT03764293) evaluated the combination of camrelizumab, an anti-PD-1 inhibitor, and rivoceranib, a highly selective VEGFR-2 tyrosine kinase inhibitor, (cam + rivo) vs sorafenib (sora) for the treatment of uHCC. Cam + rivo significantly improved median overall survival ([mOS] 22.1 months [mo] vs 15.1 mo) and median progression-free survival ([mPFS] 5.6 mo vs 3.7 mo) compared to sora. This post-hoc analysis evaluated the impact of baseline albumin-bilirubin (ALBI) grade and Child-Pugh (CP) class on survival outcomes. Methods: In this randomized, open-label, international, multicenter, phase 3 study, patients were randomized 1:1 to receive cam 200 mg IV Q2W + rivo 250 mg PO QD (n=272) or sora 400 mg PO BID (n=271). Median overall survival (mOS), median progression free survival (mPFS), objective response rate (ORR), disease control rate (DCR), and safety were assessed by baseline ALBI grade and CP class. Results: mOS, mPFS, DCR, and ORR improved with cam + rivo vs sora regardless of baseline liver function (Table). Although treatment-related grade 3/4 AEs occurred at a greater rate in the cam + rivo arm vs the sora arm, the rate of these events was similar for patients with baseline ALBI grade 1 and grade 2 (cam + rivo, 82.1% and 81.7% vs sora, 53.9% and 54.0%, respectively). Median time-to-deterioration (mTTD) to CP class B was similar between treatment arms for ALBI grade 1 (not evaluable [NE], NE) and grade 2 (cam + rivo, 10.1 mo; sora, 10.6 mo; HR, 0.99). Conclusions: In this post-hoc analysis of Study CARES-310, the efficacy of cam + rivo was superior to sora regardless of baseline liver function as measured by both ALBI grade and CP class. Despite a higher rate of grade 3/4 AEs, there was no detrimental effect of cam +rivo on liver function in patients with both well- and moderately- preserved liver function compared to sora. These results support cam + rivo as a potential new first-line treatment option for patients with uHCC regardless of baseline liver function. Clinical trial information: NCT03764293 . [Table: see text]
Gender disparities in the National Institutes of Health funding for gastrointestinal oncology.
Authors: Sara Khan, Aruba Sohail, Janta Ukrani, Ibrahim Zahid, Faraz Eshaghi, Kainat Khan, Shaival Thakore, Michael Vishal Jaglal, Muhammad Zain Farooq
Journal: Journal of Clinical Oncology (2024)

763 Background: Traditionally, there has been an under-representation of women in academic fields, thus making them less likely to receive grants. This study examines the trend of funding allocation of R01 grants in Gastrointestinal oncology by the National Institutes of Health with specific focus on the distribution of funding between gender. Methods: The data were retrieved from the NIH RePORTER (Research Portfolio Online Reporting Tools Expenditure) using gastrointestinal oncology-related search terms from 2018-2021. The gender was categorized using Genderize. The number of citations, publications, H-index, and seniority were obtained from Scopus and Web of Science in December 2022. Consumer Price Index was used to adjust funding amount to 2021 equivalent U.S. dollars. Linear regression was used for analysis. Results: A total of 1426 NIH-funded R01 grants amounting to 626.6 million were awarded for gastrointestinal oncology research. Women (n=391; 27.4% [95% CI: 25.1%-29.7%]) received fewer grants than men (n=1035; 72.6% [95% CI: 70.3%-74.9%]). From 2018-2021, there was no significant difference in the number of grants awarded among both men (263 to 259, p=0.65) and women (90 to 105, p=0.12). Similarly, there was no significant change in the grant amount (in millions) awarded among men (114.7 to 111.2, p=0.86) and women (39.8 to 47.9, p=0.19). Colorectal cancer accounted for the greatest proportion of grants (n=528; 37.0% [95% CI: 34.5%-39.5%]), amounting to 235.9 million. Of the 481 co-PIs, 405 (84.2% [95% CI: 80.9%-87.5%]) were men and 76 (15.8% [95% CI: 12.5%-19.1%]) were women. Male PIs as compared to female PIs had a higher h-index (52 vs 40, p&lt;0.001), a higher number of publications (160 vs 111, p&lt;0.001), and were cited more (13324 vs 6371, p&lt;0.001). Funding amount was significantly associated with gender (β=0.06, p=0.02), number of publications (β=0.17, p&lt;0.01) and institution (p&lt;0.01). Conclusions: Our analysis shows continued gender disparity as only 27% of total R01 grants towards gastrointestinal oncology were granted to females during the fiscal years of 2018-2021. Thus, a collaborative effort is needed to close the divide and advance gender equality. [Table: see text]
Racial/ethnic disparities in the effectiveness of atezolizumab plus bevacizumab (A+B) vs. tyrosine kinase inhibitors (TKIs) among veterans with unresectable hepatocellular carcinoma (uHCC).
Authors: David Edward Kaplan, Amie Tan, Cheryl Xiang, Fan Mu, Sairy Hernandez, Sarika Ogale, Manasvi Sundar, Yilu Lin, Lizheng Shi, Amit G. Singal
Journal: Journal of Clinical Oncology (2024)

448 Background: The etiology of liver disease and HCC often differs by race and ethnicity, which may lead to potential differential effectiveness of immunotherapy (IO) by race/ethnicity. However, clinical trials for HCC have historically had limited racial diversity. Emerging data has characterized the real-world effectiveness of A+B, the standard of care for first-line (1L) uHCC. This study assessed whether there is racial/ethnic difference in the effectiveness of A+B compared to TKIs, including sorafenib (S) or lenvatinib (L). Methods: A population-based retrospective analysis was conducted using data from the Veterans Health Administration (VHA) Data Warehouse. Non-Hispanic White, African American (AA), and Hispanic patients diagnosed with uHCC between 2017 and 2022 who initiated 1L A+B (on or after 2020), S, or L were selected. Kaplan-Meier analyses and multivariable Cox regression analysis with race/ethnicity as a treatment modifier (adjusting for age, region, extrahepatic metastases, etiology, presence of cirrhosis, comorbidity index, prior local therapies, Child-Pugh [CP] class, and Albumin-Bilirubin [ABLI] grades) were conducted to investigate the racial/ethnic differences in the effectiveness of A+B vs S or L. Results: Of 1,738 patients, 1,140 were White (20% A+B, 56% S, 24% L), 437 were AA (25% A+B, 50% S, 25% L), and 161 were Hispanic (22% A+B, 57% S, 21% L). Compared to Whites, a significantly higher proportion of AAs had underlying hepatitis C (87% vs 56%, p&lt;0.05). There was a trend towards a lower proportion of CP B and C and less ascites in AAs compared to Whites. Table shows median OS (mOS) by race and regimen, along with hazard ratios (HRs) from the multivariate analysis. The survival benefit associated with A+B compared with S or L was numerically greater in AA patients versus White patients, although the difference did not achieve statistical significance. Conclusions: In this real-world cohort of 1L uHCC patients, A+B demonstrated a significant survival advantage over TKIs across racial/ethnic groups. Understanding the factors contributing to the effectiveness of A+B across racial/ethnic groups could provide valuable insights for guiding future trials and initiatives aimed at addressing racial disparities in HCC. [Table: see text]