tbuckley/cabot-search huggingface dataset:
Investigating racial, gender, and socioeconomic disparities in early-onset versus late-onset colorectal cancer: An analysis using the NIH All of Us database.
Authors: Yong Eun, Rahman Adesoji Olusoji, Noah Osei, Ibrahim Omore, Meena Ahluwalia
Journal: Journal of Clinical Oncology (2024)

e15520 Background: Colorectal cancer (CRC) is a significant public health concern, with disparities based on race, gender, and socioeconomic status increasingly recognized. The incidence of early-onset CRC (EOCRC) is rising, highlighting the need for detailed examination of disparities in EOCRC compared to late-onset CRC (LOCRC). This study utilizes the NIH All of Us database to explore these disparities. Methods: We conducted a cross-sectional analysis of 266,520 participants from the NIH All of Us Registered Tier Dataset v7. CRC cases were identified based on at least two recorded diagnoses in electronic health records. Participants were categorized into EOCRC if diagnosed before age 50 and LOCRC if diagnosed at age 50 or above. We compared demographic and socioeconomic variables, including gender, race/ethnicity, income, education, and smoking status, between the groups, using questionnaire responses. Statistical analyses were performed using R. Results: The average age at diagnosis was 42.1 years for EOCRC patients and 63.7 years for LOCRC patients. The EOCRC group had a higher proportion of females (57.8%) compared to the LOCRC group (49.2%, p = 0.006). Whites constituted the majority in both categories, but Hispanics were significantly more represented in the EOCRC group (21.1%) compared to the LOCRC group (11.1%, p &lt; 0.001). Individuals with a higher income (more than $100,000 per year) were more prevalent in the EOCRC group (29.9%) than in the LOCRC group (17.7%, p &lt; 0.001). There was no significant difference in education levels between the two groups (p = 0.52). A history of smoking 100 or more cigarettes was less common in EOCRC patients (32.8%) than LOCRC patients (48.1%, p &lt; 0.001). Conclusions: This analysis highlights significant disparities in racial and gender representation as well as income level. Despite observed differences between the two groups, Hispanics, females, and higher income alone may not explain the only influencing factors as other cofounders, like insurance level, may have impacted the result. Cigarette exposure was more prevalent in the LOCRC group, which may represent a stronger environmental influence on CRC within this group. These findings highlight the need for further research to understand the underlying causes of these disparities and to develop targeted interventions. By addressing these disparities, we can move towards more equitable outcomes across all populations. [Table: see text]
Trophoblast cell-surface antigen 2 is a biomarker and potential therapeutic target in human colon cancer.
Authors: Qingli Li, Wei He, Xin Cheng, Lina He, Xiaojiao Cheng, Shuiping Tu
Journal: Journal of Clinical Oncology (2024)

e15514 Background: Trophoblast cell-surface antigen 2 (TROP2), a transmembrane glycoprotein in epithelial cells, is implicated in malignant progression, notably in breast cancer therapy. However, the clinicopathologic aspects of TROP2 in colorectal cancer (CRC) are unclear. This study aims to explore the association between TROP2 expression and clinicopathological features in CRC and investigate the inhibitory effects of the anti-TROP2 antibody-SN-38 conjugate (ADC-TROP2) on colon cancer cells. Methods: A retrospective analysis of 1296 CRC patients who underwent colorectomy at Renji Hospital, Shanghai Jiaotong University School of Medicine, was conducted. Immunohistochemistry determined the expressions of TROP2, HER2, and PD-L1 in colon cancer tissues. Statistical analyses, including the chi-square test and Cox proportional hazards model, assessed associations. Sacituzumab Govitecan (ADC-TROP2 drug) cytotoxicity on human cancer cells was determined using the MTT method. Results: TROP2 was predominantly expressed at the cell membrane of cancer tissues, with 50% of cases TROP2-positive. The overexpression of TROP2 (staining extension 2+ or 3+) were found in 356 (27.5%) cases. The clinicopathological features of all 1296 patients based on the TROP2 expression in their cancer cells were summarized in Table 1. Compared to TROP2 negativity expression, the high TROP2 expression was significantly associated with the advantaged tumor stage (III/IV, P = 0.022), high tumor invasion depth (T3/T4, P = 0.002), lymph node metastasis (N1/N2, p = 0.026), HER-2 expression (2+/3+, p = 0.013) ,PD-L1 CPS (CPS≤5,P = 0.007). Sacituzumab Govitecan exhibited stronger inhibition in TROP2-positive human CRC cells in TROP2-negative CRC cells compared to TROP2-negative cells and the control SN-38 agent. Conclusions: TROP2 expression positive in 50% of CRC cases is associated with with advantaged tumor stage, high tumor invasion depth, lymph node metastasis. Sacituzumab Govitecan demonstrates potent targeting of TROP2-positive CRC cells, suggesting TROP2 as a potential biomarker for clinical prognosis and therapeutic targeting in colon cancer. [Table: see text]
Use of artificial intelligence–based digital pathology to predict outcomes for immune checkpoint inhibitor therapy in advanced gastro-esophageal cancer.
Authors: Feyisope Eweje, Zhe Li, Matthew Gopaulchan, Armin Attaranzadeh, Leon Kloker, Yuming Jiang, Maximilian Diehn, Guoxin Li, Ruijiang Li
Journal: Journal of Clinical Oncology (2024)

4013 Background: Accurate prediction of response and survival outcomes with anti-PD-1/PD-L1 immune checkpoint inhibition (ICI) remains a significant challenge in gastro-esophageal cancers. In this study, we use an artificial intelligence (AI)-based single-cell analysis of digitized whole-slide H&amp;E images (WSIs) to predict objective response and survival benefit of ICI in two independent cohorts of gastro-esophageal cancer patients. Methods: WSIs were obtained from 82 ICI-treated advanced gastroesophageal cancer patients (gastric, esophageal, and gastro-esophageal junction adenocarcinoma and squamous cell carcinoma) at Stanford University for discovery, and 189 ICI-treated advanced gastric adenocarcinoma patients at Southern Medical University for external validation. Deep learning models were deployed for automated tumor area detection and segmentation of cell nuclei within WSIs. We developed a fully automated cell annotation approach by leveraging multiplex immunofluorescence and trained a deep learning model to classify nuclei into four cell types from H&amp;E (tumor cells, lymphocytes, neutrophils, and macrophages). A total of 66 features were computed to quantify cell composition and cell-cell interactions within the tumor microenvironment. Treatment outcomes were assessed using progression-free survival (PFS) and best objective response per the Response Evaluation Criteria in Solid Tumors (v1.1), with statistical significance reported at the 95% confidence level. Results: In the training cohort, a spatial feature characterizing lymphocyte and neutrophil interaction had the strongest association with PFS (hazard ratio = 0.44, 95% CI 0.24-0.79, P = 0.0046). In the validation cohort, the spatial biomarker positive population had significantly improved PFS compared to the spatial biomarker negative population (hazard ratio = 0.41, 95% CI 0.27-0.61, P &lt; 0.0001; median time to event: 19 months vs 9 months). For predicting objective response in the validation cohort, a multivariate model combining the spatial features achieved AUROC = 0.81 compared to AUROC = 0.65 for PD-L1 CPS (P = 0.0014), while combining the multivariate model with PD-L1 CPS achieved AUROC = 0.84. Conclusions: A single-cell computational pathology approachidentifies spatial biomarkers with predictive utility for determining ICI treatment outcomes in advanced gastro-esophageal cancer. Further validation of these findings is being pursued in additional cohorts.
Safety and efficacy of IBI389, an anti-CLDN18.2/CD3 bispecific antibody, in patients with advanced pancreatic ductal adenocarcinoma: Preliminary results from a phase 1 study.
Authors: Jihui Hao, Li Zheng, Dai Ruihong, Ying Jieer, Qi Xu, Li-Wei Wang, Yongdong Jin, Ying Zhao, Yueyin Pan, Lulu Liu, Jun Zhang, Yuping Sun, Zuoxing Niu, Jun Yao, Dong Hua, Mingjun Zhang, Dai Guanghai, Yulong Zhang, Hui Zhou, Feng Bi
Journal: Journal of Clinical Oncology (2024)

4011 Background: CLDN18.2 expression has been observed in various solid tumors. In pancreatic ductal adenocarcinoma (PDAC), positive CLDN18.2 expression was reported in nearly 60% patients (pts), indicating its potential as a novel target for anti-tumor therapy. IBI389 is an anti-CLDN18.2/CD3 bispecific antibody that induces immune synapse formations by linking CD3 molecules in T-cell receptor complexes and CLDN18.2 antigens on the membrane of tumor cells. Herein, we report preliminary result from a phase I study to evaluate safety and efficacy of IBI389 in pts with PDAC. Methods: EligibleCLDN18.2-positivepts with locally advanced, refractory or metastaticPDAC who failed or were intolerant to standard treatments were enrolled. IBI389 monotherapy was intravenously administered at 6 dose levels (5-600 µg/kg, Q3W or Q2W) during the 2-stage dose escalation and the dose expansion. In dose levels ≥ 30 µg/kg, the step-up dosing strategy with priming dose of 3 to 10 µg/kg was applied. The primary objective was safety. Secondary objective was efficacy assessed by investigator per RECIST v1.1 including objective response rate (ORR) and disease control rate (DCR). Results: As of January 9, 2024, a total of 64 CLDN18.2-positive PDAC pts were enrolled (males: 64.1%, females:35.9%, median age: 60.0 years, stage IV: 84.4%). All patients received prior therapy with a median of 2 lines (range: 1 to 5). Treatment-related adverse events (TRAEs) occurred in 62 (96.9%) pts including 35 (54.7%) pts had grade ≥3 TRAEs. The most common grade ≥3 TRAEs (≥5%) were gamma-glutamyl transferase increased (20.3%), lymphocyte count decreased (9.4%) and nausea (7.8%). Cytokine release syndrome (CRS) related adverse events occurred in 33 (51.6%) pts with no grade ≥3 CRS occurred. TEAEs leading to dose interruption and treatment discontinuation occurred in 24 (37.5%) and 3 (4.7%) pts. Preliminary efficacy of IBI389 was observed in pts with CLDN18.2 expression ≥10% (immunohistochemistry 2+/3+) at 600 µg/kg. As of January 31, 2024, there were 23 evaluable pts including 7 pts with PR and 9 pts with SD. The ORR was 30.4% (95%CI: 13.2-52.9) and DCR was 69.6% (95%CI: 47.1-86.8). The median duration of response (DoR) and progression-free survival (PFS) was not reached. More updated data on safety and efficacy will be presented at the meeting. Conclusions: IBI389 showed manageable safety profiles in pts with advanced PDAC. Preliminary efficacy was observed, including in pts with relatively low expression of CLDN18.2. Clinical trial information: NCT05164458 .
Racial differences in genomic profiles and clinical outcomes of patients with colorectal carcinoma: A single institution retrospective study.
Authors: Abraham Titus, Alexander Lund, Gaurav Sharma, Daisy E Escobar, Ahmed Abdalla
Journal: Journal of Clinical Oncology (2024)

e15582 Background: In the era of precision oncology, there is an immediate need to study the heterogeneity of molecular biology and clinical outcomes in racially diverse colorectal cancer (CRC) patients. Black patients are known to have poorer outcomes compared to their white counterparts. Understanding differences in patients’ molecular and genomic profiles may help explain these racial disparities. Methods: Demographic and clinical outcome data was abstracted from medical records of colorectal cancer patients who were diagnosed between 2008 and 2021 at The University of South Alabama. Tumor only next generation sequencing (NGS) of DNA (592 or WES) and RNA (WTS) was performed at Caris Life Sciences (Phoenix, AZ). Overall survival (OS) was defined as time from diagnosis to death or last contact. Descriptive analyses were performed using t-test and chi-square test, survival analyses were performed using Kaplan-Meier method and Log rank test (GraphPad Prism version 10.1.1). Results: 66 patients with CRC were included, 73% were white and 27% were black. The median age for white patients was 60.5 years and for black patients was 55.5 years (p = 0.049). In the white population, 52.1% of the patients were male and 47.9% were female. In the black population, 33.3% were male and 66.7% were female. The most common sites of malignancy for white patients were rectum (32.6%) and sigmoid (26.1%), whereas for black patients the most common sites were sigmoid (27.8%) and cecum (22.2%). Overall, the most common mutations were TP53 (68.2%), APC (65.2%), KRAS (47%), SMAD4 (16.7%), and FBXW7 (13.6%). The prevalence rates of TP53 (77.8 vs 64.6%), APC (72.2 vs 62.5%), KRAS (66.7 vs 39.6%), and SMAD4 (27.8 vs 14.6%) trended higher in black patients, with KRAS being statistically significant (p = 0.049). FBXW7 trended higher in white patients (14.6 vs 11.1%). Eleven (23%) white patients had a variant of uncertain significance in the ATM gene, which was not observed in black patients. More white patients had stage IV disease compared to black patients (69% vs 50%). No statistically significant difference in OS was found between races (HR 0.68, 95% CI of 0.35 to 1.3, p = 0.2). However, white patients had a median OS of 1334 days compared to 927 days for black patients. Conclusions: White and black CRC patients have unique molecular tumor profiles that may better explain the differences in survival. Our results warrant larger studies with racially and ethnically diverse patient populations to explore these racial disparities and close the gap in colorectal cancer care.
Final overall survival results from phase 3 SPOTLIGHT study evaluating zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin 18 isoform 2 (CLDN18.2)+, HER2−, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.
Authors: Kohei Shitara, Eric Van Cutsem, Florian Lordick, Peter C. Enzinger, David H. Ilson, Manish A. Shah, Rui-Hua Xu, Sara Lonardi, Kensei Yamaguchi, Yi-Ping Hung, Bozena Kukielka-Budny, Pranob P. Bhattacharya, Maria Matsangou, Ran Li, Diarmuid Martin Moran, Radhika Ranganath, Rupesh Pophale, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2024)

4036 Background: The phase 3 SPOTLIGHT study showed statistically significant improvements in progression-free survival (PFS) and overall survival (OS) with 1L zolbetuximab + modified folinic acid, 5-FU, and oxaliplatin regimen (mFOLFOX6) vs placebo (PBO) + mFOLFOX6 in pts with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma at prespecified interim and later updated analyses. We present the prespecified final OS analysis. Methods: Pts were randomly assigned 1:1 to zolbetuximab IV 800 mg/m 2 (cycle 1, day [D] 1) followed by 600 mg/m 2 (every 3 weeks) + mFOLFOX6 IV (D1, D15, D29) for four 42-day cycles or to PBO + mFOLFOX6; pts without PD continued with zolbetuximab or PBO, + folinic acid and 5-FU at investigator’s discretion, until PD or discontinuation criteria were met. The primary endpoint was PFS per RECIST v1.1 by IRC. OS was a key secondary endpoint; additional secondary endpoints were objective response rate (ORR) and safety. Ad hoc analyses examined PFS and OS in per-protocol set population (PPS; pts adherent to protocol) and time to progression (TTP) by best overall response (BOR). Results: At data cutoff (September 8, 2023), 565 pts were assigned to zolbetuximab arm (n = 283) or PBO arm (n = 282). In zolbetuximab vs PBO arms, median follow-up was 18.04 vs 17.91 mo for PFS and 33.28 vs 31.38 mo for OS, respectively. Efficacy results are summarized in Table. Median PFS and OS were significantly longer in zolbetuximab vs PBO arms. Separation of PFS and OS curves occurred earlier in the PPS population analysis (excluded majority of early withdrawals) compared with the ITT population. ORR was similar between treatment arms in ITT and pts with measurable lesions – despite this, TTP for patients with BOR of CR/PR was numerically longer in zolbetuximab vs PBO arms. Safety and tolerability were maintained with no new findings. Conclusions: Zolbetuximab + mFOLFOX6 continued to demonstrate statistically significant and clinically meaningful improvement in PFS and OS vs PBO + mFOLFOX6, with no new safety signals—supporting zolbetuximab + mFOLFOX6 as a new standard of care option for 1L treatment of pts with CLDN18.2+, HER2–, LA unresectable or mG/GEJ adenocarcinoma. Clinical trial information: NCT03504397 . [Table: see text]
Effect of phosphoproteomic subtyping of gastric cancer on chemotherapy and guidance of targeted cancer therapy.
Authors: Hirokazu Shoji, Hidekazu Hirano, Yosui Nojima, Daigo Gunji, Akina Shinkura, Satoshi Muraoka, Yuichi Abe, Ryohei Narumi, Chioko Nagao, Masahiko Aoki, Kazutaka Obama, Kazufumi Honda, Kenji Mizuguchi, Takeshi Tomonaga, Takaki Yoshikawa, Ken Kato, Narikazu Boku, JUN Adachi
Journal: Journal of Clinical Oncology (2024)

4050 Background: Gastric cancer is the fifth most common malignancy and the fourth leading cause of death from malignant neoplasms worldwide, and advanced unresectable or recurrent advanced gastric cancer (AGC) has a poor prognosis, so further therapeutic development is needed. However, only a few molecular targeted agents are effective for AGC, and precision medicine using genomic profiling has limited scalability due to the low rate of alterations matched to single pharmacotherapy and complex networks of signal transduction activated by multiple oncogenic proteins. Thus, it is imperative to establish a new concept of precision medicine adapt to the dynamic changes in cancer. Methods: We collected endoscopic biopsy specimens from 84 chemo-naïve gastric cancer patients. We also serially collected endoscopic biopsy specimens from 9 AGC patients receiving 2nd line therapy (pre-treatment: 9 patients, post-treatment [2 months later]: 6 patients, and end of treatment: 2 patients). Each specimen was immediately snap frozen in liquid nitrogen within 20 s after collection. Ultra deep proteome and phosphoproteome analysis were performed by multiplex analysis using TMT reagent. Genomic analysis was performed by using a targeted high-multiplex PCR-based NGS panel. Results: Ultrasensitive mass spectrometry-based proteomics using 84 chemo-naïve gastric cancer specimens quantified an average of 21000 phosphorylation sites and clearly divided gastric cancer into subtype 1 (proliferative type, 35%), subtype 2 (EMT type, 15%), and subtype 3. (OxPhos type, 50%). The association between these subtypes with TCGA subtypes was low. Subsequent analysis using serially collected gastric cancer specimens from 9 patients unveiled the dynamic transitions within cancer tissues, along with the concomitant rewiring of the kinome network, ultimately resulting in the acquisition of the EMT subtype throughout the course of treatment. We investigated elaborate intracellular signaling related to EMT in gastric cancer and validate therapeutic approaches targeting AXL in vitro and in vivo. Conclusions: Our proof-of-concept of phosphoproteome analysis of fresh-frozen endoscopic biopsy specimens is capable of not only defining cancer subtyping but also capturing dynamic cancer signaling changes in response to therapy. In particular, serial biopsy analysis can track the cancer evolution which is expected to provide resources for the development of new treatments and biomarkers for AGC adaptively in the future.
A phase 1 study to evaluate the safety and preliminary efficacy of minnelide given alone or in combination with paclitaxel in advanced gastric cancer.
Authors: Sung Hee Lim, Ashok K Saluja, Jung Yong Hong, Seung Tae Kim, Shweta Lavania, Somnath Pandey, Vineet K Gupta, Mohana Velagapudi, Jeeyun Lee
Journal: Journal of Clinical Oncology (2024)

4033 Background: Minnelide is a water-soluble disodium salt variant of triptolide, an HSP70 inhibitor. Studies using pancreatic cancer cell lines and human xenograft transplants demonstrated that Minnelide prevents tumor progression, increases survival, and causes tumor regression. This study aims to evaluate the safety and antitumor activity of Minnelide and its combination with paclitaxel in patients with advanced gastric cancer (AGC). Methods: This open-label, single-center, dose-escalation phase I study recruited adult patients with previously treated advanced gastric cancer. Patients received Minnelide per oral (PO) daily starting with 1.0 mg for 3weeks and 1week rest schedule, escalating to 1.25mg, and 1.5mg. In combination Regimen, patients received Minnelide starting at a dose of 0.25 mg and escalating by 0.25mg to 1.25mg plus paclitaxel 60-80 mg/m 2 intravenously on Day 1, 8, and 15 of each cycle, administered in 4-week cycles. The primary objective was to assess the safety and determine the recommended phase II dose (RP2D). Secondary objectives included preliminary efficacy using RECIST v1.1, and survival analysis. Results: Among Regimen A (n = 11), two patients experienced dose-limiting toxicity (DLTs) (Minnelide 1.5 mg: Grade 3 abdominal pain). No DLTs occurred in combination treatment, Regimen B &amp; C (n=25). The MTD was Minnelide 1.25 mg once daily for 21days Q4 weeks as monotherapy. The most common Grade ≥3 AEs were neutropenia (19.4%) and abdominal pain (11.1%). In Regimen C, 71.5% achieved either a partial response or a stable disease with the median PFS of 4.5 months, and the median OS of 10.7 months. Notably, patients without previous exposure to paclitaxel (n = 4) in the last 2 cohorts of Regimen C, had a confirmed ORR of 50.0%, DCR of 75.0%, the median PFS was 5.3 months (95% CI NE-NE) and the median OS has not reached as some of the patients are still receiving treatment. Conclusions: The combination of Minnelide plus paclitaxel as salvage treatment in AGC patients showed meaningful clinical activity with a manageable safety profile. Based on this Phase I experience a Phase II will be initiated in AGC patients. Clinical trial information: NCT05566834 .