tbuckley/cabot-search huggingface dataset:
A phase II trial of CapeOX plus nivolumab for early relapsed HER2-negative gastric cancer (JACCRO GC-11: FirSTAR trial).
Authors: Hiroyuki Arai, Eisuke Inoue, Masanori Terashima, Eishi Baba, Nobuhisa Matsuhashi, Kei Muro, Toshifumi Yamaguchi, Satoshi Yuki, Wataru Ichikawa, Masashi Fujii, Yu Sunakawa
Journal: Journal of Clinical Oncology (2024)

TPS423 Background: Fluoropyrimidine-based post-operative chemotherapy is one of the standard adjuvant therapies for curatively resected gastric cancer (GC). 1,2 The current standard first-line chemotherapy consists of fluoropyrimidine and oxaliplatin combined with nivolumab in advanced HER2-negative GC patients including cases with a recurrence &gt; 6 months after completion of post-operative chemotherapy, based on the CheckMate 649 and ATTRACTION-4 trials. However, in GC patients with early recurrence during or ≤ 6 months after completion of post-operative 5-FU based chemotherapy, optimal treatments remain to be established. A previous phase II study showed that capecitabine plus cisplatin is an active regimen for early relapsed GC after post-operative S-1 monotherapy. 3 This trial aims to investigate the efficacy of capecitabine plus oxaliplatin (CapeOX) plus nivolumab for patients with early relapsed HER2-negative GC. Methods: This is a multicenter single-arm phase II trial. The main eligibility criteria include: histologically confirmed HER2-negative adenocarcinoma of stomach or esophagogastric junction; radiologically diagnosed recurrence during or ≤ 6 months after post-operative chemotherapy with S-1 or S-1 plus docetaxel conducted for stage II/III GC after curative resection; age ≥ 18 years; ECOG performance status 0-1; having measurable lesions according to RECIST ver. 1.1; and adequate oral intake and organ functions. Enrolled patients will receive 21-day cycles of nivolumab with CapeOX at the following dose until disease progression or unacceptable toxicities: capecitabine, 1000 mg/m 2 twice per day on day 1-14; oxaliplatin, 130 mg/m 2 on day 1; and nivolumab, 360 mg on day 1. The primary endpoint is objective response rate (ORR), and the secondary endpoints include overall survival, progression-free survival, disease control rate, duration of response, and safety. PD-L1 combined positive score will be tested for the association with efficacy. We assume null ORR of 20% and alternative ORR of 32%. With two-sided alpha level of 10% and 80% power, sample size would be calculated as 85. Thus, a total of 92 patients are planned for enrollment within a 2.5-year accrual period. Enrollment opened in March 2023. Clinical trial information: jRCTs031220572. 1. N Engl J Med. 2007;357:1810-20. 2. J Clin Oncol. 2019;37:1296-1304. 3. Gastric Cancer. 2018;21:811-8. Clinical trial information: jRCTs031220572 .
Liquid biopsy-based comprehensive genomic profiling to reveal mutational landscape in real-world patients with gastrointestinal cancer.
Authors: Haoran Tang, Xiaogang Zhang, Feng Xie, Yue Zhang, Shidong Jia
Journal: Journal of Clinical Oncology (2024)

735 Background: Molecular characteristics hold substantial clinical significance in cancer. Previous research has elucidated the molecular classification of gastrointestinal (GI) cancers, leveraging biomarkers like gene alterations, MSI, EBV status, and chromosomal instability. However, most of these studies relied on tissue biopsies. Limited investigations have been documented regarding the characterization of molecular profiles through liquid biopsy. Here we present a comprehensive genomic profiling study conducted on advanced GI cancer patients using blood samples. Methods: This prospective study is a part of a global initiative focused on molecular biomarker screening across various solid tumors. Here we report the early result of 106 unresectable GI cancer patients, encompassing those with advanced disease or experiencing relapse after prior treatments. The cohort comprises 66 colorectal cancer (CRC) patients, 34 gastric cancer (GC) patients, and 6 esophageal cancer (EC) patients. Each patient contributed a 10-mL blood sample for comprehensive circulating tumor DNA (ctDNA) analysis. The study employed PredicineCARE, a 152-gene, NGS-based liquid biopsy assay, to profile somatic gene variations within this patient population. Results: The study revealed a total of 1,597 somatic mutations, with 1,077 occurring in CRC, 448 in GC, and 72 in EC. Additionally, 722 gene copy number variants were identified, with 288 in CRC, 351 in GC, and 83 in EC patients. In CRC, the most frequently altered genes (prevalence &gt; 20%) included TP53 (58%), APC (45%), KRAS (33%), and BRCA2 (22%). Conversely, in GC, the most altered genes were TP53 (59%), TERT (35%), FAT1 (29%), ARID1A (26%), and FGFR4 (24%). Among the 6 EC patients, 3 carried TP53 variations, with variations in APC (N=2), ERCC5 (N=2), FAT1 (N=2), and EGFR (N=1) also observed. The mutation burden in CRC (median 3.73 mut/Mb) and GC (median 3.57 mut/Mb) displayed no significant differences. However, the mutation burden in CRC was significantly higher than that in EC (2.24 mut/Mb) (p=0.04). A similar pattern was observed between GC and EC but did not reach statistical significance (p=0.10) due to limitations in cohort size. Furthermore, the assay identified patients carrying both germline and somatic mutations related to homologous recombination deficiency (HRD). In CRC patients, 5 had MLH1 germline mutations, 6 had MSH2 mutations (5 were germline), 4 had MSH6 germline mutations, 2 had PMS2 somatic mutations, and 1 had an EPCAM germline mutation. While in GC patients, 2 had MLH1 germline mutations, 1 had an MSH6 mutation, and 1 had a PMS2 somatic mutation. Conclusions: This study elucidated the comprehensive mutational landscape of advanced gastrointestinal cancer through liquid biopsy, thereby contributing novel biomarkers for clinical diagnosis and facilitating targeted therapy mechanism investigations.
Validation of a novel web-based application for hepatic arterial infusion floxuridine dosing.
Authors: Carleton Scott Ellis, Snigdha Nutalapati, Jessica Jane Moss, Mautin S. Barry-Hundeyin, Prakash Pandalai, Joseph Kim, Reema Anil Patel, Michael J. Cavnar
Journal: Journal of Clinical Oncology (2024)

15 Background: Hepatic arterial infusion (HAI) floxuridine (FUDR) dosing is a complex, multifactorial process with weight-based dosing dependent on the fold change of aspartate aminotransferase, alkaline phosphatase, and total bilirubin relative to reference values from preceding cycles and compounded over time. Given the complexity of dosing calculations and lack of experience with this treatment in community centers, HAI is typically administered only at tertiary oncology centers with limited access for rural disadvantaged patients. We developed an online tool to automate the dosing of FUDR to broaden safe and effective administration of HAI. Methods: The FUDR dosing algorithm developed at Memorial Sloan Kettering Cancer Center was digitalized as eDoseHAI, a novel multi-layer architecture web application tool featuring JavaScript (front-end), C# RESTful API (back-end) and Azure SQL server (data storage with Splunk data lake event registration). To validate this tool, manual dosing from patients who received ≥1 dose of HAI FUDR at our institution 6/2020-8/2023 was retrospectively compared to app-based dosing. Mismatch between app-based dosing and historical manual dosing was designated as dosing errors, excluding intentional adjustments based on physician discretion. Results: Internal validity was tested by entering records into eDoseHAI from 54 patients who received a total of 370 FUDR cycles (median 6; range 1-19). Ten patients (18.5%) were found to have unintentional dosing errors (e.g., delayed dose reductions) during treatment, impacting 52 cycles (14.1%). The median cycle at first error was 3 (range 2-6), impacting a median of 5 cycles (range 3-12). Dosing errors occurred in only 11.1% of the 45 patients supervised by a senior HAI physician, compared to 55.6% of the 9 patients supervised by three less experienced HAI physicians. Dosing accuracy improved over time; among the 14 patients on active HAI therapy, only 1 had an identified dosing error. eDoseHAI was able to reliably and accurately calculate dosing for all patients. Conclusions: HAI FUDR dosing is nuanced and complex, such that dosing errors occurred even with senior HAI oncologists. eDoseHAI is a web-based application tool designed to improve accuracy and thus safety of HAI dosing. We plan to further validate eDoseHAI using external data from an international HAI consortium, and to conduct a phase II clinical trial in which our team supervises FUDR dosing by community oncologists using eDoseHAI's supervisory mode with a goal to disseminate HAI therapy to disadvantaged rural patients who lack access.
Clinical impact of <i>KRAS</i> mutations in metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Carter Norton, Jarrod Smith, Zach Rubnitz, Grace H. Tan, Christopher Duane Nevala-Plagemann, Heloisa P. Soares, Ignacio Garrido-Laguna, Vaia Florou
Journal: Journal of Clinical Oncology (2024)

619 Background: Mutations in the KRAS oncogene occur in most PDAC and lead to the activation of the KRAS protein. Little is known about the differential impact of KRAS mutations on the outcomes of patients receiving standard of care cytotoxic treatments for metastatic disease. KRAS inhibitors are emerging as promising options for this disease and understanding the impact of distinct KRAS mutations in patient outcomes is needed. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database from 5,369 patients. Adult patients with diagnosis of metastatic PDAC who received at least one line of systemic therapy and had sufficient data available were included in this analysis. Median time to next treatment (TTNT) and overall survival (OS) time were calculated for three common first-line treatments and KRAS mutations. TTNT and OS were calculated for each permutation of treatment and each KRAS mutation. Hazard ratios (HR) were generated for each KRAS mutation and treatment, accounting for potentially confounding variables. Results: Of the 5,369 patients, 2,472 met the inclusion/exclusion criteria. G12C had the shortest median OS (7.5 mo) and G12R had the longest (9.1 mo). Overall, KRAS mutation-positive patients had a median OS of 8.6 mo, compared to 11.7 mo for KRAS Wild Type (WT) patients. A Cox Proportional Hazard analysis of OS across KRAS mutation status found that G12C, G12V, G12D, and Other Non G12/13 KRAS had significantly higher HR than KRAS WT. A comparison of the three common first-line interventions for metastatic PDAC showed that FOLFIRINOX had the longest median TTNT (5.3 mo) and the longest OS (10.2 mo), while Gemcitabine had the shortest TTNT (2.6 mo) and OS (5.9 mo). A Cox Proportional Hazard analysis of OS across all patients found that Gemcitabine and Gemcitabine with Nabpaclitaxel had significantly higher HR than FOLFIRINOX. FOLFIRINOX had the longest TTNT in the G12C, G12V, G12D, G12R, and other non-G12/G13 KRAS groups (see table). Conclusions: Our data suggest that FOLFIRINOX has a longer TTNT than other first-line regimens for KRAS G12C, G12V, G12D, and G12R. KRAS G12C was associated with the shortest OS among common KRAS mutations.[Table: see text]
INTERCEPT Program of circulating tumor DNA (ctDNA) testing for minimal residual disease (MRD) in colorectal cancer (CRC): Results from a prospective clinical cohort.
Authors: Giulia Maddalena, Andrew Jared Pellatt, Madhulika Eluri, Christine Megerdichian Parseghian, Kathryn Aziz, Kristin Alfaro, Robert J. Kell, Alisha Heather Bent, Ryan W Huey, Abhineet Uppal, Tsuyoshi Konishi, Michael J. Overman, Maria Pia Morelli, Jason Willis, John Paul Y.C. Shen, Kanwal Pratap Singh Raghav, Timothy E. Newhook, Van K. Morris, Arvind Dasari, Scott Kopetz
Journal: Journal of Clinical Oncology (2024)

27 Background: Minimal residual disease, defined by ctDNA+ in the absence of macroscopic of disease, represents a new and clinically poorly defined subset of patients (pts). While observational cohorts have been reported on the prognosis of MRD, there is little information on the impact of returning and acting on ctDNA results on the subsequent ability to detect radiographic disease. Here we provide real-world evidence form a large prospective cohort where ctDNA testing was routinely performed and returned to pts and providers, providing opportunities to understand the prognostic performance of ctDNA in practice, including the rate of false negatives defined as radiographic recurrence without detectable ctDNA. Methods: The INTERCEPT program enrolled pts undergoing curative intent surgery for stages II-IV CRC at MD Anderson Cancer Center. A tumor-informed MRD assay (Signatera) was drawn post-operatively and every 3 months as per established reimbursement guidelines. Pts enrolled between Jan-Dec 2022 were included with follow up through Aug, 2023. Post-op timepoint was defined as any test within 6.5 months of surgery to include adjuvant therapy. A false negative result was defined as a negative test but with radiographic detection of recurrence within the subsequent 4 months. Results: A total of 1,140 pts were included, with 44.7% female and 39% with advanced disease. At least one ctDNA+ result was obtained in 338 patients (29.6%). When limited to pts with a post-operative/post-adjuvant timepoint (n= 520) and a median follow up of 10.4m, the 12m DFS was 94.2% for ctDNA-, and 54.3% for pts with at least 1 ctDNA+ test (median DFS of 14.9m); HR 17.67 (95% CI: 10.08 – 30.99), p&lt;0.0001. When segregated by stage, ctDNA remained the most important predictor of outcomes [Table], such that pts with stage IV ctDNA- had better prognosis than pts with stage II ctDNA+ (38.9% vs 87.7% 12mDFS, p=.002). For 15 pts, we detected a false negative ctDNA, representing a rate of 1.3% (15/1140) corresponding to a negative predictive value (NPV) of 98.1%. Conclusions: In this first prospective real-world ctDNA program, MRD testing had a high NPV (98.1%) with very few false negative cases. The prognostic importance of ctDNA was confirmed and exceeded the risk prediction of stage alone, underlying and supporting the importance of introducing the test in practice and the need to investigate interventional studies, as are ongoing in the INTERCEPT program (crcmrd.org). [Table: see text]
Total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC): Real-world experience from a tertiary Asian cancer center.
Authors: Meng Wang, Yong Xiang Gwee, Zhaoting Lin, Wei Peng Yong, Raghav Sundar, Hon Lyn Tan, Joan RE Choo, Ker Kan Tan, Bettina Lieske, Wai Kit Cheong, Teng Hwee Tan, Jeremy Chee Seong Tey, Cheng Ean Chee, Gloria Hui Jia Chan
Journal: Journal of Clinical Oncology (2024)

39 Background: Multiple studies of TNT for LARC have shown improved pathological complete response (pCR) rate and disease-free survival (DFS). However, real-world data in Asia is limited. Methods: Patients (pts) diagnosed with LARC at National University Cancer Institute, Singapore were discussed at a multidisciplinary tumor board. Patients were eligible for TNT if they had cT2/3N+ or cT4Nany, threatened circumferential resection margin (CRM) and adequate organ function. TNT protocol was systemic chemotherapy with 5-6 cycles of mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) or 3-4 cycles of XELOX (capecitabine, oxaliplatin) followed by short- or long-course chemoradiation (CRT), then 3 cycles of mFOLFOX6 or 2 cycles of XELOX. Clinical outcomes included rates of clinical complete response (cCR), pCR, surgery type, R0 resection and DFS. Baseline pt demographics, laboratory results and tumor characteristics were analyzed against these outcomes. Results: 173/205 pts who were diagnosed with rectal cancer between February 2020 and November 2022 had LARC and 47 received TNT. Median age was 65 (range: 33-79), 68.1% male, 78.7% were Chinese, 19.2% had cT4 tumors, 87.2% node positive and 80.9% had CRM involvement. Median tumor distance from anal verge was 6cm (range: 1-15cm) on colonoscopy and 5cm (range: 2-12cm) on magnetic resonance imaging. 95.7% received XELOX, 87.0% had long-course CRT and 83.0% completed all cycles of systemic chemotherapy and CRT. 44.7% had dose reduction of systemic therapy and 4.3% required emergent surgery due to local complications during TNT. After TNT completion, 7 pts did not pursue surgery – 3 achieved cCR (6.4%) and adopted a watch-and-wait approach, 2 had disease progression (PD), and 2 declined. Of those who underwent surgery, 75.0% had sphincter-preserving surgery and 85.0% achieved R0 resection. 2.1% (n =1) achieved pCR. Rates of tumour regression grade (TRG) 0, 1, 2, 3 were 7.5%, 15.0%, 67.5% and 10.0%, respectively. After a median follow up of 21.7 months (range: 9.3 – 41.6 months), 21.3% (n = 10) had disease recurrence and 14.9% (n=7; 5 from PD, 1 from surgery-related complication, 1 unrelated to treatment) passed away. 1-year DFS rate was 88.7% (95% CI 75.0% - 95.2%). Conclusions: This is the first Asian study reporting real-world data of TNT for LARC since its wide-scale adoption. pCR rates appear lower than reported studies. Understanding the limitation of retrospective studies, further analysis is ongoing to determine if factors other than sequence of modality can contribute to the observed findings.
Clinicopathological features and clinical outcomes in individuals with Krukenberg tumors of colorectal origin.
Authors: Colin P Bergstrom, Cindy Wang, Daniel King, Albert Y. Lin, George A. Fisher
Journal: Journal of Clinical Oncology (2024)

191 Background: Krukenberg tumors (KT) are metastases to the ovary generally originating from a gastrointestinal primary such as colorectal carcinoma. The prognosis is poor with KT, and clinicopathological features associated with clinical outcomes have not been extensively studied. The study aimed to investigate the associations of clinicopathological features with outcomes in patients with KT of colorectal carcinoma (CRC) origin. Methods: This retrospective study utilized medical records and patient registries to identify 160 patients with a confirmed histopathological diagnosis of KT at Stanford University Medical Center between 2000 and 2020. Data collection included demographics, historical, clinicopathological, treatment and outcome variables. The primary tumor type was (N, %): CRC (101, 63.1%); gastric (24, 15%), breast (13, 8.1%); small bowel (10, 6.2%), other (12, 7.5%). Statistical analysis was performed using Chi-squared, Mann-Whitney U, and log-rank Kaplan-Meier analysis. Results: Analysis of the CRC cohort subdivided by location of the primary, N: 45 vs. 56, right colon (R) vs. left colon (L) revealed no significant difference in median age at diagnosis of KT, race/ethnicity, oligometastatic disease, histopathological differentiation or ovarian tumor volume. Patients with R vs L sided CRC primaries had a higher proportion of synchronous presentation at the time of KT diagnosis (75.6% vs 41.1%, R vs L, p&lt;0.001). Time to progression was not different, but overall survival (OS) was shorter in R CRC (767 vs. 1246 days, R vs. L, p &lt;0.01). By Kaplan-Meier analysis, patients with R CRC had a shorter OS (log-rank p=0.016). In the subgroup with unilateral KT, R sided CRC primaries involved the R ovary (85%) whereas L-sided CRC primaries involved the L ovary (70%) ( χ2, p&lt;0.002). Patient with bilateral (B) versus unilateral (U) had a larger ovarian tumor volume (2,073cm 3 vs. 307 cm 3 , p&lt;0.01) but no difference in oligometastatic disease, chronicity, time to progression or overall survival. There was no statistical difference (p=0.93) between the association of bilateral KT inter-ovarian tumor size and CRC Laterality within individual patients. Conclusions: In this study, KT tumors predominantly originate from CRC. The clinical features of R versus L CRC, such as chronicity and OS are conveyed prognostically in patients with KT. Individuals with L CRC exhibited a better overall prognosis compared to those with R CRC. In patients with unilateral KT metastasis to ipsilateral ovary is significantly associated with location of CRC and is suggestive of a retrograde lymphatic or transcoelomic route of metastatic spread. Further studies are needed to confirm these findings and to elucidate ovarian organ tropism mediators that facilitate development and growth in metastatic ovarian cancer.
Use of micronuclei DNA from erythrocytes in early-stage colorectal cancer detection.
Authors: Xingyun Yao, Haobo Sun, Jie Pan, Yurong Jiao, Xiangxing Kong, Chengcheng Liu, Fangchao Zhu, Fei Meng, Honghao Liang, Yanfei Cao, Jun Li, Xiaofei Gao
Journal: Journal of Clinical Oncology (2024)

25 Background: Current development in stool- and cell-free DNA (cfDNA)-based technologies have demonstrated promising potentials in colorectal cancer (CRC) diagnosis. However, early detection of CRC and advanced adenoma (AA) remains challenging. Micronuclei (MN) are extranuclear bodies containing chromatin segments resulting from errors in DNA repair. Elevated levels of MN+ erythrocytes have been studied in genotoxicity testing and cancer diagnosis. We have developed a method (WO2021/228246 A1) for purifying and sequencing micronuclei DNA (mnDNA) in erythrocytes from peripheral blood. Here, we compared mnDNA between healthy donors (HDs) and CRC patients and explored its application for early cancer diagnosis. Methods: Peripheral blood (1ml) was obtained from a training cohort of 987 individuals, a validation cohort of 246, and an independent test cohort of 193. mnDNA was isolated and sequenced from erythrocytes. Genome-wide analysis identified distinctive mnDNA features between HD and CRC. Predictive models using these features were developed to differentiate CRC and AA from HDs. A clinical trial comparing mnDNA with an approved multitarget stool DNA test (sDNA-FIT) was also conducted on 60 individuals (42 HDs, 6 AAs, and 12 CRCs). Results: Genome-wide analysis of mnDNA revealed substantial differences in distribution patterns between HDs and CRC patients. The predictive model built on mnDNA features achieved an AUC of 92.98% (95%CI: 87.85-98.12%), with an 88.64% sensitivity and 92.75% specificity in the independent test cohort. The model identified early-stage (stage I-II) CRC and AA with sensitivities of 83.33% or 69.56%, respectively. Comparing mnDNA to sDNA-FIT showed superior overall sensitivity (83.33% vs. 61.11%), AA sensitivity (83.33% vs. 16.66%), with comparable specificity (85.71% vs. 88.10%). Conclusions: Our results demonstrate that mnDNA from a small amount of peripheral blood enable accurate detection of AA and early-stage CRC. As a type of cytoplasmic DNA, mnDNA can provide a valuable tool for early cancer detection, offering different underlying mechanisms compared to current methods. A larger clinical study (NCT05875584) is ongoing and will further validate the application of mnDNA in early cancer detection.