tbuckley/cabot-search huggingface dataset:
Refining first-line treatment decision in RAS wildtype (RAS-WT) metastatic colorectal cancer (mCRC) by combining clinical biomarkers: Results of the randomized phase 3 trial FIRE-3 (AIO KRK0306).
Authors: Julian Walter Holch, Alexander Ohnmacht, Sebastian Stintzing, Kathrin Heinrich, Benedikt Westphalen, Lena Weiss, Ludwig von Weikersthal, Thomas Decker, Alexander Kiani, Florian Kaiser, Tobias Heintges, Christoph Kahl, Frank Kullmann, Werner Scheithauer, Hartmut Link, Heinz-Gert Hoeffkes, Markus H. Moehler, Dominik Paul Modest, Michael Menden, Volker Heinemann
Journal: Journal of Clinical Oncology (2024)

13 Background: Optimal patient selection for first-line treatment targeting epithelial growth factor receptor (EGFR) in RAS-WT mCRC is based on primary tumor sidedness (PTS) with anti-EGFR being the preferred option for patients with left-sided mCRC (LC). Right-sided mCRCs (RC) are preferentially treated in combination with bevacizumab targeting vascular endothelial growth factor (VEGF). Here, improvement in patient selection was evaluated by combining clinical biomarkers beyond PTS using the randomized phase III trial FIRE-3. Methods: FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in patients with RAS-WT mCRC. Besides PTS, further clinical biomarkers were evaluated in pairwise combinations using Cox regression models and model-based recursive partitioning with Weibull models to predict treatment benefit of either treatment arm regarding overall survival (OS): age, sex, liver-limited disease status (LLD) and baseline carcinoembryonic antigen serum level (CEA). The resulting P-values of second-order interactions were adjusted using Holm-Bonferroni correction. The model with the best test statistics and P-value was chosen for further evaluations. Results: In 400 patients with RAS-WT mCRC, a model combining PTS and LLD status best predicted treatment outcome of either treatment arm (c-index = 0.603, p=0.005). Here, a significant survival benefit of FOLFIRI/Cet over FOLFIRI/Bev was evident in patients with LC/non-LLD (HR 0.62, p=0.02) compared to LC/LLD (HR 0.83, p=0.40). In patients with RC, FOLFIRI/Bev was significantly associated with increased OS compared to FOLFIRI/Cet when patients suffered from non-LLD (HR 2.09, p=0.010). However, patients with RC/LLD rather had a benefit from FOLFIRI/Cet compared to FOLFIRI/Bev (HR 0.59, p=0.218). Conclusions: Combining clinical biomarkers PTS and LLD status might improve optimal patient selection for targeted first-line treatment in RAS-WT mCRC. Validation in further data sets is warranted. Clinical trial information: NCT00433927 .
A randomized phase II/III study to evaluate the safety and efficacy of disitamab vedotin (DV) plus toripalimab and chemotherapy/trastuzumab as first-line treatment for HER2-expressed, locally advanced, or metastatic gastric cancer.
Authors: Lin Shen, Guoliang Ding, Dan Feng, Jianmin Fang
Journal: Journal of Clinical Oncology (2024)

TPS427 Background: For HER2-positive (IHC 2+/FISH-, IHC 3+) advanced gastric cancer/gastroesophageal junction cancer (GC/GEJ), trastuzumab in combination with chemotherapy is the standard first-line treatment. Adding pembrolizumab to trastuzumab and chemotherapy significantly improves objective response rate. However, the overall survival results did not meet statistical significance. DV, a novel humanized anti-HER2 antibody conjugated with monomethyl auristatin E (MMAE) via a cleavable linker. We aimed to evaluate DV combined with toripalimab and chemotherapy/ trastuzumab as first-line treatment for HER2-expressed (IHC 1+, 2+ or 3+) locally advanced or metastatic GC/GEJ. Methods: This is a randomized, seamless phase II/III trial. Key eligibility criteria include participants confirmed GC/GEJ and systemic treatment naïve. In phase II period, participants will be divided into two cohorts. Ninety participants with HER2-positive (IHC2+ FISH+ or IHC3+) will be randomly (1:1:1) assigned to receive DV every 2 weeks (Q2W) plus toripalimab Q2W and oxaliplatin and capecitabine (CAPOX) every 3 weeks (Q3W), or DV plus toripalimab and trastuzumab Q3W, versus toripalimab plus trastuzumab and CAPOX. Forty participants with HER2-low (IHC1+ or IHC2+/FISH-) will be randomly (1:1) assigned to receive DV plus toripalimab and CAPOX, versus toripalimab and CAPOX. In phase III period, HER2-positive participants will be randomly (1:1) assigned to receive DV plus toripalimab and CAPOX or trastuzumab versus CAPOX plus trastuzumab±anti-PD-1 antibody, based on results from phase II, and evolution of treatment landscape. HER2-low participants will be randomly (1:1) assigned to receive DV plus toripalimab and CAPOX versus CAPOX±anti-PD-1 antibody based on evolution of stand of care. The primary endpoint is PFS by IRC in PD-L1 CPS ≥5 population. To the best of our knowledge, this is the first Phase III clinical trial exploring the combination of anti-HER2 ADC with trastuzumab and chemotherapy in first-line GC/GEJ. This trial began in August 2023 and has enrolled 4 patients at the time of submission. Clinical trial information: NCT05980481 .
Amplified Sciences PanCyst Pro Panel to accurately identify non-mucinous pancreatic cyst fluid.
Authors: Mini Thomas, Daniel Sheik, Kaleb Byers, U. Chinna Rajesh, Curtis Ramsey, V. Jo Davisson
Journal: Journal of Clinical Oncology (2024)

617 Background: Pancreatic cysts are rarely symptomatic, and, consequently, are detected incidentally during routine imaging analyses for unrelated disorders. Guidelines for diagnosis of pancreatic cysts rely on imaging and supportive analyses of fluid extracted during endoscopic ultrasound with fine-needle aspiration (EUS-FNA). Unfortunately, currently available protein markers and assays are not sufficiently accurate to rule-out patients in whom a non-mucinous pancreatic cyst has formed. Since non-mucinous pancreatic cysts seldom progress to cancer, this patient population is at risk of being subjected to the severe physical, emotional, and financial burdens associated with unwarranted surveillance, testing, and possible surgical intervention. Furthermore, identification of mucinous pancreatic cysts does not establish the risk of progression to cancer (rule-in) or the need for surgical intervention. Methods: To address the unmet needs in pancreatic cyst diagnosis, Amplified Sciences has combined a panel of markers with a clinically translated surface enhanced Raman spectroscopy (SERS)-based protease activity assay as a rule-out diagnostic tool. The tri-analyte panel was tested on a cohort of 185 retrospective samples gathered from three separate institutions (UPMC, IU Health, and UCSF) and consumed only 12 µL of cyst fluid per sample. The goals of this study were to establish the negative predictive value (NPV) of this panel prior to translation to a CLIA-regulated laboratory and create a preliminary algorithm for analysis. Results: The results of this statistically powered study show that protease activity outperforms carcinoembryonic antigen (CEA), a current standard diagnostic marker for pancreatic cyst fluid, in sensitivity, specificity, and NPV. Furthermore, in combination, the tri-analyte panel identifies non-mucinous pancreatic cysts with 99% sensitivity and a negative predictive value &gt;95%. Conclusions: These results support the use of this panel in clinical settings as a diagnostic tool to rule-out patients from surgical intervention, as well as the use of SERS as an optical detection mode for clinical diagnostics. Future work will continue to address the unmet need for improved diagnostic information through multiplexed analyses of markers that consume comparatively minimal volume of pancreatic cyst fluid samples. Studies will also seek to build on the SERS platform by introducing more dyes, substrates, assays, and analytical methods. Amplified Sciences would like to acknowledge significant efforts to build the clinical samples cohort from Gina Zhu, Kelli Ifuku, and Dr. Kimberly Kirkwood from USCF, Christine Decapite and Dr. Randall Brand from UPMC, and Michele Yip-Schneider and Dr. C. Max Schmidt from IU Health.
Patterns of presentation and delivery of care of appendiceal neoplasms in the largest municipal health care delivery system in the United States.
Authors: Armaan Ahmed, Jennifer Whittington, Zahra Shafaee
Journal: Journal of Clinical Oncology (2024)

14 Background: Appendiceal neoplasms (AN) are rare tumors with a broad spectrum of referral and treatment patterns. NYC Health+Hospital (HHC) is the largest municipal health care system in the United States. Here, we study patterns of presentation and management of AN in this safety-net setting. Methods: We identified 92 patients in HHC with AN between 01/01/2017 to 07/01/2023. Statistical analyses were performed in Python. Results: There were 38 (41.3%) mucinous neoplasms, 24 (26.1%) adenocarcinomas, 23 (25.0%) neuroendocrine, and 7 (7.6%) ex-goblet cell adenocarcinomas. 16 cases of pseudomyxoma peritonei were identified. The median age at diagnosis was 55 (IQR: 45-65). 49% were Hispanic, and African Americans were the largest racial block (28%). 50% of cases presented as appendicitis. Appendectomy and a second surgical intervention were more common in this group (p&lt;0.001 and p=0.044, respectively). Other surgical interventions included colon resections and cytoreduction ± Hyperthermic intraperitoneal chemotherapy. Among the patients with mucinous neoplasm or adenocarcinoma, 35 had multidisciplinary tumor board discussion (15 mucinous neoplasm and 20 adenocarcinomas). The median follow-up period was 22.0 months (95% CI: 11.5-30.7 months). Surveillance modalities included CT (75%), CEA (74%), and colonoscopy (35%). 85% remained within HHC during treatment. 16 patients were planned to have chemotherapy, including 9 pseudomyxoma peritonei cases. 5 patients did not follow through, and the other cases had a median of 10 cycles. The following adjuvant chemotherapy regimens were employed: 50% FOLFOX, 20% FOLFIRI, 20% XELODA, and 10% CapeOX and FOLFIRI. There were 2 cancer-related deaths (pseudomyxomas). Excluding pseudomyxomas, none had evidence of disease at the last follow-up. Conclusions: Minorities and immigrants constitute the majority of the population of HHC. 50% of AN presented as appendicitis emphasizing the need for a robust system to identify these cases. Despite challenges encountered in providing long-term oncological care, HHC has treated and provided vigorous follow-up for this underserved population. [Table: see text]
Health-related quality of life (HRQoL) in patients with metastatic colorectal cancer (mCRC) treated with sotorasib and panitumumab (pmab) versus trifluridine/tipiracil (T/T) or regorafenib (rego) in CodeBreaK 300.
Authors: Dominik Paul Modest, Marwan Fakih, Lisa Salvatore, Taito Esaki, David Paez Lopez-Bravo, Julien Taieb, Michalis Karamouzis, Erika Ruiz-Garcia, Tae Won Kim, Yasutoshi Kuboki, Fausto Meriggi, David Cunningham, Kun-Huei Yeh, Chiara Cremolini, Qui Tran, Emily Chan, Joseph Chao, Istvan Matyas Majer, Filippo Pietrantonio
Journal: Journal of Clinical Oncology (2024)

10 Background: CodeBreaK 300 (NCT05198934) is a phase 3, multicenter, randomized, open-label study, evaluating sotorasib 960 mg (soto960) + pmab, sotorasib 240 mg (soto240) + pmab against investigator’s choice T/T or rego in patients with chemorefractory KRAS G12C-mutated mCRC. The study met its primary endpoint and demonstrated statistically significant improvement in progression-free survival with both doses of sotorasib. This analysis evaluated patient-reported outcomes (PROs) as secondary and exploratory endpoints in CodeBreaK 300. Methods: Change in PRO scores from study baseline through week 8 was compared for soto960+pmab and soto240+pmab vs the control group using a mixed effect model for repeated measures. PRO instruments included the Brief Fatigue Inventory, the Brief Pain Inventory, and the European Organisation for Research and Treatment of Cancer Core 30-item Quality of Life questionnaire. Time to deterioration (TTD) were assessed using Kaplan-Meier plots and Cox proportional hazard models. All analyses were conducted on patients with baseline and at least one post-baseline PRO score. Results: 160 pts were randomized 1:1:1 to soto960+pmab (n=53), soto240+pmab (n=53), or T/T or rego (n=54). Compliance rates for PRO assessments were high (&gt;83%) and similar across the three treatment groups. Least square (LS) mean changes from baseline in fatigue at its worst, pain at its worst, physical functioning (PF), and global health status (GHS)/QoL favored the two sotorasib dose groups (Table). The 95% confidence intervals (CI) suggested improvement in pain at its worst and PF for both sotorasib dose groups, and improvement in GHS/QoL for the soto960+pmab group versus the control group. TTD hazard ratios &lt; 1 indicated a trend in delayed deterioration for patients treated in both sotorasib dose groups. The 95% CIsuggested delays with respect to fatigue at its worst and PF for the soto240+pmab group. Conclusions: In CodeBreaK 300, both doses of sotorasib resulted in better HRQoL and a trend to decreased risk of deterioration vs the control group. In addition to improved clinical outcomes, these findings provide further evidence on the benefit of soto+pmab in patients with chemorefractory mCRC. Clinical trial information: NCT05198934 . [Table: see text]
A novel early cancer detection approach for pancreatic cancer.
Authors: Maarten F. Bijlsma, Patrick Christian Strasser, Maximilian Christoph Schneider, Norbert Thumfart
Journal: Journal of Clinical Oncology (2024)

613 Background: Pancreatic adenocarcinoma (PDAC) is commonly diagnosed at advanced stages, leading to high mortality rates. Earlier detection of PDAC is associated with improved long-term survival, but effective population-level screening is not available. There is therefore an urgent need to improve early detection of PDAC. Wholomics has developed a PDAC-specific proprietary early detection test, using cancer-specific molecular signatures in peripheral blood. Methods: We conducted a retrospective analysis of serum samples from the Amsterdam UMC Liquid Biopsy Center. Three cohorts were included in this study: 1) A cohort of healthy control subjects, 2) patients with a histopathologically confirmed diagnosis of PDAC spanning stages I through IV, and 3) patients with a confirmed diagnosis of chronic pancreatitis. Peripheral blood samples of cancer patients were taken before treatment or surgery. Wholomics used its proprietary technology to quantitatively analyse all serum specimens. Disease-specific molecular signatures were identified and used to develop computational biomarkers specific to both pancreatic pathologies (chronic pancreatitis and pancreatic cancer) and to pancreatic cancer individually. A comparative analysis was conducted employing multiple machine learning algorithms, which were subjected to a 10-fold cross-validation procedure. The accuracy, specificity and sensitivity of the best-performing algorithm is reported. Results: This retrospective study included 50 healthy controls, 12 patients with chronic pancreatitis, and 42 patients with pancreatic cancer (12 stage I, 15 stage II, 9 stage III, 6 stage IV). Applying Wholomics´ technology, an accuracy of 99.1% in differentiating the chronic pancreatitis and pancreatic cancer patients from the healthy controls was achieved. A specificity of 98.0% and a sensitivity of 100.0% were reached. Furthermore, pancreatic cancer patients and chronic pancreatitis patients were differentiated with 95.2% accuracy. Wholomics was also capable of differentiating between early stage (stages I and II) and late-stage (stages III and IV) pancreatic cancer with an accuracy of 100%. Conclusions: Taken together, this study demonstrates that disease-specific molecular signatures in peripheral blood can distinguish patients with PDAC from healthy individuals and patients with pancreatitis with very high accuracy. If validated in additional cohorts, this method could be evaluated as a screening test for PDAC to allow for early detection and improve patient outcomes.
A modified triplet combination of docetaxel, oxaliplatin, and fluorouracil for gastric cancer (GC) with peritoneal carcinomatosis (PC) and inoperable malignant bowel obstruction (MBO): A multi-center, non-randomized, three-cohort, phase II trial (Zhen Jing).
Authors: Jian Xiao, Shanshan Li, Xiaohui Zhai, Wanjia Hong, Taiyuan Cao, Xiaoru Lin, Lishuo Shi, Meiyu Hu, Rongqin Zhang
Journal: Journal of Clinical Oncology (2024)

TPS426 Background: For GC, PC is ranked as the most common in relapse and the second common in metastasis. MBO is a frequent and preterminal complication of PC, which has been reported to have a poor overall survival (OS) of only 3 months without effective treatment. Medical therapy of gastroenteric drainage and symptomatic drugs is the cornerstone management for MBO, just alleviating symptoms. Interventional therapy and surgery are effective but indicated in limited patients (pts) with strict selection. Chemotherapy is the mainstay treatment for metastatic GC but its role in MBO is poorly defined. Only a few retrospective studies are available, showing conflicting results on obstruction clearance (OC) and OS. Methods: We are conducting the Zhen Jing trial in five Chinese centers to investigate the tolerability and efficacy of a dose-sense regimen of docetaxel, oxaliplatin and fluorouracil in MBO from GC. Cohort A is for pts in first-line setting. Cohort B is for second-line setting. Cohort C is for pts who have failed to two or more regimens. Eligible pts will receive the same experimental regimen every 28 days: docetaxel 25 mg/m 2 on days 1, 8, 15; oxaliplatin 85 mg/m 2 on days 1, 15; fluorouracil 1200 mg/m 2 24-hour infusion on days 1, 8, 15. A Simon's two-stage optimal design is applied (table below). The primary endpoint is 60-day OC rate. Secondary endpoints are 30-day OC rate, time to OC, OC duration, safety, overall survival and quality of life. Till July 2023, a total of 34 pts has been enrolled (16 in cohort A, 9 in cohort B, 9 in cohort C). Inclusion Criteria: 18-75 years old; Eastern Cooperative Oncology Group performance status ≤ 3; adenocarcinoma of stomach or gastroesophageal junction; peritoneal carcinomatosis established by imaging data or pathological evidence; MBO below the Treitz ligament based on clinical grounds or radiological findings; inappropriate for operation judged independently by two surgeons; written informed consent. Exclusion Criteria: Treated by a combination regimen containing all the study drugs; allergy to any of the study drugs; HER-2 gene overexpression; high microsatellite instability or mismatch repair deficiency; strangulated obstruction; active gastrointestinal bleeding; uncontrolled active infection; unstable heart diseases; severe lung diseases; central nervous system diseases; concomitant cerebral or meningeal metastasis; surgery or stent are required. Clinical trial information: NCT04840264 . [Table: see text]
Developing cell-free DNA (cfDNA) epigenetic signature (ep-Sig) for early detection of malignant transformation of intraductal papillary mucinous neoplasms (IPMN).
Authors: Ashish Manne, Soumya Jogi, Amir Sara, Ankur Sheel, Sravan Jeepalyam, Ashwini K. Esnakula
Journal: Journal of Clinical Oncology (2024)

616 Background: Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers with poor outcomes. Around 20% arise from premalignant lesions (PML) including IPMN. Current guidelines recommend risk stratifying IPMN based on the location, size, and imaging characteristics after first diagnosis, followed by endoscopic ultrasound (EUS) in high-risk populations, and annual or bi-annual imaging. This approach can be improved with cfDNA testing. Traditional mutation testing in cfDNA is not useful secondary to their poor prevalence/detection rates. We propose ep-Sig to improve surveillance and early detection of PDA transformation. Methods: We curated an 11-gene cfDNA ep-Sig from the literature with a proven role in the malignant transformation of IPMN. Evidence suggests that epigenetic changes in every gene of this panel have a role in carcinogenesis in IPMNs. We compared RNA and gene expression of the genes in this ep-Sig between normal (NT) and PDA tissues using a web-based tool, TNMplot.com that uses the data from the Gene Expression Omnibus of the National Center for Biotechnology Information (NCBI-GEO) or Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and The Genotype-Tissue Expression (GTEx) repositories was used create this tool. It uses Mann-Whitney or Kruskal-Wallis tests to compute statistical significance. We used cell-free epigenome atlas (CFEA) database to examine the prevalence of these markers in cfDNA of PDA patients. Results: RNA expression of all the genes from the ep-Sig combined was significantly lower in PDA than NT (0.45, p=3.13e-26). Gene expression was 8/11 genes was lower in PDA tissues than NT (0.44, p=3.13e-26). The other 2 genes were not detected in the tested samples. Prevalence of all the markers in ep-Sig was &gt; 90%. Conclusions: Our proposed ep-Sig has a high prevalence in PDA patients and has reliable preliminary evidence in tissues suggesting its diagnostic value. This study is the first step in developing non-invasive cfDNA testing with the potential to improve the current surveillance strategies for IPMN pending larger prospective studies.
Demographic and social vulnerability factors associated with late diagnosis of gastrointestinal cancers.
Authors: Muhammad Sohaib Khan, Jennie Meier, Mithin Nehrubabu, Gilbert Zvikomborero Murimwa, Sean Young, Lisa Dimartino, Syed Mohammad Ali Kazmi, Javier Salgado Pogacnik, Sam C. Wang, Adam C. Yopp, Herbert J. Zeh, Patricio M. Polanco
Journal: Journal of Clinical Oncology (2024)

610 Background: Almost 30% of gastrointestinal cancers (GI) are diagnosed at an advanced stage. These patients have a poor prognosis with no curative options. Certain demographic and social factors adversely impact health outcomes. However, these have not been well studied in the context of late diagnosis of GI cancers. Methods: Texas and California cancer registries, merged with CDC’s Social Vulnerability Index (SVI) database, were used to identify patients diagnosed with gastric, colorectal, pancreatic and liver cancer from 2004 to 2019. To determine the association of demographic and 16 social vulnerability factors, while accounting for differences in tumor characteristics, univariate and multivariate logistic regression analysis (MVA) was performed for each cancer separately. Results: In total, 589,405 patients were included. Of these 166,910 (28.3%) patients had metastasis at diagnosis. This included 55%, 39%, 21%, and 17% of all pancreatic, gastric, colorectal and liver cancers respectively. On MVA, odds of metastatic cancer at presentation decreased with increasing age (except for pancreatic cancer where odds increased). Across all 4 cancer types, females and Asians had decreased odds while Blacks, uninsured and patients on Medicaid had increased odds of metastatic cancer at diagnosis. Poverty below 150% increased odds of metastatic pancreas, liver, and colorectal cancers at diagnosis. Odds were decreased for households with adults aged over 65 years for pancreas, colorectal and gastric cancers. Conclusions: This study has identified multiple demographic and social factors associated with odds of having metastatic GI cancer at diagnosis. Interventions aimed towards these at-risk populations offer an opportunity for early diagnosis and improved survival.[Table: see text]