tbuckley/cabot-search huggingface dataset:
Clinical and prognostic characteristics of early onset metastatic pancreatic cancer.
Authors: Andrea Pretta, Riccardo Giampieri, Federico Nichetti, Pina Ziranu, Alessio Lupi, Erika Cimbro, Paola Andena, Cristiano Felicetti, Chiara Carlotta Pircher, Eleonora Gusmaroli, Clelia Donisi, Francesca Balconi, Stefano Mariani, Eleonora Lai, Marco Puzzoni, Valeria Pusceddu, Rossana Berardi, Monica Niger, Mario Scartozzi
Journal: Journal of Clinical Oncology (2024)

702 Background: In the last decade several studies have shown an increase in the incidence of early-onset PDAC (EO-PDAC), conventionally defined as cancer that occurs in adults between the ages of 18 and 49. Clinical and prognostic data on this setting are limited and conflicting. The aim of our study was to evaluate the clinical, and prognostic differences in a large group of patients with early onset mPDAC. Methods: We retrospectively collected data from 368 patients affected with metastatic pancreatic ductal adenocarcinoma, from 3 different Italian Institutions. All patients had one or more metastatic sites, and received first-line chemotherapy. The main objective of the study was to evaluate the median overall survival in EO-PDAC patients compared to late onset PDAC (LO-PDAC), while secondary endpoint was evaluations of mPFS. Statistical analysis was performed with the MedCalc package. Results: 30 (8,1%) patients were early onset and 338 (91,9%) were late onset; median age was 46 (±5) and 68 (±8), respectively. M/F ratios were 1:1 in both group. In the overall population mOS was significantly lower in EO-PDAC patients: 10,0 versus 15,0 months ( p = 0,03). Furthermore, mPFS was significantly lower in EO-PDAC patients: 5,0 versus 8,0 months ( p = 0,04). ORR obtained from 244 pts were: 11% in EO-PDAC and 24,7% in LO-PDAC. Conclusions: The results of our work, although limited by the retrospective nature of the study, showed a worse prognosis for patients with early onset PDAC compared to late onsets. Further investigations will be needed to better understand this growing group of patients from a molecular and therapeutic point of view.
Prognostic value of the CRM status in pancreatic ductal adenocarcinoma: Data from a regional cancer registry.
Authors: Philipp Morakis, Irina Surovtsova, Jasmin Schuhbaur, Daria Kokh, Claudia Winzler, Gertrud Szotyori-Artz, Juliane Schütz, Waldemar Uhl, Andrea Tannapfel, Thomas Seufferlein
Journal: Journal of Clinical Oncology (2024)

632 Background: Ductal pancreatic adenocarcinoma (PDAC) still has a dismal prognosis even when deemed resectable. A cancer free resection margin (R0) is associated with a more favourable prognosis than the presence of tumour cells at resection margin (R1). However, the precise definition of the R0 status is still a matter of debate in PDAC. For a more accurate determination of R0 in PDAC the concept of circumferential resection margins (CRM) has been introduced. However, an international standardized nomenclature of CRM is still missing, and the clinical value of the CRM concept is not yet fully established. Here we evaluate whether the CRM status as defined in the national German S3 guideline is an independent prognostic factor in PDAC using data from the regional cancer registry of the State of Baden Württemberg in Germany. Methods: Data from the cancer registry of the State of Baden-Württemberg, Germany were collected, using documented patients diagnosed with invasive ductal adenocarcinoma of the pancreas between 2015 and 2020. The R-status was assessed according to the national German S3 guideline with R0 wide/CRM- when CRM is &gt; 1mm, R0 narrow/CRM+ when CRM is £ 1 mm from the tumour and R1 when tumour cells are found at the resection margin. Progression free survival (PFS) as well as 3-year overall survival (OS) were assessed using Kaplan-Meier statistics and multivariable Cox regression models (adjusted for age, pN stage, primary tumor location and systemic treatment). Results: In total we identified 1098 cases surgically treated for pancreatic cancer and fulfilling the inclusion criteria. 340 patients had an R0 wide/CRM- resection, 410 patients an R0 narrow/CRM+ resection, and 348 patients an R1 resection. The R0 wide/CRM- status was associated with a significantly increased median 3-year OS rate compared to the other two groups (51,5%, 37,4% and 26,7% for R0 wide/CRM-, R0 narrow/CRM+ and R1, respectively). mPFS was also longer in the R0 wide/CRM- group. These findings were robust with regards to grading. 5-FU based adjuvant treatment was mainly mFOLFIRINOX and show better outcome as compared to gemcitabine-based treatments. Conclusions: The present study was performed using real world data reflecting actual clinical settings. The results obtained are in good agreement with data from clinical trials, including the prognostic role of the R- and N- Status as well as the efficacy of adjuvant chemotherapy protocols used.
PROOF 301: Results of an early discontinued randomized phase 3 trial of the oral FGFR inhibitor infigratinib vs. gemcitabine plus cisplatin in patients with advanced cholangiocarcinoma (CCA) with an <i>FGFR2</i> gene fusion/rearrangement.
Authors: Ghassan K. Abou-Alfa, Ivan Borbath, Sameek Roychowdhury, Lipika Goyal, Angela Lamarca, Teresa Macarulla, Rachna T. Shroff, Do-Youn Oh, Milind M. Javle, Catalin Tamas, David M Savastano, David Friedrich Van Veenhuyzen, Cindy Xu, Jacki Solanas, Elizabeth Freas
Journal: Journal of Clinical Oncology (2024)

516 Background: Infigratinib (BGJ398), an oral inhibitor of fibroblast growth factor receptor (FGFR)1-3 with demonstrated clinical activity and a manageable adverse event profile in a phase 2 study in patients with previously treated, unresectable or metastatic CCA with an FGFR2 fusion or other rearrangement, represented one of the few targeted treatment options after progression on first-line therapy, as per FDA conditional approval. The confirmatory phase III trial PROOF 301 of infigratinib versus gem/cis as frontline treatment of FGFR2 Gene Fusions/Translocations CCA was early discontinued. Here we report the efficacy and safety in the patients accrued prior to termination. Methods: Eligible patients were randomized 2:1 to infigratinib 125 mg on days 1-21 of a 28-day cycle vs intravenous gemcitabine (1000 mg/m 2 ) + cisplatin (25 mg/m 2 ) on days 1 and 8 of a 21-day cycle. The primary endpoint was progression-free survival (PFS), confirmed by blinded independent central review (BICR). Secondary endpoints included overall survival (OS), investigator determined PFS, overall response rate (ORR), best overall response (BOR), disease control rate (DCR), duration of response (DOR), and safety and tolerability. Crossover to the investigational arm was permitted at progression. Results: Over 40 months, a total of 1127 patients were pre-screened at 120 sites and 48 enrolled. In a 2:1 randomization, 29 patients received infigratinib and 19 received gem/cis. Upon progression, 2 patients crossed over from gem/cis to infigratinib. Median PFS (95% CI) by BICR was 7.4 (5.4, not evaluable [NE]) and 8.0 (3.4, NE) months with infigratinib and chemotherapy, respectively. The ORRs by BICR were 37.9 % with infigratinib and 15.8 % with gem/cis. Grade 3–4 adverse events occurred in 79.3% and 58.8% patients treated with infigratinib and chemotherapy. Conclusions: Infigratinib showed a preliminary signal of efficacy in the first-line treatment of FGFR2-rearranged CCA, but due to early termination of the study, the power is insufficient to draw conclusions regarding its efficacy in comparison to gem/cis. This study highlights the challenge of performing confirmatory studies in biomarker-selected subpopulations of rare tumors and the importance of exploring alternative approaches to delivering confirmatory data for regulatory purposes. Clinical trial information: NCT03773302 .
Role of circulating tumor DNA in metastatic appendiceal neoplasms: A systematic review.
Authors: Moazzam Shahzad, Sean P. Dineen, Mamoon Ahmed, Ahmad Basharat, Muhammad Fareed Khalid, Jawad Noor, Muhammad Kashif Amin, Iman Imanirad
Journal: Journal of Clinical Oncology (2024)

757 Background: Circulating tumor DNA (ctDNA), tumor DNA fragments detected in blood sourced from primary malignancy, is an emerging non-invasive tool in oncology for screening, diagnosis, and surveillance. Here, we analyze its utility in patients with metastatic appendiceal neoplasms. Methods: Following PRISMA guidelines, PubMed, Cochrane, and Clinicaltrials.gov were searched for ‘Appendiceal Neoplasms’ AND ‘Circulating Tumor DNA’. Four original studies reporting the role of ctDNA in appendiceal cancer were included after screening 195 articles. Results: A total of 196 patients were included in the review. (Table) The total number of collected samples was 209 and 41% were tested positive for ctDNA. Singh et al. 2023 reported eight stage IV appendiceal cancer patients with the median age of 64.5 (45-75) years. 37.5% were tested positive for ctDNA while 37.5% had undetectable ctDNA despite having residual peritoneal disease and 25% had insufficient DNA from tumor specimen. López-Rojo et al. 2020 reported 50% ctDNA positive rate. All included patients had KRAS mutation and received hyperthermic intraperitoneal chemotherapy (HIPEC). On 36.5 months follow-up all the patients were alive but one out of two ctDNA positive patients had a relapse at 39 months follow-up. Kothary et al. 2022 reported 51% ctDNA positivity and 11% had longitudinal ctDNA measurements available which correlated well with their disease course. Zeineddine et al. 2023 collected 160 blood samples from 147 patients. Of 75% with radiographically metastatic disease, 38% had positive ctDNA while out of 25% with no radiographically metastatic disease, 38% had positive ctDNA. The overall survival and progression free survival for ctDNA positive patients was 46.2 months and 60 months, respectively, versus not reached for ctDNA negative patients. When stratified according to tumor grade, the ctDNA detection rate was 22% for well-differentiated, 39% for moderately differentiated, and 49% for poorly differentiated tumors. Conclusions: The use of ctDNA in metastatic appendiceal tumor is not widespread and detection rates are heterogenous. It was observed more in poorly differentiated appendiceal cancers but further studies are needed to evaluate its utility in clinical practice. [Table: see text]
Germline testing in patients with early-onset pancreatic cancer (EOPC).
Authors: Hamid Ehsan, James Thomas Symanowski, Arunkumar Krishnan, Aly Athens, Katherine Wilson, Katie Tobik, Sara Elrefai, Mohamed E. Salem, Jimmy J. Hwang, Darryl Chang, Kunal C. Kadakia
Journal: Journal of Clinical Oncology (2024)

639 Background: EOPC, defined as pancreatic cancer (PC) diagnosed at 60 years of age or younger, is associated with significant life years lost. Approximately 5-10% of average-onset PC have an underlying germline etiology. Currently NCCN &amp; ASCO guidelines recommend germline testing in all pts w PC. However, there is limited data regarding to what extent pts with EOPC pursue recommended germline testing. We examined the findings from genetic evaluation in EOPC. Methods: A retrospective review of EOPC pts at the Levine Cancer Institute who underwent clinical genetic assessment between January 2019 and December 2021 was performed. Data on clinicodemographic, family history, and genetic testing results were obtained and analyzed descriptively. Results: We identified 69 EOPC pts who were evaluated by genetics. Baseline characteristics include median age of 55 years (range 25-60) with 52% male, 48% white, 23% black, and 52% with current or prior tobacco use. At presentation, 41% and 59% had metastatic and non-metastatic disease, respectively. Eight (12%) pts declined germline testing. Among the 61 who underwent germline testing, 30 (49%) pts had negative testing, 21 (34%) had only variants of uncertain significance, and 10 (16%) had pathogenic/likely pathogenic germline variants (PVs). The most frequently seen PVs were ATM (20%), BRCA1 (20%), BRCA2 (10%), MLH1 (10%), NTHL1 (10%), PTCH1 (10%), CFTR (10%) and one (10%) with multiple pathogenic germline findings including RAD51 and BRCA1. Among the 10 pts with PVs, only two reported any first or second-degree family members with cancer. Conclusions: In this cohort of EOPC at a large community multi-site cancer center, 16% of patients had germline PVs, higher than reported in older patients with PC. Only 20% of pts w PVs reported first or second-degree family members with cancer and highlights the importance to recommend germline testing independent of family history even among EOPC cohorts. Further investigation to clarify reasons for refusal of germline testing in EOPC should be evaluated.
Overall survival and long-term safety with ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: Final analyses from INTRIGUE.
Authors: John Raymond Zalcberg, Robin Lewis Jones, Jean-Yves Blay, Suzanne George, Hans Gelderblom, Patrick Schöffski, Margaret von Mehren, Yoon-Koo Kang, Albiruni Ryan Abdul Razak, Jonathan C. Trent, Steven Attia, Axel Le Cesne, Erika Davis, Haroun Achour, Matthew L. Sherman, Rodrigo Ruiz-Soto, Sebastian Bauer, Michael C. Heinrich
Journal: Journal of Clinical Oncology (2024)

748 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with 3 or more kinase inhibitors, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. In the second interim analysis of overall survival (OS) from the phase 3 INTRIGUE study, the OS event rate was 41% in the all-patient (AP) intent-to-treat (ITT) population, and OS was similar between treatment arms in both the KIT exon 11 ITT and AP ITT populations. Here, we present the final OS and updated safety from INTRIGUE. Methods: INTRIGUE (NCT03673501) is an open-label, phase 3 study of adults with advanced GIST who had disease progression on or intolerance to imatinib. Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 weeks on/2 weeks off) and was stratified by KIT mutational status and imatinib intolerance. OS was a key secondary endpoint (the primary endpoint of progression-free survival was reported previously); final OS analysis was prespecified to occur with ≥200 and ≥145 events in the AP ITT and KIT exon 11 ITT populations, respectively. Data cutoff was March 15, 2023. Results: Of 453 pts, 444 received treatment; 40 remain on treatment (ripretinib, 28/223 [13%]; sunitinib, 12/221 [5%]). Treatment discontinuation was due to progressive disease (PD) by independent radiologic review (56%), PD by investigator (11%), clinical PD (6%), withdrawal of consent (6%), and adverse events (AEs; 5%). Fewer pts discontinued treatment due to AEs with ripretinib vs sunitinib (3% vs 6%). There were 211 OS events (47%) in the AP ITT population and 151 OS events (46%) in the KIT exon 11 ITT population. OS was similar with ripretinib vs sunitinib in the 2 ITT populations (Table). Fewer pts had grade 3/4 treatment-emergent AEs with ripretinib vs sunitinib (43% vs 67%). Dose interruptions and reductions were lower with ripretinib vs sunitinib. Median treatment duration for ripretinib vs sunitinib was 7.9 vs 6.5 months. Conclusions: In the finalOS analysis from the INTRIGUE study, OS was similar between treatment arms. The safety profile remained consistent and more favorable for ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib. Clinical trial information: NCT03673501 . [Table: see text]
Trends in incidence and survival of early-stage pancreatic ductal adenocarcinoma in the United States.
Authors: Gerardo Perrotta, Yazan Abboud, Arsen Osipov, Ghada Mohamed, Mohamad El Helou, Stephen Jacob Pandol, Simon K. Lo, Srinivas Gaddam
Journal: Journal of Clinical Oncology (2024)

633 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor survival with nearly 80% mortality within the first year after diagnosis. There have been modest incremental improvements in survival over the last decade, however the reason for this improvement is unclear. The aim of this study is to evaluate the trends of diagnosis and survival in the last two decades using large public national databases. Methods: Incidence rates of PDAC between 2001 and 2020 (age-adjusted to the 2000 US standard population) were evaluated in the United States Cancer Statistics (USCS) database, representing approximately 98% of the US population. The data was analyzed with SEER*Stat using Joinpoint regression. A survival analysis was subsequently conducted using the American College of Surgeons’ (ACS) National Cancer Database (NCDB), of PDAC cases diagnosed between 2004 and 2015.Survival outcomes were stratified by AJCC stage. Kaplan-Meier survival curves were generated, and log-rank tests were conducted to assess differences in survival between stages. Cox proportional hazards model was employed to estimate hazard ratios and adjust for potential confounders. The analysis was performed with IBM SPSS 24. Results: From 2001 to 2020, the age-adjusted incidence rate of early-stage PDAC increased from 1.1 to 2.8 (per 100,000 person-years), while locally advanced PDAC increased from 3.6 to 4.3, and from 6.4 to 7.7 for metastatic PDAC (all p&lt;0.01). The Annual Percent Change (APC) was 5.7 for Early-Stage PDAC (95% CI 5.1-6.4), 1.4 for locally advanced (95% CI 0.8-1.9), and 0.8 for Metastatic PDAC (95% CI 0.6-1.1). The incidence rate ratio (IRR) almost doubled for early-stage PDAC, increasing from 0.10 to 0.19. Conversely, for metastatic and locally advanced stages, the IRR decreased from 0.58 to 0.52 and 0.32 to 0.29, respectively. Survival analysis revealed 5-year overall survival rates of 74%, 69%, 57%, and 33% for stages 0, IA, IB, and IIA, respectively, with an overall improvement from 2004 to 2015. This increase was consistent among all age groups, genders, and races. Stages IA and IB demonstrated larger increases 45.9% and 56.6%, respectively (IA: 47% in 2004 to 75% in 2015; IB: 38% in 2004 to 68% in 2015). Conclusions: This study highlights a marked increase in the incidence of early-stage PDAC, surpassing the overall incidence increase, suggesting improving diagnostic capabilities over the last two decades. Furthermore, the substantial improvement in 5-year survival rates for stages IA and IB indicates progress in the management of early-stage PDAC. These findings emphasize the importance of continued efforts in early detection and treatment strategies for PDAC.
Clinical validation of Northstar Response, a novel methylated ctDNA therapy response monitoring assay in patients with advanced GI cancer undergoing active treatment.
Authors: Ilyas Sahin, Doga Kahramangil, Sherise C. Rogers, Brian Hemendra Ramnaraign, Pravalika Manda, Matthew Gordon Varga, Gary A. Palmer, Patrick Peiyong Ye, Thomas J. George
Journal: Journal of Clinical Oncology (2024)

756 Background: ctDNA is a non-invasive way to holistically assess the tumor. Several assays developed for therapy response monitoring rely on variant allele frequencies to detect scarce somatic variants in the blood. In contrast, methylated ctDNA measurement has shown promise as a treatment monitoring biomarker without requiring a tumor biopsy, yet accuracy is limited in ability to precisely quantify the amount of methylation present in the ctDNA. The CLIA-approved Northstar Response assay (BillionToOne, Inc.) quantifies on average 90 methylated loci, a 10-fold increase in signal over the average tissue-informed assays. Methods: This prospective, observational study assesses the clinical validity of Northstar Response, a quantitative methylated ctDNA therapeutic response monitoring assay that does not require prior tumor tissue. A cohort of 100 advanced cancer patients with a variety of GI malignancies submit serial ctDNA measurements in a blinded fashion. Eligibility includes advanced GI cancer patients starting a new line of systemic therapy (IO, targeted, chemo or combination) who are not pregnant or s/p organ or bone marrow transplantation. Blood samples are collected at baseline, at the time of imaging, and at least two intermediate time points (~30 days and 60 days post tx initiation). The primary endpoint is to measure the concordance and temporal relationship between disease progression measured by ctDNA compared to RECISTv1.1, clinical confirmation, or death. A Cox proportional hazards model will be used to quantify the association between the change in tumor methylation score (TMS; total methylated tumor molecules per 1000 assayed genomic equivalents) and clinical progression. The cohort will be split equally between a training and validation set. Results: Enrollment began in June 2023 and continues. To date, 28 patients with a variety of advanced GI cancers (table) have been enrolled with 37 samples processed. All samples have passed established QC metrics with average turn-around-time from receipt of sample to final report of 9.1 days (95% were &lt;15 days). TMS ranged from &lt;120 to &gt;160,000 across individual samples, indicating that the assay can detect a broad range of tumor load in blood. We detected a median of 69 methylated loci per sample (range 4-451). Out of 21 pts, 17 had at least one sample with TMS measured above the noise floor of 120. Conclusions: The Northstar Response assay can consistently detect ctDNA across a variety of advanced GI cancers. Enrollment continues with formal comparison to clinical progression planned. Additional data on the complete training set will be available at the meeting.[Table: see text]