tbuckley/cabot-search huggingface dataset:
Epidemiology, treatment patterns, and humanistic and economic burden of biliary tract carcinoma: A systematic and targeted literature review.
Authors: Shital Kamble, Kaushal Desai, Seongjung Joo, Prabhakar Pandey, Shilpi Swami, Magdiel Habila, Usha Malhotra, Adam Hall, Urvi Khatri, Jyothsna Nathani
Journal: Journal of Clinical Oncology (2024)

443 Background: Patients with biliary tract cancers (BTC) are typically diagnosed at late stage, with limited treatment options. As such, BTC is associated with poor prognosis, high economic burden and reduced health-related quality of life (HRQoL). As the treatment paradigm is evolving, with multiple immunotherapies showing promise, this study aimed to assess the current disease and treatment landscape. Methods: Systematic literature reviews (Embase, MEDLINE, Cochrane, NHS-EED; database inception to Feb 10, 2023) were conducted for HRQoL and economic burden. Targeted literature reviews (Embase, MEDLINE) were conducted for epidemiology (Jan 01 2017–Feb 06 2023) and treatment guidelines/patterns (Jan 01 2012–Feb 06 2023). Conference abstracts were also searched (2019–2022). Eligibility criteria included global studies (English language) in adults with metastatic and/or unresectable BTC. Results: Overall, 264 studies were included (epidemiology=170, treatment guidelines=14, treatment patterns=50, HRQoL=12, economic burden=18). In the US, Europe and Asia, age-standardized incidence rates were 5.04, 8.39–8.78 and 9.1–10.1 (per 100,000 person-years) and prevalence rates were 0.01%, 0.02–0.34% and 0.02–2.61%, respectively. Treatment pattern studies were mainly from Asia, Europe (n=19 each) and North America (n=10). Gemcitabine [gem]-based chemotherapy was most common in 1L BTC (24–100%) and fluorouracil-based regimens were common in 2L+ BTC (12.3–74.3%). Median overall survival (mOS) for gem-based and fluorouracil-based 1L regimens were 7.7–14.8 months and 7–16.7 months, respectively. Disease progression/toxicity frequently led to treatment discontinuation/dose modifications. In the US, use of non-guideline-based regimens increased by line of therapy (LOT). Among the clinical studies (n=5) reporting HRQoL in 1L, n=4 assessed gem-based combinations. BTC impaired HRQoL domains for anxiety, tiredness (EORTC QLQ-BIL21), work productivity, activity impairment (WPAI scale) and depression (PHQ-9). BTC was associated with substantial economic burden. Mean total all-cause healthcare costs per patient per month (PPPM) increased by LOT (US; 1L: $19,589–25,517, 2L: $22,617–29,721, 3L: $23,256–33,534). US healthcare resource utilization in 1L was driven by outpatient visits (98%), emergency department visits (33–80%) and hospitalization (70–80%). Mean hospital stay ranged from 0.6–7 days PPPM. Conclusions: Epidemiology data varied between Western and Asian populations, but gem-based chemotherapy was identified as the standard of care across regions. There is high unmet need in advanced BTC, as existing options are characterized by poor survival outcomes and considerable economic burden. These findings indicate a need for novel approaches for the management of BTC.
FOENIX-CCA4: A phase 2 study of futibatinib 20 mg and 16 mg in patients with advanced cholangiocarcinoma (CCA) and fibroblast growth factor receptor 2 (<i>FGFR2</i>) fusions/rearrangements.
Authors: Teresa Macarulla, Takashi Mizuno, Giovanni Brandi, Jin Li, Ming-Huang Chen, Jung Hun Kang, Kathia Cristina Abdalla, Piotr Jan Wysocki, Nuno Couto, Bailey Anderson, Hamdy Elsayed, Parvez Mantry
Journal: Journal of Clinical Oncology (2024)

TPS572 Background: In 2022, the U.S. FDA approved futibatinib, a covalently binding inhibitor of FGFR1–4, for previously treated patients with advanced intrahepatic CCA and FGFR2 fusions/rearrangements. In the pivotal phase 2 FOENIX-CCA2 study, futibatinib 20 mg once daily (QD) resulted in an objective response rate (ORR) of 42% by independent review and a median duration of response (DOR) of 9.7 months. Futibatinib was tolerable and had a manageable safety profile. 1 Limited phase 1 data suggest futibatinib may also have antitumor activity at a lower dose (16 mg QD), with fewer dose modifications required for adverse events. 2 The aim of FOENIX-CCA4is to confirm the clinical benefit of futibatinib 20 mg QD and explore the safety and efficacy of futibatinib 16 mg QD in previously treated patients with advanced CCA and FGFR2 fusions/rearrangements. Methods: In this global, phase 2, randomized, open-label study (NCT05727176), patients with CCA harboring FGFR2 fusions/rearrangements who have received ≥1 line of gemcitabine/platinum-based therapy for advanced/metastatic disease will be randomized 1:1 to futibatinib at a starting dose of 20 mg or 16 mg QD continuously on a 21-day cycle. Randomization will be stratified by the number of prior lines of systemic therapy for advanced disease (1 vs ≥2). Futibatinib will be continued until progressive disease or unacceptable toxicity. Tumor response will be assessed at baseline, every 6 weeks for the first 12 weeks, and every 9 weeks thereafter until radiographic progressive disease or initiation of new anticancer therapy. The primary endpoint is ORR according to Response Evaluation Criteria in Solid Tumors version 1.1, as assessed by blinded independent central review (analyzed when all patients responding to futibatinib have ≥6 months’ follow-up from the first onset of response). DOR is a key secondary endpoint. Other secondary endpoints are progression-free survival, overall survival, safety, and quality of life. Sample size (120 patients) was estimated on the assumption that if the lower ORR between futibatinib 16 mg and 20 mg is 32% (with ≥60 patients per arm), the probability of correctly selecting the treatment arm with a true ORR of 42% is 0.87. Enrollment is ongoing in Europe, the US, and Asia-Pacific. 1. Goyal L et al. N Engl J Med. 2023;388:228–39. 2. Meric-Bernstam F et al. Cancer Discov. 2022;12:402–15. Clinical trial information: NCT05727176 .
Front-line use of FOLFOXIRI plus bevacizumab and subsequent therapies in metastatic colorectal cancer (mCRC).
Authors: Afsaneh Barzi, Orsolya Lunacsek, Federica Pisa, Xiaoyun Pan, Helene Ostojic, Zdravko Vassilev
Journal: Journal of Clinical Oncology (2024)

45 Background: Emerging data shows that the higher incidence of mCRC in younger patients (pts) is accompanied by more aggressive front-line treatment with chemotherapies, such as FOLFOXIRI+bevacizumab (triplet+bev). We explored the use of triplet+bev and subsequent therapies in a representative sample of community practices in the USA. Methods: This was a retrospective study using the nationwide de-identified Flatiron Health Electronic Health Record-derived database from January 1, 2013, to February 28, 2023. The use of triplet+bev and subsequent treatments were analyzed in pts with newly diagnosed mCRC (≥18 years [yrs] of age) by oncologist-defined, rule-based line of treatment (LOT) and age (18–49, 50–64, and ≥65 yrs). Results: Of 24,285 eligible pts, 14%, 37%, and 49% were 18–49, 50–64, and ≥65 yrs at treatment initiation, respectively (Table). Triplet+bev use in any LOT was the most prevalent in the youngest age group (18–49 yrs) at 7% (Table). Two-thirds (67%) received triplet+bev in first line (1L) and 23% in second line (2L), 57% were male, and 34% had a KRAS mutation (23% missing). From 2013 to 2022, triplet+bev use in newly treated pts increased; this trend was more pronounced in pts 18–49 yrs (Table). Among pts not censored before the end of the respective LOT, median duration of 1L and 2L triplet+bev was 25.1 and 21.6 weeks, respectively (Table). For non-censored pts with and without a KRAS mutation, respectively, median duration of triplet+bev was 26.1 vs 23.5 weeks in 1L and 21.6 vs 16.5 weeks in 2L. Most frequently used new agents after 1L triplet+bev included anti-EGFR (panitumumab or cetuximab; 19%), TAS-102 (12%), regorafenib (10%), and capecitabine (3%). Most frequently used new agents after 2L triplet+bev were TAS-102 (21%), anti-EGFR (17%), regorafenib (15%), and pembrolizumab (8%). Conclusions: Our study shows that the use of triplet+bev has increased in pts with mCRC over time, particularly in those &lt;50 yrs. Most frequent subsequent therapies across all pts following 1L and 2L triplet+bev included TAS-102, anti-EGFR, and regorafenib. Future research is needed to identify the optimal treatment strategies after triplet+bev. [Table: see text]
Clinicopathological characteristics and lymph node metastasis rates in early gastric lymphoepithelioma-like carcinoma: Implications for endoscopic resection.
Authors: Tae-Se Kim, Byung-Hoon Min, Yang Won Min, Hyuk Lee, Jun Haeng Lee, Poong-Lyul Rhee, Ji Yeong An, Jae J. Kim
Journal: Journal of Clinical Oncology (2024)

321 Background: We aimed to clarify the clinicopathological features and the rate of lymph node metastases (LNM) of early gastric lymphoepithelioma-like carcinoma (LELC). Methods: We compared the clinicopathological characteristics of 82 LELC and 5758 well- or moderately differentiated (WD or MD) tubular adenocarcinoma patients who received gastrectomy for single early gastric cancer (EGC). Results: Compared to the control group, early LELC patients were younger, had a higher prevalence of proximally located tumors, more frequent Epstein-Barr virus (EBV) infection, more frequent deep submucosal invasion (SM2 or SM3, 85.4% versus 29.9%, P &lt; 0.001) but less frequent lymphatic invasion (4.9% versus 16.2%, P = 0.009). Among tumors with deep submucosal invasion, early LELC patients had smaller tumor sizes, less frequent lymphatic invasion (5.7% versus 40.1%, P &lt; 0.001) and a lower rate of LNM (7.1% versus 19.4%, P = 0.016) than the control group. LNM rates of LELC patients with mucosal, shallow submucosal invasion (SM1) and deep submucosal invasion were 0%, 0%, and 7.1%, respectively. Lymphatic invasion was the only significant risk factor in the regression analysis for LNM in LELC patients. Among 12 patients with mucosal or shallow submucosal invasion and 27 patients with deep submucosal invasion having small tumor sizes (less than 2 cm) and no lymphatic invasion, there was no LNM. Conclusions: Given the low rate of LNM, the same curability criteria of ESD for WD or MD EGC may be applied to early LELC and even more flexibly for those considered non-curative ESD only because of deep submucosal invasion.
A phase II study to evaluate the safety and efficacy of anlotinib combined with penpulimab for advanced refractory biliary tract cancer.
Authors: Xiaojun He, Kai Tan, Xilin Du
Journal: Journal of Clinical Oncology (2024)

TPS582 Background: Although with modest efficacy, mFOLFOX is recommended as standard second-line chemotherapy for advanced biliary tract cancer (BTC). Several clinical trials are exploring the combination treatment of antiangiogenic drugs and immune checkpoint inhibitors. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor targeting VEGFR1/2/3, FGFR1-4 and PDGFRα/β, which effectively blocks tumor neovascularization and growth. Previous phase I/II clinical trials suggested that anlotinib combined with PD-(L)1 inhibitors as second-line therapy was well tolerated and showed clinical anti-tumor activity in advanced biliary tract cancer (NCT03825705, NCT03996408, ChiCTR1900022003, ChiCTR2000037847). Penpulimab is a novel humanized anti-PD-1 IgG1 antibody with complete removal of Fc receptor mediated effect, and featuring slow antigen binding off-rate and high receptor occupancy. In this study, we explore anlotinib plus penpulimab as a chemo-free combination for second-line and above therapy. Methods: This is a prospective, single-arm, phase II study. BTC patients (pts) failed after the first-line treatment, aged 18-75 and an ECOG PS of 0-1 were recruited.Eligible pts received anlotinib (12mg, po, d1-14, q3w) and penpulimab (200mg, iv, d1, q3w) until disease progression, unacceptable toxicity or up to 2 years. The primary endpoint was Objective Response Rate (ORR). Secondary endpoints included Overall survival (OS), Progression-Free Survival (PFS), Disease Control Rate (DCR) and safety. Based on a two-sided test for one proportion with 5.0% type I error, 80% power to detect an improvement in ORR from 5% to 22%, there will be 27 pts enrolled considering 20% of pts dropping out. Clinical trial information: ChiCTR2300069126 .
Genetic testing of Japanese patients with serrated polyposis syndrome: A multicentric study.
Authors: Akinari Takao, Tatsuro Yamaguchi, Hidetaka Eguchi, Yasushi Okazaki, Hideki Ishikawa, Kiwamu Akagi, Hideyuki Ishida
Journal: Journal of Clinical Oncology (2024)

75 Background: Serrated polyposis syndrome (SPS) is a rare condition associated with an increased risk of colorectal cancer. Previous studies have identified germline truncating variants of the RNF43; however, patients harboring these variants comprise a small part of those with SPS, in most of whom the causative gene remains unknown. To date, no study has described the genetic features of Japanese patients with SPS. The present study aimed to identify candidate causative genes of SPS in Japanese patients. Methods: Captures for equal to or more than 55 gene regions were performed using Agilent HaloPlex or Ion AmpliSeq technologies in SPS patients enrolled in The Study Group for Establishment of Diagnosis of Hereditary Gastrointestinal Tract Cancer Syndromes Based on a Next-Generation Sequencing Technology (SGHGCS). Whole exome sequencing of tumor tissue was performed whenever a candidate gene was identified. Results: Eleven patients (four males, seven females) were enrolled. Of these, nine had a history of colorectal cancer; four had a family history of colorectal cancer; and two had a family history of polyposis. Genetic testing identified two variants of VUS, POLD1 c.670C&gt;T (p.R224C) and BRCA2 c.4169T&gt;G (p.L1390W). Additionally, a nonsense variant, BUB1:c.1543G&gt;T p.Gly515Ter was deemed likely to be pathogenic. The patient with the BUB1 variant was 47-year-old female with transverse colon cancer with more than 50 serrated polyps. She was a non-smoker. The variants detected in the transverse colon cancer did not include the canonical variants in common colorectal cancer, such as APC, KRAS or TP53 and were mostly transition substitutions (C&gt;T). Conclusions: BUB1 was identified as a novel candidate causative gene of SPS in a patient with SPS with no smoking habit. These findings will hopefully contribute to our understanding of the genetic basis of SPS.
Early molecular assessment to predict prognosis in patients who respond to chemotherapy on initial imaging in pancreatic cancer.
Authors: Fumiaki Watanabe, Koichi Suzuki, Toshiki Rikiyama
Journal: Journal of Clinical Oncology (2024)

683 Background: It is helpful to predict early the response to anticancer drugs in non-resectable solid tumors. The purpose of this study is to evaluate whether circulating tumor DNA (ctDNA) helps predict prognosis in patients with non-resectable pancreatic cancer who have received first-line FFX or GnP therapy and have responded to treatment (CR, PR, SD groups) on initial imaging. Methods: A total of 61 patients with non-resectable pancreatic cancer treated with FFX (N=22) and GnP (N=39) as first-line therapy were included in the study. Before and after chemotherapy treatment (median 42 days, after two courses), KRAS-mutated ctDNA was measured using droplet digital PCR with CA19-9. We defined the Responder group as those with CR, PR, or SD other than PD on initial imaging and the molecular assessment as the change in KRAS-mutated ctDNA before and after treatment. (1) No appearance of KRAS-mutated ctDNA before and after treatment was defined as molecular negative (mNT); (2) disappearance of KRAS-mutated ctDNA or decrease in copy number after treatment was defined as molecular response (mR); (3) new appearance of KRAS-mutated ctDNA or increase in copy number after treatment was defined as molecular progressive disease (mPD). We investigated whether the increase or decrease of CA19-9 before and after treatment (Increase group, decrease group) and the molecular assessment were useful as prognostic factors in the Responder group. Results: Male: female = twenty-nine: thirty-two. There were fourteen patients in the locally advanced group and forty-seven patients in the distant metastatic group, both of whom were considered non-resectable. Thirty-eight patients received any second-line treatment. The prognosis of fourteen patients with PD on initial imaging was significantly worse than that of the Responder group (N=47) (Responder: PD=18.4: 9.2 months, p=0.000108). The molecular assessment in the responder group showed 30 patients in mNT group, 10 patients in mR group, and 7 patients in mPD group. The MST was 21.7, 13.2, and 13.2 months. In univariate analysis, increased CA19-9 (Increase group) and mPD were associated with worse prognosis (Increase: Decrease=13.6: 18.4 months, p=0.0487), (mPD: mNT+mR=13.2: 21.7 months, p=0.0194) and the only independent prognostic factor in multivariate analysis was mPD (Hazard ratio=3.005, p=0.0361). Conclusions: The prognosis of patients with molecular negative or molecular response after chemotherapy is relatively good (MST; 21.7 months), and efforts should be made to continue GnP and FFX. In contrast, the prognosis of patients with molecular progressive disease in the responder group is worse. Therefore, strict follow-up and change of anticancer drugs, including palliation, should be considered.
Tislelizumab (TIS) plus chemotherapy (Chemo) vs placebo (PBO) plus chemo as first-line (1L) treatment of advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC): Health-related quality of life (HRQoL) outcomes in the RATIONALE-305 study.
Authors: Marcia Cruz-Correa, Rui-Hua Xu, Markus H. Moehler, Do-Youn Oh, Ken Kato, David R. Spigel, Hendrik-Tobias Arkenau, Josep Tabernero, Anastasia V. Zimina, Yuxian Bai, Jianhua Shi, Keun-Wook Lee, Hidekazu Hirano, Lucjan S. Wyrwicz, Roberto Pazo Cid, Hui Xu, Tao Sheng, Gisoo Barnes
Journal: Journal of Clinical Oncology (2024)

290 Background: RATIONALE-305 (NCT03777657), demonstrated statistically significant and clinically meaningful improvements in overall survival (OS) with TIS + chemo (n=501) over PBO + chemo (n=496) as 1L treatment in patients (pts) with advanced G/GEJC. This analysis examined HRQoL outcomes of the RATIONALE-305 study at final analysis. Methods: Adults with previously untreated, unresectable, or metastatic GC/GEJC, were randomized (1:1) to TIS 200 mg or PBO IV once every 3 weeks plus investigator-choice of chemo. HRQoL was assessed using EORTC QLQ-C30 and the QLQ-STO22. A mixed model for repeated measures using PRO endpoints at clinical Cycles 4 and 6 was performed. Time to deterioration was examined. Results: TIS + chemo had improved outcomes than PBO + chemo (Table) as indicated by least-squares mean change from baseline to Cycle 6 for QLQ-C30 GHS/QoL (2.52 [95% CI:0.29 to 4.74]), physical functioning (2.46 [95% CI: 0.49 to 4.43]), fatigue (-3.01 [95% CI: -5.78 to -0.24]), and the STO22 index score (-1.62 [95% CI: -3.12 to -0.12]), as well as maintaining upper gastrointestinal (GI) symptoms (-1.74 [95% CI: -3.55 to 0.06)] and pain (-1.88 [95% CI: -4.03 to 0.27]). Pts receiving TIS + chemo had a lower risk for deterioration of GHS/QoL (0.77 [95% CI: 0.60 to 0.98]), physical functioning (0.72 [0.57 to 0.92]), STO22 index score (0.64 [0.45 to 0.92]), pain/discomfort (HR: 0.74 [0.58-0.96]), and upper GI symptoms (0.73 [0.56 to 0.95]). Conclusions: Pts treated with TIS + chemo had better HRQoL outcomes vs pts treated with PBO + chemo, particularly for GHS/QoL, physical functioning, fatigue, GC/GEJC symptoms, pain/discomfort, and upper GI symptoms These results, along with prolonging of OS and other secondary efficacy endpoints, as well as a tolerable safety profile, support the benefit of TIS + chemo as a potential 1L treatment option for GC/GEJC. Clinical trial information: NCT03777657 . [Table: see text]
Incidence patterns of colorectal cancer in Norway 1993-2022 by age, site, and morphology.
Authors: Mari Fjørtoft Ystgaard, Tor Åge Myklebust, Jørgen Smeby, Inger Kristin Larsen, Tormod Kyrre Guren, Elin H. Kure, Kjell Magne Tveit, Bengt Glimelius, Marianne G. Guren, Julian Hamfjord
Journal: Journal of Clinical Oncology (2024)

44 Background: The incidence of colorectal cancer (CRC) has decreased or stabilized in most high-income countries, but an alarming increase is observed in younger adults. Norway has high CRC incidence, which increased until the past two decades, then stabilized. A national screening program started in 2022; hence, this study is on a screening-naïve population. We aim to describe up-to-date incidence patterns of CRC, with emphasis on age-specific differences in tumor site and morphology. Methods: We extracted data on all CRC cases diagnosed 1993 to 2022 from the Cancer Registry of Norway, with completeness estimated to be &gt;99%. Data was stratified by age groups (20-49, 50-74, and ≥75), sex, primary tumor location and morphology. Age-adjusted incidence rates were calculated using Stata 17 and analyzed using Joinpoint regression to provide annual percentage change (APC) and average annual percentage change (AAPC) of incidence rates. Results: There were 107 524 cases eligible for analysis. In the age group ≥75, overall incidence increased (AAPC 0.8), mainly caused by right-sided colon cancer (RCC), which increased until 2016 (APC 2.5), followed by a slight decrease (APC -0.9). The age group 50-74 had stable incidence (AAPC -0.2). Incidence in the age group 20-49 increased (AAPC 1.3), caused by left-sided colon cancer (LCC) and rectal cancer (RC). When stratifying on morphology, incidence of mucinous carcinomas was stable (AAPC -0.6), approx. 10% of all CRC cases. Neuroendocrine neoplasms (NEN) increased in all age groups (AAPC 4.2), accounting for only 1.4% of all CRC cases; but contributed somewhat to the overall incidence in age group 20-49, in particular RC where 8.8% of cases were NEN. In the age group 20-49, adenocarcinomas had an AAPC of 1.4, mucinous carcinomas -0.8, and NEN 4.1. Conclusions: We found an increasing incidence of CRC in the youngest (&lt;50) and elderly (≥75). LCC and RC incidence increased in the youngest age group, still increasing up until 2022. In contrast, the increase in the elderly was mostly due to RCC. Different incidence patterns of primary tumor locations in younger and older age groups may imply differences in etiology and prognosis, different biological features and possibly therapeutic implications. [Table: see text]
Biochemotaxis‐Oriented Engineering Bacteria Expressing GLP‐1 Enhance Diabetes Therapy by Regulating the Balance of Immune
Authors: Yifei Wang, Yupeng Shi, Xueyuan Peng, Tongtong Li, Chenglin Liang, Wenhao Wang, Mengyang Zhou, Jiali Yang, Jingliang Cheng, Zhenzhong Zhang, Lin Hou
Journal: Advanced Healthcare Materials (2024)

Abstract Glucagon like peptide‐1 (GLP‐1) is an effective hypoglycemic drug that can repair the pancreas β cells and promote insulin secretion. However, GLP‐1 has poor stability and lacks of target ability, which makes it difficult to reach the site of action to exert its efficacy. Here, GLP‐1‐expressing plasmids are introduced into the Escherichia coli Nissle 1917 (EcN) and a lipid membrane is formed through simple self‐assembly on its surface, resulting in an oral delivery system (LEG) capable of resisting the harsh environment of the gastrointestinal tract. The system utilizes the chemotactic properties of probiotics to achieve efficient enrichment at the pancreatic site, and protects islet β cells from destruction by regulating the balance of immune cells. More interestingly, LEG not only continuously produces GLP‐1 to restore pancreatic islet β cell function and secrete insulin to control blood sugar levels, but also regulates the intestinal flora and increases the richness and diversity of probiotics. In mice diabetes models, oral administration of LEG only once every other day has good biosafety and compliance, and achieves long‐term control of blood glucose. Therefore, this strategy not only provides an oral delivery platform for pancreatic targeting, but also opens up new avenues for reversing diabetes.