tbuckley/cabot-search huggingface dataset:
Artificial intelligence (AI)-powered tumor microenvironment (TME) analysis to identify potential biomarkers for ICIs with or without bevacizumab in hepatocellular carcinoma (HCC).
Authors: Hong Jae Chon, Gwangil Kim, Beodeul Kang, Jung Yong Hong, Haeyoun Kang, Sohyun Hwang, Sung Hwan Lee, Sanghoon Jung, Chansik An, Won Suk Lee, Seulki Kim, Yoojoo Lim, Siraj Mahamed Ali, Chan-Young Ock, Ho Yeong Lim, Chan Kim
Journal: Journal of Clinical Oncology (2024)

549 Background: While immunotherapies have been approved for use in HCC patients, there is a need for validated predictive biomarkers that correlate with treatment outcomes. We investigated whether AI-powered spatial analysis of non-cancerous cells within the TME can be potential biomarkers for ICIs with or without bevacizumab in advanced HCC. Methods: Analysis of images of H&amp;E-stained slides was conducted by an AI model, Lunit SCOPE IO in pre-treatment tumor samples of 163 HCC patients treated with atezolizumab plus bevacizumab as first-line ( n=82), or monotherapies of nivolumab or pembrolizumab as ≥ second-line ( n=81) at CHA Bundang Medical Center or Samsung Medical Center. We analyzed the correlation between clinical outcomes after the treatment and AI-powered TME-related variables, including TILs and endothelial cells, within intratumoral or stromal areas. Inflamed immune phenotype (IIP) was defined as cases exhibiting enrichment of intratumoral TILs. Results: Baseline characteristics, including Child-Pugh liver classification, Barcelona Clinic Liver Cancer stage, and hepatitis B virus, were well-balanced between treatment regimens. IIP was predictive of longer progression-free survival (PFS) of nivolumab or pembrolizumab monotherapy (median PFS 4.7 months for IIP vs. 2.2 months for non-IIP; hazard ratio [HR] 0.50; 95% confidence interval [CI] 0.25-0.99; p=0.042), but not PFS of atezolizumab plus bevacizumab (median PFS 6.8 months vs. 6.2 months; HR 0.92; 95% CI 0.50-1.69; p=0.762). PFS of atezolizumab plus bevacizumab was significantly longer in cases harboring intratumoral endothelial cell density in the highest quartile (median PFS 6.7 months for upper 25% vs. 3.9 months for lower 75%; HR 0.51; 95% CI 0.27-0.97; p=0.037), while there was no significant difference in PFS of pembrolizumab or nivolumab monotherapy (median PFS 2.3 months vs. 2.8 months; HR 1.02; 95% CI 0.59-1.77; p=0.935). Conclusions: AI-powered TME analysis shows IIP is predictive of longer PFS with ICI monotherapies, whereas intratumoral endothelial cell density is specifically associated with PFS of atezolizumab plus bevacizumab in advanced HCC. The latter finding may suggest efficacy of combined VEGFRi and ICI activity is dependent on the amount of baseline tumor vasculature.
Anlotinib plus TQB2450 (PD-L1 blockade) combined with nab-paclitaxel and cisplatin as first-line treatment for advanced biliary tract cancer: A single-arm, open-label phase II clinical trial.
Authors: Shui-Ling Jin, Shishi Qiao, Ren-Feng Li, Weijie Zhang, Wei He, Chang Su, Lu-Hao Li, Jie Pan, Wen-Zhi Guo, Hong Zong
Journal: Journal of Clinical Oncology (2024)

498 Background: Efficacy and prognosis of chemotherapy in first-line setting for patients with advanced biliary tract cancer (BTC) was dismal currently. Recently, PD-1/PD-L1 blockades combined with dual chemotherapy in first-line setting exhibited superior efficacy for patients with BTC. Nevertheless, it's important to highlight that both the TOPAZ-1 and KEYNOTE-966 trials had reported a median OS of less than 13 months. This underscored the necessity for further advancements to meet the demands of clinical practice. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, demonstrated promising therapeutic activity as second-line therapy for patients with BTC. Therefore, this study was designed to explore the efficacy and safety of anlotinib plus TQB2450 (PD-L1 blockade) combined with nab-paclitaxel and cisplatin as first-line therapy in advanced BTC. Methods: Patients with previously untreated metastatic or locally advanced BTC (ICC, ECC, GBC) were recruited and treated with anlotinib (10mg, po, d1~14, q3w) and TQB2450 (1200mg, iv, d1, q3w) plus nab-paclitaxel (200mg/m 2 , iv, d1, q3w) and cisplatin (60mg/m 2 , iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 using CT scans every two cycles. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 20. Primary endpoint was ORR and secondary endpoints included safety, DCR, PFS, OS and biomarker explore. Results: From April 2023 to Aug 2023, a total of 18 patients were enrolled, 14 patients who had received first tumor response were included in this analysis. The best overall response indicated that there were 6 PR (42.9%), 7 SD (50.0%) and 1 PD (7.1%). Therefore, the preliminary ORR was 42.8% (95%CI: 17.7%-71.1%), DCR was 92.9% (95%CI: 66.1%-99.8%). Median PFS of the 14 patients was not yet reached. Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-emergent adverse events among the 18 patients with the incidence &gt;30% were leukopenia (67%), fever (39%), pain in extremity (33%) and malaise (28%). Common grade ≥3 treatment-emergent adverse events were leukopenia (28%), fever (6%), malaise (6%), stomachache (6%), oral mucositis (6%), thrombocytopenia (6%), vomit (6%), rash (6%) and hypotension (6%). Conclusions: Preliminary results suggested that anlotinib plus TQB2450 combined with nab-paclitaxel and cisplatin as first-line therapy in advanced BTC exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more patients consecutively. Clinical trial information: NCT05812430 .
Tumor genomics and sidedness to predict outcomes in metastatic colorectal cancer (mCRC).
Authors: Patrick M Boland, Julia Quintanilha, Gerald Li, Allison Clark, Erik Carlson, Samantha Morley, Ali Aboosaiedi, Jerry W. Mitchell, Jeffrey S. Ross, Ryon Graf, Dustin A. Deming, Christopher Hanyoung Lieu
Journal: Journal of Clinical Oncology (2024)

207 Background: Tumor sidedness is a prognostic factor and predictive parameter for EGFR monoclonal antibody (mAb) treatment in mCRC. Sidedness is believed to be a surrogate for genomic differences. This study aimed to evaluate genomics vs. tumor sidedness in anticipating outcomes in mCRC. Methods: We included patients (pts) with microsatellite stable mCRC tested by Foundation Medicine tissue comprehensive genomic profiling assay. Patient data was obtained by the US-based de-identified Flatiron Health-Foundation Medicine real-world clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (1/2011–3/2023). Genomic alterations (GA) in 324 genes were compared between right and left side tumors using Fisher’s exact test, adjusted for multiple comparisons. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were compared by Cox proportional hazard models adjusted for prognostic features in pts receiving 1 st line chemotherapy (chemo) + EGFR mAb or bevacizumab (bev). Multivariable analyses including prognostic features, sidedness and GA were performed. Comparisons of the explanatory power of genomics vs. sidedness were performed by the likelihood ratio test (LRT). Results: 3845mCRC pts (2584 left and 1261 right) were included. GA in APC, TP53, ARID1A, and FBXW7 were more prevalent in left side, while GA in BRAF, KRAS, AMER1A, PIK3CA, RNF43, BCOR, PTEN, SMAD4, MAP2K1, and BCOR in right side. 2109 pts received chemo + EGFR mAb or bev. Multivariable analyses identified BRAF, KRAS, MAP2K1, and APC as independently associated with outcomes. Pts were classified as having GA in RAS pathway (RASalt: KRAS/NRAS, BRAF, or MAP2K1), APC (APCalt), both RAS pathway and APC (APC/RASalt), and none. RASalt group had less favorable outcomes while APCalt group had more favorable outcomes, regardless of treatment received and sidedness. LRT indicated that when genomics was added to the sidedness evaluation, there was an improvement in outcome prediction (p&lt;0.001), but not when sidedness was added to genomics. Conclusions: Tumor genomics better explains differences in outcomes than sidedness in 1 st line treatment in mCRC. [Table: see text]
Exocrine pancreatic insufficiency as a possible predictor of pancreatic cancer development.
Authors: James Gore, Karina G. Romo, James Peeples, Abdullah A. Noor, Gabriel I. Uwaifo
Journal: Journal of Clinical Oncology (2024)

679 Background: Chronic and acute pancreatitis are established risk factors for pancreatic cancer. Chronic pancreatitis and pancreatic cancer are also common causes of exocrine pancreatic insufficiency (EPI), which is characterized by inadequate pancreatic secretion of exocrine digestive enzymes. Although the association between EPI and pancreatic cancer has been thought to be linked by preceding chronic pancreatitis, it is unclear if EPI, regardless of etiology, is a risk factor or early marker for pancreatic cancer or cancer in general. Methods: This is a retrospective observational study utilizing the electronic health records of Ochsner Health System, Louisiana, over a 3-year period from January 2017 to January 2020 to identify patients with a diagnosis of EPI by ICD-10 codes. Two cohorts were reviewed: patients with EPI (n=677) and patients with pancreatitis (n=1852). Both history of acute and/or chronic pancreatitis were included in the pancreatitis cohort. The cohorts were compared based on cancer prevalence at the start and end of the 3 year observation period. Results: In the EPI cohort, the cancer prevalence was 15.95% (108) at start, and 43.9% (297) at end, (p&lt;0.05); and pancreatic cancer prevalence at start was 6.65% (123) and 29.8% (552) at end (p&lt;0.05). In the pancreatitis cohort, the cancer prevalence was 5.4% (100) at start and 15.9% (294) at end (p&lt;0.05); and pancreatic cancer 0.8% at start and 5% at end (p&lt;0.05). Conclusions: Over a 3 year period, the rise in prevalence of general cancer and pancreatic cancer was higher in the EPI cohort compared to the pancreatitis cohort. Additionally, there was a statistically significant 2.8-fold increase in prevalence of cancer diagnosis and 4.5-fold increase in prevalence of pancreatic cancer diagnosis in the EPI cohort over the 3 year observation period. Though this is an observational study, it suggests the possibility that EPI, regardless of etiology, may be an independent predictor/risk factor for the development of future cancer in general and pancreatic cancer in particular. In addition it appears that this risk potential is substantively greater than that from a history of pancreatitis alone.
A retrospective analysis of the efficacy and safety of imatinib in elderly patients with advanced gastrointestinal stromal tumor.
Authors: Takahito Awatsu, Hidekazu Hirano, Kunihito Matsuguma, Toshiharu Hirose, Natsuko Tsuda Okita, Hirokazu Shoji, Atsuo Takashima, Ken Kato
Journal: Journal of Clinical Oncology (2024)

730 Background: Gastrointestinal stromal tumor (GIST) is a rare mesenchymal tumor arising from the gastrointestinal tract, characterized by a high predominance of the elderly population. Imatinib is the standard first-line therapy for advanced GIST with a median survival of around 4 years in pivotal clinical trials. However, clinical data for the elderly population is not known well. The aim of this study is to evaluate the efficacy and safety of imatinib for advanced GIST in the elderly population in comparison with the non-elderly population. Methods: We extracted clinical data of patients with advanced GIST treated with imatinib as first-line therapy at our institution between January 2010 and July 2023. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and adverse events (AEs) were assessed and compared between the elderly group (age: ≥ 70 years, E group) and the non-elderly group (age: &lt; 70 years, NE group). Multivariable analyses were performed using Cox proportional hazard models to evaluate the prognostic significance of age groups. Results: A total of 91 patients were included in this analysis with 32 patients in the E group and 59 patients in the NE group with a median follow-up duration of 39.8 months. Patient characteristics were as follows (the E group vs. the NE group): median age 76 (70–90) vs. 54 (29–69) years, male: 50% vs. 56%, performance status 0: 19% vs. 63%, disease status (: 47% vs. 44%), stomach primary 44% vs. 34%, KIT mutation (exon 11: 50% vs. 61%), and maximum tumor diameter (≥8cm: 66% vs. 51%). The proportion of patients with a reduced starting dose of imatinib was significantly higher in the E group (34% vs. 2%, p &lt;0.0001). Median PFS in the E group and the NE group were 29.4 months and 60.0 months (HR=2.04, log-rank p=0.035). Median OS in the E group and the NE group were 91.5 months and not reached (HR=2.74, log-rank p=0.02). ORR was 53% in the elderly group and 66% in the non-elderly group (p=0.32). In for OS, age was not an independent prognostic factor (HR=2.09, p=0.14) with a significant independent prognostic factor of disease status (unresectable/initially metastatic vs. recurrent (reference): HR=3.58, p=0.03). The occurrence of ≥ grade 2 non-hematologic AEs was more common in the elderly group compared to the non-elderly group (78% vs. 32%, p&lt;0.001). Conclusions: The elderly population with advanced GIST may achieve a survival period comparable to that observed in pivotal trials with imatinib. Even with reduced doses of imatinib, careful monitoring is necessary because of the high frequency of non-hematologic ≥ grade 2 AEs in the elderly population.
Phase II results of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer: NRG-GI005 (COBRA) phase II/III study.
Authors: Van K. Morris, Greg Yothers, Scott Kopetz, Shannon L. Puhalla, Peter C. Lucas, Atif Iqbal, Patrick M Boland, Dustin A. Deming, Aaron J. Scott, Howard J Lim, Samuel A. Jacobs, Theodore S. Hong, Norman Wolmark, Thomas J. George
Journal: Journal of Clinical Oncology (2024)

5 Background: For patients (pts) with colon cancer (CC), the detection of circulating tumor DNA (ctDNA) is associated with persistent disease after resection and outperforms traditional clinical and pathological features in prognosticating recurrence risk. We hypothesized that for pts with low-risk stage II CC, a positive ctDNA status after resection may identify those who benefit from adjuvant chemotherapy. Methods: In this prospective phase II/III clinical trial, pts with resected stage II CC without traditional high risk features and whom the evaluating oncologist deems suitable for active surveillance (i.e., not needing adjuvant chemotherapy) were randomized 1:1 to two arms: standard-of-care/observation (Arm A), or ctDNA assay directed therapy (Arm B). Postoperative blood was analyzed for ctDNA with the Guardant LUNAR assay, covering CC-relevant mutations and CC-specific methylation profiling. Arm B pts with ctDNA detected were treated with 6 mos of adjuvant (CAPOX or FOLFOX) chemotherapy. Primary endpoint for the phase II study was clearance of ctDNA at the 6-mo timepoint. A 1-sided Fisher exact test was used to compare ctDNA clearance between Arm A and Arm B among the first 16 pts with ctDNA detected at baseline. If p&gt;.35, the study would be stopped for futility of ctDNA clearance but would otherwise continue to phase III if p≤.35. We present the results of the pre-planned phase II analysis. Results: 635 pts were randomized (Arm A: 318; Arm B: 317). One pt with ctDNA detected in Arm B declined protocol-directed chemotherapy but was included in the intention to treat analysis. Among the first 16 pts with ctDNA detected at baseline for the primary endpoint analysis, clearance of ctDNA after 6 mos was observed in 3/7 pts (43%, 95% CI 10-82%) in the control arm and in 1/9 pts (11%, 95% CI 0.3-48%) in the experimental arm after chemotherapy (p=.98). There were no unanticipated toxicities in those treated with chemotherapy. Conclusions: The phase II endpoint was not met and further enrollment has been halted based upon pre-specified study stopping rules utilizing the original assay. No improvement in ctDNA clearance was observed after 6 mos of chemotherapy for pts with ctDNA detected following resection of stage IIA CC. Future trials evaluating ctDNA as an integral biomarker for minimal residual disease determination must account for assay specificity in this pt population. Support: U10CA180868, -180822; UG1CA189867; Guardant Health. Clinical trial information: NCT04068103 .
Mucin 5 AC (MUC5AC) to predict pathologic treatment response (TR) to neoadjuvant chemotherapy (NAT) in resected-pancreatic ductal adenocarcinoma (R-PDA).
Authors: Ashish Manne, Ankur Sheel, Amir Sara, Anne M. Noonan, Lianbo Yu, Wancai Yang, John L. Hays, Arjun Mittra, Pannaga G. Malalur, Shafia Rahman, Sameek Roychowdhury, Rifat Elkatib, Ning Jin, Jordan M. Cloyd, Mary Dillhoff, Aslam Ejaz, Ashwini K. Esnakula
Journal: Journal of Clinical Oncology (2024)

690 Background: MUC5AC is a gel-forming glycoprotein that exists in two major glycoforms in PDA. We studied the differential expression and predictive value of heavily glycosylated mature MUC5AC (MM) detected in the apical (Ap) and/or extracellular region (EC) and less-glycosylated immature MUC5AC (IM) detected only in the cytoplasm (Cy) in R-PDA. Methods: R-PDA formalin-fixed paraffin-embedded tissue blocks from January 2010 to June 2021 were obtained from the Ohio State University biorepository. Immunohistochemistry was performed to study the expression for MM and IM using monoclonal antibodies 45M1 and CLH2, respectively, and H-scores were calculated. Analysis of variance (ANOVA), t-tests, and Wilcoxon tests were used for statistical analysis. Results: Tissue samples from 100 R-PDA (43 received NAT and 57 had upfront surgery (UpS)) were available for testing. The median age of diagnosis was 65 years, and 50% were females. MM and IM were positive in 96% R-PDA (MM-95% Ap and 72% EC).In the NAT group, 89% (n=38) had 5-fluorouracil (5FU) based (36 FOLFIRINOX and 2 FOLFOX), and the rest received gemcitabine (Gem)-based therapy; patients received a median of 6 cycles of NAT; 37% (16) had preoperative chemoradiation (CRT) after NAT; 63% (27) had adjuvant systemic therapy (AST); pathologic objective response (OR = near complete or partial) and no response (NR) to NAT was reported in 63% (27) and 37% (16), respectively. In UpS group, 92% and 4% had AST (48 Gem-based, 4 5FU-based) and adjuvant CRT, respectively. The median time to recurrence (mTTR) and overall survival of the group was 15 and 33 months (m), respectively. NAT group had significantly (p&lt;0.05) lower EC-positive MM (mean H-score 108 vs. 151), IM (mean H-score 122 vs. 162), and mTTR (11 vs 15 m) than UpS group. IM levels were directly proportional to the response (near complete (mean H-score 98) &lt; partial (105) &lt; NR (152) &lt; UpS (162), p=0.04). Other TR results are discussed in the table. Conclusions: MUC5AC (IM &gt; MM) is a potential predictive marker for TR among PDA patients, specifically among those receiving FOLFIRINOX. These associations must be validated in further prospective studies.[Table: see text]
Health-related quality of life (HRQOL) with pembrolizumab (pembro) plus trastuzumab (tras) and chemotherapy (chemo) in first-line HER2-positive (HER2+) advanced gastric cancer: KEYNOTE-811 trial results.
Authors: Yelena Y. Janjigian, Akihito Kawazoe, Jianming Xu, Sara Lonardi, Jean-Philippe Metges, Lucjan S. Wyrwicz, Lin Shen, Yuriy Ostapenko, Mehmet Bilici, Maeve Aine Lowery, Adriana Valderrama, Yanfen Guan, Kan Li, Chie-Schin Shih, Sun Young Rha
Journal: Journal of Clinical Oncology (2024)

286 Background: In the phase 3 KEYNOTE-811 study (NCT03615326), first-line (1L) pembro with tras + chemo (pembro arm) yielded superior PFS and improved ORR with durable responses versus placebo (pbo) with tras + chemo (pbo arm) in pts with HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, notably in pts with PD-L1 combined positive score (CPS) ≥1. Key prespecified exploratory HRQOL outcomes supporting these data are presented. Methods: Pts with untreated histologically or cytologically confirmed advanced HER2+ G/GEJ adenocarcinoma, measurable disease per RECIST v1.1 by investigator, and ECOG PS of 0 or 1 were randomly assigned 1:1 to receive pembro 200 mg or pbo IV every 3 weeks (Q3W) with tras + chemo (cisplatin + 5-fluorouracil or capecitabine + oxaliplatin). HRQOL was evaluated in pts who received ≥1 dose of study treatment and completed ≥1 pt-reported outcome (PRO) assessment. End points were least squares mean (LSM) change from baseline, time to deterioration (TTD), and overall improvement/stability rate in prespecified subscales of EORTC QLQ-C30, QLQ-STO22, EuroQol EQ-5D-5L. LSM changes from baseline were analyzed at wk 24 when prespecified completion and compliance rates of ~60% and 80%, respectively, were met, based on review of blinded data. Results: In the PRO analyses, 685 pts were evaluable (345 pembro with tras + chemo; 340 pbo with tras + chemo). Median time from randomization to data cutoff (May 25, 2022) was 28.4 mo (range, 9.3-42.6). Completion rates were &gt;92% at baseline and &gt;55% at wk 24 for all assessments in both arms. Similar changes in PRO scores from baseline to wk 24 were observed for the pembro versus pbo arms (Table). Similar percentages of pts in each arm had improved or stable scores for the EORTC QLQ-C30 GHS/QOL and physical functioning scales and EORTC QLQ-STO22 subscales. TTD was similar between arms for all prespecified subscales. Conclusions: The addition of pembro to tras + chemo did not negatively affect HRQOL during treatment. Combined with safety and efficacy data, these results support the use of pembro with tras + chemo for first-line treatment of pts with HER2+ advanced gastric cancer. Clinical trial information: NCT03615326 . [Table: see text]