bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world treatment trends and outcomes in elderly patients with metastatic colorectal cancer in the United States.
Authors: Trunk Andrew , Baron Margaret Kelsey , Smith Jarrod , Pappas Lisa M. , Haaland Ben , Florou Vaia , Nevala-Plagemann Christopher Duane , Garrido-Laguna Ignacio
Published: June 2023

3591

Background: Prospective data to guide management of elderly patients with metastatic colorectal cancer (mCRC) is limited. Whether elderly patients derive the same degree of benefit from doublet chemotherapy as younger patients is not well understood. In this study we utilized real-world data from patients in the United States (US) to evaluate treatment trends and compare overall survival (OS) in younger versus older patients with mCRC who receive first-line (1L) chemotherapy. Methods: The nationwide Flatiron Health electronic health record-derived de-identified database was used to select patients ≥50 years old (yo) with mCRC treated with 1L fluoropyrimidine-based chemotherapy with or without the addition of targeted therapy. Overall survival from the initiation of 1L therapy, stratified by receipt of a doublet or single agent cytotoxic chemotherapy regimen was assessed independently within three age cohorts (50-69; 70-74, ≥75) using both a cox proportional hazard model and a propensity score weighted analysis to control for potential confounding variables. A subgroup analysis was performed in patients receiving bevacizumab as part of 1L therapy. Results: Of 14,440 patients who received 1L chemotherapy, 5,874 (40.7%) were ≥70 yo, including 3,656 (25.4%) who were 75 or older. Doublet chemotherapy was received by 7,505 (87.6%) patients age 50-64 yo, 1892 (85.3%) patients age 70-74 yo, and 2297 (62.2%) patients age 75 and above. In all three groups, multivariate analysis of single agent chemotherapy vs doublet chemotherapy showed a benefit to doublet chemotherapy with a hazard ratio of 1.14, (95% CI 1.04-1.24, p = 0.006), 1.22 (95% CI 1.05-1.42, p = 0.011) and 1.19 (95% CI 1.10-1.29, p < 0.001), respectively. Similar results were noted when comparing doublet to single agent chemotherapy in the age 70-74 and ≥75 groups using a propensity score weighted analysis. In the subgroup of patients age ≥70 who received 1L bevacizumab, 2,604 received doublet chemotherapy and 441 received single agent chemotherapy. Median OS was 19 mos (95% CI: 18-20) vs 13 (95% CI: 11-15) vs with a propensity score weighted HR of 1.35 (95% CI 1.12-1.63, p = 0.001). Conclusions: A smaller percentage of patients over age 75 receive 1L doublet chemotherapy for mCRC in the US compared to patients age 50-69 or 70-74. Regardless of age, patients who receive doublet fluoropyrimidine-based chemotherapy appear to have improved overall survival compared to single agent chemotherapy. This retrospective US data is in contrast with recently presented data from a prospective phase III trial in Japan (JCOG1018). Elderly patients in the US should not be excluded from receiving doublet chemotherapy for mCRC without further prospective data.
The significance of mucin on rectal MRI in patients with locally advanced rectal cancer being considered for watch-and-wait after neoadjuvant therapy.
Authors: Judge Sean , Malekzadeh Parisa , Corines Marina J , Gollub Marc J , Horvat Natally , Saltz Leonard B. , Cercek Andrea , Romesser Paul Bernard , Crane Christopher H , Wei Iris H , Widmar Maria , Pappou Emmanouil , Nash Garrett Michael , Smith Jesse Joshua , Paty Philip , Garcia-Aguilar Julio , Weiser Martin R.
Published: June 2023

3614

Background: Neoadjuvant therapy (NAT) leads to a clinical complete response (cCR) in a significant proportion of patients with locally advanced rectal cancer (LARC) allowing for possible non-operative management. Along with physical exam and proctoscopy, magnetic resonance imaging (MRI) is used to evaluate for residual tumor following NAT. The presence of mucin on MRI leads to uncertainty about residual disease and appropriateness of watch-and-wait strategy (WW) in patients with no evidence of disease on proctoscopy (endoscopic cCR). We set out to determine the impact of radiographic mucin in patients with LARC after NAT. Methods: MRI reports between July 2016 to January 2020 at Memorial Sloan Kettering Cancer Center were queried for the presence of mucin in the tumor bed on post-treatment rectal MRI in patients with LARC following NAT. The clinicodemographic, pathologic, and outcomes data from these patients were compiled and analyzed. Results: Seventy-one patients were included in the final analysis who fit the pre-specified inclusion criteria (Table). Of the 71 patients with mucin present on post-treatment MRI, 19 patients (27%) entered a watch-and-wait (WW) strategy and 52 patients (73%) were planned for surgery (non-WW). Comparing the WW and non-WW cohorts, there was no difference in age, sex, clinical nodal status, or neoadjuvant regimen. Patients entering a WW protocol had a higher proportion of cT1-T2 tumors (32%) compared to non-WW (4%) (P < 0.01). All WW patients had endoscopic cCR, while only one non-WW patient achieved endoscopic cCR. Of 52 non-WW patients, 49 underwent resection and 3 did not have surgery due to disease progression. The pathologic complete response (pCR) rate in the non-WW patients who underwent surgery was 10%. Of 19 WW patients, 4 experienced regrowth (21%), while 15 (79%) have no local regrowth, with a median follow up of 4.2 years (range 2.4-6.3 yrs). Two patients (11%) experienced distant failure. Conclusions: The presence of mucin after NAT for LARC should not necessarily preclude a WW strategy in otherwise appropriate candidates who achieve an endoscopic cCR. [Table: see text]
Treatments and clinical outcomes in stage II colon cancer (CC) patients (pts) with 12-gene Oncotype DX Colon Recurrence Score assay-guided therapy: Real-world data.
Authors: Brenner Baruch , Shulman Yakatherina , Hubert Ayala , Man Sofia , Geva Ravit , Ben-Aharon Irit , Fennig Shlomit , Mishaeli Moshe , Yarom Nirit , Bar-Sela Gil , Brenner Ronen , Shay Ayelet , Soussan-Gutman Lior , Voet Hillary , Bareket-Samish Avital , Liebermann Nicky
Published: June 2023

3620

Background: The role of adjuvant chemotherapy (CT) in stage II CC is debated. The validated 12-gene Oncotype DX Colon Recurrence Score test provides a Recurrence Score (RS) result (range, 0-100) which estimates recurrence risk (RR) in stage II/III pts. We studied treatment and clinical outcomes in CC pts in whom treatment decisions incorporated the RS result. Methods: This prospectively designed cohort study included all stage II, MMR-P, CC pts who underwent the 12-gene Oncotype DX testing through Clalit between 1/2011 and 12/2016 and had available data with minimum 3-yr follow-up. Kaplan-Meier (KM) estimates and log-rank tests were used to compare RR and CC specific mortality (CCSM) between RS categories. Multivariable analysis (MVA) identified variables associated with RR/CCSM. Results: The analysis included 938 pts. Median age, 68 (IQR, 60-76) yrs; 96% had T3 tumors, and 89% had ≥12 nodes examined. Median RS was 26 (IQR, 19-33). The 3 RS categories (0-29, 30-40, and 41-100) included 65%, 24%, and 11% of pts, respectively. The overall CT use rate was 24%, with a significant difference between the 3 categories (14%, 36%, and 60%, respectively, P< .0001). Pts with very low RS (0-15) comprised 14% of the cohort (CT use rate, 11%). Younger pts, and those with invasion/perforation/obstruction were more likely to receive CT. Clinical outcomes with a median follow up of 6.9 (IQR, 5.5-8.6) yrs are presented (Table). Among untreated pts, KM estimates for RR and CCSM differed significantly between the 3 RS categories ( P< .0001). Outcome of untreated RS 0-15 pts was excellent. In an MVA model, male sex, presence of invasion/perforation/obstruction and higher RS category (RS 41-100 vs 0-29 and vs 30-40, but not RS 30-40 vs 0-29) were associated with increased RR. For CCSM, the results were similar, but this time age ≥70 yrs replaced sex as a significant prognostic variable. Clinical outcomes within each RS group did not differ significantly between treated and untreated pts, but were numerically better with CT in the RS 41-100 group. Conclusions: This real-world analysis showed that the RS results provide independent prognostic information in stage II CC. Further studies are needed to investigate the potential role of the RS result as a predictor of CT benefit, but the data suggest that this benefit may be limited to pts with high RS results. [Table: see text]
Liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): 12- and 18-month survival rates from the phase 3 NAPOLI 3 trial.
Authors: O'Reilly Eileen Mary , Melisi Davide , Macarulla Teresa , Pazo Cid Roberto A. , Chandana Sreenivasa R , De La Fouchardiere Christelle , Dean Andrew Peter , Kiss Igor , Lee Woo Jin , Goetze Thorsten Oliver , Van Cutsem Eric , Paulson Scott , Bekaii-Saab Tanios S. , Pant Shubham , Hubner Richard , Xiao Zhimin , Chen Huanyu , Benzaghou Fawzi , Wainberg Zev A.
Published: June 2023

4006

Background: Liposomal irinotecan + 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA and Europe for mPDAC following progression with gemcitabine-based therapy. A phase 1/2 study (NCT02551991) demonstrated promising anti-tumor activity in patients with mPDAC who received first-line liposomal irinotecan 50 mg/m2 + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin 60 mg/m2 (NALIRIFOX). Here, we present results from NAPOLI 3 (NCT04083235), a randomized, open-label, phase 3 study investigating the efficacy and safety of NALIRIFOX compared with nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 (Gem+NabP) as first-line therapy in patients with mPDAC. Methods: Eligible patients with histopathologically/cytologically confirmed untreated mPDAC were randomized (1:1; stratified by Eastern Cooperative Oncology Group [ECOG] performance status, geographic region and presence/absence of liver metastases) to receive NALIRIFOX on days 1 and 15 of a 28-day cycle or Gem+NabP on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate (ORR) and safety. OS was evaluated when at least 543 events were observed using a stratified log-rank test with an overall one-sided significance level of 0.025. Results: Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) were included. Baseline characteristics were balanced between arms. At a median follow-up of 16.1 months, 544 events had occurred. Median OS was 11.1 months in the NALIRIFOX group versus 9.2 months in the Gem+NabP group; median PFS was 7.4 months versus 5.6 months. Median (95% CI) duration of response was 7.3 (5.8–7.6) and 5.0 (3.8–5.6) months in patients who received NALIRIFOX and Gem+NabP, respectively. Grade 3/4 treatment-emergent adverse events occurring in at least 10% of patients receiving NALIRIFOX versus Gem+NabP included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%). Conclusions: First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvement in OS and PFS compared with Gem+NabP in patients with mPDAC. The NALIRIFOX safety profile was consistent with the profiles of the regimen components and generally manageable. Clinical trial information: NCT04083235 . [Table: see text]
A phase 2 study of HLX07 as monotherapy or combination therapy in patients with locally advanced, unresectable, or metastatic esophageal squamous cell carcinoma.
Authors: Huang Jing , Liu Yun , Wu Tao , Liu Zhen-yang , Zhou Jin , Yuan Yuan , Yang Mudan , Liu Bo , Tan Zhenbo , Zhuang Wu , Chen Jiayan , Liu Yanqing , Yu Haoyu , Wang Qingyu , Zhu Jun
Published: June 2023

4029

Background: Esophageal cancer is one of the most common cancers worldwide with esophageal squamous cell carcinoma (ESCC) being the predominant histological subtype. Most patients are diagnosed at the advanced stage, and the prognosis remains poor. About 40–84% of ESCC cases showed overexpression of EGFR which was related to shorter overall survival and disease-free survival, indicating that treatment targeting EGFR could be a new strategy. This study aimed to evaluate the efficacy and safety of HLX07, a novel recombinant humanized anti-EGFR monoclonal antibody (mAb), as monotherapy or combination therapy in patients with locally advanced, unresectable/metastatic ESCC. Methods: In this open-label, multicenter phase 2 study, patients aged 18–75 years with histologically or cytologically confirmed locally advanced, unresectable/metastatic ESCC or esophageal adenosquamous carcinoma were enrolled. Patients with no prior systemic antitumor therapy were assigned to group A and given HLX07 1000 mg plus serplulimab 200 mg (anti-PD-1 mAb) and chemotherapy (5-FU 2400 mg/m2 + cisplatin 50 mg/m2), Q2W IV. Patients who had failed first-line immuno-chemotherapy combination or at least two lines of other systemic antitumor therapy were assigned to group B and given HLX07 monotherapy (1000 mg Q2W IV). The primary endpoints were objective response rate (ORR) and progression-free survival (PFS) assessed by an independent radiological review committee and investigators per RECIST v1.1. Secondary endpoints included other efficacy measures, safety, pharmacokinetics, immunogenicity, and biomarker explorations. Results: As of February 4, 2023, 49 patients were enrolled in group A (n=30) and group B (n=19), with a median age of 64.5 and 59.0 years, respectively. 26 (86.7%) patients in group A and all patients in group B were male. The median follow-up duration was 2.9 months, and the preliminary efficacy was presented. Among the 42 efficacy evaluable patients (29 in group A and 13 in group B), investigator-assessed ORRs were 55.2% (95% CI 35.7–73.6%) and 23.1% (95% CI 5.0–53.8%) in the respective groups. Investigator-assessed median PFSs were not reached in group A and 1.5 months (95% CI 1.2–not evaluable) in group B. 15 (50.0%) patients in group A and 5 (26.3%) in group B had grade ≥3 treatment-emergent adverse events (AEs). AEs of special interest were observed in 16 (53.3%) and 11 (57.9%) patients, respectively, most commonly rash (43.3% vs 47.4%) and hypomagnesemia (33.3% vs 36.8%). No drug-related death was reported. Conclusions: The encouraging antitumor activity and manageable safety profile support further development of HLX07 as a new treatment option for patients with advanced ESCC, both in first-line and late-line settings. Clinical trial information: NCT05221658 .
Cell free DNA (cfDNA) assessment of esophagogastric (EG) cancer using MSK-ACCESS.
Authors: Cytryn Samuel Louis , Solit David B. , Walch Henry S. , Chatila Walid Khaled , Maron Steven Brad , Vakiani Efsevia , Brannon Angela Rose , Ladanyi Marc , Schultz Nikolaus , Berger Michael F. , Janjigian Yelena Y.
Published: June 2023

4036

Background: The incidence of EG cancer is rising, the treatment paradigm is increasingly complex, and the role of predictive biomarkers is critical in selecting optimal therapies. Therefore, longitudinal, non-invasive methods to characterize dynamic tumor molecular profiles, such as cfDNA, are needed. Methods: Patients with EG cancer receiving care at Memorial Sloan Kettering (MSK) had cfDNA analysis with an ultrasensitive capture based liquid biopsy for detection of somatic alterations in 129 cancer associated genes (MSK ACCESS). Tumor samples were analyzed with MSK-IMPACT, a capture based next generation sequencing (NGS) platform. Results: 100 patients with EG adenocarcinoma underwent cfDNA analysis to evaluate for molecular residual disease with MSK ACCESS. 85 (85%) had tissue NGS with MSK IMPACT. Median TMB was 5.3 mut/Mb (IQR 2.6-7.4) and median number of alterations per sample was 11 (IQR 7-17). 71% had TP53 mutations and 22% had an ERBB2 amplification (amp). 79 (79%) patients had cfDNA obtained prior to treatment (50 [63%] metastatic disease; 29 [37%] localized disease) and 21 (21%) at the time of progression. Alterations were detectable on cfDNA more frequently in patients with later stage disease (p=0.031) and fewer alterations per sample were detected compared to tissue NGS (mean difference 14, 95% CI 10-18, p<0.001). The most common were TP53 (62%), CDKN2A (12%), PIK3CA (10%), ARID1A (10%), and ATM (10%). TP53 was detected with increasing frequency in patients with later stage disease (p=0.004). However, amplifications, which included ERBB2, MYC, EGFR, and FGFR2, were detected exclusively in those with stage IV disease (p=0.005) and cfDNA was less sensitive in detecting amplifications compared to tissue NGS (p<0.001). This is notable as HER2 positivity is determined in part by ERBB2amp. 25 of 30 HER2+ patients had both tissue NGS and cfDNA. 19 (76%) had ERBB2amp on tissue NGS and only 8 (32%) had ERBB2amp on cfDNA (p=0.004). Additionally, copy number was lower on cfDNA compared to tissue NGS (mean difference 13, 95% CI 1.3-24.9, p=0.02) and IHC 3+ tumors were more likely to have ERBB2amp detected than IHC 2+ tumors (p=0.049). However, alterations along the MAPK, PI3K, WNT, and TGF-β pathways, which are associated with trastuzumab resistance and poor survival, were detected with similar frequency on both platforms (40 v 32%, p=0.77). Conclusions: Our findings in this large prospective analysis highlight the utility of cfDNA with MSK ACCESS as a complimentary tool for molecular characterization in patients with EG cancer. cfDNA in EG cancer. [Table: see text]
Advancing individualized care in advanced gastroesophageal cancers (GEC): A quality improvement initiative.
Authors: Strickland Matthew , Delcuze Bethany , Dewald Ilona , McKinnon Kelly E. , Carter Jeffrey D. , Heggen Cherilyn
Published: June 2023

4051

Background: Biomarkers have become increasingly important in the treatment of metastatic gastroesophageal cancers (mGEC) with new targeted and immune-based therapies relying on biomarkers to identify patients who may benefit from these therapies. Here, we aimed to identify real-world challenges mGEC care teams face in implementing biomarker testing and evidence-based treatment choices. Methods: In July–September 2022, 74 health care professionals (HCPs) who treat mGEC at 3 US community oncology clinics completed surveys assessing practice patterns, challenges, and confidence related to treating mGEC. HCPs (N = 24) participated in interdisciplinary audit and feedback (AF) sessions to examine clinical evidence and develop clinic-specific action plans to address identified gaps. Results: Participating practices reported that ~22% of their practice is dedicated to GEC care. Participants represented the interprofessional GEC care team: medical oncologists (27%), radiation oncologists (1%), surgeons (1%), advanced practice professionals (32%), nurse/nurse navigators (32%), and other HCPs (5%). Providers reported testing for HER2, EGFR, FGFR, NTRK, microsatellite instability, tumor mutational burden, and PD-L1 in ~55-65% of advanced GEC patients. Most providers reported HER2 testing at time of diagnosis (91%) with 18% reporting testing at time of clinical or radiologic progression and 24% when new metastases are detected. Top reported barriers to use of predictive biomarker testing were long turnaround times for tests (32%) and keeping up to-date with current testing recommendations (23%). Top reported challenges in selecting therapies for GEC were keeping up with clinical evidence (35%) and delayed, pending, or unavailable biomarkers at the time of treatment selection (20%). Clinic action plans focused on specific gaps including (1) improved HCP education on guideline-concordant biomarker use (2) improving testing turnaround times, and (3) improving referrals to clinical trials based on biomarker results. The educational intervention increased correct identification of guideline concordant treatment for stage IV esophageal cancer (48% pre- and 72% post-AF) and confidence in use of biomarkers for treatment decision-making for patients with GEC (high/very high in 46% pre- and 72% post-AF). Conclusions: While molecular testing is becoming increasingly critical for mGEC care, HCPs report challenges with testing workflows and difficulty keeping up with developments in clinical data and guidelines. Clinic-specific interventions to improve biomarker workflows and ongoing educational initiatives to keep HCPs informed of the latest evidence-based best practices in biomarkers and associated therapies can address these gaps to improve outcomes for patients with GEC.
Early experience with nivolumab, gemcitabine, and lenvatinib for fibrolamellar hepatocellular carcinoma.
Authors: Kent Paul , Tasse Jordan C , Schadde Erik , Kato Tom , Humar Abhinav , Fisher Oliver M , Dixon Matthew , Stockwell Tom , Cornelius Albert , Kim Thomas , Ellison Jessica
Published: June 2023

4076

Background: Fibrolamellar Carcinoma (FLC) is a rare deadly form of liver cancer affecting adolescents and young adults (AYA), presenting at an advanced stage, with up to 80% relapse, and no proven systemic therapies. Effective systemic therapies could convert patients to resectable or prolong progression free survival (PFS) and overall survival. Because of reported successes with nivolumab + lenvatinib (LEN) and of Gemcitabine (GEM) + LEN, and the potential synergy of GEM with NIV through elimination of myeloid suppressor cells in the tumor microenvironment, we offered NIV+LEN+GEN (NLG) to relapsed/refractory FLC patients ineligible for clinical trials. Our objective is to describe our initial experience using NLG in high risk AYA FLC patients. Methods: We reviewed the records of all FLC patients discussed at the FibroFighters National Tumor Board who received NLG. Results: Twenty-five patients (10F,15M), median age 20 (7-56), all stage IV, received a total of 322 cycles of NLG (median 11 cycles/patient,19 neoadjuvant, 1 adjuvant, 4 both). The median number of relapses, prior systemic therapies, and surgeries were 2(0-6), 3(0-6), and 2(0-7) respectively. Most patients had failed NIV+LEN (n = 8) or GEM+LEN (n = 7) prior to starting NGL. The 17 patients with at least one evaluation had a mean follow up of 10 months (3-23) and 18 cycles (6-38) of NGL with the best response by RECIST 1.1 of CR(1), PR(6), SD(10), and PD(0), for an objective response rate (PR+CR) of 41% and disease control rate (CR+PR+SD) of 100%, and estimated best volume response median of -20% (-89%,+10%). There have not yet been any progressions. Three of the 7 who were too soon for imaging, have had resolution of ascites. The PFS and Overall Survival at 6, 9, and 12 months are: 1.0/1.0, 0.82/0.82, 0.67/0.67. Two of 17 with carcinomatosis have no evidence of disease on PET and MRI after 10 cycles. Twenty-two of 24 are continuing NGL. Nine of 16 unresectable patients became surgical candidates, of these 4 showed > 50% necrosis histologically at surgery. 13 of 17 showed necrosis on imaging. Eleven of 16 are currently in their longest PFS since diagnosis. Sixteen patients had serial tumor-informed circulating DNA (Signatera) during therapy: Five became negative (0.0 mean tumor molecules/ml plasma), and overall mean drop was -27% (-93%, +111%). No patients have stopped therapy. The most common toxicities were hypertension and fatigue in 25% and 20% respectively, grade 1 or 2. There have been no grade 3 or 4 toxicities to date. Conclusions: Our retrospective experience with NGL for FLC offers another potential systemic option for patients who are not surgical candidates or with multiple relapses. NGL was well tolerated and provided excellent disease control to patients with few options. Prospective trials are needed.
Liquid-biopsy detection of FGFR2 and other actionable rearrangements in GI malignancies.
Authors: Kasi Pashtoon Murtaza , Lee Jessica Kim , Tukachinsky Hanna , Pasquina Lincoln W , Vanden Borre Pierre , Decker Brennan James , Pavlick Dean C. , Allen Justin , Parachoniak Christine , Schrock Alexa Betzig , Lovly Christine M. , Oxnard Geoffrey R. , Subbiah Vivek
Published: June 2023

4085

Background: Actionable rearrangements (RE) represent an emerging therapeutic target for GI malignancies. However, there remains uncertainty whether liquid biopsy (LBx) assays testing circulating tumor DNA (ctDNA) can detect RE with the same fidelity as tissue biopsy. Here we report the performance of ctDNA-based comprehensive genomic profiling (CGP) for the detection of RE leveraging an FDA-approved >300-gene platform, with a focus on data from patients with GI malignancies. Methods: An institutional research database of clinical CGP results for tissue biopsy (TBx, FoundationOneCDx) and LBx (FoundationOneLiquid CDx) from patients with cancers of the GI tract was reviewed. Sensitivity for FGFR2 RE was studied in patients with cholangiocarcinoma (CCA) or carcinoma of unknown primary (CUP) and both TBx and LBx CGP available. Results: Across 7870 GI LBx, 1094 predicted pathogenic RE were detected in 826 cases (10%) including 283 oncogenic kinase RE, 686 inactivating RE, and 125 other gain-of-function RE. FGFR2 was the most frequently rearranged gene, enriched in CCA (4.4%, 37/833) and stomach (3.0%, 11/368). EGFR RE (38) occurred across 6 cancer types and included 8 fusions, 15 c-terminal truncations, 4 intragenic deletions/inversions, and 3 kinase domain duplications. BRAF RE (31) were detected among in colorectal (22) and pancreas (9) cases. LBx detected 44 exon 3 skipping (protein stabilizing) RE in CTNNB1 (beta-catenin) across all samples. Other frequent activating RE were detected in MYC (36), FGFR3, RET, ROS1 (21 each), and ALK (13). Potentially targetable inactivating RE were detected in BRCA1 (28), ARID1A (24), STK11 (22), PTEN (17), TSC2 (14), and BRCA2 (8). Focusing on CCA, FGFR2 RE were more prevalent in cases with elevated (≥1%) ctDNA tumor fraction (TF, 26/342, 7.6%), matching the prevalence in TBx (7.8%, 505/6,492) with a similar spectrum of fusion partners seen for both TBx and LBx (30% BICC1, 70% rare for both). In 13 CCA/CUP patients positive for FGFR2 RE by TBx, LBx detected 12 (92%) including 8 different fusion partners; the false negative case had TF <1%. In 11 CCA LBx samples with FGFR2 resistance mutations detected, LBx CGP successfully detected a driver FGFR2 RE in 10 and driver C382R mutation in 1. Conclusions: Rearrangements are represented across GI malignancies, including many that result in known oncogenic drivers that may be targetable with available therapies. We observe reliable detection of FGFR2 fusions in ctDNA, in contrast to some prior publications. ctDNA represents a pragmatic analyte for detection of rearrangements and other actionable alterations, offering timely result return when tissue is inadequate or unavailable. [Table: see text]
Real-world multicentre analysis of patients with hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (A+B): Efficacy, esophagogastroduodenoscopy (EGD) uptake and bleeding complications.
Authors: LEE Cha Len , Freeman Mark , O'Donnell Conor , Moffat Gordon Taylor , Kosyachkova Ekaterina , Lyubetska Hanna , Meyers Brandon M. , Gordon Vallerie Lynn , Ding Philip Q. , Kay Aileigh , Bucur Roxana , Cheung Winson Y. , Knox Jennifer J. , Tam Vincent C.
Published: June 2023

4105

Background: The IMbrave150 trial established A+B as a standard of care for HCC and an EGD within 6 months (mos) of starting treatment to detect esophagogastric varices and prevent bleeding complications was advised. However, the value of performing EGD in all patients (pts) is unknown. Methods: We conducted a retrospective analysis of all HCC pts treated with A+B between July 2020 to August 2022 at 5 cancer centres from the Canadian provinces of Ontario, Alberta and Manitoba (members of the HCC-CHORD Consortium). Pts characteristics and treatment history including efficacy, EGD details and bleeding events were collected. Overall survival (OS), progression-free survival (PFS) and response rate (RR) were calculated. A comparative analysis was conducted to compare the correlation between the EGD uptake and bleeding events. Results: A total of 112 pts were identified (median age 66 years, 87% male, 24% East Asian, 67% liver cirrhosis, 33% HCV, 25% HBV, 15% NASH, 23% BCLC B, 71% BCLC C, 91% Child-Pugh A, 29% main portal vein invasion, 45% ALBI grade 1 and 54% ALBI grade 2). Prior to systemic, 61% had locoregional therapies. 90% received A+B as first-line therapy, while 9% received it as second-line and 1% as third-line. Outcomes of pts treated with A+B are shown. Before starting A+B, 78 pts (70%) had completed an EGD within 6 mos. Of these, 32 pts (41%) had evidence of varices on EGD, and 15 (20%) required treatment with either banding or beta-blockers. All bleeding events in this population was 15% (n=17). Bleeding rates in the EGD and non-EGD groups were 18% (n=14) and 9% (n=3), respectively. Bleeding adverse events were 5%(n=6) gastrointestinal vs 10%(n=11) non-gastrointestinal (6 epistaxis, 1 ecchymosis, 1 periodontal and 3 unspecified). The GI bleeding rates in the EGD and non-EGD groups were 6% (n=5) and 3% (n=1). Conclusions: Outcomes of HCC pts treated with A+B in Canada are comparable to those observed in the IMbrave150 trial. Our study detected and treated varices at twice the rate of the IMbrave150 trial among the EGD group, reflecting real-world treatment of a high-risk population. Yet, pts who had no EGD before starting A+B, presumably due to a low risk of portal hypertension based on physicians’ judgement, did not experience more bleeding/GI bleeding than those who had an EGD. This supports the approach of selective EGD prior to A+B, and more guidelines are needed in this area. Outcomes and response rate of patients(pts) treated with Atezolizumab with Bevacizumab in this study. [Table: see text]
FDA analysis of treatment efficacy based on etiology of hepatocellular carcinoma.
Authors: Saung May Tun , Fan Jiaxin , Cheng Joyce , Shen Yuan-Li , Casak Sandra J. , Lemery Steven , Fashoyin-Aje Lola A.
Published: June 2023

4117

Background: Retrospective analyses of trial-level data report that etiology of hepatocellular carcinoma (HCC) (e.g., viral versus [vs.] non-viral) may influence efficacy of systemic therapies used in advanced HCC. FDA conducted an analysis of 9 randomized controlled trials (RCTs; n=5,417) to assess treatment effects based on drug class, treatment line, and HCC etiology. Methods: FDA conducted a retrospective, exploratory analysis of 3 RCTs comparing first line (1L) treatment with anti-programmed cell death (ligand)-1-containing regimens (αPD-[L]1) to single-agent anti-vascular endothelial growth factor therapy (αVEGF), and 6 RCTs comparing second line (2L) treatment consisting of αPD-(L)1 or αVEGF to placebo. For each line of treatment (1L or 2L), meta-analyses of overall survival (OS) were performed for the overall treatment effect and by disease etiology, viral (hepatitis B [HBV], or hepatitis C [HCV]) vs. non-viral. Subgroup analyses were performed to investigate the confounding effect of subsequent therapy (yes vs. no) and region (Asian vs. non-Asian) on etiology. Trial-level hazard ratios (HRs) and 95% confidence intervals (CI) were mostly calculated using patient-level data submitted to FDA. Pooled HRs and CIs were calculated using a random-effects model. Results: While 1L αPD-(L)1 improved OS compared to 1L αVEGF in the overall population (HR [95% CI]: 0.8 [0.73, 0.88]), treatment effects were comparable for viral (HR [95% CI]: 0.75 [0.6, 0.92]; n=1,435) and non-viral (HR [95% CI]: 0.83 [0.72, 0.95]; n=979) subgroup analyses, and not influenced by subsequent therapy or region. Analyses based on specific viral infection (i.e., HBV or HCV), showed that improvement in OS for αPD-(L)1 vs. αVEGF appeared larger for HBV (HR [95% CI]: 0.7 [0.59, 0.82]; n=833) compared to HCV (HR [95% CI]: 0.83 [0.6, 1.16]; n=602). Treatment effects were also comparable in 2L for different etiologies for both αPD-(L)1 (HR [95% CI] for viral: 0.76 [0.62, 0.93]; n=529 and non-viral: 0.85 [0.65, 1.11]; n=337) and αVEGF (HR [95% CI] for viral: 0.79 [0.69, 0.9]; n=1,288 and non-viral: 0.74 [0.63, 0.88]; n=849), and not influenced by subsequent therapy. Nonetheless, compared to placebo, αPD-(L)1 had a larger treatment effect with HBV (HR [95% CI]: 0.69 [0.5, 0.94]; n=459) compared to non-viral etiologies. Conclusions: The results did not demonstrate that etiology of HCC was predictive of OS for both treatment classes based on retrospective, exploratory meta-analyses of 9 RCTs; however, the treatment effects may be more pronounced in patients with HBV who received αPD-(L)1 as 1L or 2L. Uncertainty remains regarding subgroup treatment effects given limited number of trials in the analyses (mostly leading to approvals), overlapping CIs, number of patients in some subgroups, retrospective nature, and exclusion of trials with inadequate data regarding etiology of HCC.
Characteristics and outcomes of patients with young-onset versus average-onset cholangiocarcinoma in the United States.
Authors: Grewal Udhayvir Singh , Dhaduk Rikeenkumar , Patel Sagar , Singh Achintya D , Chau Justin James , Chakrabarti Sakti
Published: June 2023

4118

Background: Cholangiocarcinoma (CCA) is a lethal malignancy originating from the epithelium lining the biliary tree, with a rising incidence in the Western world. CCA is commonly diagnosed after the age of 50 years, referred to as average-onset CCA (AOCCA), which has known risk factors and predictors of overall outcomes. However, robust data regarding the characteristics and outcomes of patients with young-onset (diagnosed <50 years of age) CCA (YOCCA) are lacking. Methods: Data on patient characteristics, tumor characteristics, incidence, and mortality were retrieved from the SEER database spanning a period from the year 2000 to 2017 (representing 48% of the US population).Intrahepatic CCA (iCCA) was identified with a topography code of C22.0 (liver) and a histology code of 8140, 8160, 8161, 8480, 8481, or 8500 or with a topography code of C22.1 (intrahepatic bile ducts) and a histology code of 8000, 8010, 8020, 8140, 8160, 8161, 8260, 8480, 8481, 8490, or 8500. Extrahepatic CCA (eCCA) was identified with a topography code of C24.1 (extrahepatic biliary ducts) and a histology code of 8000, 8010, 8020, 8140, 8160, 8161, 8260, 8480, 8481, 8490, or 8500, or for any case with a topography code of C22.0, C22.1, or C24.0 and a histology code of 8162 (Klatskin tumor). A comparison was made between the patients with YOCCA and AOCCA. Trends in incidence were analyzed using the Joinpoint regression model. Overall survival distributions were estimated using the Kaplan-Meier method. Results: A total of 28,367 patients were included in the analysis, which included 2,082 (7.34%) patients with YOCCA. We noted an increase in the incidence of YOCCA over the study period (annual percentage change=+2.53, p=0.003). The majority of the patients in the YOCCA group were males (54.66%), White (50%), and had iCCA (71.9%). When compared to AOCCA, these patients were more likely to be males (54.7% vs 52.4%, p=0.048), non-White (39.8% vs 35.5%, p=0.007), and have a diagnosis of iCCA (71.9% vs 65.7%, p<0.0001). Patients in the YOCCA group were more likely to present with regional spread (31.6% vs 28.4%, p<0.0001) and metastatic disease (31.9% vs 25.6%, p<0.0001). YOCCA patients were also more likely to receive surgery (33.3% vs 22.7%, p<0.0001) and chemotherapy (62.6% vs 37.3%, p<0.0001) compared to patients in the AOCCA group. Patients with YOCCA had a significantly better median overall survival (13 months vs. 7 months, p<0.001) than patients with AOCCA. Conclusions: The current analysis showed a significant increase in the incidence of YOCCA over the 17 years of the study period. Patients with YOCCA were more likely to be non-White, males and present with iCCA. Despite presentation with advanced-stage disease (with regional spread or metastatic disease), patients with YOCCA were more likely to receive cancer-directed therapy and had better overall survival than patients with AOCCA.
Genomic characterization of somatic mutations by race and ethnicity in pancreatic cancer defined through AACR project GENIE.
Authors: Maldonado J. Alberto , Tai Chin-Hsien , Alewine Christine
Published: June 2023

4138

Background: KRAS, TP53, SMAD4, and CDKN2A are widely recognized as the most common somatic mutations amongst patients with pancreatic ductal adenocarcinoma (PDAC); however, previous genomic studies have disproportionately included non-Hispanic White (NHW) patients with little to no inclusion of racial and ethnic minorities, particularly non-Hispanic Black (NHB) and Hispanic patients. Additionally, little is known about the distribution of KRAS point mutations in PDAC in specific racial and ethnic groups. Here, we describe somatic mutation differences in a larger and more racially and ethnically representative PDAC cohort than previously characterized. Methods: PDAC mutational data was downloaded from AACR Project GENIE (Genomics Evidence Neoplasia Information Exchange) v13.0, an international data registry of sequenced tumor samples from nearly 150,000 patients, on cBioPortal. PDAC cancer type was identified using OncoTree code. NHW, NHB, Hispanic (of any race), and Asian patients were then selected. Mutational frequency was calculated for all mutations. The primary objective was to compare the mutation frequencies between NHW and other races with respect to the most common mutations. To maximize power, we included any mutation with a frequency ≥5.0% where testing for mutation of that gene had been performed in at least 150 patients. Specific point mutations in KRAS were also extracted with stratification for racial and ethnic group. Fisher’s Exact Test was used to calculate the statistical significance of the differences in mutation frequency between NHW and minority groups. Results: Patients in the PDAC cohort included 5,292 individuals (NHW N = 4296, 80.7%; NHB N = 264, 5.0%; Hispanic N = 460, 8.7%; Asian N = 299, 5.7%). As compared to the NHW group, NHB patients had higher rates of TP53 (78.7% vs 69.0%, P = 0.0006) and PTPRT (5.3% vs 1.8%, P = 0.0095) mutations but fewer GNAS (0.4% vs 2.8%, P = 0.0097) mutations while Asian patients had higher frequency of ARID1A mutations (13.0% vs 8.8%, P = 0.024). KRAS G12D mutation was more prevalent in Hispanic patients (47.0% Hispanic vs 41.1% NHW, P = 0.0238), although rate of KRAS mutation overall was the same. Prevalence of KRAS G12C mutation was equivalent amongst all groups with an overall 1.6% frequency. Conclusions: Understanding the genomic landscape of PDAC is critical as we move towards increased use of targeted therapies to treat this disease. In this study, TP53, PTPRT, GNAS, and ARID1A mutations were shown to occur at different frequencies in specific racial and ethnic groups. G12D mutation of KRAS was disproportionately increased in Hispanics. These differences in molecular landscape amongst racial and ethnic groups could contribute to precision medicine strategies used to address this deadly disease.
Clinical utility of next generation sequencing (NGS) on circulating tumor DNA (ctDNA) in patients (pts) with pancreatic cancer (PC).
Authors: Keane Fergus , Saadat Lily , O'Connor Catherine , Chou Joanne F. , Brannon Angela Rose , Cowzer Darren , Crowley Fionnuala , Debnath Neha , Bowman Anita , Xu Fei , Park Wungki , Zervoudakis Alice , Balogun Fiyinfolu , Varghese Anna M. , Yu Kenneth H. , Kelsen David Paul , Capanu Marinela , Berger Michael F. , Wei Alice Chia-chi , O'Reilly Eileen Mary
Published: June 2023

4154

Background: ctDNA provides opportunities for identifying targeted therapies, a source to conduct NGS when tissue acquisition is infeasible, detection of minimal residual disease (MRD), and identification of resistance mutations. There are limited large data sets to inform clinical utility and limited correlation of NGS of ctDNA and tumor in PC. Herein, we evaluate the ctDNA detection rate in multiple cohorts of PC and report the ctDNA-tissue genotype concordance in PC at Memorial Sloan Kettering (MSK). Methods: Pts with PC at MSK who had ctDNA prospectively collected using the MSK-ACCESS 129 gene ctDNA NGS assay, were identified. ctDNA detection was defined as the identification of a mutation, copy number (no.) alteration or structural variant. Tissue-based NGS using MSK-IMPACT gene assay was performed for pts with adequate tissue, and matched with ctDNA by date. Clinical, pathologic and outcome data were abstracted. Data are summarized with descriptive statistics. Overall survival (OS) estimated by Kaplan-Meier method from date of ctDNA draw to death/last follow up. Results: From 08/2019 to 07/2022, N= 414 pts with PC and ≥ 1 ctDNA sample included. Median age 69 years (range 29-92), female N=206 (50%). Stage at ctDNA collection: Stage I-III N= 203 (49%); Stage IV N= 211 (51%). ctDNA detection rate by no. of involved organs; 0 organs (MRD), N=7/30 (23%); 1-2 organs, N=158/270 (58.5%); 3-4 organs, N=82/102 (80.4%); >5 organs, 12/12 (100%). CtDNA detection rate by site of metastasis; Liver only, 75/99 (76%); peritoneum only, 15/25 (60%); lung only, 10/22 (45%). In pts with detected ctDNA median CA 19-9 was 494 U/mL (range 0, 247674) vs 100 U/mL (range 1, 22360) in pts with undetected ctDNA. In pts with detected ctDNA median CEA was 7 ng/mL (range 1, 2020) vs 4 ng/mL (range 1, 99) in pts with undetected ctDNA. In stage IV untreated pts, median OS 13 months(m) (95% CI; 7.3, 16) and 10 m (95% CI; 5.6, -) for ctDNA detected vs undetected, respectively. ctDNA detection rates by stage, and concordance between ctDNA and tissue-based NGS for common driver mutations KRAS, TP53, CDKN2A and SMAD4 in N=131 matched pairs are summarized in the table. Conclusions: ctDNA detection rates are high (89%) in pts with untreated stage IV PC, with high concordance between ctDNA and tissue-based NGS (87% - 95%). In untreated stage I-III PC, detection and concordance rates are lower (<50%). Detection rates are associated with disease burden, site of metastasis, CA 19-9/CEA levels. ctDNA is a promising tool in detection of somatic alterations in PC, particularly in stage IV disease, and is a complementary adjunct to tumor-based NGS. [Table: see text]
Impact of novel pan-RAS inhibitors on efficacy and resistance to AMG-510 and MRTX-1133 in pancreatic cancer cell lines.
Authors: Arshad Tariq , Donninger Howard , von Baby Becca , Ferrill Rachel , Burlison Joe , Trent John , Clark Geoffrey J.
Published: June 2023

4155

Background: Mutant-activated RAS genes are the most frequently mutated gene family associated with cancer (almost 30% of all cancers contain a mutant RAS gene). KRAS is the predominant isoform mutated in cancer and is the isoform exclusively mutated in pancreatic ductal carcinoma (PDAC). Since almost all PDAC cases harbor a mutant RAS, it is arguably the most RAS-addicted tumor type. There is now considerable evidence implicating mutant KRAS as a driver of PDAC. Recently, several mutant KRAS-targeted therapies (sotorasib and adagrasib) have been developed and show promise in PDAC patients. We have developed a direct inhibitor of RAS with a predicted unique interaction region capable of directly binding to wild-type H- and K-RAS, but which shows preferential binding for KRAS G12D and G12C mutants. This novel inhibitor disrupts the RAS effector domain and blocks the ability of RAS to signal through its effectors. Methods: We used in silico virtual library screening to identify an initial candidate inhibitor which was effective at inhibiting the 3D growth of PDAC cells without affecting their growth in 2D. Subsequent iterative rounds of medicinal chemistry was then performed to identify a series of derivatives with enhanced activity, as determined by 3D growth inhibition assays and effects on Ras signaling, as determined by Western blot analysis of phosphor-ERK, phosphor-Akt and activation of Ral A. Results: Our series of RAS inhibitors effectively block PDAC cell growth in 3D without impacting their 2D proliferation and suppress the interaction of KRAS with its effector cRAF. The inhibitors also effectively inhibit RAS signaling in mutant RAS containing PDAC cells. Since our novel compounds are predicted to bind to RAS at a different site to either AMG-510 (G12C specific inhibitor) and MRTX-1133 (G12D specific inhibitor), we tested the co-operativity of our compounds with these existing agents. Our compounds enhanced the anti-proliferative effects of both MRTX-113 and AMG-510 in mutant KRAS G12D and G12C PDAC cells, respectively. Conclusions: We have developed a series of novel RAS inhibitors that directly bind preferentially to mutant KRAS that may serve as new mutant KRAS-targeted therapeutics, and that may also have the potential to enhance the efficacy or suppress the resistance of AMG-510 and MRTX-1133.
Prognostic significance of pretreatment immune cell infiltration in muscle invasive bladder cancer treated with definitive chemoradiation: Analysis of NRG RTOG 0524 and 0712.
Authors: Deek Matthew Pierre , Shetty Amol , Song Yang , Efstathiou Jason A. , Feng Felix Y , Shipley William U. , Simko Jeff , Mouw Kent William , Miyamoto David Tomoaki , Pollack Alan , Michaelson Dror Dror , Zietman Anthony L. , Coen John , Dahl Douglas M. , Jani Ashesh B. , Souhami Luis , Chang Brian K. , Lee R. Jeffrey , Pugh Stephanie L. , Tran Phuoc T.
Published: June 2023

4523

Background: Chemoradiation therapy (CRT) is an organ conserving approach in the treatment of locally advanced bladder cancer. Chemoradiation is thought to potentially result in immunogenic stimulation, and bladder cancer is often a tumor with high immune cell infiltration. Thus, we aimed to profile the tumor immune microenvironment of bladder cancer and identify prognostic immune biomarkers for CRT response by profiling tumor samples from NRG/RTOG 0524 and 0712, two prospective trials of CRT in muscle invasive bladder cancer (MIBC). Methods: Pretreatment tissue samples from both trials were profiled using Cofactor Genomics ImmunoPrism, an RNA sequencing assay that uses gene expression profiles to quantify immune cell populations in the tumor microenvironment (TME). Differential gene expression was estimated for different immune cell type proportions across samples. Kaplan-Meier survival analysis and log rank tests were performed to evaluate differences in overall survival (OS) stratified by genes influenced by immune cell proportions or genes associated with immune response signatures. Results: A total of 70 samples (43 from RTOG 0524 and 27 from RTOG 0712) underwent analysis using the ImmunoPrism assay. Immune cell proportions were as follows: CD8 T cells: median 1.2%, CD4 T cells: median 0.8%, Treg cells: median 9.2%, CD19 B cells: median 5.1%, M2 macrophages: median 0.8%, M1 macrophages: median 0%. Unbiased clustering based on gene expression profiles driven by immune cell proportions demonstrated two groups: cluster 1 with a low percentage of immune cells and shorter OS (median 31 months) and cluster 2 with a high percentage of immune cells and longer OS (median 101 months, p = 0.036). Higher expression of genes associated with T cell infiltration ( CD8A and ICOS) was associated with improved OS (104 vs 35 months, p = 0.028, HR = 0.48 (0.25 – 0.94), p = 0.031) as was higher expression of IDO1, which is associated with the interferon gamma pathway (104 vs 35 months, p = 0.042, HR = 0.49 (0.24 – 0.99), p = 0.046). Conclusions: Bladder tumors have a wide range of immune cell infiltration in the TME. Increased immune cell proportions are prognostic for OS following CRT, as well as a higher expression of genes associated with T cell infiltration interferon gamma signaling. These findings have implications for the integration of immunotherapy in the definitive management of MIBC; and can be explored further in the ongoing NRG/SWOG 1806 trial.