tbuckley/cabot-search huggingface dataset:
Association of longitudinal changes of genomic alteration of circulating tumor DNA with treatment response in pancreatic cancer.
Authors: Jin Ho Choi, Sang Hyub Lee, Woo Hyun Paik, Junyeol Kim, Tae Seung Lee, Myeong Hwan Lee, In Rae Cho, Ji Kon Ryu, Yong-Tae Kim
Journal: Journal of Clinical Oncology (2024)

701 Background: Recently, the evaluation of circulating tumor DNA (ctDNA) in pancreatic cancer (PC) patients has gained attention for detection of mutation profile. However, the concordance between tissue next-generation sequencing (NGS) and ctDNA NGS remains unclear. Additionally, the dynamics of genomic alterations during treatment or disease progression are not well understood. Methods: In this prospective cohort study conducted at Seoul National University Hospital from Jan 2022, tissue samples from endoscopic ultrasound-guided fine needle biopsies and blood samples were collected from PC patients. Genomic DNA from the treatment naïve primary tissue and ctDNA from the blood obtained before any treatment and during follow-up with anti-cancer treatment were obtained. Genomic alternation was analyzed based on targeted NGS based panel deep sequencing including 41 genes. Results: The concordance of genomic alteration profiles between tissue NGS and ctDNA NGS was evaluated in 55 patients, and the mutation detection rate of patients who were diagnosed as stage I or II disease were 100% (14 of 14) in tissue NGS and 86% (12 of 14) in ctDNA NGS. That of patients who were diagnosed as stage III or IV disease was 92.7% in tissue NGS (38 of 41) and 90% (37 of 41) in blood ctDNA NGS. Among the study patients, the longitudinal changes of genomic mutation profile were evaluated in the patients at the first treatment response assessment, and patients with progressive disease showed significantly greater amounts of mutations including newly detected Tier1/2 variants than baseline and the previous response assessment. Conclusions: In conclusion, there is comparable mutation detection between tissue genomic DNA and blood ctDNA. The significant increase in ctDNA mutations during disease progression suggests their association with immune evasion and cancer evolution. Further studies utilizing our prospective cohort are needed to explore clinical implications of these results.
Enhanced blood-based colorectal cancer screening with improved performance in detection of early stage disease.
Authors: Sven Duenwald, William Young Greenwald, Yupeng He, Liyang Xiong, Elmira Forouzmand, Daniel Gaile, Anton Valouev, Victoria M. Raymond, AmirAli Talasaz, Darya Chudova
Journal: Journal of Clinical Oncology (2024)

68 Background: Blood based colorectal cancer (CRC) screening has been validated for use in average risk populations (ECLIPSE NCT#04136002; Guardant Health, USA). Here we present the performance of an enhanced version of a blood-based screening test developed to optimize detection of low shedding tumors by leveraging epigenomic features of cell-free DNA (cfDNA). Test performance was assessed across screen-relevant individuals from the intended use population, including a collection of screen-detected CRC and enriched cohort of individuals with endoscopy finding of CRC. Methods: We trained a regression model to classify whether aberrant cfDNA originated from individuals with CRC or non-ACN individuals and compared performance to an original model in a fixed set of screen-relevant samples sequenced to a median of 11M reads per sample across a panel approximately 1Mb in size. Model optimization focused on identifying training settings and samples to maximize detection of low shedding screen-relevant tumors and introduced noise reduction techniques to minimize technical variation. The final enhanced model was trained in over 4500 samples; the calling cut-off was set targeting 90% specificity in the average-risk population following US-Census age distribution. Analytical Limit of Detection (LoD) was estimated using ~5,000 in silico dilution samples generated from blood samples from 25 CRCs and ~1,650 non-ACNs. Results: This training approach yielded a 2X improvement in the analytical LoD95 (0.004% vs 0.008%) compared to the original model validated in the ECLIPSE trial. The model also yielded an increase in overall CRC clinical sensitivity from 84% to 91%, N=45, with notable sensitivity improvement from 76% to 88% in detecting early localized stage I/II CRC, N = 25, while maintaining specificity at 91%. Conclusions: This enhanced cfDNA-based CRC screening blood test shows improved performance in early stage CRC detection demonstrating the potential of continuous improvement in the performance of cfDNA-based screening tests powered by data and clinical insights.
Phase 1b/2, open-label dose-escalation and -expansion study evaluating trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with HER2+ and HER2-low gastric cancer (GC): DESTINY-Gastric03 (DG-03).
Authors: Yelena Y. Janjigian, Saeed Raoufmoghaddam, Magdalena Sztachelska, Megan Winter, Satya (Nanu) Das
Journal: Journal of Clinical Oncology (2024)

TPS424 Background: T-DXd is approved for treatment of advanced/metastatic HER2+ GC after a trastuzumab-based regimen. The efficacy of T-DXd in advanced HER2+ (IHC 3+ or IHC 2+/ISH+) GC has been shown (confirmed objective response rate [ORR], 43% vs 12% with standard chemotherapy) in previously treated Japanese or South Korean pts (DG-01) and in Western pts with progression on a trastuzumab-containing regimen (confirmed ORR, 42%; DG-02). Also, antitumor activity was shown in pts with HER2-low GC (confirmed ORR, 26.3% [IHC 2+/ISH−], 9.5% [IHC 1+]) in DG-01. Other studies have shown benefits of immunotherapies combined with trastuzumab and other chemotherapies for treatment of HER2+ GC. The DG-03 trial is evaluating the safety and efficacy of T-DXd in combination with chemotherapy and/or immunotherapy in HER2-expressing GC. Previously, confirmed ORRs of 50% and 43% were reported with T-DXd + 5-fluorouracil (5-FU) and T-DXd + capecitabine (Cap), respectively, in the second-line or later setting in part 1 of DG-03. The protocol was amended to add an additional arm in part 2 and a new part 3, which will investigate T-DXd in combination with a fluoropyrimidine and volrustomig (MEDI5752), a PD-1/CTLA-4 bispecific antibody, in pts with HER2+ and HER2-low (IHC 2+/ISH− or IHC 1+) GC. Methods: DG-03 (NCT04379596)is a multicenter, dose-escalation (part 1) and -expansion (parts 2 and 3) study in HER2-expressing, locally advanced or metastatic, unresectable gastric, gastroesophageal junction, or esophageal adenocarcinoma. In arm F of part 2, pts with previously untreated HER2+ GC will be treated with T-DXd + investigator’s choice of 5-FU or Cap + pembrolizumab. In part 3, pts with previously untreated HER2+ (arm 3A) or HER2-low (arm 3B) GC will receive T-DXd + investigator’s choice of 5-FU or Cap + volrustomig. The primary endpoint in parts 2 and 3 is investigator-assessed confirmed ORR per RECIST v 1.1. Secondary endpoints include safety, duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and immunogenicity. Clinical trial information: NCT04379596 .
Real-world experience with trastuzumab deruxtecan among patients with gastric cancer: 4 month-interim analysis of an all-patient post-marketing surveillance study in Japan.
Authors: Hisato Kawakami, Kazuhiro Uchino, Wataru Hashimoto, Kei Muro
Journal: Journal of Clinical Oncology (2024)

273 Background: Interstitial lung disease (ILD) is an important identified risk in the Japanese risk management plan of trastuzumab deruxtecan (T-DXd). In Japan, all-patient post-marketing surveillance (PMS) is underway to investigate the risk of ILD among patients with gastric cancer treated with T-DXd in a real-world setting. We present an interim analysis of the large-scale all-patient PMS. Methods: This is an observational, multicenter, all-patient PMS (jRCT2001200001) with an observation period of 12 months that enrolled all patients treated with T-DXd for HER2-positive unresectable advanced or recurrent gastric cancer between Sep 2020 and Dec 2021. This interim analysis is based on safety data from the first 4 months of all enrolled patients. All potential ILD (identified based on the pre-specified list of AE terms) reported by physicians were adjudicated by an independent ILD adjudication committee (ILD-AC). The incidence of ILD was calculated from adjudicated drug-related ILD. Results: The interim analysis set included 1074 patients with median age of 70 years (range: 23-100). Of the 1074 patients, 1051 (97.9%) received T-DXd as third-line or later treatment. One hundred and eight patients (10.1%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) 2 or greater, and 32 (3.0%), 3 (0.3%), and 23 (2.1%) patients had severe renal impairment (15≤ creatinine clearance (CL) &lt;30 mL/min), end-stage renal disease (CL &lt;15 mL/min), and ILD/radiation pneumonitis at baseline, respectively (all of which were defined as exclusion criteria in clinical trials of T-DXd). Median initial dose of T-DXd was 6.4 mg/kg (range: 3.1-6.4). Median treatment duration of T-DXd was 4.0 months (range: 0.7-4.0). During the first 4 months from the initial treatment, T-DXd was discontinued in 50.9% (547/1074) of patients. The most common reasons for treatment discontinuation were disease progression (n=390, 71.3%), adverse events other than ILD (n=76, 13.9%), and ILD (n=56, 10.2%). All potential ILD that occurred during the first 4 months were adjudicated by ILD-AC, and the incidence of all grades, grade ≥3, and grade 5 adjudicated drug-related ILD were 5.2% (n=56), 1.5% (n=16) and 0.7% (n=7), respectively. Of the 56 patients with adjudicated drug-related ILD, 54 (96.4%) discontinued T-DXd. The incidence of adjudicated drug-related ILD by time from initial treatment of T-DXd were 0.7% (7/1074) at ≤ 1 month, 2.0% (19/949) at 1-2 months, 2.7% (22/829) at 2-3 months, and 1.2% (8/652) at 3-4 months. Conclusions: The interim analysis revealed patient experiences and treatment profiles of T-DXd and the incidence of ILD during the first 4 months since initial treatment in a real-world setting in Japan. The final analysis including a risk factor analysis for ILD of the ongoing PMS is planned.
Camrelizumab combined with concurrent chemoradiotherapy for locally recurrent esophageal cancer: A single-arm, open-label study.
Authors: Ruinuo Jia, Junqian Zhang, Yaowen Zhang, Shuoguo Li, Manxi Sheng, Jianguang Ma, Anping Zheng, Chuntao Tian, Jianli Wang, Liuyan Li, Shegan Gao
Journal: Journal of Clinical Oncology (2024)

371 Background: Local recurrence is the main failure pattern after radical treatment of esophageal cancer. There is no uniform treatment specification for such patients(pts) so far. The combination of immune checkpoint inhibitors and concurrent chemoradiotherapy (CCRT) has emerged as a novel strategy to treat esophageal cancer. This research was to evaluate the efficacy and safety of camrelizumab (ICI targeting PD-1) combined with CCRT in the treatment of locally recurrent esophageal cancer. Methods: This open clinical study planned to enroll 62 pts with locally recurrent esophageal cancer following radical treatment who aged 18-75 years with ECOG performance status of 0-1. Pts received the following treatments: camrelizumab (200 mg q2w, continuous medication until disease progression, intolerable toxicity, or withdrawal); simultaneous radiotherapy (the total radiation dose was 50-50.4 Gy, which was given by 25-28 fractions, 5 fractions per week, with 1.8-2 Gy for each fraction); chemotherapy (capecitabine, 625mg/m2, bid, oral, d1-5, qw, total 5 weeks). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results: Between Feb 2022 and Jul 2023, 14 pts with a median age of 71 years old had been enrolled. Among the evaluable pts, the ORR was 69.2% (9/13), the DCR was 100.0% (13/13). With a median follow-up of 16.0 months (95% CI 13.5-18.5), the median PFS was 7.6 months (95% CI 4.2–11.0), the median OS was 18.6 months (95% CI NE–37.6) in the full analysis set. The incidence of any grade adverse events (AEs) was 100.0% and that of grade ≥3 AEs was 57.1% of 14 pts. The most common AEs included lymphocyte count decreased (11/14, 78.6%), neutrophil count decreased (5/14, 35.7%), white blood cell count decreased (5/14, 35.7%) and anemia (5/14, 35.7%). The most grade ≥3 AE was lymphocyte count decreased (6/14, 42.9%). No new safety signals or treatment-related deaths were observed. Conclusions: Current results suggested the promising efficacy and acceptable safety of camrelizumab combined with CCRT in pts with locally recurrent esophageal cancer. The study enrollment is ongoing, and further survival and safety data will be reported in the future. Clinical trial information: NCT04390945 .
Impact of acquired RAS, BRAF and PIK3CA mutation at 8 weeks on the efficacy of anti-EGFR monoclonal antibodies in metastatic colorectal cancer.
Authors: Takeshi Yamada, Kozo Kataoka, Keita Mori, Toshihiro Kudo, Manabu Shiozawa, Naoto Takase, Kazuma Ito, Kei Kimura, Jihyung Song, Nobuhisa Matsuhashi, Toshimitsu Miyasaka, Jesse Yu Tajima, Naohito Beppu, Hirotsugu Eda, Yuka Oi, Kentaro Yamazaki, Masataka Ikeda
Journal: Journal of Clinical Oncology (2024)

193 Background: Recent studies indicate that the emergence of RAS/BRAF mutation sometimes occurs during initial anti-EGFR monoclonal antibody (mAb)-based treatment in metastatic colorectal cancer (mCRC). However, limited data was available regarding the timing and frequency of the emergence of RAS/BRAF mutation, and its impact on the efficacy of anti-EGFR mAb. With this background, we conducted an observational study to monitor RAS, BRAF, and PIK3CA mutation status by ctDNA in RAS/BRAF wt mCRC. Methods: RAS-trace is a pilot study to monitor RAS, BRAF, and PIK3CA mutation status by ctDNA, using NGS-based Plasma-Safe-SeqS technology for RAS/BRAF wt (diagnosed from tissue samples) mCRC treated with anti-EGFR mAb as a first-line chemotherapy. ctDNA- RAS/BRAF/PIK3CA status evaluated at baseline, 8, 12, 16, 20, 24, 36, 48 weeks and disease progression. The primary endpoint was the time to the acquired RAS mutations. The results of ctDNA at baseline and 8 weeks are presented. Results: Forty-two patients were enrolled, and 40 and 39 were used in the analysis of ctDNA at baseline and 8 weeks, respectively. All patients received mFOLFOX6 plus cetuximab (N=32) or panitumumab (N=8). At baseline, RAS, BRAF, and PIK3CA mutations were detected in 3, 3, and 1 of the 40 patients, respectively. One patient had both KRAS and BRAF mutations. Baseline ctDNA mutations were not associated with the presence of liver metastases, tumor sidedness, early tumor shrinkage, depth of response or skin rash ≥Grade 2. At 8 weeks, RAS, BRAF, and PIK3CA mutations were detected in 3, 2, and 0 among the 39 patients, respectively. One patient had both KRAS and BRAF mutations. ctDNA mutations at 8 weeks were not associated with the presence of liver metastases, tumor sidedness, or early tumor shrinkage, however, they were associated with depth of response and had a tendency of skin rashes ≥ Grade 2 (Table). Conclusions: Emergence of RAS/BRAF/PIK3CA mutations at 8 weeks may be related to the response of anti-EGFR mAb. The association of ctDNA status with survival outcomes will be presented in 2025. Clinical trial information: jRCT1050210160 . [Table: see text]
Real-world clinical efficacy of epidermal growth factor receptor inhibitors (EGFRi) in patients with early-onset (eo), metastatic colorectal cancer (mCRC).
Authors: Hideaki Bando, Toshihiro Misumi, Harlan Pittell, Dionne Ng, Eri Tajima, Trevor Joseph Royce, Ivy Altomare, Prashni Paliwal, Yoshihiro Aoyagi, Kazuya Mizuguchi, Motoko Suzuki, Yuriko Takeda, Takayuki Yoshino, Atsushi Ohtsu
Journal: Journal of Clinical Oncology (2024)

36 Background: The incidence of eo CRC (age of onset: &lt;50 years) is rising globally, although specific reasons remain unknown. In a prior study using the ARCAD database, the addition of EGFRi to chemotherapy (chemo) significantly improved progression-free survival (PFS) in late-onset (lo) KRAS wild-type (wt) left-sided mCRC patients (pts); however, no such effect was observed in eo mCRC pts (Jin Z et al., 2022). Methods: This retrospective study used the nationwide Flatiron Health electronic health record-derived de-identified database of adult patients diagnosed with mCRC on/after January 1, 2013 with data cut-off on June 30, 2023. The cohort included pts with RAS/BRAF wt and left-sided primary tumors who were treated with first-line (1L) chemo+EGFRi, chemo+bevacizumab (bev), or chemo alone. Associations of disease onset and 1L therapy with real-world overall survival and time to next treatment (rwOS, rwTTNT) were assessed using Kaplan-Meier methods and hazard models adjusted for clinical confounders including year of metastatic diagnosis, group stage at initial diagnosis, site of disease, gender, race/ethnicity, and ECOG performance status. Results: Among 895 left-sided RAS/BRAF wt mCRC pts, 216 and 679 pts had eo and lo mCRC, respectively. In pts treated with chemo+EGFRi vs chemo alone, the adjusted hazard ratio (HR) (95% CI) of rwTTNT was 0.93 (0.56-1.53) and 0.77 (0.58-1.02) for eo and lo pts, respectively; the adjusted HR (95% CI) of rwOS was 0.96 (0.51-1.83) and 0.78 (0.57-1.07) in eo and lo pts, respectively. In pts treated with chemo+bev vs chemo alone, the adjusted HR (95% CI) of rwTTNT was 1.00 (0.62-1.60) and 0.75 (0.58-0.97) for eo and lo pts, respectively; the adjusted HR (95% CI) of rwOS was 0.97 (0.54-1.75) and 0.78 (0.58-1.03) in eo and lo pts, respectively. Conclusions: Adding EGFRi to chemotherapy suggested potential improvements in rwTTNT and rwOS in lo pts but not in eo pts, similar to findings from the prior ARCAD database study. Such differences in outcomes, similarly observed in pts treated with chemo+bev, underscore the need for tailored therapeutic strategies. Given the wide confidence intervals in this study, future research with larger patient cohorts or longer follow-up may yield more precise estimates of these differences. [Table: see text]
Impact of revising colorectal cancer screening guidelines on health care resources in Canada.
Authors: Brendan Chia, Yibing Ruan, Carl J. Brown, Darren R Brenner, Jonathan M. Loree
Journal: Journal of Clinical Oncology (2024)

78 Background: The rising incidence of early-onset colorectal cancer (CRC) has prompted U.S. organizations to lower the recommended CRC screening age for average risk adults from 50 to 45 years old, while Canadian programs remain unchanged. Canadian guidelines also differ from the U.S. in preferentially screening with a fecal immunochemical test (FIT) and recommending against colonoscopies as a screening test. Differences in national healthcare administration warrants investigation into the resource impact of updating screening guidance in Canada. Methods: Microsimulation modeling was performed using OncoSim (version 3.6) to project health and economic outcomes of different CRC screening strategies based on Canadian population data. Four simulated birth cohorts of the Canadian population born between 1973–1992 were tracked for a 40-year span from the year the oldest in each cohort turned 40 until the youngest in the same cohort turned 75. Colorectal adenoma rates were adjusted according to cohort risk ratios estimated from historical incidence data to reflect real-world CRC rates. Outcomes were reported for the cumulative cohort. Results: Compared to FIT screening at age 50, FIT screening at 45 reduced deaths by 5,220, incidence by 11,980, and added 96,100 health-adjusted life years (HALY). Colonoscopy screening at age 45 led to 17,870 fewer deaths, 74,250 fewer cases and added 314,960 HALYs. FIT and colonoscopy screening at age 45 had incremental costs of CAD$3,259 and $7,881 per HALY gained vs. a FIT at age 50, respectively. Across screening strategies, the greatest benefits were observed in the youngest cohort. Colonoscopy screening at age 45 resulted in 10,679,540 more total colonoscopies than the current capacity of 8,966,979 with FIT screening at age 50. Lowering the screening age to 45 with a FIT increased colonoscopy demand by 329,555. The total cost of CRC care (screening, diagnosis and treatment) increased with lower screening ages and colonoscopy first modalities, while the cost of CRC management (diagnosis and treatment) decreased with lower screening ages and colonoscopy first approaches. Conclusions: Adjusting current CRC screening guidelines demonstrates significant resource implications with proportional health benefits. Lower screening ages and colonoscopy first approaches have the largest resource demand and greatest health outcomes, while the incremental cost per HALY gained for all screening strategies is modest compared to standard benchmarks. [Table: see text]
Timing of primary tumor resection after systemic chemotherapy initiation among patients with metastatic colon cancer.
Authors: Munir Buhaya, Baqir Jafry, Syed Mohammad Ali Kazmi, Emina Huang
Journal: Journal of Clinical Oncology (2024)

65 Background: In patients with resectable, metastatic colon cancer, the optimal timing of definitive resection of the primary tumor after initiation of chemotherapy remains unclear. Our goal is to identify factors that influence the interval between chemotherapy and definitive surgical management, and its impact on overall survival. We hypothesize that patients with shorter chemotherapy-to-surgery intervals (less than 60 days or about 2 months) compared to 61-180 days (2-6 months) or greater than 180 days (&gt; 6 months), will have the worst overall survival. Methods: We conducted a retrospective analysis of all patients diagnosed with metastatic colon cancer from 2004-2016 who underwent resection of both primary tumor and distant metastatic site from the National Cancer Database (NCDB). Among those who received chemotherapy prior to surgery, we calculated the interval days between initiation of chemotherapy and primary tumor resection. Descriptive analysis, logistic regression, and overall survival was performed comparing patients with chemotherapy-to-surgery intervals of &lt;60, 60-180, and &gt;180 days. Results: A total of 2,238 patients were included, of which 143 (6%), 1446 (65%), and 649 (29%) were in the &lt;60, 60-180, and &gt;180 days groups, respectively. Similar distribution of patients across groups was observed for age, gender, insurance status, income, education level, distance travel, and Charlson-Deyo scores. Poorly differentiated tumors were more frequent in the &lt;60 days group (12% vs 2-9% for other grades, p=0.001) as well as presence of lymphovascular invasion (8% vs 4%, p = 0.006). The odds of receiving care at an academic facility were lower in the &lt;60 days group (OR: 0.52, 95% CI 0.273-0.994). Overall survival was significantly reduced in the &lt;60 days group compared to 60-180 days (HR= 0.562, 95% C: 0.38-0.82). Conclusions: In this retrospective study from a national database, shorter chemotherapy-to-surgery interval (&lt;60 days) was associated with poorly differentiated tumors and lymphovascular invasion. The odds of receiving surgery in &lt;60 days of receiving chemotherapy was lower in academic/research facilities. A reduction in overall survival was observed in the shorter interval (&lt;60 days) group compared to longer intervals. More research is needed to define the optimal chemotherapy-surgery interval and factors that influence this.