tbuckley/cabot-search huggingface dataset:
Surgical decision making in locally advanced esophageal adenocarcinoma.
Authors: Van Christian Sanderfer, Alexis Holland, Erin E. Donahue, Reilly Shea, Ella Schwarzen, Nicholas Mullis, Sophia Bellavia, Kunal C. Kadakia, Jonathan C. Salo
Journal: Journal of Clinical Oncology (2024)

299 Background: Trimodality therapy consisting of chemoradiation followed by surgery (CRT+S) is considered optimal therapy for locally advanced adenocarcinoma (ACA) of the esophagus, yet the morbidity of surgery is substantial. We used CT-derived body composition and age to categorize patients into perioperative surgical mortality risk groups. Among patients with locally advanced esophageal ACA who were treated with CRT, the benefit of surgery (CRT+S) was examined in low-risk and high-risk patients. Methods: The association of perioperative mortality with age and skeletal muscle gauge (SMG) was estimated using a group of 290 patients undergoing esophagectomy of various histologies between 2010 and 2022. CT scans were analyzed to calculate SMG as the product of skeletal muscle area and skeletal muscle density. Logistic regression models were used to evaluate the association of age and SMG with 90-day surgical mortality. Patients were classified based on their predicted probability of 90 day mortality into low and high risk groups, where high risk was defined as the highest-risk 25% of patients. This model was then applied to the study cohort of patients with ACA. Log-rank tests were used to compare overall survival by treatment (CRT vs CRT+S) in the high risk and low risk groups. Results: Of 316 patients with locally advanced ACA treated with CRT, 254 underwent surgery (CRT+S). 90-day post operative mortality in the CRT+S group was 5.1%. 74 patients were categorized as high-risk and 242 as low-risk. Among low-risk patients, 213 (88.0%) were treated with surgery (CRT+S) and had a significantly longer overall survival compared to CRT (p&lt;0.0001), with median survival of 40.6mo (95% CI 32.3, 55.5) in the CRT+S group and 17.3mo (95% CI 13.3, 36.4) in the CRT group. Among 74 high risk patients, 41 (55.4%) were treated with surgery. We did not find a difference in overall survival between the surgical group (CRT+S) and the group treated with CRT alone (p=0.34). The median survival was 27.4mo (95% CI 15.8, 32.9) in the CRT group compared to 23.0mo (95% CI 14.7, 54.4) in the CRT+S group. Conclusions: Our retrospective study demonstrated that for low-risk patients with adenocarcinoma of the esophagus, there is a survival benefit to the addition of surgery. Conversely, we failed to detect a survival benefit to the addition of surgery in the highest-risk quartile of patients. Measurement of body composition may help identify a high-risk subset of patients with locally advanced adenocarcinoma of the esophagus who may benefit from forgoing surgery after chemoradiation.
Characterizing outcomes of ERBB2-amplified biliary tract cancer.
Authors: Daniel Aaron Fox, Jaime Haro-Silerio, Deepak Bhamidipati, Funda Meric-Bernstam, Shubham Pant, Jeffrey S. Ross, Zishuo Ian Hu, Eugene Jon Koay, Ethan B. Ludmir, Hop Sanderson Tran Cao, Ching-Wei D. Tzeng, Yun Shin Chun, Jean-Nicolas Vauthey, Timothy E. Newhook, Zeyad Metwalli, Peiman Habibollahi, Veronica L. Cox, Hyunseon Kang, Milind M. Javle, Sunyoung S. Lee
Journal: Journal of Clinical Oncology (2024)

492 Background: A subset of biliary tract cancers (BTC) feature amplification (amp) of the human epidermal growth factor receptor 2 ( ERBB2) gene. The prognostic role and treatment in these patients (pts) are poorly understood. This study aims to characterize the clinical outcomes and molecular profiles of ERBB2-amp BTC. Methods: We conducted a retrospective analysis of clinical outcomes data and next-generation sequencing (NGS) at MD Anderson (MDA) and Foundation Medicine (FMI) from 2009-2023 in pts with ERBB2-amp BTC including all classes of genomic alterations (GA) in other genes. Progression-free survival (PFS) and overall survival (OS) were assessed by the log-rank test. Results: 80 pts (MDA) were identified with ERBB2-amp BTC with documented treatment and NGS data. Pts (Table) who received ERBB2-directed therapy (22.4 vs. 12.0 m, p=0.004), surgery (21.0 vs. 12.0 m, p=0.002), local therapy with RT/ablation/Y90 (excluding surgical pts, 20.6 vs. 11.6 m, p = 0.0001) had significantly longer OS. Median PFS (mPFS) without ERBB2-directed therapy for 1 st , 2 nd , and 3 rd line systemic therapy was 4.1, 3, and 2.2 m. mPFS with all ERBB2-directed therapy was 4.1 m, but that of gemcitabine (gem)-based plus trastuzumab (tt) and 5FU-based plus tt was 7.8 and 3.8 m (p=0.018). The most common concurrent-GA at MDA, any co-amps (72.7%; 19.2 vs. 20.3 m, p=0.69) and TP53 inactivating mutation (70.4%; 16.6 vs. 14.9 m, p=0.89), had no OS association; 3 rd most common co-GA found, CDK12 amp (46.4%), had a trend toward a better OS (19.2 vs. 14.3 m, p=0.089). FMI database showed ERBB2 amp in 3.2%, 5.4%, and 8.9% in intrahepatic cholangiocarcinoma (iCCA), extrahepatic CCA, and gallbladder cancer. The most common co-GA included TP53, CDKN2A/B, and CCNE1. FGFR2 fusions (iCCA) were mutually exclusive with ERBB2 amp (0%, MDA/FMI); IDH1 (iCCA) with ERBB2 amp, 5.7 and 4.3% (MDA and FMI). Conclusions: ERBB2-amp BTC has shorter mPFS or mOS without ERBB2-directed therapy, surgery, or local therapy, suggesting clinical benefit from multi-disciplinary care and targeted therapy. Co-GA with ERBB2-amp did not demonstrate a significant association with survival outcomes. [Table: see text]
A prospective multicenter phase II trial of total neoadjuvant therapy for locally advanced rectal cancer in JAPAN: ENSEMBLE-1 study.
Authors: Yoshinori Kagawa, Jun Watanabe, Koji Ando, Mamoru Uemura, Akira Inoue, Koji Oba, Ichiro Takemasa, Eiji Oki
Journal: Journal of Clinical Oncology (2024)

123 Background: The short- and long-term prognosis of total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC) is elucidated in the world. We evaluated the feasibility and safety of TNT for patients with LARC in Japan. Methods: This prospective, multicenter, open-label, single-arm phase II trial was conducted at five institutions. The key eligibility criteria were age ≥20 years, LARC within 12 cm from the anal verge, and cT3-4N0M0 or TanyN+M0 at the time of diagnosis that enabled curative resection. Preoperative short-course radiation therapy (SCRT) 5 Gy × 5 days (total 25 Gy) + CAPOX (6 courses) followed by total mesorectum excision (TME) was the treatment protocol. Non-operative management (NOM) was allowed if clinical complete response (cCR) was obtained in the preoperative evaluation. The primary endpoint was the pathological complete response (pCR) rate. With a pCR rate threshold of 5%, an expected value of 28%, a one-sided significance level of 5%, and a power of at least 80%, the sample size required by the exact binomial distribution method would be ≥19 patients. Considering a few dropouts, ineligible cases, and patients in which resection was not performed, the target sample size was set to 27 patients. Results: Thirty patients (male, n=26; female, n=4; median age, 62.5 [44-74] years; cT [T2, n=1; T3, n=25; T4, n=4]; cN [N0, n=13; N1, n=13; N2, n=4]) were enrolled. The final analysis included 30 patients in total. The completion rates were 100% for SCRT and 83% for CAPOX. TME and NOM were performed in 20 and seven patients, respectively. pCR was observed in six patients (30% [95% CI 14.0%–50.8%]). The primary endpoint was met. pCR+cCR was observed in 13 (43.3%) patients at TME or restaging. There were no treatment-related deaths. Grade ≥3 (CTCAE ver. 5.0) adverse events (≥20%), including diarrhea (23.3%) and neutropenia (23.3%). The median follow-up period was 21.8 (10.9-29.6) months. Recurrences in three patients (10.0%) were observed. In NOM, regrowth (28.6%) in two patients occurred, of which one patient was performed TME and one patient is on chemotherapy. Conclusions: ENSEMBLE-1 demonstrated satisfactory pCR and cCR, and well-tolerated safety of TNT for patients with LARC in JAPAN. Further long-term prognosis observation is required. A phase III trial, ENSEMBLE (NCT05646511/jRCTs031220342) is currently ongoing in JAPAN. Clinical trial information: jRCT s051200113 .
Metastatic site and clinical outcome of patients with deficient mismatch repair metastatic colorectal cancer treated with an immune checkpoint inhibitor in the first-line setting.
Authors: Bahar Saberzadeh Ardestani, Jeremy Clifton Jones, Robert R. McWilliams, David Tougeron, Thorvardur Ragnar Halfdanarson, Rosine Guimbaud, Joleen M. Hubbard, Clémence Flecchia, Qian Shi, Emily Linda Alouani, Bassam Bassam Sonbol, Jonathan Ticku, Zhaohui Jin, Julien Taieb, Frank A. Sinicrope
Journal: Journal of Clinical Oncology (2024)

55 Background: Nearly one-half of deficient mismatch repair (d-MMR) metastatic colorectal cancers (mCRC) demonstrate durable responses to immune checkpoint inhibitors (ICIs). Given preclinical data indicating that liver metastases sequester activated CD8 + T cells from systemic circulation, we examined clinical outcome by metastatic site. Methods: In a retrospective cohort of patients with d-MMR mCRCs treated at multiple centers in France (n=66), we sought to validate data from a U.S. cohort, and then performed pooled analysis (n=104). All patients received first-line ICI monotherapy. Metastatic site was analyzed in relationship to tumor response (RECIST version 1.1), and progression-free survival (PFS) by multivariable stratified Cox regression after adjustment for covariates. Results: Objective responses were achieved in 38/66 (58%) patients in the validation cohort. Best tumor response included 13 (20%) complete responses (CR), 25 (38%) partial responses (PR), 16 (25%) stable disease, and 11 (17%) progressive disease (PD). One-year and 5-year PFS rates were 73% and 67%, respectively; 18 (27%) patients progressed during immunotherapy. Best tumor response was attenuated in patients with liver metastasis ( P=0.03). Presence of liver metastasis, but not other sites, was associated with significantly poorer PFS after adjustment for covariates (HR adj 2.82; 95%CI, 1.08-7.39; P adj =0.03). In a pooled analysis, liver metastasis remained significantly and independently associated with poorer PFS (HR adj 3.18; 95%CI, 1.52-6.67; P adj =0.002) and with attenuated tumor best response (P=0.01). Conclusions: Metastasis to the liver, but not other sites, was validated as an independent factor associated with poorer response and survival after ICI treatment in d-MMR mCRCs. These data underscore the need for novel therapeutic strategies in these patients. [Table: see text]
Safety and short-term efficacy of adjuvant nivolumab after neoadjuvant docetaxel, cisplatin, and fluorouracil for locally advanced esophageal squamous cell carcinoma.
Authors: Mashiro Okunaka, Daisuke Kotani, Kazuma Sato, Naoto Fujiwara, Saori Mishima, Kohei Shitara, Takeo Fujita, Takashi Kojima
Journal: Journal of Clinical Oncology (2024)

271 Background: Efficacy and safety of adjuvant nivolumab has been demonstrated in patients with locally advanced esophageal cancer who received neoadjuvant chemoradiotherapy followed by surgery and had residual pathological disease in the CheckMate-577 trial. Although neoadjuvant docetaxel, cisplatin, and fluorouracil (DCF) is the standard neoadjuvant therapy for patients with locally advanced esophageal squamous cell carcinoma (ESCC) in Japan based on the JCOG1109 study, the safety and efficacy of adjuvant nivolumab in this population remains unclear. Here, we report the short-term safety and efficacy of adjuvant nivolumab after neoadjuvant DCF in patients with locally advanced ESCC. Methods: We retrospectively reviewed medical records of patients who received adjuvant nivolumab after neoadjuvant DCF and surgery for locally advanced ESCC from Nov 2021 to Jun 2023 at National Cancer Center Hospital East. Pathological stage was classified by UICC-TNM 8 th edition. Adverse events were assessed according to CTCAE v5.0. Disease-free survival (DFS) was calculated by Kaplan-Meier method. Results: The study included a total of 33 patients with a median age of 67 years (range, 56-77), of which 29 patients were male. All patients had residual pathological disease, with ypStage I/II/III/IV of 5/1/16/11 patients. Median time from surgery to the initiation of adjuvant nivolumab was 10.6 weeks (range, 7.1-16.4 weeks). Treatment-related adverse events (TRAEs) occurred in 27 patients (82%), with pruritus (n = 13, 39%), rash (n = 7, 21%), hypothyroidism (n=7, 21%), xerosis (n = 6, 18%), diarrhea (n = 5, 15%), hypopituitarism (n = 5, 15%), pneumonitis (n = 1, 3%), and hepatic dysfunction (n = 1, 3%). Among these TRAEs, one patient developed grade 3 of hepatic dysfunction, which resolved with corticosteroid. TRAEs which led to discontinuation of nivolumab were hepatic dysfunction (n = 1, 3%), diarrhea (n = 1, 3%), and pneumonitis (n = 1, 3%). No treatment-related death was observed. With a median follow-up of 10.3 months, 1-year DFS rate was 63.3% (95% CI, 39.8-79.7%). Among 9 patients who experienced recurrence (locoregional; n = 3, distant; n = 6), 8 patients received subsequent therapy, including systemic chemotherapy (n = 5) and salvage chemoradiotherapy (n = 3). Conclusions: The safety and short-term efficacy of adjuvant nivolumab after neoadjuvant DCF and surgery was comparable to the results of the CheckMate-577 trial. Our study suggests that adjuvant nivolumab might be a possible treatment option in patients with locally advanced ESCC patients with residual pathological disease after neoadjuvant DCF followed by surgery.
PD1 and CD39 expression on tumor infiltrating lymphocytes in patients with gastric cancer.
Authors: Takafumi Okayama, Nobuo Tsukamoto, Toshihiro Suzuki, Kiyotaka Mochizuki, Junichi Sano, Hiromi Nagata, Daiki Terajima, Takumi Habu, Mitsumasa Yoshida, Kazuma Sato, Naoto Fujiwara, Masahiro Yura, Takeo Fujita, Manami Shimomura, Kazunobu Oonuki, Kyoko Fukuda, Yasushi Uemura, Tetsuya Nakatsura, Takahiro Kinoshita
Journal: Journal of Clinical Oncology (2024)

377 Background: Activation and clonal expansion of tumor antigen-specific T cells in cancer patients are crucial for immunotherapies. Recent reports indicate that CD39 is a marker to distinguish tumor-reactive CD8 T cell populations from bystander populations. In gastric cancer (GC), anti-CD39 antibody, anti-PD-1 antibody, and FOLFOX combination therapy may be effective therapy at AACR 2022. Methods: We retrospectively reviewed the data of 62 GC patients who underwent gastrectomy at our hospital (2017 - 2018) and examined their rejected specimen’s immune-microenvironment using immunohistochemistry. Then we prospectively enrolled 16 GC patients. Their tumor tissue and tumor-infiltrating lymphocytes (TILs) were extracted from surgical specimens, these fractions were subjected to the RNA-seq analysis ( n = 3), CD107a degranulation assay ( n = 7) and 3H-Thymidine incorporation assay ( n = 7). Results: The densities of CD39 + CD8 TILs positively correlated with the densities of CD4 T cells and B-cells in GC tissues ( P = 0.01, &lt; 0.01, respectively). Furthermore, higher densities of CD39 + CD8 TILs in GC patients were associated with better overall survival ( P &lt; 0.01). We classified TILs into four groups based on expression levels of the PD-1 and CD39. The proportion of CD39 + CD8 T cells was significantly higher in GC tissues than their PBMCs ( n = 13) and non-cancerous tissues ( n = 4). CD39 + PD-1 + CD8 (DP) TILs in primary tumors were elevated expression of multiple inhibitory receptors such as LAG3, TIGIT and reduced expression of IL-2 by RNA-seq analysis. T cells expanded in vitro from DP-TILs ( n = 5) efficiently recognized autologous tumor cells in CD107a assay compared with other populations, and considered to be tumor-reactive T cells fraction. However, since these DP TILs in primary tumors show exhausted phenotypes, capacities to kill tumor are expected to be reduced in the tumor-microenvironment (TME). By adding ATP to the DP-TILs in vitro at the concentration reported in the TME, we observed reduction of cell proliferation by 3H-thymidene incorporation assay and of degranulation by CD107a assay, and we observed recovery of these changes by adding anti-CD39 inhibitory antibody. Conclusions: DP-TILs may have superior T cell receptors recognizing tumor-antigens and contribute to tumor eradication, especially when administrated anti-CD39 antibody.
<i>APC</i> as a high-utility mutational biomarker that may identify subpopulations of patients with <i>mutant</i> <i>RAS/BRAF</i> and right-sided colorectal cancer (CRC) who derive benefit from EGFR inhibitors (EGFRi).
Authors: Ramya Thota, Timothy Yeatman, Nishant Gandhi, Mingli Yang, Michael Schell, Lance Pflieger, Andrey Loboda, Michael Nebozhyn, Andrew Elliott, Joanne Xiu, George W. Sledge, Moh'd M. Khushman, Emil Lou, Sanjay Goel, Warren Jack Pledger
Journal: Journal of Clinical Oncology (2024)

56 Background: Although, EGFRi including Cetuximab (CTX) and Panitumumab (PMB) is restricted to KRAS wild-type ( KRAS WT ) tumors, ~50% of patients still fail to respond to therapy. Using a transcriptional signature as a surrogate for cetuximab response, we previously reported that mutations in APC ( APC MUT ) and TP53( TP53 MUT ) might predict cetuximab sensitivity, particularly in RAS WT tumors (Yang M. et al., 2019). The current study aimed to use real world EGFRi treatment and survival data to independently validate these mutations as predictive, high-utility biomarkers of benefit to specific subpopulations of CRC. Methods: CTX/PMB-treated CRC specimens (n=1846) with clinical outcomes and NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) were tested at Caris Life Sciences (Phoenix, AZ). All analyses were performed in MSS tumors, determined by immunohistochemistry of MMR proteins and/or NGS. Tumors with likely pathogenic mutations in KRAS, NRAS or BRAF were considered as RAS MUT /BRAF MUT , or RAS WT /BRAF WT if no mutation was detected for each gene. Survival on EGFRi was calculated from the initiation of EGFRi to last contact (E-OS) or last dose of EGFRi (E-TOT) using Kaplan-Meir method. Results: While concurrent TP53 MUT / APC MUT were associated with improved E-OS compared to TP53 MUT alone (hazard ratio [HR]=0.565, p&lt;0.00001), APC MUT tumors were associated with improved E-OS independent of TP53 mutation status. Compared to APC WT , APC MUT were associated with longer E-OS in RAS/BRAF mutant as well as wild-type subpopulations and in left- and right- sided tumors. Furthermore, APC MUT were associated with improved E-TOT in PMB treated tumors independent of RAS/BRAF mutation status and tumor sidedness (HR range:0.59-0.75, all p&lt;0.05). Conclusions: Our data suggests that the simple application of a high-utility mutational biomarker ( APC), may increase the eligibility for successful EGFRi therapy in a substantial subpopulation of RAS/BRAF mt patients as well as right-sided CRC, potentially altering the standard of care. Further validation of this biomarker in a prospective clinical trial is warranted. [Table: see text]
Preliminary efficacy and safety of fruquintinib as maintenance therapy after first-line treatment in metastatic colorectal cancer (mCRC): A multicenter, randomized, open-label clinical trial (the FRONT study).
Authors: Xiaojing Xu, Yiyi Yu, Qing Liu, Yan Wang, Yuehong Cui, Wei Li, Qian Li, Yi Feng, Li Liang, Shan Yu, Minzhi Lv, Tianshu Liu
Journal: Journal of Clinical Oncology (2024)

126 Background: Maintenance therapy and discontinuation of treatment are options to mCRC patients who response to first-line treatment. We conducted this study to evaluate the efficacy and safety of fruquintinib as maintenance therapy after first-line treatment for mCRC. Methods: This is an ongoing, multicenter, open-label, randomized clinical trial. Patients (pts) with unresectable right-sided mCRC or RAS-mutant left-sided mCRC, who hadn’t suffer disease progression after first-line standard treatment (chemotherapy with or without bevacizumab) for four to six months, were eligible. According to the protocol, 110 patients would be randomly assigned (2:1) to fruquintinib (FR) group (4mg once daily for 21 days, followed by 7 days off in 28 day cycles) or observation (OB) group via interactive web response system. The primary endpoint was progression-free survival (PFS). Results: Up to Aug 22, 2023, 28 and 14 patients had been enrolled in FR group and OB group, of whom the median age was 61 (44 to 73) vs. 66.5 (36 to 81), including 20 (71%) vs. 10 (71%) males, respectively. 26 (93%) vs. 11 (79%) patients were RAS-mutant. In the full analysis set (FAS), the median PFS were 5.26 (95% CI: 3.71-19.12) months and 2.99 (95% CI: 1.91-4.63) months (HR=0.36; p=0.0158). 25 and 13 pts from two groups received at least one response evaluation after baseline, respectively. The disease control rate (DCR) was 88.00% (22/25) vs. 53.85% (7/13) (OR=6.29, 95% CI: 1.31-36.7; p=0.0267). As to the per-protocol set (PPS), since 6 pts in FR group initiated with a lower dose (3mg), the number of patients was 22 vs. 14. The median PFS were 6.51 (95% CI: 3.88-19.12) months and 2.99 (95% CI: 1.91-4.63) months (HR=0.25; p=0.0061). The DCR was 89.47% (17/19) vs. 53.85% (7/13) (OR=7.29, 95% CI: 1.32-58.9; p=0.0331). The common AEs in FR group were hypertension, hand-foot syndrome, fatigue, rash, oral mucositis, and proteinuria, while AEs of grades≥3 were hand-foot syndrome, hypertension, oral mucositis, and proteinuria. Conclusions: Fruquintinib at a moderate dose level indicated better outcomes of PFS as a maintenance therapy after first-line therapy with acceptable toxicity for patients with mCRC. Clinical trial information: NCT04296019 .