tbuckley/cabot-search huggingface dataset:
Changes in circulating immune biomarkers following nivolumab with or without ipilimumab for metastatic anal cancer (NCI9673).
Authors: Van K. Morris, Joshua Ochieng, Kristen Keon Ciombor, Blase N. Polite, Sarbajit Mukherjee, John C. Krauss, Anthony F. Shields, Olivia Aranha, John L. Hays, Syed Mohammad Ali Kazmi, Benjamin Adam Weinberg, Al B. Benson, Christopher Hanyoung Lieu, Syma Iqbal, Howard S. Hochster, Lianchun Xiao, Cara L. Haymaker, Cathy Eng
Journal: Journal of Clinical Oncology (2024)

3 Background: Approximately 25% of patients (pts) with squamous cell carcinoma of the anal canal (SCCA) develop metastatic disease. The ETCTN-led NCI9673 phase II trial evaluated PFS of the anti-PD-1 antibody nivolumab (N) with or without the anti-CTLA-4 antibody ipilimumab (I) in metastatic SCCA. We analyzed serial blood samples from NCI9673 for immune biomarker profiling following N or N+I. Methods: PBMCs from 47 pts (24 N, 23 N+I) were collected at pretreatment (N=47), week 9 (N=26), and at progression (N=15). Immune cell populations - effector CD4 T cells, CD8 T cells, natural killer (NK) cells, and regulatory T cells - were analyzed by flow cytometry for immune inhibitory (PD-1, CTLA-4, TIM-3, LAG-3, TIGIT) and immune stimulatory (OX40, ICOS) expression. Mean expression (as percentage of cells with any expression) for each biomarker at a matched time point was compared between the N and N+I arms by a corrected student’s t test, with an alpha= .10 for significance. Changes in mean expression for each biomarker were compared by one-way ANOVA. Results: Mean TIGIT expression at baseline was highest on CD4 and CD8 T-cells relative to other immune checkpoint biomarkers (p&lt; .0001 for all subsets; see Table). N+I was associated with higher TIGIT expression on CD4 cells at progression than for N alone (21.3% vs. 10.9%, p=.08). Among NK cells, TIGIT expression decreased at progression relative to baseline for N (14.1% vs. 5.9%, p=.06). Relative to non-responders, responders to N had OX40 expression that increased on CD4 T cells but decreased on NK cells at week 9 relative to baseline. Conclusions: In previously metastatic SCCA pts, TIGIT expression was greater on CD4 and CD8 T cells and was modulated on differing immune cell populations according to treatment arm. These data not only implicate T and NK cells in mediating treatment effect following single agent and/or combination immunotherapy, but also support the exploration of TIGIT as a potential novel target for treatment of metastatic SCCA.[Table: see text]
Progression pattern and post-progression survival following atezolizumab and bevacizumab treatment in advanced hepatocellular carcinoma.
Authors: Satoshi Kobayashi, Taito Fukushima, Makoto Ueno, Makoto Chuma, Kazushi Numata, Kota Tsuruya, Yoshitaka Arase, Shunji Hirose, Tatehiro Kagawa, Nobuhiro Hattori, Tsunemasa Watanabe, Kotaro Matsunaga, Haruki Uojima, Hisashi Hidaka, Chika Kusano, Manabu Morimoto, Shin Maeda
Journal: Journal of Clinical Oncology (2024)

539 Background: Although the combination of atezolizumab and bevacizumab (ATZ + BEV) is a standard treatment for advanced hepatocellular carcinoma (HCC), strategies for addressing treatment failure and prognostic factors of post-progression survival remain unestablished. Methods: We conducted a multicenter retrospective study to evaluate post-progression survival following ATZ + BEV treatment in patients with advanced HCC. We classified the patients into four groups: BCLC stage B with or without new intrahepatic lesions (BCLCp-B1 and BCLCp-B2, respectively) and BCLC stage C without or with new extrahepatic lesions (BCLCp-C1 and BCLCp-C2, respectively) at the time of progression. Results: Of the 204 patients who started ATZ + BEV treatment between October 2020 and September 2022, 110 showed disease progression, with 25, 8, 55, and 22 showing the BCLCp-B1, BCLCp-B2, BCLCp-C1, and BCLCp-C2 stages of the disease, respectively. Specifically, patients with the BCLCp-B1 stage of the disease showed better overall survival than those with the BCLCp-B2, BCLCp-C1, and BCLCp-C2 stages (hazard ratios: 2.19 (95% confidence interval [CI], 0.61–7.86), 2.16 (95% CI, 1.13–4.11), and 2.97 (95% CI, 1.42–6.23) for HCC stages BCLCp-B2, BCLCp-C1, and BCLCp-C2, respectively). Via multivariable analysis, we identified the BCLCp-C1 and BCLCp-C2 stages, as well as performance status, Child-Pugh class, and alpha-fetoprotein as poor prognostic factors for post-progression survival. Conclusions: BCLCp-B1 stage was identified as a better prognostic factor for post-progression survival following ATZ + BEV treatment compared with BCLCp-B2 stage as well as BCLCp-C1 and BCLCp-C2 stages. This may help in making decisions regarding subsequent treatment after ATZ + BEV.
Nivolumab in patients (pts) with advanced gastrointestinal (GI) cancers with high plasma tumor mutational burden (pTMB): Results from a SCRUM-Japan GOZILA phase II trial.
Authors: Yoshiaki Nakamura, Taito Esaki, Tomohiro Nishina, Yoshito Komatsu, Satoshi Yuki, Eiji Shinozaki, Hiroya Taniguchi, Takeshi Kato, Ken Kato, Shogo Nomura, Takashi Ikeno, Yukiko Ishiguro, Koji Takahashi, Tsukiko Higuchi, Akihiro Sato, Justin Iver Odegaard, Takeshi Kuwata, Kouji Matsushima, Tetsuya Nakatsura, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2024)

98 Background: TMB is a biomarker for immune checkpoint inhibitors (ICIs). Analysis of circulating tumor DNA (ctDNA) has the potential to non-invasively identify pts likely to benefit from ICIs by assessing pTMB. We conducted a phase II basket trial as part of the SCRUM-Japan GOZILA umbrella/basket trial to evaluate the efficacy and safety of nivolumab monotherapy in pts with advanced GI cancers with high pTMB. Methods: Eligibility criteria included histologically confirmed unresectable or recurrent GI cancers; ECOG PS of 0 or 1; refractory or intolerant to the standard therapies; and high pTMB identified by Guardant360 CDx, a 74-gene ctDNA assay. Pts received intravenous nivolumab monotherapy of 360 mg every 3 weeks until progressive disease. The primary endpoint was objective response rate (ORR) per investigator assessment. The pTMB score was calculated by adjustment of mutation count by tumor fraction, and initial pTMB thresholds were determined based on previously reported ORR for ICI treatment for each GI cancer in the cohort. The cohort 2 proceeded only for esophageal cancer, and an ultra-high TMB cohort was created to include pts in the top 2% for pTMB scores. Results: Fifty-one pts with high pTMB in the cohort 1/2 (n=32) and the ultra-high TMB cohort (n=19) were enrolled. The median duration of follow-up was 7.5 months (range, 0.9–51.3). Deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) was observed in 1 pt in cohort 1/2 and 2 in ultra-high TMB cohort. The ORR was 12.5% and 21.1%, with median duration of response of 14.0 months and not reached, respectively. In an exploratory analysis of the overall population, pts with esophageal cancer had the highest ORR of 33.3% (4/12), followed by pancreatic (1/6, 16.7%) and colorectal cancer (3/27, 11.1%). Of 2 pts with proficient MMR/non-MSI-H colorectal cancer who had a response, 1 had a POLE mutation. Pts with response tended to have higher pTMB score (median, 26 vs. 8). dMMR/MSI-H (HR=0.16; 95% CI, 0.02–1.18), PD-L1 CPS ≥1 (HR=0.55; 95% CI, 0.29–1.01), and absence of liver metastasis (HR=0.36; 95% CI, 1.48–5.14) were significantly associated with longer progression-free survival. Treatment-related grade 3–4 adverse events occurred in 3 pts (9%) in the cohort 1/2 and 3 (16%) in the ultra-high TMB cohort, with no treatment death in either cohort. Conclusions: Nivolumab demonstrated antitumor activity in pretreated pts with advanced GI cancer and high pTMB. These results suggest that the use of pTMB potentially identify patients who may benefit from ICI treatment. Clinical trial information: UMIN000033182 .
Alteration of metabolic syndrome and the risk of colorectal cancer in individuals younger than 50 years.
Authors: Eun Hyo Jin
Journal: Journal of Clinical Oncology (2024)

81 Background: Colorectal cancer (CRC) is a significant global health concern, with a rising incidence of early-onset cases in individuals under 50. This trend may be influenced by various factors, including metabolic syndrome (MetS), obesity, dietary habits, and lifestyle choices. However, the impact of changing MetS status on the risk of early-onset CRC remains understudied. Methods: A total of 3,340,635 Korean national insurance beneficiaries that received two consecutive biennial mandatory health exams (2009–2011) were followed-up until 2019. Participants were categorized into MetS-free, recovered, developed, or persistent groups. The study assessed CRC risk patterns associated with these MetS dynamics, considering factors like age, sex, smoking, alcohol consumption, exercise, and income status. Results: Among 20-39-year-olds, those with persistent MetS had a 16% higher risk of CRC (adjusted hazard ratio [aHR] 1.16; 95% CI, 1.00–1.33) compared to MetS-free individuals. Furthermore, persistent MetS was associated with a 29% higher risk of rectal cancer in this age group, while recovery from MetS also increased rectal cancer risk by 28%. Among 40-49-year-olds, the MetS-persistent group had a 22% higher risk of CRC (aHR 1.22; 95% CI, 1.14-1.30), with a 34% higher risk of distal colon cancer, while those who developed MetS showed a 26% higher risk of CRC compared to the MetS-free group. Conclusions: This study highlights that the persistence of MetS in young adults is associated with an increased risk of early-onset CRC. The findings suggest that managing MetS in young individuals through lifestyle modifications, such as weight reduction and regular exercise, could be beneficial in reducing the risk of early-onset CRC.
Clinical risk factors for splenic hilar nodal metastasis in remnant gastric cancer after distal gastrectomy.
Authors: Ryota Sakon, Takaki Yoshikawa, Rei Ogawa, Masahi Nishino, Kenichi Ishizu, Masahiro Watanabe, Takahiro Kinoshita, Takeyuki Wada, Tsutomu Hayashi, Yukinori Yamagata
Journal: Journal of Clinical Oncology (2024)

270 Background: Splenectomy is usually considered to be required for complete dissection of splenic hilar lymph node (#10 LN) in gastric cancer (GC). Although spleen-preserving D2 was established for the advanced GC not invading the grater coverture based on the JCOG0110 clinical trial, D2 gastrectomy with splenectomy remains the standard procedure for the advanced GC involving grater coverture in Japan. However, the applicability of this treatment for remnant gastric cancer (RGC) is unclear because the lymphatic flow and lymphatic metastatic pattern may have been changed after initial gastrectomy. There are no guidelines for splenic hilar nodal dissection for RGC. In this study we evaluated risk factors for #10 nodal metastasis in RGC. Methods: This study retrospectively examined RGC patients who received gastrectomy with #10 nodal dissection after distal gastrectomy at two high-volume cancer centers in Japan between 1998 and 2015. Results: 99 patients were entered in this study. The #10 nodal metastatic rate was 12.1% (12/99). Initial gastrectomy was performed for benign in 42 patients and for malignant in 52 patients. The median duration from the initial gastrectomy was 20 (1-55) years. Main tumor location was lesser curvature in 46 patients, anterior wall in 11, greater curvature in 19, posterior wall in 11, and the whole in 12. Large type 3(≥8cm) and type 4 were found in 18 cases. The median tumor size was 50 (10-232) mm. The depth of invasion was cT1 in 31 patients, cT2 in 19, cT3 in 11, cT4a in 28, and cT4b in 10. Histology was differentiated type in 46 patients and undifferentiated type in 56. Completion gastrectomy was performed in 98 patients and partial gastrectomy in 1. 89 patients underwent splenectomy. The univariate analysis showed that tumor location (lesser curvature vs others, p=0.027) and depth of invasion (cT1-3 vs cT4, p=0.032) were significant risk factors for #10 nodal metastasis. By multivariate analysis, these two factors remained significant. Metastasis to #10 nodal metastasis was 0% (0/28) in patients without both risk factors, 11-12% in those with at least one risk factor, and 30% (6/20) in those with both risk factors. Conclusions: The tumors not confined to the lesser curvature and cT4 were significant risk factors for #10 nodal metastasis of RGC after distal gastrectomy. Splenectomy should be considered for complete splenic hilar nodal dissection when these risk factors are positive.
Real-world (RW) testing patterns of serum lactate dehydrogenase (LDH) and its prognostic value among patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Heinz-Josef Lenz, Orsolya Lunacsek, Helene Ostojic, Xiaoyun Pan, Emmanuelle Dochy, Zdravko Vassilev, Nasreen Khan
Journal: Journal of Clinical Oncology (2024)

46 Background: LDH is a potential prognostic biomarker of outcomes for pts with mCRC. This retrospective, observational cohort study describes RW LDH testing patterns and assesses LDH as a prognostic factor for overall survival (OS) in pts receiving chemotherapy (CT) for mCRC in the USA. Methods: Pts with mCRC, ≥18 years (yrs) of age, who initiated first line (1L) CT (index date) between January 1, 2016, and November 30, 2022, were identified in the nationwide de-identified Flatiron Electronic Health Record-derived database. Practice patterns for LDH testing are described. Pts were categorized into normal vs abnormal LDH baseline (≤3 months prior to/at index date) value based on the lab reference range. Prognostic relationship between normal vs abnormal LDH baseline value and OS was assessed using Kaplan-Meier and multivariate Cox proportional-hazards model. Results: Of 15,329 eligible pts, 57% were male, 49% were ≥65 yrs of age and 66% had ECOG performance status 0–1; 59% had stage IV disease at initial diagnosis; 29% had a KRAS mutation (at any time ≤30 days post-index; 35% not tested). Median time from mCRC diagnosis to index was 35 days. Most common 1L regimens were FOLFOX ± bevacizumab (48%), FOLFIRI ± bevacizumab (15%), and capecitabine (13%). Median follow up from index date was 15.6 months (mos); 60% died. LDH testing was performed in 2,547 pts (17%) during baseline and 3,379 pts (22%) post-index. Among those with ≥1 LDH test during each line of therapy (LOT), median number of LDH tests per pt was 4–6 and median time from line initiation to first LDH test was 7–10 days across the first five LOTs (Table). Among LDH tested pts during follow-up (n=3,379), 21% and 40% had abnormal and normal LDH values at baseline, respectively (39% missing). Demographic characteristics of abnormal vs normal LDH pts were similar; abnormal LDH pts were more likely to be ≥65 years (52% vs 49%), African American or Black (12% vs 7%), and reside in the Northeast (30% vs 21%). Median OS (95% CI) in pts with normal vs abnormal baseline LDH was 29.9 (28.3, 31.7) mos vs 16.8 (14.8, 18.2) mos. In multivariate Cox proportional-hazards model, pts with abnormal baseline LDH values had higher risk of death (HR 1.91, p&lt;0.0001) after adjustment for pt demographic and clinical characteristics. Conclusions: In RW clinical practice in the USA, only one-fifth of mCRC pts receiving CT undergo LDH testing even though LDH value has been found to be a prognostic factor of OS. Efforts to increase LDH testing may help guide treatment decisions in this setting. [Table: see text]
Prognostic value of circulating tumor DNA following local therapy in colorectal cancer with liver metastases.
Authors: Conor O'Donnell, Michael H. Storandt, Jessica L. Mitchell, Zhaohui Jin
Journal: Journal of Clinical Oncology (2024)

26 Background: Local therapies have the potential to cure a portion of patients with colorectal cancer with liver-only metastatic disease (CRLM). Peri-operative chemotherapy has not been shown to improve overall survival when added to local therapy in CRLM. Circulating-tumor DNA (ct-DNA) may have potential to help guide management decisions following local therapy. Methods: We conducted a retrospective analysis of health records of CRLM patients who had tumor-informed ct-DNA (Signatera) measurement following curative-intent local therapy prior to August 30th, 2023. Disease-free survival (DFS) was defined as the time from ct-DNA test until radiographic evidence of disease. Descriptive characteristics of the cohort, ct-DNA results and their impact on adjuvant therapy decisions were recorded. Survival analysis was carried out using R software v4.3.1 with survival and survminer packages. The Kaplan–Meier method was used to estimate the survival distribution. Log-rank test was used for comparison. A multivariable Cox proportional hazards model was used to assess prognostic factors associated with DFS ( coxph). Results: 27 patients with CRLM underwent local therapy followed by ct-DNA collection. The median age was 61 years, 67% were male, and 85% were White. Molecular characteristics: KRAS 31%, NRAS/BRAF 0%, microsatellite instability 4%. The median time from initial diagnosis to treatment of liver disease was 21.0 months. 63% of patients received less than 6 months of systemic therapy prior to local therapy. ct-DNA was checked prior to definitive therapy in 12 cases and was positive in 5 cases (detection rate of 42%). Liver-directed therapy involved: resection (n=15), ablation (6), radiation (2) or a combination (4). The median follow-up time from liver-directed therapy was 13.2 months. Post-local therapy chemotherapy was initiated prior to recurrence in 59% of cases. ct-DNA results contributed to immediate post-management decisions in 15% of cases. There were 14 radiographic recurrences (11 to liver only, 3 to other sites). Positive ct-DNA on initial testing following local therapy was associated with poorer DFS in univariate analysis and was the only prognostic factor identified on multivariable analysis. Conclusions: ct-DNA positivity following local therapy for CRLM is associated with earlier recurrence. Baseline testing before local therapy may be important for interpretation of testing results post-local therapy, given frequent missed disease detection. Additional clinical trial data is needed to explore ct-DNA-guided treatment decisions in CRLM. [Table: see text]
Prognostic effects of co-occurring <i>TP53</i> and <i>KRAS</i> aberrations in patients with advanced biliary tract cancer.
Authors: Taro Shibuki, Yoshiaki Nakamura, Makoto Ueno, Masayuki Furukawa, Yasuyuki Kawamoto, Shinji Itoh, Kumiko Umemoto, Kentaro Sudo, Taroh Satoh, Nobumasa Mizuno, Akinori Asagi, Naohiro Okano, Satoshi Shimizu, Tanios S. Bekaii-Saab, John H Strickler, Takao Fujisawa, Hideaki Bando, Takayuki Yoshino, Chigusa Morizane, Masafumi Ikeda
Journal: Journal of Clinical Oncology (2024)

538 Background: In biliary tract cancer (BTC), TP53 is the most commonly altered gene and may co-occur with KRAS alteration. The presence of a co-alterations in of TP53 and KRAS is associated with poor prognosis in many cancers. In patients (pts) with advanced BTC, the prognostic implications of such co-alterations have not been fully investigated. Methods: This is a pooled analysis of SCRUM-Japan GOZILA and MONSTAR-SCREEN-1 and -2 studies. Genomic profiling was conducted with Guardant360 for plasma in GOZILA, FoundationOne CDx for tissue and FoundationOne Liquid CDx for plasma in MONSTAR-SCREEN-1, and CARIS MI Profile for tissue in MONSTAR-SCREEN-2. Pts with advanced BTC receiving systemic therapy were included in this study. Results: Among 636 pts with advanced BTC, 85 had TP53/KRAS co-alteration, 293 had TP53, 44 had KRAS, and 214 had neither KRAS nor TP53 alteration (WT/WT). Tumors with TP53 alteration had significantly higher level of tumor mutation burden (TMB) compared to the other groups (3.8 mut/Mb for TP53/KRAS, 5.0 mut/Mb for TP53, 2.8 mut/Mb for KRAS, and 2.5 mut/Mb for WT/WT, respectively, P&lt;0.001). In addition, the frequency of microsatellite instability-high (MSI-High) in the TP53/KRAS group (11.0%) was significantly higher compared to the TP53 group (3.1%, P&lt;0.05), and the WT/WT group (0.6%, P&lt;0.001), respectively. The objective response rate of first-line therapy in the TP53/KRAS group (8.2%) was significantly lower than in the other groups (20.8% for TP53, 23.3% for KRAS, and 19.7% for WT/WT groups, P=0.035). There was no pts treated with durvalumab plus gemcitabine and cisplatin. Two pts with TP53/KRAS alteration and MSI-High received pembrolizumab monotherapy, and partial response was achieved with a progression-free survival of 9.4 and 22.0 months. The median overall survival (OS) for pts treated with first-line therapy of the TP53/KRAS, KRAS, TP53, and WT/WT groups were 13.6 (95% confidence interval [CI], 11.5-15.5), 14.3 (95%CI, 9.7-25.9), 18.8 (95%CI, 16.9-20.6), and 22.7 months (95%CI, 20.4-25.9), respectively. Multivariate analysis identified TP53/KRAS alteration (hazard ratio [HR] 2.14, 95%CI 1.43-3.22, P&lt;0.001), number of detected variants (≥2) (HR 1.50, 95%CI 1.04-2.16, P=0.029), locally advanced (HR 1.72, 95%CI 1.05-2.83, P=0.033), and metastatic status (HR 1.78, 95%CI 1.39-2.28, P&lt;0.001) as independent prognostic factors for shorter OS. Conclusions: Patients with advanced BTC with co-occurring TP53/KRAS alterations have worse prognosis. Interestingly, the presence of these co-alterations was associated with a higher likelihood of MSI-High phenotype.