tbuckley/cabot-search huggingface dataset:
The TGF-beta pathway alterations in young-onset colorectal cancer.
Authors: Deniz Can Guven, Morgan Ferrell, Cyndi Gonzalez, Richard Giza, Svea Cheng, Masood Pasha Syed, Tara Magge, Aatur D. Singhi, Anwaar Saeed, Ibrahim Halil Sahin
Journal: Journal of Clinical Oncology (2024)

218 Background: Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related deaths worldwide. The epidemiological evidence suggests an increased incidence of young-onset CRC, defined as the CRC in individuals 50 years old or younger. The TGF-beta alterations are among the pivotal events in the CRC carcinogenesis. However, the rate of mutations leading to TGF-beta alterations are yet to be defined in young-onset CRC. Therefore, we conducted a bioinformatics analysis of the mutations associated with TGF-pathway alterations according to age (≤50 years of age vs. &gt;50 years) and primary tumor location (colon vs. rectum). Methods: We used published genomic data of 6286 patients with CRC from the 16 CRC datasets included in the cBioPortal database. The presence of mutations in the following genes was used to define TGF-beta alterations: TGFBR2, TGFB2, TGFBRAP1, TGFBR1, TGFBR3, TGFB1I1, TGFBI, TGFB1, TGFBR3L, TGFB3, TGFA, SMAD1-9, BMPR2, BMPER, BMP3, BMP2K, BMP1, BMP5, BMP10, BMPR1A, BMP15, BMP7, BMP23, BMP4, BMP6, BMPR1B, BMP8B, BMP8A. The presence of TGF-beta alterations according to the age (≤50 years of age vs. &gt;50 years) were evaluated with Chi-square tests. The association between primary tumor distribution (colon vs. rectal) and age were evaluated across patients with and without TGF-beta pathway alterations. The effect of WNT pathway alterations on the overall survival and survival after the metastatic stage was evaluated with Kaplan-Meier survival curves. A type-I error level of 5% (p&lt;0.05) was considered the threshold limit for statistical significance. Results: A total of 2280 patients with available age data was included in the analyses.The mutations associated with TGF-beta pathway alterations was more common &gt;50 years of age compared to ≤50 years of age. (28% vs. 17.4%, p&lt;0.001). Additionally, mutations associated with TGF-beta pathway alterations were more frequent in colon cancer compared to rectum (25.4% vs. 18.7, p&lt;0.001). While progression-free survival was higher in patients with mutations associated with TGF-beta pathway alterations (12.5 vs. 10.7 months, p=0.012), the overall survival (59.6 vs. 58.9 months, p=0.896) and survival after metastatic stage (49.7 vs. 56.5 months, p=0.109) were similar across two groups. Conclusions: In this study, we observed a higher rate of mutations associated with TGF-beta pathway alterations in older CRC patients compared to patients with young-onset CRC. Furthermore, the mutations associated with TGF-beta pathway alterations were more frequent in colon primaries. The overall survival was independent of these mutations. Further research is required to delineate the association between TGF-beta pathway alterations and onset of CRC, as well as the CRC prognosis.
Association between TP53 gain of function and loss of function mutational subgroups and survival in pancreatic adenocarcinoma.
Authors: Nitzan Zohar, Edik Matthew Blais, Adam Mueller, Dzung Thach, Patricia Miren de Arbeloa, Lynn McCormick Matrisian, Emanuel Petricoin, Michael J. Pishvaian, Andrew Eugene Hendifar, Atrayee Basu Mallick, Harish Lavu, Charles J. Yeo, Babar Bashir, Avinoam Nevler
Journal: Journal of Clinical Oncology (2024)

694 Background: TP53 is a commonly mutated tumor suppressor in pancreatic adenocarcinoma (PDAC) but the clinical implications for different classes of TP53 variants remain unclear. In contrast to loss of function (LOF) mutations, TP53 gain of function (GOF) mutations alter DNA conformational binding (e.g. R175H, G245S, R249S, R282H) or modify DNA contact hotspots (e.g. R248Q, R248W, R273H) and are associated with aggressive phenotypes. Here, we analyze progression-free survival (PFS) on standard therapies and overall survival (OS) of PDAC patients (pts) within TP53 mutational subgroups: GOF, LOF, and wild type (WT). Methods: We analyzed longitudinal outcomes across 775 pts with next generation DNA sequencing (NGS) results from Perthera’s Real-World Evidence database who received at least 1 line of therapy in the advanced setting for PDAC. PFS was evaluated from initiation of 1st line for advanced disease until discontinuation. Hazard ratios and p-values were computed via Cox regression when comparing OS relative to date of advanced diagnosis and PFS on subsets who received 1st line FOLFIRINOX (FFX) or 1st line gemcitabine/nab-paclitaxel (GA). Differences in frequencies of genomic alterations between TP53 mutational subgroups were analyzed by Fisher’s exact test. Results: In the TP53 LOF subgroup, median PFS on 1st line GA was significantly worse than 1st line FFX (Table) but this difference was not observed in TP53 GOF or WT subgroups. Irrespective of 1st line therapy choice, median OS in the WT subgroup (2.1y [1.8-2.4]) was significantly longer (p&lt;0.05) than pts with TP53 GOF (1.5y [1.3-2.1]) or TP53 LOF (1.4y [1.3-1.5]). KRAS mutations were enriched (unadjusted p&lt;0.05) for co-occurrence with TP53 in GOF (93.7%) and LOF (93.3%) subgroups relative to WT (74.5%). Mutations in BRCA1/2 were less common in the TP53 GOF subgroup (2.5%) relative to LOF (5.1%) and WT (11.6%). ATM mutations as well as an expanded set of genomic alterations within the DDR pathway were also enriched with similar trends (GOF&lt;LOF&lt;WT). Other potentially confounding factors will be discussed in the context of multivariate OS/PFS analyses. Conclusions: TP53 mutations correlated with worse prognosis in advanced PDAC. Potential predictive associations favoring FFX over GA in the TP53 LOF subgroup (but not in GOF or WT subgroups) warrant further exploration. [Table: see text]
Tislelizumab combined with POFI (irinotecan, paclitaxel, oxaliplatin and 5-FU/levoleucovorin) as first-line treatment of advanced gastric/gastroesophageal junction adenocarcinoma (AGC): Preliminary results of a single-arm, open-label phase I/II trial (SYLT-023).
Authors: Rongbo Lin, Ye Zaisheng, Zhuo Changhua, Shenghong - Wei, Zhixiong Li, Shen Zhao, Liyu Su
Journal: Journal of Clinical Oncology (2024)

331 Background: Tislelizumab is a humanised IgG4 monoclonal antibody with high affinity and binding specificity for PD-1. Combined with fluoropyrimidine + platinum (XELOX or FP), it is approved in China as first-line treatment of advanced gastric cancer (AGC). Both irinotecan and paclitaxel have also shown antitumor activity in advanced gastric/gastroesophageal junction adenocarcinoma. In this phase I/II study, we explore the safety, tolerability, and efficacy of tislelizumab + irinotecan, paclitaxel, oxaliplatin and 5-FU (POFI) as first-line treatment of HER-2 negative, pMMR AGC. Methods: In a phase I dose finding study using a standard 3+3 design, subjects received four escalating dose levels (dl) of irinotecan/paclitaxel (mg/m 2 ): 135/45 (dl #1), 150/45 (dl #2), 135/67.5 (dl #3), and 135/90 (dl #4) in combination with tislelizumab 200 mg plus oxaliplatin 85 mg/m 2 , levoleucovorin 200 mg/m 2 , and 5-FU 2400 mg/m 2 for 46 hours every 2 weeks. Primary endpoints were safety, tolerability, and recommended phase 2 dose (RP2D). Results: Fifteen subjects with treatment naïve AGC were enrolled (3 each in dl #1, dl #2, and dl #3 and 6 in dl #4). The median age was 65 years (range 36-72); 80% were male. Two subjects (13.3%) were diagnosed with gastroesophageal junction cancer, 9 (60%) had poorly differentiated disease, and 5 (33.3%) had liver metastasis. PD-L1 CPS scores were: 5 (n=5); 1 (n=1); and 0 (n=9). All subjects were evaluated for dose-limiting toxicity (DLT). One DLT (grade 4 neutropenia) occurred within 28 days in dl #4. No maximum tolerated dose was reached; the RP2D was dl #4. All subjects had ≥1 treatment-related adverse event (TRAE) and 10 (66.7%) had ≥1 grade 3-4 TRAE per NCI CTC-AE 5.0. The most frequent grade 3-4 TRAEs were neutropenia (n=8; 53.3%), anemia (n=2; 13.3%), and increased glutamyl transpeptidase (n=2 pts; 13.3%). Confirmed objective response rate in 13 subjects with measurable disease was 100% (1 complete response [CR], 12 partial responses [PR]) per RECIST 1.1. Of the 2 subjects with non-measurable disease, one was a CR and the other was non-CR/non-PD. Survival data are immature. Conclusions: Tislelizumab+POFI was well tolerated and showed preliminary antitumor activity. A phase II study at the RP2D is ongoing. Clinical trial information: NCT05319639 .
Atezolizumab plus bevacizumab (A+B) in patients with unresectable hepatocellular carcinoma (uHCC): Real-world experience from a US community oncology network.
Authors: David Cosgrove, Amie Tan, Andrew Osterland, Sairy Hernandez, Sarika Ogale, Sami Mahrus, John Murphy, Thomas W Wilson, Gregory A. Patton, Arturo Loaiza-Bonilla, Amit G. Singal
Journal: Journal of Clinical Oncology (2024)

447 Background: A+B is the standard first-line (1L) treatment for uHCC based on the IMbrave150 trial, which demonstrated superior efficacy over sorafenib with longer median overall survival (19.2 vs 13.4 months) and progression-free survival (6.8 vs 4.3 months) among patients with Child Pugh (CP) A cirrhosis. Evidence about A+B use and outcomes in routine clinical practice, including in patients with impaired liver function, remains limited. Methods: This retrospective observational study included adult patients who initiated 1L A+B for uHCC within The US Oncology Network between 1/1/2019 and 8/31/2022 (followed through 11/30/2022) using structured and unstructured electronic health records (EHR) based data. CP classes were reported by physicians or derived from risk factors. Kaplan-Meier methods were used to assess real-world overall survival (rwOS) and progression-free survival (rwPFS) from initiation of A+B. Exploratory subgroup analyses were conducted by CP class, albumin-bilirubin (ALBI) grade, liver disease etiology, and race/ethnicity. Results: We identified 374 patients with uHCC who initiated 1L A+B during the study period. Compared with patients enrolled in IMbrave150 (n=336), those treated with A+B in clinical practice were older (median age: 69 vs 64 years), had worse liver function (CP A: 61% vs 100%; ALBI Grade &gt;1: 66% vs 43%), and had poorer performance status (ECOG PS&gt;1: 18% vs 0%). At a median follow-up of 5.6 months, 78% (n=293) had discontinued treatment. Among them, 57% discontinued was progression and 4% discontinued due to toxicity alone. Median rwOS was 13.2 months (95%CI: 9.5–15.9) and median rwPFS was 6.4 months (95%CI: 5.1–7.7). Subgroup results are shown (Table). Conclusions: In community oncology settings, 1L A+B demonstrates effectiveness in diverse patient cohorts, including those with impaired liver function, non-viral liver disease, and racial/ethnic minorities. Predictive biomarkers can help identify subgroups who may most benefit from 1L A+B. [Table: see text]
Impact of somatic genomic alterations in patients with metastatic colorectal cancer in a minority-rich academic medical center.
Authors: Jessica Jang, Moisey Khanimov, Devin Johnson, Chenxin Zhang, Jee-Young Moon, Carolina Bernabe, Chaoyuan Kuang
Journal: Journal of Clinical Oncology (2024)

215 Background: Genomic alterations in metastatic colorectal cancer (mCRC) play a pivotal role in the clinical manifestations of the disease. Mutations have been associated with the age of onset of mCRC, tumor location, and metastatic sites. We conducted a retrospective study to explore the relationship between the genomic profile and clinical phenotype in a distinct patient population predominantly comprised of Hispanic and Black patients with mCRC. Methods: Patients with mCRC with available next-generation sequencing (NGS) treated at Montefiore Einstein Comprehensive Cancer Center (MECCC) who were diagnosed from January 2000 - January 2023 were included. Molecular testing was collected from: Perthera, Guardant, Caris, and Foundation One. The following parameters were collected: race, ethnicity, age of CRC diagnosis, age of metastatic diagnosis, metastatic sites, NGS profile, tumor location, and lines of treatment. Mutations were categorized into one of eight distinct pathways: cell cycle, MAP Kinase, WNT, homologous recombination, DNA damage repair, epigenetic modifications, transcription, &amp; cell death. The primary endpoint was to examine the relationship between individual genetic alterations or any of these eight pathways and the clinical parameters. Results: 169 patients with microsatellite stable (MSS) mCRC were included (median age at diagnosis 59 years, 42% Hispanic, 38% Black). 148 distinct genetic alterations were discovered across our population, of which roughly half fit into one of eight clinical pathways. In concordance with previously published data, we found a significant association between PTEN and right-sided tumors (38% mutated in right-sided vs. 16% mutated in left-sided, p&lt;.001). Cell cycle pathway mutations and SMAD4 mutations were associated with an earlier age of both primary CRC (p=.001 &amp; p=.042, respectively) and metastatic diagnosis (p=&lt;.001 &amp; p=.013, respectively). CDK8 mutations were associated with atypical sites of metastases (p=.045). Conclusions: This analysis sought to deepen the understanding of how genomic alterations impacted the clinical phenotype in our population of mCRC patients. We identified previously undescribed associations between mutations in the cell cycle pathway and SMAD4 versus age of CRC diagnosis. As molecular sequencing in CRC continues to advance, these relationships may be further elucidated, which can potentially help guide treatment and identify higher-risk patients.
Anlotinib combined with penpulimab and hepatic artery infusion chemotherapy (HAIC) in the first-line treatment of unresectable hepatocellular carcinoma.
Authors: Gong-Rang Chen, Ting Zhong, Jian-Hua Cai, Juan Liang
Journal: Journal of Clinical Oncology (2024)

TPS579 Background: Hepatic arterial infusion chemotherapy (HAIC) is recommended as a treatment option in patients with advanced hepatocellular carcinoma (HCC). Anlotinib plus penpulimab, a humanized anti-PD-1 IgG1 antibody, has shown encouraging activity in the treatment of advanced HCC in an open-label phase II trial (NCT 04172571). Considering different anti-malignancy mechanisms, combining systemic and locoregional therapies may show a potential synergic effect and promising preliminary efficacy results in advanced HCC. Consequently, the aim of this study is to assess the efficacy and safety of Anlotinib, Penpulimab, plus HAIC for advanced HCC. Methods: Trial design: This single-arm, prospective, phase II study will include treatment-naive adult (≥18 years) patients with advanced HCC, ECOG PS 0-2, and Child-Pugh class A-B. A total number of 26 patients will be enrolled for treatment until disease progression or intolerable toxicity. Patients will receive anlotinib(10 mg, p.o., qd, d1-14, q3w), penpulimab (200 mg, i.v., d1, q3w) and HAIC (d1- d2) with the FOLFOX regimen (oxaliplatin 85-130 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 48 hours) for 4-6 cycles, followed by maintenance therapy with anlotinib and penpulimab for up to 2 years. The primary endpoint is objective response rate (ORR)), evaluated using RECIST 1.1. Secondary endpoints are median PFS and overall survival (OS), disease control rate (DCR) per RECIST 1.1, quality of life (QOL) and safety. Recruitment for this study will complete in December 2024.
Serum angiopoietin-like protein 2 level in patients who received bevacizumab-containing chemotherapy for metastatic colorectal cancer.
Authors: Jung Hoon Kim, Jae-Joon Kim, Sung Yong Oh, Sang-Bo Oh, Youngkyung Jeon, Kyung Wook Hong, Seung-Jin Kwag
Journal: Journal of Clinical Oncology (2024)

209 Background: Anti-angiogenic agents are important for treating patients with advanced colorectal adenocarcinoma, however, their efficacy is not long-lasting and survival benefits are modest. Reliable biomarkers and novel targets for angiogenesis are still required in this era. Angiopoietin-like protein 2 (AGLP-2) is an emerging biomarker for angiogenesis in cardiovascular disease, but its role in the oncology area is yet to be elucidated. Methods: Serum samples from patients with advanced colorectal carcinoma treated with bevacizumab-containing chemotherapy were retrospectively studied. Blood samples at baseline and at disease progression of the first line systemic therapy were selected. Serum angiopoietin-like protein 2 (AGLP-2) concentrations were measured using ELISA kit, serial changes, and the relationship with progression-free survival and overall survival on the systemic therapy were statistically analyzed. Results: 68 patients were enrolled. Their median age was 66 years old (range, 38-82), and 14 (20.6%) patients had metastatic lesions at 3 or 4 organs. The median serum AGLP-2 levels at baseline and at disease progression (PD) were 41,618 pg/ml (95% confidence interval (CI) 34,560-40,713), and 49,706 pg/ml (95% CI 39,853-49,017), respectively. There was a tendency of difference between AGLP-2 levels at baseline and at PD ( p=0.057). Patients whose baseline serum AGLP-2 levels with 40,000 pg/ml or above showed relatively shorter overall survival (median 31.4 months with 95% CI, 14.4-38.6) compared with patients with serum AGLP-2 level below 40,000 pg/ml at baseline (median 38.6 months with 95% CI, 23.6-127.3), but not statistically significant ( p=0.0946). There was no survival difference observed according to serum AGLP-2 levels at disease progression on the first line bevacizumab-containing chemotherapy. Conclusions: Serum angiopoietin-like protein-2 has potential as a new target for novel anti-angiogenic therapy in metastatic colorectal cancer.
A randomized controlled trial of CAPEOX vs observation in patients with early-stage colorectal cancer with positive MRD after curative surgery (CAREME).
Authors: Ke-Feng Ding, Qian Xiao, Jianbin Xiang, Yiming Zhou, Jun Song, Yixin Xu, Xue-Feng Huang, Min Chen, Jinlin Du, Ketao Jin, Xiaoyu Dai, Zhonglei Shen, Taiyuan Li, Shanping Ye, Wei Cui, Yibin Zhao, Wenbin Chen, Xiaofei Cheng, Haixing Ju, Qian Zhang
Journal: Journal of Clinical Oncology (2024)

TPS225 Background: Most patients (pts) with early-stage colorectal cancer (CRC) have a good prognosis, but some still relapse shortly after surgery. Effective methods to assess the risk of recurrence in these pts and guide adjuvant chemotherapy (ACT) decision-making are lacking. Increasing studies have shown that circulating tumor DNA (ctDNA) can detect minimal residual disease (MRD) and identify pts with a high risk of recurrence. ACT could improve survival of MRD-positive pts with stage Ⅱ CRC suggested by recent studies, whether it is appropriate for those with stage Ⅰ or clinically low-risk stage Ⅱ CRC remains unknown. Methods: CAREME is a multicenter randomized controlled clinical trial aimed at investigating the benefit of chemotherapy for MRD-positive pts with early-stage CRC. Pts with resected stage Ⅰ or Ⅱ CRC will be evaluated by oncologists. Those who did not receive neoadjuvant therapy and are deemed suitable for active surveillance (i.e., ACT is not needed) will undergo a postoperative ctDNA test using MinerVa MRD assay (a tumor-informed assay covering 769 cancer-related genes). Pts with mismatch repair-deficient tumors will be excluded and stage Ⅱ pts should have no traditional high-risk features according to clinical practice guidelines. Pts with positive ctDNA (N = 38) will be equally randomized into two groups: treatment group (Arm A) or surveillance group (Arm B). Arm A will receive 8 cycles of CAPEOX therapy while pts in Arm B will not receive any ACT; both groups will undergo ctDNA tests at 6 months after randomization and be followed up every 3 months. The primary endpoint is 18-month recurrence-free survival, and a key secondary endpoint is ctDNA clearance at 6 months after randomization. Tumor samples from the pts will be collected for MRD assay and exploratory research. Accrual started in February 2023. Support: Genecast Biotechnology Company. Clinical trial information: NCT05699746 .
Relative and collective contribution of liver and bile duct cancer risk factors among minority groups in California.
Authors: M. Cecilia Monge B., Gabriela Arroyo Figueroa, Tim F. Greten
Journal: Journal of Clinical Oncology (2024)

439 Background: Liver and Bile Duct Cancer is a significant public health concern with higher incidence rates observed among people belonging to racial and ethnic minority groups compared to non-Hispanic White people. This study aims to understand which underlying factors contribute most to this disparity in liver and bile duct cancer. Methods: The California Health Maps database was analyzed from 2015-2019, including 58 counties: consistent with the SEER census and CDC PLACES Project. Variables examined included race, ethnicity, age, health insurance status, foreign-born status, rural residence, obesity prevalence, socioeconomic status, smoking status, and percentage of individuals receiving preventative care. Linear regression analysis was used to determine which factors significantly predict higher prevalence of liver and bile duct cancer. Results: The population consisted of 39,283,494 people, predominantly Hispanic (39%) with 38.7% being non-Hispanic White; 15.5% Asian or Pacific Islander and 6.2% non-Hispanic Black. Hispanic people accounted for 21% of the 868,882 total cancer cases and 33% of the 22,439 cases of liver and bile duct cancers reported. Race and ethnicity were the most substantial predictors of liver and bile duct cancer prevalence; counties with a higher monitory population exhibited higher incidence rates (Hispanic: R=0.39; p=0.003, Black: R=0.39; p=0.004, White: R=-0.55; p&lt;0.0001, Asian: R=0.33; p=0.01). Being foreign-born (R=0.45; p=0.0008), residing in non-rural areas (R= -0.33; p=0.01), and lacking preventative care (women: R= -0.30; p=0.03, men: R= -0.37; p=0.006) were also significantly associated with increased liver and bile duct cancer incidence rates (Table). Conclusions: This study highlights the association of race, ethnicity, and access to healthcare services with higher incidence rates of liver and bile duct cancer among Hispanic and non-Hispanic Black people compared to non-Hispanic White people. Addressing these disparities is crucial for promoting equitable health outcomes in liver and bile duct cancer. [Table: see text]