tbuckley/cabot-search huggingface dataset:
Distinctive clinical and molecular aberrations of colorectal cancer patients with ovarian metastases.
Authors: Alexandria Lenyo, Cathy Eng, Deepa Magge, Kristen Keon Ciombor
Journal: Journal of Clinical Oncology (2024)

e15595 Background: Ovarian metastases (OM) from colorectal cancer (CRC) are a rare phenomenon. There are limited data detailing outcomes from surgical interventions on OM. However, there is a lack of studies integrating genetic aberrations identified in these patients with clinical characteristics. Methods: We conducted a retrospective review of CRC patients with OM. Demographic variables of interest included age and stage at diagnosis, time from diagnosis to discovery of OM, laterality of OM, primary tumor sidedness, and choice of chemotherapy. Next Generation Sequencing was utilized to collect solid tumor DNA sequencing, in addition to cell-free DNA (cfDNA). Results: A cohort of 12 MSI-S patients was identified between December 2023 and January 2024. Median age of diagnosis was 42.5 y/o. Demographics noted: Primary tumor sidedness included descending colon [58%; 86% of these sigmoid] and ascending colon (42%). AJCC T4 (50%) with OM at presentation (83%); unilateral (58%); 57% in the left ovary. 67% of patients underwent bilateral salpingo-oophorectomy (BSO), 25% unilateral resection, and 8.3% had no resection. 9 patients continue to receive treatment; 3 patients are deceased. Tissue NGS data was available for 75% of patients. The most common mutations were p53 (100%), APC (88%), KRAS (G12A, G12C and G12D; 38%), and PIK3CA (25%). cfDNA data was available for 58% of patients; common mutations were APC (86%), p53 (71%), KRAS [G12C (2); G12D; 43%), PMS2 (29%), BRAF V600E (14%) and BRAF amplification (14%). Conclusions: In our cohort, CRC patients with OM were of early age onset with sigmoid &gt; ascending colon cancer with similar molecular alterations by tissue and cfDNA noting increased KRAS aberrations. Hence, NGS should be completed in all CRC as an opportunity to further characterize potentially actionable mutations in patients with OM, expanding precision oncology availability to this select patient population.
Adjuvant chemotherapy in clinical local advanced CRC following preoperational therapies and pT0-3N0M0 diagnosis (CANWATCH).
Authors: Jun Huang, Ping Liu, Zheng Liu, Yong Li, Fengyun Pei, Qijun Yao, Zhimin Liu, Fang He, Yandong Zhao, Meijin Huang, Jianping Wang
Journal: Journal of Clinical Oncology (2024)

TPS3645 Background: Adjuvant chemotherapy is often deemed unnecessary in pathological stage II colorectal cancer (CRC) following initial surgery without high-risk factors for recurrence. However, the efficacy of adjuvant chemotherapy for pT1-3N0M0 CRC following preoperative chemotherapy or chemoradiotherapy remains uncertain. Some cases of clinical locally advanced CRC (cTxN1-2M0), which are down-staged to pT0-3N0M0 after preoperative chemotherapy or chemoradiotherapy, may not truly require adjuvant chemotherapy due to the down-staging effects of preoperative treatments or false-positive imaging diagnosis of lymph nodes. Methods: CANWATCH is a multicenter, open-label, randomized, phase III study with a parallel design conducted in China. Patients were randomly assigned (1:1) to the wait-and-watch group or the adjuvant chemotherapy group. Enrollment and random assignment were performed using a computerized randomization management system. Patients in the wait-and-watch group did not receive adjuvant chemotherapy but were followed up periodically, while patients in the adjuvant chemotherapy group continued to receive adjuvant chemotherapy based on 5-FU or 5-FU analogues (mFOLFOX6 or Capeox). This study is the first prospective randomized controlled study to assess the necessity of adjuvant chemotherapy for patients with locally advanced CRC who received neoadjuvant therapy and achieved a down-staging to pT0-3N0M0. The study aims to provide precise clinical evidence for individualized precision treatment in locally advanced CRC patients. Key inclusion criteria included preoperative clinical tumor stage III (cTxN1-2M0) CRC, pathologically confirmed CRC adenocarcinoma by endoscopic biopsy, postoperative pathological stage T0-3N0M0 without high-risk factors for recurrence, and patient ability to understand and sign written informed consent. Main exclusion criteria were a history of other malignant tumors, complications requiring emergency surgery (occlusion, sub-occlusion, massive hemorrhage, and abscesses), colorectal tumor extension toward the abdominal wall and/or adjacent organs preventing immediate R0 resection of liver metastases, non-resectable lymph node metastasis, American Society of Anesthesiologists (ASA) grading ≥ IV, and/or Eastern Cooperative Oncology Group (ECOG) score ≥ 2. A total of 650 patients are planned to be enrolled in this study, and 301 patients have been enrolled as of February 6, 2024. The study is registered with ClinicalTrials.gov (NCT03748485) and is ongoing. Clinical trial information: NCT03748485 .
The impact of COVID-19 and missed diagnosis of colorectal cancer.
Authors: Atharva Rohatgi, Cheng-I Liao, Caitlin Ruth Johnson, Daniel Stuart Kapp, John K Chan
Journal: Journal of Clinical Oncology (2024)

e15598 Background: To evaluate the impact of COVID-19 pandemic on colorectal cancer diagnosis based on sex, age, race, and regions within the US. Methods: Data on colorectal cancer incidence were obtained from the United States Cancer Statistics (USCS) program from 2001-2020. SEER*Stat 8.4.1.2 and Joinpoint regression program 5.0.2 were used to calculate estimated and actual incidence rates per 100,000 adults. Rates were age-adjusted as appropriate. We compared actual colorectal cancer incidence rates in the year 2020 to estimated rates based on trends from 2001-2019 with sub-analyses for sex, age, race, and region. Results: From 2001 to 2019, there were 2,627,565 identified cases of colorectal cancer in the United States. In 2019, prior to the pandemic, the incidence rate of colorectal cancer was the highest in males at 42.26 per 100,000 compared to 32.18 in females. The overall cancer incidence was 36.87 per 100,000 in both males and females in the US. Based on the data from 2001 to 2019, colorectal cancer decreased by 2.20% per year (p &lt; 0.001). Using these prior trends, it was expected that the incidence of colorectal cancer to be 36.44 per 100,000 adults (115,392 total cases) in 2020. However, the reported incidence was only 32.47 per 100,000 (102,798). Thus, there were 10.9% (12,594) less colorectal cancer cases than expected. The missed diagnosis rate was more pronounced in males compared to females, where 11.90% and 10.84% less colorectal cancer cases were detected compared to expected in 2020, respectively. Based on age, the cases missed were the highest amongst middle aged adults, with 13.56%, 13.49%, and 13.05% cases missed for the age groups between 50-54, 65-69, and 70-74 respectively. Based on racial and ethnic groups, we found that Non-Hispanic Asians and Pacific Islander (NHAPI) had the greatest number of missed cases at 14.38% compared to 11.98%, 11.36%, and 11.27% of Non-Hispanic Black (NHB), Non-Hispanic White (NHW), and Hispanic adults, respectively. The discrepancy between expected and actual number of cases by U.S. region ranged from the highest in the Southern (11.64%) to the lowest in the Western (10.92%) region. An intersectionality analysis showed that 40–44-year-old NHAPI females residing in the Western region had the largest discrepancy at 47.96%. Conclusions: The reported colorectal cancer cases significantly declined during the pandemic. Males, middle age, NHAPI and NHB race and ethnicity, and those residing in the Southern region had the most number of missing cases. Due to the widespread prevalence of colorectal cancers, more mitigating factors are needed to improve the access to care for patients in these at-risk groups to improve diagnosis and detection of colorectal cancer and its associated mortality.
Liquid biopsy multiomics enable clinical triage for early colorectal cancer diagnosis.
Authors: Michael Sha, Hiromi Tanaka, Rachel Chuang, Shuo Shen, Larry Pastor, Mauro Scimia, Maria Antonia Bianco, Giancarlo Troncone, Simone Scimia, Umberto Malapelle, Francesco Pepe, Gianluca Russo, Andrew Y. Fu, Di Li, Aiguo Zhang
Journal: Journal of Clinical Oncology (2024)

e15599 Background: Colorectal cancer (CRC) is the second most common cause of cancer death in the United State. Despite advancements in screening, diagnosis, and treatment, the disease remains a formidable public health issue. In 2023, approximately 153020 individuals were diagnosed with CRC and 52550 will die from the disease. In order to meet early diagnostic, we developed this multiomics assay to enable clinical triage for liquid biopsy screening. Methods: Xenonucleic acid (XNAs) are artificial genetic polymers that retain the Watson-Crick base-pairing capability and exhibit high chemical and biological stability. They can be employed as molecular clamps in RT-qPCR due to the stronger hybridizing/binding capability seen in XNA/DNA duplexes than DNA/DNA duplexes. We are developing an XNA-based multiplex RT-qPCR assay for APC, BRAF, CTNNB1, KRAS, NRAS, PIK3CA, SMAD4 and TP53 gene mutation panel and CRC 9 genes methylation panel combined with multiplex protein panel, called Coloscape TM Plus. We enrolled in FIT positive subjects of both genders, aged 50-74, attending the CRC screening program, we tested 152 plasma samples, 75 health, 50 AA and 27 early CRC with this multiomics assay. Results: The assay results showed that its sensitivity was about 44% (95% CI: 0.302- 0.587) and specificity about 80% (95%CI: 0.689- 0.880) for advanced adenoma (AA). For CRC stage I and II, its sensitivity is about 63% and 78% with 80% specificity separately. Conclusions: The primary data has shown that this low cost and rapid turnaround time multiomics assay has a comparable sensitivity for early colorectal cancer diagnostic.
International, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI).
Authors: Anthony B. El-Khoueiry, Tae-You Kim, Jean-Frédéric Blanc, Olivier Rosmorduc, Thomas Decaens, Philippe Mathurin, Philippe Merle, Farshid Dayyani, Gianluca Masi, Tiziana Pressiani, Peter Robert Galle, Ken Hatogai, Yuko Ishii, Henrik Seidel, Udo Mueller, Stacey Anastasia Kalambakas, Mohamed Bouattour
Journal: Journal of Clinical Oncology (2024)

4007 Background: The optimal second-line treatment for HCC after ICI is not established. Regorafenib is approved for treatment of advanced HCC after sorafenib. The primary aim of this study was to evaluate the activity of regorafenib plus pembrolizumab in patients with advanced HCC who progressed on only one prior ICI regimen. Methods: Patients aged ≥18 years, CP Class A, BCLC stage B or C, and ECOG PS of 0 or 1 received oral regorafenib 90 mg once daily 3 weeks (wk) on/1 wk off plus i.v. pembrolizumab 400 mg every 6 wk. The daily regorafenib dose could be escalated to 120 mg after the first 4-wk cycle of regorafenib if tolerated. Pembrolizumab dose reductions were not allowed. Cohorts were defined by prior treatment: Cohort 1 = atezolizumab + bevacizumab; Cohort 2 = any other ICI regimen (alone or combination). Primary endpoint was overall response rate (ORR) by independent central review (RECIST 1.1). Results: 95 patients were treated in 8 countries; Cohort 2 appeared to have more favorable disease characteristics (Table). Most common prior ICIs in Cohort 2 were durvalumab (30%), nivolumab (30%), ipilimumab (22%), and pembrolizumab (19%). Overall, median follow up was 7.1 months (mo). Median duration of regorafenib/pembrolizumab treatment (including interruptions, delays) was shorter in Cohort 1 vs Cohort 2 (11.0/9.4 wk vs 21.4/24.1 wk). ORR was 5.9% in Cohort 1 and 11.1% in Cohort 2; stable disease rates were 48.5% and 63.0%, respectively. Median PFS was 2.8 mo in Cohort 1 and 4.2 mo in Cohort 2. Overall, treatment-emergent adverse events (TEAE) were grade 3 in 56% of patients and grade 4 in 5%; drug-related grade 3 and 4 TEAE occurred in 37% and 3%, respectively. One patient (Cohort 1) had a grade 5 drug-related TEAE (cardiac arrest). Most common drug-related TEAE were palmar-plantar erythrodysesthesia syndrome (39%), asthenia (33%), decreased appetite (32%), diarrhea (28%), and hypertension (20%). Biomarkers assessed in paired biopsies (baseline and wk 6/day 1) showed on-treatment reductions in macrophages and angiogenesis RNA signatures. Conclusions: To our knowledge, this is the first prospective evaluation of a kinase inhibitor plus an ICI following first-line ICI therapy for HCC. Regorafenib plus pembrolizumab had modest activity in second line after first-line ICI regimens. The safety profile of the combination was consistent with those of either drug. Optimal treatment for patients with advanced HCC who progress after an ICI regimen remains an unmet need. Biomarker findings will be detailed in presentation. Clinical trial information: NCT04696055 . [Table: see text]
Updated results and biomarker analyses from the phase 2 trial of nab-paclitaxel plus sintilimab as second-line therapy for advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (G/GEJA).
Authors: Zhichao Jiang, Wen Zhang, Lin Yang, Yongkun SUN, Yun-Bo Zhao, Wei Deng, Liang Cui, Aiping Zhou
Journal: Journal of Clinical Oncology (2024)

4037 Background: Sintilimab plus Nab-paclitaxel (nab-PTX) has exhibited promising efficacy and safety in the second line (2L) treatment of PD-1/PD-L1 inhibitor naïve advanced G/GEJA (ZC Jiang et al 2022 ASCO GI). This update presents the latest findings on efficacy, survival outcomes and exploration of biological markers. Methods: We collected blood samples from the advanced G/GEJA patients (pts) who were enrolled in our Phase 2 clinical trial and treated with sintilimab plus nab-PTX. Target-capture deep sequencing of 1,021 genes was conducted to identify somatic variants in circulating tumor DNA (ctDNA) from the baseline plasma samples (N=55) and disease progression samples of the pts with PFS &gt;4 months (N=17). And T cell repertoire sequencing was performed on pretreatment samples (N=55) as well as on paired blood samples obtained during the first tumor evaluation (N=45). Results: From Nov 2019 to Sep 2022, 58 pts were enrolled, with a median follow-up of 20.9 months (95% CI 17.04-24.76) until July 10, 2023. The objective response rate (ORR) and disease control rate (DCR) were 44.8% and 79.3%, respectively. The median progression free survival (mPFS) and median overall survival (mOS) were 4.8 months (95%CI 3.06-6.54) and 11.8 months (95%CI 10.43-13.17). Analysis of baseline ctDNA revealed a notably higher prevalence of EPHB1 mutation in non-responders (PD+increased SD) compared to responders (CR+PR+decreased SD) (21.43% vs. 0%, P=0.022). Pts with EPHB1 mutation showed a significantly increased risk of disease progression (HR 3.86, 95% CI 0.43-34.41, p=0.013) and death (HR 4.49, 95% CI 0.43-46.93, p=0.005) compared to wild-type EPHB1 pts. In contrast to high ctDNA level (mean tumor molecules [MTM] per mL of plasma, cutoff value=2999.7), low ctDNA level demonstrated a significantly reduced risk of disease progression (HR 1.88, 95% CI 1.05-3.37, p=0.034). Dynamic T cell receptor (TCR) diversity analysis during baseline and the initial tumor assessment showed a significant post-treatment increase in the Shannon index within the responder group (P=0.045, median Shannon index change: responder 0.43 vs. non-responder -0.49). An increased Shannon index was correlated with significantly prolonged mPFS (HR 0.44, 95% CI 0.22-0.91, P=0.009), while no significant difference was observed in mOS (HR 0.74, 95% CI 0.36-1.54, P=0.399). A negative correlation between the Shannon index and MTM was observed (R=-0.37, P=0.009). Conclusions: 2L-treatment with sintilimab plus nab-PTX maintains favorable efficacy in advanced G/GEJA pts without prior PD-1/PD-L1 inhibitor treatment. EPHB1 mutation and dynamic change of TCR could serve as potential predictive factors. Further investigation is warranted. Clinical trial information: NCT04140318 .
FGF19-FGFR4 axis as the inaugural target for determining the efficacy of advanced esophageal cancer treatment.
Authors: Wei Wang, Shuimiao Lin, Qin Zeng, Wenjie Li, Tongxin Liu, Xiaomei Zhou, Rong Wang, Ziyi Luo, Dehua Wu
Journal: Journal of Clinical Oncology (2024)

4035 Background: Advanced esophageal cancer (EC) remains a fatal stage with limited survival benefits from current treatments due to lack of specific targets. Esophageal squamous cell carcinoma (ESCC) is the most common type observed in EC cases. Studies have shown that around 40% of ESCC cases exhibit amplification of chromosome 11q13, which includes genes like FGF19, FGF3, FGF4, and CCND1. Among these, FGF19 and its receptor FGFR4 play crucial roles in cancer progression. Blocking the FGF19-FGFR4 axis could potentially disrupt tumor progression. Anlotinib, a multi-targeting tyrosine kinase inhibitor, targets VEGFR2, PDGFR, and FGFR1-4. In this study, we analyzed the next-generation sequencing (NGS) data from our cohort of advanced EC patients to identify potential therapeutic targets based on their genetic mutations. We also investigated whether FGF19 amplifications could enhance sensitivity to anlotinib-based treatments. Methods: The study was conducted as a retrospective analysis at our institution from October 2017 to August 2021. To be included in the study, patients had to be between 18 and 75 years old, have confirmed metastatic and/or recurrent EC with measurable lesions, and have detailed clinical information without any other primary tumors. We used NGS to analyze the mutation landscape in advanced EC patients. Additionally, we investigated the therapeutic effects of blocking the FGF19-FGFR4 axis by retrospectively analyzing the outcomes of advanced EC patients who received anlotinib-based treatments, which target the FGFR family. We compared overall survival (OS), progression-free survival (PFS), and best response between advanced EC patients with and without FGF19 amplifications who received anlotinib-based treatments. Results: A total of 50 patients with advanced EC (47 with squamous carcinoma and 3 with adenocarcinoma) underwent NGS testing. FGF19 amplifications were the third most common mutation, occurring in 46% of patients, following TP53 (88%) and CCND1 (48%). Among the 26 patients receiving anlotinib-based treatment, 13 (50%) had FGF19 amplifications. Patients with FGF19 amplifications had a 69.2% objective response rate (ORR) and a 100% disease control rate (DCR). None of the 13 patients with FGF19 amplifications developed progressive disease (PD). Patients with FGF19 amplifications showed significant improvements in ORR (69.2% vs. 12.5%, p=0.011) and median PFS (5.3 vs. 2.7 months, HR=0.10, 95%CI: 0.02-0.56, p=0.0015) compared to those without FGF19 amplifications. Improvements in DCR (100% vs. 75%, p=0.06) and median OS (8.7 vs. 7.2 months, HR=0.44, 95CI%: 0.12-1.59, p=0.2) were also observed, albeit not statistically significant. Conclusions: Anlotinib-based therapy showed improved clinical outcomes in patients with FGF19 amplifications. This suggests that targeting FGF19 amplifications could be a promising approach for treating advanced ESCC.
A phase II clinical evaluation of radiofrequency ablation (RFA) combined with regorafenib and toripalimab in patients with colorectal cancer with liver metastases.
Authors: Zhiqiang Wang, Hui Ouyang, Huiyan Luo, Fei Gao, Man Mie, Chao Ren, Ji-Bin Li, Haiyan Fu, Jin Shan Huang
Journal: Journal of Clinical Oncology (2024)

3566 Background: In several clinical studies, the combination of anti-programmed cell death protein 1 (anti-PD-1) antibodies with targeted antiangiogenic agents has demonstrated clinical benefits for patients with metastatic colorectal cancer (mCRC). However, individuals with liver metastases have shown suboptimal responses. Prior preclinical study indicates a synergistic efficacy of radiofrequency ablation (RFA) when employed in conjunction with immunotherapy. The study aimed to explore whether RFA combined with regorafenib and toripalimab (an anti-PD-1 antibody) could provide better outcomes in patients with colorectal cancer liver metastases. Methods: Using Simon's two-stage design, a total of 32 subjects were required for enrollment, with10 subjects included in stage 1. If there were no or less patients having response, the study would be terminated; otherwise, it would proceed to stage 2, enrolling an additional 22 subjects. The cohort consisted of 10 microsatellite stable (MSS) mCRC patients with multiple liver metastases who had previously failed fluorouracil, oxaliplatin, irinotecan, with or without targeted therapy. RFA was performed on a single hepatic lesion, with others designated as target lesions. Treatment with regorafenib and toripalimab commenced one week post-RFA, following a 4-week cycle. Toripalimab was administered intravenously biweekly, and regorafenib was given orally at daily dose of 80 mg (three weeks on, one week off, in a 4-week period). The primary endpoint was response rate. Results: Ten patients (3 women) were enrolled in this study, with ages ranging from 26 to 76 years (median: 52 years), and 60% being 52 years or older.Seventy percent had ECOG performance status (PS) of 0; 60% had primary colon tumors; 90% presented with synchronous liver metastases, and 80% had both intrahepatic and extrahepatic metastases. Half of the participants achieved stable disease; however, none exhibited confirmed partial or complete responses. The median progression-free survival was 3.3 months, and the median overall survival reached 11.3 months. The median number of cycles was two (range: 0.5 to 3), with 60% undergoing at least two cycles. Adverse events (AEs) included hand-foot syndrome, liver dysfunction, fatigue, abdominal distension, and thrombocytopenia. The most frequently reported AE was hand-foot syndrome, occurring in 50% of patients. Serious AEs (grade≥3) potentially related to treatment included hand-foot syndrome and hyperbilirubinemia, each with an incidence of 10%. Notably, one patient experienced hyperprogression during immunotherapy. Conclusions: The combination of RFA, regorafenib, and toripalimab has not shown encouraging efficacy in patients with CRC liver metastases. However, the observed safety profile is acceptable. Clinical trial information: NCT05485909 .