tbuckley/cabot-search huggingface dataset:
The expand indication of HER2 targeted therapies by monitoring of circulating tumor cells.
Authors: Koichi Suzuki
Journal: Journal of Clinical Oncology (2025)

482 Background: Despite success in the HER2 targeted therapies for metastatic gastric cancer patients, the conventional assessment of HER2 status in tumor tissue specimens is still under debate. Methods: On-chip sorting system was used for the isolation of circulating tumor cells (CTCs). The fluorescence signal intensity &gt; 50 is set to be a threshold value for distinguishing between positive and negative HER2 on CTCs. Epithelial mesenchymal transition (EMT) was assessed by the vimentin and cytokeratin. DNA was extracted from CTCs and applied to the cancer gene panel. Results: In 27 patients with metastatic gastric cancer, 13 patients showed HER2 positive in tumor tissues (Group A) who were treated with cytotoxic agents and HER2-targeted therapy while 14 patients exhibited negative and treated with cytotoxic agents. In these 14 patients, 8 patients showed HER2 positive (Group B) and 6 patients displayed HER2 negative (Group C) on CTCs. HER2 expression on CTCs was associated with EMT (p&lt;0.001). Increased expression of EMT was seen in Group A and B, indicating they are likely to have metastasis. Group B exhibited worse PFS than others (13.8 M in A, 7.0 M in B and not reached in C, p=0.012). In addition, genomic analysis identified cancer gene mutations, some of which were involved in mechanisms underlying EMT and were shared between Group A and B. Considering HER2 expression on CTCs in Group B, an additional HER2-targeted therapy may be beneficial. Conclusions: Our study suggests that monitoring of circulating tumor cells leads to the expand indication of the HER2 targeted therapies in patients with metastatic gastric cancer.
Landscape of <i>MET</i> genomic alterations in colorectal cancer (CRC).
Authors: Faiza Yasin, Dean Pavlick, Jeffrey S. Ross, Michael Cecchini
Journal: Journal of Clinical Oncology (2025)

247 Background: MET signaling is implicated in the tumorigenesis of many solid tumors, including CRC. MET-targeted therapies are approved in non-small cell lung cancer with novel agents in clinical trials for tumors with MET exon 14 splice site mutations, MET amplifications, and recently MET expression. There is emerging therapeutic interest in targeting MET in CRC. Methods: Tumor samples from 50,500 cases of clinically advanced CRC were analyzed by hybrid capture-based comprehensive genomic profiling (CGP) that evaluated all classes of genomic alterations (GA). MSI-high status, tumor mutational burden (TMB), genomic ancestry, trinucleotide mutational signatures, and homologous recombination deficiency signature (HRDsig) were assessed for patients with activating MET GA. PD-L1 expression was determined by IHC (Dako 22C3 with TPS scoring system). Results were compared using the Fisher exact test with the Benjamini-Hochberg adjustment. Results: A total of 502 (1.0%) cases of activating GA of MET (METmut) were identified, including 418 cases (0.83%) with MET amplification (METamp), 10 (&lt;0.1%) rearrangements, and 78 (0.1%) short variant (SV) mutations with 19 (&lt;0.1%) cases of MET exon 14 splice site mutations. When compared with MET wild-type (METwt) CRC, the METmut CRC were of similar age (median 62 years), and numerically more likely to be male (61.4% vs 56.0%; P=.05). There were no differences in genomic ancestry (72% European ancestry for both groups). The METmut CRC featured more cases with a POLE signature (3.6% vs 0.4%; P=&lt;0.0001) and more GA per tumor (7 vs 5; P&lt;0.0001). MSI-high status was similar in both groups, with 4.2% in METmut and 6.0% in METwt (P=0.28). TMB levels were numerically higher in the METmut cases (TMB ≥ 10 mutations/Mb at 12.2% vs 9.0%; P=0.058). Low level PD-L1 expression (1-49% TPS) was similar in both groups (13.9% in METmut vs 13.3% in METwt), and while not statistically significant, high level PD-L1 expression (&gt;50% TPS) was higher in the METmut group (4.3% vs 1.6%; P=0.056). The frequencies of HRDsig+ CRC were rare and similar in both groups with 1.5% in METmut and 1.7% in METwt. METmut CRC had lower frequencies of GA in KRAS (34.7% vs 48.8%; P&lt;0.0001), NRAS (1.8% vs 4.2%; P=0.011), APC (72.5% vs 78.2%; P=0.009) and PIK3CA (12.2% vs 18.9%; P=0.0004), and higher frequencies of GA in CDK6 (10.2% vs 0.6%; P&lt;0.0001), EGFR (5.2% vs 0.2%; P=0.0002), ERBB2 (9.6% vs 5.2%; P=0.0004), HGF (8.0% vs 0.8%; P&lt;0.0001), POLE (4.2% vs 0.5%; P=0.005) and TP53 (84.1% vs 75.9%; P&lt;0.0001). In METmut CRC, ERBB2 alterations were 4.1% amplifications, 2.9% sequence mutations, 0.9% with more than one mutation. BRAF V600E was seen in 5.9% in METmut CRC and 8.4% of METwt. Conclusions: CGP reveals significant differences in the genomic landscapes of METmut CRC and METwt CRC, which may guide selection of potential rational drug combinations with novel MET-targeted therapies.
Acquired gene alterations potentially related to resistance to anti-HER2 therapy in HER2-positive metastatic colorectal cancer (mCRC).
Authors: Celine Hoyek, Binbin Zheng-Lin, Angelo Pirozzi, Oluseyi Abidoye, Cody Eslinger, Naoko Iida, Yoshiaki Nakamura, Ryne Ramaker, Mohamad Bassam Sonbol, Christina Wu, Mitesh J. Borad, Daniel H. Ahn, Masafumi Ikeda, Taro Shibuki, Takayuki Yoshino, John H Strickler, Tanios S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2025)

277 Background: While HER2-targeted therapies benefit patients (pts) with advanced HER2-positive mCRC, the development of resistance remains inevitable. This study aims to explore the landscape and frequency of genetic alterations putatively associated with acquired resistance to anti-HER2 therapy in HER2-positive mCRC. Methods: In this retrospective-multicenter international study involving Mayo Clinic, Duke Cancer Center and National Cancer Center Hospital East (Japan), we descriptively compared comprehensive genomic analyses from tissue or blood samples of pts with HER2-positive CRC pre-treatment and post-treatment with HER2-targeting agents. Results: A total of 36 pts were included in this study. 29 (80%) had HER2-positive mCRC as confirmed by immunohistochemistry (IHC) and fluorescent in situ hybridization (ISH), the remaining pts had HER2 amplification detected on blood or tissue . 34/36 (94%) pts were administered their first anti-HER2 agent after progressing on ≥2 prior lines of treatment. The most common anti-HER2 regimen administered was trastuzumab/pertuzumab (50%, 18/36), followed by trastuzumab-tyrosine kinase inhibitors (TKIs) (tucatinib or neratinib) (30%, 11/36) and trastuzumab deruxtecan (14%, 5/36). Putative genomic mechanisms of acquired resistance were detected in 72% (26/36), while the remaining pts lacked new genomic alterations that might explain resistance to anti-HER2 therapy, suggesting alternative escape mechanisms. Acquired alterations in downstream or alternate bypass pathways were identified in 72% (26/36) of pts; most commonly in the RAS/RAF pathway and in EGFR (34.6%, 9/26 each), followed by 27% (7/26) of pts with MET point mutations (mts) and amplification; activating muts in PI3K/AKT and in 27% (7/26), most commonly CDK12 (60%, 4/7) . HER2 receptor alterations were detected in 3 pts (8.3%), all of whom received trastuzumab-tucatinib and included HER2 L755S, HER2 V777L, HER2 D769Y, HER2 G727A and HER2 S310F, which are known to cause resistance to , however, information about tucatinib resistance is not yet available. Other altered pathways included AR, RB, NOTCH and HRD. Two pts lost HER2 expression on blood and tissue NGS post anti-HER2 therapy. Conclusions: The emergence of resistance might be in part related to acquired alterations that constitutively activate signaling pathways parallel or downstream of HER2, bypassing HER2 inhibition. Additional histologic studies, deep mutational scanning, larger populations and correlative analysis are needed to validate these findings.
The impact of adherence to NCCN and BCLC treatment guidelines on survival in HCC: A single center study.
Authors: Kanan Alshammari, Manar Almuntashri, Shahad Alajmi, Halah Alhwsawi, Taeef Alsulami, Mohammad Arabi, Ashwaq Alolayan, Mohammad Alkaiyat, Husam Shehata, Mohammad Ahmad Algarni
Journal: Journal of Clinical Oncology (2025)

561 Background: Hepatocellular carcinoma (HCC) is a prevalent and lethal disease in Saudi Arabia, and globally. Guidelines such as Barcelona Clinic Liver Cancer (BCLC) and National Comprehensive Cancer Network (NCCN) are used to guide therapy for this disease. Adherence to these guidelines should lead to better outcomes. We aim to examine the adherence to guidelines and its impact on survival in a real world setting. Methods: This retrospective cross-sectional study was conducted at the Ministry of National Guard for Health Affairs, Riyadh, Saudi Arabia. Study included all adult patients with HCC who were diagnosed between 2020 and 2023, and presented at our HCC multidisciplinary tumor board (MDT). Data extracted included demographics, clinical and disease characteristics, treatment modalities, and survival status. Chi-square tests, and Kaplan-Meier survival analysis were used to explore relationships between tumor characteristics, adherence to NCCN and BCLC guidelines, and survival outcomes. Adherence to guidelines were assessed by two independent physicians. Results: The study included 208 patients with HCC, the majority were males (73%) with a mean age of 73 years. Less than half of the patients (41.7%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Tumor staging showed that 35% of the patients had BCLC stage D. Child pugh class A and B were equally present in 45% of the patients. Moreover, 24% of the patients had distant metastases or vascular invasion (in portal vein) placing them in BCLC stage C. It is noteworthy that Alpha-Fetoprotein (AFP) was abnormal (&gt;8ng/ml) in 58% of the patients, 18% of them had AFP of more than 400ng/ml. Additionally, the prevalence of comorbid conditions were remarkable for liver cirrhosis being present in 85% of patients, while diabetes mellitus and hypertension each present in 63% of patients. Finally, survival analysis showed a median survival of 16.8 months in all patients with HCC (range 0-47.8 months). Adherence to guidelines were high, with 97.6% (n=203) following NCCN guidelines and 70.7% (n=147) following BCLC guidelines. Following both guidelines showed better survival with mean of 37 months (SD=1.841) in patients with child pugh class A (n=53), and mean survival of 24 months (SD=2.251) in patients with child pugh class B (n=74). Conclusions: Adherence to NCCN guidelines was high in our MDT presented patients compared to BCLC guidelines adherence which was lower, but with comparable survival outcomes.
Comprehensive landscape of FGFR variations and prognosis revelance in colorectal cancer from circulating tumor DNA and tissue gene analyses in 2083 patients.
Authors: Xiaoshuang Lyu, Runkai Cai, Bohan Han, Yanhong Deng
Journal: Journal of Clinical Oncology (2025)

278 Background: FGFR genomic alterations have been identified, and several FGFR inhibitors are approved for various malignancies, including bladder and cholangiocarcinoma. However, limited studies have shown FGFR alterations and their prognostic impact in colorectal cancer (CRC). Methods: This retrospective analysis involved tissue and blood samples from a single-institute cohort (The Sixth Affiliated Hospital of Sun Yat-sen University) of stage I-IV CRC patients from 2014 to 2024. FGFR genomic alterations were analyzed using tissue NGS and plasma ctDNA. Disease-free survival (DFS) for stages I-III and progression-free survival (PFS) for stage IV were compared between FGFR-altered and negative CRC patients, matched in a 1:2 ratio. Validation of genomic alterations and their prognostic impact was conducted using cBioPortal and TCGA data. Results: FGFR alterations were found in 7.89% of 608 tissue samples and 10.95% of 2083 ctDNA samples. The most frequent alteration was FGFR1 amplification in all cohorts, along with FGFR2 p.R165W and FGFR3 p.A634T mutations in ctDNA. FGFR alterations correlated with younger age, left-sided colon tumors, adenocarcinomas, poor differentiation, advanced TNM staging, and multi-organ metastasis. Prognostic analysis showed a higher proportion of FGFR alterations in stage IV patients (66.23% vs. 59.14%), lower rates of no evidence of disease (NED) (6.62% vs. 17.68%), and significantly shorter PFS (median 17 vs. 20 months, HR 2.184, p=0.007). In stages I-III, FGFR-altered patients also had a lower NED rate (79.22% vs. 82.19%) and significantly shorter DFS (median 13 vs. 29 months, HR 2.833, p=0.002). Among frequent alterations, FGFR1 amplification was significantly associated with poor prognosis (PFS 17 vs. 20 months, HR 2.221, p=0.014; DFS 13 vs. 29 months, HR 2.964, p=0.002), while others showed no significant correlation. In stage IV patients receiving bevacizumab, FGFR1 alteration was linked to significantly shorter PFS (p=0.0021). KEGG analysis indicated FGFR1 was associated with angiogenesis pathways. FGFR alteration profiles and prognostic outcomes were consistent across tissue samples, ctDNA analyses, and databases. Conclusions: Our study outlines the genomic landscape and prognostic significance of FGFR in CRC, highlighting FGFR1 amplification as the dominant alteration. FGFR alterations were associated with poorer outcomes, as reflected in lower NED rates and shorter DFS and PFS. FGFR1 amplification was notably linked to reduced DFS and PFS, and it correlated with shorter PFS in patients receiving bevacizumab, indicating a potential link to resistance against bevacizumab. ctDNA n=2083 Tissue genen=608 cBioPortal Databasen=6998 FGFR Total 228/10.95% 48/7.89% 528/8.0% FGFR1 76/3.65% 29/4.77% 264/4.0% FGFR2 78/3.74% 10/1.64% 125/1.9% FGFR3 104/4.99% 10/1.64% 139/2.1%
A study of the homologous recombination deficiency signature (HRDSig) status of advanced esophageal squamous cell carcinoma (AESCC) by utilizing comprehensive genomic profiling (CGP).
Authors: Zakee Mohamed Jiffry, Dean Pavlick, Ethan Sokol, Ryon P Graf, Alexa Betzig Schrock, Gerald Li, Julia Quintanilha, Jerry W. Mitchell, Tamara Jamaspishvili, Jeffrey S. Ross, Alina Basnet
Journal: Journal of Clinical Oncology (2025)

485 Background: The role of poly-ADP-ribose polymerase (PARP) inhibitors is currently under investigation as a potential therapeutic option for AESCC. Homologous recombination deficiency signature status (HRDSig) positivity has been shown to predict biallelic loss of BRCA1/2 which may simultaneously portend a worse prognosis and a sensitivity to poly-ADP-ribose polymerase (PARP) inhibitors. In this study, we attempt to characterize the genomic alterations present in AESCC based on HRDSig status utilizing comprehensive genomic profiling (CGP) techniques. Methods: 2,029 cases of AESCC underwent comprehensive genomic profiling with an examination of all genomic alterations (GA). MSI high status, tumor mutation burden (TMB) levels, genomic ancestry and genomic trinucleotide signatures were determined from the sequencing data. HRDSig status was calculated using a broad set of genome-wide copy number features (PMID 37769224). Results were compared using the Fisher exact system with the Benjamini-Hochberg adjustment to correct for false discovery. Results: 154 (7.6%) of the 2029 AESCC cases featured a positive HRDSig status (HRDSig+). The age (66-67) and gender (58%-63% male) distribution were similar in the HRDSig+ and HRDSig- AECSS cases as was the frequency of GA/tumor (9 for both). The median TMB was higher in the HRDSig+ (6.3 vs 3.8; P&lt;.0001) as was frequency of TMB &gt; 10 mutations/Mb (19.5% vs 10.0%; P=.004). An APOBEC trinucleotide signature was also more frequent in the HRDSig+ AESCC (11.0% vs 5.4%; P=.05). As anticipated, GA in genes associated with HRD including BRCA1 (10.4% vs 1.4%; P&lt;.0001) and BRCA2 (14.3% vs 2.0%; P&lt;.0001) was present. MTOR pathway activating mutations were also more frequent in the HRDSig+ AESCC group including PTEN (13.0% vs 7.3%; P=.06). Conclusions: With a 7.6% frequency, HRDSig+ status is a relatively rare event in AESCC. CGP with determination of HRDSig status in AESCC may prove useful in tailoring PARP inhibitor-based treatment regimens and may potentially uncover other genomic alterations that can aid in designing targeted therapy combinations in future. Characteristics of comprehensive genomic profiling of clinically advanced esophageal squamous cell carcinoma by HRDSig status. AESCC HRDSig- (n=1875) AESCC HRDSig+ (n=154) P-value Pathogenic genomic alterations BRCA1 1.4% (26) 10.4% (16) 0.00 BRCA2 2.0% (36) 14.3% (22) 0.00 PTEN 7.3% (137) 13.0% (20) 0.06 COSMIC trinucleotide signature APOBEC 5.4% (101) 11.0% (17) 0.05 Tumor mutational burden (TMB) Median TMB (range) (IQR) 3.8 (0-85) (2.5-6.3) 6.3 (0-61) (3.8-8.8) 0.00 TMB≥10 mut/Mb 10.0% (188) 19.5% (30) 0.00
Effectiveness of the Colorectal Cancer Alliance's digital screening quiz and navigation model for promoting CRC screening.
Authors: Kimberley Lynn Newcomer, Alex Guevara, Dionne Christopher, Marianne Pearson, Dammie Brown
Journal: Journal of Clinical Oncology (2025)

97 Background: Evaluating the effectiveness of a Colorectal Cancer screening navigation model delivered in a digital platform offered by a patient advocacy organization. Designed as a digital screening quiz tool and live navigation to promote CRC screening, the Colorectal Cancer Alliance’s Screening Quiz is a risk stratification tool that connects respondents to live certified cancer care navigators delivering evidence-based interventions to increase CRC screening, education and patient and family support. The framework utilizes small and mass media, one-on-one education and patient navigation services to help address and reduce barriers to care. Research on these critical interventions shows that on-time screening for CRC leads to better outcomes. Methods: The Screening Quiz has been promoted through social sharing, community outreach, and media, including influencer campaigns to increase outreach to at-risk communities. Questions assess personal and family history, hereditary syndromes, and demographics to provide a CRC screening recommendation based on current USPSTF guidelines. Respondents overdue for screening are triaged to the Alliance’s patient navigation team. This interaction includes phone calls and emails for symptomatic individuals/high risk for CRC, telephone and email for average-risk uninsured, and emails for average-risk insured. At-risk individuals are connected to resources, such as financial assistance, free at-home screening tests, and colonoscopy scheduling services. Results: July 2022 to July 2024, the Screening Quiz provided over 50,000 screening recommendations. The median age of respondents was 46; 32% of respondents were between the ages of 45 to 64. Of the respondents, 29% were male and 71% were female. Most were White (79.2%), but nearly half of those who opted into navigation identified as BIPOC, including 16.7% Black/AA, 6.6% Asian, and 2.1% AI/AN. Additionally, 8.4% of respondents identified as ethnically Hispanic/Latino with another race. Most respondents were symptomatic (66.6%) but 6.5% were asymptomatic high-risk. These two groups represented 88% of 1,869 respondents triaged to patient navigation. Conclusions: The digital Screening Quiz, combined with live navigation, represents a promising approach for increasing CRC screening rates and addressing care gaps compared to traditional methods. The Alliance’s ability to engage at-risk communities through its national network of volunteers and partners, combined with evidence-based interventions, positions it well to continue closing screening gaps. Going forward, the Alliance aims to leverage its relationships with healthcare providers and community organizations further to expand the reach of its CRC screening efforts.
Alteration of gut microbiota in patients with advanced hepatocellular carcinoma.
Authors: Thanakorn Charoenthanadhol, Kosin Wirasorn, Aumkhae Sookprasert, Jarin Chindaprasert, Thanachai Sanlung, Piyakarn Watcharenwong, Siraphong Putraveephong, Jutarop Phetcharaburanin
Journal: Journal of Clinical Oncology (2025)

641 Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of cancer-related death worldwide. Despite advancements in treatment, such as novel combinations of immunotherapy and targeted therapy or dual immunotherapy, the prognosis remains poor due to a lack of predictive biomarkers for treatment response. Gut microbiota alterations have been proposed as both potential diagnostic biomarker and predictive biomarker. However, data in this field are not well-established and are mostly derived from studies conducted in China and Western countries, which may not fully reflect the situation in Thailand. Methods: Fecal samples were collected from pre-treated advanced HCC patients who visited medical oncology outpatient clinic at Srinagarind hospital, Khon Kaen University (HCC group = 27) and analyzed using 16S rRNA sequencing of gut microbiota. Additional sequenced data from a healthy population (Control group = 31) who had no underlying disease and had normal liver ultrasonography were retrieved from a previous study conducted by Khon Kaen University (Cholangiocarcinoma Screening and Care Program, CASCAP). The datasets were compared using the Wilcoxon rank-sum test to analyze the alteration of gut microbiota between HCC group and control group. Results: The HCC group exhibited significantly lower biodiversity index (p&lt; 0.001) than control group in terms of richness, Shannon diversity index and Simpson’s index. The HCC group had significantly higher relative abundance of the phylum Proteobacteria (p&lt; 0.001), Firmicutes (p&lt; 0.001) and a lower abundance of the phylum Actinobacteria (p&lt; 0.001) compared to the control group. Additionally, the HCC group had significantly higher relative abundance of Stenotrophomonas, Granulicatella, Ruminococcus, Blautia, Phascolarctobacterium, Butyricoccus, Streptococcus, Escherichia-Shigella, Flavonifractor, Haemophilus and Lachnospira at the genus level. Further analysis of relative abundance of gut microbiota at the genus level and clinical prognostic parameters showed positive correlation between Streptococcus and 6-month survival status. Conclusions: Gut microbiota profile in patients with advanced HCC was significantly altered from healthy control group. This could be the evidence of microbial dysbiosis and may potentially be biomarker for prognosis.