tbuckley/cabot-search huggingface dataset:
Disease monitoring using plasma-based circulating tumor DNA (ctDNA) assays in rare malignancies.
Authors: Shenduo Li, Dana Connor, Lyndsey Lane Fournier, Sarika Rao, Rami Manochakian, Yanyan Lou, Yujie Zhao
Journal: Journal of Clinical Oncology (2024)

e15046 Background: ctDNA assays can be used to assess molecular residual disease, and the value of ctDNA monitoring in disease surveillance and treatment response assessment has been demonstrated in colon, breast, lung, and bladder cancers. However, the data of ctDNA in rare cancers has been lacking. We conducted this retrospective study to investigate the potential roles of ctDNA monitoring in rare tumors in both surveillance and response evaluation. Methods: ctDNA assay results of 12 patients (pts) with rare cancers including adrenocortical carcinoma (ACC) (4 pts), salivary gland cancers (3 pts), pleural or peritoneal malignant mesothelioma (4 pts), and anaplastic thyroid cancer (ATC) (1pt) undergoing treatment or surveillance in 2023 at Mayo Clinic Florida were analyzed. The trends of ctDNA levels were correlated with radiographic images findings. Results: Among the 12 patients, ctDNA was detected in at least one time point in 9 (75%) pts, including 1 (100%) ATC pt, 2 (66%) salivary gland pts, 3 (75%) malignant mesothelioma pts, and 3 (75%) ACC pts. Among these 9 pts, 5 pts had ctDNA collected at more than one timepoints, and the trends of ctDNA levels were consistent with image findings in all 5 pts. Among these 5 pts, one pt received definitive surgery for ACC with clearance of ctDNA after the surgery and one salivary gland cancer pt was undergoing surveillance and later developed disease progression. The other 3 pts were undergoing palliative systemic therapy and had responded to treatments. Conclusions: ctDNA was detectable in majority of the patients with rare malignancies reviewed in this study, including ACC, ATC, pleural or peritoneal malignant mesothelioma, and salivary gland cancers. Further study is warranted to investigate the role of ctDNA monitoring in surveillance and treatment response evaluation in rare malignancies.
Pre- and post-radical surgery comparative quantification of circulating tumor cells and circulating tumor-associated cells.
Authors: Rajan Datar, Vineet Datta, Dadasaheb Akolkar, Rohit Chougule, Shoeb Patel, Pradyumna Shejwalkar, Archana Adhav, Apurva Dalvi, Darshana Patil
Journal: Journal of Clinical Oncology (2024)

e15056 Background: Classical Circulating Tumor Cells (CTCs) are defined as EPCAM+, PanCK+, CD45-, whereas, Circulating Tumor Associated Cells (CTACs) are defined as EPCAM+, PanCK+, CD45+/-. CTACs comprise a heterogenous mix of tumor-associated cells including classical CTCs, cancer stem cells, circulating micro-emboli, tumor cell fused macrophages and other tumor-educated cells including junction endothelial and stromal cells. These cells play either a causative or synergistic role in the metastatic spread of cancer. Although it has been speculated that CTCs and CTACs would be rapidly cleared once tumor burden diminishes, the effect of radical surgery in cases of solid organ cancers and the change in the quantum of these cells after surgery has not been fully explored. Methods: We obtained 15 ml peripheral blood from 20 patients diagnosed with solid organ cancers comprising head and neck (11/20, 55%), breast (4/20, 20%), and colorectal (5/20, 25%) before and immediately after (within 24 hrs.) radical surgery. Peripheral Blood Mononucleated Cells (PBMCs) were isolated after RBC lysis and CTCs and CTACs were identified and enumerated from the same sample using differential apoptosis based negative enrichment followed by fluorescent imaging. Results: Pre-surgery, CTCs ranged from 12 to 0 cells per ml and 0 to 2 per ml post-surgery. CTACs ranged from 17 to 11057 cells per ml and, post-surgery, from 4 to 2041 cells per ml of blood. After surgery, CTCs were eliminated in 19/20 (95%) specimens, and in 1/20 (5%) specimens, there was a slight increase in the number of CTCs post-surgery. In 16/20 (80%) patients, the CTACs reduced by &gt; 80%; in 2/20 (10%) patients, the CTACs reduced by &gt; 50%-&lt;80% and, in 2/20 (10%) patients, CTACs increased by &gt; 5%. Conclusions: The enumeration of CTCs appears to correlate with the tumor burden pre- and post-surgery. On the other hand, although there appears to be a significant reduction in CTACs, residual cells of this phenotype appear to persist. The clinical correlation of this divergent trajectory of CTCs and CTACs pre- and post-surgery warrants further long-term studies.
Performance of surufatinib in treating advanced neuroendocrine neoplasms: Insights from a real-world study.
Authors: Linhui Zhu, Xuan Ye, Youjun She, Wensheng Liu, Qiong Du, Qing Zhai
Journal: Journal of Clinical Oncology (2024)

e15124 Background: Current comparisons of targeted treatments for advanced neuroendocrine neoplasms (NENs)-specifically surufatinib, sunitinib, and everolimus—are lacking. This study aims to assess their efficacy and safety in a real-world setting. Methods: A retrospective, observational study was conducted at Fudan University Shanghai Cancer Center, including patients with advanced NENs prescribed surufatinib, sunitinib or everolimus between July 2020 and April 2023. The primary outcome was median progression-free survival (PFS), and secondary outcomes included objective response rate (ORR), disease control rate (DCR) and adverse events (AE). Results: A total of 123, 56 and 68 locally advanced or metastatic NEN patients treated with surufatinib, sunitinib or everolimus were enrolled. In pancreatic NENs (pNEN), surufatinib demonstrated superior efficacy over sunitinib and everolimus combined (mPFS: 8.67 vs 6.37 months, P=0.02; ORR: 17.1% vs 8.3%). Specifically, surufatinib outperformed sunitinib (mPFS: 8.67 vs 6.40 months, P=0.04; ORR: 17.1% vs 10.9%) and everolimus (mPFS: 8.67 vs 5.37 months, P=0.05; ORR: 17.1% vs 3.8%) individually. In extrapancreatic NENs (epNEN), surufatinib showed enhanced efficacy compared to everolimus (mPFS: 9.47 vs 6.70 months, P=0.15; ORR: 8.3% vs 5.3%). On multivariate Cox analysis, male, functional status, Ki67 index&gt;20%, previous SSA and germline mutation, poor differentiation, liver metastasis, multi treatment lines were identified as negative effect (P&lt;0.05) for PFS in pNEN and epNEN patients respectively. The most common adverse events (AEs) were hypertension (12.2%) in surufatinib-treated patients, manageable with medication. Sunitinib led to decreased neutrophil counts (10.7%), and everolimus was associated with anemia (4.4%). Conclusions: Utilizing real-world data, this study reveals surufatinib significantly enhances progression-free survival (PFS) over sunitinib and everolimus in advanced neuroendocrine neoplasms (NENs), guiding future targeted treatment choices.
A phase II study of liposomal irinotecan-based chemotherapy with or without PD-1 inhibitor in patients with unresectable locally advanced or metastatic biliary tract cancer.
Authors: Jieer Ying, Xiangdong Cheng, Qi Xu, Jingjing Li, Yiwen Zhuo, Yanping Liu, Jing Yuan
Journal: Journal of Clinical Oncology (2024)

e15077 Background: Clinical outcomes for advanced biliary tract cancer (BTC) patients (pt) progressed on first-line therapy remain dismal. Liposomal irinotecan (LI) (HE072) is a formulation encapsulating I in a lipid bilayer vesicle and was approved in China in September 2022. It was used with 5-fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic pancreatic cancer progressing on gemcitabine treatment. We conducted an phase II study to investigate HE072 in combination with 5-FU and LV with or without a novel PD-1 inhibitor SG001 in patients with advanced BTC progressed on prior gemcitabine-based chemotherapy. Methods: This is a multi-center, non-randomized, open label phase II study in pts with unresectable locally advanced or metastatic BTC. Key inclusion factors were ECOG PS 0-1, prior gemcitabine-based chemotherapy, evidence of disease progression with at least one measurable lesion and adequate haematological/organ function. Key exclusion factor was brain metastases. Pts were treated with liposomal irinotecan (70 mg/m 2 ) plus LV (400 mg/m 2 f) and 5-FU (2400 mg/m 2 ) with or without SG001 (240mg) IV every 2 weeks for up to 2 years in absence of disease progression or unacceptable toxicity. Tumor assessments based on RECIST 1.1 were performed every 6 weeks by investigators. Primary endpoint was objective response rate (ORR). Secondary endpoints include progression free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Results: As of April 25, 2023, 17 BTC pts were enrolled into liposomal irinotecan-based chemotherapy arm (n = 7) and liposomal irinotecan-based chemotherapy plus SG001 arm (n = 10). ORR and DCR were 14.3% and 71.4% for chemotherapy arm, 20% and 40% for chemotherapy+ SG001 arm. Median OS and PFS for chemotherapy arm was 11.5(95% CI, 3.9-NE) and 4.2(95% CI, 1.4-NE) months, and for chemotherapy+PD-1 arm was 15.3 (95% CI, 3.6-17.0) and 3.8(95% CI, 1.4-6.9) months. All pts experienced treatment-related adverse events (TRAEs). The incidence of grade≥3 TRAEs was 58.8%(10/17), which occurred in 57% (4/7) of pts treated in chemotherapy arm vs 60% (6/10) in chemotherapy+SG001 arm. Among all patients, the most frequent grade ≥3 TRAEs were fatigue (29.4%), neutropenia (23.5%) and leukopenia (23.5%). One grade 4 TRAE leading to dose reduction in liposomal irinotecan was febrile neutropenia in chemotherapy arm. There were no treatment-related deaths. Conclusions: These preliminary results suggested that liposomal irinotecan plus 5-FU and LV was well-tolerated and showed promising and durable clinical activity in advanced BTC pts progressed on first-line treatment. Combined use of SG001 further improved clinical outcome in these pts without increased toxicity. Combination of liposomal irinotecan, 5-FU, LV and PD-1 inhibitor is a treatment strategy which is worthy of further exploration.
Safety and clinical efficacy of IOA-289, a novel autotaxin inhibitor, plus gemcitabine and nab-paclitaxel (GnP) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Davide Melisi, Alberto Quinzii, Monica Valente, Anna Maria Di Giacomo, Giovanni Amato, Elena Simonetti, Camilla Zecchetto, Simona Casallino, Luigi Leta, Luisa Messineo, Lucia Mendo, Tracey Hammett, Marcel Deken, Giusy Di Conza, Paramjit Kaur, Michael M. F. Lahn, Michele Maio
Journal: Journal of Clinical Oncology (2024)

e15130 Background: Autotaxin (ATX) plays a critical role in inflammation and resistance mechanisms in a wide range of malignancies. IOA-289 is a novel inhibitor of ATX, with anti-fibrotic, immune-enhancing and anti-tumour activity. This first-in-human trial evaluated safety and tolerability, pharmacokinetic (PK)/pharmacodynamic (PD) profile of IOA-289 in combination with GnP. Methods: IOA-289 was investigated, in untreated mPDAC, in a dose escalation study evaluating the continuous twice daily dosing (BID). IOA-289 was initially administered for 7 days as a monotherapy (Cycle 0) before adding GnP at standard doses in 3 weekly schedule followed by 1 week pause (Cycle 1 onwards). Primary objective: Safety and tolerability. Secondary objectives: PK; PD (e.g., plasma LPA and serum CA19-9); radiographic responses (RECIST 1.1); PFS and OS. Results: Cohort 1 assessed the safety at 100 mg BID (n = 4), cohort 2 at 200 mg (n = 4), and cohort 3 at 400 mg (n = 5). Safety assessment shows no treatment-emergent adverse events led to study drug discontinuation, or a dose limiting toxicity. Most toxicities were consistent with the known toxicity profile of GnP. Median time on treatment for cohort 1 was 4.8 months, for cohort 2 and cohort 3 patients are still under treatment and clinical outcomes are not yet established but are projected to surpass the observation from cohort 1. Five patients are currently remain active on treatment No clinical responses were observed in cohort 1. In cohort 2, 2 out of 4 patients (50%) achieved a Partial Response (PR) at cycle 5 and 7 respectively, which was confirmed and durable. No mature data is available yet for later cohorts. Exposure to the compound resulted in reductions in multiple LPA species, with a protocol-defined inhibition of &gt; 50% for over 24 hrs. Consistent reductions in levels of CA19-9 have been observed since cohort 2 (200 mg BID), with &gt; 50% reduction already from cycle 2, with durable reductions lasting longer than 4 months. No mature data is available for later cohorts. Conclusions: IOA-289 is well tolerated at all dose levels in combination with standard GnP. Patients in the higher dose cohorts are experiencing robust CA19-9 reductions consistent with ORR. Occurrence of PRs occurred later than compared to historical controls and were durable, suggesting a differentiated mode of action. Clinical trial information: NCT05586516 .
Simultaneous detection of tumor-derived mutations in DNA and RNA extracted from a single circulating tumor cell based on droplet digital polymerase chain reaction.
Authors: Jaesung Choi, Sehwan Park, Aejin Jeong, Hanbyeol Kim, Sehyung Pak, Min-Ji Song, Jungwon Kim, Hai-Chon Lee
Journal: Journal of Clinical Oncology (2024)

e15053 Background: Androgen receptor splice variant 7 (AR-V7) is a constitutively activated isoform of AR and has been associated with resistance to AR-targeted therapies and development of metastatic castration-resistant prostate cancer. Confirmation of AR-V7 expression is important step in prostate cancer diagnosis and determining the appropriate drug, however, the detection of AR-V7 with tissues has limitations, such as the clinical challenge to poorly accessible tumor tissues before and after therapy. In addition, KRAS mutations serve as a prognostic biomarker for the administration of appropriate anti-cancer drugs in patients with various cancers, including non-small cell lung cancer (NSCLC). Here, we developed the process for the simultaneous detection of AR-V7 and KRAS mutation in CTCs using isolation with CytoGen’s Smart Biopsy ™ System with droplet digital polymerase chain reaction (ddPCR) with high sensitivity and specificity, overcoming the limitations of tissue biopsy. Methods: ddPCR assays were performed to detect the KRAS G12C mutation using CTC gDNA and to evaluate the absolute levels of AR-V7 using CTC mRNA. Analytical validation was performed using NSCLC NCI-H358 and prostate cancer 22Rv1 cells (10 and 5 cells each), which harbor KRAS G12C and AR-V7, respectively, spiked into 5 mL of healthy blood to mimic CTC. CTCs were isolated using CytoGen's Smart Biopsy™ System. Oligo-dT magnetic beads were used to isolate mRNA from CTCs, and gDNA was isolated from the mRNA-depleted CTC lysates using the AllPrep DNA/mRNA Nano Kit. PCR and droplet reading for each assay were performed on the QX200 AutoDG Droplet Digital PCR System. Results: As a result of CTC KRAS G12C detection using the ddPCR™ KRAS G12/G13 Screening Kit, the mutated KRAS gene was successfully detected in as few as 5 NCI-H358 cells. In the results of CTC AR-V7 detection using the custom TaqMan ddPCR assay, transcripts (AR-V7 and HPRT1) were successfully detected even with only 5 22Rv1 cells. These results suggest that CytoGen's Smart Biopsy™ System could be applied to the simultaneous detection of DNA/RNA mutated genes in clinical NSCLC and prostate cancer patients with detection technology requiring high sensitivity and specificity. Conclusions: Accurately detecting multiple genetic mutations in CTCs is a challenging because CTCs are very rare in the blood. In this study, we developed the process to simultaneously extract and detect DNA mutations and RNA splicing variants in CTCs using CytoGen's Smart Biopsy™ System. This process, along with the results from our ongoing clinical trials, could provide information for the diagnosis and appropriate treatment of patients with various cancers, including NSCLC and prostate cancer.
Pharmacogenomic diversity of clinically significant cancer treatment biomarkers in ancestrally diverse US population.
Authors: Ekokobe Fonkem, Folefac Aminkeng, Chuck Hay, Mona M Al-Gizawiy, Jaimy Pettit, Jennifer M Connelly, Kathleen M Schmainda
Journal: Journal of Clinical Oncology (2024)

e15099 Background: Cancer Health Disparities (CHD), in the US is well documented. The is significant evidence of CHD treatment related outcomes along ancestry lines. Africans and Hispanics generally have higher rates of adverse drug reactions (ADR), and poorer survival and response rates when compared to Europeans and Asians. The causes of CHD treatment related outcomes are poorly understood but it is plausible to believe that CHD has a genetic basis, given that human genomic variations underlie both disease susceptibility and treatment outcomes. Our goal is to determine the genetic basis of CHD treatment related outcome, with a particular focus on under-represented and underserved populations. Methods: We will deploy pharmacogenomic (PGx) differentiation analyses using a comprehensive patient database and correlative banked tissue (~ 2,000 patients) from MCW, together with 3 international cohorts as comparators (Africans = 372, Asians = 1,250 and Europeans = 958) to: Interrogate clinically significant cancer treatment PGx biomarkers and characterize the variation across different populations. Assess the implications of genetic admixture on CHD treatment related outcomes. Evaluate the intersection of genetic diversity with pharmacogenomic diversity. Explore the distribution of age, gender, diagnosis, treatments, response, ADRs, survival, comorbidities, and concomitant medication. Results: Our initial results point to a significant genetic contribution to CHD treatment related outcomes. The enrichment of genetic risk factors for therapeutic failure, ADRs or poorer survival in patients of African vs European descent, explains the increased sensitivity to ADRs, poorer response rates, and decreased survival in patients of African vs European descent. We will extend this analysis to a multi-ethnic US cohort including Africans, Hispanics, Europeans, Asians, and First Nations. Conclusions: There is extensive PGx diversity within the US population, hence, coupling preemptive PGx testing with genetic testing is imperative for a truly equitable delivery of healthcare. There is a need for diversified representation of all population in cancer research to level the gaps in CHD. The identification of the genetic basis of CHD treatment related outcomes is imperative for predicting outcomes, and the implementation of preemptive PGx and precision medicine. [Table: see text]
Clinical efficacy of a next-generation sequencing (NGS) and immunohistochemistry (IHC) panel in patients with advanced cancer in Argentina.
Authors: Florencia Cantarella, Andrea Mendoza Bertelli, Romina Girotti, AnaClara Marino, Esteban Brest, Delfina Dibarbora, Yamil Mahmoud, Florencia Veigas, Diego Hernán Enrico, Florencia Tsou, Juan A. Lacava, Luciano Piazzoni, Aldo Alejandro Riso, Gastón L. Martinengo, Andres Rodriguez, Zenon Beguelin, Sebastian Cerrato, Ignacio Jerez, Ruben Salanova
Journal: Journal of Clinical Oncology (2024)

e15154 Background: The analysis of somatic genomic alterations, evaluation of DNA mismatch repair (MMR) proteins, and examination of PD-L1 expression in tumor biopsies are crucial for prognosis and informed therapeutic decisions. However, their clinical implementation in Argentina faces challenges due to economic costs and lack of evidence. To address this, we conducted a retrospective study to assess the impact of this molecular panel testing on treatment decisions and clinical management of cancer patients in Argentina. Additionally, we evaluated its ability to detect clinically relevant alterations and analyzed the frequency and co-occurrence of mutations in our cohort. Methods: Tumor tissue samples from 266 patients with primary tumors, representing 26 different anatomical sites (53% lung cancer), underwent molecular testing using the Optimus panel developed by Biomakers. The assay integrates somatic sequencing of 52 genes through NGS with IHC assessment of MMR and PD-L1 proteins. A retrospective evaluation of the clinical effectiveness of the test was conducted on 133 patients. Genomic and clinical data were analyzed using R with the pairwise Fisher’s exact test applied for statistical analysis. Results: This panel facilitates molecular characterization, identifying clinically relevant genetic alterations in 65% of patients and detecting deficiency in MMR proteins in 3%. Findings align with global clinical trial availability for identified alterations in 97% of cases. KRAS is the most frequently mutated gene (38%), followed by EGFR (19%), PIK3CA (12%), BRAF (9%), CDK4, and CTNNB1 (5% each), correlating with lung cancer overrepresentation. Simultaneous alterations in EGFR, PIK3CA, CTNNB1, and KIT genes were observed. Pan-tumoral interaction analysis revealed mutual exclusivity between KRAS mutations and those in EGFR, BRAF, CDK4, and CTNNB1. CTNNB1 mutations co-occurred with EGFR mutations, akin to KIT and PDGFRA (p&lt;0.05). The retrospective analysis indicated that the Optimus panel contributed to clinical management of patients in 56% of cases, with 85% detecting clinically relevant variants, aiding treatment definition in 74% of these cases. Conclusions: The Biomakers-developed Optimus panel empowers the molecular characterization of genomic and proteomic biomarkers across tumor types. Its significance in clinical practice lies in contribution to vital decision-making processes, particularly in treatment selection.
Multi-omics study on the molecular mechanism of anlotinib in regulating tumor metabolism.
Authors: Yu Lu, Xuedan Han, Lufeng Zheng, Hongwei Zhang, Xiaoman Li
Journal: Journal of Clinical Oncology (2024)

e15121 Background: Anlotinib, an orally administered small molecule inhibitor of receptor tyrosine kinases (RTKs), exerts significant anti-angiogenic and vascular normalization effects. However, the mechanisms underlying its involvement in tumor metabolic reprogramming are still unclear. This study aims to investigate the distribution and expression levels of metabolites within tumors after anlotinib treatment using spatial metabolomics analysis. Methods: This study involves spatially analyzing the distribution differences of metabolites post-anlotinib administration and integrating transcriptomics and proteomics to explore the internal mechanisms of anlotinib action at a molecular level. Results: By integrating the transcriptomics and proteomics analyses, we identified that anlotinib treatment primarily modulated four metabolic pathways, including taurine and hypotaurine metabolism, steroid synthesis, pentose phosphate pathway, and lipid biosynthesis. This regulation significantly influenced the metabolic levels of compounds such as sulfonic acids, cholesterol, inositol phosphate pyrophosphate, and palmitoyl-CoA in the tumor, thereby impacting tumor initiation and progression. Conclusions: This study provides potential metabolic biomarkers for anlotinib treatment in tumors, and may identify potential biomarkers and pathways associated with the therapeutic efficacy of anlotinib treatment.