tbuckley/cabot-search huggingface dataset:
Reviewing the recurrence rates in stage I-III HR or ER positive breast cancer in obese patients given multi-modal weight loss plan post-treatment with aromatase inhibitors.
Authors: Matthew Joseph, Asim Ahmad, Abigail Benton
Journal: Journal of Clinical Oncology (2024)

15 Background: Aromatase inhibitors (AIs) in the treatment of endocrine recepter positive breast cancer stages I-III, poses significant challenges in the management of obesity. Obesity is not only associated with an increased risk of breast cancer incidence but also with higher rates of cancer recurrence and poorer treatment outcomes. Moreover, the use of AIs, while effective in reducing estrogen levels and preventing ER or HR positive breast cancer recurrence, may exacerbate weight gain and metabolic disturbances in obese individuals. Weight management strategies have experienced increased attention in breast cancer survivors in recent years, especially overweight or obese individuals. Novel data makes it possible to infer that obesity management activities and multimodal programs that incorporate dietary counseling and physical activity can reduce recurrence rates. Methods: Participants in this study were individuals with Stage I-III endocrine receptor positive breast cancer who had completed adjuvant therapy and had a BMI in the 40s or 50s, increasing risk of recurrence. Eligible patients were identified based on the start date for endocrine therapy. High-risk patients were then assigned to either the intervention or control group. Those in the intervention group received access to a dietician, along with informational pamphlets on physiology and weight loss strategies. Additionally, they were offered discounts to certain gyms or provided free access to fitness facilities. Both intervention and control groups were briefed about the study, with those in the intervention group encouraged to utilize the provided resources for weight management. Results: The evidence from our study will underscore the potential benefits of multimodal weight loss interventions in overweight or obese breast cancer survivors, particularly in improving anthropometric outcomes and enhancing overall quality of life. Conclusions: While the studies included in our analysis demonstrated reductions in body weight, BMI, and waist circumference, as well as improvements in quality of life measures, there remains a notable gap in understanding the impact of these interventions on breast cancer recurrence rates, especially in the context of endocrine-positive breast cancer treated with Aromatase Inhibitors (AIs).
Infiltrating B-cell subtypes and associated hub genes in nasopharyngeal carcinoma identified from integrated single-cell and bulk-RNA sequencing data.
Authors: Fangyan Zhong, Tianzhu Lu, Junjun Chen, Lin Zhang, Zhiliang Liu, Chunhong Guan, Xiaopeng Xiong, Xiaochang Gong, Jingao Li
Journal: Journal of Clinical Oncology (2024)

135 Background: Nasopharyngeal carcinoma (NPC) is associated with lymphocyte infiltration; however, the majority of research on NPC has focused on the role of T cells, with relatively little known about the roles of B cells and their subtypes. Therefore, we evaluated the prognostic value of CD20+ B cell density and B-cell subtypes along with their functional enrichment and hub genes in NPC. Methods: The prognostic value of CD20+ B-cell density for distant metastasis-free survival (DMFS), overall survival (OS), and progression-free survival (PFS) was explored by immunohistochemistry using multivariate analysis. Transcriptomic expression data from Gene Expression Omnibus (GEO) datasets were analyzed to identify B-cell subtypes and their functional enrichment in NPC tissues. Pseudotime trajectory analysis was performed to evaluate the B-cell differentiation trajectory and hub genes were identified using Cytoscape software. Results: Patients with NPC exhibiting a high infiltrating density of CD20 + B cells showed significantly better 5-year DMFS, OS, and PFS compared to those of patients with a low infiltrating density. Naïve B cells, switched memory B cells, exhausted B cells, and plasma cells were identified as key B-cell subtypes infiltrating NPC tumors, with naïve B cells showing the highest infiltration levels associated with a better prognosis. Naïve B cells were closely associated with immune pathways and the hub genes were typical markers for T and B cells. Conclusions: A high infiltrating density of B cells showed strong prognostic value in patients with NPC. Naïve B cells may play an important role in tumor immunity for NPC.
Targeted degradation of undruggable proteins using a novel heterobifunctional proteomimetic platform.
Authors: Max Mu Wang
Journal: Journal of Clinical Oncology (2024)

47 Background: Of the ~20,000 proteins in the human genome, only a subset can be modulated via traditional pharmacological approaches. “Undruggable” targets currently include proteins with pivotal roles in cancer pathogenesis. Our work aims to introduce a new paradigm for engaging these clinically relevant proteins using a modular platform we term the HYbrid DegRAding Copolymers (HYDRACs). HYDRACs multiplex targeting warheads with degradation inducers and have long circulation times plus high cell uptake. Preliminary studies on MYC and RAS, targets of great pharmaceutical interest, highlight the potential of this platform to revolutionize drug design. Methods: HYDRACs containing MYC or RAS targeting peptides randomly copolymerized with degrons were synthesized using ROMP. Fluorescent and biotin-tags were incorporated for use in uptake and pull-down assays. Viability following treatment with MYC-HYDRACs was performed in multiple cell lines with both cellular (MYC-independent lines) and polymer composition controls. Target engagement was assessed via immunoprecipitation and circular dichroism with protein degradation monitored by WB. Unbiased whole proteome analysis and RNAseq were done to confirm observed effects were selectively on-target. In vivo efficacy and biodistribution was assessed in tumor-bearing mice. Results: HYDRACs show high levels of cell uptake and antiproliferative effects at sub-micromolar concentrations in a formulation- and target-dependent manner. Cells treated with MYC-HYDRACs displayed reduced MYC protein levels, which were rescued by proteasome or neddylation inhibition. Swapping out the degron for various validated E3 ligase recruiters maintained MYC degradation, highlighting the “plug-and-play” nature of this approach. On-target activity was confirmed via RNAseq. Biophysical analysis showed strong HYDRAC-protein interactions, orthogonally supported by the presence of target protein following pull-down of biotin-terminated HYDRACs. Target protein degradation only occurred following treatment with an intact HYDRAC compound. Mice bearing MYC-CaP tumors showed delayed tumor growth following treatment with MYC-HYDRACs, with compound accumulation in the tumor for up to 72 h following a single injection. Generalizability was demonstrated against RAS, with RAS-HYDRACs capable of degrading KRAS across multiple different alleles, acting as a pan-KRAS degrader. Conclusions: We present a novel platform technology that addresses the challenges inherent to peptide delivery approaches. HYDRACs have the potential to dramatically alter the drug discovery landscape, allowing for the development of cancer-relevant target modulators for which there are no current viable therapies. We envision the HYDRAC platform as a generalizable approach to designing degraders of proteins of interest, greatly expanding the therapeutic armamentarium for TPD.
Restriction of YWHAB-mediated YAP cytoplasmic retention as a novel mechanism underlying stemness maintenance and chemo-resistance in peritoneal metastasis of ovarian cancer: A comparative proteomic study.
Authors: Lin Qiu, Chang Liu, Wenxin Ma, Zhuo Yang
Journal: Journal of Clinical Oncology (2024)

122 Background: Ovarian cancer (OC) peritoneal metastasis (OCPM) is a significant cause of high mortality of OC. To investigate the mechanisms underlying OCPM stemness maintenance and resistance, we characterized proteomic alterations in residual OCPM tissues after neoadjuvant chemotherapy (NACT), and verified restriction of YWHAB-mediated YAP cytoplasmic retention as a novel important mechanism. Methods: Tumor specimens from HGSOC patients underwent proteomic analysis using TMT and REACTOME for pathway and GO analysis. The OVCAR3 cell line, derived from malignant ascites, and formalin-fixed samples were used for Immunohistochemistry. Ovarian cancer stem-like cells, including cisplatin-resistant cells, were cultured, and ALHD activity was measured by qPCR and ALDEFLUOR Kit. Western blot and Co-IP were used for protein analysis. Sphere formation and limiting dilution assays were performed in vitro and in vivo using BALB/c nude mice, and FACS quantified OCSCs. YWHAB-knockdown cells were created via plasmids, lentivirus, and transfection. Statistical tests included paired and unpaired t-tests, one-way ANOVA, and ELDA for limiting dilution. Data are shown as mean ± SD, with *p&lt; 0.05, **p&lt; 0.01, ***p&lt; 0.001 indicating significance. Results: TMT-based proteomics identified 324 differentially expressed proteins in post-NACT OCPM tissues, with 179 upregulated and 145 downregulated. Bioinformatics revealed novel targets in key pathways, including TUBB, VCP in Hedgehog, YWHAB in Hippo, TLA1/2, SPTA1 in MAPK, and FASN in NOTCH. YWHAB downregulation was confirmed in pPR OCPM tissues and cells, serving as a marker to differentiate pNR from pCR/pPR OCPM (AUC = 0.7673). YWHAB inhibition in pCR OCPM cells enhanced stemness, as seen in sphere formation, OCSC percentages, CD133 expression, ALDH activity, and tumorigenicity. It also induced cisplatin resistance. YWHAB inhibition reduced cytoplasmic YAP retention and increased nuclear YAP, enhancing transcriptional activity. YAP5SA expression negated the effects of YWHAB depletion on stemness and resistance in pCR OCPM cells. Conclusions: In summary, this study explored the potential mechanisms underlying OCPM stemness maintenance and resistance by employing proteomic analysis, and revealed a novel YWHAB-mediated mechanism. This finding indicates that YAP would an important target for eradicating YWHAB-restricted OCSCs in OCPM.
Effect of heterozygosity loss of HLA-I on immune evasion and promotion of non-small cell lung cancer brain metastasis and immunotherapy resistance.
Authors: Jiefei Han, Yi Lin, Wenbin Li
Journal: Journal of Clinical Oncology (2024)

209 Background: HLA-I play a crucial role in T cell recognition and killing of tumor cells as well as in PD-1/PD-L1 immunotherapy. Loss of heterozygosity (LOH) of HLA-I alleles has been found to be common in lung cancer patients and influences immune escape during tumor evolution. This study aims to explore the incidence of HLA-I LOH in intracranial metastases of advanced non-small cell lung cancer patients with brain metastasis and its impact on the efficacy of immunotherapy. Methods: A total of 29 patients with non-small cell lung cancer brain metastasis were included in this study. All enrolled patients underwent either percutaneous biopsy or surgical resection of intracranial metastases and had tissue specimens from the primary lung lesions. Whole-exome sequencing was performed on all primary/metastatic lesions to determine HLA-I typing/LOH and calculate tumor mutation burden (TMB). Additionally, we assessed the expression levels of CD8 T cells in the tumor immune microenvironment. Among the enrolled patients, 20 received PD-1/PD-L1 treatment. Results: Among the enrolled patients, 82.8% (24/29) had heterozygous HLA-I typing, with HLA-I LOH present in 25% (6/24) of patients' primary lesions and 58.3% (14/24) in brain metastatic lesions. Analysis of TMB in different lesions revealed a median TMB of 7.8 mut/Mb in lesions with intact HLA-I and 11.4 mut/Mb in lesions with HLA-I LOH. Notably, the median TMB in brain metastatic lesions with HLA-I LOH was 13.2 mut/Mb, higher than that in HLA-I LOH primary lung lesions (10.1 mut/Mb). Immunohistochemistry demonstrated that CD8 T cell expression levels were lowest in brain metastatic lesions with HLA-I LOH and highest in intact HLA-I primary lung lesions. Among patients who received immunotherapy, four cases exhibited inconsistent lesion responses, with stable or regressing primary lesions but progressive intracranial metastases. Survival analysis revealed that patients with HLA-I LOH in brain metastases had significantly lower PFS compared to those without (4.1 months vs. 6.9 months, P &lt; 0.05), with no significant difference in OS. Conclusions: This study indicates that the incidence of HLA-I LOH in brain metastases of lung cancer is higher than that in primary lung lesions, accompanied by higher TMB, possibly due to the ineffective presentation of tumor antigens resulting in the accumulation of mutations in lost HLA-I. Moreover, tumors with HLA-I LOH have reduced levels of CD8 T cell infiltration, suggesting impaired tumor antigen presentation impedes immune cytotoxicity. These phenomena contribute to the poorer efficacy of immunotherapy in such patients. In conclusion, HLA-I LOH may be one of the important mechanisms of immune escape in lung cancer brain metastases.
A novel cell-free multi-omics approach for enhancing multi-cancer early detection.
Authors: Thien-Chi Van Van Nguyen, Anh-Nhu Nguyen, Thien-Phuc Hoang Nguyen, Hanh Thi-Hue Nguyen, Trung-Hieu Tran, Tien-Anh Nguyen, Trang Thi Tran, Trong Hieu Nguyen, Hoa Giang, Minh-Duy Phan, Hoai-Nghia Nguyen, Le Son Tran
Journal: Journal of Clinical Oncology (2024)

103 Background: While circulating tumor DNA (ctDNA)-based assays for multi-cancer early detection (MCED) have shown significant potential, their performance is hindered by the limited amount and inherent variability of ctDNA, particularly in cancer types with low ctDNA shedding. To enhance the accuracy of MCED, recent studies have focused on profiling cell-free RNA (cfRNA), which is secreted not only by tumor cells but also by other cell types to reflect the systemic tumor responses. Herein, we developed a novel cell-free multi-omics approach integrating cfDNA and cfRNA analyses from a single blood draw to improve the sensitivity of an MCED assay, especially for detecting low-shedding ctDNA cancer types. Methods: We recruited 535 healthy subjects and 287 patients across five cancer types (77 breast cancers, 102 colorectal cancers, 35 gastric cancers, 34 liver cancers, and 42 lung cancers). We established a multi-omics workflow to comprehensively profile cfDNA signatures (methylation, fragment length, motif ends, and copy number alterations), and cfRNA signatures (cfmRNA). Distinctive signatures were identified to differentiate cancers from healthy subjects and used for constructing robust machine learning classifiers. Results: We identified multiple significantly different features distinguishing cancer from healthy individuals, with 81% originating from cfDNA. Notably, cfmRNA features, accounting for 19% of total significant features, were mainly enriched in immune-related pathways, reflecting tumor-immune cell interactions. The cfDNA-based model achieved 81.2% accuracy, with highest performance in detecting liver cancer (100%) and 64%, 42%, and 36.4% for breast, colorectal, and gastric cancers, respectively, at 93% specificity. Combining cfDNA and cfRNA signatures increased sensitivity to 73%, 71%, and 46% for breast, colorectal, and gastric cancers. Overall, the multi-omic model achieved 85.6% accuracy and 72.7% sensitivity for detecting five cancer types at 92.6% specificity. Conclusions: The cell-free multi-omics approach holds potential for improving ctDNA-based MCED tests by simultaneously profiling both cfDNA and transcriptomic cfmRNA from a single blood draw. Validation on larger cohorts could lead to a paradigm shift in cancer screening practices.
Efficacy of combination of immune checkpoint inhibitors, chemotherapy, and targeted therapy in advanced/refractory cancer.
Authors: Philip A. Salem, Lorenzo Gensini, William G.B. McCallum, John Hanna, Thomas M. Wheeler, Randall A. Stenoien, Khaled W. Jabboury
Journal: Journal of Clinical Oncology (2024)

41 Background: The treatment of advanced/refractory malignancies continues to pose a major challenge, and it is associated with poor outcome. It has been shown that in some cancers, the combination of chemotherapy (CT) with immune checkpoint inhibitors (ICIs), or CT with targeted therapy (TT), are superior to chemotherapy alone. Consequently, in our treatment program (ICTriplex), TT was added to CT plus ICIs. These three modalities have convergent efficacy with divergent toxicity. Our prior data were previously reported (1-3). Methods: Treatment with ICTriplex was highly personalized and was tailored to the individual patient and their specific cancer. It was designed based on diagnosis, prior therapy, and genomic profiling. Between March 2017 and January 2024, 56 patients (pts) with advanced malignancies were treated: 31 females and 25 males, with a median age of 58. Tumor types included: lung (12), pancreas (8), colorectal (8), biliary tract (5), breast (4), stomach (4), melanoma (3), ovary (3), sarcoma (3), cervix (2), glioblastoma (2), Hodgkin’s (1), and thymoma (1). 43 pts received prior therapy: 14 received ICIs, 23 TT, and 42 CT. The agents used in ICTriplex were: 6 ICIs primarily nivolumab and pembrolizumab, 12 CT primarily taxanes, gemcitabine, and platinum, and 23 TT, primarily bevacizumab and erlotinib. Response was evaluated by both PET/CT and CT scans. A complete remission was achieved when metabolic activity completely resolved on PET/CT. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier estimator. Results: The overall response rate (ORR) was 88%. A complete remission (CR) occurred in 29 pts (52%), and a partial remission (PR) in 20 pts (36%). Of the 12 pts with lung cancer, 9 (75%) achieved CR and of these, 4 pts had brain metastases that completely resolved without radiation. Of the 8 pts with pancreatic cancer, 4 (50%) achieved CR. 4 of 5 pts with biliary tract cancer achieved CR. Toxicity was reasonable in all pts except for 3 who died from complications possibly related to ICIs. The median PFS was 11 months, and the median OS was 15 months. The achievement of CR and the PD-L1 + status, resulted in a statistically significant better PFS (p= 0.00; p= 0.02) and OS (p=0.00; p= 0.005). Patients with lung cancer showed a better PFS (p= 0.02) with the median at 19 months, and the median OS was 36 months. Potential predictors of unfavorable prognosis, such as receiving prior treatment, did not impact patients' clinical outcome. Conclusions: ICTriplex is a very effective treatment for advanced cancer that has become resistant to conventional therapy or with no available standard therapy. We strongly recommend this therapeutic approach for the treatment of such patients. 1. ASCO 2019 (e14254) 2. ASCO 2020 (e15150) 3. ASCO 2022 (e14590).
Prognostic value of immuno-nutritional status in patients with cancer treated by immune checkpoint inhibitors.
Authors: Ming-Chun Kuo
Journal: Journal of Clinical Oncology (2024)

226 Background: The treatment efficacy of immune checkpoint inhibitors (ICIs) may relate to tumor factors or host factors, such as systemic inflammation status or nutritional status. In this study, we investigated the prognostic value of immuno-nutritional status in cancer patients treated by ICIs, and develop nomogram models for predicting overall survival (OS). Methods: We used Chang Gung Research Database to retrospectively evaluate cancer patients who received ICIs during January 2015 to December 2021. Patients had double cancer or received only one cycle of ICI were excluded. All patients were divided into a training cohort and a validation cohort. The training cohort was used to analyze the risk factors and develop nomogram models. The models were validated by the validation cohort. The univariate analysis, stepwise multivariate analysis, receiver operator characteristics (ROC) analysis were used to find out the independent risk factors. The calibration plot were used to evaluate the reliability of the models. Results: All patients (3219 cases) could be categorized into lung cancer (22.1%), genitourinary cancer (14.9%), upper gastrointestinal tract cancer (8.1%), colorectal cancer (3.1%), hepatocellular carcinoma (24.6%), pancreatobiliary cancer (3.8%), head and neck cancer (12.9%), melanoma (4.0%), breast cancer (1.9%) and lymphoma (0.5%). 80.2% of patients received anti-PD1, 19.8% of patients received anti-PD-L1. In training cohort, the cut-off value was set for neutrophil-to-lymphocyte ratio (NLR), total lymphocyte count (TLC), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), prognostic nutrition index (PNI) and hemoglobin-albumin-lymphocyte-platelet (HALP) score. The above risk factors showed significant difference in median OS in validation cohort respectively (Table). The multivariate analysis demonstrated that NLR, PNI and HALP score were independent risk factors in predicting OS. The hazard ratio were 1,439 (95% CI 1.149-1.801), 0.689 (95% CI 0.549-0.865) and 0.784 (95% CI 0.626-0.982) respectively. Conclusions: We developed nomogram models to investigate the immuno-nutritional status and predict the OS of cancer patients who received ICIs therapy. High NLR, low PNI and low HALP score were associated with worse OS. [Table: see text]
Machine learning-based noninvasive diagnostic classifiers for the prediction of cancer tissue of origin using serum microRNAs.
Authors: Andrew Zhang, Hallgeir Rui, Hai Hu
Journal: Journal of Clinical Oncology (2024)

101 Background: Noninvasive multi-cancer early detection (MCED) with or without tissue of origin (TOO) has the potential to reduce cancer-related mortality by analyzing circulating cell-free nucleic acids and/or proteins in blood. Accurate prediction of TOO following a positive MCED test would guide selection of confirmatory tests, thereby expediting the definitive diagnosis and prompt initiation of the most appropriate treatment, tailored to the specific cancer type. Here, we report the development of machine learning-based diagnostic classifiers that predict TOO for 13 cancer types with high accuracy using serum microRNAs. Methods: Eight serum miRNA microarray datasets from GEO totaling 6,283 patients across 13 cancer types were used in this study. The patients were split, with an approximate 3:2 ratio, into a training (n=3,844) and a validation set (n=2,439). An ensemble of classifiers was constructed in the training set via the “one vs. rest” approach, thus one classifier for each cancer type. Random forest models with recursive feature elimination (RFE) selected the optimal set of miRNAs that was fed into support vector machine models to generate a prediction probability for each cancer type. The type with the highest probability was considered the predicted cancer type. The performance of these classifiers was evaluated in the validation set in two steps with the 1st using all cancer types and the 2nd using the top 2 or 3 cancer types from the 1st step to achieve a refined prediction. Results: RFE selected 426 miRNAs for building the 13 classification models. In the validation set comprising 2,439 patients across 12 cancer types, the classifiers correctly predicted cancer types for 1,922 (79%) samples based on the highest prediction probability. The accuracy increased to 92% and 95% based on top 2 and 3 predictions. In particular, based on top 3 predictions, the accuracy was &gt;95% for bladder, breast, prostate, gastric, glioma and lung cancers, &gt;85% for ovarian, liver and esophageal cancers, 78% for pancreatic cancer and sarcoma, and 67% for colorectal cancer. Conclusions: With 95% accuracy in narrowing TOO down to 3 organ sites, the miRNA-based TOO classifiers could be used clinically as a reflex test for the simple and highly accurate MCED screening models previously developed ( Cancers 2022,14:1450; ESMO 2024). Together, they support the development of an inexpensive, accurate and noninvasive blood test for MCED with TOO.