tbuckley/cabot-search huggingface dataset:
A set of molecular biomarkers as an indicator of cancer risk.
Authors: Sonalika Singhal, Kevin Gardner, Sandeep K. Singhal, Donald Sens
Journal: Journal of Clinical Oncology (2024)

e12563 Background: Biomarkers are molecular indicators of a biological status and are often used to determine the presence or absence of cancer Molecular changes in both in of cancer cells and their surrounding environment including, blood other body fluids, and tissues that react to the cancer provide biomarker materials that may be effective predictor of disease risk or disease outcome. Effective biomarkers for the disease associated risk and early detection of cancer improves potential patient outcome. An emerging theme is to develop multi-omics panels of biomarker with sufficient sensitivity and specificity for the pre-symptomatic detection of cancer. We applied approximately 300 genomics and proteomics-based genomics (PbG) biomarkers, to identify a panel of biomarkers associated with different types of cancers using patient and donor RNA samples collected from platelets Platelet RNA mirrors the RNA of nucleated cells and can be an important indicator of tissue states particularly in under pro-inflammatory conditions [PMC9555784]. Methods: Publicly available RNA-seq data of N = 2351 blood platelet samples, (including n= 390 asymptomatic controls) from 18 different tumor types was analyzed to identify the panel of biomarkers associated with highest risk cancers. Approximately 300 genomic and PbG signatures (developed from gene expression-based signatures on patients stratified according to protein expression (IHC) and survival. The predictive value of each gene signature (including commercial once ROR, OncotypeDx, etc.) was evaluated by logistic regression modeling in univariate and multivariate settings. Results: Out of 300 biomarkers, we found a set of PbG biomarkers including ratio of BRG1 expression between nuclear and cytoplasm, cytoplasmic C-terminal-binding protein 2 (CtBP2) in express in cytoplasm and ratio of nucleus and cytoplasm, Nucleus Tripartite motif-containing 28 (TRIM28), Vascular endothelial growth factor (VEGF), Mitogen-activated protein kinases (MAPK), androgen receptor (AR) express in Nuclear vs cytoplasm, Glycoprotein 78 (Gp78) in cytoplasm, E2F3, and a member of the epidermal growth factor (EGF) receptor family (ERBB2) are highly predictive (0.77 (0.76 ~ 0.79)) of cancer associated risk on a multivariate training/validation setting. The BRG1 biomarker has the highest odds ratio (11.33) within model, known for coordinating and maintaining key signaling pathways that promote oncogenesis in different cancer types including leukemia, breast, and prostate cancer. Cancer Risk model = 3.4 - 1.01 ERBB2 + 0.3 GP78_Cyto - 3.2 AR_Nucl + 0.7 CtBP2_NucVsCyto - 0.3 E2F3 - 0.99 AR_NucVsCyto + 0.87 VEGF - 1.9 MAPK + 2.43 BRG1_NucVsCyto + 1.35 TRIM28_Nucl + 1.23 CtBP2_Cyto. Conclusions: Utilizing novel genomic, and proteomic technologies, risk prediction and early detection of cancer could identify patients at a time when outcomes are superior and treatment is manageable. Further evaluation of this model is recommended.
Genomic alterations in DNA damage response (DDR) genes in HR+/HER2- metastatic breast cancer (mBC) and impact on clinical efficacy with sacituzumab govitecan (SG): Biomarker results from TROPICS-02 study.
Authors: Aditya Bardia, Yi Zhang, Frederik Marmé, Peter Schmid, Javier Cortes, Sara M. Tolaney, Yajia Zhang, Oh Kyu Yoon, Wendy Verret, Meghna Das Thakur, Hope S. Rugo
Journal: Journal of Clinical Oncology (2024)

1075 Background: In the phase 3 TROPiCS-02 study, SG, a Trop-2–directed antibody-drug conjugate coupled to SN-38 as the payload, demonstrated clinically meaningful improvement in survival outcomes over chemotherapy in patients (pts) with pretreated HR+/HER2- mBC. SN-38 leads to double-stranded DNA damage, therefore we hypothesized that in tumors with defective DDR machinery, SG may provoke synthetic lethality. We report on comprehensive genomic analysis of DDR gene variants and the impact on SG clinical efficacy in this patient population. Methods: Pts with HR+/HER2– mBC who received prior taxane, endocrine therapy (ET), CDK4/6 inhibitor, and 2-4 prior lines of chemotherapy were randomized to receive SG (10 mg/kg IV days 1 and 8, every 21 days) or treatment of physician’s choice (TPC) until disease progression or unacceptable toxicity. DDR gene deleterious variants were identified using whole exome sequencing (WES) on archival or screening tumor tissues based on 142 DDR pathway genes annotated in the Kyoto Encyclopedia Genes and Genomes (KEGG) database and Human DNA Repair Gene database; association between these variants and clinical outcomes was evaluated using Cox regression model as Hazard Ratio (HR) with 95% Confidence Intervals (CI). Results: Of 543 patients included in the intent-to-treat (ITT) population, WES data was available for 195 (36%) – clinicopathological features were similar between ITT and WES dataset (median age = 57 vs 58 for SG and 55 vs 55 for TPC; prior lines of chemotherapy &gt;2 lines = 59% vs 57% for SG and 58% vs 55% for TPC). Estrogen Receptor (ER)&gt;10% and prior lines of chemotherapy were comparable between WT and MUT in SG arm and in TPC arm. Overall, 114 (58%) of tumor samples had ≥1 deleterious alteration with BRCA2, PRKDC, ATM being the most common alterations. The primary results are included (Table). Although all patients demonstrated improved efficacy with SG vs TPC, patients with DDR mutant MBC had numerically greater benefit in PFS vs WT (MUT HR= 0.61; WT HR= 0.76) and OS (MUT HR = 0.68; WT HR= 0.82). Conclusions: While SG benefit over TPC was observed in both DDR WT and DDR MUT HR+/HER2– mBC, numerically greater benefit was observed for patients with DDR deficient tumors, suggesting possible synergy between the DDR pathway and SG’s anti-tumor effect. Further study of the synergistic effects of SG in combination with agents targeting DDR pathway are warranted. Clinical trial information: NCT03901339 . [Table: see text]
Current and future immunotherapeutic approaches in pancreatic cancer treatment
Authors: Pooya Farhangnia, Hossein Khorramdelazad, Hamid Nickho, Ali-Akbar Delbandi
Journal: Journal of Hematology & Oncology (2024)

Abstract Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy.
Male breast cancer survival in Mexico between 2007 and 2016: A retrospective cohort.
Authors: Sergio Contreras, Haydee Cristina Verduzco-Aguirre, Rodrigo Huerta-Gutierrez, Eucario León-Rodriguez, Martin Lajous
Journal: Journal of Clinical Oncology (2024)

1116 Background: Male breast cancer represents around 1% of all breast cancers worldwide. Due to its rarity, it is more likely to be diagnosed at advanced stages than in women, and survival rates tend to be lower than in female patients. Information about survival in male breast cancer in low- and middle-income countries (LMIC) is scarce. Methods: We conducted a retrospective cohort study cross-linking nationwide reimbursement claims for breast cancer cases between 2007 and 2016 treated within the Seguro Popular health financing scheme to a national mortality registry in Mexico. Age, municipality of residence, clinical stage, and year of treatment initiation were described. Facilities were classified according to location, total breast cancer patient volume, and type of funding. We estimated 5-year overall survival (OS) with 95% confidence intervals (95% CI) through the Kaplan Meier method and used the log-rank test to compare differences between patient groups. Patients with in situ disease and missing data for clinical stage were excluded from survival analyses. Results: We identified 268,703 claims representing 60,846 patients, from which 328 were male (0.53%). Median age was 56 years (IQR 48-67). At treatment initiation, 20.7% of patients had early disease, 46.3% had locally advanced (LA) disease and 15.5% metastatic disease; clinical stage information was missing in 16% of patients Most patients (86.6%) were treated at public facilities, and 40.5% were treated at high volume facilities. With a median follow-up of 4.1 years, five-year OS in the whole cohort was 64.3% (CI 95% 58.1-71.2). In patients with early-stage disease, 5-year OS was 78.7% (95% CI 67.0-92.4), in LA disease 66.3% (95% CI 58.4-75.3) and in metastatic disease 39.7% (95% CI 27.5-57.5) (p &lt;0.001). Patients with LA disease treated at a private facility had improved 5-year OS (88.9%) compared to those who were treated at a public facility (62.8%) (p=0.033). We did not find any other significant differences in survival according to patient or facility characteristics, including patient volume. Conclusions: These results represent the largest cohort to describe survival in men with breast cancer in Latin America. We found a larger proportion of men diagnosed with metastatic disease than described in women in Mexico, and lower than expected survival in patients with early-stage and LA disease.
Prevalence of somatic PIK3CA mutations in hormone receptor-positive metastatic breast cancer: The Indian experience.
Authors: Aastha Goel, Ajay Gogia, Sandeep Mathur, Archana Sasi, Atul Batra, S.V.S Deo, Pranay Tanwar, Chandra Prakash Prasad
Journal: Journal of Clinical Oncology (2024)

e13047 Background: The phosphatidylinositol 3-kinase (PI3K) inhibitors have been found to improve survival outcomes in hormone receptor-positive metastatic breast cancer (MBC) and are FDA-approved in this setting after progression on hormonal therapy. However, real-world data from India on the prevalence of PIK3CA mutations is scarce. Methods: This is a retrospective study including patients with hormone receptor-positive breast cancer registered at our center between January 2017- and December 2023 who developed metastatic disease on follow-up after getting appropriate treatment (adjuvant /neoadjuvant) as per institutional protocol. The PIK3CA mutation testing was done on the biopsy specimen. FDA-approved therascreen PIL3CA RGQ PCR kit from Qiagen was used and the assay is a real-time qualitative PCR test for the detection of 11 mutations phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) gene (Exon 7: C420R; Exon 9: E542K, E545A, E545D [1635G&gt;T only], E545G, E545K, Q546E, Q546R; and Exon 20: H1047L, H1047R, H1047Y) using genomic DNA (gDNA) extracted from formalin-fixed, paraffin-embedded (FFPE) breast tumor tissue. The clinical demographics of patients with PIK3CA mutations were extracted from the hospital database and represented descriptively. Results: A total of 80 consecutive patients with hormone-positive breast cancer at relapse were screened and 26 were found to have PIK3CA mutations (32.5%) of which 24 were female (92.3%). The median age of patients with mutated PIK3CA cases was 50 years (range: 31 to 72 years). The clinical stage of disease at presentation was: stage II in 11.5%, IIIA in 23.1%, and IIIB in 65.4% of cases. The median time of relapse was 21 months from diagnosis (range: 10 to 42 months). The disease sites at relapse were multiple in 23 patients (88.46%) [including central nervous system (CNS) relapse in 3 patients) and CNS (brain) only in 3 patients (11.54%). The mutations detected included H1047R (3140A&gt;G at exon 20) in 8 cases, E545K (1633 G&gt;A at exon 9) in 5 cases, Q546R (1637 A&gt;G at exon 9) in 4 cases, E542K (1624 G&gt;A at exon7) in 3 cases and synchronous mutations (E542K/E545K at Exon 7) in 3 cases and (H1047R/H1047L at exon 20 ) in 3 cases. Only eight patients received alpelisib with fulvestrant due to financial constraints. Conclusions: This is the first Indian study that describes the prevalence of PIK3CA mutations in hormone-positive breast cancer at relapse. Around one-third of patients harbor this mutation and 23.1% of cases have CNS involvement at relapse. The most common PIK3CA mutation detected was H1047R (exon 20) followed by E545K (exon 9).
SE-GAP-ResNet: A machine learning model for abnormal breast detection.
Authors: Juan Manuel Gorriz Saez, Shuihua Wang, Yudong Zhang
Journal: Journal of Clinical Oncology (2024)

e12579 Background: Breast cancer is the most common cancer in women worldwide. Although screening has improved early-stage detection, challenges like high false positives and heavy workloads for radiologists persist, emphasizing the importance of early identification of breast irregularities, including masses and micro-calcifications. Methods: We use a subset of the mini-MIAS dataset, randomly choosing 100 abnormal and 100 healthy images, with abnormal images categorized into six sub-types. Preprocessing involves removing noises and excluding background and muscle regions. Our classifier is the ResNet-34 model, a deep convolutional neural network with 34 layers, known for effective pattern identification in medical images. Enhancements include: (1) The Squeeze-and-Excitation (SE) block boosts neural network discriminative power by dynamically recalibrating channel or feature importance. Integrated into ResNet-34, it forms the backbone network, enhancing the identification of relevant patterns for improved diagnostic accuracy. (2) Complex patterns at the system's output are condensed into a common disease pattern through global average pooling (GAP). This reduces model parameters, enhances interpretability, and facilitates the extraction of essential diagnostic information from the entire image. (3) Feature vectors from different layers are concatenated to merge low-level and high-level features. Low-level features encompass fundamental visual attributes such as pixel intensity and texture, while high-level features involve more complex patterns and structures, including organ shapes and anomalies. (4) We employ multiple-way data augmentation techniques to augment the training set, including rotation, translation, scaling, Gamma correction, and shear. The resultant model is referred to as SE-GAP-ResNet. Results: After 10 iterations of 10-fold cross-validation, SE-GAP-ResNet exhibited notable performance with a sensitivity of 95.60%, specificity of 93.30%, precision of 93.49%, accuracy of 94.45%, and an F1 score of 94.51%. Outperforming three state-of-the-art approaches, as shown in the table, two-sample t-tests confirm that SE-GAP-ResNet achieves significantly superior performance (p&lt;0.05). Conclusions: SE-GAP-ResNet excels in identifying breast abnormalities. We aim to enhance the AI system by adding a multi-class diagnosis framework and the capability to predict lesion regions, with the goal of substantially reducing callback rates for abnormal breast diagnoses and improving diagnostic accuracy and efficiency. [Table: see text]
Effect of transcription factor WT1 on triple-negative breast cancer metastasis through PFKFB4-mediated glycolysis.
Authors: Tingting Zhao, Yuqin Zhou, Xiujuan Wu, Zaihui Peng, Pingping Gao, Na Sun, Yi Zhang, Xiaowei Qi
Journal: Journal of Clinical Oncology (2024)

e13145 Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high probability of metastasis as well as a lack of specific targets and targeted therapeutics. Preliminary study suggested that Wilms' tumor gene 1 (WT1) is highly expressed in breast cancer patients with poor prognosis and may promote TNBC metastasis, but the underlying mechanism remains poorly defined. Methods: WT1 expression was evaluated by immunohistochemistry (IHC) in breast cancer patients. Kaplan–Meier survival analysis was performed to assess the prognostic significance of WT1 expression. WT1 was silenced in MDA-MB-231 and BT549 cells or overexpressed in HCC1806 cells. qRT-PCR and Western blot were used to detect the WT1 expression in tissues and cells. Wound healing assays, transwell assays and 3D spheroid assays were used to examine the migration and invasion abilities in TNBC cells. The lung metastasis model of mice was used to evaluate metastasis of TNBC in vivo. Chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) and transcriptome sequencing (RNA-seq) were performed to find PFKFB4, a downstream target gene for WT1. ChIP-PCR and dual-luciferase reporter assays were used to explore the transcriptional regulation of PFKFB4 by WT1. Seahorse XF glycolysis stress assay, glucose uptake assay, and lactate production assay were used to investigate the role of WT1 in regulating glycolysis metabolites. Results: WT1 was highly expressed in TNBC and correlated to poor prognosis in TNBC patients. Functional assays revealed that WT1 promoted TNBC cell metastasis in vitro and in vivo. Our mechanistic investigations demonstrated that WT1 promoted TNBC cells migration and invasion by transcriptionally activating the expression of PFKFB4.This action leaded to increased glycolytic capacity, glucose uptake, and lactate production in cancer cells, therefore promoting metastasis of TNBC. Clinically, the combined expression of WT1 and PFKFB4 provides a reliable predictive biomarker for the prognosis of TNBC patients. Conclusions: Our findings reveal a molecular mechanism of WT1 promoting TNBC metastasis, which provides new targets for the precision treatment of TNBC and new perspectives for the development of targeted metabolic anticancer drugs.
Pathological complete response rate to anthracycline versus non−anthracycline based chemotherapy regimens in localized and regional HER2 neu positive breast cancer.
Authors: Osama M. Halaweh, Maram AlAbbad, Abdulrahman Alshehri, Saud Alsubait, Riyadh AlDaabil, Samer Abushullaih
Journal: Journal of Clinical Oncology (2024)

e12632 Background: Debate over the need of anthracycline as part of neoadjuvant chemotherapy in HER2-neu early breast cancer was addressed in many trials with results favoring similar outcomes with or without anthracycline. This was not adopted fully in Saudi Arabia because of concern regarding ethnic differences in response to treatment. We conducted this retrospective analysis to evaluate if there is any difference in pathological complete response rate (PCR) in patients with early HER2-neu positive breast cancer depending on neoadjuvant chemotherapy regimen. Methods: Patients with HER2-neu positive early breast cancer who were treated with neoadjuvant chemotherapy at Johns Hopkins Aramco Healthcare (JHAH) facility between the year 2018 and 2022 were all evaluated for pathological subtype, HER2-neu status and type of neoadjuvant chemotherapy administered. Pathological response status was evaluated in all patients and PCR was measured to see if there was any difference depending on the use of anthracycline (AC) or non-anthracycline (non-AC) based chemotherapy regimen. Patient demographics, tumor characteristics, clinical stage, treatments and outcomes were collected via JHAH’s oncology registry. Categorical variables are reported as frequencies and percentages. The association between chemotherapy regimen AC vs non-AC based and PCR was analyzed using Fisher Exact Test. p-value &lt;0.05 was considered statistically significant. Analyses were conducted using JMP version 15. Results: In this study 59 HER2-neu positive early breast cancer patients were identified. We examined their clinical characteristics and treatment outcomes. Median age was 57. The most prevalent histology was invasive carcinoma of no special type (79.66%), Estrogen receptor positivity was observed in 72.88% of patients, while progesterone receptor positivity was seen in 62.71% of cases. Majority of patients were alive (96.61%) at the time of data collection. There was no significant difference in clinical stage in both groups. The association between chemotherapy type and pathological response was assessed. Among patients receiving AC chemotherapy (n=29), 55.17% achieved PCR, while for patients receiving Non-AC chemotherapy (n=30), the PCR rate was 50%. However, this difference was not statistically significant (p-value = 0.8). Conclusions: In our cohort of HER-neu positive early breast cancer patients who received neoadjuvant therapy there seems to be no significant difference in PCR with AC or Non-AC based chemotherapy regimens. This is concordant with the international trends.
Utidelone plus bevacizumab for the treatment of HER2-negative breast cancer brain metastases (U-BOMB): A multicenter, single-arm phase II study.
Authors: Min Yan, Huimin Lv, Xinlan Liu, Geng Cuizhi, Shusen Wang, Yuhua Song, Zhenzhen Liu, Limin Niu, Mengwei Zhang, Yajing Feng
Journal: Journal of Clinical Oncology (2024)

1081 Background: The primary treatment for brain metastases in patients with HER2-negative advanced breast cancer is predominantly local therapies like radiotherapy, owing to the limited efficacy of systemic therapies. Prior research has demonstrated utidelone's significant permeability across the blood-brain barrier and the preliminary effectiveness of bevacizumab for breast cancer brain metastases. Consequently, this study investigated the efficacy and safety of utidelone combined with bevacizumab in the treatment of advanced breast cancer brain metastases. Methods: This study was a single-arm, multi-center phase II clinical trial (NCT05357417). Eligible patients were aged 18 years or older with either radiotherapy-naive or progressive brain metastases post-radiotherapy, presented with asymptomatic or symptomatic brain metastases associated with HER2-negative breast cancer.Patients received intravenous bevacizumab (15 mg/kg on day 1 of each 3-week cycle) and utidelone (30 mg/m 2 on days 1 to 5 of each cycle) until intolerance or disease progression. The primary endpoint was central nervous system objective response rate (CNS-ORR), as assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. Results: Between May 5, 2022, and October 25, 2023, a total of 46 patients were recruited, with a median age of 52.5 years (range, 33 to 69). Among them, 35 patients had untreated CNS lesions, while 11 had progressive brain metastases after local radiotherapy. The CNS-ORR was 43.5% (95% confidence interval [CI], 28.9%-58.9%). As of January 8, 2024, the median duration of follow-up was 14.6 months, and the median progression-free survival (PFS) was 7.7 months (95% CI: 5.5-10.8) as shown in Table. The 12-month overall survival (OS) rate reached 74.4% (95% CI: 60.0%-92.3%). The most common grade 1-2 adverse events (AEs) were peripheral neuropathy (87.5%), decreased neutrophil count (62.5%), anemia (47.5%), diarrhea (37.5%), and increased alanine aminotransferase (25%). No grade 3 or higher treatment-related AEs occurred. Conclusions: This study preliminarily shows promising efficacy and manageable safety of the combination of utidelone and bevacizumab in the treatment of HER2-negative metastatic breast cancer patients with brain metastases. Clinical trial information: NCT05357417 . [Table: see text]