tbuckley/cabot-search huggingface dataset:
ESR1 mutations kit performance with SensID ESR1 reference set 1% AF.
Authors: Jack Paveley, Ryan Nana, Ava Read, Kimberly Jane Howard, Lucy Astley, Christine Hoy, Anna Gasior, Sara Rollinson, Colette Whitfield, Joanna Gorniak
Journal: Journal of Clinical Oncology (2024)

e13087 Background: Oestrogen receptor 1 (ER/ ESR1) mutations have arisen as crucial biomarkers for endocrine therapy resistance in ER positive metastatic breast cancer. Detecting these mutations is key for understanding acquired resistance during treatment. Current clinical trials, exploring ESR1 mutation prevalence during various treatments, often use expensive and time-consuming next-generation sequencing (NGS)-based assays or digital PCR (dPCR) assays that require specialist equipment. The APIS ESR1 Mutations Kit offers a cost effective, rapid, and highly sensitive (≤ 1% MAF) alternative to NGS, and dPCR assays. This targeted, qPCR-based assay detects eleven ESR1 mutations across ESR1 exons 5 (E380Q), 7 (S463P) and 8 (P535H, L536R/Q/H/P, Y537C/S/N and D538G). Designed for circulating-free DNA (cfDNA) samples, it reduces the need for invasive procedures in clinical settings, providing researchers in both centralised and decentralised laboratory settings the flexibility to explore ESR1 mutations with precision. Here, we demonstrate the performance of the APIS ESR1 Mutations Kit using the first commercially available cfDNA reference set (SensID ESR1 Reference Set 1% AF cfDNA) for nine ESR1 mutations (Table). Methods: The SensID ESR1 standards were assessed with the APIS ESR1 Mutations Kit. All vials were diluted with nuclease-free water to 3 ng/µL, resulting in 15 ng total input per reaction. Samples were run according to the APIS ESR1 Mutations Kit handbook. All PCR runs were performed using a QuantStudio 5 Dx (ThermoFisher) instrument. Results: The APIS ESR1 Mutations Kit successfully detected all ESR1 mutations, with expected target calls for the nine mutations at 1% MAF. No false positive results for the remaining mutation targets were observed. Similarly, no false positives for any mutation targets were reported for vial 5, containing the wildtype (WT) sample, reaffirming the kit’s accuracy in distinguishing WT and mutant samples. Conclusions: The ESR1 Mutations Kit demonstrated highly sensitive and specific detection of the SensID ESR1 Reference Set 1% AF cfDNA, confirming the kit’s LoD of ≤ 1% MAF with externally validated samples. [Table: see text]
Effect on cardiovascular outcome of sodium-glucose co-transporter-2 (SGLT2) inhibitors among patients with cancer treated with anthracycline: A systematic review and meta-analysis.
Authors: Chalothorn Wannaphut, Phuuwadith Wattanachayakul, Sakditad Saowapa, Ben Ponvilawan, Manasawee Tanariyakul, Jakrin Kewcharoen, Pitchaporn Yingchoncharoen, Noppawit Aiumtrakul, Jared David Acoba
Journal: Journal of Clinical Oncology (2024)

e24001 Background: Sodium-glucose-co-transporter-2 (SGLT2) inhibitors have shown benefit in reducing cardiovascular outcomes in diabetes patients. Anthracycline therapy is associated with a risk of cardiomyopathy. However, the impact of SGLT2 inhibitors in the prevention of cardiomyopathy and heart failure in cancer patients undergoing anthracycline treatment remains unclear. Thus, we conducted a systematic review and meta-analysis to explore the effect of the prevention of cardiovascular outcomes in patients with cancer and diabetes who had received anthracycline therapy. Methods: We systematically reviewed Medline and EMBASE databases from inception to January 2024 for studies focusing on cancer patients with a history of anthracycline therapy. Eligible studies had to report relative risk (RR) with 95% confidence intervals for the clinical endpoints of mortality outcomes and the risk of HF exacerbation, comparing cohorts with and without SGLT2 inhibitor use. Results: Our study included 4 retrospective cohort studies in the meta-analysis (n = 6,708, 24% received SGLT2). There was significantly lower all-cause mortality in the SGLT2 inhibitors group (pooled RR of 0.52, 95% CI 0.35-0.77, I2 64%). However, there were no differences in the risk of heart failure exacerbation (pooled RR of 0.67, 95% CI 0.39-1.14, I2 17%). Conclusions: Our study found that anthracycline-treated cancer patients using SGLT2 inhibitors experienced lower all-cause mortality compared to the control group. A randomized clinical trial is necessary to further elucidate these findings.
A phase I clinical study to evaluate the safety, tolerability, immunogenicity, pharmacokinetics and preliminary efficacy of SCB-219M in patients with chemotherapy-induced thrombocytopenia (CIT): An interim analysis.
Authors: Yongsheng Wang, Ke Xie, Nan Xu, Yuyao Yi, Shan Huang, Bin Ye, Xing Gao, Wei Tan, May Yang, Danmei Su, Rong Xu, Jing Yuan, Peng Liang
Journal: Journal of Clinical Oncology (2024)

e15015 Background: CIT is a serious, chemotherapy-associated complication observed in a wide range of cancer patients with various types of cancer. Incidence of CIT can occur in about 15-25% of patients undergoing standard chemotherapy regiments with platinum, taxane and/or gemcitabine-based regimen. CIT can lead to chemotherapy dose delay or dose reduction, and potentially bleeding events. Currently, there is no FDA-approved therapy for CIT. SCB-219M, a thrombopoietin receptor agonist (TPO-RA) mimetic bispecific Fc-fusion protein produced from CHO cells can efficiently raise PLT count under normal and pathological conditions in laboratory animals. Methods: This is a single-arm, multi-center, open-label, dose escalation Phase Ia clinical study to evaluate the safety, tolerability, and immunogenicity, PK profile and preliminary efficacy of a single ascending dose of SCB-219M administered one day after a chemotherapy in prior CIT patients with malignant solid tumors and lymphoma. The study design of accelerated titration combined with "3 + 3" is used, and the number of subjects planned to enroll is 12 to be assigned to 4 cohorts with 2, 6, 10 and 15 mg/kg subcu administration of SCB-219M, respectively. Enrollment criteria include episode of CIT experienced (&lt;75 × 10 9 /L in PLT count) in prior cycle of chemotherapies and PLT count has recovered to &gt;75 × 10 9 /L prior to initiation of this study . The chemotherapy regimen allowed include either mono or combination chemotherapy (including targeted therapy and/or immunotherapy). The observation period of dose-limiting toxicities (DLTs) is 21 days. Chemotherapy is planned at each study site. There will be no change in the planned dose or frequency of chemotherapy in the study. Results: As of Dec 20, 2023, 9 prior CIT patients including 3 at 15 mg/kg were enrolled. SCB-219M was well tolerated. There were no SAEs or AESIs (Adverse Event of Special Interest) observed. DLT was not reached. A favorable PK profile, in particular in serum availability (AUC) and half-life (T1/2) was obtained. All 9 prior CIT patients in the study maintained PLT counts &gt;75 x 10 9 /L from 1-week following chemotherapies with a single dose of SCB-219M, and durable responses experienced through at least 3 weeks. Conclusions: In this interim analysis, drug safety, PK profile and durable efficacy are expected to support SCB-219M dosing interval of ≥2-weeks or a single dosing regimen within a chemotherapy cycle. Accordingly, a Phase Ib trial evaluating repeated dosing of SCB-219M is planned to initiate in 2024. Clinical trial information: NCT05426369 .
TERT-associated DNA polymerases genes link CAF and CD8+ T Cells to improve immunotherapy response rate across multiple cancers.
Authors: Zhiwen Luo, Xu Che, Yaoyu Xie, Yiqiao Deng, Yun Che, Xingang Bi, Hong Zhao, Xinyu Bi
Journal: Journal of Clinical Oncology (2024)

e14669 Background: The cancer cells exhibit heightened basal levels of responses to DNA breaks, accumulating DNA polymerases family (DNA-pol) as repair protein, thereby increasing DNA mutation and neoantigens. Based on this, we investigated the potential of DNA-pol as an immunotherapy biomarker and its underlying mechanism. Methods: We conducted a pan-cancer analysis of DNA-pol gene dysregulation in 6366 samples. Normal fibroblast, cancer-associated fibroblast, and CD8+ T cells were cultured from cancer patients (3 esophagus, 5 lung, 5 renal, and 3 liver cancer), then treated them with PD-L1 inhibitor or overexpressing TERT for RNA-seq and proteomics. 996 multiple cancer cases with ICIs were collected to test biomarker efficiency. A phase II clinical trial is evaluating and exploring our biomarker in mechanism prospectively. Results: We defined a distinct signature score of DNA-pol genes upregulated in cancer (DNA-pol-up) and linked to worse prognosis (HR=1.2). DNA-pol-up program dysregulation led to immune processes alteration and was related to upstream activation of TERT signaling (z-score=3.6) in ingenuity pathway analysis and linked to immunologically active tumors by recruiting CD8+ T cell and downregulating CAF. DNA-pol-up score was elevated in PD-L1-treated CAF and TERT-overexpressed CD8+ T cell, in MSI-H cancer, also related to more neoepitope peptides, TMB (Rho=0.54), cancer stemness (Rho=0.78), and tumor purity (Rho=0.29). Cancers that activate this program carried distinct genomic profiles with PIK3CA, KRAS, and TP53 mutations. This signature was an independent predictor for ICIs response (OR=2.52), even outperforming cytolytic activity, MSI, TMB (OR=0.9). In 12 clinical trial datasets, this signature could stratify the responding patients (maxAUC=0.762). In our phase II clinical trial, 34 liver cancer were enrolled with 4-year follow-up, it also has a satisfactory performance in predicting the ORR (AUC=0.699) and classifies mortality rate (HR=2.5), meanwhile verified its relationship with detailed potential molecular mechanism. Conclusions: Our findings identify a distinct transcriptional pattern of DNA-pol genes across cancers, which highlighted the role of DNA-pol family genes in predicting the immunotherapy response for the first time, and TERT could be a novel vaccine candidate for improving immunotherapy response.
Pathological evaluation of tumor immune microenvironment before first-line anti-PD1 plus anti-angiogenic therapy in patients with unresectable hepatocellular carcinoma (HCC): Towards a prediction for treatment efficacy.
Authors: Jun Chen, Mingzhen Zhou, Xintao He, Xiaohong Pu, Hongyan Wu, Sidong Chen, Yang Wang, Lei Jiao, Baorui Liu, Jie Shen
Journal: Journal of Clinical Oncology (2024)

e14662 Background: Immune checkpoint inhibitor (ICI) combined with anti-angiogenic therapy is the standard first-line treatment for unresectable HCC patients. However, most patients do not derive durable benefit and will progress faster. Simultaneously, sufficient clinically validated biomarkers to stratify patients are lacking in HCC. Recent studies have shed a light on the strong connection between immunotherapy efficacy and tumor immune microenvironment (TIME) in HCC. Thus, this study aims to investigate TIME features before treatment to develop a potential way for survival prediction which may optimize risk stratification. Methods: A total of 84 unresectable HCC patients who received first-line ICI plus anti-angiogenic therapy at Nanjing Drum Tower Hospital were included. 4 multiplex immunohistochemistry (mIHC) panels containing 18 biomarkers were developed to thoroughly evaluate immune cells in TIME before therapy, such as cytotoxic T cells, tissue-resident memory T cells, macrophages and neutrophils. TIME features were then extracted from raw image by digital pathology, including cell subpopulation abundance and spatial profiling. We identified a list of TIME features associated with objective response rate (ORR), progression free survival (PFS) and overall survival (OS), and developed a TIME-based risk score (TIS) in our cohort using machine-learning. Results: After data cleaning, a total of 78 patients with complete clinical information and TIME features were included and split into training and validation sets. A higher positive rate of CD103+ cells and CD8+ cells were observed in responder, while patients with higher CD66b+ positive rate showed shorter PFS and OS. In terms of spatial profiling, tumor cells accompanied with more CD8+ cells were associated with longer PFS and OS, while longer distance from CD14+ cells and CD66b+ cells to tumor cells favored longer PFS and OS. Regarding PFS prediction, our machine-learning model TIS included both immune cell abundance and spatial features. Stratifying patients in the low- and high-risk groups using TIS revealed prolonged PFS (p&lt;0.0001, HR: 0.24, 95%CI [0.13-0.45]) and OS (p = 0.00057, HR: 0.27, 95%CI [0.12-0.60]) in TIS low-risk group. Moreover, ORR in TIS low-risk group was 52.9% (17/34) and 15.9% (7/44) in TIS high-risk group. Univariable and multivariable analysis demonstrated that TIS was an independent predictor for ORR (p = 0.0017), PFS (p = 0.00065) and OS (p = 0.00042). Independent validation is still awaited. Conclusions: This study demonstrates that our machine-learning based risk score can improve treatment response and survival prediction using TIME features, which provides the potential to optimize risk stratification before first-line treatment for unresectable HCC patients.
Rethinking rectal cancer management through COVID: Real word evidence in a public hospital in the south of Brazil.
Authors: Lucas Fernando Fabra, Marta Nassif Pereira Lima, Rodrigo Perez Pereira, Sergio Jobim Azevedo, Claudio Tarta, Valentina De Souza Stanham, Laura Lessa Gaudie Ley, Debora Oliveira Hütten
Journal: Journal of Clinical Oncology (2024)

e15620 Background: Treatment of locally advanced rectal cancer is based on a combination of radiotherapy and chemotherapy, either as adjuvant, neoadjuvant or total strategies. Short course radiotherapy followed by neoadjuvant chemotherapy, as described in the RAPIDO trial, was chosen by our Oncology, Radiotherapy and Coloproctological tumor board at Hospital de Clínicas de Porto Alegre during the COVID19 pandemic as a measure to reduce hospital visits and thus the possibility of transmission and infection by the SARS-COV-2 virus. Methods: We performed an observational analysis, including all patients treated with short course radiotherapy for locally advanced rectal cancer, at the Hospital de Clínicas de Porto Alegre in the period between January 2020 and March 2023. Metastatic patients were included, either treated with curative or palliative intent. Demographic characteristics, clinical staging, timing of chemotherapy, radiotherapy and surgery were analyzed. Clinical response was evaluated through sigmoidoscopy and clinical rectal exam. Patients with complete clinical response were offered the watch and wait strategy or surgery, after careful discussion of the possible benefits and risks. Results: Ninety-six patients were submitted to short course radiotherapy in the period described. Seven (7) patients were excluded; 89 patients were included in the final analysis. Fifty-five percent were male; mean age was 62 ±12.5 years; 52.8% were ECOG 1 at the diagnosis. Median CEA value at diagnosis was 7 ng/mL (CI 95%:4.4 - 9.8). Sixty-four percent were stage III, 31.4% stage IV, 3.3% stage II. Ninety-eight percent completed the programmed radiotherapy treatment. Only two patients received less than 25Gy. Forty-nine percent of patients completed the whole planned chemotherapy treatment; 15.7% were treated with palliative intent chemotherapy and 5.6% couldn’t receive chemotherapy for other reasons. Clinical response data were available in 62 patients: the main reason for unavailable clinical response was metastatic disease. Disease control was achieved in 98.4% of the cases, with only 1 patient having progressive disease during treatment (1.6%). The overall clinical response rate was 72.6%, 25.8% had stable disease and 24.2% complete clinical response. Fifteen of the 16 patients that presented with complete clinical response opted into a watch and wait strategy, achieving a 1-year disease free survival of 86.6%. Conclusions: Adopting the RAPIDO approach had a positive outcome in our advanced rectal cancer population. Short course radiotherapy followed by chemotherapy achieved excellent rates of disease control. Almost 25% of the non-metastatic patients undergoing RAPIDO treatment achieved complete clinical response opting into a watch and wait program.
The relationship between mismatch repair (MMR) proteins status and the response to conventional neoadjuvant therapy in colorectal cancer (CRC).
Authors: Junyong Weng, Ruoxin Zhang, Zhonglin Zhu, Shanbao Li, Zilan Ye, Qi Liu, Xinxiang Li
Journal: Journal of Clinical Oncology (2024)

e15627 Background: MMR proteins status is not routinely detected in CRC patients. Neoadjuvant use of immune checkpoint inhibitors (ICIs) in deficient mismatch repair (dMMR) CRC patients can achieve a pathological complete response (pCR) rate of 60-100%. Conversely, dMMR/MSI-H patients may exhibit a poor response to conventional neoadjuvant therapy, although supporting evidence is limited. Methods: We retrospectively collected clinical data from patients who underwent neoadjuvant chemoradiotherapy or chemotherapy at Fudan University Shanghai Cancer Center from 2008 to 2021, excluding those who received neoadjuvant ICIs. MMR proteins were detected using immunohistochemistry on surgical samples or preoperative colonoscopy biopsy samples, and some patients underwent genetic testing to evaluate their microsatellite status. This study included M0 CRC patients with complete tumor regression grading (TRG) assessment and MMR/MSI status. Responses were assessed using TRG evaluation (AJCC-TRG system) on the primary tumor. Results: Among 1005 patients, the median age was 57 years (range: 19-95), with 643 males (64.0%) and 362 females (36.0%). Seventy-two (7.2%) had right colon cancer, 80 (8.0%) had left colon cancer, and 853 (84.9%) had rectal cancer. Fifty-five (5.5%) had dMMR, and 950 (94.5%) had proficient mismatch repair (pMMR). In dMMR patients, defective proteins included hMLH1 and PMS2 combined in 22 patients, hMSH6 in 14 patients, PMS2 in 9 patients, hMSH6 and hMSH2 combined in 6 patients, hMLH1 in 2 patients, hMLH1 and hMSH6 combined in 1 patient, and hMSH6, PMS2, and hMSH2 combined in 1 patient. Compared to pMMR patients, dMMR patients showed either no response or poor response to conventional neoadjuvant therapy, with no patients exhibiting TRG = 0/1. One hundred and eleven (11.7%) pMMR patients showed a good response (TRG = 0/1). There was no statistically significant difference in overall survival between the two groups of patients (HR, 1.547; 95% CI: 0.9221-2.596; P = 0.172). Conclusions: Although our study is retrospective and some patients with pCR lacked MMR expression information, we can still conclude that dMMR patients have a poor response to conventional neoadjuvant therapy, and neoadjuvant ICIs treatment may be a better choice for dMMR patients. We recommend routine immunohistochemistry of MMR proteins in preoperative colonoscopies to guide the development of neoadjuvant strategies. [Table: see text]
Detection of TROP2: Ushering in a new choice in the treatment of patients with special types of invasive breast cancer.
Authors: Yueping Liu, Jinze Li, Hanxu Jiang, Huiyan Deng, Haoyue Sun, Xudi Liu
Journal: Journal of Clinical Oncology (2024)

1106 Background: TROP2 has become an attractive new therapeutic target in breast cancer (BC). TROPiCS-02 trial shows that the sacituzumab govitecan(SG) which is the TROP2 ADC drug can significantly benefit the survival of patients with TNBC and HR+/HER2- BC, and the 2023 ASCO guideline recommends that TROP2 detection is not necessary before the SG treatment. However, less than 5% BC patients of special subtype were included in clinical trials, and the TROP2 expression of them is not yet known. The aim of our study is to compare the expression of TROP2 in different special types of BC, and provide reference for targeted treatment of these patients. Methods: We retrospectively retrieved tissues from 383 patients diagnosed with special type of BC and undergoing surgical resection at our institution from 2018 to 2023. Including metaplastic carcinoma (MBC), mucinous carcinoma (MC), adenoid cystic carcinoma, cribriform carcinoma, carcinoma with apocrine differentiation, neuroendocrine carcinoma and tubular carcinoma. Classify them as TNBC or HR+/HER2- BC. Applying H-score to evaluate the TROP2 expression, H-score&lt;100, 100~200, and 201~300 classified as low, moderate and high expression. Results: Expression of TROP2 is higher in tubular and cribriform carcinoma, while in MBC and MC is significantly lower (χ 2 =66.756, P&lt;0.001) (Table). Low expression of TROP2 is associated with low clinical staging ( P&lt;0.05), no lymph node metastasis ( P&lt;0.05), and high-grade tumor infiltrating lymphocytes ( P&lt;0.05). Moreover, TROP2 had the lowest expression in MBC, with a median H-score of 45. There are 78.13% (43/55) cases showed H-score&lt;100, with 27.3% (15/55) of cases showing no expression of TROP2 at all. It is worth noting that MBC is highly invasive and has a poor prognosis, but the expression level of TROP2 is very low in mesenchymal cells, while in squamous differentiated tumor tissue, the expression level of TROP2 is high, and the overall H-Score score is low ( P&lt;0.001). Conclusions: This study is the first preliminary study on the TROP2 expression in special types of breast cancer. Although the current ASCO guideline recommends not testing TROP2, but our study shows it is pretty low or even not expressed in MBC and MC. Notably, the lack of expression in the mesenchymal and spindle cell subtypes may be highly indicates that they lack epithelial tumor cells expressing TROP2 as vectors, resulting in the inability to exert the therapeutic effect of ADC, we suggest routine testing of TROP2. [Table: see text]