Biomarkers Of Treatment Response Research Articles

Challenges in Implementing Comprehensive Precision Medicine Screening for Ovarian Cancer

Precision medicine has revolutionised targeted cancer treatments; however, its implementation in ovarian cancer remains challenging. Diverse tumour biology and extensive heterogeneity in ovarian cancer can limit the translatability of genetic profiling and contribute to a lack of biomarkers of treatment response. This review addresses the barriers in precision medicine for ovarian cancer, including obtaining adequate and representative tissue samples for analysis, developing functional and standardised screening methods, and navigating data infrastructure and management. Ethical concerns related to patient consent, data privacy and health equity are also explored. We highlight the socio-economic complexities for precision medicine and propose strategies to overcome these challenges with an emphasis on accessibility and education amongst patients and health professionals and the development of regulatory frameworks to support clinical integration. Interdisciplinary collaboration is essential to drive progress in precision medicine to improve disease management and ovarian cancer patient outcomes.

Circulating tumor DNA as a predictive biomarker for treatment response and survival in metastatic colorectal cancer

PurposeTo explore the potential of circulating tumor DNA (ctDNA) as a prognostic biomarker to predict treatment response and survival outcomes in patients with metastatic colorectal cancer (mCRC).MethodsA retrospective analysis was conducted on 134 patients with mCRC who were treated between January 2020 and December 2021. The patients were classified into ctDNA-negative and ctDNA-positive groups based on plasma ctDNA detection. Demographic, clinical, and laboratory parameters, treatment response, survival outcomes, and adverse events were recorded and analyzed.ResultsNo significant differences were observed in baseline characteristics between the two groups. Compared to the ctDNA-positive patients, ctDNA-negative patients exhibited superior outcomes, including a higher objective response rate (65.22% vs. 46.15%), disease control rate (81.16% vs. 63.08%), progression-free survival (8.24 ± 1.02 vs. 7.86 ± 0.91 months), overall survival (24.58 ± 3.58 vs. 23.27 ± 3.46 months), and 1-year survival rate (73.91% vs. 55.38%). The ctDNA-positive group had a significantly higher incidence of adverse events. Correlation analyses revealed significant associations between ctDNA status, tumor markers, treatment response, and survival outcomes.ConclusionsctDNA is a promising noninvasive biomarker for predicting treatment response, survival, and adverse events in mCRC, potentially guiding personalized therapeutic strategies.

Serum IL-6 concentration is a useful biomarker to predict the efficacy of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma.

This study aims to identify biomarkers for treatment response of atezolizumab plus bevacizumab (Atezo+Bev) in patients with hepatocellular carcinoma (HCC). 96 patients who received Atezo+Bev or lenvatinib as a first-line systemic therapy were enrolled as the training group after propensity score matching (PSM), and 42 patients treated with Atezo+Bev were enrolled as the validation group. 17 serum cytokines were measured by Luminex multiplex assay at the start of treatment. For further assessment of the association between cytokine levels and the tumor microenvironment (TME), immunohistochemistry (IHC) was performed on pre-treatment liver biopsy specimens. In the derivation set, multivariate analysis identified elevated IL-6 as an independent risk factor in the Atezo+Bev group (HR 5.80: p<0.01), but not in the lenvatinib group; in a subset analysis of patients with low IL-6, PFS was longer in the Atezo+Bev training group than in the lenvatinib group (p = 0.02). A validation study also showed a significantly longer prognosis in the low IL-6 group for both PFS (p = 0.0001) and OS (p = 0.03). Serum IL-6 had a positive correlation with tumor IL-6 expression (ρ = 0.56, p < 0.0001) and an inverse correlation with the CD8/CD163-positive cell count ratio (ρ = -0.4, p < 0.01). Serum IL-6 levels are thought to be involved in the suppression of tumor immunity and are useful in predicting the therapeutic effect of Atezo+Bev treatment.

The anti-inflammatory role of therapeutic ultrasound and low-level laser in chronic rhinosinusitis: A fractional exhaled nitric oxide outcome hypothesis

Chronic rhinosinusitis is defined as a complex of disorders whose main feature is nasal and paranasal sinus mucosal inflammation for at least three months. Inflammation plays a key role in chronic rhinosinusitis. Fractional exhaled nitric oxide is used to monitor eosinophilic airway inflammation in the human lower airways. Fractional exhaled nitric oxide levels are paradoxically low in some chronic rhinosinusitis patients. This has been attributed to sinus ostia obstruction. However, a recent study has demonstrated that fractional exhaled nitric oxide levels could serve as a chronic rhinosinusitis inflammation biomarker independent of lower airway inflammatory disease and could be used as a treatment response biomarker. Therapeutic ultrasound and low-level laser therapy have been used in chronic rhinosinusitis management. Through a variety of mechanisms, ultrasound enhances bacterial killing. Low level laser therapy increases nitric oxide release and ATP levels. It also reduces inflammation and accelerates tissue repair. Fractional exhaled nitric oxide levels could be used to evaluate the anti-inflammatory actions of therapeutic ultrasound and low-level laser therapy in chronic rhinosinusitis patients. A hypothesis that fractional expired nitric oxide measurements could be a useful biomarker to evaluate their potential anti-inflammatory mechanisms and monitor their treatment efficacy is proposed. This could contribute to a better understanding of these therapies in chronic rhinosinusitis management. An improved understanding of treatment efficacy could lead to improved management strategies.

Development and external evaluation of a self-learning auto-segmentation model for Colorectal Cancer Liver Metastases Assessment (COALA)

ObjectivesTotal tumor volume (TTV) is associated with overall and recurrence-free survival in patients with colorectal cancer liver metastases (CRLM). However, the labor-intensive nature of such manual assessments has hampered the clinical adoption of TTV as an imaging biomarker. This study aimed to develop and externally evaluate a CRLM auto-segmentation model on CT scans, to facilitate the clinical adoption of TTV.MethodsWe developed an auto-segmentation model to segment CRLM using 783 contrast-enhanced portal venous phase CTs (CT-PVP) of 373 patients. We used a self-learning setup whereby we first trained a teacher model on 99 manually segmented CT-PVPs from three radiologists. The teacher model was then used to segment CRLM in the remaining 663 CT-PVPs for training the student model. We used the DICE score and the intraclass correlation coefficient (ICC) to compare the student model’s segmentations and the TTV obtained from these segmentations to those obtained from the merged segmentations. We evaluated the student model in an external test set of 50 CT-PVPs from 35 patients from the Oslo University Hospital and an internal test set of 21 CT-PVPs from 10 patients from the Amsterdam University Medical Centers.ResultsThe model reached a mean DICE score of 0.85 (IQR: 0.05) and 0.83 (IQR: 0.10) on the internal and external test sets, respectively. The ICC between the segmented volumes from the student model and from the merged segmentations was 0.97 on both test sets.ConclusionThe developed colorectal cancer liver metastases auto-segmentation model achieved a high DICE score and near-perfect agreement for assessing TTV.Critical relevance statementAI model segments colorectal liver metastases on CT with high performance on two test sets. Accurate segmentation of colorectal liver metastases could facilitate the clinical adoption of total tumor volume as an imaging biomarker for prognosis and treatment response monitoring.Key PointsDeveloped colorectal liver metastases segmentation model to facilitate total tumor volume assessment.Model achieved high performance on internal and external test sets.Model can improve prognostic stratification and treatment planning for colorectal liver metastases.Graphical

The role of type 2 diabetes in the severity of adult asthma.

This review summarizes recent basic, translational, and clinical research on type 2 diabetes (T2D) and its relationship with asthma severity in the context of T2D mechanisms and asthma outcomes. Several clinical asthma outcomes, such as lung function and exacerbations, demonstrate a strong association between T2D and asthma and support that T2D contributes to worse asthma outcomes. Multiple mechanisms underlying those observed associations, and their representative biomarkers, have been proposed. However, prospective, controlled human studies in the context of both T2D and asthma are limited. T2D is associated with worse asthma outcomes and more severe asthma. Yet patients with more severe or uncontrolled asthma are also at a higher risk for systemic steroid exposure, which worsens glycemic control and metabolic dysregulation. Preclinical and translational studies point to metabolic dysregulation as a driver of airway inflammation. Addressing these metabolic pathways through T2D treatment may, in turn, directly or indirectly improve clinical asthma outcomes. While additional research is needed to identify biomarkers of risk and treatment response in metabolic asthma, this review highlights the importance of considering T2D as a clinically relevant asthma comorbidity.

Biomarkers of systemic treatment response: MR images of intratumoral fat deposition in colorectal liver metastases (CRLM) after chemotherapy.

Colorectal cancer cells containing mobile lipids are said to be an early indicator of chemotherapy effects. The objective of the study was to examine the frequency and clinical relevance of intratumoral fat deposition in colorectal liver metastases (CRLM) post-chemotherapy using dual-echo chemical shift gradient-echo magnetic resonance imaging (MRI). A retrospective analysis of 98 patients with CRLM diagnosed between 2017 and 2022 (69M, mean age 62.87 ± 10.73years old) who had an MRI after chemotherapy was performed. On dual-echo chemical shift gradient-echo MRI, intratumoral fat deposition of CRLM was evaluated. A signal intensity drop of ≥ 12% in opposed-phase images vs. in-phase images indicated intratumoral fat. After chemotherapy, the presence of fat deposition was correlated with patients' overall survival. Before and after chemotherapy, 0 (0%) and 29 (29.59%) patients exhibited intratumoral fat. The number of CRLM ranged from 1 to 25 with a median of 3 and a mean size of 32.58 ± 22.95mm. The groups had statistically different survival times. Overall survival was shorter for patients with intratumoral fat deposition in CRLM (32months (24-60, 95% CI)) than for patients without fat deposition in CRLM (48months (36-NA, 95% CI)). In our group, nearly 30% of CRLM patients exhibited intratumoral fat after chemotherapy. Patients with intratumoral fat deposition in CRLM have a shorter overall survival time. The presence of fat in CRLM correlates with a poor long-term prognosis.

Myositis‐specific/associated autoantibodies as diagnostic keys and disease drivers

AbstractBackgroundMyositis‐specific autoantibodies (MSAs) and myositis‐associated autoantibodies (MAAs) have emerged as crucial biomarkers in idiopathic inflammatory myopathies (IIMs).MethodsThis review synthesizes recent research on MSAs and MAAs in various IIM subtypes.ResultsSpecific autoantibodies correlate with distinct clinical manifestations and pathological features. For example, anti‐MDA5 antibodies are linked to rapidly progressive interstitial lung disease, while anti‐TIF1‐γ antibodies are associated with increased malignancy risk in adult dermatomyositis. Animal models have demonstrated the pathogenic potential of certain antibodies, such as anti‐TIF1‐γ, anti‐SRP, and anti‐HMGCR, in inducing experimental myositis.ConclusionsUnderstanding the roles of MSAs and MAAs is crucial for elucidating disease mechanisms, developing targeted therapies, and improving patient outcomes. Further research is needed to fully characterize their functional implications and explore their potential as biomarkers for disease activity, prognosis, and treatment response.

Potential Prognostic Protein Biomarkers in Tears From Noninfectious Uveitis Patients Under Biologic Treatment as a Prelude to Personalized Medicine.

Adalimumab (ADA) is a systemic biological treatment option approved for the treatment of noninfectious uveitis (NIU); however, up to 40% of patients do not respond to the drug, either in a primary or secondary manner. Here, we evaluated the proteomic profile of patients with NIU who fail to ADA to identify proteins implicated in intraocular inflammation, as well as potential biomarkers for treatment response and novel therapeutic targets. Cross-sectional observational study of patients with NIU under ADA treatment for six or more months. Tears were collected with microcapillary tubes and protein analyzed by data-independent acquisition/sequential window acquisition of all theoretical mass spectra. Differentially expressed proteins (DEPs) were defined based on the fold change between their expression in nonresponders (NR) and responders (R). Protein network and gene ontology analysis were performed. The χ2 test for trend and receiver operating characteristic (ROC) curves were used to evaluate potential biomarkers of treatment response. Twenty-nine DEPs, 14 upregulated and 15 downregulated, were detected in NR. These proteins were mainly related to enhanced neutrophil effector functions and redox imbalance. ROC analysis identified defensin-1,3 (DEF-1,3), biotinidase, and ATP-binding cassette transporter A1 as potential biomarkers for treatment response. This is the first study on a clinical cohort of patients with noninfectious uveitis that identifies tear proteins related to neutrophil hyperactivation as drivers of the persistent intraocular inflammation observed in NR to ADA and provides evidence that targeting interleukin 6, Janus kinases, or the complement cascade could be potential alternative therapeutic strategies in these patients. Our results indicate the potential of high-throughput proteomics to provide insights into the underlying pathological mechanisms of persistent intraocular inflammation observed in patients who do not adequately respond to anti-TNF treatment and the value of tear proteomics as a tool for personalized medicine.

Predictors of outcomes after gastric peroral endoscopic myotomy for refractory gastroparesis: a systematic review

Background: Gastroparesis is a debilitating gastroduodenal disorder for which gastric peroral endoscopic myotomy (GPOEM) has emerged as an efficacious treatment option. However, response to GPOEM varies between 50-80%, such that preoperative predictors of treatment success are needed to guide patient selection. Methods: We performed a systematic review to identify predictors of clinical and functional response to GPOEM among adult patients with gastroparesis (PROSPERO: CRD42023457359). MEDLINE, Embase, and CENTRAL databases were searched systematically for studies reporting outcomes after GPOEM in September 2023. A narrative synthesis of predictive factors on univariable and multivariable analysis was performed with consideration of response rates via meta-analysis, and evaluation of discrimination if prognostic models were developed. ROBINS-E was used for risk of bias assessment. Results: Of 1899 articles reviewed, 30 were included. The GPOEM response rate was 63.1% (95% confidence interval 56.3%-69.5%) with most studies defining clinical success on the basis of improvement in gastroparesis cardinal symptom index (87%, 26/30). Older age, shorter duration of gastroparesis, non-diabetic etiology, lower body mass index, and response to intrapyloric botulinum toxin were associated with positive response to GPOEM on multivariable analyses. Predictors on physiological tests such as EndoFLIP or gastric emptying scintigraphy were inconsistent. No prognostic models underwent external validation. Conclusion: Currently, there are limited reproducible predictors of response to GPOEM among patients with refractory gastroparesis. Robust prospective studies investigating scalable, reproducible, and actionable biomarkers of treatment response are required.

Abstract A003: CD45 positive circulating tumor cells as a prognostic marker in prostate cancer

Abstract Prostate cancer is one of the most common types of cancer among male patients worldwide, making early diagnosis and effective treatment crucial for improving patient survival rates. In this regard, circulating tumor cells (CTCs) have garnered attention as an important biomarker for cancer staging and monitoring treatment response. In prostate cancer, CTCs are typically identified as keratin+/CD45- cells, with additional markers such as PSA or PSMA also being used. The conventional CTC identification way have dismissed CD45+/keratin+ double-positive cells as artifacts by nonspecific binding during the staining process. However, recent studies have reported the presence of CD45+/keratin+ CTCs in various types of cancers, highlighting metastatic potential and their ability to evade the immune system. These findings require re- examination of the role for the double positive CTCs. Therefore, this study aimed to identify the presence of CD45+ CTCs in prostate cancer and to assess their clinical significance. Blood samples were collected from 80 prostate cancer patients, followed by unbiased isolation of CTCs, which were stained using PSA, keratin, and CD45. The detected CTCs were categorized based on CD45 expression, and the clinical relevance of each group was validated using patient information. Through this study, we aimed to confirm whether the CD45+ CTCs can be a clinical indicator in prostate cancer. The results revealed that CD45+ CTCs accounted for 90% of all detected CTCs, likely due to their high immune evasion capabilities. Additionally, in 17% of the patients, only CD45+ CTCs were detected, indicating the potential to expand CTC detection even in patients where CTCs were previously undetected using conventional criteria. The number of CD45+ CTCs was significantly higher in patients with progressive disease compared to those with complete or partial response, showing greater statistical significance than analyses using CD45- CTCs. Furthermore, the number of PSA+ CTCs was closely linked to changes in plasma PSA levels, suggesting they could be used as a supporting marker to enhance the accuracy of current plasma PSA tests. These findings indicate that CD45+ CTCs in prostate cancer are not merely artifacts of nonspecific binding but are indeed meaningful cells closely related to cancer progression. This study suggests that CD45+ CTCs have the potential to be utilized as a prognostic biomarker in prostate cancer. By including CD45+ CTCs, which were previously overlooked in conventional CTC analysis methods, more sensitive and accurate cancer monitoring could be achieved. In-depth future studies on the clinical applicability of CD45+ CTCs could significantly contribute to predicting prognosis and developing personalized treatment strategies for prostate cancer patients. Citation Format: Hyeongjung Woo, Woon-Hae Kim, Hyun Young Shin, Hyerin Jung, Hyung Ho Lee, Minseok S. Kim, Jae Young Joung. CD45 positive circulating tumor cells as a prognostic marker in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A003.

Abstract PR017: A T-cell signature in circulating cell-free DNA at time of diagnosis predicts response to checkpoint inhibition

Abstract Immune checkpoint inhibitors (ICI) are increasingly used as first line of treatment in a range of cancer types, owing to their efficacy and advantageous toxicological profile. Currently, PD-L1 expression and tumor mutation burden (TMB) are the most common biomarkers to select patients for ICI treatment, yet response to ICI remains highly variable between patients, necessitating more accurate early predictors of treatment response. Circulating cell-free DNA (cfDNA) originates from dying cells throughout the body, each molecule carrying unique epigenetic features of its cell-type of origin. Most studies on cfDNA focus on tumor-derived fragments for diagnostics or minimal residual disease detection. However, variations in the contribution of immune cells and other stromal cell populations could provide important clues to classify a tumor with respect to treatment. To address this, we collected tumor and adjacent normal tissue as well as cfDNA from the blood of 33 patients enrolled in the LUD2015-005 trial in which ICI were administered to patients with non-resectable esophageal adenocarcinoma (EAC) for four weeks, before adding standard-of-care chemotherapy (ICI+CTX). For each patient, we took samples at diagnosis, before ICI+CTX, during and at the end of treatment. Tissue and cfDNA samples were sequenced using TET-Assisted Pyridine-borane Sequencing (TAPS), a method recently developed in Oxford which provides genome-wide high-depth, base- resolution DNA methylation and mutation information from low-input samples. We then selected a representative set of high-purity tumor tissue samples and combined them with whole- genome TAPS data from 9 healthy blood cell types and 5 gastrointestinal tissues to generate a GI-specific atlas of cell-type specific methylation. This atlas allows us to accurately quantify the contribution of tumor and 14 healthy cell types to the cfDNA collected from each patient at each timepoint. Strikingly, the presence of T-cell derived cfDNA at time of diagnosis (tDNA) is a strong positive predictive marker of overall survival (p=0.0024). In contrast, the fraction of tumor-resident T-cells, estimated by either bulk tissue TAPS or RNA sequencing, correlated only weakly with treatment response in this cohort, indicating that T-cell activity is more accurately captured by tDNA. Furthermore, we find that patients with a combination of high TMB and high tDNA have an 80% 2-year survival probability, as opposed to below 25% for others, suggesting that tDNA is derived from T-cells actively engaging tumor cells with high neoantigen load. In summary, we demonstrate that T-cell turnover, as reflected in differential methylation in a set of marker regions spanning only 24kb, is a promising biomarker of treatment response, especially when combined with neoantigen load: in the presented cohort, all but one long-term survivors (alive at last follow up &amp;gt; 3 years after diagnosis) were tDNA positive with high TMB. This demonstrates the power of cfDNA composition analysis for risk stratification in ICI treatment. Citation Format: Phil Xie, Zohar Etzioni, Chun-Xiao Song, Richard P Owen, Mark R Middleton, Xin Lu, Benjamin Schuster-Boeckler. A T-cell signature in circulating cell-free DNA at time of diagnosis predicts response to checkpoint inhibition [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR017.

Abstract PR014: Robust disease monitoring using CSF liquid biopsies collected from children undergoing cellular therapy for malignant central nervous system tumors

Abstract Background: Central nervous system (CNS) tumors remain the leading cause of cancer-related mortality in children, necessitating more effective treatment options. Chimeric Antigen Receptor T-cells (CAR-T) have emerged as a promising strategy to treat CNS tumors, with B7H3 (CD276) representing an attractive target due to its high expression across a broad range of entities. B7H3-CAR-T therapy is currently being evaluated in a St. Jude Children’s Research Hospital Phase I clinical trial (NCT05835687) for the treatment of relapse/refractory pediatric CNS tumors. Monitoring disease progression after CAR-T infusion by magnetic resonance imaging (MRI) remains challenging, emphasizing the need for more sensitive biomarkers of treatment response. Detection of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) liquid biopsies holds tremendous potential for minimal residual disease (MRD) monitoring in the clinical setting. Here, we leverage CSF liquid biopsies for longitudinal disease profiling in pediatric CNS tumor patients receiving B7H3-CAR-T immunotherapy. Methods: CSF samples were collected from Ommaya reservoirs of 9 pediatric patients with relapse/refractory CNS tumors undergoing B7H3-CAR-T therapy. CSF was sampled at study enrollment, and weekly intervals pre- and post-infusion. Cell-free DNA (cfDNA) was extracted from 115 longitudinally collected CSF samples and subjected to enzymatic methylation sequencing (EM-seq). Implementation of a custom computational workflow enabled detection of tumor-derived copy number variations (CNVs), estimation of malignant vs. non-malignant fractions, and molecular classification of tumor entity. Results: Tumor-derived CNVs were detected in 7/9 (78%) CSF samples collected at enrollment, prior to immunotherapy. Liquid biopsy-inferred CNV profiles and entity classifications were highly concordant with matched tumor tissue profiles. Chromosomal alterations that were restricted to CSF profiles indicated clonal evolution. Increased ctDNA burden was repeatedly observed after B7H3-CAR-T infusions, suggesting subclinical antitumor activity. Transient subclonal alterations emerging in response to treatment were also identified in a subset of patients. Conclusions: EM-seq is a feasible method for serial tracking of ctDNA burden in patients receiving cellular immunotherapy. CSF liquid biopsies capture the global landscape of tumor heterogeneity and genetic alterations that arise during therapy, providing a sensitive platform for detecting clinical response and disclosing potential mechanisms of treatment resistance. Citation Format: Anna Kostecka, Kyle S Smith, Katie Han, Hong Lin, Deanna Langfitt, Tara Walhart, Stephen Gottschalk, Giedre Krenciute, Christopher DeRenzo, Kelsey Bertrand, Paul A Northcott. Robust disease monitoring using CSF liquid biopsies collected from children undergoing cellular therapy for malignant central nervous system tumors [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR014.

TMET-20. A METABOLIC BIOMARKER IN GLIOBLASTOMA: A PROMISING APPLICATION OF CO-POLARIZED [1-13C]PYRUVATE AND [1-13C]DEHYDROASCORBATE

Abstract BACKGROUND Noninvasive biomarkers for treatment response in glioblastoma are needed to improve patient outcomes. Our understanding of redox biology in treatment resistance is rapidly evolving, and interrogation of tumor metabolism represents an ideal opportunity to meet this need. In this study, the utility of co-hyperpolarized [1-13C]pyruvate and [1-13C]dehydroascorbate (HP PA/DHA) to simultaneously evaluate brain tumor metabolism and oxidative stress in orthotopically implanted mice is investigated. METHODS To characterize HP PA/DHA, mice were treated with 0-4mM diethyl maleate and 1D slab dynamic acquisitions were performed over the mouse brain. As an initial evaluation of the utility of HP DHA/PA in brain tumors, athymic nude mice (n=8) underwent orthotopic U87 glioblastoma implantation. After treatment with 8Gy in one fraction, mice were injected with HP DHA/PA dissolved in D2O. T2-weighted and 13C Chemical Shift Imaging sequences were obtained on a 3T MRI using a quadrature double-tuned 1H/13C volume coil. RESULTS HP DHA/PA detected differential lactate and vitamin C generation over the mouse brain. Treatment with diethyl maleate, which depletes the cofactor glutathione, diminished fractional vitamin C generation (0.1 vs 0.03, p=0.0009). Elevation in tumor lactate generation was seen in untreated (125.1±17.6µM, p=0.005) and radiated mice (149.4±32.6µM, p=0.01). Treatment with radiation generated higher vitamin C concentrations in tumors relative to contralateral brain (46.8±4.8µM, p=0.002). Radiated tumors were distinguished by higher ratio of lactate to vitamin C compared to untreated tumor controls (3.7 vs 2.5, p=0.07), and the same relationship was preserved between treated and untreated non-tumor brain. CONCLUSION The ratio of vitamin C/lactate detects the metabolic effects of radiation in brain tumors, inspiring its’ potential as a biomarker for treatment response. To further characterize these findings, examination of survival and modulation of radiosensitivity are ongoing.

BIOM-08. LEVERAGING CSF PROTEOMICS TO OPTIMIZE CNS LYMPHOMA MANAGEMENT

Abstract INTRODUCTION Despite exquisite responses to initial therapy for CNS lymphoma (CNSL), relapse is common and overall responses are disappointing compared to other non-CNS diffuse large B-cell lymphomas. Incorporation of multi-agent intraventricular chemotherapy (MAIVC) alongside systemic therapy is novel. Identification of minimally-invasive biomarkers of response to MAIVC are necessary but lacking. The objectives of this study were to 1) identify baseline cerebrospinal fluid (CSF)-based proteomic predictive biomarkers of MAIVC treatment response and 2) identify tumor burden markers for longitudinal monitoring of MAIVC treatment response in CNSL. METHODS A cohort of patients with primary or secondary CNSL that were treated with MAIVC at Penn State Health (2015-2021) was included. Each MAIVC cycle was administered via Ommaya reservoir and included a 2-drug combination comprised of methotrexate, rituximab, cytarabine, etoposide, topotecan, gemcitabine, or thiotepa. Patient-matched CSF was sampled at pre- and post-therapeutic endpoints and profiled using shotgun proteomics. Patients were grouped by treatment response status. Early responders were defined as patients that achieved malignant cell-free CSF within 6 MAIVC cycles, whereas never responders were those patients that i) did not achieve malignant cell-free CSF by endpoint or ii) required salvage surgery or radiation during MAIVC. RESULTS 59 patients were included (21 primary; 38 secondary CNSL) with a median age of 66 years (range 25-90) and median number of MAIVC cycles of 8 (range 2-23). A proteomic-based classifier, comprised of SGCE, LCP1 and AGRN, discriminated between early and never responders with an AUROC of 0.95. Comparison of CSF at baseline (&amp;lt;3 cycles MAIVC) vs. post-treatment (&amp;gt;12 cycles MAIVC) identified H3F3A, YWHAE, LCP1, CA1 and GAPDH as tumor burden biomarkers. CONCLUSION Here we developed a proteomic signature capable of predicting CNSL patient response to MAIVC, with potential to improve clinical decision making. Furthermore, the biomarkers associated with tumor burden represent important indicators of treatment response. Ongoing efforts are underway to evaluate these candidates as actionable therapeutic targets.

BIOM-23. DEUTERIUM METABOLIC IMAGING OF RESPONSE TO PRECISION THERAPY IN BRAF-V600E MUTANT GLIOMAS

Abstract Oncogenic BRAF-V600E mutations are frequently observed in low- and high-grade gliomas in adults and children. BRAF transduces signals from receptor tyrosine kinases to downstream effectors such as MEK1/2 and ERK, which regulate both metabolism and proliferation. The combination of the BRAF-V600E inhibitor dabrafenib and the MEK1/2 inhibitor trametinib (Dab/Tra) improves patient survival. However, there is considerable variation in the durability of response, underscoring the need for early biomarkers of treatment response. Magnetic resonance imaging (MRI), which is the gold standard for patient management, does not reliably assess response to therapy. Since the BRAF/MEK pathway regulates metabolism, the goal of this study was to determine whether Dab/Tra induces alterations in glucose metabolism that can be leveraged for non-invasive imaging. Using gene expression profiling, in vivo metabolomics, and stable isotope tracing, we show that Dab/Tra downregulates glucose metabolism to lactate in human and murine BRAF-V600E mutant models (AM38, 2341). In vivo infusion with [U-13C]-glucose in mice bearing intracranial AM38 tumors confirmed that Dab/Tra downregulates glucose metabolism to lactate in the tumor in vivo. Mechanistically, Dab/Tra destabilizes hypoxia inducible factor-1a and downregulates glycolytic genes, including SLC2A1, HK2, PFKFB3, and LDHA. Deuterium metabolic imaging (DMI) is a novel, clinical stage method of tracing glucose metabolism in vivo. Our studies show that lactate production from [6,6-2H]-glucose is reduced in AM38 and 2341 cells treated with Dab/Tra. Importantly, lactate production is reduced within 48 h of treatment with Dab/Tra in mice bearing intracranial AM38 tumors at the clinical magnetic field strength of 3T. Furthermore, this drop in 2H-lactate production is observed in the absence of MRI-detectable volumetric alterations and is predictive of extended survival. Collectively, our studies mechanistically link BRAF/MEK inhibition with downregulation of glycolysis and identify [6,6’-2H]-glucose as a novel contrast agent for imaging early response to therapy. Clinical translation of our studies will enable precision imaging of response to therapy for patients with BRAF-mutant gliomas.

CTIM-32. PHASE I/II STUDY OF STEREOTACTIC RADIOSURGERY WITH CONCURRENT OLAPARIB FOLLOWED BY ADJUVANT DURVALUMAB AND PHYSICIAN’S CHOICE SYSTEMIC THERAPY IN SUBJECTS WITH BREAST CANCER BRAIN METASTASES (SOLARA)

Abstract BACKGROUND Despite progress in the treatment of brain metastasis for HER2+ breast cancer, outcomes for patients with HER2-negative breast cancer brain metastases remain poor. Preclinical studies show inhibitors of poly(ADP-ribose) polymerase (PARP) are effective in combination with radiation therapy as a DNA damage response inhibitor. Triple-negative breast cancer (TNBC) has higher rates of homologous recombination deficiency compared to other subtypes, and together with HER2-negative, BRCA-mutated breast cancer would be particularly sensitive to PARP inhibition. PARP inhibition has also demonstrated promising efficacy combined with immunotherapy in patients with germline BRCA-mutant and metastatic TNBC in clinical trials. In addition, immunotherapy with stereotactic radiosurgery (SRS) is associated with favorable intracranial control and survival in patients with brain metastases. We hypothesize that this biologically-driven combination will enhance local control of SRS-treated brain metastases through synergy with PARP inhibition, while controlling micrometastatic disease via potentiation of the immune response. METHODS We are conducting a multi-institution, Phase I/II trial of SRS plus olaparib, followed by durvalumab (with physician’s choice systemic therapy), for patients with TNBC (any BRCA status) or HER2-negative with BRCA-mutated (germline or somatic) breast cancer brain metastases [NCT04711824]. A total of 41 patients are planned for enrollment at 8 sites. The primary objectives are to evaluate safety and tolerability (Phase I) and determine intracranial disease control at 6 months (Phase II). Secondary objectives include assessing intracranial and global progression-free survival, overall survival, and intracranial and extracranial response rate. Exploratory objectives will assess potential biomarkers of treatment response, including changes in circulating tumor cells and DNA in blood and cerebrospinal fluid, germline and tumor mutations in DNA repair pathway genes, and PD-L1 expression, as well as quality of life and patient-reported outcomes. As of May 2024, phase I has been completed without dose-limiting toxicity, and phase II is currently enrolling. Funding/drug provision from AstraZeneca.

DDDR-38. TRANSLATIONAL STEPS OF THE ANTITUMOR PEPTIDE TAT-CX43266-283 AS A TREATMENT FOR GLIOBLASTOMA: EGFR AS A TREATMENT RESPONSE BIOMARKER AND RESULTS OF COMBINATION THERAPY IN A PRECLINICAL RESECTION MODEL

Abstract Glioblastomas (GBM) are the most malignant primary brain tumors, and they remain incurable. Despite the current standard of care (surgical resection of the tumor and administration of chemotherapy and radiotherapy) some GBM stem cells (GSCs) remain in the brain parenchyma causing tumor recurrence. The Src-inhibitory peptide TAT-Cx43266-283 has shown promising antitumor results in GBM preclinical models, reducing GSC viability and increasing survival in GBM-bearing mice. Here we have investigated some of the main gaps to overcome when translating preclinical results to the clinic, to promote the progress of TAT-Cx43266-283 as a clinical therapy to fight GBM. First, we investigated biomarkers of treatment response to design a more targeted therapy. We assessed cell viability after treatment with TAT-Cx43266-283 in 13 patient-derived GSC lines and we found a stronger treatment response in those GSCs that had alterations in the Epidermal Growth Factor Receptor (EGFR). This was further confirmed in several murine GBM lines. Importantly, we found that treatment with TAT-Cx43266-283 was more effective in vitro than temozolomide or the classical EGFR inhibitor, erlotinib. Moreover, we showed that EGFR participates in TAT-Cx43266-283 response together with Src, by decreasing EGFR and EGFRvIII activity in some GSCs and increasing survival in mice bearing tumors with EGFR alterations. Next, we studied the effect of TAT-Cx43266-283 in a clinical context by administering it in a murine model of tumor resection. We analyzed the histopathology of this GBM model, uncovering histological features typical of human GBM. We found that resection alone improved, although not significantly, GBM-bearing mice survival. However, tumors that regrew after resection exhibited more aggressive features. Importantly, the combination of tumor resection and TAT-Cx43266-283 achieved better survival outcomes and showed reduced invasive features. Altogether, these results serve as a base for future clinical investigations and support the therapeutic potential of TAT-Cx43266-283 as a treatment for GBM.

BIOM-36. DETECTION OF CIRCULATING TUMOR DNA (CTDNA) IN CEREBROSPINAL FLUID (CSF) IN PATIENTS WITH GLIOBLASTOMA TREATED IN PHASE I CLINICAL TRIAL

Abstract BACKGROUND As circulating tumor DNA (ctDNA) has been shown to be a source of tumor-specific biomarkers, liquid biopsy has emerged as a novel noninvasive tool in diagnosis, disease monitoring and treatment selection in several solid tumors. However, its use in brain tumors remains challenging because ctDNA is commonly not detected in blood. Thus, CSF (cerebrospinal fluid) has emerged as a potential source of ctDNA in the context of brain tumors. PATIENTS AND METHODS We prospectively evaluated the detection of ctDNA in CSF (CSF-ctDNA) +/- blood of patients with pre-treated MTAP-deleted glioblastoma, currently treated in a phase I clinical trial evaluating PRMT5 inhibitors. We did CSF samples at C2D15 and at progression, after patient’s oral and written consent. CSF was collected by lumbar puncture and analyzed with a panel of 35 genes including IDH1-2, TERT promoter and EGFR. Blood was collected, synchronously with CSF, by peripheral veinous punction and analyzed with the Foundation One Liquid CDx panel. RESULTS Between January and April 2024, five patients were included. All of them undergone initial surgical resection and received at least one previous systemic treatment associated with radiotherapy. At least one somatic mutation was identified in each patient, including EGFR amplification in 2/5 patients (40%). CSF was not available at baseline. One patient provided CSF only at progression. Four patients provided CSF at C2D15 on treatment, and among them, one patient was also collected at progression. At data cut-off, one patient was still on treatment. We identified a detectable level of CSF-ctDNA in only one patient with occipital tumor localization, with detection of EGFR amplification known at diagnosis. Synchronous blood analysis showed only clonal hematopoiesis variants. CONCLUSION We showed in this small cohort of patients that detection of CSF-ctDNA is technically feasible. The type of panel used might be optimized for this population especially to monitor patients as a potential surrogate biomarker for treatment response.

Metabolomics for the identification of biomarkers in endometriosis.

Endometriosis affects the quality of life in women during their reproductive years, causing immense pain and can result in infertility. It is characterized by inflammation and the growth of the endometrium outside the uterine cavity. Metabolomics has the potential to resolve the major bottleneck of endometriosis which is delay in diagnosis due to the invasive diagnostic approach.In this review, the author has summarized the identified biomarkers of endometriosis from different bodily fluids. Metabolomics promises a non-invasive diagnostic approach for endometriosis that could aid in earlier diagnosis and prognosis. Patients with endometriosis keywords were searched in correspondence with the assigned keywords, including metabolomics from PubMed, from its inception to Dec 2023. The relevant studies from this search were extracted and included in the study. This article provides information regarding metabolomics studies in endometrisis. We demonstrated that metabolomics is about to change the world of endometriosis by analyzing and detecting the diagnosis, prognosis, mortality and treatment response biomarkers.