Therapy Response Research Articles

Trauma history and course of therapy in a naturalistic cognitive behavior therapy outpatient sample: An archive data study.

Cognitive Behavior Therapy (CBT) is an effective treatment for anxiety and depression disorders. Nonetheless, nearly 50% of all patients do not respond. Besides other factors, nonresponse may be linked to traumatic life events. This study aims to assess the relationship between trauma history, applied therapy interventions, and therapy outcomes. We analyzed data from 340 CBT outpatients diagnosed with a depression or anxiety disorder and possibly a trauma history treated under naturalistic conditions. Based on their therapy files, we collected information on trauma history, diagnoses, applied interventions, and severity of depression and anxiety symptoms at the start and end of therapy. The relationship between trauma, diagnoses, and intervention use and the development of depression and anxiety symptoms was analyzed using Linear Mixed Models. Patients with a trauma history reported higher pre- and posttreatment symptom severity than those without trauma. No differences in applied interventions or decrease in symptom severity were found between patients with and without a trauma history. Specialized interventions were seldom applied. Although no differences between patients with and without a trauma history were found in therapy response, patients with a trauma history maintained higher levels of symptom severity. These results indicate a need for more personalized interventions and evidence-based guidelines to personalize CBT for patients with a trauma history and high symptom severity.

Machine-learning developed an iron, copper, and sulfur-metabolism associated signature predicts lung adenocarcinoma prognosis and therapy response

BackgroundPrevious studies have largely neglected the role of sulfur metabolism in LUAD, and no study has combine iron, copper, and sulfur-metabolism associated genes together to create prognostic signatures.MethodsThis study encompasses 1564 LUAD patients, 1249 NSCLC patients, and over 10,000 patients with various cancer types from diverse cohorts. We employed the R package ConsensusClusterPlus to separate patients into different ICSM (Iron, Copper, and Sulfur-Metabolism) subtypes. Various machine-learning methods were utilized to develop the ICSMI. Enrichment analyses were conducted using ClusterProfiler and GSVA, while IOBR quantified immune cell infiltration. GISTIC2.0 and maftools were utilized for CNV and SNV data analysis. The Oncopredict package predicted drug information based on GDSC1. TIDE algorithm and cohorts GSE91061 and IMvigor210 evaluated patient response to immunotherapy. Single-cell data was processed using the Seurat package, AUCell package calculated cells geneset activity scores, and the Scissor algorithm identified ICSMI-associated cells. In vitro experiments was conducted to explore the role of ICSMRGs in LUAD.ResultsUnsupervised clustering identified two distinct ICSM subtypes of LUAD, each with unique clinical characteristics. The ICSMI, comprising 10 genes, was constructed using integrated machine-learning methods. Its prognostic power was validated in 10 independent datasets, revealing that LUAD patients with higher ICSMI levels had poorer prognoses. Furthermore, ICSMI demonstrated superior predictive abilities compared to 102 previously published signatures. A nomogram incorporating ICSMI and clinical features exhibited high predictive performance. ICSMI positively correlated with patients gene mutations, and integrated analysis of bulk and single-cell transcriptome data revealed its association with TME modulators. Cells representing the high-ICSMI phenotype exhibited more malignant features. LUAD patients with high ICSMI levels exhibited sensitivity to chemotherapy and targeted therapy but displayed resistance to immunotherapy. In a comprehensive analysis across various cancers, ICSMI retained significant prognostic value and emerged as a risk factor for the majority of cancer patients.ConclusionsICSMI provides critical prognostic insights for LUAD patients, offering valuable insights into the tumor microenvironment and predicting treatment responsiveness.

Use of selpercatinib in a patient with <i>RET</i>-mutated non-small cell lung cancer: case report

Background. The use of the modern targeted drugs in patients with non-small-cell lung cancer (NSCLC) with certain somatic alterations (genetic alterations in EGFR, ALK, ROS1, BRAF, RET genes, etc.) provides a significant increase in overall and disease-free survival with an acceptable toxicity profile. The use of RET inhibitors, such as selpercatinib, has significantly improved prognosis in NSCLC patients with RET gene translocation, since chemotherapy and immunotherapy in this cohort of patients are ineffective options. The RET gene translocation occurs rarely (2–3 % of cases among lung adenocarcinoma), but detection of this genetic alteration with subsequent administration of targeted therapy significantly improves the prognosis of the disease. Case report. We present a clinical case of the efficacy of targeted therapy with selpercatinib in a 60-year-old patient with RET-positive NSCLC. Methods to eliminate toxicity after selpercatinib therapy and therapy response are described. Results. Second-line selpercatinib therapy resulted in partial response in our patient with lung adenocarcinoma and the presence of translocation in RET gene. Adverse effects from targeted therapy were minimized or eliminated by the use of concomitant therapy, temporary cancellation of targeted therapy with subsequent dose reduction and gradual return to full therapeutic doses. Conclusion. This case demonstrates the high significance and importance of genetic testing in patients with lung adenocarcinoma not only for the most common mutations, but also for rarer somatic alterations, such as translocation in the RET gene. Detection of this translocation and subsequent administration of appropriate targeted therapy significantly improves the prognosis of patients.

Targets in the Tumour Matrisome to Promote Cancer Therapy Response

The extracellular matrix (ECM) is composed of complex fibrillar proteins, proteoglycans, and macromolecules, generated by stromal, immune, and cancer cells. The components and organisation of the matrix evolves as tumours progress to invasive disease and metastasis. In many solid tumours, dense fibrotic ECM has been hypothesised to impede therapy response by limiting drug and immune cell access. Interventions to target individual components of the ECM, collectively termed the matrisome, have, however, revealed complex tumour-suppressor, tumour-promoter, and immune-modulatory functions, which have complicated clinical translation. The degree to which distinct components of the matrisome can dictate tumour phenotypes and response to therapy is the subject of intense study. A primary aim is to identify therapeutic opportunities within the matrisome, which might support a better response to existing therapies. Many matrix signatures have been developed which can predict prognosis, immune cell content, and immunotherapy responses. In this review, we will examine key components of the matrisome which have been associated with advanced tumours and therapy resistance. We have primarily focussed here on targeting matrisome components, rather than specific cell types, although several examples are described where cells of origin can dramatically affect tumour roles for matrix components. As we unravel the complex biochemical, biophysical, and intracellular transduction mechanisms associated with the ECM, numerous therapeutic opportunities will be identified to modify tumour progression and therapy response.

Exploring non-coding RNA mechanisms in hepatocellular carcinoma: implications for therapy and prognosis

Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths in the world. The development and progression of HCC are closely correlated with the abnormal regulation of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Important biological pathways in cancer biology, such as cell proliferation, death, and metastasis, are impacted by these ncRNAs, which modulate gene expression. The abnormal expression of non-coding RNAs in HCC raises the possibility that they could be applied as new biomarkers for diagnosis, prognosis, and treatment targets. Furthermore, by controlling the expression of cancer-related genes, miRNAs can function as either tumor suppressors or oncogenes. On the other hand, lncRNAs play a role in the advancement of cancer by interacting with other molecules within the cell, which, in turn, affects processes such as chromatin remodeling, transcription, and post-transcriptional processes. The importance of ncRNA-driven regulatory systems in HCC is being highlighted by current research, which sheds light on tumor behavior and therapy response. This research highlights the great potential of ncRNAs to improve patient outcomes in this difficult disease landscape by augmenting the present methods of HCC care through the use of precision medicine approaches.

Identification and validation of a prognostic anoikis-related gene signature in papillary thyroid carcinoma by integrated analysis of single-cell and bulk RNA-sequencing.

Papillary thyroid carcinoma (PTC) prognosis may be deteriorated due to the metastases, and anoikis palys an essential role in the tumor metastasis. However, the potential effect of anoikis-related genes on the prognosis of PTC was unclear. The mRNA and clinical information were obtained from the cancer genome atlas database. Hub genes were identified and risk model was constructed using Cox regression analysis. Kaplan-Meier (K-M) curve was applied for the survival analysis. Immune infiltration and immune therapy response were calculated using CIBERSORT and TIDE. The identification of cell types and cell interaction was performed by Seurat, SingleR and CellChat packages. GO, KEGG, and GSVA were applied for the enrichment analysis. Protein-protein interaction network was constructed in STRING and Cytoscape. Drug sensitivity was assessed in GSCA. Based on bulk RNA data, we identified 4 anoikis-related risk signatures, which were oncogenes, and constructed a risk model. The enrichment analysis found high risk group was enriched in some immune-related pathways. High risk group had higher infiltration of Tregs, higher TIDE score and lower levels of monocytes and CD8 T cells. Based on scRNA data, we found that 4 hub genes were mainly expressed in monocytes and macrophages, and they interacted with T cells. Hub genes were significantly related to immune escape-related genes. Drug sensitivity analysis suggested that cyclin dependent kinase inhibitor 2A may be a better chemotherapy target. We constructed a risk model which could effectively and steadily predict the prognosis of PTC. We inferred that the immune escape may be involved in the development of PTC.

ØCD: protocol for the development and evaluation of a cognitive-behavioral prevention program for obsessive-compulsive disorder

BackgroundObsessive-compulsive disorder (OCD) imposes significant burdens on individuals, families, and healthcare systems and the COVID-19 pandemic appears to have exacerbated OCD symptoms. Currently, there are no validated prevention programs for OCD, highlighting a critical gap in mental health services. This study aims to develop and validate the first ØCD prevention program, for at-risk adults, utilizing cognitive-behavioral therapy (CBT) and exposure response prevention (ERP) techniques.MethodsA single-blind, randomized controlled trial comparing the ØCD prevention program to a waitlist control group will be conducted. Participants, at-risk adults (18–65 years) with subclinical OCD symptoms (OCI-R score ≥ 12), will be recruited for the study. The ØCD prevention program compresise of six online group sessions incorporating CBT and ERP techniques over three modules. The primary outcomes are OCD symptom severity (measured by the Obsessive-Compulsive Inventory- revised form; OCI-R), depression symptoms (measured by the Patient Health Questionnaire; PHQ-9), and anxiety symptoms (measured by the Generalised Anxiety Disorder 7-item; GAD-7). Secondary outcomes include OCD-related beliefs, experiential avoidance, resilience, quality of life, uncertainty intolerance, automatic thoughts, and distress. Outcome measures will be collected at baseline, at completion of the intervention, and one year later (follow-up). At follow-up, we will also analyze the OCD diagnostic incidence, using the Structured Clinical Interview for DSM-5. We will employ a multivariate analysis of variance (MANOVA) to explore whether significant differences exist between groups across dependent variables. To compare the OCD incidence levels from the pre-test to the follow-up we will use the chi-squared test.DiscusionThe present study may contribute novel data on the efficacy of OCD prevention approaches, leading to the development of an evidence-based OCD prevention program that could alleviate individual and societal burdens associated with OCD.Trial registrationThis trial was approved by the University Ethical Review Authority (937/ 28.11.2023) at Babeș-Bolyai University and is registered on clinicaltrials.gov (ID: NCT06262464).

Transient response to high‐dose niacin therapy in a patient with NAXE deficiency

AbstractBackgroundNAXE‐encephalopathy or early‐onset progressive encephalopathy with brain edema and/or leukoencephalopathy‐1 (PEBEL‐1) and NAXD‐encephalopathy (PEBEL‐2) have been described recently as mitochondrial disorders causing psychomotor regression, hypotonia, ataxia, quadriparesis, ophthalmoparesis, respiratory insufficiency, encephalopathy, and seizures with the onset being usually within the first three years of life. It usually leads to rapid disease progression and death in early childhood. Anecdotal reports suggest that niacin, through its role in nicotinamide adenine dinucleotinde (NAD) de novo synthesis, corrects biochemical derangement, and slows down disease progression. Reports so far have supported this observation.MethodsWe describe a patient with a confirmed PEBEL‐1 diagnosis and report his clinical response to niacin therapy. Moreover, we systematically searched the literature for PEBEL‐1 and PEBEL‐2 patients treated with niacin and details about response to treatment and clinical data were reviewed. Furthermore, we are describing off‐label use of a COX2 inhibitor to treat niacin‐related urticaria in NAXE‐encephalopathy.ResultsSo far, seven patients with PEBEL‐1 and PEBEL‐2 treated with niacin were reported, and all patients showed a good response for therapy or stabilization of symptoms. We report a patient exhibiting PEBEL‐1 with an unfavorable outcome despite showing initial stabilization and receiving the highest dose of niacin reported to date. Niacin therapy failed to halt disease progression or attain stabilization of the disease in this patient.ConclusionDespite previous positive results for niacin supplementation in patients with PEBEL‐1 and PEBEL‐2, this is the first report of a patient with PEBEL‐1 who deteriorated to fatal outcome despite being started on the highest dose of niacin therapy reported to date.

Plasma proteome profiling reveals dynamic of cholesterol marker after dual blocker therapy

Dual blocker therapy (DBT) has the enhanced antitumor benefits than the monotherapy. Yet, few effective biomarkers are developed to monitor the therapy response. Herein, we investigate the DBT longitudinal plasma proteome profiling including 113 longitudinal samples from 22 patients who received anti-PD1 and anti-CTLA4 DBT therapy. The results show the immune response and cholesterol metabolism are upregulated after the first DBT cycle. Notably, the cholesterol metabolism is activated in the disease non-progressive group (DNP) during the therapy. Correspondingly, the clinical indicator prealbumin (PA), free triiodothyronine (FT3) and triiodothyronine (T3) show significantly positive association with the cholesterol metabolism. Furthermore, by integrating proteome and radiology approach, we observe the high-density lipoprotein partial remodeling are activated in DNP group and identify a candidate biomarker APOC3 that can reflect DBT response. Above, we establish a machine learning model to predict the DBT response and the model performance is validated by an independent cohort with balanced accuracy is 0.96. Thus, the plasma proteome profiling strategy evaluates the alteration of cholesterol metabolism and identifies a panel of biomarkers in DBT.

Skin-directed therapy and biologic response modifiers in mycosis fungoides

The most common and widespread type of cutaneous T-cell lymphoma is mycosis fungoides (MF), and it has a multiphasic clinical and biological course, with early stages being indolent for many years and later stages being faster and more aggressive. The clinical stage has a significant impact on the management and course of treatment: in the early stages, skin-directed therapies (SDT) plus/or biologic response modifiers (BRM); in the later stages, radiotherapy and/or systemic therapies. Even though national and international societies and groups periodically update their clinical recommendations, there is still no universally accepted approach. This paper reviews and discusses the various SDT and BRM options, either separately or in combination.

Construction of exosome-related genes risk model in kidney cell carcinoma predicts prognosis and immune therapy response.

Renal cell carcinoma (RCC) is one of the most prevalent types of urological cancer. Exosomes are vesicles derived from cells and have been found to promote the development of RCC, but the potential biomarker and molecular mechanism of exosomes on RCC remain ambiguous. Here, we first screened differentially expressed exosome-related genes (ERGs) by analyzing The Cancer Genome Atlas (TCGA) database and exoRBase 2.0 database. We then determined prognosis-related ERGs (PRERGs) by univariate Cox regression analysis. Gene Dependency Score (gDS), target development level, and pathway correlation analysis were utilized to examine the importance of PRERGs. Machine learning and lasso-cox regression were utilized to screen and construct a 5-gene risk model. The risk model showed high predictive accuracy for the prognosis of patients and proved to be an independent prognostic factor in three RCC datasets, including TCGA-KIRC, E-MTAB-1980, and TCGA-KIRP datasets. Patients with high-risk scores showed worse outcomes in different clinical subgroups, revealing that the risk score is robust. In addition, we found that immune-related pathways are highly enriched in the high-risk group. Activities of immune cells were distinct in high-/low-risk groups. In independent immune therapeutic cohorts, high-risk patients show worse immune therapy responses. In summary, we identified several exosome-derived genes that might play essential roles in RCC and constructed a 5-gene risk signature to predict the prognosis of RCC and immune therapy response.

Diagnostic value of 18F-FDG PET/CT versus diffusion-weighted MRI in detection of residual or recurrent tumors after definitive (chemo) radiotherapy for laryngeal and hypopharyngeal squamous cell carcinoma: A prospective study.

Despite advances in treatment, residual or recurrent tumors after definitive (chemo) radiotherapy for laryngeal and hypopharyngeal squamous cell carcinoma (SCC) remain a challenge in clinical management and require accurate and timely detection for optimal salvage therapy. This study aimed to compare the diagnostic value of Fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) in detecting residual or recurrent tumors after definitive (chemo) radiotherapy for laryngeal and hypopharyngeal SCC. A prospective study was conducted on 30 patients who presented with new symptoms after definitive (chemo) radiotherapy for laryngeal (n = 21) and hypopharyngeal (n = 9) carcinoma. Both 18F-FDG PET/CT and DW-MRI were performed and histopathologic analysis served as the standard of reference. Histopathology showed 20 patients as positive and 10 as negative for tumors. 18F-FDG PET/CT detected all tumors correctly but was falsely positive in one case. DW-MRI detected tumors in 18 out of 20 positive patients and correctly excluded tumors in all negative patients. The sensitivity and specificity of 18F-FDG PET/CT were 100% and 90%, respectively, while the values for DW-MRI were 90% and 100%, respectively. The study concludes that 18F-FDG PET/CT is slightly superior to DW-MRI in detecting residual or recurrent tumors after definitive (chemo) radiotherapy for laryngeal and hypopharyngeal SCC. The combined use of 18F-FDG PET/CT and DW-MRI can potentially improve specificity in therapy response evaluation.

Prospects of liquid biopsy in the prognosis and clinical management of gastrointestinal cancers

Gastrointestinal (GI) cancers account for one-fourth of the global cancer incidence and are incriminated to cause one-third of cancer-related deaths. GI cancer includes esophageal, gastric, liver, pancreatic, and colorectal cancers, mostly diagnosed at advanced stages due to a lack of accurate markers for early stages. The invasiveness of diagnostic methods like colonoscopy for solid biopsy reduces patient compliance as it cannot be frequently used to screen patients. Therefore, minimally invasive approaches like liquid biopsy may be explored for screening and early identification of gastrointestinal cancers. Liquid biopsy involves the qualitative and quantitative determination of certain cancer-specific biomarkers in body fluids such as blood, serum, saliva, and urine to predict disease progression, therapeutic tolerance, toxicities, and recurrence by evaluating minimal residual disease and its correlation with other clinical features. In this review, we deliberate upon various tumor-specific cellular and molecular entities such as circulating tumor cells (CTCs), tumor-educated platelets (TEPs), circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), exosomes, and exosome-derived biomolecules and cite recent advances pertaining to their use in predicting disease progression, therapy response, or risk of relapse. We also discuss the technical challenges associated with translating liquid biopsy into clinical settings for various clinical applications in gastrointestinal cancers.

Laminin-associated integrins mediate Diffuse Intrinsic Pontine Glioma infiltration and therapy response within a neural assembloid model

Diffuse Intrinsic Pontine Glioma (DIPG) is a highly aggressive and fatal pediatric brain cancer. One pre-requisite for tumor cells to infiltrate is adhesion to extracellular matrix (ECM) components. However, it remains largely unknown which ECM proteins are critical in enabling DIPG adhesion and migration and which integrin receptors mediate these processes. Here, we identify laminin as a key ECM protein that supports robust DIPG cell adhesion and migration. To study DIPG infiltration, we developed a DIPG-neural assembloid model, which is composed of a DIPG spheroid fused to a human induced pluripotent stem cell-derived neural organoid. Using this assembloid model, we demonstrate that knockdown of laminin-associated integrins significantly impedes DIPG infiltration. Moreover, laminin-associated integrin knockdown improves DIPG response to radiation and HDAC inhibitor treatment within the DIPG-neural assembloids. These findings reveal the critical role of laminin-associated integrins in mediating DIPG progression and drug response. The results also provide evidence that disrupting integrin receptors may offer a novel therapeutic strategy to enhance DIPG treatment outcomes. Finally, these results establish DIPG-neural assembloid models as a powerful tool to study DIPG disease progression and enable drug discovery.

Metacognitive therapy versus exposure and response prevention for obsessive-compulsive disorder – A non-inferiority randomized controlled trial

ObjectiveExposure with response prevention (ERP) is the first-line treatment for obsessive-compulsive disorder (OCD). However, refusals, dropouts and the required high time and logistic effort constitute barriers to the use of ERP. In a non-inferiority randomized controlled trial, we compared metacognitive therapy (MCT) to exposure with response prevention (ERP) as treatments for OCD. Method74 outpatients received 12 weekly sessions of either manualized MCT or ERP, with primary outcomes assessed by blinded assessors using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at pre-treatment, mid-treatment, post-treatment, and 6-month follow-up. Secondary outcomes included measures of depression and anxiety. Non-inferiority margin was specified at no less than d = 0.38 below the improvement reached by ERP, corresponding to a difference of about 3 points on the Y-BOCS. ResultsDrop-out rates were low (<14%) and similar in both groups. Linear models indicated non-inferiority of MCT to ERP at post-treatment, but not at 6-month follow-up. While both groups showed comparable Y-BOCS improvements, the MCT group demonstrated a significantly greater reduction in state anxiety scores at post-treatment and follow-up. ConclusionsOverall, MCT was not inferior to ERP, especially at post-treatment, suggesting it could be a treatment alternative. However, further research is needed to explore differential treatment indications.

Assessment of Hypoxia in Breast Cancer: Emerging Functional MR Imaging and Spectroscopy Techniques and Clinical Applications.

Breast cancer is one of the most prevalent forms of cancer affecting women worldwide. Hypoxia, a condition characterized by insufficient oxygen supply in tumor tissues, is closely associated with tumor aggressiveness, resistance to therapy, and poor clinical outcomes. Accurate assessment of tumor hypoxia can guide treatment decisions, predict therapy response, and contribute to the development of targeted therapeutic interventions. Over the years, functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) techniques have emerged as promising noninvasive imaging options for evaluating hypoxia in cancer. Such techniques include blood oxygen level-dependent (BOLD) MRI, oxygen-enhanced MRI (OE) MRI, chemical exchange saturation transfer (CEST) MRI, and proton MRS (1H-MRS). These may help overcome the limitations of the routinely used dynamic contrast-enhanced (DCE) MRI and diffusion-weighted imaging (DWI) techniques, contributing to better diagnosis and understanding of the biological features of breast cancer. This review aims to provide a comprehensive overview of the emerging functional MRI and MRS techniques for assessing hypoxia in breast cancer, along with their evolving clinical applications. The integration of these techniques in clinical practice holds promising implications for breast cancer management. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 1.

Multi-omic profiling reveals potential biomarkers of hepatocellular carcinoma prognosis and therapy response among mitochondria-associated cell death genes in the context of 3P medicine

Multi-omic profiling reveals potential biomarkers of hepatocellular carcinoma prognosis and therapy response among mitochondria-associated cell death genes in the context of 3P medicine

Abstract PO2-13-06: Analysis of Antibody Response to SV-BR-1-GM Therapeutic Vaccine in Breast Cancer Patients Using Human Protein Microarrays: Potential Correlations with Therapy Response

Abstract Background: Therapeutic cancer vaccines aim to stimulate the immune system by utilizing tumor antigens to trigger an antitumor response. In our clinical trials, we have focused on evaluating the efficacy of the breast cancer cell line secreting GM-CSF, SV-BR-1-GM as a therapeutic vaccine, and we have observed encouraging clinical outcomes. The SV-BR-1-GM regimen has been used alone (“monotherapy”, ClinicalTrials.gov NCT03066947 – study completed) and in combination with checkpoint inhibitors (“combination”, ClinicalTrials.gov NCT03328026 – study ongoing). To further improve the therapeutic efficacy of this vaccine we have initiated a study to characterize patient’s immune response to this treatment. It has been demonstrated that cancer vaccines can generate both humoral and cellular immune responses. However, predicting immune responses to cancer vaccines, especially when whole cells are employed as immunogens, presents significant challenges. We present here a preliminary analysis of the antibody response to SV-BR-1-GM in breast cancer patients using antigen arrays. Methods: Large-scale protein arrays are versatile and sensitive platforms for antibody specificity evaluation. The HuProt™ Human Proteome Microarray (CDI Laboratories, Inc., Baltimore, Maryland, United States) provides the largest number of unique, full-length, individually purified human proteins on a single microscope slide. This allows thousands of interactions to be profiled in a high-throughput manner. We utilized here an unbiased human protein microarray platform encompassing &amp;gt;21,000 proteins and isoforms from ~19,000 unique genes to identify IgG and IgM responses against self-antigens elicited by treatment. Serum samples from SV-BR-GM-treated patients were analyzed, comparing pre- and post-treatment. The human serum samples were probed at 1:1000 dilution. After sample processing and data collection the raw signal intensities on all arrays were quantile normalized using CDI software. Heatmaps were generated using MetaboAnalyst 5.0, which utilizes the R pheatmap package (version 0.7.7). For paired analysis, fold changes (FCs) were calculated by determining the ratio between paired pre- and post-treatment samples, resulting in one FC per pair. The means of these FCs (pair means) were then computed. ANOVA tests were performed using the RStatix R package, which automatically determines the appropriate Type I, II, or III errors for the analysis. Results: By using this approach, we were able to evaluate a broader range of antigens compared to previous investigations. Using a variety of statistical approaches, potential correlations with patient survival on SV-BR-1-GM were evaluated. Antibody responses to galectin antigens demonstrated the most consistent relationships with survival. Further confirmation with additional patients and prospective analysis are needed to fully understand relationships with clinical benefit and survival. Citation Format: Miguel Lopez-Lago, Mingjin Chang, Giuseppe Del Priore, Vikas Bhardwaj, Patience Cournoo, Pedro Ramos, Tyler Hulett, Charles Wiseman, William Williams. Analysis of Antibody Response to SV-BR-1-GM Therapeutic Vaccine in Breast Cancer Patients Using Human Protein Microarrays: Potential Correlations with Therapy Response [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-13-06.

Abstract PO3-14-05: Integration of metabolomics and transcriptomics to Reveal Potential Biomarkers Associated with Treatment Response of Neoadjuvant Therapy in HER2+ Breast Cancer

Abstract Background: Neoadjuvant therapy (NAT) has become the standard treatment for early human epidermal growth factor receptor 2 positive (HER2+) breast cancer. For patients with HER2+ breast cancer, achieving a pathologic complete response (pCR) is highly indicative of their prognosis. However, not all HER2+ breast cancer patients could benefit from the NAT, about 40%-50% patients could not achieve pCR at surgery, even if they used the present standard neoadjuvant regime of TCbHP (taxane, carboplatin, trastuzumab and pertuzumab). This study was conducted to explore potential indicators associated with neoadjuvant efficacy of TCbHP in HER2+ breast cancer. Methods: Consecutive HER2+ breast cancer patients, who received and completed NAT with TCbHP regime and subsequent surgery at Chongqing University Cancer Hospital were prospectively enrolled. LC-MS and GC-MS platform-based untargeted metabolomics were performed to determine the metabolic profiles of plasma samples from these patients at different time points during treatment period. Random forest (RF) was used to establish predictive models based on pre-therapeutic metabolic traits. The potential monitors for the treatment response were obtained by time series analysis. Transcriptome analysis was performed in available samples to identify differentially expressed genes (DEGs) before treatment. qRT-pCR was used to detect DEGs in tastuzumab-sensitive and -resistant cell lines. Metabolic and transcriptomic data were integrated to explore substantially altered pathways that might be responsible for drug resistance. Results: From July 20, 2020 to May 28, 2021, a total of 40 HER2+ breast cancer patients with 120 plasma samples were eligible and recruited for this study. Of whom 21 (52.5%) patients achieved pCR and 19 (47.5%) achieved non-pCR, there are no significant difference in baseline clinicopathological features between pCR and non-pCR patients. There were significant differences in plasma metabolic profiles between non-pCR and pCR groups before and during treatment. A total of 100 differential metabolites were identified between pCR and non-pCR patients at pre-therapeutic period, which were markedly enriched in 40 metabolic pathways. Four key metabolites [sophorose, N-(2-acetamido)iminodiacetic acid, taurine and 6-hydroxy-2-aminohexanoic acid] were selected by RF analysis. The AUC value to discriminate pCR and non-PCR group to NAT of the single potential metabolite or combined panel of these metabolites were more than 0.910. 18 metabolites exhibit a potential for monitoring efficacy. Among 163 DEGs identified by RNA-seq, some genes might associate with trastuzumab resistance detected by qRT-PCR in cell lines. 39 altered pathways were found abnormally expressed at both the transcriptional and metabolic levels, including ABC transporters, protein digestion and absorption, mineral absorption, et al. Conclusion: By metabolomics analysis, we have both offered a road map of the molecular alterations underlying NAT of TCbHP regime in HER2+ breast cancer and a preliminary analysis of a unique metabolic signature that might be used to distinguish non-pCR from pCR patients. Metabolomics integrated with transcriptomics analysis could assist for gaining new insights into biochemical pathophysiology and might facilitate the development of new treatment targets for insensitive patients. Citation Format: Ningning Zhang, Yuxin Huang, Guanwen Wang, Yimei Xiang, Zhouhong Jing, Junjie Zeng, Feng Yu, Xianjun Pan, Wenqi Zhou, Xiaohua Zeng. Integration of metabolomics and transcriptomics to Reveal Potential Biomarkers Associated with Treatment Response of Neoadjuvant Therapy in HER2+ Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-14-05.

Abstract LBO1-02: Pathologic complete response (pCR) of neoadjuvant therapy with or without atezolizumab in HER2-positive, early high-risk and locally advanced breast cancer: APTneo Michelangelo randomized trial

Abstract Background: Neoadjuvant dual targeting of HER2 with trastuzumab (H) and pertuzumab (P) plus chemotherapy is the standard of care for high-risk HER2-positive (HER2+) breast cancer (BC). Compelling data show the contribution of the immune system in prognosis and response/resistance to HER2 directed therapies, supporting combination of immune checkpoint inhibitors with anti HER2 antibodies. We designed APTneo to test the role of adding atezolizumab to neoadjuvant dual targeting of HER2 with chemotherapy, and the value of also using anthracyclines in this setting. Methods: In this multicenter open label phase III trial (NCT03595592), 661 patients (pts) with high-risk early and locally advanced (LA) centrally confirmed HER2+ BC were randomized to neoadjuvant HPCT (H and P d1, carboplatin and paclitaxel iv d1 and 8) given q3 wks for 6 cycles w/o (n=223, ARM A) or with atezolizumab 1200 mg iv d1 (n=438, ARM B). In Arm B pts were randomized to Arm B1 (n=218) to receive anthracycline and cyclophosphamide (AC) + atezolizumab iv d1 q3 wks for 3 cycles followed by HPCT + atezolizumab for 3 cycles, or to arm B2 (n=220) to receive HPCT + atezolizumab for 6 cycles. After surgery pts continued adjuvant HER2 directed therapies w/wo atezolizumab until completion of 1 year. Among intent-to-treat (ITT) pts, 44.8% were LABC, 35% hormonal receptor (HR) negative and 30.4% PD-L1 positive. Primary endpoint is event-free survival (EFS) of Arm B vs A. A key secondary endpoint is the rate of pCR (ypT0/Tis, ypN0) w/wo atezolizumab. Primary population for all efficacy endpoints is ITT. We also assessed baseline PD-L1 status (Ventana SP142) and stromal Tumor Infiltrating Lymphocytes (sTILs). Results: pCR rate in Arm B (57.8%) vs Arm A (52.0%) was not significantly increased (adjHR 1.33, 95% CI 0.95-1.86; p=0.091). Also, the difference in pCR rate in Arm B1 (61.9%) vs Arm B2 (53.6%) was not significant (adjHR 1.402, 95% CI 0.95-2.07; p=0.089). Compared to Arm A, Arm B1 had a 9.9% significantly higher pCR rate (multivariate analysis in Table). The different pCR rate in arms B1 and A was similar regardless of HR and PD-L1 status. High sTILs (≥30%) and PD-L1positive tumors had a higher likelihood of pCR in all arms. Serious adverse events (SAE) after start of therapy occurred in 6.8% pts in Arm A and 14.1% in Arm B (p=0.0064). SAE were numerically more frequent in Arm B1 than Arm B2 (16.7% and 11.6%, respectively), due to hematological toxicity with AC. Immune-related SAE were quite infrequent and similar in B1 (4.7%) and B2 (7.8%), respectively. No grade 5 AE did occur. Conclusions: Addition of atezolizumab to chemotherapy and HP did not significantly increase the rate of pCR in women with HER2+ BC. An exploratory analysis showed that adding atezolizumab to neoadjuvant AC followed by HPCT led to higher pCR rate compared to HPCT and atezolizumab. This could be because of anthracyclines themselves or to drug-drug enhancement of anthracyclines and immune modulation. Atezolizumab did not cause major tolerability issues. Molecular studies of collected biospecimens are ongoing. Patients will continue to be followed up for EFS and overall survival analyses. Table. Supported in part by unrestricted grant from Hoffman-La Roche, Ltd, Switzerland Citation Format: Luca Gianni, Elisabetta Munzone, Mauro Mansutti, Giampaolo Bianchini, Yann Izarzuzaga, Elena Rota Caremoli, Luc Dirix, Lucia Del Mastro, Santiago González-Santiago, Andreas Schneeweiss, Jose Ponce, Chiun-Shen Huang, Pauline Wimberger, Sevilay Altintas, Miguel Martín, Nicoleta Antone, Christian F. Singer, Ugo De Giorgi, Ana Godoy Ortiz, Hans-Joachim Lueck, Riccardo Spezia, Angelica Fasolo, Giuseppe Viale, Pinuccia Valagussa. Pathologic complete response (pCR) of neoadjuvant therapy with or without atezolizumab in HER2-positive, early high-risk and locally advanced breast cancer: APTneo Michelangelo randomized trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr LBO1-02.