Large Cohort Of Patients Research Articles

Pharmacogenetics of tenofovir drug transporters in the context of HBV: Is there an impact?

BackgroundCurrent treatments for chronic hepatitis B management include orally administered nucleos(t)ide analogues, such as tenofovir (TDF), which is an acyclic adenine nucleotide analogue used both in HBV and human immune deficiency virus (HIV). The course of HBV infection is mainly dependent on viral factors, such as HBV genotypes, immunological features and host genetic variables, but a few data are available in the context of HBV, in particular for polymorphisms of genes encoding proteins involved in drug metabolism and elimination.Consequently, the aim of this study was to evaluate the potential impact of genetic variants on TDF plasma and urine concentrations in patients with HBV, considering the role of HBV genotypes. MethodsA retrospective cohort study at the Infectious Disease Unit of Amedeo di Savoia Hospital, Torino, Italy, was performed. Pharmacokinetic analyses were performed through liquidi chromatography, whereas pharmacogenetic analyses through real-time PCR. FindingsSixty - eight patients were analyzed: ABCC4 4976 C>T genetic variant showed an impact on urine TDF drug concentrations (p = 0.014). In addition, SLC22A6 453 AA was retained in the final regression multivariate model considering factors predicting plasma concentrations, while ABCC4 4976 TC/CC was the only predictor of urine concentrations in the univariate model. InterpretationIn conclusion, this is the first study showing a potential impact of genetic variants on TDF plasma and urine concentrations in the HBV context, but further studies in different and larger cohorts of patients are required.

Cannabinoid levels description in a cohort of patients with chronic and neuropathic pain treated with Cannabis decoction: A possible role of TDM

The phytocomplex of Cannabis is made up of approximately 500 substances: terpeno-phenols metabolites, including Δ-9-tetrahydrocannabinol and cannabidiol, exhibit pharmacological activity.Medical Cannabis has several pharmacological potential applications, in particular in the management of chronic and neuropathic pain. In the literature, a few data are available concerning cannabis pharmacokinetics, efficacy and safety.Thus, aim of the present study was the evaluation of cannabinoid pharmacokinetics in a cohort of patients, with chronic and neuropathic pain, treated with inhaled medical cannabis and decoction, as a galenic preparation.In this study, 67 patients were enrolled. Dried flower tops with different THC and CBD concentrations were used: Bedrocan® medical cannabis with THC level standardized at 19% and with a CBD level below 1%, Bediol® medical cannabis with THC and CBD level standardized at similar concentration of 6.5% and 8%, respectively.Cannabis was administered as a decoction in 47 patients and inhaled in 11 patients. The blood withdrawn was obtained before the new dose administration at the steady state and metabolites plasma concentrations were measured with an UHPLC-MS/MS method.Statistically significant differences were found in cannabinoids plasma exposure between inhaled and oral administration of medical cannabis, between male and female and cigarette smokers.For the first time, differences in cannabinoid metabolites exposures between different galenic formulations were suggested in patients. Therapeutic drug monitoring could be useful to allow for dose adjustment, but further studies in larger cohorts of patients are required in order to confirm these data.

Persistent intracranial steno-occlusion from calcified embolism: a treatment challenge.

Calcified arterial cerebral embolism is a rare occurrence among large and medium vessel occlusions causing ischemic stroke and its diagnosis and treatment is a challenge. The sources of calcified embolism might be a calcific atheroma from the aortic arch and carotid artery, but also heart valve disease has been reported in the literature. Calcified embolism is frequently simultaneous on multiple vascular territories. The prognosis of patients is usually poor, including patients treated by using endovascular thrombectomy (EVT) and this diagnosis could be easily missed in the acute phase. In addition, the optimal secondary prevention has not been yet fully stated. We are presenting two cases of acute stroke due to calcified embolism in the middle cerebral artery (MCA) coming from a complicated carotid atheroma, non-stenosing in the first case (a 49years old man) and stenosing in the second case (a 71years old man) without clinical indications to intravenous thrombolysis and/or EVT, extensively investigated in the acute phase and followed-up for over 12months with a favorable clinical course and the persisting steno-occlusion in the involved MCA. In both cases, antiplatelet treatment and targeting of vascular risk factors were done without recurrences in the follow-up period. Cerebral calcified embolism has been reported in 5.9% of cases of acute ischemic stroke in a single center series and only in 1.2% of a large retrospective cohort of EVT-treated patients. In both series the prognosis was poor and only one third of EVT-treated patients had functional independence at 3-months follow-up. The natural history of these subtype of ischemic stroke is relatively poorly understood and both etiological diagnosis and treatment have not yet defined. It is possible that some cases might be underdiagnosed and underreported. Calcified cerebral embolism is a rare cause of stroke, but it is largely underreported and both acute phase and secondary preventive treatment have to be defined.

Clinical validation of C12FDG as a marker associated with senescence and osteoarthritic phenotypes.

Chronic conditions associated with aging have proven difficult to prevent or treat. Senescence is a cell fate defined by loss of proliferative capacity and the development of a pro-inflammatory senescence-associated secretory phenotype comprised of cytokines/chemokines, proteases, and other factors that promotes age-related diseases. Specifically, an increase in senescent peripheral blood mononuclear cells (PBMCs), including T cells, is associated with conditions like frailty, rheumatoid arthritis, and bone loss. However, it is unknown if the percentage of senescent PBMCs associated with age-associated orthopedic decline could be used for potential diagnostic or prognostic use in orthopedics. Here, we report senescent cell detection using the fluorescent compound C12FDG to quantify PBMCs senescence across a large cohort of healthy and osteoarthritic patients. There is an increase in the percent of circulating C12FDG+ PBMCs that is commensurate with increases in age and senescence-related serum biomarkers. Interestingly, C12FDG+ PBMCs and T cells also were found to be elevated in patients with mild to moderate osteoarthritis, a progressive joint disease that is strongly associated with inflammation. The percent of C12FDG+ PBMCs and age-related serum biomarkers were decreased in a small subgroup of study participants taking the senolytic drug fisetin. These results demonstrate quantifiable measurements in a large group of participants that could create a composite score of healthy aging sensitive enough to detect changes following senolytic therapy and may predict age-related orthopedic decline. Detection of peripheral senescence in PBMCs and subsets using C12FDG may be clinically useful for quantifying cellular senescence and determining how and if it plays a pathological role in osteoarthritic progression.

Developmental uterovaginal anomalies and histologic findings in transgender patients receiving gender-affirming hysterectomies: A large case series.

To describe the incidence of uterovaginal anomalies and histologic findings in transgender and nonbinary (TGNB) patients seeking hysterectomies. All patients receiving gender-affirming hysterectomies between 2013 and 2023 were retrospectively reviewed. Primary outcomes included uterovaginal anomalies and histological findings. Multivariable logistic regressions were performed to evaluate relationships between variables of interest and whether they predict findings of uterovaginal anomalies, inactive endometrium, adenomyosis, leiomyoma, endometriosis, and cervical atrophy. 278 patients received hysterectomies at an average age of 29.2 ± 8.3 years. Seven patients (2.5%) were found to have a developmental anomaly, including two bicornuate uterus (0.7%), two unicornuate uterus (0.7%), one septate uterus (0.4%), and two vaginal septum (0.7%). 60 patients (21.6%) were found to have inactive endometrium and 26 patients (9.4%) had cervical atrophy. Although 262 patients (94.2%) were on testosterone therapy, hormone duration was not a significant predictor of any uterine findings. This study describes uterovaginal anomalies in a large cohort of patients receiving gender-affirming hysterectomies. Although long-term testosterone use is commonly believed to be associated with endometrial and cervical atrophy, this study shows no such association.

Clinical and genetic characterization of a large cohort of patients with premature ovarian failure

Clinical and genetic characterization of a large cohort of patients with premature ovarian failure

Evaluation of miR-148a-3p and miR-106a-5p as Biomarkers for Prostate Cancer: Pilot Study.

MicroRNAs (miRNAs) are a class of small non-coding RNAs that may function as tumor suppressors or oncogenes. Alteration of their expression levels has been linked to a range of human malignancies, including cancer. The objective of this investigation is to assess the relative expression levels of certain miRNAs to distinguish between prostate cancer (PCa) from benign prostatic hyperplasia (BPH). Blood plasma was collected from 66 patients diagnosed with BPH and 58 patients with PCa. Real-time PCR technology was used to evaluate the relative expression among the two groups for miR-106a-5p and miR-148a-3p. The significant downregulation of both miRNAs in plasma from PCa versus BPH patients suggests their potential utility as diagnostic biomarkers for distinguishing between these conditions. The concurrent utilization of these two miRNAs slightly enhanced the sensitivity for discrimination among the two analyzed groups, as shown in ROC curve analysis. Further validation of these miRNAs in larger patient cohorts and across different stages of PCa may strengthen their candidacy as clinically relevant biomarkers for diagnosis and prognosis.

Mesenteric Ischemia after Cardiac Surgery.

Mesenteric ischemia (Me-Is) after cardiac surgery is underreported in present literature but has still earned the bad reputation of a dismal prognosis. This study adds clinical outcomes in a large patient cohort. Between 2009 and 2019 of the 22,590 patients undergoing cardiac surgery at our facility 106 (0.47%) developed Me-Is postoperatively. Retrospective patient data was analyzed. Additionally, patients were stratified by outcome-survivors and nonsurvivors. Patients were predominantly male (n = 68, 64.2%), mean age was 71.2 ± 9.3 years. Most procedures were elective (n = 85, 80.2%) and comprised of more complex combined procedures (50.9%) and redos (17.9%). Mean EuroSCORE II averaged 10.9 ± 12.2%. Survival at 30 days was 49.1% (n = 52). Clinical baseline and procedural characteristics did not differ significantly between survivors and nonsurvivors. The median postoperative interval until symptom onset was 5 days in both groups. Survivors were more frequently diagnosed by computed tomography and nonsurvivors based on clinical symptoms. Me-Is was predominantly nonocclusive (n = 84, 79.2%). Laparotomy was the main treatment in both groups (n = 45, 78.8% vs. n = 48, 88.9%, p = 0.94). Predictors of mortality were maximum norepinephrine doses (hazard ratio [HR] 8.29, confidence interval [CI] 3.39-20.26, p < 0.0001), lactate levels (HR 1.06, CI 1.03-1.09), and usage of inotropes (HR 2.46, CI 1.41-4.30). The prognosis of Me-Is following cardiac surgery is poor-independently from diagnostic or treatment patterns. There exists a significant asymptomatic time period postoperatively, in which pathophysiologic processes seem to cross the Rubicon. After clinical demarcation, the further course can almost no longer be influenced.

Electrocardiographic abnormalities in patients with microtia

The main objective of this study was to investigate the incidence and characteristics of electrocardiographic abnormalities in patients with microtia, and to explore cardiac maldevelopment associated with microtia. This retrospective study analyzed a large cohort of microtia patients admitted to Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, from September 2017 to August 2022. The routine electrocardiographic reports of these patients were reviewed to assess the incidence and characteristics of abnormalities. The study included a total of 10,151 patients (5598 in the microtia group and 4553 in the control group) who were admitted to the Plastic Surgery Hospital of Peking Union Medical College. The microtia group had a significantly higher incidence of abnormal electrocardiographies compared to the control group (18.3% vs. 13.6%, P < 0.01), even when excluding sinus irregularity (6.1% vs. 4.4%, P < 0.01). Among the 1025 cases of abnormal electrocardiographies in the microtia group, 686 cases were reported with simple sinus irregularity. After excluding sinus irregularity as abnormal, the most prevalent abnormalities was right bundle branch block (37.5%), followed by sinus bradycardia (17.4%), ST-T wave abnormalities (13.3%), atrial rhythm (9.1%), sinus tachycardia (8.3%), and ventricular high voltage (4.7%). Less common ECG abnormalities included atrial tachycardia (2.1%), ventricular premature contraction (2.4%), and ectopic atrial rhythm (1.8%). atrioventricular block and junctional rhythm were present in 1.2% and 0.9% of the cases, respectively. Wolff Parkinson White syndrome and dextrocardia had a lower prevalence, at 0.6% and 0.9%, respectively. The occurrence of electrocardiographic abnormalities in microtia patients was found to be higher compared to the control group. These findings highlight the potential congenital defect in cardiac electrophysiology beyond the presence of congenital heart defect that coincide with microtia.

A Systematic Review and Meta-Analysis of microRNA Profiling Studies in Chronic Kidney Diseases.

Chronic kidney disease (CKD) represents an increasing health burden. Evidence suggests the importance of miRNA in diagnosing CKD, yet the reports are inconsistent. This study aimed to determine novel miRNA biomarkers and potential therapeutic targets from hypothesis-free miRNA profiling studies in human and murine CKDs. Comprehensive literature searches were conducted on five databases. Subgroup analyses of kidney diseases, sample types, disease stages, and species were conducted. A total of 38 human and 12 murine eligible studies were analyzed using Robust Rank Aggregation (RRA) and vote-counting analyses. Gene set enrichment analyses of miRNA signatures in each kidney disease were conducted using DIANA-miRPath v4.0 and MIENTURNET. As a result, top target genes, Gene Ontology terms, the interaction network between miRNA and target genes, and molecular pathways in each kidney disease were identified. According to vote-counting analysis, 145 miRNAs were dysregulated in human kidney diseases, and 32 were dysregulated in murine CKD models. By RRA, miR-26a-5p was significantly reduced in the kidney tissue of Lupus nephritis (LN), while miR-107 was decreased in LN patients' blood samples. In both species, epithelial-mesenchymal transition, Notch, mTOR signaling, apoptosis, G2/M checkpoint, and hypoxia were the most enriched pathways. These miRNA signatures and their target genes must be validated in large patient cohort studies.

Abstract PO1-14-10: Comprehensive clinicogenomic characterization of inflammatory breast cancer

Abstract BACKGROUND: Inflammatory breast cancer (IBC) is a rare type of breast cancer associated with a unique clinical presentation and overall poor outcomes, recognized as a distinct category by the AJCC staging system. The biological mechanisms driving the IBC phenotype are relatively undefined—partially due to a lack of comprehensive, large-scale genomic studies and limited clinical cohorts. Here, we report one of the largest, subtype-informed clinicogenomic characterizations of IBC to date. METHODS: A retrospective analysis of 2457 patients with metastatic breast cancer who underwent targeted tumor-only DNA-sequencing (OncoPanel, up to 447 cancer-associated genes) was performed at Dana-Farber Cancer Institute. Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV) and tumor mutational burden (TMB) comparisons were made between IBC and non-IBC cases. Median follow-up was 28.1 months. RESULTS: Our profiled cohort included 140 patients with IBC specimens (n = 68 primary tumors, 72 metastatic tumors) and 2317 patients with non-IBC specimens (n = 702 primaries, 65 local recurrences, 1550 metastases). Of these, 87.4% of patients were White, 4.7% Black, 3.6% Asian or Pacific Islander, and 4.3% other/unknown. Clinicopathologic differences between IBC and non-IBC cases were consistent with previous reports—including younger age at diagnosis of metastatic disease (51 vs 54 years, p = 0.04), and a higher proportion of grade 3, estrogen receptor-negative and HER2-positive tumors (p &amp;lt; 0.001). Among the hormone-receptor (HR)-positive subtype, IBC tumors showed a significant enrichment in Luminal B (LumB)-inferred disease (62.5% vs 39.8%, p &amp;lt; 0.005), defined as tumors with grade 3 or progesterone receptor staining &amp;lt; 10%. The most recurrent somatic alterations spanning all subtypes in IBC were TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%) and GATA3 (8%). A multivariate logistic regression analysis accounting for HR and HER2 status revealed a significant enrichment in TP53 SNVs in IBC vs non-IBC (OR 2.08 [95% CI 1.34-3.24], adjusted p-value 0.04). Frequency of TP53 alterations in IBC vs non-IBC cases was 85.1% vs 64.3% in HER2-positive and 50.0% vs 27.7% in HR-positive disease—with an enrichment of TP53 mutations in IBC LumB-inferred tumors vs non-LumB (64% vs 26%, p &amp;lt; 0.05). When comparing HR+ IBC LumB vs HR+ non-IBC LumB cases, TP53 mutations were again enriched (p &amp;lt; 0.05)—suggesting LumB-like histopathology is not the only driving feature of TP53 enrichment in HR+ IBC. TMB did not differ substantially between IBC and non-IBC and no other statistically significant enrichments were observed, including when grouping mutations into six canonical cancer pathways (cell cycle, Notch signaling, PI3K pathway, RTK/RAS signaling, TP53 pathway and WNT signaling). CONCLUSIONS: Taken together, this study provides a comprehensive landscape of somatic alterations in a large cohort of patients with metastatic IBC and non-IBC. Our data support a lack of major genomic differences other than enrichments in TP53 mutations and an associated LumB-like histopathology. These results both reinforce the importance of TP53 mutations in IBC biology and suggest additional analyses beyond somatic DNA-level changes are warranted. Future efforts with the DFCI IBC cohort will assess germline-somatic interactions, non-genomic or transcriptomic characterizations, and potential environmental influences to better understand the mechanisms driving this unique disease. Citation Format: Nolan Priedigkeit, Beth Harrison, Melissa Hughes, Robert Shue, Yvonne Li, Gregory Kirkner, Claire Remolano, Sarah Strauss, Janet Files, Anne-Marie Feeney, Ayesha Mohammed-Abreu, Ana Garrido-Castro, Romualdo Barroso-Sousa, Brittany Bychkovsky, Faina Nakhlis, Jennifer Bellon, Tari King, Bruce Johnson, Lynette Sholl, Deborah Dillon, Beth Overmoyer, Sara Tolaney, Andrew Cherniack, Nancy Lin, Filipa Lynce. Comprehensive clinicogenomic characterization of inflammatory 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 PO1-14-10.

Abstract PO2-09-12: The magnitude and temporal variations of socioeconomic inequalities in quality of life after early breast cancer: results from the multicentric French CANTO cohort

Abstract Objective Previous studies showed that various outcomes in patients with early breast cancer (EBC), from incidence to survival, were influenced by social factors. However, there is limited research on the socioeconomic inequalities in quality of life (QoL) after treatment for EBC, and the magnitude and changes over time of these inequalities have not been quantified. This study examines the socioeconomic inequalities in QoL and their time trends among a large cohort of patients with EBC. Methods We conducted a comprehensive longitudinal analysis using data from the prospective multicentric CANTO study (CANcer TOxicity, NCT01993498), which included participants with EBC enrolled between 2012 and 2018. QoL was assessed using the summary score of the EORTC QLQ-C30 questionnaire at the time of diagnosis and 1 and 2 years post-diagnosis. We included patients with complete QoL data at diagnosis and 2 years post-diagnosis. Analyses were conducted for three indicators of socioeconomic status separately: self-reported financial difficulties, household income and educational level. We first analyzed trajectories of QoL by socioeconomic status from diagnosis to Year 1 and Year 2. Then, social inequalities in QoL were estimated using the regression-based slope indexes of inequality (SII) and compared across the follow-up periods. The SII represents the absolute change in the QLQ-C30 summary score along the two extremes of the socioeconomic gradient, taking into account the intermediate groups and their relative sizes. The analyses were adjusted for age at diagnosis, Charlson comorbidity index, disease stage, use and type of endocrine therapy, use and type of chemotherapy, breast surgery, radiotherapy use, and lymph node management. Results In the 5915 analyzed patients, compared to those with higher socioeconomic status, those reporting a high level of financial difficulty, lower income, or lower education were younger, most often premenopausal, with comorbidities, diagnosed with stage III BC, and treated with mastectomy and axillary lymph node dissection. There were no differences between socioeconomically-defined groups concerning BC histology, grade and IHC-defined subtype. Social inequalities in QoL at baseline were statistically significant for all socioeconomic status indicators (SIIfinancial difficulties = -7.6 [-8.9;-6.2], SIIincome= -4.0 [-5.2;-2.8]) and SIIeducation= -1.9 [-3.1;-0.7]). In multivariable analyses, social inequalities significantly increased (interaction p&amp;lt; 0.05) in Year 1 (SIIfinancial difficulties = -11.1 [-12.8;-9.4], SIIincome= -6.5 [-8.0;-5.0] and SIIeducation= -5.0 [-6.6;-3.5]) and Year 2 (SIIfinancial difficulties = -10.7 [-12.2;-9.1], SIIincome= -6.7 [-8.0;-5.3] and SIIeducation= -4.7 [-6.1;-3.3]) suggesting a widening socioeconomic gap in QoL outcomes irrespective of pre-diagnosis health, tumor characteristics and treatment. Similar results were observed in subgroups defined by menopausal status (pre/postmenopausal) and type of systemic treatment (chemotherapy, endocrine therapy). Conclusion Our study highlights and quantifies the association of several individual socioeconomic indicators with the QoL of patients with EBC in France. The magnitude of socioeconomic inequalities in QoL increased over time after EBC diagnosis in a country with a strong welfare system and universal healthcare coverage. In the era of precision medicine, these results underscore the importance of developing interventions to improve precision care, considering the conditions in which people are born, grow, work, live and age and the wider set of forces and systems shaping the conditions of daily life. Citation Format: José Luis Sandoval, Antonio Di Meglio, Arlindo Ferreira, Maria Alice Franzoi, Fabrice André, Barbara Pistilli, Christelle Jouannaud, Marion Fournier, Philippe Rouanet, Asma Dhaini Mermeche, Paul Cottu, Sibille Everhard, Anne-Laure Martin, Silvia Stringhini, Idris Guessous, Ines Vaz Luis, Gwenn Menvielle. The magnitude and temporal variations of socioeconomic inequalities in quality of life after early breast cancer: results from the multicentric French CANTO cohort [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 PO2-09-12.

Abstract PS14-03: Delayed and post-treatment immune toxicities in patients with breast cancer receiving immune checkpoint inhibitors

Abstract Background: Immune checkpoint inhibitors (ICI) have improved outcomes in patients (pts) with breast cancer, however identification and management of immune-related adverse events (irAE) remains challenging. Delayed irAE have been observed, occurring even after ICI cessation. Prior analyses of delayed irAE have focused on patients with melanoma, lung, and head &amp; neck cancer but data in patients with breast cancer are lacking. Methods: We identified pts with breast cancer who received ICI at our institution between 2012 and 2022 using pharmacy administration records. Charts were reviewed for delayed and post-treatment irAE. Delayed irAE were defined as occurring &amp;gt;90 days after ICI start; post-treatment irAE were defined as occurring &amp;gt;60 days after ICI discontinuation. Events were categorized as irAE if provider notes indicated that the toxicity was related to or possibly related to ICI. Results: 320 consecutive pts with breast cancer (219 metastatic, 96 localized disease) underwent treatment with ICI, of which 79 (25%) developed delayed irAE (40 with metastatic disease, 39 with localized disease). 54 pts had triple negative breast cancer (TNBC), 22 had hormone receptor positive (HR+) disease, and 4 had HER2+ disease. 44 pts received ICI on a clinical trial. The median number of ICI doses was 8, and the median length of follow-up after the first ICI infusion with 29 months. For delayed iRAE, median time to onset was 183 days (range 91-1800 days) with a total of 103 delayed irAE events (see table). 24 pts (7.5%) developed a post-treatment irAE with a total of 27 events. For post-treatment irAE, median time to onset was 112 days after ICI cessation (range 69-1100 days) and median time on ICI was 63 days (range 22-1724 days). 11 of 24 patients who experienced a post-treatment irAE also experienced an irAE while on treatment. Hypothyroidism, colitis, adrenal insufficiency, and hepatitis were the most common irAE at all time points. Rash primarily occurred while still on ICI. All irAE at any time point either self-resolved, resolved with systemic steroids, or continued with indefinite hormone replacement. 45 irAE required systemic steroids, not including hydrocortisone replacement for adrenal insufficiency. There were no grade 4 or 5 irAEs. Conclusions: This is the first evaluation of delayed/post-treatment irAE in a large cohort of patients with breast cancer. 79 pts (25%) experienced delayed irAEs occurring ≥ 90 days after ICI start, with median time to onset of 183 days. 89% of patients with delayed irAE also experienced an irAE at an earlier time point, indicating that early irAE may be a risk for delayed irAE. 24 pts (7.5%) experienced post-treatment irAE with median onset of 121 days after ICI cessation. Diagnosis of delayed irAE requires heightened awareness and prompt treatment. Future work is needed to identify key clinical and molecular markers that predict risk for delayed irAE to better inform treatment &amp; monitoring. Table. Parameter Number of pts (%) Total pts receiving an ICI 320 Delayed irAE 79 (25) &amp;gt;1 delayed irAE 21 (27% of pts with delayed irAE) Patients with delayed irAEs who also had irAE occurring &amp;lt; 90 days after ICI start 70 (89% of pts with delayed irAE) Post-treatment irAE 24 (7.5) Types of delayed irAE (&amp;gt;90 days after ICI start) Any Grade Grade 3 Hypothyroidism 24 (23) 1 (1) Colitis/Diarrhea 19 (18) 3 (3) Rash 14 (14) 0 Adrenal Insufficiency/Hypophysitis 11 (11) 4 (4) Hepatitis 10 (10) 3 (3) Pneumonitis 4 (4) 1 (1) Arthralgia 4 (4) 0 Diabetes mellitus 3 (3) 0 Mucositis 2 (2) 1 (1) Neuropathy 2 (2) 0 Neutropenia 2 (2) 1 (1) Bronchitis 1 (1) 0 Fever 1 (1) 0 Neuromuscular Weakness 1 (1) 0 Autoimmune Hemolytic Anemia 1 (1) 1 (1) Myocarditis 1 (1) 1 (1) Acid Reflux 1 (1) 0 Sarcoidosis 1 (1) 0 Vitiligo 1 (1) 0 Types of post-treatment irAE (&amp;gt;60 days post ICI cessation) Any Grade Grade 3 Hypothyroidism 7 (26) 2 (7) Colitis 7 (26) 3 11) Adrenal Insufficiency/Hypophysitis 6 (22) 1 (4) Hepatitis 4 (15) 3 (11) Arthralgia 1 (4) 0 Neuropathy 1 (4) 0 Neutropenia 1 (4) 1 (4) Rash 1 (4) 0 Citation Format: Saya Jacob, Samantha Fisch, Carolyn Face, Laura Huppert, Zoe Quandt, Laura Quintal, Michelle Melisko, Melanie Majure, Jo Chien, Anne Blaes, Hope Rugo. Delayed and post-treatment immune toxicities in patients with breast cancer receiving immune checkpoint inhibitors [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 PS14-03.

Abstract PS06-08: Longitudinal Neoadjuvant and Post-operative Evaluation of Circulating Tumor DNA in Early Breast Cancer using a Tumor-Informed Assay: Updated Analysis of the TRACER Cohort

Abstract Background: ctDNA is detectable in early breast cancer (EBC) using sensitive assays and treatment-related changes in ctDNA are associated with clinical response. RaDaR® (NeoGenomics), a tumor-informed assay, has been shown to detect circulating tumor DNA (ctDNA) prior to clinical recurrence. We retrospectively quantified ctDNA using RaDaR in serial samples from a large cohort of patients with EBC receiving standard neoadjuvant therapy (NAT). Methods: Unselected patients with EBC were enrolled prior to NAT in the TRACER cohort from 2015 onwards. Plasma samples were collected at baseline, during treatment, perioperatively, and in follow-up. For patients with available tissue for assay generation, RaDaR was performed on all available plasma timepoints. Clinical and pathologic characteristics (assessed on core biopsy), treatment, and outcomes were recorded. Results: Of 128 patients evaluated, 9 (7.0%) were excluded from this analysis due to panel quality control metrics, leaving 119 patients (41 ER+, 32 TNBC, 46 HER2+) with 681 individual timepoints (median=6, range: 1-12). 103/119 patients (86%) received neoadjuvant anthracycline- and taxane-based chemotherapy. Median followup from diagnosis was 3.8 years (range: 0.6-6.3 years) and 16 recurrences have occurred (9 ER+, 6 TN, 1 HER2+). 114 patients had a baseline plasma sample collected prior to NAT, in which the detection rate was 77% (70% ER+, 90% TNBC, 76% HER2+), with a median estimated variant allele frequency (eVAF) of 0.0823% (range: 2.90E-5 - 7.5%). All patients with clinical recurrence had ctDNA detected at baseline. Baseline detection was associated with tumor grade (p=0.050) but not size (p=0.65) or clinical nodal status (p=0.36). There were non-significant associations between eVAF and grade (p=0.097) and eVAF and tumor size (p=0.086). Persistent ctDNA detection midway through neoadjuvant therapy (pre-cycle 5) was associated with an increased risk of recurrence in patients with ER+ (HR: 10.27, 95%CI: 1.61-65.4; p=0.014) and TNBC (HR: 20.17, 95%CI: 1.97-206.4; p=0.011). Residual cancer burden (RCB) status further stratified the risk of recurrence; those with RCB-2/3 disease and ctDNA detected pre-cycle 5 were at the highest risk. Few patients had detectable ctDNA in pre- or initial post-operative specimens, all of which had residual disease (non-pCR). 9/16 patients with clinical recurrence had evaluable post-operative and follow-up samples for lead time calculation; ctDNA was detected prior to recurrence in 7/9 (78 %), with a median lead time of 152 days (range: 13-699 days). Of the 2 patients without a positive test, one had an ipsilateral local recurrence (grade 2, 1.8 mm), the other had a negative, but borderline, test 72 days prior to recurrence (solitary 8 mm lung nodule on PET). Follow up is ongoing for two patients with ctDNA detected but no recurrence at data cutoff (time since last positive test: 0.60 and 1.78 years). Any ctDNA detection postoperatively or in follow-up was strongly associated with disease recurrence (HR: 37.35, 95%CI: 2.7-520.7; p&amp;lt; 0.0001). Conclusion: RaDaR detects ctDNA in most patients prior to the initiation of NAT for EBC. Changes in ctDNA levels during treatment and its presence are associated with clinical outcomes. Prospective evaluation and integration of RaDaR testing into clinical trials are warranted. Further analysis of ctDNA detection, clinical outcomes, and genomic data will be presented at the meeting. Citation Format: Mitchell Elliott, Jesus Fuentes Antras, Philippe Echelard, Aaron Dou, Zachary Veitch, Philippe Bedard, Eitan Amir, Michelle Nadler, Nicholas Meti, Nancy Gregorio, Elizabeth Shah, Celeste Yu, Nathan Campbell, Christodoulos Pipinikas, Karen Howarth, Lillian Siu, Hal Berman, David Cescon. Longitudinal Neoadjuvant and Post-operative Evaluation of Circulating Tumor DNA in Early Breast Cancer using a Tumor-Informed Assay: Updated Analysis of the TRACER Cohort [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 PS06-08.

A Novel RP-UHPLC-MS/MS Approach for the Determination of Tryptophan Metabolites Derivatized with 2-Bromo-4'-Nitroacetophenone.

Many biologically active metabolites of the essential amino acid L-tryptophan (Trp) are associated with different neurodegenerative diseases and neurological disorders. Precise and reliable methods for their determination are needed. Variability in their physicochemical properties makes the analytical process challenging. In this case, chemical modification of analyte derivatization could come into play. Here, we introduce a novel fast reversed-phase ultra-high-performance liquid chromatography (RP-UHPLC) coupled with tandem mass spectrometry (MS/MS) method for the determination of Trp and its ten metabolites in human plasma samples after derivatization with 2-bromo-4'-nitroacetophenone (BNAP). The derivatization procedure was optimized in terms of incubation time, temperature, concentration, and volume of the derivatization reagent. Method development comprises a choice of a suitable stationary phase, mobile phase composition, and gradient elution optimization. The developed method was validated according to the ICH guidelines. Results of all validation parameters were within the acceptance criteria of the guideline, i.e., intra- and inter-day precision (expressed as relative standard deviation; RSD) were in the range of 0.5-8.2% and 2.3-7.4%, accuracy was in the range of 93.3-109.7% and 94.7-110.1%, limits of detection (LODs) were in the range of 0.15-9.43 ng/mL, coefficients of determination (R2) were higher than 0.9906, and carryovers were, in all cases, less than 8.8%. The practicability of the method was evaluated using the blue applicability grade index (BAGI) with a score of 65. Finally, the developed method was used for the analysis of Alzheimer's disease and healthy control plasma to prove its applicability. Statistical analysis revealed significant changes in picolinic acid (PA), anthranilic acid (AA), 5 hydroxyindole-3-acetic acid (5-OH IAA), and quinolinic acid (QA) concentration levels. This could serve as the basis for future studies that will be conducted with a large cohort of patients.

Abstract PO3-14-04: Prognostic value of systemic inflammatory markers in neoadjuvant chemotherapy for breast triple negative cancer with pembrolizumab: development of a nomogram

Abstract Introduction: Systemic inflammatory markers derived from peripheral blood cells, such as the neutrophil-lymphocyte ratio (NLR), derived neutrophil-lymphocyte ratio (dNLR), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR), have shown promise as prognostic markers for various cancer types. Inflammation plays a crucial role in cancer development, progression, metastasis, and resistance to treatment. However, only a few preoperative biomarkers have been identified as independent prognostic markers. Systemic inflammatory markers offer a reliable and easily accessible approach for prognosis evaluation. Materials and Methods: This study evaluated two groups of patients who received neoadjuvant chemotherapy for triple-negative breast cancer outside of clinical trials. The first group underwent neoadjuvant chemotherapy in 2021 with the EC X4 and weekly paclitaxel regimen, whereas the second group received neoadjuvant chemotherapy in 2022 following the KEYNOTE-522 study protocol with pembrolizumab. A total of 44 patients were included, with 23 patients in the pembrolizumab group. The NLR was defined as the absolute blood neutrophil count divided by the absolute lymphocyte count, and the derived neutrophil/lymphocyte ratio (dNLR) was defined as the absolute neutrophil count divided by the derived lymphocyte count (absolute leukocyte count —neutrophil count). The PLR was defined as the absolute platelet count divided by the absolute lymphocyte count. The LMR was defined as the absolute lymphocyte count divided by the absolute monocyte count. The association between systemic inflammatory markers (NLR, dNLR, PLR, and LMR) and pathological complete response (pCR) was analyzed using statistical tests. Inflammatory markers were evaluated at the time of diagnosis, at the time of chemotherapy regimen change, and two weeks before surgery. The χ2 test or Fisher’s exact test was used to analyze the correlation between the inflammatory indices and clinicopathologic parameters. Student’s t-test was used to compare different groups of continuous parametric data. Results: The pCR rates were 67% in the standard therapy group and 87% in the pembrolizumab group. There were no significant differences in other clinical characteristics between the two groups. The NLR, dNLR, PLR, and LMR at 6 months showed statistically significant differences compared to baseline levels. This difference was more evident in patients undergoing pembrolizumab therapy. ROC curves for the pembrolizumab group demonstrated an area under the curve (AUC) of 0.737, indicating a strong correlation between these systemic inflammatory markers and pCR. Based on these data, a nomogram was constructed to predict the likelihood of achieving pCR in patients undergoing neoadjuvant pembrolizumab therapy. Conclusion: This study highlights the potential of systemic inflammatory markers as prognostic indicators in patients with TNBC undergoing neoadjuvant chemotherapy. The significant differences observed in the pembrolizumab group and the high AUC of the ROC curves suggest the utility of these markers in predicting treatment response. The developed nomogram provides a practical tool for clinicians to estimate the probability of pCR based on NLR, dNLR, PLR, and LMR. Further research and validation are required to confirm the clinical utility of these markers in larger patient cohorts. Nomogram –insert figure image– ROC curve –insert figure image– Citation Format: Filippo Giovanardi, Giancarlo Bisagni, Elisa Gasparini, Alessandra Bologna, Roberto Di Cicilia, Gabriella Moretti, Claudia Degli Esposti, Carmine Pinto. Prognostic value of systemic inflammatory markers in neoadjuvant chemotherapy for breast triple negative cancer with pembrolizumab: development of a nomogram [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 PO3-14-04.

Abstract PO5-10-07: Risk factors associated with secondary cancers in AYA patients with breast cancer. A SEER database study

Abstract Background Adolescents and young adults (AYA) diagnosed with breast cancer face unique challenges and have distinct characteristics compared to older patients. While primary breast cancer remains a significant concern, the risk of developing secondary cancers in this population is also of great importance. This study aimed to identify these risk factors by analyzing a large cohort of AYA breast cancer patients using SEER (Surveillance Epidemiology and End Result) Database. Methods Patients were identified from SEER Research Data 17, from 2000 to 2019. Patients aged 18-39 years with breast cancer and at least 1 year of survival were identified. Secondary cancers were then identified and included any disease site. Patient demographic and clinical characteristics were summarized by secondary cancer status using Mann-Whitney U and Fisher’s exact tests. Overall survival from the initial breast cancer diagnosis was summarized by secondary cancer status using standard Kaplan-Meier methods, where the median and 3/5-year rates were estimated with 95% confidence intervals. Comparisons were made using the log-rank test. SAS v9.4 (Cary, NC) was used at a significance level of 0.05. Results A total of 47,912 AYA breast cancer patients were identified, of which 2,886 (6.0%) developed a secondary cancer at least 1 year after the initial breast cancer diagnosis. When comparing patients with and without secondary cancers, we observed significant differences with respect to age at initial breast cancer diagnosis, race, stage, nodal status, surgical procedure, ER status, PR status, Her2 status, and sub-type (Table 1). The analysis of overall survival showed that, from the time of breast cancer diagnosis, there was no statistically significant difference between patients with and without secondary cancers. However, this may be due to an immortal time bias. Breast was the most common site of secondary cancer (67%) followed by gynecological (7%), colorectal (3.7%), skin (3.4%) lung and hematologic (2.7%) Compared to other subtypes, TNBC patients were found to have much shorter time to secondary cancer development of 38 months compared to Her2+ and ER/PR+ (40 and 45 months respectively, P&amp;lt; 0.001). Black and Hispanic individuals were found to have higher rates (7.4% and 6.3%) and earlier development of secondary cancer (76 months and 74 months) as compared to whites and Asians (5.9% and 5%, 88 months and 81 months, P&amp;lt; 0.001 and P&amp;lt; 0.002 respectively). Conclusion This study identified several risk factors associated with the development of secondary cancers in AYA breast cancer patients such as age at initial breast cancer diagnosis, race, stage, nodal status, surgical procedure and sub-type. Higher rates and early development of secondary cancer were observed among TNBC subtype and Black and Hispanic races that calls for further investigation and tailored interventions to improve outcomes in specific patient populations. Table 1 showing significant differences in characteristics AYA breast cancer patients who developed secondary breast cancer compared to those who did not Citation Format: Sheeba Ba Aqeel, Alankrita Taneja, Shipra Gandhi. Risk factors associated with secondary cancers in AYA patients with breast cancer. A SEER database study [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 PO5-10-07.

Abstract PO3-03-07: Patterns of Chemotherapy Utilization among Elderly Patients with Early-Stage Triple-Negative Breast Cancer

Abstract Background: Patterns of adjuvant and neoadjuvant chemotherapy use among patients with breast cancer have changed over time. Historically, adjuvant chemotherapy has been the standard treatment approach for patients with triple-negative breast cancer after surgical resection, aiming to eliminate any remaining cancer cells and reduce the risk of recurrence. Advancements in treatment strategies, research findings, and clinical guidelines have contributed to shifts in cancer care approaches, with an increase in the use of neoadjuvant chemotherapy. In this study, we explore chemotherapy utilization in a large cohort of elderly patients diagnosed with early-stage triple-negative breast cancer (TNBC). Methods: Data were obtained from the SEER- and Texas Cancer Registry (TCR)-linked Medicare databases. We identified female patients aged 66 years or older, diagnosed with early-stage (localized or regional disease) TNBC between 2010 and 2017 with claims until 2019. We identified the use of chemotherapy using HCPCS codes from outpatient and physician’s carrier claims. We used descriptive statistics and analyzed overall chemotherapy utilization and time trends of neoadjuvant versus adjuvant use via the Cochran-Armitage trend test, and evaluated factors associated with chemotherapy use via logistic regression models. This study adhered to the STROBE reporting guidelines for cohort studies. Results: Among 8,848 patients with localized or regional stage TNBC (median age 74) a total of 5,159 (58%) were treated with chemotherapy. The rate of chemotherapy utilization increased yearly from 52% in 2010 to 66% in 2017 (p&amp;lt; 0.001). After multivariable adjustment, any chemotherapy use was associated with recent year of diagnosis (OR=1.77; 95%CI 1.54-2.04), regional stage compared to localized (OR=3.78; 95%CI 3.34-4.27), and Northeastern region compared to South (OR=1.2; 95%CI 1.06-1.37). Conversely, decreased chemotherapy use was associated with age ≥76 (OR=0.24; 95%CI 0.2-0.27), being single (OR=0.76; 95%CI 0.67-0.86), and higher comorbidity score (OR=0.69; 95%CI 0.61-0.78). Among chemotherapy-treated patients, 3,808 (73.8%) received it in the adjuvant setting, 722 (14.0%) received it in the neoadjuvant setting, and 629 (12.2%) received chemotherapy both preoperatively and postoperatively. Among those who were treated with any chemotherapy, the percentage of patients treated with neoadjuvant chemotherapy increased from 15.2% in 2010 to 37.4% in 2017 (p&amp;lt; 0.001). Among patients treated with chemotherapy, neoadjuvant chemotherapy use was associated with recent year of diagnosis (OR=3.38; 95%CI 2.77-4.12), regional stage (OR=3.28; 95%CI 2.86-3.77), and inversely associated with older age (OR=0.77; 95%CI 0.64-0.94), non-White, non-Hispanic, non-Black race or ethnicity (OR=0.64 95%CI 0.45-0.94), non-metro area (OR=0.61; 95%CI 0.5-0.74), and Northeastern region (OR=0.66; 95%CI 0.56-0.78). Conclusion: Our study highlights the significant changes in patterns of adjuvant and neoadjuvant chemotherapy use among elderly patients with early-stage TNBC. We observed an increasing trend in chemotherapy utilization, with a notable shift from adjuvant to neoadjuvant treatment. This transition reflects the evolving landscape of cancer care and the adoption of more personalized approaches to treatment, with increased utilization of neoadjuvant chemotherapy offering opportunities for better risk assessments and tailored treatment strategies. Citation Format: Catalina Malinowski, Xiudong Lei, Sharon Giordano, Marianna Chavez. Patterns of Chemotherapy Utilization among Elderly Patients with Early-Stage Triple-Negative 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 PO3-03-07.

Abstract PS16-07: Tumor infiltrating lymphocyte stratification refines AJCC TNM staging based outcomes of early-stage triple negative breast cancer treated with neoadjuvant anthracycline-free, docetaxel and carboplatin chemotherapy

Abstract Background: Stromal tumor-infiltrating lymphocytes (sTILs) quantification is associated with pathological response to neoadjuvant chemotherapy (NAC) and long term outcomes in setting of adjuvant anthracycline based chemotherapy. A previous study in TNBC patients treated with adjuvant anthracycline chemotherapy shows that at a cut point of 30%, sTILs can up and downstage traditional AJCC stage groups. Additive impact of sTILs on refining outcomes beyond pathological response and TNM stage for patients treated with anthracycline-free chemotherapy is not known. This study aimed to investigate impact of sTILs on outcomes in a large cohort of TNBC patients treated with Docetaxel plus carboplatin NAC. Methods: Patients with stage I (T size &amp;gt; 1cm) to III TNBC scheduled to receive 6 cycles of NAC docetaxel (75 mg/m2) plus carboplatin (AUC 6) (TCb) every 3 weeks from two studies (NCT01560663 and NCT02302742) were combined for this analysis. sTILs were evaluated on pre-treatment H&amp;E slide using standard criteria centrally by one of the investigators (RS). Pathological complete response (pCR) was defined as ypT0/is ypN0. Logistic regression analysis was used to examine the effect of multiple variables on Event free survival (EFS) and overall survival (OS). Results: For 474 patients included in this analysis, median age was 52 years, 8% were Black, 13% had germline BRCA1/2 mutation, 44% had clinical Lymph node (LN) positive disease and 13%, 62% and 25% respectively had TNM stage I, II and III disease. Median sTILs were 5% (range 1-95%) and 25% had &amp;gt;30% sTILs. pCR and RCB 0+1 rates were 50.2% and 60.4% respectively. On multivariable analysis, T stage (OR=0.51, p=0.030), nodal status (OR=0.56, p=0.028), Ki67 (OR=2.74, p&amp;lt; 0.001) and sTILs (OR=2.01, p=0.014) were associated with pCR. pCR rate in those with sTILs &amp;lt; 30 vs sTILs &amp;gt;30 was 45.9% and 63.9% respectively (p=0.0014). At median follow-up of 58 months, 5 years EFS was 81.05% in all patients, 93.94% in those with pCR and 68.67% in those without pCR, 5 year OS was 84.83% in all patients, 96.53% in those with pCR and 74.13% in those with residual disease. On multivariate analysis lower T stage, negative LN status and increasing sTILS were associated with better EFS (T stage: HR =1.98, p=0.018; LN status: HR=2.92, p&amp;lt; 0.001; sTILs: HR:0.46, p=0.04) and OS (T stage: HR=1.89, p=0.040; LN status: HR=3.13, p=0.001; sTILs: HR=0.30, p=0.008). At a cut-point of 30%, sTILs up and downstaged anatomic AJCC TNM stage groups (table 1). Conclusions and Relevance: In patients treated with anthracycline-free TCb chemotherapy, sTILs were independent predictors of EFS and OS beyond clinicopathological features. Notably, 30% sTILs cut-point stratified outcomes beyond anatomical TNM staging. These, findings can aid in patient stratification for chemotherapy backbone de-escalation in future trials and have the potential to inform patient selection for adjuvant treatment escalation and de-escalation trials. Tumor infiltrating lymphocyte stratification refines AJCC TNM staging based outcomes of early-stage triple negative breast cancer treated with neoadjuvant anthracycline-free, docetaxel and carboplatin chemotherapy. Table. Citation Format: Miguel Martín, Rachel Yoder, Roberto Salgado, María del Monte-Millán, Enrique Álvarez, Isabel Echavarria, Joshua Staley, Coralia Bueno-Muiño, Yolanda Jerez Gilarranz, Andrew Godwin, María Cebollero, Oscar Bueno, José Ángel García-Sáenz, Fernando Moreno Antón, Uriel Bohn, Henry L Gómez, Tatiana Massarrah, Sara López-Tarruella, Priyanka Sharma. Tumor infiltrating lymphocyte stratification refines AJCC TNM staging based outcomes of early-stage triple negative breast cancer treated with neoadjuvant anthracycline-free, docetaxel and carboplatin chemotherapy [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 PS16-07.

Abstract PS11-01: Brain metastases in metastatic breast cancer: prevalence per line of treatment and cumulative incidence in a cohort of 18075 real-world patients

Abstract BACKGROUND Historic data suggest that incidence of brain metastasis (BM) is relatively distributed over time in HER2-positive (HER2+) breast cancer (BC), occurs early in triple negative BC (TNBC), and occurs late in hormone receptor-positive (HR+) metastatic BC (mBC). However, the timing of BM relative to line of therapy has not been well described. We describe the prevalence per line of therapy and cumulative incidence of BM in a large real-world cohort of patients (pts) with mBC, by BC subtype and line of therapy. METHODS This analysis used data from the longitudinal US Flatiron Health de-identified database, which provides unstructured and structured electronic health record-derived data from &amp;gt;2.6 million pts with cancer in ~800 unique sites of care. Eligible pts had initiated a first line of treatment (index data) for mBC up to March 1, 2021, to allow for ≥2 years potential follow-up time. Baseline characteristics were assessed, and pts categorized by HER2 and HR status: 1) HR+, HER2+; 2) HR+, HER2–, 3) HR–, HER2+ and 4) TNBC (i.e., negative for HR and HER2). For the last two categories, HER2-low subsets were defined based on immunohistochemistry results (1+, 2+, or equivocal). Lines of therapy were derived using both treatment regimens and progression data. The primary outcome was the first diagnosis of BM. The prevalence of BM was evaluated by subtype, at the index date, and by the line of therapy. The cumulative incidence function (CIF) of BM was used to estimate the risk of BM in pts free of BM at the index date, and death was treated as a competing event. RESULTS Overall, 18075 pts were included (HR+, HER2+: 3062 pts [16.9%]; HR–, HER2+: 902 pts [5.0%]; HR+, HER2–: 12331 pts [68.2%] [HR+, HER2-low: 7062 (39.1%)]; TNBC: 1780 pts [9.8%] [HR–, HER2-low: 725 pts (4.0%)]). Median age at the index date was 64 years (interquartile range: 54, 73) and 10271pts (56.8%) had visceral metastasis. In total, 5951 pts (32.9%) had de novo disease, 12090 (66.9%) had recurrent disease, and 34 (0.2%) did not have available data for mBC type. The table shows the number of pts by line of therapy, prevalence of BM, and cumulative incidence of BM from the index date. Of the included pts, 1306 (7.2%) had a BM at the index date; the CIF was run on the remaining 16973 pts. Overall, 2248 pts (13.2%) had an incident BM event during follow-up (HR+, HER2+: 578 events; HR–, HER2+: 237 events; HR+, HER2–: 1119 events [HR+, HER2-low: 619 events]; TNBC: 314 events [HR–, HER2-low: 124 events]), 9314 had a competing event, and 5411 were censored. By fourth-line therapy, the prevalence of BM was 26.1% in HR+, HER2+; 37.1% in HR–, HER2+; 24.7% in TNBC (HR–, HER2-low: 27.9%); but remained low at 7.2% in HR+, HER2– (HR+, HER2-low: 9.4%). The cumulative incidence of BM at 60 months was 23% in HR+, HER2+, 34% in HR–, HER2+, 10% in HR+, HER2–, and, 22% in TNBC. Overall, the HER2-low subsets had BM prevalence and cumulative incidence that were very close to those that were HER2–. CONCLUSIONS This large analysis of real-world data demonstrates that the prevalence of BM across pts with mBC differs by tumor subtype and by line of therapy. Conversely, HER2-low status may have limited impact. The cumulative incidence of BM was highest in the HR–, HER2+ and TNBC subgroups, and lowest in the HR+, HER2– subgroup; despite this, due to the high proportion of HER2–, HR+ mBC cases, the HR+, HER2– group represented the largest number of BM events. These data emphasize the need for clinical and biologic predictors of BM and for strategies to prevent their onset, and provide information on the impact of BM inclusion and exclusion criteria in clinical trials for pts with mBC. Number of patients by line of therapy, prevalence of BM, and cumulative incidence of BM from the index date BM, brain metastasis; HR, hormone receptor, pts, patients; TNBC, triple negative breast cancer. Citation Format: Sarah Sammons, Jose Leone, Thibaut Sanglier, Peter Lambert, Filippo Montemurro, Raf Poppe, Eleonora Restuccia, Sara Tolaney, Nancy Lin. Brain metastases in metastatic breast cancer: prevalence per line of treatment and cumulative incidence in a cohort of 18075 real-world patients [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 PS11-01.