Real-world Cohort Of Patients Research Articles

Novel prognostic staging system for patients with de novo metastatic breast cancer: A real-world experience.

e13167 Background: De novo metastatic breast cancer (dnMBC) is a heterogenous disease with variable survival rates. For newly diagnosed, non-MBC, the AJCC staging system incorporates non-anatomical factors, biomarkers and grade, in addition to tumor size and nodal status to define the prognostic stage group. These variables and other disease-related factors, such as sites of metastasis, have been associated with survival in MBC. Despite this, the current staging system groups all patients with dnMBC into a single prognostic group. More tools are needed to help clinicians relay important prognostic information to patients with dnMBC. Plichta et al. [1] utilized large population data sets to develop a novel staging system for dnMBC, which successfully stratified patients into four prognostic groups (IVA-D) based on disease-related variables. In this study, we sought to validate this staging system in an independent, real-world cohort of patients with dnMBC. Methods: We used a retrospective cohort of patients with MBC who received treatment in the Koontz Center for Advanced Breast Cancer (KABCC) at St. Luke’s Cancer Institute, a community-based healthcare system in the Kansas City metro area. The KABCC is a multidisciplinary clinic dedicated solely to the care of patients with MBC. Patients with dnMBC were assigned prognostic stage IVA, IVB, IVC, and IVD according to the system developed by Plichta et al. [1]. Overall survival (OS) was compared between groups using Kaplan-Meier analysis and the log-rank test. We also performed a stratified analysis based on age at diagnosis, <60 years versus ≥60 years. Results: Ninety-seven patients with dnMBC were included in the analytic cohort. Mean age at diagnosis was 60 years, and most patients self-identified as non-Hispanic White (71.1%) or Black (22.7%). Nine patients were assigned stage IVA (9.3%), 39 stage IVB (40.2%), 32 stage IVC (33%) and 16 stage IVD (16.5%). Most stage IVA were HER2 positive (66.7%), while most stage IVD were triple-negative (56.3%). OS differed significantly between the four stage groups, with mortality rates increasing as stage increased. This was true in both the overall population (p<0.001) and when patients were stratified by age at diagnosis (both p<0.05) (Table). Conclusions: In an independent, real-world cohort of patients with dnMBC, a novel prognostic staging system that incorporates biomarkers, T-stage, grade, and sites of metastasis successfully stratified patients into four prognostic groups. Our findings help to confirm the utility of this staging system in dnMBC. [Table: see text]

Survival in a Real-World Cohort of Patients With Transthyretin Amyloid Cardiomyopathy Treated With Tafamidis: An Analysis From the Transthyretin Amyloidosis Outcomes Survey (THAOS)

In the pivotal Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality rates, leading to its approval in many countries for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM). Real-world evidence on survival in patients with ATTR-CM following tafamidis treatment has not been extensively reported. The Transthyretin Amyloidosis Outcomes Survey (THAOS) was a longitudinal, observational, phase 4 study of patients with transthyretin amyloidosis and asymptomatic participants carrying pathogenic transthyretin variants. Patients from THAOS with a predominantly cardiac phenotype at enrollment were included, and survival was analyzed according to tafamidis treatment status (treated or untreated). Results are based on the completed THAOS dataset. In tafamidis-treated (n = 587) and tafamidis-untreated (n = 854) patients, respectively, median age at enrollment was 77.7 and 76.4 years, 91.8% and 90.0% were male, and 91.8% and 83.8% had wild-type disease. Survival rates (95% CI) at 30 and 42 months, respectively, were 84.4% (80.5-87.7) and 76.8% (70.9-81.7) in tafamidis-treated patients, and 70.0% (66.4-73.2) and 59.3% (55.2-63.0) in tafamidis-untreated patients. Survival rates in genotype subgroups (wild-type and variant) were similar to those of the overall cohort. Survival rates were better in a contemporary cohort, as reflected by a sensitivity analysis performed in patients enrolled after vs before 2019. No new safety signals were identified. In this real-world cohort of patients with ATTR-CM, survival rates were higher than in ATTR-ACT and consistent with more recent reports, suggesting early diagnosis and treatment with tafamidis has improved life expectancy in ATTR-CM. These results provide further evidence supporting tafamidis' safety and effectiveness. ClinicalTrials.gov identifier: NCT00628745.

A digital pathology AI model to predict immune-oncology biomarker status and pembrolizumab response in a real-world cohort of patients with colorectal and breast cancer.

e13617 Background: Deep learning (DL) algorithms have garnered significant attention for prediction of biomarker status in digitized tissue slides. Here, we trained and validated a digital pathology algorithm to predict microsatellite instability (MSI)/mismatch repair deficiency (MMRd) in colorectal cancer (CRC) and PD-L1 status in breast cancer (BC) using a large real-world patient cohort. Methods: H&E and immunohistochemistry (IHC) slides of CRC and BC from Caris Life Sciences (Phoenix, AZ) with known biomarker status were digitally scanned (CRC: N=27,494, 6.6% MSI-high by next-generation sequencing [NGS]; N=25,788, 6.4% MMRd by IHC; BC: N=16,069, 15.8% PD-L1+ by IHC). A transformer-based DL model (Wagner, Sophia J., et al., 2023) was trained to predict biomarker status, with 5-fold cross-validation. Accuracy, F1 score, area under the curve (AUC), and other metrics were calculated comparing the model to NGS/IHC “truth”. Risk stratification was performed on holdout datasets of pembrolizumab-treated CRC (N=422-454) and triple negative breast cancer (TNBC; N=513) pts. Post-treatment overall survival (OS) was calculated from start of pembrolizumab to last contact, per insurance claims data. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated by Cox-Proportional hazards and compared between model and “truth”. Results: When applied to holdout datasets for biomarker prediction, the validated model achieved AUC of 0.78-0.95. In CRC and BC, performance was better among primary specimens than metastatic. For MSI-H/MMRd risk stratification in pembrolizumab-treated CRC, HR for OS were comparable between model and “truth” for primary and metastatic cohorts. When applied to the TNBC holdout dataset, the model performed better than “truth” for PD-L1 risk stratification in pembrolizumab-treated pts. Conclusions: A digital pathology DL model predicts biomarker status with high accuracy and is non-inferior to NGS/IHC for risk stratification of pembrolizumab-treated CRC and TNBC pts. These results support further investigation of AI algorithms developed from large datasets as possible rapid screening tools for biomarker detection in molecular testing programs. [Table: see text]

Treatment rates and reasons for non-treatment in a real-world cohort of patients with pancreatic cancer.

e13554 Background: The proportion of patients who receive treatment for pancreatic ductal adenocarcinoma (PDAC) and reasons for non-treatment in real-world patient populations are poorly understood. Our study aims to determine treatment rates, predictors for non-treatment, and the rationale for declining treatment in a well-defined, diverse, community-based patient population. Methods: We identified all adult patients with PDAC (n = 3852) between 2010 and 2020 through the Kaiser Permanente Northern California Cancer Registry. Patients were stratified by age and tumor characteristics to determine rates of oncologic therapy. Multivariable logistic regression was used to assess how covariates were associated with receiving treatment. A detailed chart review of all patients ≤ 65 years and a random sample of 100 patients > 65 years with non-metastatic disease who did not receive treatment was performed to better understand the reasons for non-treatment. A random sample of 20 patients with metastatic disease who did not receive treatment were also reviewed. Results: Of patients with PDAC, 77.7% of patients with non-metastatic and 56.2% with metastatic disease received any cancer-directed treatment. A multivariate analysis showed no statistically significant differences by race/ethnicity or gender. Increasing age was a significant negative predictor of treatment. Charlson comorbidity index (CCI) did not influence treatment rates in patients with non-metastatic PDAC, but in patients with metastatic disease those with CCI 3+ had a decreased odds of receiving treatment. Of patients ≤ 65 years with non-metastatic disease, 90.3% were seen by an oncologist, and of those patients 89.3% were offered treatment. The primary reason for declining treatment was patient/family preference in 80.8%, followed by PDAC-related frailty in 11.5%, and medical comorbidity/other malignancy in 7.69%. Similarly, of patients > 65 years with non-metastatic disease, the majority were also seen by an oncologist, offered treatment, and declined due to personal preference. The same trends were noted in patients with metastatic PDAC. Conclusions: A significant proportion of patients with PDAC did not receive cancer-directed treatment in a real-world, community-based patient population, and this was more likely for patients with metastatic disease. Race and gender did not influence whether patients received treatment in this fully insured patient population and comorbidity had a small effect. Patients of increasing age, however, were less likely to receive treatment. Most patients who did not initiate treatment did so primarily due to patient/family preference despite being offered cancer-directed therapy by their treatment team. These findings may help guide the development and utilization of patient decision-aids in PDAC to improve goal concordant care that accounts for patients’ preferences and values.

The association of hormone receptor expression level and clinical efficacy of CDK4/6 inhibitor in hormone receptor-positive, HER2-negative metastatic breast cancer.

e13069 Background: In patients with hormone receptor-positive, HER2-negative metastatic breast cancer (HR+ HER2- MBC), the correlation between the level of expression of HR and the clinical efficacy of CDK4/6 inhibitors remains undefined. Methods: We identified consecutive patients with HR+ HER2- MBC starting a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib) plus either an aromatase inhibitor or fulvestrant between Jan 2018 - Oct 2023 from an institutional cancer registry. Expression level of HR was stratified as high (H) (Allred score 7-8), moderate (M) (Allred score 5-6) or low (L) (Allred score 3-4) for both estrogen (ER) and progesterone receptors (PR). Patients were evaluated from start of treatment to December 2023, last visit or death, whichever came earlier. Median progression-free survival (mPFS) and overall survival (mOS) were endpoints. We evaluated the association of HR expression levels with mPFS and mOS using log-rank test and multivariate Cox regression modelling. Results: We examined data from 436 women with HR+ HER2- MBC. Median age at treatment was 60.5 yr. Majority of patients received the treatment in the first-line setting (72.5%), with palbociclib (54.1%), ribociclib (31.9%) and abemaciclib (14.0%) as the CDK4/6 inhibitor. In the population that received first-line treatment, ER expression levels were H (83.5%), M (11.4%) and L (5.1%) respectively. ER expression levels were strongly associated with mPFS and mOS. For ER H, M and L expressions, mPFS were 29.4m, 9.2m and 2.9m ( p<0.001); mOS were 52.1m, 40.6m and 11.6m ( p<0.001), respectively. In multivariate analysis, ER expression levels remain strongly predictive for both mPFS and mOS after adjustment for clinicopathological risk factors (ER L vs H, mPFS HR 10.6, p<0.001; mOS HR 4.66, p<0.001; ER M vs H, mPFS HR 4.90, p<0.001; mOS HR 2.06, p=0.05). Findings were similar for the second line and beyond population. In the ER-high expression cohort, the PR expression levels also correlate strongly with treatment efficacy and survival, with mPFS of 40.8m, 24.5m, 24.0m, 14.1m ( p<0.001) and mOS of NR, 53.3m, 48.1m, 26.9m ( p<0.001) respectively for PR H, M, L and zero expressions. Conclusions: In this real-world cohort of patients with HR+ HER2- MBC, we observed that the semi-quantitative HR expression level subgrouping is a strong predictor for the efficacy of treatment with CDK4/6 inhibitors. In contrast to patients with high HR expression levels, the small population with ER-low expression derived very limited benefits from the standard endocrine therapy with CDK4/6 inhibitors. Our findings provided a practical tool to guide the selection of the appropriate systemic therapy for individual patients.

Cardiotoxicity from bruton tyrosine kinase inhibitors (BTKi)—an analysis of an administrative health claims database

BackgroundFirst generation Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib have been associated with cardiovascular toxicities. Newer generation BTKi (e.g.,acalabrutinib and zanabrutinib) have been associated with lower incidence of cardiotoxicity in clinical trials.ObjectiveGiven paucity in real-world data on the overall cardiac risk factor profile, especially with the newer BTKi, our study evaluated the incidence of cardiotoxicity with various BTKi among a large, commercially insured population of patients.MethodsWe performed a retrospective cohort analysis of all adults with a diagnosis of B-cell malignancy undergoing treatment with BTKi acalabrutinib and ibrutinib between January 2018 and June 2020 using Optum’s de-identified Clinformatics® Data Mart Database. We then identified patients who had pre-existing cardiac disease one year prior to starting BTKi. New incidence of atrial fibrillation/flutter, hypertension, bleeding, ventricular tachycardia/fibrillation and sudden cardiac death from the time of index presciption were compared with standard Chi Square or Student t-test where appropriate. Multivariate logistic regression models were also estimated to evaluate for confounding.ResultsA total of 1691 patients were included in the final analysis. 1595 (94%, median age 75 (19–90) years, 61% male gender) patients received ibrutinib, and 96 (6%, median age 73.5 (32–90) years, 62.5% male gender) patients received acalabrutinib. The median duration of drug exposure of ibrutinib was 238 (2-1084) days vs. 150 (30–870) days for acalabrutinib. There was lower new incidence of atrial fibrillation/flutter (4.6%-vs-17%, p = 0.013), hypertension (6.3%-vs-25%, p = NS), sudden cardiac arrest/death (0% vs. 1.5%, p = NS) in the acalabrutinib group compared to ibrutinib, of which only the lower incidence of atrial fibrillation/flutter was statistically significant. This was despite the finding of a higher prevalence of atrial fibrillation/flutter at baseline in patients receiving acalabrutinib.ConclusionsThere was lower incidence of new atrial fibrillation/flutter with acalabrutinib when compared to ibrutinib in a real-world cohort of patients.

Real-world outcomes of patients with resected stage III melanoma treated with adjuvant therapies.

Both immunotherapy (IO) and targeted therapy (TT) are used as adjuvant (adj) treatment for stage III melanoma, however, data describing real-world outcomes are limited. In addition, a significant proportion of patients relapse, for whom best management is unclear. The aim of our study was to assess the efficacy, and safety of adj anti-PD1 IO and TT in a real-world cohort of patients with resected stage III melanoma, and further delineate patterns of recurrence and treatment strategies. We retrospectively analyzed 130 patients who received adj therapy (100 anti-PD1 IO and 30 TT). At a median follow-up of 30 months, median relapse-free survival (RFS) was 24.6 (95% CI, 17-not reached [NR]) versus 64 (95% CI, 29.5-NR) months for the TT and IO groups, respectively (p = 0.26). Median overall survival (OS) was NR for either subgroup. At data cutoff, 77% and 82% of patients in TT and IO arms were alive. A higher number of grade ≥3 treatment-related adverse events (AEs) were noted in the IO group (11% vs. 3%), however, a higher proportion of patients permanently discontinued adj therapy in the TT group (43% vs. 11%) due to toxicity. Strategies at relapse and outcomes were variable based on location and timing of recurrence. A significant number of patients who relapsed after adj IO received a second round of IO. Among them, patients who were off adj IO at relapse had superior second median RFS (mRFS2), compared to those who relapsed while on adj IO; mRFS2 was NR versus 5.1 months (95% CI, 2.5-NR), respectively, p = 0.02. In summary, both TT and IO yielded prolonged RFS in a real-world setting, however, longer follow-up is needed to determine any potential OS benefit. Adj therapy, particularly TT, may not be as well tolerated as suggested in clinical trials, with lower completion rates (59% vs. 74%) in a real-life setting. Overall, patients who relapse during adj therapy have poor outcomes, while patients who relapse after discontinuation of adj IO therapy appear to benefit from IO re-treatment.

Different dosing strategies of pembrolizumab in the treatment of NSCLC: A real-world retrospective observational study.

e23264 Background: Immune checkpoint inhibitors lack a dose-response relationship, allowing optimisation of dosing strategies that may reduce drug use. Pembrolizumab received its initial regulatory approval for the treatment of non-small cell lung cancer (NSCLC) at weight-based dosing (2 mg/kg every 3 weeks (Q3W)), as employed in pivotal clinical trials demonstrating its efficacy and safety. This dosing regimen was later replaced by the currently approved flat-dosing (200 mg Q3W or 400 mg Q6W) in all indications, potentially increasing drug use. This retrospective observational study evaluates differences in pembrolizumab use for different dosing strategies in a real-world patient cohort. Methods: Overall, 124 advanced NSCLC patients, treated with first-line pembrolizumab monotherapy at a single institution, were included. During the observation period, pembrolizumab flat-dosing was employed, with possible extensions of treatment administrations. Patient and treatment data were obtained from medical records. Duration of treatment was calculated from day 1 of first cycle to last day of last cycle, excluding treatment delays due to adverse events. Pembrolizumab use was calculated for 3 dosing strategies: i) as actually received, ii) as flat-dosing, iii) as body-weight dosing, capped at 200 mg Q3W. It is presented as median dose Q3W and cummulative dose in the whole cohort. Results: Included patients had a median weight of 73 kg (IQR: 65-84) and received a total of 1600 mg of pembrolizumab (IQR: 800-3600) over 24 weeks (IQR: 12-60). The median pembrolizumab dose was i) 190 mg Q3W (IQR: 172-200) as actually received by patients, and would be ii) 200 mg Q3W (IQR: 200-200) in case of flat dosing, and iii) 146 mg Q3W (IQR: 130-168) in case of body-weight dosing. Overall, total pembrolizumab dose in the whole cohort was i) 283,600 mg actually used, and would be ii) 327,800 mg in flat-dosing, and iii) 251,200 mg body-weight dosing, resulting in a 23.4% reduction of drug use in weight-adjusted vs flat-based dosing. Conclusions: Pembrolizumab dosing adjusted to body weight, as initially approved, would reduce drug use vs the currently approved flat-dosing, reaching nearly a 25% reduction in our cohort of patients.

Phenotyping Hepatic Immune-Related Adverse Events in the Setting of Immune Checkpoint Inhibitor Therapy.

We present and validate a rule-based algorithm for the detection of moderate to severe liver-related immune-related adverse events (irAEs) in a real-world patient cohort. The algorithm can be applied to studies of irAEs in large data sets. We developed a set of criteria to define hepatic irAEs. The criteria include: the temporality of elevated laboratory measurements in the first 2-14 weeks of immune checkpoint inhibitor (ICI) treatment, steroid intervention within 2 weeks of the onset of elevated laboratory measurements, and intervention with a duration of at least 2 weeks. These criteria are based on the kinetics of patients who experienced moderate to severe hepatotoxicity (Common Terminology Criteria for Adverse Events grades 2-4). We applied these criteria to a retrospective cohort of 682 patients diagnosed with hepatocellular carcinoma and treated with ICI. All patients were required to have baseline laboratory measurements before and after the initiation of ICI. A set of 63 equally sampled patients were reviewed by two blinded, clinical adjudicators. Disagreements were reviewed and consensus was taken to be the ground truth. Of these, 25 patients with irAEs were identified, 16 were determined to be hepatic irAEs, 36 patients were nonadverse events, and two patients were of indeterminant status. Reviewers agreed in 44 of 63 patients, including 19 patients with irAEs (0.70 concordance, Fleiss' kappa: 0.43). By comparison, the algorithm achieved a sensitivity and specificity of identifying hepatic irAEs of 0.63 and 0.81, respectively, with a test efficiency (percent correctly classified) of 0.78 and outcome-weighted F1 score of 0.74. The algorithm achieves greater concordance with the ground truth than either individual clinical adjudicator for the detection of irAEs.

Clinical characteristics, prognosis, and immunotherapy outcome in pediatric melanoma: Analysis from a large Chinese cohort.

10050 Background: Malignant melanoma in children and adolescents is rare, with limited data on Chinese populations.To assess the clinical characteristics, survival, prognostic factors, and the efficacy of immunotherapy in a real-world cohort of Chinese pediatric patients with melanoma. Methods: This is a retrospective, cohort study included pediatric melanoma patients between February, 2005 and May, 2021, with a median follow-up time of 76.7 months. Data analyses were conducted in May, 2023. This study enrolled patients from Sun Yat-sen University Cancer Center, the biggest cancer institution in South China for cancer prevention, diagnosis and treatment. Inclusion criteria for this study were as follows: 1) histopathologically confirmed diagnosis of melanoma; 2) Age ≤18 year; 3) with complete clinical data on sex, age, histopathological features, etc. The exclusion criteria was secondary malignant melanoma. Main outcomes and measures were patient’s OS and EFS. Results: 43 patients were enrolled, with median age of 138.9 (range 13.1-215.0) months, including 30 cutaneous melanoma, 7 meningeal melanoma, 5 mucosal melanoma, and 1 uveal melanoma. The frequency of BRAF V600E mutation was 16.7% (4/24). Mismatch repair proteins were normally expressed (7/7), and the positive rate of programmed cell death ligand 1 expression was 55.6% (5/9). The event-free survival and overall survival of cutaneous, mucosal and meningeal melanoma were 46.7±9.1% vs 75.0±21.7% vs 16.7±15.2% ( P = 0.010), 65.5±8.9% vs 75.0±21.7% vs 16.7±15.2% (P< 0.001), respectively. Survival of cutaneous melanoma were associated with pathological type, ulceration, Clark level, disease spread, sentinel lymph node status, tumor stage and Ki-67 expression. 5 of 9 patients who were treated with PD-1 inhibitors (5 with PD-1 inhibitors alone, 3 with PD-1 inhibitors plus angiogenesis inhibitors, 1 with combination of anti-PD1, anti-angiogenic inhibitors plus chemotherapy) were evaluable with the overall response rate of 20%. The most common immune-related adverse event was hypothyroidism. Conclusions: This is the largest real-world study in pediatric melanoma patients in Asia. The prognosis of mucosal melanoma was favorable, followed by cutaneous melanoma, and meningeal melanoma had the worst prognosis. PD-1 antibody combined with angiogenesis inhibitors maybe a promising choice in pediatric melanoma.

Dalbavancin as sequential therapy in infective endocarditis: Real-life experience in elder and comorbid patients

ObjectivesThis study aimed to evaluate the effectiveness of dalbavancin as sequential therapy in patients with infective endocarditis (IE) due to gram positive bacteria (GPB) in a real-life heterogenous cohort with comorbid patients. MethodsA single center retrospective cohort study including all patients with definite IE treated with dalbavancin between January 2017 and February 2022 was developed. A 6-month follow-up was performed. The main outcomes were clinical cure rate, clinical and microbiological relapse, 6-month mortality, and adverse effects (AEs) rate. ResultsThe study included 61 IE episodes. The median age was 78.5 years (interquartile range [IQR] 63.2–85.2), 78.7% were male, with a median Charlson comorbidity index of 7 (IQR 4–9) points. Overall, 49.2% suffered native valve IE. The most common microorganism was Staphylococcus aureus (26.3%) followed by Enterococcus faecalis (21.3%). The median duration of initial antimicrobial therapy and dalbavancin therapy were 27 (IQR 20–34) and 14 days (IQR 14–28) respectively. The total reduction of hospitalization was 1090 days. The most frequent dosage was 1500mg of dalbavancin every 14 days (96.7%). An AE was detected in 8.2% of patients, only one (1.6%) was attributed to dalbavancin (infusion reaction). Clinical cure was achieved in 86.9% of patients. One patient (1.6%) with Enterococcus faecalis IE suffered relapse. The 6-month mortality was 11.5%, with only one IE-related death (1.6%). ConclusionThis study shows a high efficacy of dalbavancin in a heterogeneous real-world cohort of IE patients, with an excellent safety profile. Dalbavancin allowed a substantial reduction of in-hospital length of stay.

Inherited Germline Variants in Urinary Tract Cancer: A Multicenter Whole-Exome Sequencing Analysis and Correlation With Clinical Features and Tumor Genomics.

This study investigates a real-world multicenter cohort of patients with urinary tract cancer (UTC), with primary disease sites including the bladder, urethra, and upper tract, who enrolled for research molecular testing of their germline and tumor. The purpose of this study was to evaluate factors that could affect the likelihood of identifying a clinically actionable germline pathogenic variant (PV). Patients with UTC were identified from 10 cancer institutes of the Oncology Research Information Exchange Network consortium. The data set comprised abstracted clinical data with germline and tumor genomic data, and comparative analyses were conducted. Clinically actionable germline PVs in cancer predisposition genes were identified in 16 (4.5%) of 354 patients. A higher proportion of patients with the urethra and the upper tract as the primary sites of disease had PVs with a prevalence of 11% (5/45), compared with only 3.6% (11/308) in those with the bladder as the primary site of disease (P = .04). There were no significant differences in markers of genomic instability (such as tumor mutational burden, microsatellite instability [MSI], and loss of heterozygosity, copy number, and chromosomal instability) between those with PVs and those without (P > .05). Of the PVs identified, 10 (62%) were in homologous recombination repair (HRR) genes, three (19%) in mismatch repair (MMR) genes, and three (19%) in genes associated with other pathways. Tissue-based assessment of genomic instability, such as MSI, does not reliably indicate germline PV. A comprehensive clinical germline testing approach that includes HRR genes in addition to MMR genes is likely to yield PVs in approximately one of 10 patients with nonbladder primary disease sites such as the upper tract and the urethra.

Therapeutic Role of Nusinersen on Respiratory Progression in Pediatric Patients With Spinal Muscular Atrophy Type 2 and Nonambulant Type 3.

Nusinersen has shown significant functional motor benefit in the milder types of spinal muscular atrophy (SMA). Less is known on the respiratory outcomes in patients with nusinersen-treated SMA. The aim of this study was to describe changes in respiratory function in pediatric patients with SMA type 2 and 3 on regular treatment with nusinersen within the iSMAc international cohort and to compare their trajectory with the natural history (NH) data published by the consortium in 2020. This is a 5-year retrospective observational study of pediatric SMA type 2 and nonambulant type 3 (age ≤18 years) treated with nusinersen. The primary objective was to compare the slopes of decline in forced vital capacity % predicted (FVC% pred.), FVC, and age when FVC dropped below 60% between the treated patients and a control group from the natural history cohort. Data on peak cough flow and the use of noninvasive ventilation (NIV) and cough assist were collected. Data were available for 69 treated patients, 53 were SMA type 2 and 16 type 3. The mean (SD) age at first injection was 8.5 (3.2) and 9.7 (3.7) years, respectively. The median (interquartile range) treatment duration was 1 (0.7; 1.9) and 1.2 (0.9; 1.9) years, respectively. At the time of the first nusinersen injection, 24 of 52 (46%) patients with SMA type 2 and 2 of 16 (13%) patients with SMA type 3 were on NIV. Forty-three of 53 (81%) and 4 of 16 (25%) patients used cough device. FVC% pred. in treated patients with SMA type 2 declined annually by 2.3% vs 3.9% in NH (p = 0.08) and in treated patients with type 3 by 2.6% vs 3.4% NH (p = 0.59). Patients treated reached FVC <60% later than untreated (12.1 vs 10 years, p = 0.05). A higher percentage of treated vs untreated patients maintained FVC% pred. equal/above their baseline after 12 (65% vs 36%) and 24 (50% vs 24%) months, respectively. NIV use among treated did not significantly change throughout 1-year follow-up. This study included the largest real-world cohort of pediatric patients with milder SMA types. The results suggest a positive role of nusinersen in delaying the respiratory decline in patients treated longer than 1 year when compared with natural history. Larger cohorts and longer observation are planned. This study provided Class III evidence that nusinersen slows progression for patients with SMA types 2 and 3 compared with a natural history cohort.

A portrait of germline pathogenic variants from a large real-world cohort of Brazilian patients with breast cancer.

10593 Background: The estimated prevalence of germline pathogenic/likely pathogenic variants (P/LP) in high and moderate penetrance (HMP) genes is around 7-10% among women with breast cancer (BC). Up to 50% of all hereditary BC cases are due to germline variants in BRCA1/2, but other HMP genes are increasing in relevance. The prevalence and spectrum of BC P/LP variants are affected by age at diagnosis, race/ethnicity, geographical region, BC molecular subtype. Methods: Retrospective cohort study to evaluate the germline profile of P/LP variants in HMP genes ( BRCA1, BRCA2, PALB2, TP53, CDH1, NF1, PTEN, STK11, CHEK2, ATM, BARD1, RAD51C and RAD51D) in women diagnosed with BC in Brazil. All patients were tested in a single reference laboratory (Oncoclinicas [OC] Precision Medicine) using multi-gene NGS panels covering from 35 to 105 genes. Primary endpoint was the prevalence of P/LP variants and VUS in BRCA1/2as well as in other HMP BC genes, in overall population and according to age and BC subtype. Clinical and pathological data were retrieved from curated Real-World Database of OC Group and used as reference for demographics comparisons. Results: This cohort involved 2,207 women with BC from 2019 to 2023. The majority of pts (79.7%) were from Southeastern Brazil, followed by Midwestern (5.6%), Southern (5.0%) and Northeastern (4.8%) Brazil. The median age at genetic testing was 47 years and most patients (59.4%) were ≤ 50 years. As reference, median age is 57 years in the overall BC population treated at OC (&gt; 20,000 during the study period). BC subtype was available in 641 cases, 264 pts (41.2%) were HR+/HER2-, 116 (18.1%) were HER2+ and 261 (40.7%) were triple negative (TNBC). In the OC Database, TNBC represents only 15% of all new BC cases. Overall, 217 (9.8%) had a P/LP in HMP genes, including 131 (5.9%) pts who had a BRCA1/2 P/LP variant and 86 (3.9%) who had a P/LP variant in other HMP BC genes. The most frequent LP/PV variants were found in BRCA2 (31%) / BRCA1 (29%) / TP53 (13%) / PALB2 (9%) / CHEK2 (9%). A TP53founder pathogenic variant (R337H) accounted for 75% of all TP53 LP/PV. The deleterious variants were more common in pts ≤50 years (12%) than in pts &gt; 50 (7%) as well as in patients with TNBC (14%) followed by HER2+ (9%) and HR+/HER2- (7%). The BRCA1/2 P/LP variants were higher in TNBC pts (8%) than in HR+/HER2- (4%) and HER2+ (3%). The overall VUS rate in the HMP genes was 20%. The most frequent VUS were found in ATM, BRCA2, NF1 and CHEK2genes. Conclusions: Studies involving germline profile of P/LP variants in cancer genes have provided a broader understanding of BC risk and have opened doors to new therapeutic or surveillance strategies across all subtypes. In Brazil, the prevalence of deleterious variants in HMP is comparable to published US and EU cohorts. However, in the real-world community practice, testing is still limited to populations with higher baseline risk for hereditary BC, such as young patients with TNBC.

Real-World Data on Tezepelumab in Patients With Severe Asthma in Germany

Tezepelumab is a novel biologic blocking thymic stromal lymphopoetin, approved for severe asthma irrespective of biomarker levels or phenotype. To characterize a real-world tezepelumab patient cohort and the efficacy among various asthma phenotypes. We performed a retrospective, multicenter study on patients with severe asthma initiating tezepelumab. Clinical response was evaluated at 3 and 6 months. We included 129 patients with an average age of 52.5 ± 13.1 years, 59.7% were female. The majority (86.0%) had increased type 2 (T2) biomarkers, 68.2% an allergic and 31.8% an eosinophilic phenotype. 23.3% of patients were biologic-naive. 22 (18.2%) patients discontinued tezepelumab therapy owing to suspected side effects or insufficient efficacy. At 6 months' follow-up, median reduction in annualized exacerbation rate was-1 [25th percentile; 75% percentile {-2.9; 0.0}], the reduction of oral corticosteroid dose among patients with long-term oral corticosteroid therapy was -5 mg [-10; 0] and the Asthma Control Test (ACT) improved by 2 [0; 5] points. A treatment response according to Biologic Asthma Response Score of 80.8% was demonstrated. There were no significant differences in treatment response between T2-high versus T2-low, early- versus adult-onset and eosinophilic versus non-eosinophilic asthma. Prior treatment with other biologics was associated with inferior treatment response. In this real-life cohort, including a large proportion of patients with history of previous biologic use and encompassing various subgroups, the majority responded to tezepelumab. Our data further suggest a steroid-sparing effect of tezepelumab.

Cancer outcomes from a real-world cohort of patients eligible for adjuvant CDK4/6 inhibitors but without genomic risk for chemotherapy: A GBECAM multicenter retrospective study.

540 Background: In the MonarchE and Natalee studies, most patients received (neo)adjuvant chemotherapy (CT). In the precision oncology era, genomic signatures such as Oncotype DX (ODX) can spare many patients of CT. Our recent Real-World data (RWD) showed that a proportion of patients with hormone receptor positive (HR+) HER2 negative (HER2-) early breast cancer (eBC) would be eligible for adjuvant abemaciclib or ribociclib without genomic indication for CT. The main question addressed in this analysis is the potential benefit of adjuvant CDK4/6i in the non-CT eligible population; for this, we evaluated cancer recurrence outcomes of these patients. Methods: This is a multicentric RWD study derived from a large dataset of patients with T1-T3, N0-N1, HR+/HER2- eBC who had an ODX performed between 2005 and 2020 and were treated across nine Brazilian institutions. Projections of CT indication by genomic criteria were based on TAILORx and RxPONDER data. Projections of adjuvant CDK4/6i indication were based on the MonarchE and Natalee inclusion criteria. Primary endpoints were 4-year invasive disease-free survival (4-yr iDFS) and 4-year distant disease-free survival (4-yr DDFS) rates in the cohort of patients potentially eligible for CDK4/6i without genomic indication for CT and who did not receive adjuvant CT in the clinical practice. Results: Of 636 patients, the ODX indicated low (&lt;11), intermediate (11-25) and high (&gt;25) genomic risk in 117 (18.4%), 408 (64.1%) and 111 (17.5%) patients, respectively. 408 patients (64.2%) had low clinical risk and 228 patients (35.8%) had high clinical risk disease. In the overall cohort, 12 (1.8%) and 67 (10.5%) pts were eligible for adjuvant abemaciclib and ribociclib, respectively, without having received adjuvant CT (both by genomic indication and clinical practice). In patients with indication of abemaciclib (median follow-up [FU] of 23 months; a maximum of 114 months), 4-yr iDFS and 4-yr DDFS rates were both 100%. In patients with indication of ribociclib (median follow-up of 33 months; a maximum of 127 months), 4-yr iDFS and 4-yr DDFS rates were both 100%. In the entire cohort, there was only one distant recurrence event, at 96 months after diagnosis, in a 55-year-old patient with stage IIB (T2N1) eBC and low genomic risk (RS=11). Conclusions: In times of rapid incorporation of both GES and adjuvant CDK4/6i, our results suggest that patients eligible for adjuvant abemaciclib and/or ribociclib in the non-CT population have a favorable short-term outcome with endocrine therapy alone. Therefore, additional data and longer follow-up are needed to clarify the role of these costly and potentially toxic agents in patients spared CT by genomic signatures.

Overall survival analysis of first line CDK4/6 inhibitors in a large real-world cohort of patients with hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer.

e13095 Background: Multiple clinical trials have demonstrated the efficacy of the commercially available CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) as upfront therapy in patients (pts) with (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC). Recently, differences in overall survival (OS) benefit in MBC and invasive disease-free survival benefit in early-stage BC suggest greater potency of abemaciclib and ribociclib compared to palbociclib. Here we report a comprehensive OS analysis of a cohort of pts with HR+/HER2- MBC treated with ribociclib, palbociclib or abemaciclib and ET in 1st line setting. Methods: We retrieved medical records of pts with HR+/HER2- MBC receiving CDK4/6i as 1st line therapy between December 2013 and October 2023 at Memorial Sloan Kettering Cancer Center. We investigated the impact of clinico-pathological characteristics and treatment type as categorical variables on OS using uni- and multivariate Cox (proportional hazard) regression model. Any p-value (p) &lt;0.05 was deemed to be statistically significant. Results: 854 pts were included in the analysis, 838 females (98%) and 16 males at birth. The median age was 56 (IQR: 48-65). Overall, 722 (84%) pts received palbociclib, 88 (11%) abemaciclib, and 44 (5%) ribociclib. Most pts received aromatase inhibitor (AI) as ET backbone (n=634, 74%); 214 received fulvestrant (35%), and 6 received tamoxifen (1%). After a median follow-up of 3.14 years (range: 1.7-4.6), the median OS of the full cohort was 54.7 months (95%CI: 50-63.1). Clinico-pathological characteristics that resulted independently associated with worse OS were: male gender at birth (HR:2, 95%CI:1.4-4), disease-free interval ≤ 2 years (HR:1.64, 95%CI:1.11-2.44), ER-low status (HR: 2.27, 95%CI:1.42-3.63), high grade(HR: 1.28, 95%CI:1.01-1.62), liver involvement (HR: 1.48, 95%CI:1.08-2.03), and number of disease sites &gt;3 (HR:1.35, 95%CI:1.03-1.78). HER2-low status was associated with better OS (HR: 0.75, 95%CI:0.59-0.96). In terms of type of treatment, there was a trend toward improved OS in patients receiving AI rather than fulvestrant or tamoxifen (HR:0.76, 95%: 0.58-1), while the type of CDK4/6i did not affect the outcome. Conclusions: Clinical parameters of early relapse, high disease burden, and intrinsic tumor aggressiveness seem to be the main drivers of poor prognosis in patients with HR+/HER2- MBC in 1st line setting. In this analysis, type of CDK4/6i did not have a significant impact on OS, although pts treated with abemaciclib and ribociclib were underrepresented in the cohort due to the earlier and prevalent use of palbociclib as the first-in-class FDA-approved CDK4/6i. These data are reassuring about the use of palbociclib suggesting that a switch of CKD4/6i is not needed in pts with ongoing treatment and demonstrated benefit.

Predictive Impact of Tumor Mutational Burden on Real-World Outcomes of First-Line Immune Checkpoint Inhibition in Metastatic Melanoma.

The choice of threshold and reliability of high tumor mutational burden (TMB) to predict outcomes and guide treatment choice for patients with metastatic melanoma receiving first-line immune checkpoint inhibitor (ICI) therapy in the real world is not well known. Using a deidentified nationwide (US-based) melanoma clinicogenomic database, we identified a real-world cohort of patients with metastatic melanoma (N = 497) who received first-line monotherapy anti-PD-1 (n = 240) or dual anti-PD-1 and anti-CTLA-4 ICI (n = 257) and had a tissue-based comprehensive genomic profiling test TMB score. TMB-high (TMB-H; ≥10 mutations per megabase [muts/Mb], n = 352, 71%) was independently predictive of superior real-world progression-free survival and overall survival versus TMB-low (<10 mut/Mb, n = 145, 29%) in both mono ICI (hazard ratio [HR], 0.45 [95% CI, 0.32 to 0.63]; P < .001; HR, 0.61 [95% CI, 0.41 to 0.90]; P = .01, respectively) and dual ICI (HR, 0.67 [95% CI, 0.49 to 0.90]; P = .009; HR, 0.61 [95% CI, 0.42 to 0.88]; P = .007, respectively) patients. Dual ICI offered no significant advantage in BRAFwt patients and unexpectedly demonstrated greatest benefit in the TMB 10-19 mut/Mb group, identifying a TMB-very high (≥20 mut/Mb, n = 247, 50%) BRAFmut patient subgroup for whom mono ICI may be preferable. TMB-H predicts superior outcomes on ICI while coassessment of BRAF status and TMB may inform first-line regimen choice.

Remote monitoring is an independent predictor of better survival in patients with ischemic cardiomyopathy and implantable cardioverter-defibrillators

Abstract Introduction Despite improvements in pharmacotherapy and advancements in invasive techniques, patients with ischemic cardiomyopathy are at high risk of adverse events and death. Strategies aimed at improving prognosis, including patient-centered individualization of care are needed. Remote monitoring (RM) of patients with heart failure, which allows for a continuous assessment of device- and some patient-related parameters, has been shown to reduce the risk of hospitalization and death, although no analyses were focused specifically on patients with ischemic cardiomyopathy after percutaneous coronary intervention (PCI). Purpose To determine whether RM is associated with outcomes in patients with ischemic cardiomyopathy after percutaneous coronary intervention. Methods The clinical, echocardiographic and angiographic data of consecutive patients with ICM and ICD or CRT-D, who had undergone PCI were obtained from the single-centre COMMIT-HF registry. Each consecutive patient with ICM was offered RM at the discretion of the treating physician. The RM center in our facility monitors patients with cardiac implantable devices in all working days. In case of any clinical, or device-related events potentially requiring reaction, patients are telephonically invited to contact healthcare system, either in the local emergency departments, or in our hospital, or outpatient clinic. Patients supervised with RM undergo routine in-person visits in the outpatient device clinic every 12 months. In the conventional arm, routine visits in the outpatient clinic occur every 6 months. The long-term data were acquired from the National Health Fund – the sole Polish healthcare provider. The primary outcome of the study was 36-month all-cause mortality. Results In the years 2009-2017, there were a total of 1019 patients with ICM and ICD, who underwent PCI, and those constituted the study group. Of those, 227 (22.3%) were monitored remotely, while the remaining were treated conventionally. The studied groups did not differ significantly, apart from that the patients with RM had a history of CABG, and had a lower mean left ventricular ejection fraction (LVEF, 26% vs 32%, p&amp;lt;0.001) than subjects without RM, while the percentage of CRT-D devices was significantly higher in patients with RM (36.2% vs 6.2%, p&amp;lt;0.001). The 36-month all-cause mortality rate was 18.9% in patients monitored remotely and 25.3% in subjects without RM (p log rank = 0.028). In the multivariable analysis, RM was identified as an independent predictor of lower mortality. The other variables independently associated with higher survival were lower age, absence of anemia, optimal glomerular filtration rate, and higher LVEF. Conclusions Remote monitoring of patients with ischemic cardiomyopathy is independently associated with lower all-cause mortality in a real-world cohort of patients with ICDs.Baseline characteristicsMultivariable analysis

Treatment patterns in a real-world cohort of patients with Wilson disease in the United States

BackgroundWilson disease (WD) is a rare and potentially fatal genetic disorder caused by accumulation of toxic levels of copper. Current treatments include chelating agents and/or zinc. We characterized real-world US treatment patterns in patients with WD.MethodsThis retrospective, observational medical chart review utilized deidentified clinical data, including treatment patterns, abstracted from patient medical charts between 01/2012 and 06/2017. Line of therapy was assessed based on disease presentation and aggregated. Index treatment was defined as the first line of therapy, followed by second line of therapy and third line of therapy. Results were summarized using descriptive statistics.ResultsA total of 225 patients were included (mean [SD] age at diagnosis: 24.7 [9.8] years). Initial disease presentation was both neurologic/psychiatric and hepatic in 52.9%, followed by neurologic/psychiatric (20.0%), hepatic (16.9%), and asymptomatic (10.2%). Median (first and third quartiles) duration of follow-up from diagnosis was 39.5 (33.8–60.4) months. The most common first line of therapy was penicillamine monotherapy in 45.5%, followed by trientine monotherapy (26.1%) and chelator/zinc combination therapy (21.2%). A total of 167/222 (75.2%) patients remained on first line of therapy during the follow-up period. Of the 13.5% who switched to second line of therapy, most changed to trientine monotherapy (53.3%). All those who switched to third line of therapy transitioned to zinc monotherapy (100.0%). Unexpectedly, 11.3% discontinued first line of therapy without transitioning to a subsequent therapy. The primary rationale for index monotherapy selection was improved efficacy (61.6%). Most discontinuations were due to side effects/tolerability (40.8%). Treatment patterns varied by initial disease presentation, practice setting, physician specialty, and geographic location.ConclusionThese results demonstrate a lack of consensus in the US regarding first-line treatment for patients with WD. Evidence-based treatment pathways informed by high-quality clinical trials for improved health outcomes are needed.