Background: Brain metastases (BMs) are common in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer, increasing morbidity and mortality. Systemic therapy for BMs can be effective, with the triple combination of trastuzumab, capecitabine, and tucatinib being a potential standard. More recently, intracranial activity of antibodyedrug conjugates has been reported, but the size of individual studies has been small. Therefore, this patient-level pooled analysis was conducted. Patients and methods: This is a patient-level pooled analysis of the prospective phase II DEBBRAH and TUXEDO-1 trials and the retrospective DFCI/Duke/MDACC cohort. Patients with evaluable active BMs (defined as newly diagnosed and untreated or progressing with measurable tumor-related size after previous local therapy) from HER2-positive breast cancer (BC) and treated with trastuzumab deruxtecan (T-DXd) included in these studies were eligible. The primary endpoint was intracranial objective response rate (ORR-IC) by Response Assessment in Neuro-Oncology (RANO)-BM criteria. Results: Overall, 37 patients were assessable for intracranial response assessment. BMs progressing after prior local therapy were present in 64.9% of patients. The median patient age was 49.1 years. All patients had received prior trastuzumab and the median number of prior systemic treatment lines was 3 (0-13). The pooled ORR-IC by RANOBM criteria was 64.9% [95% confidence interval (CI) 47.5% to 79.8%] with low heterogeneity observed between the studies included. The clinical benefit rate by RANO-BM was 81.1% (95% CI 64.8% to 92.0%). The median progression-free survival was 13.3 months (95% CI 8.4-22.6 months) and the median overall survival was 22.5 months (95% CI 14.9 months-not achieved) with high heterogeneity between studies and numerically longer in patients with few prior treatment lines. Quality of life remained stable throughout treatment, with no new safety concerns. Conclusions: This patient-level pooled analysis of DEBBRAH, TUXEDO-1, and the DFCI/Duke/MDACC cohort indicates clinically relevant intracranial activity of T-DXd in patients with active HER2-positive BC, BMs, and extensive systemic pretreatment. The results therefore support the use of T-DXd when clinically indicated irrespective of BMs.

History of malignant disease is a common exclusion criterion in clinical cancer trials, yet data on the impact of cancer survivorship on outcome in gastroesophageal cancer patients are scarce. Retrospective association analyses of self-reported prior or concurrent malignancies with patient characteristics, tumor characteristics, symptoms and overall survival (OS) were performed in 1491 gastroesophageal cancers patients treated between 01/01/2000 and 31/12/2021 at the Medical University of Vienna. Of 1491 patients 255 (18

Further evaluation of HER3 expression in BM of breast and lung cancer.

Background:Brain metastases (BM) frequently occur in patients with non-small cell lung cancer (NSCLC) with actionable genomic alterations (AGA). Targeted therapies (TTs) improve outcomes, but differences in BM screening and eligibility criteria across trials make comparisons challenging. While stage IV NSCLC guidelines recommend BM screening, it is not mandatory, and imaging techniques vary. Methods:Registrational and phase II/III trials of FDA/EMA-approved TTs for advanced NSCLC with AGA, published since 2012, were included. Main focus of the review was evaluation of baseline brain screening practices across trials. Information on BM follow-up, BM incidence, and BM-related outcomes was retrieved. Results:Of 51 trials, 71% mandated baseline BM screening, and 27% mandated follow-up imaging for all patients. MRI was specified for BM assessment in 31% of the trials. BM incidence at baseline was high, up to 40% in the first-line setting. While most trials included patients with BM, eligibility criteria varied, and 43% of trials prespecified BM-related outcomes; 56% of phase III trials used BM as a stratification factor. Conclusion:This review highlights the increasing attention to BM screening in NSCLC TT trials. However, substantial heterogeneity remains in BM eligibility, screening, outcomes, and follow-up. Standardizing these aspects in future trials is essential.

Background: A significant proportion of women in reproductive age are diagnosed with diffuse gliomas, resulting in the need to address the safety of pregnancy in patient consultation. However, data on glioma progression after and during pregnancy are sparse and controversial. Methods: Female adult patients in their reproductive years (>= 18 years and <46 years) with histological diagnosis of glioma between 01/01/2000 and 01/12/2019 from 2 academic centers have been included in the study. Reclassification according to the 2021 WHO classification of CNS tumours was performed. The cohort was divided into 3 groups, defined as (A) nulliparae, (B) primi-/multiparae before glioma diagnosis, and (C) primi-/multiparae after glioma diagnosis. Survival analyses were performed in a time-dependent manner with parity as timedependent covariate. Results: 159/368 females met our inclusion criteria, resulting in 47 (29.6 %) nulliparae, 88 (55.3 %) primi-/ multiparae before glioma diagnosis and 24 (15.1 %) primi-/multiparae after glioma diagnosis. Median follow-up was 127.4 months (range 0.7-341.9), and median overall survival and progression free survival were 247.6 months (range 0.4-269.1) and 67.9 months (range 0.7-341.9), respectively. Overall, 113/159 (71.1 %) patients had tumour progression and 53/159 (33.3 %) deceased. In total, 57.4 % of the nullipara, 76.1 % of the primi-/ multipara before glioma diagnosis and 79.1 % of the primi-/multipara after glioma diagnosis groups experienced tumour progression (p > 0.05). In multivariate time-dependent analysis, primi-/multiparae after glioma diagnosis presented with shorter progression free (HR 2.45, p = 0.0079), but not overall survival (HR 0.54, p > 0.05) in comparison to the other two groups. Conclusion: Pregnancy after glioma diagnosis was associated with shorter progression free survival. Longer follow-up as well as larger cohorts are needed to investigate a potential impact on overall survival.

The hemostatic system is tightly interconnected with cancer. Research has focused predominantly on thrombotic complications, but less is known about bleeding and bleeding risk prediction. Growth differentiation factor (GDF)-15 has previously emerged as a prognostic biomarker for bleeding. The aim of this study was to investigate the association and predictive ability of GDF-15 for bleeding risk in patients with cancer. The CAT-BLED (Vienna Cancer, Thrombosis, and Bleeding) study is a prospective, observational cohort study including cancer patients initiating systemic anticancer therapies. Patients were followed for up to 2 years for thrombotic and bleeding events. The primary outcome was major bleeding. GDF-15 was measured at inclusion and at 3 and 6 months of follow-up. A total of 779 patients (48% women, median age 62 years, 15% on therapeutic anticoagulation) were included. During a median follow-up period of 18 months, 79 patients (10.1%) experienced major bleeding (12-month cumulative incidence 8.8%; 95% CI: 6.7-10.9). Higher GDF-15 levels were independently associated with increased major bleeding risk (adjusted subdistribution HR per doubling: 1.29; 95% CI: 1.04-1.59), and patients with levels greater than the cohort median (1,864 ng/L) had a significantly higher 12-month cumulative incidence (13.1% vs 4.6%; P < 0.001). This association remained robust in follow-up measurements at 3 and 6 months. GDF-15 showed moderate to good discrimination for predicting 6-month major bleeding risk (C statistic = 0.69; 95% CI: 0.60-0.77). GDF-15 was not associated with venous thromboembolism but was strongly associated with mortality (adjusted HR: 1.37; 95% CI: 1.25-1.50). GDF-15 levels predict major bleeding risk in cancer patients and are not associated with venous thromboembolism, making GDF-15 a particularly promising biomarker for bleeding risk prediction.

Kaplan-Meier curves of patients with BM of A) Luminal-BCa B) HER2+ BCa C) TN-BCa, and D) NSCLC patients stratified according to the intensity of HER3 expression determined by IHC.

The prognosis of diffuse gliomas previously classified as “lower-grade” is heterogeneous and complicates clinical decisions. We aimed to investigate the molecular profile of clinical outliers to gain insight into biological drivers of long and short-term survivors. Here, patients aged ≥ 18 years and diagnosed with diffuse glioma, WHO grade II/2 or III/3 were included. Short-term survivors (STS) were defined as overall survival (OS) < 1 years, and long-term survivors (LTS) as OS > 10 years. DNA methylation profiling was performed using the Illumina EPIC 850k platform. In total, 385 patients (294 LTS, 91 STS) were included. Median overall survival was 234 months (95

Baseline characteristics of patients used for genome-wide DNA-methlyation analysis, stratified into HER3-positive and HER3-negative

Immune cell infiltration in BM of the three subtypes of BCa: Luminal (A), HER2-positive (B) and Triple-negative breast cancer (TNBC) (C).

BACKGROUND:Improved prognostic stratification, including imaging-based parameters, is needed to guide treatment decisions in IDH-mutant glioma. METHODS:In this bicentric retrospective study, 457 patients with IDH-mutant glioma and [18F]fluoroethyltyrosine or [11C]methionine positron emission tomography (PET) prior to radiotherapy or systemic treatment were included. Associations of maximum and mean tumor-to-background ratios (TBRmax/TBRmean) and PET-positive volume (PET volume) with time to next intervention (TTNI) and overall survival (OS) were analyzed. RESULTS:Overall, 251 (54.9%) patients with astrocytoma and 206 (45.1%) with oligodendroglioma were included. In patients with astrocytoma who underwent PET before resection, measurable disease according to PET RANO 1.0 criteria was associated with shorter TTNI compared to no/non-measurable disease (median 46.0 vs. 67.9 months; P = .004). Univariable analysis showed an association of TTNI with TBRmax, TBRmean, and PET volume in astrocytoma and PET volume in oligodendroglioma. Multivariable analyses including age, WHO grade, extent of resection, postoperative treatment, and magnetic resonance imaging (MRI)-based tumor extent indicated an association of TTNI with TBRmax (HR 1.48 [95%CI: 1.09-2.01]) and TBRmean (HR 1.93 [95%CI: 1.14-3.27]) in astrocytoma and PET volume (HR [10 ml increase]: 1.18 [95%CI: 1.03-1.36]) in oligodendroglioma. In astrocytoma, also OS was related to TBRmax (HR: 1.40 [95%CI: 1.13-1.74]), TBRmean (HR: 1.97 [95%CI: 1.21-3.22]), and PET volume (HR: 1.23 [95%CI: 1.10-1.37]) in univariable analysis. Further analyses considering timepoint of PET showed consistent results. CONCLUSIONS:In this retrospective study, amino acid PET parameters were associated with outcome in newly diagnosed IDH-mutant glioma. Future clinical trials should include PET imaging to define imaging-based prognostic signatures.

2005 Background: BM and LMD are common and severe complications of solid cancers with high morbidity, poor prognosis, and limited treatment options. Antibody drug conjugates (ADCs) have shown high intracranial overall response rates (IC-ORR) in HER2-positive mBC and EGFR -mutated NSCLC patients (pts). HER3-DXd, an ADC combining an anti-HER3 antibody with a topoisomerase (topo) I inhibitor, has shown promising results in mBC and aNSCLC pts. Since HER3 is highly expressed in aNSCLC and mBC CNS metastases, we hypothesized HER3-DXd may have clinical activity in BM from mBC and aNSCLC pts, and LMD from any solid tumor. Methods: TUXEDO-3 (NCT05865990) is an international, multicenter, multicohort, single-arm, phase II trial enrolling pts with BM from mBC (cohort 1), aNSCLC (cohort 2), and LMD from any solid tumor (cohort 3). Key inclusion criteria were: Pts ≥18 years old, histologically documented disease, ECOG PS 0-2, and left ventricular ejection fraction ≥50% in all cohorts; newly diagnosed/progressing BM with ≥1 brain lesions ≥10mm by MRI, and ≥1 line of prior systemic treatment, in cohorts 1 and 2; LMD per EANO-ESMO in cohort 3. Pts received HER3-DXd 5.6 mg/kg IV Q3W until disease progression, unacceptable toxicity or withdrawal for any reason. Primary endpoint was IC-ORR per local investigator according to RANO-BM in cohorts 1 and 2, and 3-month OS in cohort 3. Sample size was based on Simon’s two-stage design. Primary endpoint was met if ≥3 IC responses (H0: ≤5%; H1: ≥25%) in cohort 1 and 2; and if ≥3 pts with 3-month OS (H0: ≤5%; H1: ≥25%) in cohort 3. Overall sample size was 60 pts with a target population of 20 pts per cohort. Results: Between December 2023 and July 2024, 61 evaluable pts were enrolled from 8 Austrian and Spanish sites. Median age (min; max) was 57.0 (35.0; 75.0), 59.5 (37.0; 72.0) and 51.5 (40.0; 66.0) years in cohorts 1, 2 and 3, respectively. At data cut-off, median follow-up (min; max) was 4.4 (1.4; 10.1), 4.3 (0.2; 11.0) and 3.5 (0.8; 8.6) months in cohorts 1, 2 and 3, respectively. Primary endpoints were met in all three cohorts. In cohort 1, 5/21 (23.8%) pts had IC response irrespective of BC subtype; 2 (40.0%) responders had received previous topo I based ADCs. In cohort 2, 5/20 (25.0%) pts had IC response. In cohort 3, 11/20 (55.0%) pts achieved 3-month OS irrespective of the LMD type. No new signals of toxicity were observed and neurological symptoms, QoL and neurocognitive function remained stable or improved over the treatment period. Tumoral HER3 expression did not correlate with treatment response. Conclusions: TUXEDO-3 is the first trial evaluating efficacy and safety of HER3-DXd in pts with BM or LMD. HER3-DXd showed substantial CNS activity in parenchymal metastases and LMD, and may be a potential novel treatment for CNS disease in cancer pts. Clinical trial information: NCT05865990 .

Existing prognostic models for breast cancer (BC) brain metastases (BM) overlook neurological symptoms. Thus, we explored the incidence and prognostic relevance of neurological symptoms in a real-world cohort of BC patients with BM. The Vienna Brain Metastasis Registry identified BC patients with BM between 1992 and 2020, categorised by subtype: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−), HER2 overexpressing (HER2+), and triple-negative (TN). A total of 716 patients with BM from BC were included. In total, 80% (573/716) of the patients presented with neurological symptoms at BM diagnosis. Across all BC subtypes, asymptomatic patients presented with a significantly longer median OS from diagnosis of BM compared to symptomatic patients (p < 0.05; log-rank test; HR+ BC 29 vs. 9 months; HER2+ BC 24 vs. 12 months; TN 12 vs. 6 months). In multivariate analysis with the BC-specific Graded Prognostic Assessment (Breast-GPA: HR:1.4; 95% CI:1.3–1.5; p < 0.001), the presence of neurological symptoms at diagnosis (HR:1.6; 95% CI: 1.4–1.9; p < 0.001) presented as independently associated with OS from time of BM diagnosis, respectively. Neurological burden at BM diagnosis independently predicts survival in BC patients. Our findings emphasise incorporating the symptom status in the prognostic evaluation and reassessing BM screening in high-risk patients during prospective clinical trials.

Protocols used for IHC stainings on the Ventana Benchmark ULTRA device

Meningiomas are the most common primary intracranial tumors of adults. For meningiomas that progress or recur despite surgical resection and radiotherapy, additional treatment options are limited due to a lack of proven efficacy. Meningiomas show recurring molecular aberrations, which may serve as predictive markers for systemic pharmacotherapies with targeted drugs or immunotherapy, radiotherapy, or radioligand therapy. Here, we review the evidence for a predictive role of a wide range of molecular alterations and markers including NF2, AKT1, SMO, SMARCE1, PIK3CA, CDKN2A/B, CDK4/6, TERT, TRAF7, BAP1, KLF4,ARID1/2, SUFU, PD-L1, SSTR2A, PR/ER, mTOR, VEGF(R), PDGFR, as well as homologous recombination deficiency, genomic copy number variations, DNA methylation classes, and combined gene expression profiles. In our assessment based on the established ESMO ESCAT (European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets) evidence-level criteria, no molecular target reached ESCAT I ("ready for clinical use") classification, and only mTOR pathway activation and NF2 alterations reached ESCAT II ("investigational") classification, respectively. Our evaluations may guide targeted therapy selection in clinical practice and clinical trial efforts and highlight areas for which additional research is warranted.

Background: Patients with cancer undergoing systemic therapies have a high risk for venous thromboembolism (VTE). Risk assessment models were developed to select high-risk subgroups that might benefit from primary thromboprophylaxis, yet currently available models reportedly underperform in contemporary cancer treatment populations and risk models across multiple time points throughout therapy are not available. Patients and methods: We, therefore, aimed to validate the Vienna CATScore, a nomogram-based model including tumor type and continuous D-dimer levels, in a prospective cohort study of patients initiating contemporary systemic anticancer therapies. The validity of the model was tested at study inclusion, 3 weeks, and 3 months after start of therapy. Results: Overall, 598 patients were included [49% women, median age 62 years (interquartile range 53-70 years)]. Most patients had stage IV disease (68.2%). The 6-month cumulative incidence of VTE was 9.2% [95% confidence interval (CI) 6.8% to 11.5%]. The Vienna CATScore demonstrated good discriminatory ability (c-statistics: 0.69, 95% CI 0.61-0.76) at study baseline and across all evaluated time points (c-statistics: 0.68, 95% CI 0.63-0.73). Applying a 6-month predicted VTE risk threshold of 8%, the CATScore effectively distinguished between low- and high-risk groups at study inclusion (7.1% versus 15.1% observed VTE risk, P = 0.004) and across all three time points (6.3% versus 13.6% observed VTE risk, P < 0.001). Assuming a 50% risk reduction with thromboprophylaxis, this threshold resulted in a number needed to treat (NNT) of 13 and 15, respectively, in the high-risk group, while the NNT was 28 and 32, respectively, in the low-risk group. Conclusions: This external validation of the Vienna CATScore confirms its effectiveness in predicting VTE risk in the initial months of state-of-the-art systemic anticancer therapies and across multiple time points.

Pathway enrichment analysis of genes associated with differentially methylated CpG sites in HER3+ vs. HER3-