High Risk Of Brain Metastases Research Articles

Brain metastasis burden and management in patients with small cell lung cancer in Canada: a retrospective, population-based cohort study

Patients with small cell lung cancer (SCLC) have historically been characterised by poor overall survival (OS) and high risk for brain metastasis (BM), but large-scale real-world evidence on clinical presentation and treatment in this population is lacking. Our aim was to describe the clinical characteristics and outcomes of patients with SCLC and BM in Ontario, Canada. This population-based, retrospective cohort study included all patients in Ontario, Canada, who were diagnosed with SCLC between April 1, 2010, and March 31, 2018. Data were analysed between June 2, 2022, and December 20, 2023. Patients with second cancer diagnosis were excluded. Patients were identified and data retrieved from the Institute for Clinical Evaluative Sciences (ICES) databases. Kaplan-Meier and multivariable Cox regression analyses were performed to compare OS between patient cohorts stratified by disease stage, BM diagnosis, and intracranial treatment modality. Propensity score-matching based on age, disease stage, time to BM, and receipt of chemotherapy was performed to compare OS between intracranial treatment modalities. 8705 patients were included (male: 4433, female: 4272). Median age at diagnosis was 68 years (interquartile range, IQR, 61-75). Median OS of all patients was 7.46 months (95% confidence interval, CI, 7.23-7.69). 32% (n=2686) of patients developed BM (synchronous, 43.7%; asynchronous, 56.3%) with median OS of 9.76 months (95% CI, 9.36-10.22). 102 (4%), 1654 (62%), and 930 (35%) patients received stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), or no treatment, respectively, for their BM in the first-line setting or after prophylactic cranial irradiation (PCI). In propensity score-matched analyses, OS from time of BM diagnosis was non-inferior between SRS- and WBRT-treated cohorts among patients who did not receive PCI (hazard ratio, HR, 0.68, 95% CI, 0.44-1.06, p=0.091, n=86) and in favour of SRS for those who received PCI prior to BM development (HR, 0.47, 95% CI, 0.31-0.72, p=0.0042, n=112). OS for patients with SCLC remains poor, and many patients present with BM. With careful selection, patients with SCLC and BM may benefit from SRS treatment. Future research should incorporate information on burden of intracranial disease and novel immunotherapies. None.

Association of Granulocyte Colony-Stimulating Factor Treatment with Risk of Brain Metastasis in Advanced Stage Breast Cancer.

The routine use of granulocyte colony-stimulating factor (GCSF) is not recommended for the prevention or treatment of chemotherapy-induced neutropenia or febrile neutropenia because risks associated with certain types of cancers, distant organ metastases, and primary tumor growth cannot be excluded. We examined the association between GCSF use and the incidence of brain metastasis (BM), as well as BM-free survival (BMFS). This retrospective cohort study included 121 stage IV breast cancer patients without confirmed BM at the time of diagnosis and who received at least one course of systematic chemotherapy or target therapy at a tertiary teaching hospital between 1 January 2014 and 31 December 2022. The effect of GCSF use on BM was assessed with other confounding factors in Cox regression analyses. In this retrospective cohort, patients who received GCSF treatment had a significantly higher incidence of BM than those who did not (34.9% vs. 13.8%, p = 0.011). Univariate Cox regression analysis showed that GCSF use, menopause status, hormone treatment, HER2 treatment, cumulative dosage, dosage density, and neutropenia were independent risk factors for BMFS (p < 0.05). GCSF users had a higher risk of BM (adjusted HR: 2.538; 95% CI: 1.127-5.716, p = 0.025) than nonusers. BM risk was significantly associated with those with neutropenia (RR: 1.84, 95% CI: 1.21, 2.80) but not with those without neutropenia (RR: 0.59, 95% CI: 0.41-0.84, Interaction p-value < 0.05). The higher the dose density of GCSF, the higher the risk compared with those who do not use GCSF (p for trend < 0.01). These preliminary results suggest that GCSF is associated with BM in patients with stage IV breast cancer who did not have BM at initial diagnosis. Further comprehensively designed large-scale observational studies are needed to confirm our preliminary results.

Application of random survival forest to establish a nomogram combining clinlabomics-score and clinical data for predicting brain metastasis in primary lung cancer.

To establish a nomogram for predicting brain metastasis (BM) in primary lung cancer at 12, 18, and 24months after initial diagnosis. In this study, we included 428 patients who were diagnosed with primary lung cancer at Harbin Medical University Cancer Hospital between January 2020 and January 2022. The endpoint event was BM. The patients were randomly categorized into two groups in a 7:3 ratio: training (n = 299) and validation (n = 129) sets. Least absolute shrinkage and selection operator was utilized to analyze the laboratory test results in the training set. Furthermore, clinlabomics-score was determined using regression coefficients. Then, clinlabomics-score was combined with clinical data to construct a nomogram using random survival forest (RSF) and Cox multivariate regression. Then, various methods were used to evaluate the performance of the nomogram. Five independent predictive factors (pathological type, diameter, lymph node metastasis, non-lymph node metastasis and clinlabomics-score) were used to construct the nomogram. In the validation set, the bootstrap C-index was 0.7672 (95% CI 0.7092-0.8037), 12-month AUC was 0.787 (95% CI 0.708-0.865), 18-month AUC was 0.809 (95% CI 0.735-0.884), and 24-month AUC was 0.858 (95% CI 0.792-0.924). In addition, the calibration curve, decision curve analysis and Kaplan-Meier curves revealed a good performance of the nomogram. Finally, we constructed and validated a nomogram to predict BM risk in primary lung cancer. Our nomogram can identify patients at high risk of BM and provide a reference for clinical decision-making at different disease time points.

Breast Tumor Cell Survival and Morphology in a Brain-like Extracellular Matrix Depends on Matrix Composition and Mechanical Properties.

Triple-negative breast cancer (TNBC) is the most invasive type of breast cancer with high risk of brain metastasis. To better understand interactions between breast tumors with the brain extracellular matrix (ECM), a 3D cell culture model is implemented using a thiolated hyaluronic acid (HA-SH) based hydrogel. The latter is used as HA represents a major component of brain ECM. Melt-electrowritten (MEW) scaffolds of box- and triangular-shaped polycaprolactone (PCL) micro-fibers for hydrogel reinforcement are utilized. Two different molecular weight HA-SH materials (230 and 420kDa) are used with elastic moduli of 148 ± 34Pa (soft) and 1274 ± 440Pa (stiff). Both hydrogels demonstrate similar porosities. The different molecular weight of HA-SH, however, significantly changes mechanical properties, e.g., stiffness, nonlinearity, and hysteresis. The breast tumor cell line MDA-MB-231 forms mainly multicellular aggregates in both HA-SH hydrogels but sustains high viability (75%). Supplementation of HA-SH hydrogels with ECM components does not affect gene expression but improves cell viability and impacts cellular distribution and morphology. The presence of other brain cell types further support numerous cell-cell interactions with tumor cells. In summary, the present 3D cell culture model represents a novel tool establishing a disease cell culture model in a systematic way.

Blood Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Promising Screening Biomarkers for Brain Metastases in Patients with Lung Cancer.

The diagnosis of brain metastases (BMs) in patients with lung cancer (LC) predominantly relies on magnetic resonance imaging (MRI), a method that is constrained by high costs and limited accessibility. This study explores the potential of serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) as screening biomarkers for BMs in LC patients. We conducted a retrospective analysis of 700 LC cases at the National Cancer Center, Korea, from July 2020 to June 2022, measuring sNfL and sGFAP levels at initial LC diagnosis. The likelihood of BM was evaluated using multivariate analysis and a predictive nomogram. Additionally, we prospectively monitored 177 samples from 46 LC patients initially without BM. Patients with BMs (n= 135) had significantly higher median sNfL (52.5 pg/mL) and sGFAP (239.2 pg/mL) levels compared to those without BMs (n = 565), with medians of 17.8 pg/mL and 141.1 pg/mL, respectively (p < 0.001 for both). The nomogram, incorporating age, sNfL, and sGFAP, predicted BM with an area under the curve (AUC) of 0.877 (95% CI 0.84-0.914), showing 74.8% sensitivity and 83.5% specificity. Over nine months, 93% of samples from patients without BM remained below the cutoff, while all patients developing BMs showed increased levels at detection. A nomogram incorporating age, sNfL, and sGFAP provides a valuable tool for identifying LC patients at high risk for BM, thereby enabling targeted MRI screenings and enhancing diagnostic efficiency.

A phase II trial combining SHR-1316, bevacizumab, and cisplatin/carboplatin in patients with TNBC with active brain metastases.

e13133 Background: Triple-negative breast cancer (TNBC) has a high risk of brain metastases (BM), leading to poor survival. Treatment options for BMs are limited, and the combination of chemotherapy and immune checkpoint inhibitor is the standard-of-care for PD-L1 positive metastatic TNBC. Platinum-based systematic therapy is the mainstay of TNBC treatment and the addition of bevacizumab has shown improvement in the progression-free survival (PFS) of patients with BM. Therefore, this study aims to investigate the efficacy and safety of SHR-1316 (anti-PD-L1) in combination with bevacizumab and cisplatin/carboplatin in TNBC patients with BMs. Methods: In this single-center phase II trial, TNBC patients with active BM received SHR-1316, bevacizumab, and cisplatin/carboplatin. Prior treatment with bevacizumab or anti-PD-1/PD-L1 were not allowed. Prior platinum was allowed only in cases of previous platinum-sensitive response. The primary endpoint was objective response rate (ORR) of central nervous system (CNS), as assessed according to the response assessment in neuro-oncology brain metastases. The secondary endpoint included clinical benefit rate (CBR) of CNS, PFS, overall survival (OS), first progression site and safety. Results: As of January 12th, 2024, a total of 23 female patients with ECOG PS≥1(100%) were enrolled. The median number of previous lines of therapy for metastatic disease was 1 (0-3). All patients had active BM, of which 87% (20/23) were BM treatment-naïve and 13% (3/23) had BM progression after previous local therapy, 26.1% (6/23) had received a prior platinum agent. Of the 23 evaluable patients, the confirmed CNS ORR was 65.2% (95%CI: 42.7%-83.6%), with 3 complete response (CR), 12 partial response (PR), 7 stable disease (SD), and 1 progressive disease (PD). The median CNS-PFS was 11.2 months (95%CI, 5.8 to not reached), median PFS was 7.6 months (95%CI, 5.7-11.9), and median OS was 13.2 months (95%CI, 9.5 to not reached). Treatment-related adverse events (TRAEs) were reported in all 23 patients, and the most common TRAEs were neutrophil count decreased (69.6%, 16/23), anemia (65.2%, 15/23), asthenia (60.9%, 14/23), Hypomagnesaemia (56.5%, 13/23), leukopenia (52.2%, 12/23) and electrocardiogram T wave abnormal (52.2%, 12/23). The incidence of grade ≥3 TRAEs was 43.5% (10/23), including neutropenia (13%, 3/23), platelet count decreased (8.7%, 2/23), and hypertension (8.7%, 2/23). Only one patient had a grade 4 TRAE (lymphocytopenia), and SHR-1316 related serious adverse event (facial nerve disorder) occurred in only one patient. No grade 5 AEs were noted. Conclusions: SHR-1316 plus bevacizumab and cisplatin/carboplatin achieves a significant improvement in CNS ORR and brings PFS and OS benefits in TNBC patients with active BMs. As an effective and safe treatment, this triple-combination warrants further investigation. Clinical trial information: NCT04303988 .

Prediction of brain metastases of breast cancer using next generation sequencing genomics.

e14004 Background: Breast cancer was the most common malignancy diagnosed in 2023 with over 300,000 new diagnoses. Though it is highly treatable when caught in early stages, metastatic disease is highly morbid. Approximately 0.4% of all cases and 7.2% of cases of metastatic breast cancer will develop brain metastases. Hormonal receptors correlate poorly with risk of brain metastasis. Predictive factors for breast cancer brain metastases remain elusive. This project aimed to identify genomic risk factors for the metastasis of breast cancer to the brain. Methods: We created a retrospective cohort of all breast cancer patients with next generation sequencing (NGS) at a comprehensive cancer center and its associated clinics. All NGS in the cohort was performed by FoundationOne. Brain metastases were defined via ICD-10 codes. Univariate analysis was performed using Fisher’s Exact test. Significance was defined as p&lt;0.05 after adjustment of multiple testing corrections performed using the Benjamini-Hockberg procedure. A multivariable logistic regression model was fit; to avoid overfitting, the maximum number of covariables was defined by requiring 10 cases for every variable included. Model fit was compared by the Akaike information criterion (AIC) statistic. SAS v9.4 was used for all analyses. Results: This final cohort included 242 patients, of which 29 (12%) developed brain metastases. Among the standard panel of 223 tested genes, 11 were significantly associated with brain metastases after multiple testing correction. Significant genes included: TP53, GATA3, PIK3CA, EP300, MSH3, NTRK1, BRCA1, CBFB, FGFR4, MAP2K2, and NOTCH2. TP53 was the most prevalent gene mutation amongst brain metastases patients. The gene was present in 79% (23/29) of all brain metastases cases and 96% (23/24) of patients with TP53 had brain metastasis. PIK3CA and GATA3 were the next most common in 10 (34%) and 6 (21%) cases respectively. In building predictive models, the optimal model included TP53, GATA3, and CBFB which presented an AIC of 33.15 and an AUC of 0.98. The best two variable model included TP53 and PIK3CA with AIC of 49.67 and AUC of 0.95. Conclusions: Among this cohort, 11 genes were found to be significantly associated with the development of brain metastases. Among them, TP53 was the most prevalent while GATA3, PIK3CA, and CBFB also contributed to predictive ability. These variables suggest high levels of predictability, though given the limited sample thorough validation will be required. However, given the numerous genes found to be associated and the significant starting predictivity, there is potential for NGS to identify those at higher risk of brain metastases. Further study and expansion of NGS will be needed to validate these results and investigate the timing of brain metastases for the potential of early detection.

Abstract PO5-03-03: Nomogram for predicting brain metastasis in early-stage breast cancer patients

Abstract Nomogram for predicting brain metastasis in early-stage breast cancer patients Background: Brain metastasis is a significant concern for patients with early-stage breast cancer, as it can have a detrimental impact on survival and quality of life. Clinical and pathological characteristics of the primary tumor may be modeled into a nomogram that can predict the risk of brain metastasis. The goal is to create a nomogram and clinical calculator to assist in selection of patients with high risk of brain metastasis to enrich patient population for accrual on clinical trials for the purpose of preventing or delaying emergence of brain metastasis, at an early stage of their disease. Methods: We reviewed all early-stage breast cancer patients (stages I to III) N=40290 from the University of Texas MD Anderson Cancer Center, Houston, TX, from 1/1/1997 to 5/8/2020. We utilized multiple predictive statistical models to identify the most relevant variables and optimal predictive criteria. Variables for the model included patient age, tumor characteristics (such as grade,hormone receptor and HER2 status) and medical treatment (such as chemotherapy and endocrine therapy). The Receiver Operating Characteristic (ROC), and its AUC (area under the curve) was used to demonstrate the performance of the multivariate model to predict the occurrence of brain metastasis at different time points (1 year, 2 years, and 5 years), distinguishing between patients who develop brain metastasis in a time-dependent manner and those who do not. Results: The results showed the following clinical variables to be statistically significant in predicting brain metastasis: younger age, high estrogen and progesterone receptor percentage, higher tumor size; use of aromatase inhibitor therapy, and use of selective estrogen receptor modulator therapy were associated with a decreased risk of brain metastasis. Higher grade, Ki-67 levels, HER2-positive status, lymphovascular invasion and the use of chemotherapy was associated with an increased risk. The AUC values for the prediction of brain metastasis at different time points are as follows: 0.85 at 1 year, 0.83 at 2 years, and 0.82 at 5 years. These values indicate that the multivariate model has good discriminative ability, with higher values indicating a better predictive performance. An AUC of 0.85 suggests that the model has a high probability of correctly distinguishing between patients who will develop brain metastasis and those who will not at 1 year. Conclusions: Our predictive tool holds promise in assisting clinicians when making informed, personalized care decisions for patients at risk of developing brain metastasis. The model will be validated using independent patient cohorts from Institut Jules Bordet, Brussel, Belgium, to assess their accuracy and reproducibility. Continued research and validation will further refine these models, increasing their reliability and their clinical/clinical research applicability. Citation Format: Akshara Singareeka Raghavendra, Nuria Kotecki, Kristofer Jennings, Ottavia Amato, Debu Tripathy, Ahmad Awada, Nuhad Ibrahim. Nomogram for predicting brain metastasis in early-stage breast cancer 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 PO5-03-03.

Abstract 6465: A population-based analysis of brain metastasis burden and management in 8705 small cell lung cancer patients

Abstract Introduction: Patients with small cell lung cancer (SCLC) have historically been characterized by poor overall survival (OS) and high risk for brain metastases (BM), but large-scale real-world evidence on clinical presentation and treatment in this population is lacking. Methods: The aim of this study was to describe the clinical characteristics and outcomes of patients with SCLC and BM in Ontario, Canada. This retrospective cohort study included all patients in Ontario, Canada, who were diagnosed with SCLC between April 2010 and March 2018. Data were analyzed between June 2022 and July 2023. Kaplan-Meier and multivariable Cox regression analyses were performed to compare overall survival (OS) between patient cohorts stratified by disease stage, BM diagnosis, or first-line intracranial treatment modality. Results: 8705 patients were included. Median age at diagnosis was 68 years (range 18-103). Median OS of all patients was 7.46 months (95% confidence interval, CI, 7.23-7.69). 32% (n=2686) of patients developed BM (synchronous, 43.7%; asynchronous, 56.3%) and had median OS of 9.76 months (95% CI, 9.36-10.22). 102, 1654, and 880 patients received stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), and no treatment, respectively, for their BM in the first-line setting or after prophylactic cranial irradiation (PCI). In propensity score-matched analyses, OS was equivocal between SRS- and WBRT-treated cohorts among patients who did not receive PCI (hazard ratio, HR, 1.18, 95% CI, 0.75-1.81) and those who received PCI prior to BM development (HR, 0.77, 95% CI, 0.53-1.13). Conclusions: Survival for patients with SCLC remains poor, and many patients present with BMs. With careful selection, patients with SCLC may benefit from SRS treatment. Citation Format: Karolina Gaebe, Anders W. Erickson, Sarah Chen, Arjun Sahgal, Benjamin H. Lok, Kelvin K. Chan, Sunit Das. A population-based analysis of brain metastasis burden and management in 8705 small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6465.

Proteomics-based Model for Predicting the Risk of Brain Metastasis in Patients with Resected Lung Adenocarcinoma carrying the EGFR Mutation.

Introduction: Epidermal growth factor receptor (EGFR) mutation is common in Chinese patients with lung adenocarcinoma (LUAD). Brain metastases (BMs) is high and associated with poor prognosis. Identification of EGFR-mutant patients at high risk of developing BMs is important to reduce or delay the incidence of BMs. Currently, there is no literature on the prediction and modeling of EGFR brain metastasis at the proteinomics level. Methods: We conducted a retrospective study of BMs in postoperative recurrent LUAD with EGFR mutation in the First Affiliated Hospital of Guangzhou Medical University. Tissue proteomic analysis was applied in the primary tumors of resected LUAD in this study using liquid chromatography-mass spectrometry (LC-MS/MS). To identify potential markers for predicting LUAD BM, comparative analyses were performed on different groups to evaluate proteins associated with high risk of BMs. Results: A combination of three potential marker proteins was found to discriminate well between distal metastasis (DM) and local recurrence (LR) of postoperative LUAD with EGFR mutation. Gene Ontology (GO) analysis of significantly altered proteins between BM and non-BM (NBM) indicated that lipid metabolism and cell cycle-related pathways were involved in BMs of LUAD. And the enriched pathways correlated with BMs were found to be quite different in the comparison groups of postoperative adjuvant therapy, tyrosine kinase inhibitor (TKI), and chemotherapy groups. Finally, we developed a random forest algorithm model with eight proteins (RRS1, CPT1A, DNM1, SRCAP, MLYCD, PCID2, IMPAD1 and FILIP1), which showed excellent predictive value (AUC: 0.9401) of BM in patients with LUAD harboring EGFR mutation. Conclusions: A predictive model based on protein markers was developed to accurately predict postoperative BM in operable LUAD harboring EGFR mutation.

Re-examining prophylactic cranial irradiation in small cell lung cancer: a systematic review and meta-analysis

Patients with small cell lung cancer (SCLC) are at high risk for brain metastases. Prophylactic cranial irradiation (PCI) is recommended in this population to reduce the incidence of brain metastases and prolong survival. We aimed to assesses the efficacy of PCI in this population in the era of routine brain imaging. To our knowledge, this is the first systematic review and meta-analysis to examine the use among patients who were radiographically confirmed not to have brain metastases after completion of first-line therapy. In this systematic review and meta-analysis, cohort studies and controlled trials reporting on the use of PCI for patients SCLC were identified in EMBASE, MEDLINE, CENTRAL, and grey literature sources. The literature search was conducted on November 12, 2023. Summary data were extracted. Random-effects meta-analyses pooled hazard ratios (HR) for the primary outcome of overall survival between PCI and no intervention groups. This study is registered with the Open Science Framework, DOI:10.17605/OSF.IO/BC359, and PROSPERO, CRD42021249466. Of 4318 identified records, 223 were eligible for inclusion. 109 reported on overall survival in formats amenable to meta-analysis; PCI was associated with longer survival in all patients with SCLC (HR 0.59; 95% CI, 0.55-0.63; p<0.001; n=56,770 patients), patients with limited stage disease (HR 0.60; 95% CI, 0.55-0.65; p<0.001; n=78 studies; n=27,137 patients), and patients with extensive stage disease (HR 0.59; 95% CI, 0.51-0.70; p<0.001; n=28 studies; n=26,467 patients). Between-study heterogeneity was significant when pooled amongst all studies (I2=73.6%; 95% CI 68.4%-77.9%). Subgroup analysis did not reveal sources of heterogeneity. In a subgroup analysis on studies that used magnetic resonance imaging to exclude presence of brain metastases at restaging among all patients, overall survival did not differ significantly between patients who did or did not receive PCI (HR 0.74; 95% CI, 0.52-1.05; p=0.08; n=9 studies; n=1384 patients). Our findings suggested that administration of PCI is associated with a survival benefit, but not when considering studies that radiographically confirmed absence of brain metastases, suggesting that the survival benefit conferred by PCI might be therapeutic rather than prophylactic. No funding.

EP12.01-46 L858R Exon 21 Mutation Is Associated with a Higher Risk of Brain Metastases in Patients with NSCLC Treated with TKI

EP12.01-46 L858R Exon 21 Mutation Is Associated with a Higher Risk of Brain Metastases in Patients with NSCLC Treated with TKI

Circulating DNA and frequency of colorectal cancer brain metastases in a presumed high-risk group

This explorative prospective observational pilot study investigated if suggested risk factors, rectal cancer and lung metastases, could add to a relevant detection rate of asymptomatic brain metastases (BM) from colorectal cancer (CRC). Secondary, prognostic biological aspects were investigated by translational analysis of plasma samples. The study enrolled patients with rectal cancer and lung metastases. At inclusion, patients underwent a standard MRI scan of the brain. Cell-free DNA (cfDNA) level was measured by a direct fluorescence assay (DFA), and circulating tumor DNA (ctDNA) by ddPCR. BM was detected in one of twenty-nine included patients. Patients had higher cfDNA levels than healthy subjects (p < 0.01). Patients with the primary tumor in situ had higher cfDNA levels than those with resected primary tumor (p < 0.01). Patients with liver involvement had higher cfDNA levels (p = 0.12) and circulating tumor DNA levels (p = 0.01) than those without liver involvement. In conclusion, the modest incidence of BM does not justify routine MRI of the brain in this selected population. cfDNA by DFA could be a valuable tool when planning treatment and follow-up for CRC patients. Future studies should focus on identifying further characteristics and biomarkers associated with a high risk of BM, enhancing the possibility for early intervention.

Significant response to the combination of pyrotinib and capecitabine in a breast cancer patient with symptomatic and active brain metastases

Background Patients with Human Epidermal Growth Factor Receptor 2 HER2 positive breast cancer have a high risk of brain metastases.

Impact of Concurrent Genomic Alterations on Clinical Outcomes in Patients With ALK-Rearranged NSCLC

IntroductionALK tyrosine kinase inhibitors have exhibited promising activity against advanced ALK-rearranged NSCLC. However, co-occurring genetic alterations, such as CDKN2A/B or TP53, may negatively affect the efficacy of targeted therapies. MethodsFrom December 2017 to December 2022, this study cohort analyzed next-generation sequencing data of 116 patients with metastatic ALK-rearranged NSCLC from five Latin American cancer centers. Clinicopathologic and molecular features were associated with clinical outcomes and risk of brain metastasis (BrM) in patients with and without concurrent somatic alterations. ResultsAll patients (N = 116) received a second-generation ALK tyrosine kinase inhibitor, and alectinib was selected in 87.2% of cases. Coalterations occurred in 62% of the cases; the most frequent were TP53 mutations (27%) and CDKN2A/B loss (18%). The loss of CDKN2A/B was associated with an increased risk of BrM, with a cumulative incidence of 33.3% versus 7.4% in the non-coaltered subgroup. Compared with patients without coalterations, patients with concurrent CDKN2A/B loss (n = 21) had a shorter median progression-free survival (10.2 versus 34.2 mo, p < 0.001) and overall survival (26.2 versus 80.7 mo, p < 0.001). In the multivariate analysis, co-occurring CDKN2A/B loss was associated with poorer progression-free survival and OS despite the presence of other somatic coalterations, TP53 mutations, BrM, and Eastern Cooperative Oncology Group Performance Status. ConclusionsThis study confirmed the worse prognostic value, which depicted co-occurring alterations in patients with ALK rearrangement. CDKN2A/B loss was substantially associated with worse outcomes and a higher risk of brain metastases. The evidence presented in our study may help select patients with ALK-positive tumors suitable for treatment escalation and closer brain follow-up.

Tucatinib and stereotactic radiosurgery in the management of HER2 positive breast cancer brain metastases.

HER2-positive breast cancer has a high risk of brain metastasis. Stereotactic radiosurgery (SRS) is standard of care for limited brain metastases. Tucatinib, a HER2-targeted tyrosine kinase inhibitor, has demonstrated intracranial efficacy in the HER2-CLIMB Trial. However, it is unknown whether tucatinib with SRS is safe or effective. A retrospective analysis of HER2-positive breast cancer treated with SRS and tucatinib for brain metastases management was performed. All patients received tucatinib and SRS for the management of active brain metastases. The primary endpoint was local and distant brain tumor control. Secondary endpoints were intracranial progression free survival (CNS-PFS), systemic PFS, overall survival (OS), and neurotoxicity. A total of 135 lesions treated with SRS over 39 treatment sessions in 22 patients were identified. Median follow-up from tucatinib initiation was 20.8months. Local brain control was 94% at 12-months and 81% at 24-months. Distant brain control was 39% at 12-months and 26% at 24-months. Median survival was 21.2months, with 12- and 24-month OS rates of 84% and 50%, respectively. Median CNS-PFS was 11.3months, with 12- and 24-month CNS-PFS rates of 44.9% at both time points. Median systemic PFS was not reached, with 12- and 24-month systemic PFS rates of 86% and 57%, respectively. Symptomatic radiation necrosis occurred in 6 (4%) lesions. No additional unexpected toxicities were noted. SRS in combination with tucatinib, capecitabine, and trastuzumab appears to be a safe and feasible treatment for HER2 + brain metastases. Further prospective evaluation of potential synergistic effects is warranted.

18F-FDG PET/CT radiomics predicts brain metastasis in I-IIIA resected Non-Small cell lung cancer

ObjectiveTo establish 18F-FDG PET/CT radiomics model for predicting brain metastasis in non-small cell lung cancer (NSCLC) patients. MethodsThis research comprised 203 NSCLC patients who had received surgical therapy at two institutions. To identify independent predictive factors of brain metastasis, metabolic indicators, CT features, and clinical features were investigated. A prediction model was established by incorporating radiomics signature and clinicopathological risk variables. The suggested model’s performance was assessed from the perspective of discrimination, calibration, and clinical application. ResultsThe C-indices of the PET/CT radiomics model in the training, internal validation, and external validation cohorts were 0.911, 0.825 and 0.800, respectively. According to the multivariate analysis, neuron-specific enolase (NSE) and air bronchogram were independent risk factors for brain metastasis (BM). Furthermore, the combined model integrating radiomics and clinicopathological characteristics related to brain metastasis performed better in terms of prediction, with C-indices of 0.927, 0.861, and 0.860 in the training, internal validation, and external validation cohorts, respectively. The decision curve analysis (DCA) suggested that the PET/CT nomogram was clinically beneficial. ConclusionsA predictive algorithm based on PET/CT imaging information and clinicopathological features may accurately predict the probability of brain metastasis in NSCLC patients following surgery. This presented doctors with a unique technique for screening NSCLC patients at high risk of brain metastasis.

Pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer and brain metastases: 3-year follow-up results from the phase 2 PERMEATE trial.

1048 Background: HER2-positive metastatic breast cancer has a high risk of brain metastases, leading to poor survival. Our phase 2 PERMEATE trial (NCT03691051) has shown the promising efficacy of pyrotinib (an irreversible pan-HER receptor tyrosine kinase inhibitor) plus capecitabine in patients with HER2-positive metastatic breast cancer and brain metastases, with an intracranial objective response rate of 74.6% (44/59) and 42.1% (8/19) in patients with radiotherapy-naïve (cohort A) and radiotherapy-treated (cohort B) brain metastases, respectively. Here we updated 3-year follow-up results from this trial. Methods: Patients received 21-day cycles of pyrotinib (400 mg orally once daily) and capecitabine (1000 mg/m2 orally twice daily on days 1-14) until disease progression or intolerable toxicity. Patients with progression isolated to the brain lesions would be withdrawn from the study, but could resume on the study treatment after local surgery or radiotherapy until the second progression at any site or death, at the discretion of the investigator. Intracranial and extracranial responses were assessed according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Progression-free survival (PFS; time from the initiation of the study treatment to progression at any site or any-cause death), overall survival (OS), and second PFS (PFS2; time from progression isolated to the brain lesions to the second progression at any site) were reported. Results: By the data cutoff date on February 8, 2023, the median follow-up duration was 40.5 months (95% CI: 39.0-43.0). Cohort A showed a median PFS of 10.7 months (95% CI: 7.6-14.9) and a median OS of 35.9 months (95% CI: 25.1-not reached). The 1-year and 3-year OS rates were 84.6% (95% CI: 76.0-94.4) and 49.8% (95% CI: 38.0-64.6), respectively. Fifteen patients with progression isolated to the brain lesions in cohort A resumed on the study treatment after local treatment, with a median PFS2 of 10.4 months (95% CI: 6.5-19.7). Cohort B showed a median PFS of 5.6 months (95% CI: 5.4-11.9) and a median OS of 31.4 months (95% CI: 22.0-not reached). The 1-year and 3-year OS rates were 78.9% (95% CI: 64.0-99.6) and 29.1% (95% CI: 13.0-60.4), respectively. Conclusions: These findings suggest the long-term survival benefit provided by pyrotinib plus capecitabine in patients with HER2-positive metastatic breast cancer and brain metastases, especially in the radiotherapy-naive cohort. Clinical trial information: NCT03691051 .

Targeting HER2 in colorectal cancer

Among the molecular subgroups of interest in metastatic colorectal cancer (mCRC), innovations are underway for tumors with overexpression of HER2 (Human Epidermal Growth Factor Receptor 2). Overexpression of the HER2 protein concerns 2 to 5% of CRC at any stage mainly located in the distal colon and rectum. Diagnosis is based on immunohistochemistry, in situ hybridization with appropriate criteria for colorectal localization, and molecular biology (NGS: next-generation sequencing). Overexpression of HER2 is a predictive factor for resistance to treatments targeting EGFR which are indicated in the case where the tumor is wild-type RAS. It seems to be associated with a poor prognosis of mCRC with a higher risk of brain metastasis. Regarding treatments targeting HER2, no randomized controlled phase III has been published to date. However, several combinations have been evaluated in phase II with clinically meaningful objective response rates: trastuzumab-deruxtecan (45%), trastuzumab-tucatinib (46%), trastuzumab-pyrotinib (45%), trastuzumab-pertuzumab (30%) ou trastuzumab-lapatinib (30%). In this literature review, we present here the current state of knowledge on the diagnostic methods of HER2 overexpression in CRC, the main clinical, molecular and prognostic characteristics, and the efficacy results of the different therapeutic combinations for the patients with HER2 overexpressed mCRC. This justifies, despite the lack of marketing authorization in France and in Europe for agents targeting HER2 in CRC, the systematic evaluation of the HER2 status, as recommended in particular by the NCCN (National Comprehensive Cancer Network).

Abstract GS5-08: Soluble E-cadherin: a novel prognostic biomarker and driver of brain metastasis in inflammatory breast cancer

Abstract Background: Inflammatory breast cancer (IBC) is a highly aggressive form of breast cancer with rapid onset and a strong propensity to spread to distant organs. Five-year overall survival (OS) rates remain poor, in part because of the high risk of brain metastasis: 19% of patients with IBC have brain metastases within the first 2 years after diagnosis. Our hypothesis for this study was that soluble E-cadherin (sEcad), an 80-kDa extracellular proteolytic fragment of full-length E-cadherin - a tumor promoter in IBC, is crucial for driving brain metastasis in IBC. Methods: We analyzed serum sEcad levels in from 348 IBC patients by ELISA. Four IBC cell lines [ER–/HER2+ (MDA-IBC3; SUM190) and ER–/HER2– (SUM149; BCX010)], human brain microvascular endothelial cells, and immortalized human astrocytes were used in this study. Stable overexpression of sEcad in IBC cell lines was achieved using lentiviral vectors. Mass spectrometry and Bio-ID-based proteomics assays, and RNA sequencing were used to identify sEcad-interacting proteins and potential mechanisms. In vivo, we studied tumor growth and brain metastasis in mice by injecting IBC cells into the mammary fatpad or tail vein, respectively, of SCID/Beige mice. Results: In IBC patients, higher serum sEcad levels correlated with poorer OS (p=0.02), earlier development of metastasis (p=0.006), and development of brain metastasis (p=0.04). On multivariable analysis, sEcad independently predicted OS (hazard ratio [HR]=2.07 [95% CI 1.19-3.60], p=0.01). In vitro, sEcad overexpression in IBC cell lines promoted anchorage-independent growth, migration, invasion, and resistance to anoikis. In vivo, sEcad-overexpressing SUM149 cells promoted primary tumor growth (p=0.007). Mice injected with sEcad-overexpressing MDA-IBC3 cells also had higher incidence of brain metastasis (100% vs 50%, p=0.03), metastatic burden (p=0.02) and number of metastases per mouse (p=0.0009), and had worse OS (p=0.0016), and brain metastasis-free survival (p=0.04), relative to controls. We further found that sEcad increased cancer cell adhesion to brain endothelial cells (p=0.01) and promoted induction of reactive astrocytes (as identified by high glial fibrillary acidic protein levels) in vitro and in vivo. Mechanistically, mass spectrometry and Bio-ID assays identified X-linked inhibitor of apoptosis protein (XIAP), a potent inhibitor of apoptotic cell death, as a novel binding partner of sEcad, which was validated through co-immunoprecipitation. Further analysis showed that sEcad bound to the BIR2 domain of XIAP. XIAP is the most potent and best-defined anti-apoptotic IAP family member, and it could induce NF-κB activation to inhibit tumor cell apoptosis Gene set enrichment analysis of RNA-seq profiling data showed activation of NF-kB signaling and downregulation of apoptotic pathways in the sEcad-overexpressing SUM149 cells compared with controls. Immunoblotting revealed that sEcad enhanced XIAP expression, activated NF-κB signaling, and inhibited cleavage of caspase-3 in IBC cells. Conclusions: We found that higher serum sEcad correlates with development of brain metastases and independently predicts poor OS in patients with IBC. We further found that sEcad promotes tumor growth and brain metastasis, perhaps via activation of XIAP/NF-κB signaling in breast cancer cells and promotion of endothelial cell adhesion and reactive astrocytosis in the brain microenvironment. These findings uncover a novel and crucial role for sEcad in brain metastasis and provide new insights and potential therapeutic targets for patients with metastatic IBC. Citation Format: Xiaoding Hu, Yun Xiong, Emilly S. Villodre, Juhee Song, Ganiraju C Manyam, Moises J Tacam, Jing Wang, Chandra Bartholomeusz, Debu Tripathy, Naoto T. Ueno, Wendy Woodward, Savitri Krishnamurthy, Junjie Chen, Bisrat Debeb. Soluble E-cadherin: a novel prognostic biomarker and driver of brain metastasis in inflammatory breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-08.