Diagnosis Of Brain Metastases Research Articles

Trastuzumab emtansine vs lapatinib and capecitabine in HER2-positive metastatic breast cancer brain metastases: A real-world study.

Trastuzumab emtansine (T-DM1) has demonstrated improvements in survival and neurological symptoms in patients with breast cancer with brain metastases (BCBM). This real-world study investigated the effectiveness of T-DM1 versus lapatinib plus capecitabine (LC) in patients with BCBM. This retrospective, observational study evaluated patients with HER2-positive BCBM using a real-world database. Eligible patients had initiated T-DM1 or LC with a prior diagnosis of brain metastasis and ≥1 prior metastatic breast cancer treatment. The primary endpoint was overall survival (OS); secondary endpoints were time to next relevant treatment or death (TTNT) and real-world progression-free survival (rwPFS). An inverse probability of treatment weighting (IPTW) approach was used to account for differences in potential baseline characteristics between treatment groups. Outcomes were described using the Kaplan-Meier method, and the average treatment effect of initiating T-DM1 versus LC was estimated using weighted Cox proportional hazard models and hazard ratio (HR). A total of 214 patients were available for analysis (T-DM1, n=161; LC, n=53). Demographics and baseline characteristics were generally well-balanced between treatment groups after weighting. After weighting, median OS was 17.7 (T-DM1) versus 9.6 (LC) months (HR, 0.55 [95% CI, 0.34-0.89]; P=0.013). Median TTNT was 9.0 (T-DM1) versus 6.0 (LC) months (HR, 0.55 [95% CI, 0.36-0.85]; P=0.005). After weighting, median rwPFS was 6.0 (T-DM1) versus 4.0 (LC) months (HR, 0.50 [95% CI, 0.36-0.69]; P<0.001). These results support the superior effectiveness and clinical relevance of T-DM1 versus LC in patients with HER2-positive BCBM in the real world.

Optimizing treatment of brain metastases in an era of novel systemic treatments: a single center consecutive series

BackgroundThe multidisciplinary management of patients with brain metastases consists of surgical resection, radiation treatment and systemic treatment. Tailoring and timing these treatment modalities is challenging. This study presents real-world data from consecutively treated patients and assesses the impact of all treatment strategies and their relation with survival. The aim is to provide new insights to improve multidisciplinary decisions towards individualized treatment strategies in patients with brain metastases.MethodsA retrospective consecutive cohort study was performed. Patients with brain metastases were included between June 2018 and May 2020. Brain metastases of small cell lung carcinoma were excluded. Overall survival was analyzed in multivariable models.Results676 patients were included in the study, 596 (88%) received radiotherapy, 41 (6%) awaited the effect of newly started or switched systemic treatment and 39 (6%) received best supportive care. Overall survival in the stereotactic radiotherapy group was 14 months (IQR 5–32) and 32 months (IQR 11–43) in patients who started or switched systemic treatment and initially did not receive radiotherapy. In patients with brain metastases without options for local or systemic treatment best supportive care was provided, these patients had an overall survival of 0 months (IQR 0–1). Options for systemic treatment, Karnofsky Performance Score ≥ 70 and breast cancer were prognostic for a longer overall survival, while progressive extracranial metastases and whole-brain-radiotherapy were prognostic for shorter overall survival.ConclusionsAssessing prognosis in light of systemic treatment options is crucial after the diagnosis of brain metastasis for the consideration of radiotherapy versus best supportive care.Graphical

Safety and efficacy of silibinin in patients with brain metastases after stereotactc radiosurgery: SUSTAIN trial.

e14012 Background: Brain metastases (BMs) account for more than one-half of all intracranial tumors. Over the past years, stereotactic radiosurgery (SRS) has become the mainstay of BMs treatment, providing high rates of local tumor control. Nevertheless, SRS alone is associated with a 30-50% risk of distant brain failure (DBF), consequently requiring careful follow-up and possible rescue treatments. Silibinin or silybin, a natural polyphenolic flavonoid, has shown promising antitumor activity, leading to improvement of BMs in patients (pts) with progressive non-small cell lung cancer. Therefore, our exploratory study aims to evaluate whether the use of a silibinin-based nutraceutical can significantly reduce DBF rate at 6 months in pts with first-diagnosed BMs treated with SRS with or without surgery. Methods: SUSTAIN is an interventional, prospective, single arm, phase II study. A total of 80 pts treated in our center are planned to be enrolled. Pts receive 2 capsules (cps) of silibinin-based nutraceutical per day for the first month after SRS and 1 cp per day thereafter. Primary endpoints are 6-month distant brain failure (DBF) rate and safety; secondary endpoint is 6-month overall survival (OS) rate. Contrast-enhanced magnetic resonance (MRI) of the brain is performed at baseline and every 12 weeks after SRS treatment; radiological response is assessed according to RANO criteria for brain metastases (RANO-BM). Results: Thirty pts has been enrolled at the time of this primary analysis (Tab1). NSCLC and breast cancer were the prevalent histologies (14 and 10 cases respectively). Twelve pts were chemotherapy naive at the time of BMs diagnosis; 10 pts has received 1 systemic therapy line and 8 pts has received 2 lines or more. Overall, the number of treated lesions was 73, with a median of 1 lesion (range 1-9). All pts underwent SRS (Fig.1), with a median prescription dose (PD) and a median prescription isodose line (IDL) of 24 Gy and 80% respectively. After a 14-month enrollment period, with a median follow-up of 9 months, 6 pts reported distant intracranial failure according to RANO-BM criteria, with a 6-month DBF rate of 20%. Only 1 treated lesion met the criteria for progression, accounting for a 6-month local control (LC) rate of 98%. Six pts died, with a 6-month OS rate of 80%. Radiological radionecrosis was detected in 3 pts (10%), who developed G1 neurological symptoms managed with low-dose dexamethasone. Two pts discontinued silibinin-based nutraceutical assumption due to G1 nausea. No other adverse events were reported. Conclusions: At about half of our enrollment target, the results show a favorable trend towards 6-month DBF rate reduction. Toxicity proved manageable, consistent with the literature and limited to gastrointestinal effects. A larger sample and longer follow-up is needed to confirm our hypothesis.

Brain metastasis of hepatocellular carcinoma- single center experience.

Although the most common intracranial neoplasm in the adult population is metastatic tumors, brain metastasis from hepatocellular carcnoma (HCC) are very rare. The aim of this study is to analyze patients with advanced HCC, in order to determine the incidence of brain metastasis and evaluate the clinicopathologic properties. The records of HCC patients treated in our university between 2011 and 2019 were reviewed retrospectively. Patient characteristics, symptoms, laboratory data, treatment modalities, and survival after both the diagnosis of HCC and detection of brain metastasis were recorded. Of the 119 hepatocellular carcinoma patients, 34 had metastasis, 8 of which were to the brain. The median time elapsed between the diagnosis of HCC and brain metastasis was 14.6 months and the median overall survival after the detection of brain metastasis was 1.6 months. In 34 patients with metastasis, median survival was 26.2 months for those without brain metastasis, whereas it was 15.8 months for those with brain metastasis ( P = 0.460). The survival times after brain metastasis were 11.6 and 3.9 months for the two patients treated with regorafenib and sorafenib after the detection of brain metastasis, respectively. In this study, it was found that patients who were clinically eligible to receive tyrosine kinase inhibitors survived longer after the detection of brain metastasis. Our study shows that multidisciplinary evaluation of these patients is vital for treatment guidance, and survival outcomes can be improved with the advancements in surgical and radiotherapy techniques even in patients with poor prognosis.

Clinical characteristics, treatment, and long-term outcome of patients with brain metastases from thyroid cancer

Brain metastases (BM) in patients with thyroid cancer (TC) are rare with an incidence of 1% for papillary and follicular, 3% for medullary and up to 10% for anaplastic TC (PTC, FTC, MTC and ATC). Little is known about the characteristics and management of BM from TC. Thus, we retrospectively analyzed patients with histologically verified TC and radiologically verified BM identified from the Vienna Brain Metastasis Registry. A total of 20/6074 patients included in the database since 1986 had BM from TC and 13/20 were female. Ten patients had FTC, 8 PTC, one MTC and one ATC. The median age at diagnosis of BM was 68 years. All but one had symptomatic BM and 13/20 patients had a singular BM. Synchronous BM at primary diagnosis were found in 6 patients, while the median time to BM diagnosis was 13 years for PTC (range 1.9–24), 4 years for FTC (range 2.1–41) and 22 years for the MTC patient. The overall survival from diagnosis of BM was 13 months for PTC (range 1.8–57), 26 months for FTC (range 3.9–188), 12 years for the MTC and 3 months for the ATC patient. In conclusion, development of BM from TC is exceedingly rare and the most common presentation is a symptomatic single lesion. While BM generally constitute a poor prognostic factor, individual patients experience long-term survival following local therapy.

Prognostic factors associated with the transition in treatment methods for brain metastases from colorectal cancer.

Treatment of brain metastases (BMs) from colorectal cancer (CRC) has transitioned with the expansion of indications for stereotactic radiotherapy. Our study aimed to assess changes in prognosis and prognostic factors associated with changes in treatment for BMs from CRC. We retrospectively surveyed treatments for and outcomes of BMs from CRC in 208 patients treated during 1997-2018. Patients were divided into two groups according to time of BM diagnosis, i.e., 1997-2013 ("first period") and 2014-2018 ("second period"). We compared overall survival between the periods and assessed how the transition impacted prognostic factors affecting overall survival, including the following prognostic factors such as Karnofsky performance status (KPS), volume-related factors (BM number and diameter), and BM treatment modalities as covariates. Of the 208 patients, 147 were treated in the first period and 61 in the second period. Whole-brain radiotherapy use decreased from 67 to 39% in the second period, and stereotactic radiotherapy use increased from 30 to 62%. Median survival after BM diagnosis improved from 6.1 to 8.5months (p = 0.0272). Multivariate analysis revealed KPS, control of primary tumor, stereotactic radiotherapy use, and chemotherapy history as independent prognostic factors during the entire observation period. Hazard ratios of KPS, primary tumor control, and stereotactic radiotherapy were higher in the second period, whereas prognostic impact of chemotherapy history before BM diagnosis was similar in both periods. Overall survival of patients with BMs from CRC improved since 2014, which can be attributed to advances in chemotherapy and the more widespread use of stereotactic radiotherapy.

Androgen Receptor Is Expressed in the Majority of Breast Cancer Brain Metastases and Is Subtype-Dependent.

We aimed to evaluate the expression of the "targetable" androgen receptor (AR) in breast cancer brain metastases (BrM). An established, retrospective 57-patient cohort with metastatic breast cancer who underwent surgery for BrM at the Sunnybrook Odette Cancer Centre between 1999-2013 was studied. AR expression in BrM samples was assessed in triplicate using immunohistochemistry (IHC). AR positive status was defined as nuclear AR expression ≥ 10% by IHC using the SP107 antibody. The median age of patients was 52 years (range 32-85 years). 28 (49%) of BrM were HER2+, 17 (30%) were hormone receptor positive (HR+)/HER2-, and 12 (21%) were triple negative breast cancers (TNBCs). 56% (n = 32/57) of BrM were AR positive, and median AR expression was 20% (CI 1.6-38.3%). AR expression was different across breast cancer subtypes; AR was most frequently expressed in HER2+ (n = 21/28), followed by HR+/HER2- (n = 9/17), and lowest in TNBC (n = 2/12) BrM (p = 0.003). Patients with AR positive versus AR negative BrM had similar overall survival (12.5 vs. 7.9 months, p = 0.6), brain-specific progression-free survival (8.0 vs. 5.1 months, p = 0.95), and time from breast cancer diagnosis to BrM diagnosis (51 vs. 29 months, p = 0.16). AR is expressed in the majority of breast cancer BrM and represents a potential therapeutic target.

Brain-Tumor Interface-Based MRI Radiomics Models to Determine EGFR Mutation, Response to EGFR-TKI and T790M Resistance Mutation in Non-Small Cell Lung Carcinoma Brain Metastasis.

Preoperative assessment of epidermal growth factor receptor (EGFR) status, response to EGFR-tyrosine kinase inhibitors (TKI) and development of T790M mutation in non-small cell lung carcinoma (NSCLC) patients with brain metastases (BM) is important for clinical decision-making, while previous studies were only based on the whole BM. To investigate values of brain-to-tumor interface (BTI) for determining the EGFR mutation, response to EGFR-TKI and T790M mutation. Retrospective. Two hundred thirty patients from Hospital 1 (primary cohort) and 80 patients from Hospital 2 (external validation cohort) with BM and histological diagnosis of primary NSCLC, and with known EGFR status (biopsy) and T790M mutation status (gene sequencing). Contrast-enhanced T1-weighted (T1CE) and T2-weighted (T2W) fast spin echo sequences at 3.0T MRI. Treatment response to EGFR-TKI therapy was determined by the Response Evaluation Criteria in Solid Tumors. Radiomics features were extracted from the 4 mm thickness BTI and selected by least shrinkage and selection operator regression. The selected BTI features and volume of peritumoral edema (VPE) were combined to construct models using logistic regression. The performance of each radiomics model was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC). A total of 7, 3, and 3 features were strongly associated with the EGFR mutation status, response to EGFR-TKI and T790M mutation status, respectively. The developed models combining BTI features and VPE can improve the performance than those based on BTI features alone, generating AUCs of 0.814, 0.730, and 0.774 for determining the EGFR mutation, response to EGFR-TKI and T790M mutation, respectively, in the external validation cohort. BTI features and VPE were associated with the EGFR mutation status, response to EGFR-TKI and T790M mutation status in NSCLC patients with BM. 3 Technical Efficacy: Stage 2.

An Efficient Approach to Mapping the Distribution of Renal Cell Carcinoma (RCC) Brain Metastases (BrM) (P10-13.003)

<h3>Objective:</h3> To assess the distribution of RCC BrM in clinical context. <h3>Background:</h3> RCC frequently presents with hemorrhagic BrMs. BrM distribution patterns and their associations with lab/clinical parameters are poorly understood. <h3>Design/Methods:</h3> We performed a retrospective analysis including RCC patients who underwent BrM resection at our institution. We reviewed gadolinium-enhanced MRI brain and CT head at the time of BrM diagnosis and assessed the presence of hemosiderin (MRI) or hemorrhage (CT) in the BrM. BrMs were marked in their corresponding anatomic location in a brain template. Public brain atlases (Faria and Liu 10.25790/bml0cm.109; Vachet, SCR_002606) were used for distribution analysis. Serum markers were correlated with imaging. <h3>Results:</h3> A total of 67 BM were analyzed from 46 patients (age 63±10years/35M), 23 synchronous BM, 9 patients had two, 6 had 3 concurrent BrMs. 97% of the lesions were spheric in shape. Mean 1D and 2D (RANO) tumor dimensions were 2.0±1.1cm and 4.7±4.9cm², respectively and correlated with neutrophil count at BrM diagnosis (r=0.3, p=0.01). Multilobar edema was seen in 36% of BrM. 82% of BrMs contained hemosiderin and 80% were hemorrhagic. Most BrMs were in the frontal (45%), parietal (21%) and occipital (18%) lobes. Posterior cerebral artery distribution contained 34% of BrM despite it supplying only 16% of brain volume. Higher platelet counts were associated with BrMs in the posterior circulation territories (p=0.05). BrM hemosiderin was associated with larger tumors (p=0.04), lower platelet counts (p=0.01) and higher hemoglobin (p=0.08). Renal vein thrombosis (RVT) at primary diagnosis was associated both BrM hemosiderin (p=0.05) and hemorrhage (p=0.03). CNS progression-free survival was shorter in those who had RVT (p=0.04), or had BrM hemosiderin (p=0.04). <h3>Conclusions:</h3> The presented mapping method offers an objective and efficient way to assess lesion distribution that reveals clinically relevant patterns. BrM hemosiderin deposits are linked to lower platelet counts and may provide prognostic information. Further analyses are underway. <b>Disclosure:</b> The institution of Dr. Kamson has received research support from Maryland Cigarette Restitution Fund. Mr. Feinaj has nothing to disclose. Dr. Elias has nothing to disclose. Mr. Yerrapragada has nothing to disclose. Dr. Bettegowda has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bionaut Labs. Dr. Bettegowda has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Rodey, Dickason, Sloan, Akin &amp; Robb, P.A.. Dr. Bettegowda has stock in OrisDx. The institution of Dr. Bettegowda has received research support from NIH. Dr. Bettegowda has received intellectual property interests from a discovery or technology relating to health care. Mr. Singla has nothing to disclose. Yasser Ged has nothing to disclose.

Long-term survival of breast cancer patients with brain metastases: subanalysis of the BMBC registry

Up to 30% of metastatic breast cancer (BC) patients develop brain metastases (BM). Prognosis of patients with BM is poor and long-term survival is rare. Identification of factors associated with long-term survival is important for improving treatment modalities. A total of 2889 patients of the national registry for BM in BC (BMBC) were available for this analysis. Long-term survival was defined as overall survival (OS) in the upper third of the failure curve resulting in a cut-off of 15 months. A total of 887 patients were categorized as long-term survivors. Long-term survivors compared to other patients were younger at BC and BM diagnosis (median 48 versus 54 years and 53 versus 59 years), more often had HER2-positive tumors (59.1% versus 36.3%), less frequently luminal-like (29.1% versus 35.7%) or triple-negative breast cancer (TNBC) (11.9% versus 28.1%), showed better Eastern Cooperative Oncology Group (ECOG) performance status (PS) at the time of BM diagnosis (ECOG 0-1, 76.9% versus 51.0%), higher pathological complete remission rates after neoadjuvant chemotherapy (21.6% versus 13.7%) and lower number of BM (n= 1, BM 40.9% versus 25.4%; n= 2-3, BM 26.5% versus 26.7%; n ≥4, BM 32.6% versus 47.9%) (P < 0.001). Long-term survivors had leptomeningeal metastases (10.4% versus 17.5%) and extracranial metastases (ECM, 73.6% versus 82.5%) less frequently, and asymptomatic BM more often at the time of BM diagnosis (26.5% versus 20.1%), (P < 0.001). Median OS in long-term survivors was about two times higher than the cut-off of 15 months: 30.9 months [interquartile range (IQR) 30.3] overall, 33.9 months (IQR 37.1) in HER2-positive, 26.9 months (IQR 22.0) in luminal-like and 26.5 months (IQR 18.2) in TNBC patients. In our analysis, long-term survival of BC patients with BM was associated with better ECOG PS, younger age, HER2-positive subtype, lower number of BM and less extended visceral metastases. Patients with these clinical features might be more eligible for extended local brain and systemic treatment.

Efficacy and safety of combined immunotherapy and stereotactic radiosurgery in NSCLCBM patients and a novel prognostic nomogram: A real-world study.

To explore the effectiveness of combined immunotherapy (IT) and stereotactic radiosurgery (SRS) and address the gap between evidence-based clinical practice and academic knowledge of optimal timing of IT relative to SRS. In addition, to meet the unmet need for an up-to-date prognostic assessment model in the era of IT. The data of 86 non-small cell lung cancer brain metastasis (NSCLCBM) patients treated with SRS to 268 brain metastases (BMs) were retrospectively extracted from our hospital database. The Kaplan-Meier analysis was employed for overall survival (OS) and a log-rank test for comparison between groups. Cox proportional hazards regression models were used to identify the significant prognostic factors. The prognostic nomogram was established utilizing the rms package of R software. IT was found to be associated with improved OS (from BM diagnosis: HR 0.363, 95% CI 0.199 - 0.661, P < 0.001; from SRS: HR 0.472, 95% CI 0.260 - 0.857, P = 0.014). Individuals who received IT in combination with SRS had better OS than those who didn't (from the day of BM diagnosis: 16.8 vs. 8.4 months, P = 0.006; from the day of SRS: 12 vs. 7 months, P = 0.037). Peri-SRS timing of IT administration was a significant prognostic factor for OS (from BM diagnosis: HR 0.132, 95% CI 0.034 - 0.517, P = 0.004; from SRS: HR 0.14, 95% CI 0.044 - 0.450, P = 0.001). Initiating IT after SRS led to superior OS than concurrent or before (from BM diagnosis: 26.5 vs. 14.1 vs. 7.1 months; from SRS: 21.4 vs. 9.9 vs. 4.1 months, respectively). Additionally, we build a nomogram incorporating IT, cumulative intracranial tumor volume (CITV), and recursive partitioning analysis (RPA), demonstrating a remarkable prognosis prediction performance for SRS-treated NSCLCBM patients. Peri-SRS IT is a promising approach in treating NSCLCBM, as improved OS was observed without significantly increasing adverse events. Receipt of IT post-SRS was associated with superior OS than those who received IT concurrently or before. Incorporating IT and CITV into the RPA index could augment its prognosis assessment value for SRS-treated NSCLCBM patients, predominantly in the wild-type.

Frequent Overexpression of HER3 in Brain Metastases from Breast and Lung Cancer.

HER3 belongs to a family of receptor tyrosine kinases with oncogenic properties and is targeted by a variety of novel anticancer agents. There is a huge unmet medical need for systemic treatment options in patients with brain metastases (BM). Therefore, we aimed to investigate HER3 expression in BM of breast (BCa) and non-small cell lung cancer (NSCLC) as the basis for future clinical trial design. We analyzed 180 BM samples of breast cancer or NSCLC and 47 corresponding NSCLC extracranial tissue. IHC was performed to evaluate protein expression of HER3, and immune cells based on CD3, CD8, and CD68. To identify dysregulated pathways based on differential DNA methylation patterns, we used Infinium MethylationEPIC microarrays. A total of 99/132 (75.0%) of BCa-BM and 35/48 (72.9%) of NSCLC-BM presented with HER3 expression. Among breast cancer, HER2-positive and HER2-low BM showed significantly higher rates of HER3 coexpression than HER2-negative BM (87.1%/85.7% vs. 61.0%, P = 0.004). Among NSCLC, HER3 was more abundantly expressed in BM than in matched extracranial samples (72.9% vs. 41.3%, P = 0.003). No correlation of HER3 expression and intratumoral immune cell density was observed. HER3 expression did not correlate with overall survival from BM diagnosis. Methylation signatures differed according to HER3 status in BCa-BM samples. Pathway analysis revealed subtype-specific differences, such as TrkB and Wnt signaling pathways dysregulated in HER2-positive and triple-negative breast cancer BM, respectively. HER3 is highly abundant in BM of breast cancer and NSCLC. Given the promising results of antibody-drug conjugates in extracranial disease, BM-specific trials that target HER3 are warranted. See related commentary by Kabraji and Lin, p. 2961.

The Role of Molecular Imaging in Patients with Brain Metastases: A Literature Review.

Over the last several years, molecular imaging has gained a primary role in the evaluation of patients with brain metastases (BM). Therefore, the "Response Assessment in Neuro-Oncology" (RANO) group recommends amino acid radiotracers for the assessment of BM. Our review summarizes the current use of positron emission tomography (PET) radiotracers in patients with BM, ranging from present to future perspectives with new PET radiotracers, including the role of radiomics and potential theranostics approaches. A comprehensive search of PubMed results was conducted. All studies published in English up to and including December 2022 were reviewed. Current evidence confirms the important role of amino acid PET radiotracers for the delineation of BM extension, for the assessment of response to therapy, and particularly for the differentiation between tumor progression and radionecrosis. The newer radiotracers explore non-invasively different biological tumor processes, although more consistent findings in larger clinical trials are necessary to confirm preliminary results. Our review illustrates the role of molecular imaging in patients with BM. Along with magnetic resonance imaging (MRI), the gold standard for diagnosis of BM, PET is a useful complementary technique for processes that otherwise cannot be obtained from anatomical MRI alone.

Abstract 4483: Distinct spatial distribution patterns of ALK-inhibitor naïve versus ALK-inhibitor treated ALK-positive NSCLC brain metastases

Abstract Background: Non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase rearrangement (ALK+) has a high affinity to form brain metastases (BrM). The cumulative incidence of BrMs in ALK+ lung cancer is over 50%, despite highly effective ALK tyrosine kinase inhibitors (TKIs) with CNS activity. Pharmacokinetic (PK) data from other CNS-active lung cancer TKIs (e.g., osimertinib) have revealed major brain white vs. gray matter drug concentration differences, raising the possibility of a PK-driven effect on BrM formation and response. This study aims to compare the size and distribution of ALK+ NSCLC BrMs at diagnosis in a TKI-naïve and TKI-exposed cohort. Methods: We retrospectively reviewed brain MRIs from the date of BrM diagnosis for patients with ALK+ NSCLC at Johns Hopkins. Demographic and clinical information were collected by chart review. Each tumor was marked in a standard space brain model in the corresponding anatomic location represented by a sphere of corresponding diameter using 3D Slicer 4.11. FreeSurfer white-gray matter atlases were used to assess BrM distribution. The data for patients who were on TKI vs TKI-naïve at the time of BrM diagnosis were then analyzed separately. T-tests were used to compare the metastatic burden (sum of BrM diameters), mean BrM diameter per patient, number of BM per patient, per individual mean of white matter exclusive (defined as no overlap with gray matter) and deep white matter (≥5mm away from gray matter) BrMs between patient groups. Results: 429 BrMs were identified in 39 patients, with 25 patients being TKI-naïve at the time of BrM diagnosis while 14 patients were on TKI therapy. TKI-exposed patients had significantly smaller BrM diameters than those in the TKI-naïve group (6.1±3.8 vs 10.2±5.5mm, p=0.02). While metastatic burden was very similar between the groups, the mean number of BrM per patient was numerically higher in the TKI-exposed group (10.6±11.9 vs 6.2±9.5; p=0.22). Notably, patients in the TKI-exposed group also had higher numbers of white matter exclusive (3.5±4.4 vs 1.4±2.0, p=0.05) and deep white matter metastases (3.2±4.3 vs 1.3±2.0, p=0.06) than those who were TKI-naïve. Conclusion: Our data highlight the differences in BrM characteristics among ALK+ NSCLC exposed to ALK TKI. TKI therapy was associated with similar BrM burden but smaller individual lesions that were more likely to be exclusive to the white matter where drug concentrations might be significantly lower. These findings suggest that suboptimal drug CNS distribution in the white matter may underly brain progression of ALK+ NSCLC despite TKI therapy. Spatial analyses evaluating ALK TKIs of varying CNS penetrance and later disease time points in more granular anatomic regions are ongoing. Citation Format: Tia Cheunkarndee, Paola Ganem, Kristen A. Marrone, Joseph C. Murray, Josephine L. Feliciano, Christine L. Hann, Susan C. Scott, David Ettinger, Valsamo Anagnostou, Patrick M. Forde, Julie R. Brahmer, Benjamin P. Levy, Vincent Lam, David O. Kamson. Distinct spatial distribution patterns of ALK-inhibitor naïve versus ALK-inhibitor treated ALK-positive NSCLC brain metastases. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4483.

Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG

BackgroundDespite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis...

The progress of microenvironment-targeted therapies in brain metastases.

The incidence of brain metastases (BrM) has become a growing concern recently. It is a common and often fatal manifestation in the brain during the end-stage of many extracranial primary tumors. Increasing BrM diagnoses can be attributed to improvements in primary tumor treatments, which have extended patients' lifetime, and allowed for earlier and more efficient detection of brain lesions. Currently, therapies for BrM encompass systemic chemotherapy, targeted therapy, and immunotherapy. Systemic chemotherapy regimens are controversial due to their associated side effects and limited efficacy. Targeted and immunotherapies have garnered significant attention in the medical field: they target specific molecular sites and modulate specific cellular components. However, multiple difficulties such as drug resistance and low permeability of the blood-brain barrier (BBB) remain significant challenges. Thus, there is an urgent need for novel therapies. Brain microenvironments consist of cellular components including immune cells, neurons, endothelial cells as well as molecular components like metal ions, nutrient molecules. Recent research indicates that malignant tumor cells can manipulate the brain microenvironment to change the anti-tumoral to a pro-tumoral microenvironment, both before, during, and after BrM. This review compares the characteristics of the brain microenvironment in BrM with those in other sites or primary tumors. Furthermore, it evaluates the preclinical and clinical studies of microenvironment-targeted therapies for BrM. These therapies, due to their diversity, are expected to overcome drug resistance or low permeability of the BBB with low side effects and high specificity. This will ultimately lead to improved outcomes for patients with secondary brain tumors.

Poor Karnofsky performance status is not a contraindication for neurosurgical resection in patients with lung cancer brain metastases: a multicenter, retrospective PSM-IPTW cohort study

BackgoundNeurosurgical resection is a standard local treatment for lung cancer brain metastases (BMs). This study aims to investigate whether neurosurgical resection provides survival benefit in lung cancer BMs with poor KPS.Materials and methodsThis multicenter retrospective study included 386 lung cancer BMs with pretreatment KPS ≤ 70 among a total of 1177 lung cancer BMs treated at three centers from August 2010 to July 2021. Data analysis was performed from July to September 2022. Inverse probability of treatment weighting (IPTW) and propensity scores matching (PSM) based on propensity scoring were used to minimize bias. The main outcome was overall survival (OS) after diagnosis of BMs. Risk factors of OS were estimated using Cox proportional hazards regression models. All Characteristics were included in the multivariate Cox regression.Results386 patients with pretreatment KPS ≤ 70 were included (age mean [SD], 57.85 [10.36] years; KPS mean [SD], 60.91 [10.11]). Among them, 111 patients received neurosurgical resection, while 275 patients did not. Baseline characteristics were balanced between groups after IPTW or PSM. Neurosurgical resection was associated with significantly better prognosis in unadjusted multivariate COX analysis (hazard ratio [HR]: 0.68, 95% confidence interval [CI]: 0.51–0.91, P = 0.01), and PSM-adjusted multivariate COX analysis (HR: 0.61, 95%CI: 0.39–0.94, P = 0.03), IPTW-adjusted multivariate COX analysis (HR: 0.58, 95%CI: 0.40–0.84, P = 0.004). OS was significantly longer in neurosurgical resection group compared with non-surgical resection group according to unadjusted data (Median OS, surgery vs non-surgery, 14.7 vs 12.5 months, P = 0.01), PSM-adjusted data (median OS, 17.7 vs 12.3 months, P < 0.01) and IPTW-adjusted data (median OS, 17.7 vs 12.5 months, P < 0.01).ConclusionsNeurosurgical resection was associated with improved survival in patients with lung cancer BMs with poor KPS, suggesting that poor KPS is not a contraindication for neurosurgical resection in these patients.

Validation and discussion of clinical practicability of the 2022 graded prognostic assessment for NSCLC adenocarcinoma patients with brain metastases in a routine clinical cohort.

The goal of this analysis is to validate the 2022 graded prognostic assessment (GPA) for patients with brain metastases from adenocarcinoma of the lung and to discuss its clinical practicability. 137 patients with adenocarcinoma of the lung were included in this analysis. The disease specific GPA for NSCLC, Lung-molGPA and the GPA for NSCLC adenocarcinoma were calculated. Overall survival was calculated for each GPA group. Additionally, expected and actual OS in the prognostic groups of the GPA available at the time of the patients' diagnosis was compared. Median overall survival (OS) from diagnosis of brain metastases was 15 months (95% confidence interval (CI) 9.7-20.3 months). The median OS in the three individual prognostic groups was 7 months for GPA 0-1, 16 months for GPA 1.5-2, 33 months for GPA 2.5-3 and not reached for GPA 3.5-4 (p<0.001). Median survival times for the individual groups were similar to those published in the original GPA publication. Regarding the expected and actual OS when using the available GPA at the time of diagnosis there was an underestimation of survival of more than 3 months for all except the worst prognosis group. We were able to validate the 2022 GPA for NSCLC adenocarcinoma patients with brain metastases in a similar cohort from a non-academic center. However, the practical applicability regarding the expected median OS might be limited due to the constantly evolving treatment landscape and the consecutive improvement in overall survival.

Advances in Brain Metastases Diagnosis: Non-coding RNAs As Potential Biomarkers.

Brain metastasis is considered the most common brain tumor. They arise from different primary cancers. The most common primary tumors giving brain metastases include breast, colorectal, lung, melanoma, and renal cancer. Depending only on history, physical examination, and conventional imaging modalities makes brain tumors diagnosis difficult. Rapid and non-invasive promising modalities could diagnose and differentiate between different brain metastases without exposing the patients to unnecessary brain surgeries for biopsies. One of these promising modalities is non-coding RNAs (ncRNAs). NcRNAscan determine brain metastases' prognosis, chemoresistance, and radioresistance. It also helps us to understand the pathophysiology of brain metastases development. Additionally, ncRNAs may work as potential therapeutic targets for brain metastases treatment and prevention. Herein, we present deregulated ncRNAs in different brain metastases, including microRNAs and long non-coding RNAs (lncRNAs), such as gastric adenocarcinoma, colorectal, breast, melanoma, lung, and prostate cancer. Additionally, we focus on serum and cerebrospinal fluid (CSF) expression of these ncRNAsin patients with brain metastases compared to patients with primary tumors. Moreover, we discuss the role of ncRNAs in modulating the immune response in the brain microenvironment. More clinical studies are encouraged to assess the specificity and sensitivity of these ncRNAs.

Impact of prior systemic therapy on lymphocytic infiltration in surgically resected breast cancer brain metastases.

Tumor-infiltrating lymphocytes (TILs) have been positively correlated with response to systemic therapy for triple-negative and HER2 + subtypes and improved clinical outcomes in early breast cancer (BC). Less is known about TILs in metastatic sites, particularly brain metastases (BM), where unique immune regulation governs stromal composition. Reactive glial cells actively participate in cytokine-mediated T cell stimulation. The impact of prior medical therapy (chemotherapy, endocrine, and HER2-targeted therapy) on the presence of TILs and gliosis in human breast cancer brain metastases (BCBM) has not been previously reported. We examined prior treatment data for 133 patients who underwent craniotomy for resection of BMs from the electronic medical record. The primary endpoint was overall survival (OS) from the time of BM diagnosis. We examined the relationship between prior systemic therapy exposure and the histologic features of gliosis, necrosis, hemorrhage, and lymphocyte infiltration (LI) in BCBMs resected at subsequent craniotomy in univariate analyses. Complete treatment data were available for 123 patients. BCBM LI was identified in 35 of 116 (30%) patients who had received prior systemic treatment versus 5 of 7 (71.4%) who had not {significant by Fisher's exact test p = 0.045}. There were no statistically significant relationships between prior systemic therapy and the three other histologic variables examined. This observation suggests that systemic therapy may interfere with the immune response to BCBMs and cause exhaustion of anti-tumor immunity. This motivates clinical investigation of strategies to enhance LI for therapeutic benefit to improve outcomes for patients with BCBMs.