Cumulative Incidence Of Brain Metastases Research Articles

Predictors of brain metastases in patients with oligometastatic solid tumours treated with stereotactic body radiation therapy.

In patients with oligometastatic disease (OMD) treated with stereotactic body radiation therapy (SBRT), those who develop brain metastases (BrM) may have poor outcomes. We aimed to investigate variables associated with BrM development in this population. Patients with ≤ 5 extracranial metastases from solid tumors treated with SBRT from 2008 to 2016 at Sunnybrook Odette Cancer Centre were included. We investigated the association between covariates and CIBrM (cumulative incidence of BrM) using Fine-Gray analysis, and progression-free survival (PFS) and overall survival (OS) using Cox regression. We investigated the association between extracranial progression and CIBrM using time-based conditional analysis. Among 404 patients, the most common primary sites were lung, colorectal, prostate, breast and kidney. Median follow-up was 49 months. Median PFS was 25 months. Median OS was 70 months. 58 patients developed BrM, and 5-year CIBrM was 16%. On multivariable analysis, number of extracranial metastases, location of metastases, total planning target volume (PTV), and time from primary diagnosis to OMD were not associated with CIBrM, although several of these variables were associated with extracranial PFS and OS. Primary site was associated with CIBrM, with colorectal and prostate cancer associated with lower CIBrM compared to lung cancer. Widespread extracranial progression (≥ 5 sites) within 24, 36, 48 and 60 months of OMD diagnosis was independently associated with higher CIBrM. In patients with OMD treated with SBRT, baseline variables related to extracranial disease burden and distribution were not associated with BrM development, while primary site and widespread extracranial progression were associated with BrM development.

Clinicopathologic and genomic features associated with brain metastasis after resection of lung adenocarcinoma

ObjectiveTo identify clinicopathologic and genomic features associated with brain metastasis after resection of lung adenocarcinoma (LUAD) and to evaluate survival after brain metastasis. MethodsPatients who underwent complete resection of stage I-IIIA LUAD between 2011 and 2020 were included. A subset of patients had broad-based panel next-generation sequencing performed on their tumors. Fine-Gray models for the development of brain metastasis were constructed, with death without brain metastasis as a competing risk. ResultsA total of 2660 patients were included. The median duration of follow-up was 71 months (95% confidence interval [CI], 69-73 months). The cumulative incidence of brain metastasis at 10 years was 9.8%. Among patients who developed a brain metastasis, the median time from surgery to brain metastasis was 21 months (interquartile range, 10-42 months). Higher maximum standardized uptake value of the primary tumor, neoadjuvant therapy, lymphovascular invasion, and stage III disease were associated with the development of brain metastasis. Among patients who underwent next-generation sequencing, a multivariable analysis identified neoadjuvant therapy, pathologic stage, and TP53 mutations as associated with development of brain metastasis. The median survival after brain metastasis was 18 months (95% CI, 13-24 months). Better performance status, lack of extracranial metastasis, stereotactic radiosurgery, and targeted therapy were associated with better survival after brain metastasis. ConclusionsBrain metastasis is common after complete resection of LUAD and often occurs within 2 years. Markers of aggressive tumor biology, including higher maximum standardized uptake value, lymphovascular invasion, and TP53 mutations, and neoadjuvant therapy are associated with brain metastasis.

EP.17A.01 The Cumulative Incidence of Brain Metastases in US Medicare Patients with ALK+ mNSCLC Treated with Second-generation ALK TKIs

EP.17A.01 The Cumulative Incidence of Brain Metastases in US Medicare Patients with ALK+ mNSCLC Treated with Second-generation ALK TKIs

A biomarker exploration in small-cell lung cancer for brain metastases risk and prophylactic cranial irradiation therapy efficacy

BackgroundSmall-cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis. Limited-stage (LS)-SCLC comprises only one-third of SCLC cases, resulting in limited molecularly targeted therapies and treatment options. Despite advances in thoracic and cranial irradiation leading to improved outcomes, a notable proportion of patients develop brain metastasis (BM), highlighting the importance of identifying high-risk patients for tailored screening and treatment strategies. Materials and MethodsWe analyzed baseline tumor biopsies from 180 LS-SCLC patients who received frontline definitive chemoradiotherapy (dCRT) using a 474-gene pan-cancer panel. The cumulative incidence of BM was calculated with death scored as a competing risk. Independent prognostic factors for BM risk were identified using the Fine-Gray model. ResultsAlterations in the cell cycle pathway, particularly RB1 mutations, were more common in patients with BM, while FLT4 mutations were more frequent in those without BM (P=0.002 and P=0.021, respectively). Significant risk factors for BM include smoking (subdistribution hazard ratio [SHR]: 1.73; 95 % confidence interval [CI]: 1.11–2.70; P=0.016), RB1 mutations (SHR: 2.19; 95 % CI: 1.27–3.81; P=0.005), and BCL3 amplification (SHR: 2.27; 95 % CI: 1.09–4.71; P=0.028). Conversely, prophylactic cranial irradiation (PCI) (SHR: 0.39; 95 % CI: 0.25–1.60; P<0.001), FLT4 mutations (SHR: 0.26; 95 % CI: 0.07–0.98; P=0.047), and NOTCH pathway alterations (SHR: 0.65; 95 % CI: 0.43–1.00; P=0.049) were associated with a lower incidence of BM in LS-SCLC. Notably, consolidation PCI therapy did not reduce the BM risk in patients with baseline RB1 mutations, with BM occurrence probabilities of 34.7 % at 20 months and 62.6 % at 40 months. ConclusionOur study yields valuable insights into the genetic characteristics of LS-SCLC patients with and without BM, aiding the development of personalized treatment strategies. Identifying risk factors associated with the incidence and timing of BM, within the standard regimen of dCRT followed by PCI, may help optimize clinical decision-making for LS-SCLC.

Elucidating the role of RBM10 in brain metastasis of EGFR19del lung adenocarcinoma.

e20501 Background: The EGFR mutation was detected in 66.3% of Asian patients with lung adenocarcinoma. Among these mutations, EGFR 19del exhibited the highest sensitivity and best response. However, it is worth noting that patients with EGFR 19del have a high cumulative incidence of brain metastases, which contributes significantly to treatment failure. Based on previous WES analysis of primary lung cancer cases and their corresponding brain metastases, RBM10 co-mutation was observed in four out of ten cases with EGFR 19del mutation, leading to decreased expression levels of RBM10. These findings suggest a potential role for RBM10 in modulating the development of brain metastases in patients with EGFR 19del lung cancer. Methods: To investigate the role of RBM10 in brain metastasis, we performed RNA-seq on the PC9 cell line to identify metabolic pathways and genes associated with RBM10 and brain metastasis. Additionally, the brain metastasis model was established by injecting PC9 cells into the left ventricle of nude mice, and the ability of PC9 cells to form brain metastases after knocking down RBM10 was confirmed through two rounds of in vivo screening using the PC9 cell line. Lipidomics analysis further validated that RBM10 affects key metabolite production. Clip-seq and RNA-seq were employed to analyze how RBM10 regulates sphingolipid metabolism. Finally, we identified key targets affecting blood-brain barrier function within the sphingolipid metabolism pathway and verified their ability to inhibit brain metastasis using both in vitro and in vivo models. Results: RNA-seq results demonstrated the regulatory role of RBM10 in the sphingolipid metabolism pathway, specifically in GALC regulation. In vitro and in vivo models revealed an enhanced brain metastasis ability of the PC9shRBM10 group. Lipidomics analysis revealed that the knockdown of RBM10 resulted in a reduction in ceramide and an elevation in SPH. Integrated RNA-seq and Clip-seq analyses demonstrated that the splicing regulation on GALC was attenuated upon RBM10 knockdown, leading to an increase in GALC expression. Furthermore, this perturbation enhanced the downstream sphingosine-1-phosphate signalling axis (SPH-SK1/2-S1P), consequently promoting increased S1P production and elevated blood-brain barrier permeability. Finally, fingolimod, an S1P inhibitor, was employed to validate its efficacy in inhibiting brain metastasis; moreover, a combination therapy comprising osimertinib and fingolimod exhibited superior capacity for suppressing brain metastasis. Conclusions: This study aims to elucidate the regulatory mechanism underlying the impact of RBM10 on sphingolipid metabolism in brain metastasis of EGFR 19del lung adenocarcinoma, to identify novel therapeutic targets for preventing brain metastasis in patients exhibiting EGFR 19del lung adenocarcinoma with low RBM10 expression.

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

Abstract BACKGROUND Historic data suggest that incidence of brain metastasis (BM) is relatively distributed over time in HER2-positive (HER2+) breast cancer (BC), occurs early in triple negative BC (TNBC), and occurs late in hormone receptor-positive (HR+) metastatic BC (mBC). However, the timing of BM relative to line of therapy has not been well described. We describe the prevalence per line of therapy and cumulative incidence of BM in a large real-world cohort of patients (pts) with mBC, by BC subtype and line of therapy. METHODS This analysis used data from the longitudinal US Flatiron Health de-identified database, which provides unstructured and structured electronic health record-derived data from &amp;gt;2.6 million pts with cancer in ~800 unique sites of care. Eligible pts had initiated a first line of treatment (index data) for mBC up to March 1, 2021, to allow for ≥2 years potential follow-up time. Baseline characteristics were assessed, and pts categorized by HER2 and HR status: 1) HR+, HER2+; 2) HR+, HER2–, 3) HR–, HER2+ and 4) TNBC (i.e., negative for HR and HER2). For the last two categories, HER2-low subsets were defined based on immunohistochemistry results (1+, 2+, or equivocal). Lines of therapy were derived using both treatment regimens and progression data. The primary outcome was the first diagnosis of BM. The prevalence of BM was evaluated by subtype, at the index date, and by the line of therapy. The cumulative incidence function (CIF) of BM was used to estimate the risk of BM in pts free of BM at the index date, and death was treated as a competing event. RESULTS Overall, 18075 pts were included (HR+, HER2+: 3062 pts [16.9%]; HR–, HER2+: 902 pts [5.0%]; HR+, HER2–: 12331 pts [68.2%] [HR+, HER2-low: 7062 (39.1%)]; TNBC: 1780 pts [9.8%] [HR–, HER2-low: 725 pts (4.0%)]). Median age at the index date was 64 years (interquartile range: 54, 73) and 10271pts (56.8%) had visceral metastasis. In total, 5951 pts (32.9%) had de novo disease, 12090 (66.9%) had recurrent disease, and 34 (0.2%) did not have available data for mBC type. The table shows the number of pts by line of therapy, prevalence of BM, and cumulative incidence of BM from the index date. Of the included pts, 1306 (7.2%) had a BM at the index date; the CIF was run on the remaining 16973 pts. Overall, 2248 pts (13.2%) had an incident BM event during follow-up (HR+, HER2+: 578 events; HR–, HER2+: 237 events; HR+, HER2–: 1119 events [HR+, HER2-low: 619 events]; TNBC: 314 events [HR–, HER2-low: 124 events]), 9314 had a competing event, and 5411 were censored. By fourth-line therapy, the prevalence of BM was 26.1% in HR+, HER2+; 37.1% in HR–, HER2+; 24.7% in TNBC (HR–, HER2-low: 27.9%); but remained low at 7.2% in HR+, HER2– (HR+, HER2-low: 9.4%). The cumulative incidence of BM at 60 months was 23% in HR+, HER2+, 34% in HR–, HER2+, 10% in HR+, HER2–, and, 22% in TNBC. Overall, the HER2-low subsets had BM prevalence and cumulative incidence that were very close to those that were HER2–. CONCLUSIONS This large analysis of real-world data demonstrates that the prevalence of BM across pts with mBC differs by tumor subtype and by line of therapy. Conversely, HER2-low status may have limited impact. The cumulative incidence of BM was highest in the HR–, HER2+ and TNBC subgroups, and lowest in the HR+, HER2– subgroup; despite this, due to the high proportion of HER2–, HR+ mBC cases, the HR+, HER2– group represented the largest number of BM events. These data emphasize the need for clinical and biologic predictors of BM and for strategies to prevent their onset, and provide information on the impact of BM inclusion and exclusion criteria in clinical trials for pts with mBC. Number of patients by line of therapy, prevalence of BM, and cumulative incidence of BM from the index date BM, brain metastasis; HR, hormone receptor, pts, patients; TNBC, triple negative breast cancer. Citation Format: Sarah Sammons, Jose Leone, Thibaut Sanglier, Peter Lambert, Filippo Montemurro, Raf Poppe, Eleonora Restuccia, Sara Tolaney, Nancy Lin. Brain metastases in metastatic breast cancer: prevalence per line of treatment and cumulative incidence in a cohort of 18075 real-world patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS11-01.

Characteristics of Long-Term Survivors With EGFR-Mutant Metastatic NSCLC

IntroductionCharacteristics of long-term survivors in EGFR-mutant (EGFRm) NSCLC are not fully understood. This retrospective analysis evaluated a multi-institution cohort of patients with EGFRm NSCLC treated in the pre-osimertinib era and sought to describe characteristics of long-term survivors. MethodsClinical characteristics and outcomes were abstracted from the electronic medical records of patients with EGFRm metastatic NSCLC who started first-line therapy before 2015. Demographics and comutations were compared between greater than or equal to 5-year survivors and less than 5-year survivors. Multivariable Cox proportional hazard and logistic regression models were used to evaluate factors associated with survival and the odds of death within 5 years, respectively. ResultsOverall, 133 patients were greater than or equal to 5-year survivors; 127 were less than 5-year survivors. Burden of pathogenic comutations including TP53 and PIK3CA was similar between greater than or equal to 5-year survivors and less than 5-year survivors. Receipt of first-line chemotherapy rather than EGFR tyrosine kinase inhibitor was similar between the groups (22% of <5-y versus 31% of ≥5-y). Baseline brain metastasis and history of smoking were associated with higher odds of death within 5 years (odds ratio = 2.16, p = 0.029 and odds ratio = 1.90, p = 0.046, respectively). Among patients without baseline brain metastases, cumulative incidence of brain metastases at 5 years was 42.3%. Both baseline and post-baseline brain metastasis were associated with worse overall survival compared with no brain metastasis (hazard ratio = 3.26, p < 0.001 and hazard ratio = 4.99, p < 0.001, respectively). ConclusionsWithin patients treated for EGFRm metastatic NSCLC before 2015, absence of brain metastasis and nonsmoking status were predictive of 5-year survival. Our findings help to define a subset of patients with EGFRm NSCLC with excellent survival outcomes who may not require intensification of initial therapy.

Abstract B004: Clinico-genomic characteristics of breast cancer brain metastasis: A multi-institutional analysis from AACR Project GENIE BPC

Abstract Purpose: The presence of Her2 amplification is associated with an increased risk of developing brain metastases. Brain metastases in breast cancer can be particularly challenging and have significant implications for prognosis and treatment. Common Her2-targeted therapies and small tyrosine kinase inhibitors have demonstrated the ability to penetrate the blood brain barrier and be effective in treating brain metastases. We investigated the clinico-genomic characteristics and the prognosis of brain metastasis in patients with breast cancer. Experimental design: Patients with breast cancer whose tumors underwent targeted sequencing from 2013-2018 at age 56 years old or younger at three institutions from the American Association of Cancer Research Genomics Evidence Neoplasia Information Exchange Biopharma Collaborative (AACR Project GENIE BPC) registry were selected for data curation. The PRISSMM data model was used for real world outcomes including overall survival. We analyzed clinical and genomic characteristics, treatment, and clinical outcome data among patients with and without brain metastases, stratified by Her2 amplification and hormone-receptor status (Her2+ vs. Her2-/HR+ vs. triple-negative breast cancer (TNBC)). We explored the top 20 most frequently altered genes that were included on at least 20% of sequencing panels. Results: A total of 1019 patients with breast cancer along with their receptor subtype information were included in the study (110 patients were excluded due to either post- mortem sequencing or unknown receptor subtype). Among them, 336 (33%) patients were identified to have developed brain metastasis (n=87 with Her2+; n=181 with Her2-/HR+; and n=68 with TNBC). At time of advanced disease, the brain was the first and only distant site of disease in 41/336 (12%) and detected with extracranial sites of disease in 22/336 (7%) patients. For patients presenting with stage I-III breast cancer, the cumulative incidence of brain metastasis at 5 years from breast cancer diagnosis was higher in those with TNBC (35%; 95% CI: 25, 50) as compared to 24% (95% CI: 16, 37) and 21% (95% CI: 15, 29) for those with Her2+ and Her2-/HR+ subtypes, respectively. Median overall survival from brain metastasis was significantly longer (log-rank p&amp;lt;0.001) for those with Her2+ disease (19m, 95% CI: 13, 36) compared to those with Her2-/HR+ (8.9m, 95% CI: 6.3, 15) or TNBC (7.4m, 95% CI: 4.6, 11). Among patients who ever developed brain metastases, IKZF3 alterations occurred in 71% (20/28) of Her2+ patients but did not occur in either Her2- subtype. Additionally, frequencies of CDK12, MYC, and PTEN alterations differed across subtypes. Conclusions: Brain involvement at metastatic presentation conferred a higher risk of death than brain-sparing metastases. Triple negative and Her2+ histologies were associated with higher risk of brain involvement at metastasis presentation. Further exploration by treatment received across receptor subtypes and genomic alterations will be presented. Citation Format: Samantha Brown, Hannah E. Fuchs, Jessica A. Lavery, Katherine S. Panageas, Nelson S. Moss. Clinico-genomic characteristics of breast cancer brain metastasis: A multi-institutional analysis from AACR Project GENIE BPC [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B004.

Antiprogrammed death ligand 1 therapy failed to reduce the risk of developing brain metastases in patients with extensive-stage small cell lung cancer: A retrospective analysis.

Immunotherapy (IO) has demonstrated promising results in treating extensive-stage small cell lung cancer (ES-SCLC), and the management of ES-SCLC brain metastases (BMs) is now receiving significant clinical attention. The objective of this study was to evaluate the role of IO in the clinical management of BMs. Between January 2020 and December 2021, the study included the records of 250 patients who were diagnosed with ES-SCLC. Overall survival (OS), progression-free survival, intracranial progression-free survival, and the cumulative incidence of BMs were calculated using the Kaplan-Meier method and were compared using the log-rank test. In addition, the Cox regression model was used to analyze prognostic factors. In the entire group, 85 patients had baseline BMs (IO plus chemotherapy [IO+ChT], n=38; ChT alone, n=47), and 165 patients (IO+ChT, n=86; ChT alone, n=79) did not have BMs at the time of initial diagnosis. The median follow-up was 22.4months. The OS benefit with first-line antiprogrammed death ligand 1 therapy was maintained regardless of whether patients had BMs (with BMs, 17.97 vs. 13.14months [p=.03]; without BMs, 18.46 vs. 15.05months [p=.047]). However, in patients without BMs, IO did not delay the median time to developing brain progression (10.84 vs. 10.74months; p=.84), and it did not significantly reduce the risk of developing intracranial metastases (the 2-year actuarial risk of developing BMs was 57.0% vs. 50.6%, respectively). Antiprogrammed death ligand 1 therapy improved OS regardless of the presence of BMs. However, IO did not delay the median time to brain progression or reduce the risk of intracranial metastasis in patients without baseline BMs. The findings of this study have important clinical implications for the future management of BMs from ES-SCLC.

Risk of brain metastases in metastatic non-small cell lung cancer without baseline brain metastasis: Pooled analysis of individualized patient data from three randomized clinical trials involving first-line atezolizumab treatment.

2032 Background: Data on the efficacy of immune checkpoint inhibitors on delaying or preventing the occurrence of brain metastases (BMs) in metastatic NSCLC without initial BMs is limited. We explored the benefit of first-line atezolizumab versus chemotherapy in the occurrence of BMs in patients without baseline BMs. Methods: Individual patient data from IMpower1301, IMpower131, and IMpower150 were pooled. All patients in the intention to treat population were analyzed. Primary endpoints included BM free survival (BMFS) and the cumulative incidence of BM. Patients without baseline BMs were categorized into two groups: patients who received treatment including atezolizumab (atezolizumab group) and patients who received comparator chemotherapies (chemotherapy group). Results: In 2543 patients without baseline BMs, 87 (3.4%) developed BM, including 58 (3.4%) and 29 (3.4%) in the atezolizumab group and the chemotherapy group, respectively. The median BMFS was 8.31 months (95% CI 7.79-8.67). The cumulative incidence of BM at 6 months, 12 months, and 24 months was 1.9%, 3.1%, and 3.8%, respectively. Compared to the chemotherapy group, BMFS was significantly improved in the atezolizumab group (8.6 months versus 7.3 months, p &lt; 0.001). After taking the competing risk events into account, no significant difference of the cumulative incidence of BM was observed between the two groups ( p = 0.671), suggesting that the significantly better BMFS in the atezolizumab group analyzed by Kaplan-Meier method should be due to the lower incidence of extracranial progression or death. Baseline bone metastasis and non-squamous NSCLC were identified as two risk factors for BM. Conclusions: In patients with NSCLC without baseline BMs, first-line atezolizumab improved BMFS but not the cumulative incidence of BM compared to chemotherapy, indicating that atezolizumab could not reduce the intrinsic risk of intracranial tumor spreading. [Table: see text]

Extensive‐stage small cell lung cancer: Is prophylactic cranial irradiation necessary in the era of immunotherapy with MRI surveillance?

AbstractObjectiveThe role of prophylactic cranial irradiation (PCI) in treating extensive‐stage small‐cell lung cancer (ES‐SCLC) has been controversial. This study aimed to comprehensively analyze the efficacy of PCI for the treatment of ES‐SCLC under active brain magnetic resonance imaging (MRI) surveillance.MethodsPatients with ES‐SCLC with no brain metastases (BM) confirmed by MRI at the time of diagnosis who responded well to first‐line chemoimmunotherapy at three general hospitals were retrospectively included. Overall survival (OS), progression‐free survival (PFS), and cumulative incidence of BM were compared between patients who underwent PCI and those who did not.ResultsIn total, 66 consecutive patients treated between March 2019 and December 2021 were included in our dataset. Seventeen patients underwent PCI (PCI group) and 49 patients did not (non‐PCI group). In comparison with the non‐PCI group, PCI did not provide OS (median OS: 18.53 vs. 17.35 months, p = 0.28) or PFS (median PFS: 8.61 vs. 7.56 months, p = 0.41) benefits. When death was counted as a competing risk, the difference in the cumulative incidence rate of BM was not statistically significant (1‐year: 12.79% vs. 38.09%; p = 0.14).ConclusionCompared to active MRI surveillance, first‐line chemoimmunotherapy followed by PCI did not improve the prognosis of patients with ES‐SCLC. Further studies are warranted to evaluate the therapeutic effects of PCI following chemoimmunotherapy.

Prophylactic Cranial Irradiation in Patients with Limited-Stage Small-Cell Lung Cancer without Brain Metastases: A Retrospective Cohort Study

<h3>Purpose/Objective(s)</h3> Previous studies showed that prophylactic cranial irradiation (PCI) reduced brain metastases and improved overall survival of patients with limited-stage small-cell lung cancer (LS-SCLC). However, brain magnetic resonance imaging (MRI), currently recognized as the preferred modality for brain metastases detection, was not routinely used for staging and reassessment in previous trials. This retrospective study aimed to reevaluate the role of PCI for LS-SCLC patients in the modern MRI era. <h3>Materials/Methods</h3> We retrospectively reviewed LS-SCLC patients treated with definitive chemoradiotherapy (≥4 cycles of chemotherapy and thoracic intensity-modulated radiotherapy [IMRT]) between 2006 and 2014 in our center. Patients who responded to initial therapy were included and subsequently reassessed for brain metastases by MRI. The cumulative incidence of brain metastases was estimated using the Fine-Grey competing risks regression model. The overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model. <h3>Results</h3> We enrolled 177 patients in this study, of which 79 were treated by PCI and 98 were not (non-PCI). The median follow-up was 76.0 months (95% confidence interval, 71.2-80.8 months). All patients achieved complete response (<i>n</i> = 50, 28.2%) or partial response (<i>n</i> = 127, 71.8%) to initial chemoradiotherapy. The cumulative incidence of brain metastases in the PCI group was lower than in the non-PCI group (6.6% vs. 30.0% at 2 years, 12.2% vs. 31.0% at 5 years, <i>P</i> = 0.004). 5-year PFS in the PCI group was significantly higher than in the non-PCI group (45.3% vs. 26.5%, <i>P</i> = 0.002). However, 5-year OS of 48.8% and 39.2% in the PCI and non-PCI groups, respectively, were similar (<i>P</i> = 0.255). In the multivariate analysis, treatment response (<i>P</i><0.001) and PCI (<i>P</i> = 0.038) were independent prognostic factors for PFS. Stratification analysis revealed that PCI did not improve 5-year PFS for patients with partial response to initial therapy (26.6% vs. 19.7%, <i>P</i> = 0.234). <h3>Conclusion</h3> In the Modern Era with MRI Surveillance, PCI is associated with a lower incidence of brain metastases and improved PFS while OS benefit wasn't observed. Patients achieving partial response to initial therapy did not gain PFS benefit from PCI. Prospective trials are still needed to further evaluate the utility of PCI for patients with LS-SCLC.

Predictive Model to Guide Brain Magnetic Resonance Imaging Surveillance in Patients With Metastatic Lung Cancer: Impact on Real-World Outcomes.

Brain metastasis is common in lung cancer, and treatment of brain metastasis can lead to significant morbidity. Although early detection of brain metastasis may improve outcomes, there are no prediction models to identify high-risk patients for brain magnetic resonance imaging (MRI) surveillance. Our goal is to develop a machine learning-based clinicogenomic prediction model to estimate patient-level brain metastasis risk. A penalized regression competing risk model was developed using 330 patients diagnosed with lung cancer between January 2014 and June 2019 and followed through June 2021 at Stanford HealthCare. The main outcome was time from the diagnosis of distant metastatic disease to the development of brain metastasis, death, or censoring. Among the 330 patients, 84 (25%) developed brain metastasis over 627 person-years, with a 1-year cumulative brain metastasis incidence of 10.2% (95% CI, 6.8 to 13.6). Features selected for model inclusion were histology, cancer stage, age at diagnosis, primary site, and RB1 and ALK alterations. The prediction model yielded high discrimination (area under the curve 0.75). When the cohort was stratified by risk using a 1-year risk threshold of > 14.2% (85th percentile), the high-risk group had increased 1-year cumulative incidence of brain metastasis versus the low-risk group (30.8% v 6.1%, P < .01). Of 48 high-risk patients, 24 developed brain metastasis, and of these, 12 patients had brain metastasis detected more than 7 months after last brain MRI. Patients who missed this 7-month window had larger brain metastases (58% v 33% largest diameter > 10 mm; odds ratio, 2.80, CI, 0.51 to 13) versus those who had MRIs more frequently. The proposed model can identify high-risk patients, who may benefit from more intensive brain MRI surveillance to reduce morbidity of subsequent treatment through early detection.

Cumulative incidence and risk factors of brain metastasis for acral and mucosal melanoma patients with stages I–III

PurposeFew studies focused on the incidence of brain metastasis in patients with acral and mucosal melanoma, and a better understanding of the incidences and predictors of brain metastasis is needed in these patients. MethodA prospectively accrued cohort of 799 patients with acral and mucosal melanoma in stages I–III from July 2011 to December 2015 at Peking University Cancer Hospital were included in this study. Competing risk models (Fine and Gray) were used to estimate the cumulative incidence of brain metastasis and compare the differences in cumulative incidence curves between different primary lesions, stages, and molecular types. ResultsAt a median follow-up time of 68.0 months, 60 of the 779 patients (7.7%) developed brain metastasis, and 261 (33.5%) patients developed extracranial metastasis. Considering the risk of competition, the cumulative incidence of brain metastasis at one year, two years, and five years after diagnosis were 5.1%, 10.2%, and 19.5%, respectively. Stage III, BRAF mutations, and NRAS mutations were associated with a high risk of brain metastasis in univariable analysis. Multivariate analysis showed BRAF mutations, and NRAS mutations had statistically correlated with an increased cumulative incidence of brain metastasis at diagnosis and all-time point of one year and two years after diagnosis. ConclusionThis study is the first to report the cumulative incidence and risk factors of brain metastasis for patients with acral and mucosal melanoma in stages I–III. Patients with BRAF and NRAS mutations had a higher incidence at diagnosis and all-time point, providing the basis for surveillance guidelines and further mechanic exploration.

Analysis of Rates of Brain Metastases and Association With Breast Cancer Subtypes in Ontario, Canada

Approximately 1 in 7 patients with metastatic breast cancer (MBC) will receive radiotherapy for brain metastases (BRM). Significant differences in cumulative incidence of BRM by breast cancer subtype may inform future BRM screening protocols. To describe cumulative incidence of BRM among patients with de novo MBC. In this population-based cohort study, population health administrative databases in Ontario, Canada, held at the ICES were used to identify patients diagnosed with de novo MBC between 2009 and 2018. Given that a code for BRM does not exist within ICES, we analyzed the incidence of radiotherapy for BRM. The median (IQR) follow-up was 19.3 (6.2-39.5) months. A total of 100 747 patients with a new diagnosis of breast cancer between January 2009 and December 2018 were identified. Of these patients, 17 955 were excluded because they had previous or subsequent malignant neoplasms, 583 were excluded because they were younger than 18 years, 974 were excluded because there was an invalid Ontario Health Insurance Plan number or a date of death on or before the index date. Among 81 235 remaining patients, 3916 were identified as having de novo MBC. Treatment with radiotherapy for breast cancer BRM. Cumulative incidence of radiotherapy for BRM accounting for the competing risk of death, and time from MBC diagnosis to brain radiotherapy. Kaplan-Meier analyses were performed for time-to-event end points. Logistic regression was used to account for confounding variables. Among 3916 patients with MBC, 1215 (31.0%) had HR-positive/ERBB2 (formerly HER2)-negative cancer, 310 (7.9%) had ERBB2-positive/HR-positive cancer, 200 (5.1%) had ERBB2-positive/HR-negative cancer, 258 (6.6%) had TNBC, and the remaining 1933 patients (49.4%) had an unknown breast cancer subtype. The median (IQR) age at diagnosis was 63 (52-75). A total of 549 (14.0%) underwent stereotactic radiosurgery or whole brain radiotherapy for breast cancer BRM. Cumulative incidence of BRM was higher among patients with ERBB2-positive/HR-negative breast cancer (34.7%), ERBB2-positive/HR-positive breast cancer (28.1%), and triple-negative breast cancer (21.9%) compared to those with HR-positive/ERBB2-negative breast cancer (12.1%). The median (IQR) time from MBC diagnosis to brain radiotherapy ranged from 7.5 (2.3-17.4) months for patients with TNBC to 19.8 (12.2-35.1) months for those with ERBB2-positive/HR-positive breast cancer. Incidence and time to development of BRM vary significantly by breast cancer subtype. A better understanding of the biology of intracranial metastatic disease may help inform potential screening programs or preventative interventions.

Clinical and molecular characteristics of advanced esophageal/GEJ cancer with brain metastasis.

e16092 Background: Brain metastasis (BRM) in gastroesophageal (GE) cancer is uncommon, but contributes to poor prognosis and significant symptom burden. While HER2 overexpression has been suggested as a potential driver of BRM, clinicopathologic and molecular determinants of BRM in GE cancer and their impact on clinical outcome remain incompletely understood. Methods: We retrospectively analyzed clinicopathologic data from 323 advanced esophageal/GEJ patients (pts) at Johns Hopkins from 2003 to 2021. Univariate and multivariate logistic regression were performed to investigate the association between several clinical and molecular features and the occurrence of BRM, with particular focus on HER2 overexpression (by IHC and FISH) and PD-L1 expression (by IHC) as measured by the combined positive score (CPS). Overall survival was estimated using the Kaplan-Meier method. Results: Median age was 64 and most pts were white (90.4%). Tumors were 73.7% esophageal primary, 82.7% adenocarcinoma, 43.8% HER2+, and 11.1% CPS ≥ 1. Cumulative incidence of BRM in overall cohort and within HER2+ subgroup was 14.6% (47 pts) and 25.4% (16 pts), respectively. Pts with BRM (not already present at time of stage IV diagnosis) had median onset of 10.8 months. Seventeen (36.2%) pts had a solitary brain lesion and 10 (21.7%) were asymptomatic. On univariate analysis, adenocarcinoma and HER2 overexpression were associated with increased risk of BRM (OR 3.45; 95% CI 0.09-0.96; p = 0.043 and OR 2.72; 95% CI 1.11-6.67; p = 0.028, respectively). Notably, the HER2 association was strengthened when HER2 equivocal tumors were re-classified as positive in an exploratory analysis (OR 3.55; 95% CI 1.38-9.14; p = 0.009). Adenocarcinoma and HER2 overexpression were collinear in the multivariate model. In pts with BRM, OS was improved in HER2+ pts (16.72 months; 95% CI 12.3-21.1 months; log-rank p = 0.039 and OR 0.33; 95% CI 0.11-0.99; Cox regression p = 0.049). CPS and primary tumor location were not associated with increased BRM. Conclusions: HER2 overexpression identifies an esophageal/GEJ molecular subtype that is significantly associated with increased risk of BRM; though with improved OS (compared to non-HER2+ BRM) and later onset CNS progression, likely reflecting durable extra-CNS control on targeted systemic therapy and a potential HER2+ subgroup with relatively indolent biology. Prevalence of asymptomatic and solitary brain lesions supports increased brain surveillance for this population.

Incidence and impact of brain metastasis in patients with hereditary BRCA1 or BRCA2 mutated invasive breast cancer

Patients with hereditary mutations in BRCA1 or BRCA2 (gBRCA1/2) and breast cancer have distinct tumor biology, and encompass a predilection for brain metastasis (BM). We looked into baseline risk of BMs among gBRCA1/2 patients. Patients with gBRCA1/2, stage I-III invasive breast cancer seen between 2000–2017 with parenchymal BMs. Among gBRCA1 with distant breast cancer recurrence, 34 of 76 (44.7%) were diagnosed with brain metastases compared to 7 of 42 (16.7%) patients with gBRCA2. In the comparator group, 65 of 182 (35.7%) noncarrier triple-negative breast cancer (TNBC) and a distant recurrence experienced BM’s. In a competitive risk analysis using death as a competing factor, the cumulative incidence of BMs was similar between gBRCA1 and noncarrier TNBC patients. The time from primary breast cancer diagnosis to detection of BMs was similar between gBRCA1 and noncarrier TNBC patients (2.4 vs 2.2 years). Survival was poor after BMs (7.8 months for gBRCA1 patients vs. 6.2 months for TNBC noncarriers). Brain was a more common site of initial distant recurrence in gBRCA1 patients versus TNBC noncarriers (26.3% vs. 12.1%). Importantly, the presence of BMs, adversely impacted overall survival across groups (HR 1.68 (95% CI 1.12–2.53), hazard ratio for death if a patient had BMs at the time of initial breast cancer recurrence vs. not). In conclusion, breast cancer BMs is common and is similarly frequent among gBRCA1 and noncarrier patients with recurrent TNBC. Our study highlights the importance of improving the prevention and treatment of BMs in patients with TNBC, gBRCA1 carriers, and noncarriers.

127P Does radiomics have added value in predicting the development of brain metastases in patients with radically treated stage III non-small cell lung cancer (NSCLC)?

Despite radical intent therapy for patients (pts) with stage III NSCLC, cumulative incidence of brain metastasis (BM) reaches 30%. Current risk stratification fails to identify these pts. Radiomics features (fts) from chest CTs have shown to have predictive value. We aimed to develop a model combining existing clinical risk factors with radiomics fts for BM development in stage III NSCLC.

Incidence of brain metastases in patients with early HER2-positive breast cancer receiving neoadjuvant chemotherapy with trastuzumab and pertuzumab

The addition of pertuzumab (P) to trastuzumab (H) and neoadjuvant chemotherapy (NAC) has decreased the risk of distant recurrence in early stage HER2-positive breast cancer. The incidence of brain metastases (BM) in patients who achieved pathological complete response (pCR) versus those who do not is unknown. In this study, we sought the incidence of BM in patients receiving HP-containing NAC as well as survival outcome. We reviewed the medical records of 526 early stage HER2-positive patients treated with an HP-based regimen at Memorial Sloan Kettering Cancer Center (MSKCC), between September 1, 2013 to November 1, 2019. The primary endpoint was to estimate the cumulative incidence of BM in pCR versus non-pCR patients; secondary endpoints included disease free-survival (DFS) and overall survival (OS). After a median follow-up of 3.2 years, 7 out of 286 patients with pCR had a BM while 5 out of 240 non-pCR patients had a BM. The 3-year DFS was significantly higher in the pCR group compared to non-pCR group (95% vs 91 %, p = 0.03) and the same trend was observed for overall survival. In our cohort, despite the better survival outcomes of patients who achieved pCR, we did not observe appreciable differences in the incidence of BM by pCR/non-pCR status. This finding suggests that the BM incidence could not be associated with pCR. Future trials with new small molecules able to cross the blood brain barrier should use more specific biomarkers rather than pCR for patients’ selection.

Benefits of Prophylactic Cranial Irradiation in the MRI Era for Patients With Limited Stage Small Cell Lung Cancer.

PurposePrevious studies have shown that prophylactic cranial irradiation (PCI) can improve the survival of patients with limited-stage small cell lung cancer (LS-SCLC). PCI is recommended for patients who respond well to chemoradiotherapy. However, whether PCI could be extrapolated to the LS-SCLC patients in the modern era of MRI is unknown. This study aimed to explore the value of PCI in patients with LS-SCLC in the era of brain MRI.MethodsThis study included 306 patients with LS-SCLC at the Cancer Hospital of China Medical University. All patients received brain MRI at diagnosis and after radiochemotherapy to exclude brain metastases. A propensity score matching was performed to reduce the influence of potential confounders. Overall survival (OS), progression-free survival (PFS), and recurrence failure types were compared between PCI and non-PCI groups.ResultsAmong the 306 eligible patients, 81 underwent PCI, and 225 did not. After propensity score matching, there was no statistical difference in baseline data between the two groups, with 75 patients in each group. PCI did not achieve OS (median OS: 35 vs. 28 months, p = 0.128) or PFS (median PFS: 15 vs. 10 months, p = 0.186) benefits. During follow-up, 30 patients (20.0%) developed brain metastases, including 13 patients (17.3%) in the PCI group and 17 patients (22.7%) in the non-PCI group. Regarding death as a competitive risk, patients who received PCI had a lower cumulative incidence of brain metastasis than those who did not (3 years: 14.7% vs. 22.7%; Gray’s test, p = 0.007).ConclusionsWhen brain MRI was performed at diagnosis and pre-PCI, PCI could reduce the cumulative rate of brain metastases, but it did not achieve survival benefits for LS-SCLC patients.