Diagnosis Of Brain Metastases Research Articles

Advances in determining the gross tumor target volume for radiotherapy of brain metastases

Brain metastases (BMs) are the most prevalent intracranial malignant tumors in adults and are the leading cause of mortality attributed to malignant brain diseases. Radiotherapy (RT) plays a critical role in the treatment of BMs, with local RT techniques such as stereotactic radiosurgery (SRS)/stereotactic body radiotherapy (SBRT) showing remarkable therapeutic effectiveness. The precise determination of gross tumor target volume (GTV) is crucial for ensuring the effectiveness of SRS/SBRT. Multimodal imaging techniques such as CT, MRI, and PET are extensively used for the diagnosis of BMs and GTV determination. With the development of functional imaging and artificial intelligence (AI) technology, there are more innovative ways to determine GTV for BMs, which significantly improve the accuracy and efficiency of the determination. This article provides an overview of the progress in GTV determination for RT in BMs.

The development of brain metastases in patients with different therapeutic strategies for metastatic renal cell cancer.

A diagnosis of brain metastasis (BM) significantly affects quality of life in patients with metastatic renal cell cancer (mRCC). Although systemic treatments have shown efficacy in mRCC, active surveillance (AS) is still commonly used in clinical practice. In this single-center cohort study, we assessed the impact of different initial treatment strategies for metastatic RCC (mRCC) on the development of BM. All consecutive patients diagnosed with mRCC between 2011 and 2022 were included at the Erasmus MC Cancer Institute, the Netherlands, and a subgroup of patients with BM was selected. In total, 381 patients with mRCC (ECM, BM, or both) were identified. Forty-six patients had BM of whom 39 had metachronous BM (diagnosed ≥1 month after ECM). Twenty-five (64.1%) of these 39 patients with metachronous BM had received prior systemic treatment for ECM and 14 (35.9%) patients were treatment naive at BM diagnosis. The median BM-free survival since ECM diagnosis was significantly longer (p = .02) in previously treated patients (29.0 [IQR 12.6-57.0] months) compared to treatment naive patients (6.8 [IQR 1.0-7.0] months). In conclusion, patients with mRCC who received systemic treatment for ECM prior to BM diagnosis had a longer BM-free survival as compared to treatment naïve patients. These results emphasize the need for careful evaluation of treatment strategies, and especially AS, for patients with mRCC.

Sex Differences in Odds of Brain Metastasis and Outcomes by Brain Metastasis Status after Advanced Melanoma Diagnosis.

Sex differences in cancer are well-established. However, less is known about sex differences in diagnosis of brain metastasis and outcomes among patients with advanced melanoma. Using a United States nationwide electronic health record-derived de-identified database, we evaluated patients diagnosed with advanced melanoma from 1 January 2011-30 July 2022 who received an oncologist-defined rule-based first line of therapy (n = 7969, 33% female according to EHR, 35% w/documentation of brain metastases). The odds of documented brain metastasis diagnosis were calculated using multivariable logistic regression adjusted for age, practice type, diagnosis period (pre/post-2017), ECOG performance status, anatomic site of melanoma, group stage, documentation of non-brain metastases prior to first-line of treatment, and BRAF positive status. Real-world overall survival (rwOS) and progression-free survival (rwPFS) starting from first-line initiation were assessed by sex, accounting for brain metastasis diagnosis as a time-varying covariate using the Cox proportional hazards model, with the same adjustments as the logistic model, excluding group stage, while also adjusting for race, socioeconomic status, and insurance status. Adjusted analysis revealed males with advanced melanoma were 22% more likely to receive a brain metastasis diagnosis compared to females (adjusted odds ratio [aOR]: 1.22, 95% confidence interval [CI]: 1.09, 1.36). Males with brain metastases had worse rwOS (aHR: 1.15, 95% CI: 1.04, 1.28) but not worse rwPFS (adjusted hazard ratio [aHR]: 1.04, 95% CI: 0.95, 1.14) following first-line treatment initiation. Among patients with advanced melanoma who were not diagnosed with brain metastases, survival was not different by sex (rwOS aHR: 1.06 [95% CI: 0.97, 1.16], rwPFS aHR: 1.02 [95% CI: 0.94, 1.1]). This study showed that males had greater odds of brain metastasis and, among those with brain metastasis, poorer rwOS compared to females, while there were no sex differences in clinical outcomes for those with advanced melanoma without brain metastasis.

Abstract PS11-06: Analysis of HER2 expression changes from breast primary to brain metastases including HER2 Low and impact on overall survival

Abstract Background: Previous studies have shown that breast cancer receptor subtype switching between matched primary and metastatic brain metastases (BrM) is common. HER2 expression at low levels, termed “HER2 Low”, has emerged as a new therapeutic biomarker for highly active antibody drug conjugates with potential intracranial activity. Trastuzumab deruxtecan is FDA approved for the treatment of HER2 Low and HER2 positive breast cancer with emerging evidence of CNS responses and clinical benefit in patients with BrM. This study aimed to investigate the relationship between HER2 expression including HER2-Low between matched breast cancer primary tumors and brain metastases. We also sought to evaluate the impact of low HER2 expression on overall survival in breast cancer brain metastases. Methods: We identified pts with MBC seen at least once at a single, NCI-designated center and had a diagnosis of BrM between 2003 and 2023. Of 1252 MBC pts with a diagnosis of BrM, 265 pts underwent resection/biopsy for BrM with available ER/PR/HER2 status. Only pts with available matched primary and BrM tissue were analyzed. HER2 expression was defined as: HER2+ (3+ or 2+/ISH amplified), HER2-Low (1+, 2+/ISH neg) or HER2-0 [by ASCO-CAP guidelines]. Estrogen receptor (ER) status was defined as ER≥1%. Multivariate overall survival (OS) analyses by Cox proportional hazard models were determined from time of BrM resection to death or last follow-up between HER2+, HER2-Low and HER2-0 patients controlling for ER and age. Results: 197 matched breast cancer primary and BrMs with available ER, PR, and HER2 testing were evaluated. Median age at BrM resection was 51 yrs. ER was positive in 48% (N=95) of BrMs. Of 265 resected BrMs, HER2 expression was found in 72%: 49.8% HER2+ (N=132), 22.2% HER2-Low (N=59), and 27.9% HER2-0 (N=74). HER2 expression by 197 primary tumors was: 57% HER2+ (N=112), 24% HER2-Low (N=48), 19% HER2 0 (N=37). Amongst 112 HER2+ primary tumors, 97% (N=109) had concordant HER2+ BrMs, 3 (2.6%) switched to HER2-Low, with 100% retaining some HER2 expression. Of 37 HER2-0 primaries, 35% (13/37) gained HER2-Low expression and 5.4% (2/37) gained HER2+ expression in the BrM. Amongst 48 HER2-Low primary tumors, half (52%) changed expression to either HER2+ (21%) or HER2-0 (31.2%) in the brain. 66 tumors had extracranial tissue biopsied prior to BrM resection available for HER2 analysis. Of 15 HER2-0 extracranial tumors, 47% gained HER2-Low and 13% gained HER2+ at time of BrMs. After adjusting for age and ER status at the time of BrMs, patients with HER2+ BrM had a statistically significant lower risk of death at time of follow up than those with HER2-Low BrM (HR=0.41, P=0.0006). The risk of death between patients with HER2-0 BrM did not differ from HER2-Low BrM after adjustment for ER and age (HR=0.96, p =0.9). Median survival from BrM resection was 12.4m, 16.1m, 47.6m for HER2-Low, HER2-0 and HER2+ respectively (p = .0004). Conclusions: HER2 expression amongst primary, extracranial and brain metastases is dynamic with frequent change. Over 40% of HER2-0 primary or extracranial tumors gain HER2 expression in the brain. These changes have therapeutic implications given HER2 targeting antibody drug conjugates with improved OS and emerging evidence of CNS activity, highlighting the need for better diagnostics, including those that do not require invasive tissue sampling, to determine HER2 status in the brain. Patients with HER2-Low and HER2-0 BrMs have inferior survival and are a clinical unmet need. Citation Format: Alyssa Pereslete, Melissa Hughes, Alyssa Patterson, Janet Files, Kyleen Nguyen, Lauren Buckley, Ashka Patel, Abigail Moore, Eric Winer, Tianyu Li, Sara Tolaney, Nancy Lin, Sarah Sammons. Analysis of HER2 expression changes from breast primary to brain metastases including HER2 Low and impact on overall survival [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 PS11-06.

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 >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.

Abstract PO2-27-09: Clinical impact of routine MRI screening for brain metastases in patients with HER2 positive or triple negative metastatic breast cancer

Abstract Background: Routine screening for brain metastases (BMs) is currently not recommended in patients with metastatic breast cancer (BC). There is a growing consensus on the need for the screening of BMs in HER2 positive and triple negative breast cancer (TNBC) because 40% of patients experience BMs throughout the disease course and systemic treatment options with intracranial efficacy are now available. However, there is a lack of prospective study data on this matter. We conducted a prospective cohort study to evaluate the role of brain MRI screening for the patient with metastatic BC. Methods: Patients who newly diagnosed metastatic HER2+ or TNBC were eligible. Screening brain MRI was planned at diagnosis and failure from first line and second line of systemic therapy. All patients underwent complete physical examination and comprehensive neurologic assessment at baseline and thereafter. Patients who diagnosed symptomatic BMs were dropped from the study and subsequent treatment including local therapies and survival data were collected. Primary endpoint was the percentage of patients diagnosed with asymptomatic BMs. Results: A total of 147 patients were enrolled between Sep 2018 and Aug 2023 at Yonsei Cancer Center. The median age was 51 years (range, 29-80) and most patients (92.5%, n=136) had good performance status (ECOG 0-1). The tumor subtypes were as follows: TNBC, 51.0%; HER2 (ER-, HER2+), 29.3%; luminal-HER2 (ER+, HER2+), 19.7%. The cumulative incidence of asymptomatic BMs was 20.4% for overall patients; 24.0% for TNBC (18/75), 14.0% for HER2 (6/43), and 20.7% for luminal HER2 (6/29). Symptomatic detection of BMs during study period was 14.7% for TNBC, 18.6% for HER2, and 6.9% for luminal-HER2. Initial local treatment was stereotactic radiosurgery in 30 patients (58.8%), whole-brain radiation therapy in 14 patients (27.5%), surgical resection in 2 patients (3.9%) and 6 patients (11.8%) did not receive any treatment for BMs. After a median follow-up of 20.1 months, the median overall survival following a diagnosis of BMs was 23.7 vs 7.3 months (hazard ratio 0.41; 95% CI, 0.17 to 0.95; P = .04) in patients with asymptomatic and symptomatic BMs, respectively. Conclusions: We identified approximately 20% of patients with HER2+ or TNBC as asymptomatic BMs. Emerging systemic therapies showed promising intracranial response would warrant the detection of asymptomatic BMs through routine MRI screening. Incidence of brain metastases by subtypes Citation Format: Gun Min Kim, Joo Hyuk Sohn, Min Hwan Kim, Seul-Gi Kim, Hyung Soon Park, Jong Hee Jang, Yong Bae Kim, Seung-koo Lee. Clinical impact of routine MRI screening for brain metastases in patients with HER2 positive or triple negative metastatic breast cancer [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 PO2-27-09.

Abstract PO1-17-09: Real-world clinical outcomes in US patients with brain metastases secondary to HR+/HER2- metastatic breast cancer treated with abemaciclib

Abstract Background: Abemaciclib has demonstrated pharmacologically relevant intracranial concentrations and antitumor activity in patients with brain metastases secondary to HR+/HER2- metastatic breast cancer (MBC). However, clinical data is limited, and further assessments are warranted. This retrospective study describes real-world outcomes following abemaciclib initiation in patients with brain metastases secondary to HR+/HER2- MBC. Methods: Data were accessed from the US nationwide Flatiron Health electronic health records-derived de-identified database from 01/01/2011 to 12/31/2021. This real-world study included adult patients with a diagnosis of HR+/HER2- MBC with brain metastases prior to abemaciclib initiation. Patient and treatment characteristics were summarized using descriptive statistics. Kaplan-Meier methods were used to assess clinical outcomes from abemaciclib initiation: time to treatment discontinuation (TTD), progression-free survival (rwPFS), overall survival (rwOS). Intracranial rw best responses were also reported. Results: This study included 82 patients (one male) diagnosed with MBC and brain metastases prior to abemaciclib initiation and the median follow-up was 12.8 months. At data cut-off, 17 (20.7%) patients remained on abemaciclib therapy. Twenty-three (28%) patients received abemaciclib as the first line of therapy for MBC. Of the 82 patients in the study, 68 (82.9%) patients used concomitant endocrine therapy. Prior to abemaciclib initiation, 25 (30.5%) patients received chemotherapy and 33 (40.2%) patients received a CDK4 and 6 inhibitor. Most patients (67.1%) initiated abemaciclib at a dose of 150 mg twice daily. The median time from diagnosis of brain metastasis to abemaciclib initiation was 2.1 months (interquartile range:1.0, 8.0); 16 (19.5%) did not undergo surgical resection or receive radiation to the brain during this time. Sixty-six (80.5%) patients received brain radiation of which 56.1% received stereotactic radiosurgery (SRS) and 47.0% received whole-brain radiation (WBRT) either alone or in combination with craniotomy/metastasectomy, intrathecal chemotherapy, or surgery. The median TTD for abemaciclib was 7.1 months (95% confidence interval [95% CI]: 4.6, 11.3); most common reasons for discontinuation were disease progression (39.0%) or adverse events (29.3%). The median rwPFS was 9.2 months (95% CI: 6.0, 11.6) and median rwOS was 20.8 months (95% CI: 13.9, 26.0). Of the patients where response data were available (n = 51), rw intracranial clinical benefit rate (CBR; complete response [CR]/partial response [PR]/stable disease [SD] ≥24 weeks of abemaciclib initiation) was 62.7% (Table 1). Conclusion: In this real-world study, most patients with brain metastases secondary to HR+/HER2- MBC who initiated abemaciclib treatment received SRS or WBRT prior to or concurrent with abemaciclib initiation. While the clinical outcomes, rwPFS and intracranial CBR were encouraging, these findings should be interpreted with caution due to the nature of the real-world study design. Table 1. Intracranial Real-World Best Responses Citation Format: Wambui Gathirua-Mwangi, Holly Martin, Dan He, Shen Zheng, Kristin Sheffield, Jincy John, Sarah Rybowski, Priscilla Brastianos. Real-world clinical outcomes in US patients with brain metastases secondary to HR+/HER2- metastatic breast cancer treated with abemaciclib [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 PO1-17-09.

Abstract PO2-04-04: Trastuzumab deruxtecan for the treatment of patients with HER2-positive breast cancer with brain and/or leptomeningeal metastases: an updated overall survival analysis using data from a multicenter retrospective study (ROSET-BM)

Abstract Background: ROSET-BM (UMIN000044995) was a multicenter, retrospective chart review study of patients (pts) who received trastuzumab deruxtecan (T-DXd) treatment for HER2-positive (HER2+) metastatic breast cancer (MBC) with brain metastases (BM) and/or leptomeningeal carcinomatosis (LMC). Primary results (data cutoff, October 31, 2021) were presented at SABCS2022 (median progression-free survival [PFS], 16.1 months; 1-year overall survival [OS] rate, 74.9%; and median follow-up duration, 11.2 months). To confirm the long-term effectiveness of T-DXd in HER2+ MBC pts with BM and/or LMC, we conducted an updated analysis using additional 1-year follow-up data. Methods: Pts who started T-DXd treatment between May 25, 2020, and April 30, 2021, were registered for ROSET-BM. For this updated OS analysis, the extended observation period ended on October 31, 2022. OS, PFS, and time to treatment failure (TTF) were evaluated. Median survival times and 95% CIs were calculated using the Kaplan–Meier method. In addition, prespecified and exploratory subgroup analyses were performed based on patient background characteristics. Univariate and multivariate Cox proportional hazards regression models were used to evaluate baseline prognostic factors for OS. Results: 104 pts from 62 institutions were included in this updated OS analysis. Median duration of follow-up was 20.4 months. Median number of prior lines of therapy was 4 (range, 1–15). Median time from first diagnosis of MBC to first administration of T-DXd was 37.5 months. Median time from first diagnosis of BM to first administration of T-DXd was 18.9 months. The prevalence of active BM, stable BM, LMC, and unclassified (image not evaluated) was 64.4% (n=67), 11.5% (n=12), 18.3% (n=19), and 5.8% (n=6), respectively. Median OS was not reached (NR) among all pts (1-year OS rate, 74.8%; 2-year OS rate, 56.0%). Subgroup analyses showed that median OS in pts with active BM was 27.0 months (95% CI, 16.4 to NR) and that median OS was NR in pts with stable BM or LMC (2-year OS rate for pts with stable BM, 71.6%; 2-year OS rate for pts with LMC, 61.6%). The results of univariate and multivariate analyses for OS showed no relevant baseline prognostic factors. Among all pts, median PFS was 14.6 months (95% CI, 10.6–20.8). Subgroup analyses showed that in pts with active BM, stable BM, and LMC, median PFS was 13.2 months (95% CI, 10.0–20.3), NR (95% CI, 5.3 to NR), and 17.5 months (95% CI, 8.3–22.1), respectively. Among all pts, median TTF was 9.3 months (95% CI, 6.3–11.8). The most common event and adverse event leading to discontinuation of T-DXd was progressive disease (37 pts, 35.6%) and interstitial lung disease (ILD; 24 pts, 23.1%), respectively. Median time to onset of an ILD event was 5.3 months (range, 0.7–20.0). ILD was grade 1 in 14 pts (13.5%), grade 2 in 3 pts (2.9%), grade 3 in 5 pts (4.8%), grade 4 in 2 pts (1.9%), and grade 5 in 0 pts. The Table summarizes the primary and updated results of ROSET-BM. Conclusion: The updated OS results of this retrospective chart review show that T-DXd has promising effectiveness in HER2+ MBC pts with long-term and heavily pretreated BM and LMC. This study was funded by Daiichi Sankyo Co., Ltd. Primary and updated results from the ROSET-BM study The updated results show that T-DXd has promising effectiveness in HER2+ MBC pts with long-term and heavily pretreated BM and LMC. Citation Format: Takashi Yamanaka, Naoki Niikura, Takahiro Nakayama, Mitsugu Yamamoto, Kazuo Matsuura, Kenichi Inoue, Sachiko Takahara, Hironori Nomura, Shosuke Kita, Miki Yamaguchi, Tomoyuki Aruga, Nobuhiro Shibata, Akihiko Shimomura, Yuri Ozaki, Shuji Sakai, Daisuke Takiguchi, Takehiko Takata, Armin Bastanfard, Kazuhito Shiosakai, Junji Tsurutani. Trastuzumab deruxtecan for the treatment of patients with HER2-positive breast cancer with brain and/or leptomeningeal metastases: an updated overall survival analysis using data from a multicenter retrospective study (ROSET-BM) [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 PO2-04-04.

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.

Abstract 6472: Response to PARP inhibitors in patients with breast cancer metastatic to the central nervous system

Abstract Background: Central nervous system (CNS) metastasis from breast cancer can be challenging to treat due to the limited blood brain barrier penetration of many systemic therapies. PARP inhibitors (PARPi) block single-strand DNA break repairs and have activity in cancers with homologous recombination repair deficiency; they are FDA approved for patients with metastatic HER2 negative breast cancer with germline BRCA1/2 mutations. While preclinical studies suggest that PARPi have CNS penetration, clinical data is limited. The goal of our study is to describe the clinical benefit of PARPi in patients with breast cancer CNS metastasis. Methods: This retrospective case series was conducted at three academic cancer centers (Johns Hopkins, Dana-Farber, and Duke) and included patients with the following criteria: (1) age≥18 years with a breast cancer diagnosis (any subtype); (2) diagnosis of parenchymal brain metastasis or leptomeningeal disease (LMD); and (3) received PARPi (olaparib, talazoparib) for CNS metastasis. Clinical and pathologic information were analyzed with descriptive statistics (median, range) and Kruskal-Wallis rank sum tests. Survival analysis was performed using Kaplan-Meier curves with log-rank p-values. Results: Although this analysis includes one center’s experience, we will present a combined dataset (N = 45) at the main conference. 11 patients were identified at Johns Hopkins. 4 (36.4%) were Black and 6 (54.5%) were White; 6 (54.5%) had ER+HER2- disease and 5 (45.5%) had TNBC at time of brain metastasis; 5 (45.5%) had BRCA1 mutations, 5 (45.5%) had a BRCA2 mutations, and 1 patient (9%) had a BARD1 mutation; 7 (63.6%) had brain metastasis and 4 (36.4%) had LMD. Median lines of therapy prior to PARPi was 6 [1 - 11]; 8 patients (72.7%) had previous CNS radiation (5 SRS and 3 WBRT) and 3 (27.3%) had previous CNS surgery. On average, patients remained on PARPi for 5 months [0.5 - 66], and overall survival (OS) time from PARPi to death was 16 months [2 - 66]. Time on PARPi was 5 months [2 - 66] for patients with brain metastasis and 3 months [0.5 - 10] for those with LMD (p=0.22). Duration of PARPi and OS did not differ significantly between ER+HER2- and TNBC (p=0.74 and 0.69, respectively), BRCA 1 and 2 (p=0.78 and 0.72, respectively), or brain and LMD metastasis (p=0.22 and 0.91, respectively). Black patients had significantly shorter PARPi duration and survival than White patients (PARPi 2 vs. 8 months, p=0.028 and OS 4 vs 18 months, p=0.028). Prior CNS radiation was significantly associated with longer PARPi duration and survival (PARPi 5 vs 1 month, p=0.02 and OS 17 vs. 3 months, p=0.032). Prior CNS surgery was significantly associated with longer PARPi duration, but not overall survival (PARPi 18 vs 3 months, p=0.05 and OS 28 vs. 7 months, p=0.14). Conclusions: PARPi are associated with significant clinical benefit in patients with breast cancer CNS metastasis. Larger data series will help confirm these observations. Citation Format: Seoho Lee, Rani Bansal, Melissa E. Hughes, Amanda E. Van Swearingen, Heather N. Moore, David O. Kamson, Solmaz Sahebjam, Greg Kirkner, Anna Gorfinkel, Sarah Sammons, Nancy U. Lin, Carey Anders, Cesar A. Santa-Maria. Response to PARP inhibitors in patients with breast cancer metastatic to the central nervous system [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 6472.

Abstract 3785: Clinical and genomic characterization of melanoma brain metastases

Abstract Introduction: Melanoma has a high propensity for brain metastasis (BM). Although advancements in brain-penetrant treatments have resulted in improved central nervous system (CNS) disease control, BMs remain a significant cause of morbidity and mortality. The molecular features of melanoma BM are poorly defined, and there is an unmet need to identify biomarkers associated with CNS-specific outcomes. Methods: We retrospectively identified 109 patients with melanoma BM who underwent craniotomy at Memorial Sloan Kettering Cancer Center (MSK) between 01/2014 and 04/2023. BM specimens were sequenced using MSK-IMPACT, an FDA-approved next-generation sequencing assay covering 341-505 genes with 700X coverage. Clinical characteristics and CNS-specific outcomes were available from 107 patients; CNS-specific radiographic endpoints were verified through direct inspection of contrast-enhanced MRI imaging by a board-certified neuroradiologist. Clinical data included baseline characteristics, prior systemic or radiotherapy (RT), and CNS-directed follow up including recording local progression of disease (POD), regional POD, and development of leptomeningeal disease (LMD).   Results: Majority (68%,73/107) patients were male with a median age at the time of primary diagnosis of 56 (range 3-88). Forty-eight patients (45%) had advanced disease (stages III and IV) at the time of initial diagnosis. At the time of BM development, half of the patients had 2-5 intracranial tumors present (50%) with a median diameter of largest BM of 33.4mm (range .9mm-64mm). The median KPS was 80 at the time of BM diagnosis, and 79% had neurologic symptoms prior to resection. 81 patients (76%) were treatment naïve at the time of resection and 56 patients (53%) developed CNS recurrence with the majority of those having local POD (29%,16/56) followed closely by regional POD of 1 lesion (25%,14/56). The most frequent genomic alterations in the cohort were TERT (87%), CDKN2A (50%), BRAF (43%), NRAS (28%), and PTEN (25%). The median fraction genome altered was 0.3047 and the median tumor mutational burden was 13.2 muts/Mb. We compared the genomic profiles of BM tumors of patients that had no progression, local POD, regional POD, and LMD. Compared to patients with no progression, patients with local POD were more likely to have RB1 alterations (18.1% vs 2.1%, p = 0.04, q = 0.83) and patients with LMD were less likely to have TERT alterations (62.5% vs 93.8%, p = 0.03, q = 0.75). Conclusions: Our analysis between genomic markers and clinical outcomes in melanoma BM reveals genomic features which may improve prediction and treatment strategies.   Citation Format: Michel Padilla Mazzeo, Henry S. Walch, Rahul Kumar, Jordan Eichholz, Claire Cooper, Nishta Nandakumar, Junchao Shen, Ishaani Khatri, Luke Del Balzo, Anna Skakodub, Emily Miao, Daniel W. Kelly, Kenny Kwok Hei Yu, Jessica Wilcox, Brandon S. Imber, Yao Yu, Yoshiya Yamada, Harish Vasudevan, Ahmet Ilica, Nikolaus Schultz, Luke R. Pike. Clinical and genomic characterization of melanoma brain metastases [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 3785.

Survival analysis of patients with brain metastases at initial breast cancer diagnosis over the last decade.

There have been significant advances in the treatment of metastatic breast cancer (BC) over the past years, and long-term outcomes after a diagnosis of brain metastases are lacking. We aimed to identify predictors of brain metastases at initial breast cancer diagnosis, describe overall survival (OS) in the past decade, and identify factors associated with OS after brain metastases diagnosis. We evaluated patients with de novo stage IV BC using the Surveillance, Epidemiology and End Results database from 2010 to 2019. Multivariate logistic regression was conducted to assess predictors of brain metastases at initial breast cancer diagnosis. OS was estimated using the Kaplan-Meier method and log rank test was used to compare differences between groups. Cox regression was used to assess associations between several variables and OS. 1,939 patients with brain metastases at initial breast cancer diagnosis were included. Factors associated with this presentation were grade III/IV tumors, ductal histology, hormone receptor (HR)-negative/human epidermal growth factor receptor 2 (HER2)-positive subtype, and extracranial metastases. Patients with HR-positive/HER2-positive disease had the longest OS (median 18 months) and 12.2% were alive at 8 years. Factors associated with shorter OS included older age, lower income, triple-negative subtype, higher grade, and visceral metastases. Over the last decade, the median OS of patients with brain metastases at initial breast cancer diagnosis remained poor; however, a substantial minority survive 5 or more years, with rates higher in patients with HER2-positive tumors. In addition to tumor subtype, OS varied according to age, extracranial metastases, and sociodemographic factors.

Clinical Outcomes of Patients with HER2 Positive Metastatic Breast Cancer to the Brain, with First-Line Trastuzumab, Pertuzumab and Chemotherapy, in a Real-World Setting.

In this observational study, we analyzed the treatment patterns and clinical outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) who developed brain metastases during their disease in a 2.7 million-member public health-provider in Israel. Newly diagnosed patients with mBC who initiated first-line treatment between January 2013 and June 2021 were identified. Time on treatment (ToT) and overall survival (OS) were assessed at a minimum of 6 months follow-up (cutoff: December 2021). We identified a total of 61 patients: 98.4% females, median age 50 years (IQR = 44-63), 85% invasive ductal tumors, 44% hormone receptor positive, 51% performance status 0-1. The median duration of follow-up was 6.2 years. All patients initiated a combination treatment of trastuzumab, pertuzumab, and chemotherapy (TPC), and 72% moved to second-line treatment during the study follow-up period (82% ado-trastuzumab emtansine). The median ToT for first-line and second-line treatments were 16.9 months (95% CI = 13.9-27.7) and 7.9 months (95% CI = 5.6-10.9), respectively. The median overall survival (OS) was 45.5 months (95% CI = 35.4-71.2) from the initiation of first-line treatment. When considering the timing of brain metastases, the median OS was 36.3 months (95% CI = 10.0-NR) for those diagnosed upfront (n = 15, 25%), 59.1 months (95% CI = 32.5-NR) for those diagnosed while on TPC (n = 25, 41%), and 40.8 months (95% CI = 35.4-NR) for those diagnosed at a later stage (n = 21, 34%). The median OS from brain metastases diagnosis was 25.1 months (95% CI = 17.0-34.6). Patients with upfront brain involvement at the time of mBC diagnosis had shorter survival compared to those who started TPC without brain metastases. Nonetheless, the overall results from this study compare favorably with previous studies and contribute to understanding the value of traditional treatment options, which will serve as a baseline for future treatment strategies in the real-world setting.

Determinants of Symptomatic Intracranial Progression After an Initial Stereotactic Radiosurgery Course

Purpose: Clinical and imaging surveillance of patients with brain metastases (BMs) is important after stereotactic radiosurgery (SRS), as many will experience intracranial progression (ITCP) requiring multidisciplinary management. The prognostic significance of neurologic symptoms at the time of ITCP is poorly understood. Materials/MethodsThis was a multi-institutional, retrospective cohort study from 2015-2020, including all patients with BMs completing an initial course of SRS. The primary outcome was overall survival (OS) by presence of neurologic symptoms at ITCP. OS, freedom from ITCP (FF-ITCP), and freedom from symptomatic ITCP (FF-SITCP) were assessed via Kaplan-Meier method. Cox proportional hazard models tested parameters impacting FF-ITCP and FF-SITCP. Results: Among 1383 patients, median age was 63.4 years, 55% were female, and common primaries were non-small cell lung (49%), breast (15%), and melanoma (9%). At a median follow up of 8.72 months, asymptomatic and symptomatic ITCP were observed in 504 (36%) and 194 (14%) patients respectively. The majority of ITCP were distant ITCP (79.5%). OS was worse with SITCP (median 10.2 vs 17.9 months, p<0.001). SITCP was associated with clinical factors including total treatment volume (P = 0.012), melanoma histology (P = 0.001), prior WBRT (P = 0.003), number of brain metastases (P < 0.001), interval of 1-2 years from primary and brain metastasis diagnosis (P = 0.012), controlled extracranial disease (P = 0.042), and receipt of pre-SRS chemotherapy (P = 0.015). Patients who were younger and received post-SRS chemotherapy (P = 0.001), immunotherapy (P < 0.001), and targeted or small-molecule inhibitor therapy (P < 0.026) had better FF-SITCP. Conclusions: In this cohort study of BM patients completing SRS, neurologic symptoms at ITCP is prognostic for OS. This data informs post-SRS surveillance in clinical practice as well as future prospective studies needed in the modern management of BMs.

Real-World Experience in Hispanic Patients With Breast Cancer and Brain Metastases Using Different Prognostic Tools

Only a small percentage of Hispanic patients have been included in studies that developed prognostic models for breast cancer and brain metastases. Therefore, there is a clear need for tools tailored to this demographic. This study assesses the efficacy of common prognostic tools in a Hispanic population. We retrospectively analyzed a data set of Hispanic patients with breast cancer and newly diagnosed brain metastases from 2009 to 2023 at a single referral center. For each prognostic tool, Kaplan-Meier curves were built. The performances of the models were compared using the area under the curve (AUC), C-statistic, and Akaike information criteria (AIC). Of 492 patients, the median time from breast cancer to brain metastasis diagnosis was 22.7 months (IQR, 12.1-53.3). The median overall survival was 11.6 months (95% CI, 9.9-13.4). All models were validated as prognostic tools (P < .001). The model with the better performance was the breast graded prognostic assessment (GPA; AIC, 402; AUC, 0.65), followed by the modified GPA (AIC, 406; AUC, 0.64), the disease-specific GPA (AIC, 407; AUC, 0.62), recursive partitioning analysis (AIC, 421; AUC, 0.62), and GPA (AIC, 422; AUC, 0.60). The breast GPA demonstrated superior accuracy in prognosticating outcomes for Hispanic patients with breast cancer and brain metastases. This underscores the critical importance of incorporating racial and ethnic diversity in creating and validating medical prognostic tools.

Development and validation of a multi-modality fusion deep learning model for differentiating glioblastoma from solitary brain metastases.

Glioblastoma (GBM) and brain metastases (BMs) are the two most common malignant brain tumors in adults. Magnetic resonance imaging (MRI) is a commonly used method for screening and evaluating the prognosis of brain tumors, but the specificity and sensitivity of conventional MRI sequences in differential diagnosis of GBM and BMs are limited. In recent years, deep neural network has shown great potential in the realization of diagnostic classification and the establishment of clinical decision support system. This study aims to apply the radiomics features extracted by deep learning techniques to explore the feasibility of accurate preoperative classification for newly diagnosed GBM and solitary brain metastases (SBMs), and to further explore the impact of multimodality data fusion on classification tasks. Standard protocol cranial MRI sequence data from 135 newly diagnosed GBM patients and 73 patients with SBMs confirmed by histopathologic or clinical diagnosis were retrospectively analyzed. First, structural T1-weight, T1C-weight, and T2-weight were selected as 3 inputs to the entire model, regions of interest (ROIs) were manually delineated on the registered three modal MR images, and multimodality radiomics features were obtained, dimensions were reduced using a random forest (RF)-based feature selection method, and the importance of each feature was further analyzed. Secondly, we used the method of contrast disentangled to find the shared features and complementary features between different modal features. Finally, the response of each sample to GBM and SBMs was predicted by fusing 2 features from different modalities. The radiomics features using machine learning and the multi-modal fusion method had a good discriminatory ability for GBM and SBMs. Furthermore, compared with single-modal data, the multimodal fusion models using machine learning algorithms such as support vector machine (SVM), Logistic regression, RF, adaptive boosting (AdaBoost), and gradient boosting decision tree (GBDT) achieved significant improvements, with area under the curve (AUC) values of 0.974, 0.978, 0.943, 0.938, and 0.947, respectively; our comparative disentangled multi-modal MR fusion method performs well, and the results of AUC, accuracy (ACC), sensitivity (SEN) and specificity(SPE) in the test set were 0.985, 0.984, 0.900, and 0.990, respectively. Compared with other multi-modal fusion methods, AUC, ACC, and SEN in this study all achieved the best performance. In the ablation experiment to verify the effects of each module component in this study, AUC, ACC, and SEN increased by 1.6%, 10.9% and 15.0%, respectively after 3 loss functions were used simultaneously. A deep learning-based contrast disentangled multi-modal MR radiomics feature fusion technique helps to improve GBM and SBMs classification accuracy.

Prognosis and clinical and molecular characteristics of patients with brain metastasis secondary to pancreatic ductal adenocarcinoma.

635 Background: Pancreatic ductal adenocarcinoma (PDAC) is a disease of poor prognosis, while secondary brain metastasis (Br-M) is reported to occur in less than 1% of patients with PDAC, with only limited data available suggesting that patients with Br-M have even worse prognosis. We sought to evaluate the prognosis, clinical, and molecular characters of patients with Br-M secondary to PDAC. Methods: The Foundry software platform was used to retrospectively query the electronic health records to identify patients diagnosed with Br-M secondary to PDAC from 2005 to 2023; clinical, molecular, and oncologic outcome data were collected. Results: Br-M was diagnosed in 44 patients with PDAC. The median follow-up was 78 months for our cohort while median overall survival (OS) from diagnosis was 47 months (95%CI=34-79 months). The median duration for Br-M detection from PDAC diagnosis was 24 months, while median OS from Br-M diagnosis was only 3 months (95%CI=2-6 months). 48% (n=21) had metastatic disease at diagnosis. Histological grade was assessed for 37 patients of which 51% (n=19) patients had poor differentiation, while 46% had moderate differentiation, and only 1 patient had a well differentiated tumor. Most of our patients received multiple lines of chemotherapy prior to Br-M development, with a median of 4 chemotherapy regimens received. The majority (73%, n=32) had ECOG performance score of 0 or 1 at Br-M diagnosis, also 82% (n=36) patients had elevated CA19-9 prior to Br-M. Metastases to more than one site other than the brain were detected in 73% (n=32), lung metastasis was the most frequently detected, followed by liver then bone (71% n=31, 66% n=29, 39% n=17, respectively). The frontal lobe was the most frequently affected (34%, n=15) followed by cerebellar affection (23%, n=10). Leptomeningeal affection was observed in (18%, n=8) patients. Targeted clinical mutation testing was done for 17 patients, KRAS was mutated in 95% (n=16) of patients, with G12V in 47% (n=8) of patients, G12D in 29% (n=5), and G12R in 18% (n=3), the second most prevalent mutation was TP53, 70% (n=12) then CDKN2A in 18% (n=3) of the patients. Surgical resection for Br-M was performed for 5 patients who had better median OS of 8.6 months followed by patients who underwent stereotactic radiosurgery (n=11) with median OS of 3.3 months, and patients who received whole brain radiation (n=20) with median OS of 2.8 months. Conclusions: This is the largest cohort for patients with Br-M form PDAC reporting thatsecondary Br-M is a late complication, associated with extremely poor prognosis, in patients who received multiple lines of therapy and have widely metastatic disease. The frontal lobe is the most frequently affected site. KRAS was the most frequently detected mutation and G12V subtype was more prevalent. surgical resection for Br-M was associated with better OS.

A systematic review of brain metastases from lung cancer using magnetic resonance neuroimaging: Clinical and technical aspects.

Brain metastases (BMs) are common in lung cancer (LC) and are associated with poor prognosis. Magnetic resonance imaging (MRI) plays a vital role in the detection, diagnosis and management of BMs. This review summarises recent advances in MRI techniques for BMs from LC. This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search was conducted in three electronic databases: PubMed, Scopus and the Web of Science. The search was limited to studies published between January 2000 and March 2023. The quality of the included studies was evaluated using appropriate tools for different study designs. A narrative synthesis was carried out to describe the key findings of the included studies. Sixty-five studies were included. Standard MRI sequences such as T1-weighted (T1w), T2-weighted (T2w) and fluid-attenuated inversion recovery (FLAIR) were commonly used. Advanced techniques included perfusion-weighted imaging (PWI), diffusion-weighted imaging (DWI) and radiomics analysis. DWI and PWI parameters could distinguish tumour recurrence from radiation necrosis. Radiomics models predicted genetic mutations and the risk of BMs. Diagnostic accuracy was improved with deep learning (DL) approaches. Prognostic factors such as performance status and concurrent chemotherapy impacted survival. Advanced MRI techniques and specialised MRI methods have emerging roles in managing BMs from LC. PWI and DWI improve diagnostic accuracy in treated BMs. Radiomics and DL facilitate personalised prognosis and treatment. Magnetic resonance imaging plays a key role in the continuum of care for BMs of patients with LC, from screening to treatment monitoring.

Clinical Practice Guidelines for Brain Metastasis From Solid Tumors.

With advancements in systemic cancer therapies, the incidence and diagnosis of brain metastases (BMs) have increased, necessitating updated clinical practice guidelines. There also were developments in neurosurgical and radiotherapeutic modalities for intracranial lesions, as well as advances in immune and targeted therapies for BMs of systemic cancers. Recently, the ASCO-SNO-ASTRO and EANO-ESMO have published clinical guidelines for BMs from solid tumors. The ASCO-SNO-ASTRO guidelines, published in 2021, underwent a systematic literature review and critical evaluation by their Expert Panel, addressing the key questions in various therapies such as surgery, radiotherapy, and systemic therapy for the recommendations. Similarly, the EANO-ESMO guidelines, also published in 2021, involved a selection of relevant literature by expert authors, with final references confirmed through consensus, focusing on prevention, diagnosis, therapy, and follow-up. This review aims to provide an overview of the recent clinical practice guidelines for BMs from solid tumors, based on these two recently developed guidelines.

Epithelial ovarian cancer and brain metastases: might the BRCA status, PARP inhibitor administration, and surgical treatment impact the survival?

ObjectiveTo evaluate disease characteristics and survival according to BRCA status, administration of poly-(ADP-ribose) polymerase inhibitors (PARPi), and surgery in patients with ovarian cancer and brain metastases.MethodsThis is a monocentric retrospective...