Extracranial Sites Research Articles

Abstract P2-10-10: The associations between brain metastasis and tumor size, nodal status, and patterns of extracranial metastasis vary by subtypes in breast cancer patients: A population-based study

Abstract Background: Brain metastasis (BM) was traditionally considered to occur in the terminal stage of breast cancer (BC) and be associated with large tumor size and nodal involvement. However, evidence suggests in triple-negative BC patients, the effects of T stage and N stage on the risk of BM were not prominent. Besides, recent studies have identified some overlap in gene expression profiles between brain and lung metastasis, but further validation in clinical settings is lacking. Therefore, one objective of our study was to determine the risk factors associated with BM in BC patients on a population-based level, focusing on the relationship between extracranial metastasis and BM. We also intended to investigate whether the associations differ across different strata by evaluating the interactions among risk factors of BM. Methods: The Surveillance, Epidemiology, and End Results database was used to select BC patients diagnosed from 2010 to 2018. We calculated the incidence proportions of BM and performed univariate and multivariate logistic regression analyses to estimate odds ratios (ORs) and 95% confidence intervals (CI) for analyses of potential risk factors of BM. Interactive effects of any suspected risk factors were evaluated using a multiplicative interaction term and adjusting for all covariates. After the statistical interactions were found, we performed stratified analyses to further test the relationships between two risk factors. Results: A total of 527,525 BC patients were selected. For patients with only one extracranial metastatic site, lung was the most common metastatic site (6.37%), followed by bone (4.12%) and liver (3.42%). Multivariate logistic regression analysis among the whole population showed age, subtype, grade, T stage, N stage, histology, and pattern of extracranial metastasis are independent predictors of BM, while sex, race, and laterality did not significantly influence risks of BM. We found significant interactions between subtype and T stage (p = 0.004) and between subtype and N stage (p = 0.002) that increased the risk of BM. In stratified analyses, the associations of BM with T stage were significant in all subtypes except HR-/HER2- (Table 1). Only in HR+/HER2+ and HR-/HER2- patients, the associations of N stage with BM were significant (p < 0.001 for both groups). The associations of T stage and N stage with BM did not differ by age. For patients with only one extracranial metastatic site, pattern of extracranial metastasis significantly interacted with subtype (p = 0.013). The association of extracranial metastatic pattern with BM was significant only among HR-/HER2- patients. Compared to patients with extracranial metastasis only to the bone, patients with extracranial metastasis only to the liver had a lower risk of BM (OR = 0.455, 95% CI: 0.219-0.948, p = 0.035), while patients with extracranial metastasis only to the lung had a higher risk of BM (OR = 1.936, 95% CI: 1.300-2.882, p = 0.001). Conclusion: Breast subtypes can modify the associations of BM with tumor size, nodal status, and pattern of extracranial metastasis. Risk elevations with higher T stage are significant among all subtypes except HR-/HER2-, indicating BM in HR-/HER2- patients may not be driven by larger tumor size. HR-/HER2- patients with lung metastasis are more susceptible to BM, providing clinical evidence for pathway overlap between brain and lung metastases. Table 1.Stratified associations between T stage and brain metastasismultivariable-adjusted OR (95% CI)p for trendp for interactionT1T2T3T4T-unknownSubtype0.004HR+/HER2-Reference1.550 (1.221-1.968)1.641 (1.227-2.194)1.816 (1.399-2.358)2.097 (1.575-2.793)< 0.001HR+/HER2+Reference0.979 (0.660-1.452)1.185 (0.741-1.894)1.605 (1.065-2.418)1.686 (1.048-2.712)0.009HR-/HER2+Reference1.410 (0.862-2.305)1.187 (0.658-2.141)1.733 (1.050-2.858)3.489 (2.030-5.998)< 0.001HR-/HER2-Reference0.993 (0.701-1.407)1.300 (0.863-1.958)1.402 (0.959-2.052)1.499 (0.940-2.388)0.126 Citation Format: Bo Shen, Jieqing Li, Mei Yang, Junsheng Zhang, Weiping Li, Kun Wang. The associations between brain metastasis and tumor size, nodal status, and patterns of extracranial metastasis vary by subtypes in breast cancer patients: A population-based study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-10-10.

Juvenile aggressive psammomatous ossifying fibroma of the maxilla: A report of three cases and review of the literature

Juvenile aggressive ossifying fibroma occurs in early life, and approximately 79% are diagnosed before the age of 15 years. Approximately 85% of cases were found in the face, while the calvarium and extracranial sites accounted for 12% and 3%, respectively. We present three females with psammomatous juvenile aggressive juvenile ossifying fibroma (JOF) of the maxilla diagnosed in our institution. While two of them were children of 11 and 12 years, the third was a 30-year-old. The histological type of JOF in all the three cases was the psammomatous type. They all had surgery with one of them having a radical maxillectomy.

Dosimetric Modeling of Lymphopenia in Patients With Metastatic Cancer Receiving Palliative Radiation and PD-1 Immune Checkpoint Inhibitors

PurposeRadiation therapy (RT)–associated lymphopenia may adversely affect treatment outcomes, particularly in the era of immunotherapy. We sought to determine dosimetric factors correlated with lymphopenia after palliative RT in a cohort of patients with advanced cancer treated with anti-PD-1 immune checkpoint inhibitors. Methods and MaterialsWe included patients with metastatic lung cancer, melanoma, or renal cell carcinoma who were treated with either pembrolizumab or nivolumab and received palliative RT to an extracranial site. Baseline and nadir absolute lymphocyte counts (ALCs) within 6 weeks of RT were recorded. Dosimetric factors were extracted from the corresponding dose-volume histograms and also used to model the dose to circulating lymphocytes via a whole-body blood flow model that simulates the spatiotemporal distribution of blood particles in major organs during RT. ResultsWe analyzed 55 patients who underwent 80 total courses of palliative RT; most (94%) were treated with 3-dimensional conformal RT. Doses to the whole body, bone, and large blood vessels (LBVs) were negatively correlated with the ALC nadir, with the strongest correlations seen at V15 (rs, –0.38, –0.43, and –0.37, and P = .0004, .0001, and .0008, respectively). Doses to other organs were not significantly correlated with the ALC nadir. The modeled dose to circulating lymphocytes was also negatively correlated with the ALC nadir and percent ALC change (for D2%, rs, –0.31 and –0.44, and P = .005 and .0001, respectively). Grade ≥3 lymphopenia was associated with LBV V15 (odds ratio [OR], 1.16; 95% CI, 1.07-1.26; P < .001), bone V15 (OR, 1.04; 95% CI, 1.01-1.08; P = .03), body V15 (OR, 1.003; 95% CI, 1.001-1.006; P = .008), and modeled lymphocyte dose (OR, 1.45; 95% CI, 1.16-1.82; P < .001). ConclusionsThe RT dose to the whole body, bone, and LBVs and the modeled dose to circulating lymphocytes were correlated with lymphopenia in patients treated with palliative RT and anti-PD-1 immune checkpoint inhibitors. These findings may inform future radiation planning in this setting.

TAMI-05. FATTY ACID SYNTHESIS IS REQUIRED FOR HER2+ BREAST CANCER BRAIN METASTASIS

Abstract Brain metastases are refractory to therapies that control systemic disease in patients with human epidermal growth factor receptor 2-positive breast cancer and the brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for brain metastatic breast cancer growth may introduce liabilities that can be exploited for therapy. Here we assessed how metabolism differs between breast tumors in brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in the brain. We determine that this phenotype is an adaptation to decreased lipid availability in the brain relative to other tissues, resulting in site-specific dependency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase reduces human epidermal growth factor receptor 2-positive breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies.

Patterns of Care for Brain Metastasis Radiotherapy (RT) in an Integrated Healthcare System: Does Increasing Utilization of Stereotactic Radiosurgery (SRS) Compared to Whole Brain RT (WBRT) Lead to Excessive Use at the End of Life (EOL)?

Previous study at our institution showed a high rate of WBRT received near the EOL. Growing evidence of improved neurocognitive and quality of life (QOL) outcomes without compromise of local control has led to increased advocacy of SRS for brain metastasis compared to WBRT. We examine our trend in patterns of care for non-small cell lung cancer (NSCLC) patients, including palliative care/hospice enrollment, and whether rate of brain metastasis RT near EOL has changed with evolving practices.Central Cancer Registry identified 4765 patients diagnosed with NSCLC at 2 facilities from 2007-17. Patients with brain metastasis were identified using natural language processing of imaging reports and confirmed by image review. Patient clinical/treatment characteristics were obtained through database linkage and manual chart abstraction. Bivariate and multivariate logistic regression analyses were performed.Of 792 patients with brain metastasis, 537 received at least 1 fraction of RT. SRS as initial treatment increased over time, comprising 10% of cases in 2007-11, 22% in 2012-16, and 52% in 2017. Number of lesions initially treated with SRS also increased: among patients with 1-3 lesions, 15% in 2007-11, 33% in 2012-16, and 68% in 2017 received SRS upfront, while 3%, 13%, and 33% of patients with 4-9 lesions received it in the respective periods. SRS for patients with 10-19 lesions was minimal, though half received SRS upfront in 2017. The proportion of patients receiving WBRT near EOL was substantial and higher than for SRS. Of 244 patients with 1-3 lesions, 64 (26%) died within 30 days of RT, comprising 25% of patients receiving WBRT and 11% receiving SRS. Older age, male sex, increasing number of extracranial metastatic sites, and inpatient consultation were independent predictors of death within 30 days of RT. Patients enrolled in palliative care/hospice were less likely to die within 30 days of RT (P = 0.048) and less likely to die as inpatients (P < 0.01).SRS utilization increased from 2007-17, particularly among patients with 1-9 lesions. Despite this increase, the proportion of patients receiving SRS near EOL was low and much less than the proportion receiving WBRT, suggesting that patients were selected well for SRS but not WBRT. As SRS is associated with shorter treatment time and lower toxicity compared to WBRT, greater SRS utilization in those without poor predictive factors may maintain QOL without risking excessive use at EOL. Early palliative care and expanding indications for upfront SRS may be considerations for decreasing the risk of treatment near the EOL.A.D. Batra: None. S. Yang: None. C. Zheng: None. D. Jiang: None. J. Rahimian: None. M.R. Girvigian: None. M.K. Gould: None. J.J. Ryoo: None.

Dosimetric Factors Associated With Lymphopenia in Metastatic Cancer Patients Receiving Palliative Radiation and PD-1 Immune Checkpoint Inhibitors

Radiation (RT)-associated lymphopenia may adversely affect treatment outcomes, particularly in the era of immunotherapy. We sought to determine dosimetric factors (DF) correlated with lymphopenia following palliative RT in a cohort of patients with advanced cancer treated with anti-PD-1 immune checkpoint inhibitors (ICIs).We included patients with metastatic lung cancer, melanoma, or renal cell carcinoma who were treated with either pembrolizumab or nivolumab and received palliative RT to an extracranial site. Baseline and nadir absolute lymphocyte count (ALC) within 6 weeks of RT were recorded. Heart, lungs, liver, kidneys, spleen, bone, and large blood vessels (LBV) were contoured for each RT course, and various DF were extracted from the corresponding dose-volume histograms (DVHs). To model RT dose to circulating lymphocytes, we also input these DVHs into a whole-body blood flow model that simulates the spatiotemporal distribution of blood particles in organs based on blood volumes and flow rates from ICRP-89. Associations between DF with ALC nadir and ALC change were assessed with Spearman correlation coefficients. DF with the strongest correlations were dichotomized at the median and evaluated for association with grade 3+ lymphopenia (ALC < 500cells/mL) post-RT by univariable logistic regression.We analyzed 55 patients who underwent 80 total courses of palliative RT; most (94%) were treated with 3D conformal RT. Doses to whole body, bone, and LBV were negatively correlated with ALC nadir, with the strongest correlations seen at V15 (rs = -0.38, -0.43, and -0.36, P = 0.0004, 0.0001, and 0.001, respectively). Doses to other organs were not significantly correlated with ALC nadir. The modeled dose to circulating lymphocytes was also negatively correlated with ALC nadir and ALC change (for D2%, rs = -0.31 and -0.38, P = 0.005 and 0.0007, respectively). Associations between these DF and grade 3+ lymphopenia are shown in the Table.RT dose to whole body, bone, and large blood vessels were correlated with lymphopenia in patients treated with palliative RT and anti-PD-1 ICIs. The modeled dose to circulating lymphocytes in our dynamic model correlated with lymphopenia as well, validating our model and enabling future investigation into dose rate and fractionation effects. These dose parameters may help guide RT planning to minimize lymphopenia risk, though additional studies are required to elicit the relative importance of each factor.

Predictors of Long-Term Survival Among Patients With Brain Metastases

The prognosis for patients with brain metastases (BrM) remains guarded, with population-based data indicating a median survival of 3-12 months. However, a subset of patients with BrM display prolonged survival. We sought to characterize the likelihood and predictors associated with survival ≥ 5 years after BrM diagnosis.We identified 1,370 patients diagnosed with BrM at a tertiary cancer center between 2008 and 2015 who either died or survived ≥ 5 years. Patients censored before 5 years were excluded from the analysis (N = 66). Multivariable logistic regression was used to characterize predictors of long-term (i.e., ≥ 5 years) survival after BrM diagnosis (odds ratios > 1 indicated a greater odds of long-term survival). Median survival for subgroups was calculated with the Kaplan-Meier method; comparisons were made with the log-rank test.Among all 1,304 patients, median survival after BrM diagnosis was 10.8 months. In total, 123 patients (9.4%) survived ≥ 5 years. On multivariable logistic regression, significant predictors of survival ≥ 5 years included: breast as the primary tumor site vs. the reference of non-small cell lung cancer (NSCLC) (OR: 2.44 [95% CI, 1.23-4.83], P = 0.01), high Karnofsky performance score (KPS) (90-100) vs. low KPS (< 90) (OR: 2.32 [95% CI, 1.48-3.62], P < 0.001), and lack of progressive extracranial disease at time of BrM diagnosis (OR: 2.33 [95% CI, 1.47-3.70], P < 0.001). Factors significantly associated with not surviving ≥ 5 years included: receipt of whole brain radiation therapy vs. the reference of SRT as initial management (OR: 0.30 [95% CI, 0.13-0.70], P = 0.005), presence of 2-4 BrM vs. 1 BrM (OR: 0.63 [95% CI, 0.40-1.00], P = 0.05), an increasing number of extracranial sites of disease (OR: 0.73 per additional site [95% CI, 0.59-0.90], P = 0.003), and an increasing number of systemic therapy regimens for metastatic disease prior to diagnosis of BrM (OR: 0.64 per additional regimen [95% CI, 0.50-0.84], P = 0.001). When limiting to patients with NSCLC for whom EGFR and ALK status were known, there were significant differences in survival among patients with an ALK rearrangement, EGFR mutation, or neither (median survival of 30.9, 15.0, and 12.7 months, respectively, P = 0.04). Subsetting patients with breast cancer based on receptor subtype, there were significant differences in survival among patients with HER2-positive, hormone receptor-positive/HER2-negative, or triple-negative breast cancer (median survival of 26.0, 11.2, and 6.5 months, respectively, P < 0.001).Although patients with BrM generally have a poor prognosis, select patients live for ≥ 5 years. Multidisciplinary teams caring for favorable sub-populations should consider the long-term impact of oncologic therapy when formulating treatment recommendations.N. Lamba: None. D.N. Cagney: Research Grant; NhTheraguix, Viewray. P.J. Catalano: None. P. Wen: None. D. Haas-Kogan: Research Grant; Novartis; Cellworks. A.A. Aizer: Research Grant; Varian. Consultant; Novartis. Advisory Board; Seattle Genetics.

Stereotactic radiosurgery combined with immune checkpoint inhibition for the treatment of melanoma brain metastases is associated with high levels of extracranial disease control and survivorship - an abscopal effect?

Abstract Aims Melanoma brain metastases (MBM) are a common presentation to the neuro-oncology MDT. Stereotactic radiosurgery (SRS) is a highly effective treatment for cerebral metastases, with at least 70% control rates of individual metastases,[1] whilst immune checkpoint blockade has revolutionised the management of metastatic melanoma in recent years.[2] Recent studies have demonstrated that immune checkpoint inhibition alone also has activity in the brain, with MBM response rates of 50% or more.[3, 4] When MBM are treated with combination immunotherapy and SRS together, 12-month intracranial progression free survival (PFS) rates of 85% have been achieved.[4, 5] The aim of the current study was to evaluate the local control of MBM treated at our tertiary referral centre, which benefits from specialist neuro-radiology peer review of SRS contour volumes, and further to investigate whether overall survival is also improved, and what the mechanism of this may be. Method A retrospective analysis of all patients treated with SRS for brain metastases at our teriary SRS centre between June 2017 – January 2020 was performed. Inclusion criteria included patients treated for MBM, who received at least 2 doses of any combination of immune checkpoint inhibition concurrently with (defined as at the time of or commenced within 3 months of) SRS. The primary endpoints were the intracranial and extracranial response rates and survival rate at 12 months. Response was defined as complete response, partial response or stable disease. Secondary endpoints included the rate of imaging-defined radionecrosis, median lesional progression free survival (mPFSlesion), non-lesional intracranial PFS (mPFSintracranial), extracranial PFS (mPFSextracranial) and overall survival (mOS), measured from the start date of SRS to the date of event or censored at the start date of data collection. Kaplan-Meier curves and survival statistics were generated using SPSS v26. Results 33 MBM from 18 patients were identified. The median follow up was 25.8 months (minimum 12 months). Of the 18 patients: the median age was 60 (IQR 48 – 72); 17 (94%) patients were ECOG performance status 0-1; the median number of extracranial disease sites was 2 (pre-immunotherapy) and 1 (pre-SRS); the median duration of immunotherapy treatment was 17.6 (12.9 – 28.5) months, and the median number of metastases treated per patient was 2. Of the 33 metastases: 31 (94%) were supratentorial; 6 (18%) underwent prior neurosurgical resection; the median GTV volume (cc) of unresected metastases was 0.5cc (0.1 – 2.7), and 21 (64%) were treated with single fraction SRS. The median OS and PFS for all subtypes were not reached. The rates of OS, PFSlesion, PFSintracranial and PFSextracranial at 12 months were 93.9%, 87.9%, 81.8% &amp; 75.8% respectively. Conclusion Our cohort of MBM patients appear to perform favourably when compared with the current literature. When compared to a recent extensive systematic review of modern management of MBM, our lesional control rate is as good as the weighted average of concurrent SRS + immunotherapy studies (87.9% vs 85.4% 12-month PFS), however we demonstrate a significantly improved 12-month OS rate (93.9% vs 52.8%) compared to the same (mOS of 15.8 – 17.4 months in other studies).[6,7] Our extra-lesional PFS is high and, compared to extracranial PFS rates from 51% at 6-months to 70.4% at 9-months in the literature,[3,4] our 75.8% control at 12 months suggests that extracranial control could drive the OS benefit. This suggests a benefit of SRS beyond the local control of MBM and questions whether patients without brain metastases may benefit from body SABR to extracranial metastases, to elicit a similar, potentially abscopal type effect.

18FDG-Positron Emission Tomography in patients with Tuberculous Meningitis: A Prospective Evaluation.

Lower yield of available diagnostic tests for tuberculous meningitis (TBM) frequently causes delay in diagnosis. Recently, 18F-fluorodeoxyglucose positron emission tomography (FDG PET) has been used in infectious disorders such as pulmonary tuberculosis; however, it is rarely used in TBM. This study was aimed to ascertain the role of FDG PET in the diagnosis and determination of the extent of disease and prognosis in patients with TBM. After excluding unsuitable patients, 25 patients were subjected to whole-body PET-computed tomography (CT) image acquisition along with separate brain protocol with an integrated PET-CT device. FDG PET was found to be abnormal in 92% patients. Extracranial FDG uptake was observed in 80% patients. Most common extracranial site of involvement was lymph nodes (60%), followed by lung (56%), vertebral body (8%), genitourinary organs (8%), and spleen (4%). FDG PET observed extracranial involvement had 80% sensitivity and 20% specificity in detecting definite TBM cases. In conclusion, FDG PET may be a useful test in TBM evaluation.

Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy.

Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) Tcells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust Tcell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.

KS01.4.A NK cells as key orchestrators in mediating the anti-tumour response to immune checkpoint blockade in melanoma brain metastases

Abstract BACKGROUND Brain metastases (BrM) are an unmet clinical need with poor prognosis. 60% of melanoma patients develop BrM. BrM are strongly understudied due to frequent exclusion from clinical trials, and hence treatment options commonly lag behind. Antibodies targeting the immune-inhibitory receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have demonstrated efficacy against melanoma BrM. Despite this, therapeutic responses are highly variable, and it is unknown why therapy fails in a high proportion of patients. Improved therapeutic strategies require a thorough understanding of potentially exploitable mechanisms of therapeutic efficacy. Our data previously implicated different immune cells, foremost CD8+ T cells, but also NK cells, in the intracranial efficacy and enhanced survival benefit of immune checkpoint blockade (ICB). Our aim here is to investigate the role of NK cells in mediating the response to ICB in melanoma BrM. MATERIAL AND METHODS To study the role of NK cells in the response to ICB in melanoma BrM, a tumour transplantation model of B16 melanoma with simultaneous extracranial (i.e., flank) and brain tumours in C57BL/6 mice was utilised. NK cells were depleted through administration of anti-asialo-GM1 NK cell-depleting antibodies. Confirmation of NK cell depletion and quantification of intratumoral immune cell populations was performed using flow cytometry. Intratumoral gene expression of key chemokines and immune mediator genes was assessed using RT-qPCR and mRNA-seq. RESULTS Highly variable response to ICB with respect to intratumoral accumulation of CD8+ T cells allowed separation of mice into responders and non-responders and revealed genes and pathways associated with response to ICB. NK cell depletion reversed the ICB-mediated increase in the accumulation of CD8+ T cells and significantly reduced the expression of genes associated with response in intracranial and extracranial tumours. The ICB-mediated significant increase in gene expression of various chemokines (i.e., Cxcl9/10) and immune mediators (i.e., Ifng, Prf1 and Gzmb) was significantly abrogated upon NK cell depletion. CONCLUSION NK cells play a critical role in the underlying mechanisms of ICB efficacy through their modulation of the tumour microenvironment and enhancement of CD8+ T cell accumulation in intracranial tumours. Targeting of NK cells may allow potentiation of ICB therapy in the brain, as well as at extracranial sites.

Phase I/II trial of concurrent extracranial palliative radiation therapy with Dabrafenib and Trametinib in metastatic BRAF V600E/K mutation-positive cutaneous Melanoma

BackgroundConcurrent treatment with BRAF inhibitors and palliative radiation therapy (RT) could be associated with increased toxicity, especially skin toxicity. Current Eastern Cooperative Oncology Group (ECOG) consensus guideline recommend ceasing BRAF inhibitors during RT. There is a lack of data regarding concurrent RT with combined BRAF and MEK inhibitors. This single-arm phase I/II trial was designed to assess the safety and tolerability of palliative RT with concurrent Dabrafenib and Trametinib in patients with BRAF-mutant metastatic melanoma. Materials and methodsPatients received Dabrafenib and Trametinib before and during palliative RT to soft tissue, nodal or bony metastases. The RT dose was escalated stepwise during the study period. Toxicity data including clinical photographs of the irradiated area was collected for up to 12 months following completion of RT. ResultsBetween June 2016 to October 2019, ten patients were enrolled before the study was stopped early due to low accrual rate. Six patients were treated at level 1 (20 Gy in 5 fractions, any location) and 4 patients at level 2a (30 Gy in 10 fractions with no abdominal viscera exposed). All alive patients completed one year of post-RT follow-up. Of the 82 adverse events (AEs) documented, the majority (90%) were grade 1 and 2. Eight grade 3 events (10%) occurred in five patients, only one was treatment-related (grade 3 fever due to Dabrafenib and Trametinib). No patients experienced grade 3 or 4 RT related toxicities, including skin toxicities. One serious AE was documented in relation to a grade 3 fever due to Dabrafenib and Trametinib requiring hospitalisation. ConclusionsThe lack of grade 3 and 4 RT-related toxicities in our study suggests that Dabrafenib and Trametinib may be continued concurrently during fractionated non-visceral palliative RT to extracranial sites.

English

Vascular anomalies are a heterogeneous group of lesions involving vascular channels including the lymphatics. They encompass a wide variety of lesions from simple capillary haemangiomas to angiosarcomas. These lesions most commonly occur as a result of developmental error during embryogenesis due to defective signal process.1 Most of these lesions occur sporadically while a few may be inherited or acquired. Inherited lesions tend to be small and multi-centric which gradually increase its size with age.2 The International Society for the Study of Vascular Anomalies has broadly classified vascular anomalies into 2 groups: 1) Vascular neoplasms and 2) Vascular malformations.3 Vascular malformations are a relatively rare group of lesions involving the endothelium and surrounding tissue of arteries and veins resulting in an abnormal arteriovenous shunting. They are categorised into 4 types: 1) Venous malformation, 2) Capillary malformation, 3) Arteriovenous malformation and 4) Lymphatic malformation. They can occur anywhere in the body from head to toe, but they are most commonly seen in the brain. The most common extra-cranial site for AV malformations is the head and neck and other common sites include limbs, trunk and viscera.4 Here, we a present a rare case of congenital AV malformation of lip in a 49-year-old male.

Abstract 90: Fatty acid synthesis is required for breast cancer brain metastasis

Abstract Brain metastases are refractory to therapies that otherwise control systemic disease in patients with human epidermal growth factor receptor 2 (HER2+) breast cancer, and the unique brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for breast cancer growth in the brain microenvironment may also introduce liabilities that can be exploited for therapy. Here, we assessed how metabolism differs between breast tumors growing in the brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in the brain. We determine that this phenotype is an adaptation to decreased lipid availability in the brain relative to other tissues, which results in a site-specific dependency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase (FASN) reduces HER2+ breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies. Citation Format: Gino B. Ferraro, Ahmed Ali, Alba Luengo, David P. Kodack, Amy Deik, Keene L. Abbott, Divya Bezwada, Landry Blanc, Brendan Prideaux, Xin Jin, Jessica M. Possada, Jiang Chen, Christopher R. Chin, Zohreh Amoozgar, Raphael Ferreira, Ivy Chen, Kamila Naxerova, Christopher Ng, Anna M. Westermark, Mark Duquette, Sylvie Roberge, Costas A. Lyssiotis, Dan G. Duda, Todd R. Golub, Shawn M. Davidson, Dai Fukumura, Véronique A. Dartois, Clary B. Clish, Matthew G. Vander Heiden, Rakesh K. Jain. Fatty acid synthesis is required for breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 90.

EPEN-12. MULTIPLE RECURRENCES OF ANAPLASTIC EPENDYMOMA WITH EXTRA AXIAL AND EXTRA NEURAL METASTASIS IN A PEDIATRIC PATIENT

BackgroundEpendymomas are the third most common CNS tumor in the pediatric population, accounting for 10% of all CNS tumors. Co-occurring extraneural and extracranial metastasis of ependymomas are extremely rare, with only 1 reported adult case in current literature. Case DescriptionWe describe the case of a patient with multiple reoccurrences of anaplastic ependymoma. Initial imaging showed a 5 x 8 x 8 cm complex cystic mass with nodular enhancing components within the left occipital lobe. The 4th ventricle was intact and imaging was negative for metastasis. Pathology following resection demonstrated perivascular pseudorosettes, areas of calcification, and increased mitotic activity. Biopsy revealed GFAP, EMA, neurofilament, INI-1, and was negative for CAM5.2, confirming anaplastic ependymoma. Methylation studies for PFA or PFB subgroup differentiation were not available. The patient had recurrences at 4-, 5-, and 6-years after his initial diagnosis. Seven years from his initial diagnosis, the patient underwent resection of four nodular lesions from the occipital lobe and surrounding soft tissue. Pathology of these lesions and the lymph nodes/soft tissue confirmed anaplastic ependymoma. A PET scan showed increase uptake in the supraclavicular lymph nodes and had multiple bilateral pulmonary nodules. Scans at 3 months post-surgery were negative for leptomeningeal metastases but showed further lymph node involvement with progression of pulmonary disease. ConclusionCo-occurring extraneural and extracranial metastasis of ependymoma is a rare occurrence across all populations. To our knowledge, this would be the first published pediatric case of anaplastic ependymoma with lymph node, soft tissue, and pulmonary involvement. Treatment of ependymoma itypically local and the utility of chemotherapy remains unclear. Treatment options for extraneural mets is very limited, illustrating the need for new therapies and further studies directed at understanding the biology of these tumors and the factors that could influence their ability to metastasize to extraneural and extracranial sites.

Clinical and pathological characteristics of breast cancer with resected brain metastasis.

1089 Background: Breast cancer brain metastasis (BCBM) has poor prognosis and limited therapeutic options. Studies have shown that BCBM may differ from their matched primary tumors in receptor subtypes and genomic characteristics. However, studies have been limited by the tissue availability of BCBM. Taking advantage of our institutional database of resected BCBM with matched primary breast samples, this study aimed to investigate the clinical and pathological characteristics of patients with resected BCBM. Methods: We performed retrospective chart review for all breast cancer patients who had resected BCBM samples at our institution over the last 20 years. Hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status of the primary breast and BCBM samples, location of BCBM, and extracranial metastases at time of BCBM diagnosis were categorized. Overall survival (OS) from time of BCBM diagnosis was calculated using the Kaplan-Meier method. Progression interval and receptor subtype switching from primary diagnosis to brain metastasis were computed and compared using Wilcoxon rank sum test and Fisher’s exact test, respectively. Results: Eighty-six patients were included in this study (median age at time of BCBM diagnosis 54.3 [range 28.3-84.0] years, median follow up 26.0 months). These included 47 HR+, 15 HER2+, 20 triple negative (TN), 4 unknown subtype breast samples, and 42 HR+, 18 HER2+, 17 TN and 9 unknown subtype brain samples. OS was significantly shorter in patients with TN compared to HR+ or HER2+ subtype, whether the TN status was in the primary breast tumor (median 20.5 vs 34.0 months, p = 0.04, thresholded at year 2) or in the brain metastasis (median 16.0 vs 34.0 months, p = 0.02, thresholded at year 2). No significant difference in OS was observed between HR+ and HER2+ groups. There was no significant difference in the progression interval from primary diagnosis to brain metastasis among receptor subtypes. From primary tumor to brain metastasis, receptor subtype switching occurred in 10 out of 73 patients (13.7%) for estrogen, 20 out of 70 (28.6%) for progesterone (PR), and 6 out of 72 (8.3%) for HER2. Receptor subtype switching did not significantly correlate with OS. Presence of extracranial metastases at time of BCBM diagnosis corresponded to significantly lower OS compared to no extracranial metastasis (16.5 vs 36.0 months, p = 0.01). No significant difference in OS was observed between patients with cerebral vs cerebellar brain metastases. Conclusions: These data indicate that patients with TN BCBM disease have the worst overall survival among all receptor subtypes. Metastases in extracranial sites at time of BCBM diagnosis significantly decreased survival. Location of the brain metastasis and receptor subtype switching from primary diagnosis to BCBM, which was relatively infrequent outside of the PR group, did not significantly correlate with OS in this limited data set.

Outcomes and safety analysis of a phase IB trial of stereotactic body radiotherapy (SBRT) to all sites of oligometastatic non-small cell lung cancer combined with durvalumab and tremelimumab.

e21212 Background: Combining local ablative and systemic therapies in patients with oligometastatic NSCLC leads to improved overall survival (OS) and progression-free survival (PFS). The potential immunostimulatory effects of ablating all visible disease with SBRT in combination with dual immune checkpoint inhibition has prompted interest, but the toxicity and benefit are unknown. Methods: We conducted a phase Ib study to investigate the safety of SBRT, with doses between 30 and 50 Gy in five fractions to all sites of disease, followed by durvalumab 1500 mg IV in combination with tremelimumab 75 mg IV every 4 weeks x 4 cycles, followed by durvalumab maintenance until progression. Eligible patients had 1-6 extracranial metastatic sites, allowing multiple metastases per location, with all lesions suitable for SBRT, ECOG performance status 0-1, no actionable driver mutation, and no prior immunotherapy. The primary endpoint was safety of this combination. Secondary endpoints include PFS and OS. Dose-limiting toxicities (DLTs) (any Grade ≥ 3 toxicity) were evaluated from the first administration of SBRT until 28 days post start of durvalumab and tremelimumab. Baseline tumor mutational burden, PD-L1 expression on post-SBRT biopsy and circulating tumor cells will be correlated with outcomes. In this first cohort analysis, we assess the safety and outcomes of the first 17 patients. Results: From 2/2018-2/2021, the first 17 pts were enrolled. Characteristics of those enrolled included: median age 68 years, female/male 4/13, squamous/non-squamous 2/15, median number of non-central nervous system (CNS) metastatic sites 2 (1-5), median number of non-CNS metastatic lesions 2 (1-9), CNS involvement 6/17 (35.3%), previous treatment 4/17 (23.5%). DLTs were seen in 2/17 (11.8%) patients; DLTs were autoimmune hepatitis and autoimmune pancreatitis. Most treatment-related adverse events (TRAEs) were grade (G) 1/2. TRAEs included: all TRAEs n = 188, 88.2% (of patients); G 3 n = 17, 29.4%; G 4 n = 1, 5.8%. There were no treatment-related deaths. Five patients discontinued treatment due to grade 3/4 immune related adverse events (IRAE). At a median follow up of 20 months 11/17 (64.7%) patients are alive with 10/17 (58.8%) with no evidence of disease (NED). Six of 17 (35.2%) patients experienced disease progression and 4/17 (23.5%) patients died of disease progression. Median PFS and OS are not yet reached. Conclusions: There were no unexpected safety signals in the cohort of patients enrolled. The incidence of grade ≥ 3 IRAEs is similar to the treatment of advanced NSCLC and no additional toxicity was observed with the addition of SBRT. Clinical outcomes look promising with median OS and PFS not yet reached at 20 months median follow up. The study continues to enroll a second cohort and results will be updated. Clinical trial information: NCT03275597.

NCCBM, a Nomogram Prognostic Model in Breast Cancer Patients With Brain Metastasis.

Purpose: Nomogram prognostic models could greatly facilitate risk stratification and treatment strategies for cancer patients. We developed and validated a new nomogram prognostic model, named NCCBM, for breast cancer patients with brain metastasis (BCBM) using a large BCBM cohort from the SEER (Surveillance, Epidemiology, and End Results) database.Patients and Methods: Clinical data for 975 patients diagnosed from 2011 to 2014 were used to develop the nomogram prognostic model. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve. The results were validated using an independent cohort of 542 BCBM patients diagnosed from 2014 to 2015.Results: The following variables were selected in the final prognostic model: age, race, surgery, radiation therapy, chemotherapy, laterality, grade, molecular subtype, and extracranial metastatic sites. The C-index for the model described here was 0.69 (95% CI, 0.67 to 0.71). The calibration curve for probability of survival showed good agreement between prediction by nomogram and actual observation. The model was validated in an independent validation cohort with a C-index of 0.70 (95% CI, 0.68 to 0.73).Conclusion: We developed and validated a nomogram prognostic model for BCBM patients, and the proposed nomogram resulted in good performance.

Epidemiology and Outcomes of Patients With Brain Metastases From Colorectal Cancer—Who Are These Patients?

Brain metastases (BMs) from colorectal cancer (CRC) are unusual; however, an increase in incidence has been reported. The evidence available on the subject is scarce, and a better understanding is warranted. We aimed to characterize the epidemiology and the outcomes of patients with BMs from CRC. A cohort of patients with BMs from CRC was retrospectively evaluated. Patients were treated in a single center between May 2008 and April 2019. BMs were confirmed by brain computed tomography or magnetic resonance imaging. A total of 247 consecutive patients were evaluated. Most patients had a left-sided primary tumor (193, 78%) and at least two extra-cranial metastatic sites (194, 78%). Ninety-six patients (39%) were RAS wild-type; 68 patients (27%) were RAS mutated; and 83 patients (34%) were not characterized. Median time from the initial diagnosis to BMs was 27.6 months (interquartile range, 13.1-46.9). Regarding local therapy, 43 patients (17.4%) were treated with BM surgery alone, 76 patients (30.8%) with radiotherapy (RT) alone, and 58 patients (23.5%) with both surgery and RT. Median overall survival (OS) was 2.9 months (95% confidence interval [CI], 2.2-3.5). Six-month and 1-year OS rates were 29% (95% CI, 23-25) and 13.5% (95% CI, 9.2-18.6), respectively. In a multivariable analysis, BM surgery alone (hazard ratio [HR], 0.56; P=.018), RT alone (HR, 0.51; P=.001), and surgery plus RT (HR, 0.27; P < .001) were associated with superior OS, whereas Eastern Cooperative Oncology Group Performance Status 3 or 4 (HR, 2.01; P=.009) and male gender (HR, 1.46; P=.012) were negative prognostic factors. RAS status was not associated with OS. BMs occur late during the course of colorectal cancer and are more common in patients with a left-sided primary tumor and a high volume of metastatic disease. BMs from colorectal cancer are still associated with an extremely poor prognosis; however, selected patients may benefit from treatment with surgical resection and radiotherapy.

Abstract PO-041: An immunologic niche of antigen presenting cells and stem-like CD8+ T-cells is present in non-small cell lung cancer brain metastases

Abstract Background: Non-small cell lung cancer (NSCLC) patients with brain metastases have a very poor prognosis. The first line treatments for NSCLC brain metastases are typically surgery and pre- or post-operative stereotactic radiosurgery (SRS) or SRS alone. However, subsequent intra-cranial failure and death is common. Importantly, we have previously shown that a unique immune niche in genitourinary malignancies correlates with the risk for disease recurrence. Accordingly, here we investigated whether this immune niche was present in brain metastases, whether it correlated with patient outcomes, and whether it was modulated by SRS. Methods: Formalin fixed paraffin embedded brain metastases were stained by immunofluorescence for CD8, PD-1, TCF-1, MHC-II and DAPI. Following successful image acquisition using fluorescent whole slide scanning, we used a custom quantitative analysis pipeline to measure the cellularity, relative cellular locations, local cellular density, and marker staining intensity. Results: We identified immune niches consisting of both stem-like TCF-1+ CD8+ T-cells and antigen presenting cells (MHC-II+) in brain metastases. TCF-1+ CD8+ T-cells were found at in areas of higher MHC-II+ cell density than the TCF-1 CD8+negative T-cells. The amount of tumor issue occupied by immune niches correlated with TCF1+ CD8+ T-cell infiltration, as well as with total CD8+ T-cell and MHC-II+ cell infiltration. Importantly, we found that higher MHC-II+ cell density correlated with longer overall survival in this cohort of patients. Additionally, we found this immune niche is preserved following pre-operative SRS. Conclusions: Our study is the first to demonstrate stem-like CD8+ T-cells in brain metastases and that these cells form an immune niche similar to those described extra-cranial tumor sites. Additionally, we report that the immune niche is preserved following SRS, which is highly clinically relevant to the use of combinatorial strategies between SRS and checkpoint blockade. Citation Format: Caroline S. Jansen, Luke del Balzo, Roshan Prabhu, Suzanna Logan, Prasanthi Chappa, Kirtesh Patel, Scott Wilkinson, Ross Lake, Hui-Kuo G. Shu, Jim Zhong, Vishal Dhere, Jeffrey Olson, Adam G. Sowalsky, Mohammad K. Khan, Haydn T. Kissick, Zachary S. Buchwald. An immunologic niche of antigen presenting cells and stem-like CD8+ T-cells is present in non-small cell lung cancer brain metastases [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-041.