Evidence Of Brain Metastases Research Articles

Abstract PO5-07-11: Use of 64Cu-DOTA trastuzumab -PET to predict response to trastuzumab-deruxtecan (TDXd) in patients with metastatic disease to the brain: Study in Progress

Abstract Background: We have utilized 64Cu-DOTA trastuzumab-PET imaging in patients with advanced breast cancer. In our experience, uptake on 64Cu-DOTA trastuzumab-PET correlated with the qualitative assessment of HER2 by IHC. In women treated with the antibody-drug conjugate (ADC), ado-trastuzumab emtansine (TDM1), we identified a threshold level of 64Cu-DOTA trastuzumab-PET uptake that predicted for lack of response to TDM1. As patients are living longer with advanced breast cancer, the incidence of brain metastasis has increased. The ADC, trastuzumab-deruxtecan (T-DXd) has demonstrated activity in patients with metastatic HER2 positive breast cancer with brain metastases. The DESTINY 04 trial included patients with HER2 1+ and 2+ disease and demonstrated superior survival compared to standard of care. It is not feasible to biopsy all brain metastases to determine tumor markers. Given the increased incidence of brain metastases in this population and the efficacy of T-DXd in patients with HER2+ metastatic disease to the brain, we initiated a study of 64Cu-DOTA trastuzumab-PET/MRI of the brain prior to institution of T-Dxd. Endpoints Primary: 1. 64Cu-DOTA-trastuzumab PET-CT will identify tumor heterogeneity of trastuzumab uptake in women with metastatic breast cancers. 2. The degree of uptake of 64Cu-DOTA-trastuzumab PET-CT will predict for response to Enhertu. Secondary: 1. Uptake of 64Cu-DOTA-trastuzumab PET-CT will be predictive of response duration to Enhertu. Eligibility: Patients must have documented recurrent breast cancer that is HER2 1+, 2+ or 3+, evidence of brain metastases by CT or MRI of the brain and are candidate for treatment with trastuzumab-deruxtecan. The CNS disease must be stable and not in need of intervention. Methods: Prior to treatment staging workups includes pathologic review of HER2 status, disease staging with 18FDG-PET or CT of the chest/abdomen/pelvis and bone scan, and 64Cu-DOTA-trastuzumab PET/MRI of the brain. After initiation of T-Dxd, MRI of the brain is repeated every 6 weeks for the first 24 weeks and every 9 weeks thereafter. Progress: We have enrolled 1 patients to date, received PET and dynamic contrast-enhanced MRI. Four lesions were analyzed in this patient. The mean values of Ktrans (volumetric perfusion to tumor, s−1) in these lesions near a prior resection cavity were 0.210 s−1, indicating sufficient perfusion for ADC uptake. Corresponding to this perfusion data, the mean SUVmax of these lesions on the 64Cu-DOTA-trastuzumab PET scans was 5.38. Citation Format: Joanne Mortimer, Kofi Poku, Jessica Liu, Russell Rockne, Chen Bihong, Ryan Woodall, Vikram Adhikarla. Use of 64Cu-DOTA trastuzumab -PET to predict response to trastuzumab-deruxtecan (TDXd) in patients with metastatic disease to the brain: Study in Progress [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-07-11.

DISP-02. PATTERNS IN THE INCIDENCE OF BRAIN METASTASIS BY RACE AND ETHNICITY: A SYSTEMATIC REVIEW

Abstract INTRODUCTION Despite advancements in cancer treatment, the incidence of brain metastases (BM) continues to rise which necessitates risk factor analyses. Although current literature indicates racial variance in BM incidence, there exists a major knowledge gap in understanding associations between race/ethnicity, BM incidence, and subtypes which emphasizes the need for a systematic review. We aimed to analyze the relationship between BM incidence, race/ethnicity, and primary cancer type. METHODS Using PRISMA guidelines, a systematic review of PubMed and Ovid databases from January 2000 to January 2023 for terms related to BM, ethnicity and race, in conjunction with incidence was conducted. Inclusion criteria comprised peer-reviewed journals with ages > 18, sample size > 100, primary malignancy diagnosis with evidence of BM, and descriptions of patient race or ethnicity. RESULTS Of 806 identified studies, 11 articles primarily utilizing US data were included for final analysis. Lung and bronchus cancers, revealed the highest incidence of BM in Asian patients, followed by Black, White, and American Indian/Alaska Natives (P< .001), despite overall increased incidence of primary cancer in Black patients. Breast cancer revealed highest BM incidence in American Indian/Alaska Natives (5.9%), followed by Black (5.0%), White (3.6%), and Asian/Pacific Islanders (3.5%) (P< .001). When compared to White and Hispanics only, Black patients had greater incidences of BM (OR: 2.26, 95% CI: 1.57–3.25). Lower incidence of BM for esophageal cancer was observed in Black patients compared to White patients (OR=0.38; 95% CI: (0.16–0.89); P= 0.026). No significant differences were observed in BM incidence for bladder, prostate, or non-small cell and small cell lung cancers. CONCLUSIONS Our review suggests that BM incidence does vary amongst racial/ethnic groups dependent on primary cancer type. Differences may be due to numerous factors, underscoring the need for more work with inclusive, diverse cohorts to tackle BM disparities.

Real-world tolerability of front-line brigatinib in patients with anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) with and without brain metastases in the United States.

535 Background: Brigatinib, a next-generation ALK tyrosine kinase inhibitor (TKI), is approved for treatment in patients with ALK+ NSCLC with a dosing schedule of 180 mg/day after a 7-day lead-in at 90 mg/day. Brigatinib has been shown through clinical trials to have improved intracranial efficacy compared to crizotinib. There is limited information regarding the real-world tolerability of brigatinib in patients with brain metastases (BM). Our study aims to assess treatment tolerability via dose reduction rates and adherence in patients treated with front-line (FL) brigatinib and stratified by evidence of BM. Methods: This retrospective cohort study utilized the IQVIA open-source pharmacy and medical claims databases. Adults (≥18 years) with ≥1 claim for brigatinib between 22 May 2020 and 31 December 2022 with no prior claims for brigatinib or other ALK-TKI therapies were identified from the pharmacy claims database and followed until the earliest of dose reduction, treatment discontinuation, or end of follow-up. Average daily dose (ADD) was calculated as the product of pill strength and quantity of pills dispensed divided by day supply. Dose reduction was defined as ≥30 days of treatment with ADD < 180 mg/day. Time to dose reduction from 180 mg/day and probability of continued therapy at ≥180 mg/day were assessed by Kaplan-Meier analysis. Adherence was defined using medication possession ratio (MPR) and calculated as the total day supply divided by the number of days from the first claim date to the last supply date of FL brigatinib. BM was defined as having ≥1 claim in the medical claims database with a diagnosis code for secondary malignant neoplasm of the brain. Results: Overall 126 patients treated with FL brigatinib were identified (median age: 57.5; 57.1% female). Median (min-max) follow-up time was 11.7 (1.0-30.7) months; 114 (90.5%) patients reached a dose of 180 mg/day, and among these 27 (23.7%) had evidence of BM. Of patients who reached a dose of 180 mg/day, 14.8% of those with BM and 18.4% with no BM (p=0.779) had a dose reduction. The probability of remaining on therapy at 180 mg/day was 86.2% at 3, 6 and 9 months and 71.8% at 12 months in patients with BM. In patients with no BM, the probabilities of remaining on therapy at a dose of 180 mg/day at 3, 6, 9 and 12 months were 89.1%, 82.6%, 70.8% and 67.1%, respectively (P=.761). Adherence was high irrespective of BM with 81.5% of patients with BM and 94.3% those without BM having MPR > 80%. Results in the overall FL brigatinib sample (with and without BM) were similar. Conclusions: Real-world data suggest that FL brigatinib is well tolerated regardless of brain metastasis status. Most FL brigatinib patients in the study achieved and maintained a daily dose of 180 mg. Dose reductions and probability of remaining on therapy were similar for patients with or without brain metastases.

Patient characteristics, treatment patterns, and clinical outcomes among patients with de novo advanced or metastatic (stage IIIB–IV) non-small cell lung cancer in a real-world setting.

e21032 Background: In the past decade, therapies targeting EGFR, KRAS, ALK, ROS1, BRAF, NTRK, MET, RET variants , and PD-L1 expression were approved and recommended for use in advanced non-small cell lung cancer (aNSCLC). This study describes real-world patient characteristics, biomarker testing, treatment patterns, and clinical outcomes in patients with de novo stage IIIB–IV aNSCLC in the United States. Methods: This is a retrospective cohort study of patients with aNSCLC using TEMPUS oncology data. Patients were included if they were diagnosed with stage IIIB, IIIC, or IV NSCLC (index date) as their primary NSCLC diagnosis between 1/1/2012 and 12/31/2020, and were >18 years of age at index. Patients with an advanced diagnosis within 90-days of their primary diagnosis were defined as having de novo aNSCLC. Patient demographics and clinical characteristics including biomarker testing for EGFR, KRAS, ALK, ROS1, BRAF, NTRK, MET, RET alterations, and/or PD-L1 expression, as well as treatment patterns, were described. Median progression-free survival (PFS) and median overall survival (OS) were stratified by stage at diagnosis (IIIB/IIIC vs IV) and evaluated by Kaplan–Meier analysis. Results: A total of 7,624 patients met the study criteria. 12.5% (n = 955) were diagnosed at stage IIIB/IIIC versus 87.5% (n = 6,669) diagnosed at stage IV. Of the de novo patients with aNSCLC, 47.6% (n = 3,632) were female, median age (IQR) was 65.3 years (58.1–72.4), 67.4% (n = 5,136) were White, and 62.7% (n = 4,781) had evidence of biomarker testing. Biomarker testing was significantly more common among patients diagnosed at stage IV (64.9%, n = 4,325) than stage IIIB/IIIC (47.7%, n = 456; p < 0.001). At index, 10.3% (n = 785) of patients had evidence of brain metastasis, 49.2% (n = 3,749) were current or former smokers, and 66.7% (n = 5,086) had non-squamous histology. 69.1% (n = 5,269) received first-line treatment with chemotherapy (58.5%, n = 3,083), chemotherapy + immune checkpoint inhibitor (ICI) (20.8%, n = 1,096), ICI monotherapy (9.5%, n = 503), tyrosine kinase inhibitors (10.4%, n = 548), or other treatments (0.7%, n = 39). Among patients with de novo aNSCLC overall at stage IIIB/IIIC and stage IV, median PFS was 5.0 months (mos) (95% CI: 4.8, 5.3), 7.2 mos (95% CI: 6.3, 8.1), and 4.8 mos (95% CI: 4.6, 4.9; p < 0.0001), respectively; median OS was 13.9 mos (95% CI: 13.3, 14.5), 19.4 mos (95% CI: 16.8, 22.0), and 13.2 mos (95% CI: 12.6, 13.8; p < 0.0001), respectively. Conclusions: Among patients with de novo aNSCLC, those diagnosed at stage IIIB/IIIC had significantly longer median PFS and OS than those diagnosed at stage IV. Many real-world patients with aNSCLC were not tested for biomarkers for which there are now approved targeted therapies. Earlier diagnosis and increased biomarker testing may improve clinical outcomes in real-world patients with aNSCLC.

Meta-analysis of efficacy outcome measures across immune checkpoint inhibitors (ICIs) and targeted therapies (TTs) in melanoma to guide future clinical trial design.

e21520 Background: Systemic treatments (Tx) for unresectable or metastatic melanoma include TTs and ICIs, with TT+ICI combinations under exploration. Heterogeneity in clinical trial sample size and subject characteristics pose obstacles for treatment class comparisons. We applied meta-analysis to elucidate Tx and covariate effects on efficacy outcomes in melanoma. Methods: A PICOS-guided literature search was conducted from 2000-2022 for TT or ICI given as monotherapy or in combination for unresectable or metastatic melanoma. Median progression-free survival (mPFS), median overall survival (mOS), and overall response rate (ORR) were recorded. Random-effects models were fit to endpoints with study arms weighted by variance. Covariate inclusion was based on likelihood-ratio tests (P < 0.05). For simulation, parameter distributions from weighted linear regression (wi ~ nstudy) of mPFS to ORR were sampled (N = 5000) with residual error scaled by mean Phase 3 arm size. ORR uncertainty was modeled by normal approximation. Results: From 134 publications, 100 (mPFS), 73 (mOS), and 111 (ORR) outcomes were retained, from 53, 44, and 63 studies, respectively, and classified by treatment. For all endpoints, Tx classification was an outcome predictor (P< 0.001). BRAFi+MEKi+PD-1 combination therapy had the greatest predicted duration of mPFS (16.7 months [11.8, 23.6]) and ORR (62.8% [53.7%, 71.1%]). mPFS and mOS outcomes were reduced by prior Tx failure and evidence of brain metastases, with mOS also impacted by elevated lactate dehydrogenase. I2 statistics for the final models were 89.0% (mPFS), 73.9% (mOS), and 51.8% (ORR). A robust correlation between ORR and mPFS (R2= 0.77, P < 0.001) was observed across all treatment classes. The predictive power of this relationship was demonstrated by simulating the probability of achieving target Phase 3 mPFS outcomes from ORR derived from as few as 20 patients. Conclusions: This meta-analysis characterizes the shifting space of Tx in unresectable or metastatic melanoma and provides a model-based framework for simulation of efficacy endpoints and trial designs for TT+ICI combinations. ORR-based predictions of trial success illustrate the value of utilizing early endpoints to inform decisions in drug development, across all Tx options in melanoma. Further investigation will include longitudinal PFS and OS modeling and refinement of PFS predictions from tumor growth metrics and clinical benefit rate.

Quality assurance and safety of hippocampal avoidance prophylactic cranial irradiation in the multicenter randomized phase III trial (NCT01780675)

ObjectiveNCT01780675, a multicenter randomized phase III trial of prophylactic cranial irradiation (PCI) versus PCI with hippocampal sparing in small cell lung cancer (SCLC) investigated neurocognitive decline and safety. As part of quality assurance, we evaluated if hippocampal avoidance (HA)-PCI was performed according to the NCT01780675 trial protocol instructions, and performed a safety analysis to study the incidence and location of brain metastases for patients treated with HA-PCI. MethodsThis retrospective analysis evaluated the quality of the irradiation given in the randomized controlled trial (RCT) comparing SCLC patients receiving PCI with or without hippocampal avoidance, using intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT). The dose distribution for each patient receiving HA-PCI was retrieved and analyzed to evaluate if the treatment dose constraints were met. A questionnaire was sent out to all participating sites, and data on radiotherapy technique, pre-treatment dummy runs, phantom measurements and treatment electronic portal imaging device (EPID) dosimetry were collected and analyzed. As part of the safety analysis, the follow-up magnetic resonance imaging (MRI) or computerized tomography (CT) scans on which cranial disease progression was first diagnosed were collected and matched to the radiotherapy planning dose distribution. The matched scans were reviewed to analyze the location of the brain metastases in relation to the prescribed dose. ResultsA total of 168 patients were randomized in the NCT01780675 trial in 10 centers in the Netherlands and Belgium from April 2013 until March 2018. Eighty two patients receiving HA-PCI without evidence of brain metastases were analyzed. All patients were treated with 25 Gy in 10 fractions. Dummy runs and phantom measurements were performed in all institutions prior to enrolling patients into the study. The radiotherapy (RT) plans showed a median mean bilateral hippocampal dose of 8.0 Gy, range 5.4–11.4 (constraint ≤ 8.5 Gy). In six patients (7.3%) there was a protocol violation of the mean dose in one or both hippocampi. In four of these six patients (4.9%) the mean dose to both hippocampi exceeded the constraint, in 1 patient (1.2%) only the left and in 1 patient (1.2%) only the right hippocampal mean dose was violated (average median dose left and right 8.9 Gy). All patients met the trial dose constraint of V115%PTV ≤ 1%; however the DmaxPTV constraint of ≤ 28.75 Gy was violated in 22.0% of the patients. The safety analysis showed that 14 patients (17.1%) developed cranial progression. No solitary brain metastases in the underdosed region were found. Two out of 11 patients with multiple brain metastasis developed metastasis in the underdosed region(s). ConclusionsThe radiotherapy quality within the HA-PCI trial is performed according to the protocol guidelines. The dose constraints to the hippocampi are met in the vast majority of cases. In all patients, the volume of the brain for which a higher dose was accepted, is according to the trial. However, within this volume there are small areas with higher doses than advised.

OS08.4.A Analysis of melanoma brain metastasis immune microenvironment through multiplex gene expression profiling

Abstract Background Novel immunotherapies based on targeting of specific immune checkpoints enabled a significant improvement of melanoma outcome, but melanoma brain metastases (BM) remain an unmet oncological need with an overall 2-year survival rate lower than 10%. Tumour immune microenvironment has been demonstrated to play a key role in BM establishment and development, but data regarding the specific milieu of melanoma BM is limited. Material and Methods Gene expression profiles of 55 samples of primary melanoma and BM were evaluated using the nCounter PanCancer IO 360 Panel (NanoString Technologies) targeting 770 mRNA involved in tumor immune microenvironment modulation. The case series consisted of 10 primary melanomas and their 10 matched BM, 25 unmatched BM, and 10 locally advanced control melanomas without evidence of BM after >5 year follow up. Results Among BM samples, most patients (25/45) were males and median age at BM diagnosis was 61,2 years with a median time to BM development of 2,1 years. Median OS from BM diagnosis was 1,3 years. Several genes resulted significantly downregulated in BM compared to primary melanomas, including SERPINB5 (p<0.001), ARG1 (p=0.0067), S100A8 (p<0.001), S100A9 (p<0.001), S100A12 (p=0.0037), IL1RN (p=0.0012), CCL21 (p=0.0012), CCL22 (p=0.0012) and CCL13 (p=0.037) and SELE (p=0.026); conversely, C7 was upregulated (p<0.001). Downregulated signatures in BM involved those associated with multiple immune cell populations, including neutrophils, dendritic cells, mast cells and Treg, as well as inflammatory chemokines, the CTLA4 immune checkpoint and ARG1 enzyme function; conversely, MAGEs-related signature was upregulated. Comparison between primary melanomas which developed BM and those which did not showed a significant overexpression of RRM2 (p=0.0247) and TNFRSF1A (p=0.032) genes in the latter group and an upregulation of the PD-1 pathway. Analysis according to tumour mutational status showed an upregulation of signatures associated with inflammatory chemokines, dendritic and myeloid cells and neutrophils. No differences were observed according to time to BM development and survival from BM diagnosis. Conclusion Our findings show that melanoma BM harbor distinct immunosuppressive mechanisms compared to primary tumors: this data elicits the importance of investigating the heterogeneity of BM microenvironment. Genes and pathways selectively overexpressed or downregulated in melanoma BM should be validated to be possibly considered as novel therapeutic targets.

Brain metastases in ovarian cancer: Association of outcomes with timing of diagnosis.

e17565 Background: Brain metastases (BM) in ovarian cancer (OC) are rare and late events during the disease course. We report our data on patients with OC who developed BM and compared the outcomes with subjects with evidence of BM at the time of diagnosis from the Surveillance, Epidemiologic, and End Results (SEER) national database. Methods: Retrospective chart review of all patients with brain metastasis in the setting of previously diagnosed ovarian cancer was performed in single NCI designated comprehensive cancer institute. Inclusion criteria were: primary cancer documented as ovarian or tubal, evidence of BM, treatment and follow up information. For comparison and due to rare nature of ovarian cancer cases with BM we utilized the SEER database. SEER data base reports only on patients with OC who had BM at the time of diagnosis. Study groups were: 1- BM at diagnosis 2- BM during disease course. Primary outcomes were overall death, and overall survival (OS) months. Secondary outcome was survival months after diagnosis of BM. Variables are reported as median and interquartile range (IQR) or number (%). Mean survival was calculated using Kaplan Meier analysis and Mantel-Cox rank test. Cox regression analysis was performed to calculate adjusted hazard ratios (HR). Results: 106 and 24 subjects were included with evidence of BM at diagnosis (Group 1, 2010-2016, SEER database) and during the disease (Group2, 1992-2017, institutional data), respectively. Age at diagnosis of OC was significantly higher in group 1 (64 year vs. 55 year, p = 0.002). In group 2, BM were diagnosed at median interval of 33.5 months. The median OS month was 3 [1, 10] months and 58 [21, 122] in group 1 and 2, respectively (p < 0.001). Although overall mortality rate was not statistically significantly different between the study groups, survival months after diagnosis of BM in group 2 was significantly higher than group 1 (14 months [4, 32] versus 3 months [1, 10], p = 0.002). Cox-regression analysis revealed 58% decrease in the hazard of overall death when the BM is diagnosed during the disease course. (Adjusted HR = 0.42, 95% CI: 0.19-0.91, p = 0.03). Conclusions: Outcomes of OC with BM is poor with high mortality rate regardless of timing of diagnosis of BM. Our study revealed that patients with diagnosis of BM during the disease course have statistically significantly longer survival after diagnosis of BM compared to those with BM at the time of diagnosis. In order to understand the occurrence of BM in OC and these differences, it is necessary to gain knowledge in the genetic and immune mechanisms that drive and allow the development of BM in ovarian cancer. This will allow for development of effective therapeutic strategies to treat BM, which is of critical importance now as we are gaining better control of peripheral disease in women with ovarian cancer.

Ovarian cancer with brain metastasis at the time of diagnosis: A surveillance, epidemiologic, and end results (SEER) database study

Brain metastases are rare and usually late event in ovarian cancer. We report a series of 106 subjects with evidence of brain metastasis at the time of diagnosis of ovarian cancer. Understanding the occurrence of brain metastases from primary ovarian cancer is an important clinical goal.

Abstract PS14-15: Real world treatment patterns and healthcare resource utilization among HER2+ metastatic breast cancer patients with and without brain metastases: A retrospective cohort study

Abstract Background: Human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is associated with increased clinical and economic burden. Patients with brain metastases (BM) have significantly worse outcomes, however, limited data exist evaluating healthcare resource utilization (HCRU) among HER2+ MBC patients with BM. Objective: To describe treatment patterns and HCRU among HER2+ MBC patients with or without brain metastases who received HER2-targeted therapy using retrospective claims data. Methods: Data obtained from the IBM Watson HealthTM MarketScan commercial claims and Medicare Supplemental database from July 2012 to December 2018 were used to evaluate HER2+ MBC patients. We describe demographic and clinical characteristics, treatment patterns by line of therapy (LOT) by the presence or absence of BM, and HCRU. The first metastatic diagnosis date was the study initiation (index) date. HCRU outcomes per patient per year (PPPY) in the follow-up period after metastatic diagnosis were measured overall and by BM vs non-BM. These HCRU outcomes included inpatient (IP) services, total length of stay (LOS), emergency room (ER) services, and outpatient (OP) services. Results: A total of 4,509 patients were included. One-hundred and three (2.3%) patients had BM and 4,406 had no evidence of BM at index. However, 590 (13.1%) developed BM after study initiation. The mean age at index was 53.7 years. Median follow-up time was 23.2 months overall (22.1 months for patients with BM at index and 23.2 months for patients without BM at index). Median time on treatment (months) was 7.6, 7.2, and 6.2 for first line (1L), 2L, and 3L, respectively. Trastuzumab-based regimens were most used across all LOTs. Trastuzumab emtansine (T-DM1) use in 1L was 0.9% (2.4% in BM and 0.9% in non-BM patients). T-DM1 use increased in 2L (9.7%) and 3L (13.0%) and differed for BM vs non-BM patients in 2L (22.6% vs 7.7%) and 3L (25% vs 10.1%). Overall, lapatinib use ranged from 1.6% (1L) to 8.3% (3L). BM patients had a higher frequency of lapatinib use compared to non-BM patients (1L: 11.8% vs 1.2%; 2L: 20.5% vs 1.8%; 3L: 21.2% vs 5.1%). The mean number of IP services PPPY was 0.6 and higher for BM patients (1.2 vs 0.5). The mean total LOS PPPY was 2.7 days and BM patients had higher total LOS (8.6 vs 2.6 days) compared to non-BM patients. The average number of ER visits PPPY was 1.2 and BM patients had higher frequency of ER visits (2.5 vs 1.2). The mean number of OP services PPPY was 57.1; however, no obvious difference was observed between BM and non-BM patients (62.1 vs 56.9). Conclusions: Among HER2+ MBC patients, there is significantly higher HCRU among BM patients compared to patients without BM. This highlights the need for more effective systemic therapies that improve outcomes and reduce disease and healthcare system burden for HER2+ MBC patients, particularly those with BM. Citation Format: Chiemeka Ike, Naomi Schwartz, Andy Surinach, Yutong Liu, Kendra DeBusk, Thomas Walters. Real world treatment patterns and healthcare resource utilization among HER2+ metastatic breast cancer patients with and without brain metastases: A retrospective cohort study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-15.

American Radium Society Appropriate Use Criteria on Radiation Therapy for Extensive-Stage SCLC.

The standard-of-care therapy for extensive-stage SCLC has recently changed with the results of two large randomized trials revealing improved survival with the addition of immunotherapy to first-line platinum or etoposide chemotherapy. This has led to a lack of clarity around the role of consolidative thoracic radiation and prophylactic cranial irradiation in the setting of chemoimmunotherapy. The American Radium Society Appropriate Use Criteria are evidence-based guidelines for specific clinical conditions that are reviewed by a multidisciplinary expert panel. The guidelines include a review and analysis of current evidence with the application of consensus methodology (modified Delphi) to rate the appropriateness of treatments recommended by the panel for extensive-stage SCLC. Current evidence supports either prophylactic cranial irradiation or surveillance with magnetic resonance imaging every 3 months for patients without evidence of brain metastases. Patients with brain metastases should receive whole-brain radiation with a recommended dose of 30 Gy in 10 fractions. Consolidative thoracic radiation can be considered in selected cases with the recommended dose ranging from 30 to 54 Gy; this recommendation was driven by expert opinion owing to the limited strength of evidence, as clinical trials addressing this question remain ongoing. Radiation therapy remains an integral component in the treatment paradigm for ES-SCLC.

Brain metastases from breast cancer

BackgroundBreast cancer (BC) is one of the commonest causes of brain metastases (BM): approximately 10–16 % of patients diagnosed with metastatic breast cancer will eventually develop BM during the course of their disease, however, certain subtypes have a higher risk of this event. The aim of this analysis was therefore to evaluate the prognosis and the pattern and imaging features of BM according to different BC subtypes. Patients and methodsWe retrospectively reviewed the case records of patients with breast cancer and evidence of brain metastases from the database of IPO Porto between 2014–2018. The data obtained were statistically analysed. ResultsWe analysed 147 patients with BM from BC. The triple-negative subtype had the shortest overall survival (OS) after BM, besides a short period of time between BC and BM. HER2 overexpressing tumors had the longest OS. The estrogen-receptor positive group had the greatest interval between initial BC diagnosis and diagnosis of BM. Larger lesions showed a heterogeneous contrast enhancement and were heterogeneous pn T2WI sequences; a hyposignal on T2*WI was also associated with larger lesions. Triple-negative BC tended to have more heterogeneous lesions on T1WI. We noticed that the hippocampus is rarely affected by metastatic lesions. ConclusionsBased on the BC subtype it is possible to make a prediction about the prognosis of the disease and some imaging features of the BM, but not about their pattern of distribution. These data support further research concerning prevention, early detection, and treatment of BM from BC.

SUN-930 A Case of Acromegaly Secondary to Ectopic Growth Hormone-Releasing Hormone (GHRH) Secretion from a Bronchial Neuroendocrine Tumour

A Case of Acromegaly Secondary to Ectopic Growth Hormone-Releasing Hormone (GHRH) Secretion from a Bronchial Neuroendocrine TumourBackgroundAcromegaly due to ectopic GHRH secretion is a rare disorder and only accounts for less than 1% of all cases of acromegaly.CaseWe present the case of a 42-year old female with acromegaly from a bronchial neuroendocrine tumour (NET) secreting GHRH. The patient presented with gradual onset of dyspnea and wheezing. Subsequent imaging (chest X-ray, CT chest) revealed a large left-sided thoracic mass. Bronchoscopy was performed and a biopsy was taken from the mass. Initial histological examination reported small cell lung carcinoma (SCLC). Therefore, she underwent chemoradiotherapy. The patient was concurrently experiencing increased digital girth, weight gain, and enlarged tongue and was therefore referred to our endocrinology clinic for evaluation of acromegaly. Investigations revealed normal ACTH, markedly elevated IGF-1 (1031 μg/L, normal 63–215 μg/L), and non-suppressed GH levels following a 75g oral glucose tolerance test. The remainder of the pituitary panel, including TSH, prolactin, FSH, LH were all normal. An MRI sella showed a completely normal pituitary and pineal gland with no evidence of brain metastasis. She thus met clinical and biochemical criteria for acromegaly but a pituitary source could not be identified. Given her history, a paraneoplastic process or ectopic GHRH-producing tumour was suspected. Further workup showed a significantly elevated circulating GHRH levels of 73 pg/mL (normal 5 – 18 pg/mL). Subsequently, a second pathologist with expertise in NETs reviewed the same biopsy specimen. The specimen was found to be a GHRH-producing well differentiated pulmonary NET with a Ki67 index of 1.5%, and thus not a SCLC. Furthermore, a somatostatin receptor scintigraphy study was done which showed evidence of a somatostatin avid receptor rich lesion in the lung, corresponding to the known tumour. Thus, what initially appeared to be a SCLC was subsequently found to be a GHRH-secreting NET, illustrating the challenges of diagnosing these rare tumours. She was treated with intramuscular sandostatin 20mg q28days and then underwent a left pneumonectomy, resulting in biochemical resolution of her acromegaly (IGF-1 219 μg/L). Genetic testing for MEN1 was also completed as there is an association between ectopic GHRH NETs and MEN-1; however, genetic testing revealed no pathogenic variants and exon deletions or duplications suggestive of MEN-1.Learning pointsDiagnosis of acromegaly due to ectopic GHRH secretion requires high clinical suspicion by the treating clinicians (e.g., endocrinologist, oncologist) as well as review of histology by expert pathologists. Our case highlights that ectopic GHRH secretion is a rare but important cause of acromegaly, which should always be suspected when a clear pituitary cause is not identified.

Identification of CD37, cystatin A, and IL-23A gene expression in association with brain metastasis: analysis of a prospective trial.

Purpose/ObjectivesWe aimed to assess the predictive value of a lung cancer gene panel for the development of brain metastases.Materials/MethodsBetween 2011 and 2015, 102 patients with lung cancer were prospectively enrolled in a clinical trial in which a diagnostic fine-needle aspirate was obtained. Gene expression was conducted on all samples that rendered a diagnosis of non-small cell lung cancer (NSCLC). Subsequent retrospective analysis of brain metastases-related outcomes was performed by reviewing patient electronic medical records. A competing risk multivariable regression was performed to estimate the adjusted hazard ratio for the development of brain metastases and non-brain metastases from NSCLC.ResultsA total of 49 of 102 patients had died by the last follow-up. Median time of follow-up was 13 months (range 0.23– 67 months). A total of 17 patients developed brain metastases. Median survival time after diagnosis of brain metastases was 3.58 months (95% confidence interval (CI) 2.17, not available). A total of 30 patients developed metastases without any evidence of brain metastases until the time of death or last follow-up. Competing risk analysis identified three genes that were downregulated differentially in the patients with brain metastases versus non-brain metastatic disease: CD37 (0.017), cystatin A (0.022), and IL-23A (0.027). Other factors associated with brain metastases include: stage T (P ⩽ 8.3e−6) and stage N (P= 6.8e−4).ConclusionsWe have identified three genes, CD37, cystatin A, and IL-23A, for which downregulation of gene expression was associated with a greater propensity for developing brain metastases. Validation of these biomarkers could have implications on surveillance patterns in patients with brain metastases from NSCLC.

Prophylactic cranial irradiation (PCI) significantly decreases risk of brain metastases in patients with bulky, higher stage small-cell urothelial cancer.

486 Background: Patients with bulky, higher-stage small cell urothelial cancer (≥T3b, N+, and/or M+) have a high risk of developing brain metastases. Siefker-Radtke et al reported a 50% risk of brain metastases in this patient population. Therefore, a prospective trial evaluating the potential benefit of PCI was undertaken. Methods: Thirty patients with stage ≥T3b, N+, and/or M+ disease (without brain metastases on MRI) were treated between 12/2008 and 5/2018 with PCI. Patients were treated to a total dose of 30 Gy in 2 Gy fractions over 3 weeks. The patient had baseline brain MRI and mini-mental status exam (MMSE) before the treatment began. After treatment, patients underwent MRI and MMSE every 3-4 months for one year and every 6 months thereafter. If the patients did not have M+ disease at diagnosis, they were also treated with neoadjuvant chemotherapy (usually consisting of cisplatin/etoposide alternating with Adriamycin/ifosfamide), followed by a radical cystectomy. The PCI was either given between the last cycle of chemotherapy and surgery or after the surgery. Both acute and chronic toxicity from PCI were measured using CTCAE 3.0. Change in the MMSE after PCI was evaluated using a t-test. Results: Twenty-nine patients were evaluable. Twenty-four patients had ≥T3b and/or N+ disease and 5 patients had M1 disease. Median follow-up was 22 months (range 8-103 months). Four patients have developed brain metastases with a median time of 11.5 months after PCI (range 3-23 months). Two of these patients have died. Nine other patients have died from progressive systemic disease, but they did not have evidence of brain metastases. PCI was well-tolerated, with no grade ≥2 toxicity seen. Acute grade 1 toxicity seen included headache, nausea, and dermatitis. MMSE were available for 19 patients with a median follow-up of 13 months (range 3-87 months). There was no significant change in the MMSE scores after the PCI when compared to baseline (p = 0.61). Conclusions: In this study, PCI decreased the risk of developing brain metastases in patients with bulky, higher-stage small cell urothelial cancer from 50% (historical) to 13.8% without significant toxicity. Clinical trial information: NCT00756639.

Abstract PD3-16: Clinical safety and efficacy of the aurora and angiogenic kinase inhibitor ENMD-2076 in previously treated, locally advanced or metastatic triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype defined by the lack of expression of the estrogen and progesterone receptors and lack of HER2 over-expression. ENMD-2076 is an orally bioavailable small molecule inhibitor of Aurora and angiogenic kinases with pro-apoptotic and antiproliferative activity in preclinical models of TNBC. Methods: This two institution, single-arm, two-stage, phase II clinical trial enrolled patients with locally advanced or metastatic TNBC refractory to 1-3 prior lines of chemotherapy in the advanced setting. Patients had ECOG PS ≤ 1, measureable disease by RECIST 1.1 and no evidence of brain metastasis. Patients were treated with ENMD-2076 250 mg PO daily with continuous dosing in 4-week cycles until disease progression or unacceptable toxicity occurred. The primary end point was 6-month clinical benefit rate (6-CBR) and secondary endpoints included time to progression (TTP), PK profile, safety and biologic correlatives in archival and fresh serial tumor biopsies in a subset of patients. Results: Between July 2012 and October 2016, 41 patients were enrolled (median age 54; range 30-73; female 40; male 1). Patients received a mean 1.7 prior lines of chemotherapy for locally advanced unresectable or metastatic disease and 80.5% received prior neoadjuvant or adjuvant chemotherapy (N=33). Thirty-six patients were evaluable per protocol for the primary efficacy analysis. Five patients (12.2%) were not included in the efficacy analysis due to: adverse events (AE) leading to discontinuation prior to objective efficacy assessment (N=3), not meeting eligibility criteria on day 1 (N=1) and withdraw of consent in cycle 1 (N=1). The study proceeded to the second stage of enrollment based on observing three 6-CBR events in Stage 1 (N=18 patients). The 6-CBR in the overall trial was 16.7% (95% exact CI: 6%-32.8%; 2 patients with PR and 4 patients with SD > 6 mos). The median duration of response or clinical benefit in these patients was 32 weeks (8 cycles). 4-CBR was 27.8% (95% exact CI: 14%-45.2%). Dose reduction occurred in 8 patients (20%) for fatigue, hypertension and proteinuria. The most common grade 3 treatment-related adverse events were hypertension (37.5%) and fatigue (10%). One patient experienced grade 4 hypertension. Analysis of serial tumor biopsies prior to and following 2 weeks of ENMD-2076 (N=8 patients), demonstrated a treatment-induced decrease in cellular proliferation (Ki-67) and microvessel density (CD34) as assessed by IHC. Immunofluorescence performed on a subset of samples demonstrated an increase in p53-family member expression following treatment, consistent with changes observed in preclinical TNBC patient-derived tumor xenograft models. Conclusions: ENMD-2076 has durable clinical activity in a subset of patients with pretreated, advanced or metastatic triple-negative breast cancer. Predictive biomarker development using archival and fresh tumor tissue is underway. Exploration of lower doses of ENMD-2076 in future clinical trials may improve tolerability. Citation Format: Diamond JR, Eckhardt SG, Pitts TM, van Bokhoven A, Aisner D, Gustafson DL, Capasso A, Elias AD, Storniolo AM, Schneider BP, Gao D, Tentler JJ, Borges VF, Miller KD. Clinical safety and efficacy of the aurora and angiogenic kinase inhibitor ENMD-2076 in previously treated, locally advanced or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-16.

Determination of Tumor Gene Expression in Non–small Cell Lung Cancer Patients Who Develop Brain Metastasis Diagnosis: Analysis of a Prospective Trial

Brain metastasis (BM) occur in 30-50% of patients with non-small cell lung cancer (NSCLC). If BM are discovered after development of symptoms, patients have worse outcomes. Biomarkers for the development of BM are lacking. The current series is a genomic analysis of a completed prospective trial in which gene expression profiling was performed on RNA samples from the time of diagnosis of NSCLC. Between 2011 and 2015, a total of 101 patients with histologically-confirmed NSCLC were prospectively enrolled onto a clinical trial in which genomic analysis was performed on the RNA from a diagnostic FNA. RNA was extracted from a single pass specimen after the diagnostic biopsies were obtained. RNA from FNA were processed for gene expression analysis, data normalization, and quality control. Classification algorithms training on frozen FNAs was used. Retrospective analysis of BM-related outcomes was performed using patient electronic medical records including: date of BM development, any metastasis, and last follow-up. A competing risk analysis was performed for the effects of the prognostic factors on the risk of developing BM vs. other metastasis. Cumulative incidence functions of BM types in each subgroups were estimated for every prognostic factor. Gray’s test was used to assess statistical significance. Genes were selected through previous analysis of microarray data sets used for training and testing. Normalization and batch correction methods were applied. Gene expression signatures were made for histology using a classification algorithm using gene array tools. A total of 49 of 101 patients died at the time of last follow-up. Median time of follow-up was 12.98 months (range 0.23 to 66.53 months). A total of 17 patients developed BM; risk of brain met was lower than 50% ( 1 – 0.842 = 0.158), so no median survival time is available. Median survival time after diagnosis of BM was 3.581 months (95% CI f 2.17 to NA ). Thirty patients developed non-BM without any evidence of BM until time of death or last follow-up. Competing risk analysis identified 3 genes that were downregulated differentially in the patients with BM vs non-brain metastatic disease: CD37 (0.0170), cystatin A (0.0221), and IL-23A (0.0271). All 3 identified genes have plausible mechanisms for increasing metastatic phenotype. Other factors strongly associated with BM include: stage T (p = < 8.29e-6),stage N (p= 6.8e-4); adenocarcinoma vs squamous did not have a enough power to detect a difference (p =0.25). We have identified 3 genes CD37, cystatin A, and IL-23A for which downregulation led to a greater propensity for developing BM. Validation of these biomarkers could have implications on surveillance patterns of the brain.

Negative impact of leukoaraiosis on the incidence of brain metastases in patients with lung cancer

The embolization of cancer cells to cerebral vessels occurs early in the multi-step metastatic process. We aimed to determine whether the presence of leukoaraiosis (LA) before treatment would predict the development of brain metastases (BM) in patients with lung cancer. Between January 2014 and June 2015, 1007 patients underwent initial (i.e., prior to any chemotherapy) or routine magnetic resonance (MR) imaging of the brain and exhibited no evidence of BM. Of these, 189 underwent repeat MR imaging; 34 of 189 patients (18%) developed new BM, whereas 155 patients did not. LA was retrospectively evaluated according to Fazekas scale on the initial screening MR images of these 189 patients. The frequency of grade 0 periventricular hyperintensity (PVH) was greater among patients with BM, compared to those without BM (p = 0.001). In a multivariate analysis, patients with adenocarcinoma (95% confidence interval [CI] 1.8–171.8) and small cell carcinoma (95% CI 1.4–172.4) respectively developed BM at 9.3- and 8.8-fold higher rates than those with squamous cell carcinoma. Patients with grade 0 PVH developed BM at a rate 3.5-, 8.6-, and 3.6-fold higher rates than those with grade 1 (95% CI 1.4–9.0), 2 (95% CI 2.4–41.9), and 3 (95% CI 1.02–15.0), respectively. Lung cancer patients with grade 0 PVH on initial MR images have a high subsequent incidence of BM. PVH is a useful method for evaluating risk of BM.

Real-world treatment patterns and outcomes in HER2 positive MBC patients with brain metastasis in the U.S. community oncology setting.

92 Background: Patients (pts) with HER2 positive (HER2+) metastatic breast cancer (MBC) have different patterns of disease and treatment (tx) from HER2 negative MBC. Brain metastasis (BM) frequently occurs and txs vary. Methods: This retrospective study included adult HER2+ MBC pts from a community oncology network electronic health record (EHR) database and diagnosed between 2009-2011, with follow-up until 11/2014. Pts with other primary tumors were excluded. Two cohorts were defined: pts diagnosed with BM and pts with no evidence of BM (NBM), and were initially matched on age and performance status at MBC diagnosis (dx) and stage. Eligibility and txs were examined in electronic chart review. Overall survival (OS) from MBC dx was estimated using a weighted Kaplan-Meier method. Results: The final sample consisted of 86 BM and 101 NBM pts. All baseline MBC demographics were similar across cohorts. Median age was 54 and 52 years for BM and NBM, respectively. The cohorts (BM:NBM) included 57%:75% Caucasians, 12%:6% Blacks, and 31%:19% other/unknown. There were fewer estrogen receptor positive pts in the BM cohort (58%:74%; p = 0.02). Except for bone (p = 0.01), both cohorts had similar prevalence of metastatic sites: liver 35%:35%; lung 31%:30%; bone 41%:62. Of all the BM pts, 54% had first CNS imaging after symptoms, 37% were first imaged for other known reasons. After BM dx, 20% had surgical resection, 67% whole brain radiation (XRT), 37% stereotactic XRT, and 22% palliative XRT (not mutually exclusive). 25% of pts had both XRT and surgery while 72% had only XRT. Among pts receiving systemic therapy after BM dx, the first regimen contained trastuzumab in 55% of pts and lapatinib in 41% of pts. Among pts changing txs after BM dx, 1/3 switched to a trastuzumab but not lapatinib-based regimen; 1/3 to a lapatinib but not trastuzumab-based regimen; 17% to a lapatinib + trastuzumab-based regimen; and 17% to non-HER2-based therapy. Weighted median OS from MBC dx for BM vs. NBM pts was 30.2 and 46.1 months (p = 0.01). Conclusions: For HER2+ MBC pts, survival was shorter for pts with BM vs. NBM and a high degree of tx variability for BM existed. Understanding how detection and tx impacts outcomes will improve care of BM pts.

Abstract OT1-03-07: A randomized, placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to paclitaxel alone as front-line therapy for triple-negative breast cancer (fRida)

Abstract Background: Breast cancer stem cells (BCSC) have the ability to self renew and generate the full range of cells that make up a bulk tumor. Experimental models and retrospective clinical observations point to BCSC as responsible for tumor recurrence and metastasis. CXCR1, one of the receptors for CXCL8, has been identified on BCSC. Reparixin, an allosteric inhibitor of CXCR1, reduced BCSC in breast cancer xenografts (Ginestier C et al., JCI 2010) both as single agent and in combination with taxane chemotherapy. In a phase Ib trial in women with metastatic HER2-negative BC, the combination of escalating doses (400 to 1200 mg three times per day) of reparixin with weekly paclitaxel resulted in a low incidence and severity of adverse reactions, a sizeable response rate and time-to-progression, with some long-term responders (Schott AF et al., SABC 2014). Trial Design: In this randomized, double-blind phase 2 trial patients will be randomized (1:1) to paclitaxel 80 mg/m2 on days 1, 8 and 15 of 28-day cycles in combination with reparixin or placebo oral tablets 1200 mg three times daily on days 1-21. Treatment continues until disease progression, unacceptable toxicity or withdrawal of consent. An independent Data Monitoring Committee has been appointed to oversee the trial. An independent Radiology Review will be performed for analysis of primary and secondary endpoints. Disease response will be assessed every 8 weeks. Patients will be followed up to 12 months after last enrolled patient completes treatment. Eligibility Criteria: Patients must be female aged ≥18 years with untreated metastatic TNBC who have relapsed &amp;gt;12 and &amp;gt;6 months after the end of a taxane- or non taxane-based (neo)adjuvant chemotherapy regimen, respectively. They must have measurable disease, ECOG PS of 0-1, adequate organ function, and no history or evidence of brain metastases (brain CT or MRI required). Tumor tissue must be available from a metastatic site or from primary tumor for confirmation of diagnosis and correlative studies. Key exclusion criteria are pre-existing peripheral neuropathy G&amp;gt;1 and any disease significantly affecting gastrointestinal function. Specific Aims: Primary: to evaluate progression-free survival (PFS) rate by independent assessment. Secondary: to determine median PFS, overall survival (OS), objective response rates and safety of the combination treatment. Exploratory: to determine median time to new tumor metastasis (TTM), proportion of patients progressing with new metastatic lesions, incidence and severity of peripheral neuropathy, and to evaluate BCSC in metastatic tissue Statistical Methods: The trial design provides 80% power to detect an increase in 6 month PFS from 30% to 50% with a 2-sided 5% significance level (Chi-square test). Kaplan-Meier curves will be produced for median PFS, OS outcomes and exploratory median TTM. Appropriate descriptive statistics will be provided for safety variables. Present Accrual and Target Accrual: Target accrual is 190 patients. Patients will be enrolled internationally in US and Europe. Contact Information: info@dompe.com Citation Format: Chang JC, Schott AF, Wicha MS, Cristofanilli M, Ruffini PA, McCanna S, Goldstein LJ. A randomized, placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to paclitaxel alone as front-line therapy for triple-negative breast cancer (fRida). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-07.