Integrated genomic and DNA methylation analysis of patients with advanced non-small cell lung cancer with brain metastases

Background Brain metastasis is a common and lethal complication of non-small cell lung cancer (NSCLC). It is mostly diagnosed only after symptoms develop, at which point very few treatment options are available. Therefore, patients who have an increased risk of developing brain metastasis need to be identified early. Our study aimed to identify genomic and epigenomic biomarkers for predicting brain metastasis risk in NSCLC patients. Methods Paired primary lung tumor tissues and either brain metastatic tissues or cerebrospinal fluid (CSF) samples were collected from 29 patients with treatment-naïve advanced NSCLC with central nervous system (CNS) metastases. A control group comprising 31 patients with advanced NSCLC who died without ever developing CNS metastasis was also included. Somatic mutations and DNA methylation levels were examined through capture-based targeted sequencing with a 520-gene panel and targeted bisulfite sequencing with an 80,672 CpG panel. Results Compared to primary lung lesions, brain metastatic tissues harbored numerous unique copy number variations. The tumor mutational burden was comparable between brain metastatic tissue (P = 0.168)/CSF (P = 0.445) and their paired primary lung tumor samples. Kelch-like ECH-associated protein (KEAP1) mutations were detected in primary lung tumor and brain metastatic tissue samples of patients with brain metastasis. KEAP1 mutation rate was significantly higher in patients with brain metastasis than those without (P = 0.031). DNA methylation analysis revealed 15 differentially methylated blocks between primary lung tumors of patients with and without CNS metastasis. A brain metastasis risk prediction model based on these 15 differentially methylated blocks had an area under the curve of 0.94, with 87.1% sensitivity and 82.8% specificity. Conclusions Our analyses revealed 15 differentially methylated blocks in primary lung tumor tissues, which can differentiate patients with and without CNS metastasis. These differentially methylated blocks may serve as predictive biomarkers for the risk of developing CNS metastasis in NSCLC. Additional larger studies are needed to validate the predictive value of these markers.

NIMG-07. BEYOND RANDOM AND NUMERIC LESIONS: DIFFERENT IMAGING PATTERNS OF CENTRAL NERVOUS SYSTEM METASTASIS BASED ON PRIMARY TUMOR LOCATION AND MOLECULAR PROFILE

The purpose of this exhibit is to discuss different imaging patterns of central nervous system (CNS) metastasis based on their primary cancer site and to review the recent literature of the particularities of CNS metastasis distribution in the era of molecular advancement in oncology. Selected cases extracted from our institutions database will be presented. The cases will be didactically organized to illustrate the most common imaging characteristics and distribution of brain metastasis based on their organ of origin, such as lung, breast, renal, skin, testicle and gastrointestinal tract. (SCHROEDER T. et al., J Neurooncol. 2020). We will also discuss the correlation between tumor imaging findings and genetic profile. We intend to review well-known CNS metastasis imaging patterns, as preferential involvement of the posterior fossa and anatomic watershed areas in cases of lung cancer (TAKANO, K. et al. Neuro-Oncology, 2016) and the rarity of parenchyma metastasis from prostate cancer (HATZOGLOU V. et al, J Neuroimaging. 2014). We will also demonstrate newly described imaging findings in correlation with primary tumors genetic mutations, such as higher incidence of leptomeningeal involvement in triple negative breast cancer and increase in the number of brain lesions in cases of EGFR positive lung cancer. Familiarity with the most prevalent imaging characteristics of central nervous system metastasis helps oncologists and radiologists not to miss out a CNS progression in case of a known tumor, and also helps to direct systemic investigation of a primary tumor when brain metastasis is the initial presentation. The correlation between molecular profile and the most common sites of CNS involvement can help on treatment planning, including brain radiation (Yanagihara TK,et al., Tomography. 2017), and also bring to discussion the mechanisms of tumor dissemination, which can be targets for future treatments.

INNV-02. ACCELERATING RESEARCH FOR BREAST CANCER BRAIN METASTASIS AND LEPTOMENINGEAL DISEASE THROUGH PATIENT-LED COLLABORATIONS

PATIENT-DRIVEN INITIATIVE OF THE METASTATIC BREAST CANCER (MBC) ALLIANCE The Breast Cancer Brain Metastasis (BCBM) Initiative: Marina Kaplan Project launched in June 2020 as an official project of the MBC Alliance which includes 32 nonprofits, 12 industry partners, and 30 individual patient advocates. The project has grown to include 35 members with representation from industry, research institutions, and individual patients. Nearly one-third of the group is comprised of patients living with brain metastases or LMD. DISPARITIES FOR PATIENTS LIVING WITH BCBM & LMD In the US, approximately 200,000 new cases of brain metastases are diagnosed each year.1 Approximately 10-15% of patients with MBC will develop brain metastases, and may be as high as 30-50% for certain subtypes.2 A diagnosis of central nervous system (CNS) metastasis often accelerates an already incurable diagnosis. CNS metastasis are difficult to image and detect, tend to have poorer prognoses with lower overall survival, and are treated with invasive therapies which can have lasting side effects. Furthermore, most clinical trials exclude patients with CNS metastasis which further hinders research. VALUES & OBJECTIVES The overarching goal of this initiative is to accelerate the scope and breadth of evidence-based CNS metastasis research by targeting entities conducting clinical trials and collaborating with them to do the following: (1) Increase the quality and quantity of basic research; (2) increase the number of clinical trials in areas where research is lacking; (3) diversify the type of clinical trial interventions; (4) eliminate restrictive eligibility criteria in clinical trials; (5) Incorporate clinically meaningful trial endpoints. References Eichler, April F et al. The biology of brain metastases-translation to new therapies. Nat Rev. Clinical oncology vol. 8,6 (2011): 344-56. doi: 10.1038/nrclinonc.2011.58 Brosnan EM, Anders CK. Understanding patterns of brain metastasis in breast cancer and designing rational therapeutic strategies. Ann Transl Med. 2018;6(9):163. doi: 10.21037/atm.2018.04.35

Research Progress and Challenges in the Treatment of Central Nervous System Metastasis of Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors and has high morbidity and mortality rates. Central nervous system (CNS) metastasis is one of the most frequent complications in patients with NSCLC and seriously affects the quality of life (QOL) and overall survival (OS) of patients, with a median OS of untreated patients of only 1–3 months. There are various treatment methods for NSCLC CNS metastasis, including surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, which do not meet the requirements of patients in terms of improving OS and QOL. There are still many problems in the treatment of NSCLC CNS metastasis that need to be solved urgently. This review summarizes the research progress in the treatment of NSCLC CNS metastasis to provide a reference for clinical practice.

SYST-06. PHASE II TRIAL OF PAXALISIB (GDC-0084) IN COMBINATION WITH TRASTUZUMAB FOR PATIENTS WITH HER2-POSITIVE BREAST CANCER BRAIN METASTASES (BCBM)

BACKGROUND The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. Paxalisib is a potent, brain-penetrant inhibitor of class I PI3K and mTOR. METHODS This is a single-center, phase II study to evaluate the efficacy of the combination of paxalisib with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive paxalisib (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to paxalisib/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha <10%. Cohort B will enroll 10 patients. The trial opened in February, 2019 and 8 patients have been enrolled. NCT03765983.

OTHR-04. Gynecological Malignancies With Metastasis To The Central Nervous System: A Case Series and Systematic Review of the Literature

Introduction Gynecologic malignancies are an increasingly common proportion of central nervous system metastatic disease. As genetic sequencing technology improves and becomes more accessible, mutations associated with CNS metastasis are easier to elucidate. The aims of this case series and systematic literature review are to describe the patient population with CNS metastatic disease from a gynecologic primary, and to investigate why the proportion of CNS metastasis from gynecologic malignancies is increasing. Ultimately, we hope to improve understanding of this subset of metastatic CNS malignancies and improve management strategies. Methods A literature review of articles describing patients from 1990–2020 who were diagnosed with CNS metastasis from a known gynecologic primary malignancy was performed. Demographics, cancer type, mutation characteristics, management for metastatic disease, progression free survival, number of CNS metastases, and location of metastatic disease were assessed. Inclusion criteria were age>18 years, diagnosis of primary ovarian, uterine, or cervical cancer with confirmed metastatic disease to the CNS, including brain parenchyma, leptomeninges, or intradural spinal cord or dural metastases. Exclusion criteria included pediatric population and bony metastases (e.g., bony spine metastases without evidence of meningeal/parenchymal invasion). Results Our review showed that patients with gynecological metastasis to the CNS generally have worse outcomes regarding overall survival, progression free survival, and quality of life than patients without CNS metastasis. Discussion Our results infer that the reported increase in incidence of CNS metastasis from gynecologic malignancies is a reflection of improvement of detection given advances in technology, improved patient follow up, and increased overall survival of patients with gynecologic malignancies. Further characterization of mutations from gynecologic malignancies associated with brain metastasis could result in development of more treatment options for patients in the future and help determine factors that contribute to developing metastasis to the CNS of various degrees, thus, potentially inform treatment strategies.

OTHR-09. Accelerating Research for Breast Cancer Brain Metastasis and Leptomeningeal Disease through Patient-led Collaborations

Patient-driven Initiative of the Metastatic Breast Cancer (MBC) Alliance The Breast Cancer Brain Metastasis (BCBM) Initiative: Marina Kaplan Project launched in June 2020 as an official project of the MBC Alliance which includes 32 nonprofits, 12 industry partners, and 30 individual patient advocates. The Marina Project has grown to include 35members with representation from industry, research institutions, and individual patients. Nearly one-third of the group is comprised of patients living with brain metastases or leptomeningeal disease (LMD). Disparities for Patients Living with BCBM & LMD In the US, approximately 200,000 new cases of brain metastases are diagnosed each year[1]. Approximately 10–15% of patients with MBC will develop brain metastases, and may be as high as 30–50% for certain subtypes[2]. A diagnosis of central nervous system (CNS) metastasis often accelerates an already incurable diagnosis. CNS metastasis are difficult to image and detect, tend to have poorer prognoses with lower overall survival, and are treated with invasive therapies which can have lasting side effects. Furthermore, most clinical trials exclude patients with CNS metastasis which further hinders research. Values and Objectives The overarching goal of this initiative is to accelerate the scope and breadth of evidence-based CNS metastasis research by targeting entities conducting clinical trials and collaborating with them to do the following: (i) Increase the quality and quantity of basic research; (ii) Increase the number of clinical trials in areas where research is lacking; (iii) Diversify the type of clinical trial interventions; (iv) Eliminate restrictive eligibility criteria in clinical trials; (v) Incorporate clinically meaningful trial endpoints [1] Eichler, April F et al. The biology of brain metastases-translation to new therapies. Nature reviews. Clinical oncology vol. 8,6 (2011): 344–56. doi: 10.1038/nrclinonc.2011.58 [2] Brosnan EM, Anders CK. Understanding patterns of brain metastasis in breast cancer and designing rational therapeutic strategies. Ann Transl Med. 2018;6(9):163. doi: 10.21037/atm.2018.04.35