Preclinical and clinical activity of DZD1516, a full blood-brain barrier-penetrant, highly selective HER2 inhibitor.

BACKGROUND: Patients with HER2-positive metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases. A potent and selective HER2 inhibitor with good blood-brain barrier (BBB) penetration is highly desirable. METHODS: The design and structure-activity relationship of DZD1516 was described. The potency and selectivity of DZD1516 were determined by enzymatic and cellular assays. The antitumor activity of DZD1516 monotherapy or in combination with HER2 antibody-drug conjugate was assessed in CNS and subcutaneous xenograft mouse models. A phase 1 first-in-human study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DZD1516 in patients with HER2+ MBC who relapsed from standard of care. RESULTS: DZD1516 showed good selectivity against HER2 over wild-type EGFR in vitro and potent antitumor activity in vivo. Twenty-three patients were enrolled and received DZD1516 monotherapy treatment across six dose levels (25-300 mg, twice daily). Dose-limiting toxicities were reported at 300 mg, and thus 250 mg was defined as the maximum tolerated dose. The most common adverse events included headache, vomiting, and hemoglobin decreased. No diarrhea or skin rash was observed at ≤ 250 mg. The mean Kp,uu,CSF was 2.1 for DZD1516 and 0.76 for its active metabolite DZ2678. With median seven lines of prior systemic therapy, the best antitumor efficacy in intracranial, extracranial and overall lesions was stable disease. CONCLUSIONS: DZD1516 provides positive proof of concept for an optimal HER2 inhibitor with high BBB penetration and HER2 selectivity. Further clinical evaluation of DZD1516 is warranted, with the RP2D being 250 mg BID. CLINICALTRIALS: gov identifier NCT04509596. Registered on August 12, 2020; Chinadrugtrial: CTR20202424 Registered on December 18, 2020.

Breast Cancer Brain Metastases: Achilles' Heel in Breast Cancer Patients' Care.

Brain metastases (BM) significantly affect the prognosis as well as the quality of life of breast cancer (BC) patients. Although advancements in neurosurgical and radiotherapy techniques improve local control and symptom management, BM remains associated with a poor prognosis. In addition, the efficacy of currently approved systemic therapies in central nervous system (CNS) compartment is still limited, especially after progression on local therapy. The blood-brain barrier (BBB) has been recognized as a mechanism of primary resistance to many chemotherapeutic agents and targeted therapies due to low drug penetration. Other mechanisms of primary and secondary resistance are still unclear and may vary across the BC subtypes. New small molecules have demonstrated efficacy in BM, in particular for the HER2-positive subtype, with a benefit in survival. A new era has begun in the field of BM, and many trials specifically designed for this population are currently ongoing. The BC research community needs to address this call with the final aim of improving the efficacy of systemic therapy in CNS compartment and ultimately preventing the occurrence of BM.

Local and systemic therapy in breast cancer patients with central nervous system metastases.

PURPOSE: As survival of patients with central nervous system (CNS) metastases from breast cancer is poor and incidence rates are increasing, there is a growing need for better treatment strategies. In the current study, the efficacy of local and systemic therapies was analyzed in breast cancer patients with CNS metastases. METHODS: Medical records from breast cancer patients with brain and/or leptomeningeal metastases (LM) treated at a tertiary referral center and a teaching hospital between 2010 and 2020 were retrospectively studied. Main outcomes of interest were overall survival (OS) and CNS progression free survival. Analyses were performed among patients with brain metastases (BM) and patients with LM, for the different systemic and local therapies for CNS metastases, and for subgroups based on breast cancer subtypes. RESULTS: We identified 155 patients, 97 with BM and 58 with LM. Median OS was 15.9 months for patients with BM and 1.5 months for patients with LM. Median OS was significantly longer for HER2-positive patients with BM (22.8 months) vs triple negative (8.4 months) and hormone receptor positive/HER2-negative (5.9 months) (P < 0.001). Patients with BM receiving both local and systemic therapy also had a longer median OS (21.8 months), compared to the other three subgroups (local therapy only: 9.9 months, systemic therapy only: 4.3 months, no therapy: 0.5 months, P < 0.001). No significant difference in OS was observed between different systemic treatment regimens. CONCLUSION: Breast cancer patients with BM show longest median OS when the subtype is HER2-positive and when they are treated with both local and systemic therapy.

Intracranial efficacy of alectinib in ALK-positive NSCLC patients with CNS metastases-a multicenter retrospective study.

BACKGROUND: Central nervous system (CNS) metastases in patients with ALK-positive non-small cell lung cancer (NSCLC) are a cause of substantial morbidity and mortality. Although alectinib had demonstrated promising intracranial efficacy in several clinical trials, data were limited on its CNS activity in real-world settings. METHODS: In this retrospective study, ALK-positive NSCLC patients with brain metastases (BM) or leptomeningeal metastases (LM) from six hospitals in China were divided into three cohorts based on the treatment history before the administration of alectinib. ALK-TKI-naive patients were enrolled in cohort 1, cohort 2 included patients who experienced intracranial progression with or without extracranial progression after treatment with crizotinib, and cohort 3 included patients who developed progression only in CNS following treatment with other second-generation ALK-TKIs. The definition and evaluation of intracranial and extracranial lesions were based on Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Sixty-five patients were eligible and included in our study (cohort 1: 20, cohort 2: 32, cohort 3: 13). For the overall population and patients with uncontrolled CNS metastases, similar intracranial response in CNS target lesions was observed: cohort 1: 81.8% and 80%; cohort 2: 76.5% and 86.7%; cohort 3: 42.8% and 33.3%. For patients in these three cohorts, 75% (6/8), 78.6% (11/14), and 83.3% (5/6) were reported to have significant improvement in CNS-related symptoms respectively. The number of patients who were in need of mannitol or corticosteroids decreased remarkably after the treatment of alectinib (p < 0.001), and there was also a steep fall-over in the number of patients with ECOG ≥2 points before and after the administration of alectinib (p = 0.003). All patients (8/8) diagnosed with LM ± BM experienced substantial alleviation in CNS-related symptoms. In cohort 1 and cohort 2, no significant difference in CNS-time to progression was found between patients with symptomatic or asymptomatic BM when treated with alectinib alone. CONCLUSIONS: Our study substantiated the potent CNS activity of alectinib in real-world settings. Patients with symptomatic and asymptomatic BM could benefit from alectinib comparatively, which indicated that alectinib alone might defer the timing of local treatment. However, our results should be treated cautiously owing to limited sample size.

Advances in the Management of Central Nervous System Metastases from Breast Cancer.

Central nervous system (CNS) metastases are common in breast cancer (BC) patients and are particularly relevant as new treatments for BC are prolonging survival. Here, we review advances in the treatment of CNS metastases from BC, including radiotherapy, systemic therapies, and the evolving role of immunotherapy. The use of radiotherapy and chemotherapy is the cornerstone of treatment for CNS metastases. However, new targeted therapies have recently been developed, including anti-HER2 agents and antibody-drug conjugates that have presented promising results for the treatment of these patients.

Clear cell sarcoma of the kidney in Austrian children: Long-term survival after relapse.

INTRODUCTION: Clear cell sarcoma of the kidney (CCSK) is a rare malignant childhood renal tumour. Recently, the central nervous system (CNS) was found to be the most frequent site of relapse associated with a poor outcome. Optimal treatment strategies are scarce. PATIENTS AND METHODS: Retrospective data analysis of all Austrian children with CCSK. They were enrolled in the Austrian-Hungarian Wilms Tumour Study (AHWTS) 1989, the SIOP93-01 or the SIOP2001 study between 1990 and 2019. Demographic, diagnostic, treatment-related variables and survival data were analysed. RESULTS: We identified 12 children with CCSK (M = 7, F = 5; median age 1.6 years). All had localised disease (stage I: 2; stage II: 2; stage III: 8) at diagnosis, and a first complete remission (CR1) was achieved in 12/12. Six patients are in an ongoing CR1 (median follow-up 10 years). Six other patients had a relapse (local 1; brain 5) a median time of 2.4 years from diagnosis. Two patients died of the disease 4 months and 2.8 years after first relapse. Four of five patients with CNS relapse are in CR2 with a median follow-up time of 9.3 years after relapse diagnosis. Relapse treatment included a combination of chemotherapy, radiation and surgery. Two children received high-dose chemotherapy followed by autologous stem cell rescue, and one child received intrathecal mafosphamide. Long-term side effects after treatment were impaired tubular renal function (n = 4), cardiomyopathy (n = 1) and growth disorders (n = 1). CONCLUSIONS: In this series, the brain was the most common site of relapse. Long-term survival after recurrence was achievable with intensive multimodal therapy.

Economic burden of central nervous system metastases in human epidermal growth factor receptor 2-positive breast cancer.

Aim: Compare healthcare resource utilization and costs among patients with HER2+ metastatic breast cancer (MBC) with and without central nervous system (CNS) metastases. Methods: Retrospective matched cohort study using IQVIA's PharMetrics® Plus claims database. Results: Patients with CNS metastases (n = 753) experienced more outpatient, emergency room and inpatient visits versus controls (n = 753; all p < 0.05). In the post-index year, median total all-cause healthcare costs were significantly higher among patients with CNS metastases versus controls ($112,402 vs $50,835; p < 0.0001); outpatient costs primarily drove the cost differential. Conclusion: More effective therapies are needed that improve clinical outcomes and reduce economic burden associated with CNS metastases in patients with HER2+ MBC.

Development of central nervous system metastases as a first site of metastatic disease in breast cancer patients treated in the neoadjuvant trials GeparQuinto and GeparSixto.

BACKGROUND: The incidence of central nervous system (CNS) metastases in breast cancer patients is rising and has become a major clinical challenge. Only few data are published concerning risk factors for the development of CNS metastases as a first site of metastatic disease in breast cancer patients. Moreover, the incidence of CNS metastases after modern neoadjuvant treatment is not clear. METHODS: We analyzed clinical factors associated with the occurrence of CNS metastases as the first site of metastatic disease in breast cancer patients after neoadjuvant treatment in the trials GeparQuinto and GeparSixto (n = 3160) where patients received targeted treatment in addition to taxane and anthracycline-based chemotherapy. RESULTS: After a median follow-up of 61 months, 108 (3%) of a total of 3160 patients developed CNS metastases as the first site of recurrence and 411 (13%) patients had metastatic disease outside the CNS. Thirty-six patients (1%) developed both CNS metastases and other distant metastases as the first site of metastatic disease. Regarding subtypes of the primary tumor, 1% of luminal A-like (11/954), 2% of luminal B-like (7/381), 4% of HER2-positive (34/809), and 6% of triple-negative patients (56/1008) developed CNS metastases as the first site of metastatic disease. In multivariate analysis, risk factors for the development of CNS metastases were larger tumor size (cT3-4; HR 1.63, 95% CI 1.08-2.46, p = 0.021), node-positive disease (HR 2.57, 95% CI 1.64-4.04, p < 0.001), no pCR after neoadjuvant chemotherapy (HR 2.29, 95% CI 1.32-3.97, p = 0.003), and HER2-positive (HR 3.80, 95% CI 1.89-7.64, p < 0.001) or triple-negative subtype (HR 6.38, 95% CI 3.28-12.44, p < 0.001). CONCLUSIONS: Especially patients with HER2-positive and triple-negative tumors are at risk of developing CNS metastases despite effective systemic treatment. A better understanding of the underlying mechanisms is required in order to develop potential preventive strategies.

The Current and Evolving Role of Radiation Therapy for Central Nervous System Metastases from Breast Cancer.

PURPOSE OF REVIEW: For patients with breast cancer who develop brain metastases, radiation therapy (RT) provides local control. Here, we review the current role for central nervous system RT, particularly focusing on the evolving role for stereotactic radiosurgery (SRS). RECENT FINDINGS: SRS treats only known CNS disease as opposed to whole-brain radiation therapy (WBRT), which treats the entire brain parenchyma. SRS has been found to cause less neurocognitive decline than WBRT. SRS is currently utilized in patients with four or fewer brain metastases, but several ongoing trials are examining the use of SRS for greater than four metastases. For patients requiring WBRT, hippocampal avoidance WBRT and memantine concurrent with and adjuvant to WBRT have been found to reduce the risk of neurocognitive decline. Both SRS and WBRT are used as a local therapy for brain metastases. SRS is increasingly preferred given fewer long-term neurocognitive side effects.

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Central Nervous System Metastases from Non-Small Cell Lung Cancer.

Central nervous system (CNS) metastases are a common complication in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), resulting in a poor prognosis and limited treatment options. Treatment of CNS metastases requires a multidisciplinary approach, and the optimal treatment options and sequence of therapies are yet to be established. Many systemic therapies have poor efficacy in the CNS due to the challenges of crossing the blood-brain barrier (BBB), creating a major unmet need for the development of agents with good BBB-penetrating biopharmaceutical properties. Although the CNS penetration of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) is generally low, EGFR-TKI treatment has been shown to delay time to CNS progression in patients with CNS metastases from EGFR-mutated disease. However, a major challenge with EGFR-TKI treatment for patients with NSCLC is the development of acquired resistance, which occurs in most patients treated with a first-line EGFR-TKI. Novel EGFR-TKIs, such as osimertinib, have been specifically designed to address the challenges of acquired resistance and poor BBB permeability and have demonstrated efficacy in the CNS. A rational, iterative drug development process to design agents that could penetrate the BBB could prevent morbidity and mortality associated with CNS disease progression. To ensure a consistent approach to evaluating CNS efficacy, special consideration also needs to be given to clinical trial endpoints. IMPLICATIONS FOR PRACTICE: Historically, treatment options for patients who develop central nervous system (CNS) metastases have been limited and associated with poor outcomes. The development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has improved outcomes for patients with EGFR-mutated disease, and emerging data have demonstrated the ability of these drugs to cross the blood-brain barrier and elicit significant intracranial responses. Recent studies have indicated a role for next-generation EGFR-TKIs, such as osimertinib, in the treatment of CNS metastases. In the context of an evolving treatment paradigm, treatment should be individualized to the patient and requires a multidisciplinary approach.

The brigatinib experience: a new generation of therapy for ALK-positive non-small-cell lung cancer.

Lung cancer remains the leading cause of cancer deaths in the world with 1.69 million deaths in 2015. A total of 85% of lung cancer cases are non-small-cell lung cancers (NSCLCs). Driver mutations associated with anaplastic lymphoma kinase (ALK) have been identified in a variety of malignancies, including NSCLC. An ALK inhibitor (crizotinib, ceritinib and alectinib) is the preferred therapeutic approach to those advanced ALK fusion variant-positive NSCLC patients. Brigatinib, a next-generation ALK inhibitor, shows promising activity in ALK-rearranged NSCLC that have previously received crizotinib with response rates in ALTA ranging from 42-50%, intracranial response 42-67% and median progression-free survival 9.2-12.9 months. Randomized Phase III trial, ALTA-1 L is investigating brigatinib in ALK inhibitor-naive patients.

Spectrum of metastatic neoplasms of the brain: A clinicopathological study in a tertiary care cancer centre.

BACKGROUND: While brain metastases (BM) are the most common causes of neurologic disorders in patients with known systemic malignancies, they can often be the initial manifestations of an undetected primary elsewhere. BM are major causes of morbidity and mortality in cancer patients. AIMS: We describe a mixed population (data from both retrospective and prospective collection) having a BM from a solid tumor. We report the percentage distribution of the most frequent types of BM, confirming the data published in the literature. This paper may play a role in presenting the Southeast Asian reality compared with the Western countries. SETTING: A tertiary-care cancer centre. MATERIALS AND METHODS: Data for 4 years were retrieved from the records of the Department of Pathology of our institute. Hematolymphoid and meningeal tumors were excluded. Hematoxylin and eosin (H and E) stained slides were reviewed, and in cases with an unknown primary, immunohistochemistry (IHC) was advised. The panel of markers was chosen based on the histomorphology on H and E sections. IHC was done in cases with an unknown primary where paraffin blocks were available. RESULTS: Lung cancer was found to be the most common primary malignancy (n = 30; 48.4%) followed by breast cancer (n = 13; 21%), colorectal cancer (n = 6; 9.6%), and skin cancer (melanoma) [n = 3; 4.8%]. CONCLUSION: The incidence of BM from lung and breast cancer was similar to that seen in the Western studies. However, BM from colorectal cancer and melanoma show a higher and lower incidence, respectively, in comparison with the Western literature.

Osimertinib readministration for central nervous system metastases in non-small cell lung cancer positive for EGFR activating mutations.

BACKGROUND: Osimertinib shows pronounced efficacy for EGFR mutation-positive non-small cell lung cancer (NSCLC) including associated central nervous system (CNS) metastases. Tumors inevitably develop resistance to the drug, however. Osimertinib is sometimes readministered after completion of standard chemotherapy. To clarify which patients might receive benefit from osimertinib readministration, we have retrospectively assessed its efficacy with a focus on CNS metastases. METHODS: A retrospective analysis of medical records was performed for 21 patients who underwent osimertinib readministration at Kyushu University Hospital between March 2016 and April 2023. CNS metastases were evaluated according to modified Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Among the 21 enrolled patients, 16 individuals had target lesions on the basis of RECIST. One (6.3%) of these 16 patients achieved a partial response to osimertinib readministration, with the remaining 15 patients showing stable or progressive disease. The median overall progression-free survival (PFS) and median overall survival for all 21 patients were 3.8 and 13.9 months, respectively. The efficacy of osimertinib readministration for CNS metastases was evaluable in eight patients including five individuals with leptomeningeal metastases. The objective response rate for CNS metastases and the improvement rate for leptomeningeal metastases were both 100%. The median PFS with regard to CNS or non-CNS lesions for these eight patients was 24.7 and 10.5 months, respectively. CONCLUSIONS: Osimertinib readministration showed limited efficacy for non-CNS lesions but excellent efficacy for CNS metastases, suggesting that such treatment is an option for EGFR-mutated NSCLC patients with CNS metastases.

Efficacy and survival outcomes of alectinib vs. crizotinib in ALK­positive NSCLC patients with CNS metastases: A retrospective study.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have transformed the treatment paradigm for patients with ALK-positive non-small cell lung cancer (NSCLC). Yet the differential efficacy between alectinib and crizotinib in treating patients with NSCLC and central nervous system (CNS) metastases has been insufficiently studied. A retrospective analysis was conducted of clinical outcomes of patients with ALK-positive NSCLC and CNS metastases treated at the Shandong Cancer Centre. Based on their initial ALK-TKI treatment, patients were categorised into either the crizotinib group or the alectinib group. Efficacy, progression-free survival (PFS), intracranial PFS and overall survival (OS) were evaluated. A total of 46 eligible patients were enrolled in the present study: 33 patients received crizotinib and 13 patients received alectinib. The median OS of the entire group was 66.8 months (95% CI: 48.5-85.1). Compared with the patients in the crizotinib group, the patients in the alectinib group showed a significant improvement in both median (m)PFS (27.5 vs. 9.5 months; P=0.003) and intracranial mPFS (36.0 vs. 10.8 months; P<0.001). However, there was no significant difference in OS between the alectinib and crizotinib groups (not reached vs. 58.7 months; P=0.149). Furthermore, there were no significant differences between patients receiving TKI combined with radiotherapy (RT) vs. TKI alone with respect to mPFS (11.0 vs. 11.7 months, P=0.863) as well as intracranial mPFS (12.5 vs. 16.9 months, P=0.721). In the present study, alectinib exhibited superior efficacy to crizotinib for treating patients with ALK-positive NSCLC and CNS metastases, especially in terms of delaying disease progression and preventing CNS recurrence. Moreover, the results demonstrated that it might be beneficial to delay local RT for patients with ALK-positive NSCL and CNS metastases.

Latest clinical research in leptomeningeal disease (LMD)-a narrative review.

BACKGROUND AND OBJECTIVE: Leptomeningeal disease (LMD) is associated with poor survival and health-related quality of life (HRQoL). There is an urgent need for clinical research in this area to improve the outcomes. The purpose of this study is to summarize the areas of active clinical research in LMD, identify the knowledge gap, and suggest future research directions. METHODS: A narrative review of clinical trials in LMD was conducted based on a search in clinicatrials.gov using the search term "leptomeningeal" under "condition or disease". Clinical trials in patients with LMD arising from solid malignancy that were labelled as "not yet recruiting", "recruiting", "enrolling by invitation" or "active, not recruiting" were included. Studies which were deemed to have significant impact on future research direction in LMD were selected for discussion. KEY CONTENT AND FINDINGS: A total of 38 clinical trials were included. Of these 38 trials, 19 are discussed in this review, with focus on their research questions and impact on future research directions. Most of the studies that were not selected for discussion focused on biomarker-driven interventions. Four key areas of research were identified, namely the (I) diagnosis, response assessment or molecular profiling of LMD (n=2); (II) advances in radiotherapy (n=3); (III) intrathecal treatment (n=13); (IV) novel drug carrier for systemic treatment (n=1). The research questions in the 19 discussed clinical trials included the tumour microenvironment of LMD, the role of novel molecular techniques in LMD, combination of radiotherapy with drugs, and cell-based immunotherapy. Among these 19 studies, 11 were phase 1 trials, 3 were phase 2 or phase 1/2 trials, 2 were phase 3 or phase 2/3 trials and the study phase was not reported in the remaining 3 studies. The existing knowledge gaps are discussed, including the lack of primary site-specific prognostic tools, cost-effectiveness studies, dedicated HRQoL assessment tools for LMD and sequencing of treatment. CONCLUSIONS: The current clinical trials in LMD offer the promise to improve the diagnosis and treatment outcomes of patients with LMD. More research is needed to overcome the potential hurdles in the current treatment and bridge the knowledge gaps as identified in this review, to improve patients' quantity and quality of survival.

Leptomeningeal Metastases: New Opportunities in the Modern Era.

Leptomeningeal metastases arise from cancer cell entry into the subarachnoid space, inflicting significant neurologic morbidity and mortality across a wide range of malignancies. The modern era of cancer therapeutics has seen an explosion of molecular-targeting agents and immune-mediated strategies for patients with breast, lung, and melanoma malignancies, with meaningful extracranial disease control and improvement in patient survival. However, the clinical efficacy of these agents in those with leptomeningeal metastases remains understudied, due to the relative rarity of this patient population, the investigational challenges associated with studying this dynamic disease state, and brisk disease pace. Nevertheless, retrospective studies, post hoc analyses, and small prospective trials in the last two decades provide a glimmer of hope for patients with leptomeningeal metastases, suggesting that several cancer-directed strategies are not only active in the intrathecal space but also improve survival against historical odds. The continued development of clinical trials devoted to patients with leptomeningeal metastases is critical to establish robust efficacy outcomes in this patient population, define drug pharmacokinetics in the intrathecal space, and uncover new avenues for treatment in the face of leptomeningeal therapeutic resistance.

Genomic Alterations Identification and Resistance Mechanisms Exploration of NSCLC With Central Nervous System Metastases Using Liquid Biopsy of Cerebrospinal Fluid: A Real-World Study.

Background: Genomic profiling of cerebrospinal fluid (CSF) can be used to detect actionable mutations and guide clinical treatment of non-small cell lung cancer (NSCLC) patients with central nervous system (CNS) metastases. Examining the performance of CSF samples in real-world settings can confirm the potential of CSF genotyping for guiding therapy in clinical practice. Patients and Methods: We included 1,396 samples from 970 NSCLC patients with CNS metastases in real-world settings. All samples underwent targeted next-generation sequencing of 1,021 cancer-relevant genes. In total, 100 CSF samples from 77 patients who had previously received targeted treatment were retrospectively analyzed to explore the mechanisms of TKI-resistance. Results: For NSCLC patients with CNS metastases, CSF samples were slightly more often used for genomic sequencing in treated patients with only distant CNS metastases compared to other patients (10.96% vs. 0.81-9.61%). Alteration rates in CSF samples were significantly higher than those in plasma, especially for copy number variants (CNV). The MSAFs of CSF samples were significantly higher than those of plasma and tumor tissues (all p <0.001). Remarkably, detection rates of all actionable mutations and EGFR in CSF were higher than those in plasma samples of treated patients (all p <0.0001). For concordance between paired CSF and plasma samples that were simultaneously tested, the MSAF of the CSF was significantly higher than that of matched plasma cfDNA (p <0.001). From multiple comparisons, it can be seen that CSF better detects alterations compared to plasma, especially CNV and structural variant (SV) alterations. CSF cfDNA in identifying mutations can confer the reason for the limited efficacy of EGFR-TKIs for 56 patients (78.87%, 56/71). Conclusions: This real-world large cohort study confirmed that CSF had higher sensitivity than plasma in identifying actionable mutations and showed high potential in exploring underlying resistance mechanisms. CSF can be used in genomics profiling to facilitate the broad exploration of potential resistance mechanisms for NSCLC patients with CNS metastases.

Risk factors of extraneural spreading in astrocytomas and oligodendrogliomas in donors with gliomas: A systematic review.

BACKGROUND: Patients with a history of primary brain tumors can be eligible for organ donation under extended criteria. The risk assessment of tumor transmission via organ transplant in primary brain tumors is primarily based on the assessment of tumor histotype and grade. Previous surgeries, chemo-/radiotherapy, and ventriculo-peritoneal shunt placement can lead to a disruption of the blood-brain barrier, concurring to an increase in the transmission risk. AIM: To investigate the role of tumor transmission risk factors in donors with oligodendrogliomas and astrocytomas. METHODS: We searched PubMed and EMBASE databases for studies reporting extraneural spreading of oligodendrogliomas and astrocytomas and extracted clinical-pathological data on the primary tumor histotype and grade, the elapsed time from the diagnosis to the onset of metastases, sites and number of metastases, prior surgeries, prior radiotherapy and/or chemotherapy, ventriculo-atrial or ventriculo-peritoneal shunt placement, and the presence of isocitrate dehydrogenase 1/2 mutation and 1p/19q codeletion. Statistical analysis was performed using R software. Statistical correlation between chemotherapy or radiotherapy and the presence of multiple extra-central nervous system metastases was analyzed using χ 2 and Fischer exact test. The Kaplan-Meier method was used to evaluate the presence of a correlation between the metastasis-free time and: (1) Localization of metastases; (2) The occurrence of intracranial recurrences; and (3) The occurrence of multiple metastases. RESULTS: Data on a total of 157 patients were retrieved. The time from the initial diagnosis to metastatic spread ranged from 0 to 325 mo in patients with oligodendrogliomas and 0 to 267 mo in those with astrocytomas. Respectively, 19% and 39% of patients with oligodendroglioma and astrocytoma did not receive any adjuvant therapy. The most frequent metastatic sites were bone, bone marrow, and lymph nodes. The lungs and the liver were the most commonly involved visceral sites. There was no significant correlation between the occurrence of multiple metastases and the administration of adjuvant chemo-/radiotherapy. Patients who developed intracranial recurrences/metastases had a significantly longer extraneural metastasis-free time compared to those who developed extraneural metastases in the absence of any intra- central nervous system spread. CONCLUSION: A long follow-up time does not exclude the presence of extraneural metastases. Therefore, targeted imaging of bones and cervical lymph nodes may improve safety in the management of these donors.

Novel approaches to the management of patients with 5-15 brain metastases: a narrative review.

BACKGROUND AND OBJECTIVE: The management of metastatic disease has been greatly influenced by molecular-based tumor classification and associated therapeutic targets, leading to a significant improvement in survival in many cases. This improvement, in both progression free survival and overall survival, has led to an increased incidence of brain metastases (BM) in a population with systemically well controlled disease or patients with promising therapeutic options available. Within this review, we discuss the paradigm of treatment for 5 to 15 BM, and how the treatment has evolved away from short-term palliation towards providing long term intracranial control. METHODS: A review of literature pertaining to treatment of multiple BM was performed. We searched in PubMed to identify literature on treatment of multiple brain metastases. Only English literature published until February 1st, 2022 was reviewed. KEY CONTENT AND FINDINGS: The management of 5-15 BM include multi-modality treatment pathways that are tailored towards each individual's primary cancer and burden of disease. Surgical resection of a dominant metastasis is still reserved for large symptomatic lesions, and is combined with post-operative local disease control. Overall, there is a shift away from whole brain radiation therapy (WBRT) due to side effect profile towards stereotactic radiosurgery (SRS). However, advances in WBRT continue to be studied, as well as the use of immunotherapy, targetable mutations, and synergistic effects between SRS and targeted therapies. CONCLUSIONS: The use of SRS to treat 5 to 15 BM is an increasingly acceptable and well-regarded practice, along with a combinatorial approach taking into account systemic options during all treatment timepoints.

Intracranial complete response for non-small-cell lung cancer patient with negative PD-L1 expression of the lung using nivolumab.

BACKGROUND: Nivolumab has shown promising results against non-small-cell lung cancer (NSCLC). However, its efficacy to treat central nervous system (CNS) metastases, specifically among programmed cell death 1 ligand 1 (PD-L1)-negative patients, remains unclear. CASE: A 66-year-old woman was diagnosed with adenocarcinoma stage II and underwent a left lower lobectomy. The histopathological evaluation revealed stage IVA with pleural dissemination. The patient did not harbor an epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement, and PD-L1 expression of the surgical specimen using 22C3 assay was 0%. Single brain metastasis was detected, and carboplatin and nab-paclitaxel were administered. After three cycles, asymptomatic multiple brain metastases were identified, and the patient was treated with nivolumab as second-line chemotherapy. Six months later, MRI revealed an intracranial complete response (CR). Nivolumab was discontinued after 23 cycles due to immune-related adverse events (irAEs) of grade 2 rash. However, its effects were sustained for 13 months after discontinuation. We were unable to evaluate the PD-L1 expression of brain metastases, which may show heterogeneity. CONCLUSION: This case demonstrates that nivolumab effectively treated a patient with negative PD-L1 expression of the lung harboring CNS metastases.