extra-CNS Disease Research Articles

Vitreoretinal lymphoma: the importance of cerebral spinal fluid evaluation at initial diagnosis

Background/aimsTo determine if patients with vitreoretinal lymphoma (VRL) and concomitant central nervous system lymphoma (CNSL) may present without brain MRI findings, but possess cerebrospinal fluid (CSF) suspicious for lymphoma.MethodsThis was...

Incidence and Predictors for Oncologic Etiologies in Chinese Children with Pituitary Stalk Thickening.

With the increasing use of magnetic resonance imaging (MRI) in the evaluation of children with endocrine disorders, pituitary stalk thickening (PST) poses a clinical conundrum due to the potential for underlying neoplasms and challenges in obtaining a tissue biopsy. The existing literature suggests Langerhans cell histiocytosis (LCH) to be the commonest (16%) oncologic cause for PST, followed by germ cell tumors (GCTs, 13%) (CCLG 2021). As the cancer epidemiology varies according to ethnicity, we present herein the incidence and predictors for oncologic etiologies in Hong Kong Chinese children with PST. Based on a territory-wide electronic database, we reviewed patients aged < 19 years who presented to three referral centers with endocrinopathies between 2010 and 2022. Records for patients who underwent at least one MRI brain/pituitary were examined (n = 1670): those with PST (stalk thickness ≥ 3 mm) were included, while patients with pre-existing cancer, other CNS and extra-CNS disease foci that were diagnostic of the underlying condition were excluded. Twenty-eight patients (M:F = 10:18) were identified. The median age at diagnosis of PST was 10.9 years (range: 3.8-16.5), with central diabetes insipidus (CDI) and growth hormone deficiency (GHD) being the most frequent presenting endocrine disorders. At a median follow-up of 4.8 years, oncologic diagnoses were made in 14 patients (50%), including 13 GCTs (46%; germinoma = 11, non-germinoma = 2) and one LCH (4%). Among patients with GCTs, 10 were diagnosed based on histology, two by abnormal tumor markers and one by a combination of histology and tumor markers. Three patients with germinoma were initially misdiagnosed as hypophysitis/LCH. The cumulative incidence of oncologic diagnoses was significantly higher in boys and patients with PST at presentation ≥6.5 mm, CDI or ≥2 pituitary hormone deficiencies at presentation and evolving hypopituitarism (all p < 0.05 by log-rank). A higher rate of GCTs was observed in Chinese children with endocrinopathy and isolated PST. The predictors identified in this study may guide healthcare providers in Asia in clinical decision making. Serial measurement of tumor markers is essential in management.

Utility of circulating tumor DNA in monitoring treatment response to immune checkpoint inhibitors in patients with advanced genitourinary cancers.

721 Background: Current methodologies for monitoring treatment response are largely based on conventional scans and/or tumor biopsies, which may be limited in their ability to accurately assess disease burden at the molecular level. Circulating tumor DNA (ctDNA) detection in blood has emerged as a prognostic and predictive biomarker and has shown to better assess treatment response in patients receiving immune checkpoint inhibitors (ICI). We conducted a prospective, pilot study to investigate the concordance of serial ctDNA detection and dynamics with radiographic response in patients with advanced GU malignancies undergoing ICI-based treatment. Methods: Twenty patients with histologically confirmed advanced GU malignancies (renal, urothelial, and prostate) were enrolled in the prospective study. All eligible patients received ICI treatment for at least 12 weeks and were followed by serial collection of blood samples every 6-8 weeks until disease progression. Conventional scans were performed approximately every 12 weeks until disease progression. Overall response rate (ORR) by investigator was reported and associated with ctDNA detection. Results: ctDNA analysis was performed on 122 plasma samples obtained from 20 patients (N=15 renal cell carcinoma; N=4 urothelial carcinoma; N=1 prostate cancer). Prior therapies to ICI-based treatment included chemotherapy (10%), hormonal therapy (5%) and anti-VEGF (5%). After study enrollment, patients received anti-PD-1 (95%), anti-CTLA-4 (30%) or anti-PD-L1 (5%) with an ORR of 70% as best response. With a median follow-up of 19 months (range: 4-48), progressive disease was observed in 7 patients. Nineteen patients had longitudinal plasma samples available and ctDNA detection at any time point was 45% (9/20). The overall concordance between ctDNA dynamics and radiographic response at 12 weeks was observed in 89% (17/19) of patients. Of these 17 concordant patients, one patient showed transient ctDNA positivity followed by clearance at the last two timepoints on treatment. The two patients with discordant results included the ones with CNS-only metastasis (ctDNA negative). Of the 7 patients who progressed on ICI, ctDNA was detected in five (71%); the remaining two had CNS-only metastases. The last patient had a single time point available on treatment that showed ctDNA-positivity and passed away 7 weeks after molecular evidence of disease. Conclusions: In this study, serial collection of blood samples for ctDNA analysis to monitor response to ICI-based therapiesin patients with advanced GU tumors was feasible. There was a high concordance rate between radiological imaging and ctDNA data, especially in extra-CNS disease. Further studies are needed to validate ctDNA as a tool to aid disease monitoring in patients treated with ICI.

Demyelinating Syndromes in Systemic Lupus Erythematosus: Data From the "Attikon" Lupus Cohort.

BackgroundThe demyelinating syndromes of the central nervous system (CNS) that occur in the context of systemic lupus erythematosus (SLE) may represent a manifestation of neuropsychiatric lupus (NPSLE) or an overlap of SLE and multiple sclerosis (MS). The differential diagnosis between the two entities has important clinical implications because the therapeutic management differs.ObjectivesTo characterize CNS demyelinating syndromes in a large SLE cohort as neuropsychiatric SLE (NPSLE) or SLE-MS overlap using a multidisciplinary approach and existing diagnostic (for MS) and classification criteria (for SLE).MethodsPatients from the “Attikon” lupus cohort (n = 707) were evaluated for demyelinating syndromes. Clinical, laboratory, and neuroimaging data were recorded for each patient. Following multidisciplinary evaluation and application of criteria, the demyelinating syndrome was attributed to either SLE or MS. Patients with transverse myelitis were not included in this study.ResultsWe identified 26 patients with demyelinating syndromes (3.7%). Of them, 12 were diagnosed as primary SLE-demyelination (46.2%) and 14 as overlap SLE-MS (53.8%). The two groups did not differ with respect to rheumatologic and neurologic manifestations or autoantibodies. SLE patients with demyelination manifested mild extra-CNS disease mainly involving joints and skin, while severe non-CNS manifestations were rare. However, these patients were less likely to have elevated IgG index (OR 0.055 95% CI: 0.008–0.40) and positive oligoclonal bands (OR 0.09 95% CI: 0.014–0.56), as well as brain lesions in the spinal cord, infratentorial, periventricular, and juxtacortical regions. A single brain region was affected in 9 patients with SLE-demyelination (75%), while all patients with MS-SLE had multiple affected brain regions. MS-SLE overlap was associated with an increased likelihood of neurologic relapses (OR 18.2, 95% CI: 1.76–188), while SLE-demyelination patients were less likely to exhibit neurological deficits (EDSS >0) at the last follow-up visit (50 vs. 78.6% in SLE-MS, respectively).ConclusionsDemyelination in the context of SLE follows a more benign course compared to a frank SLE-MS overlap. Extension of follow-up will ascertain whether patients with SLE-demyelination evolve to MS, or this is a bona fide NPSLE syndrome.

Systemic chemotherapy in patients with brain only metastatic breast cancer: A retrospective analysis.

1093 Background: The treatment of patients with brain only metastatic breast cancer (BO-MBC) remains very challenging. There is also very limited literature informing on appropriate treatment or natural history of this entity. Systemic chemotherapy in addition to targeted therapy and/or anti-estrogen treatment is often used, but little is known if it adds to the overall or disease free survival. In this retrospective study, we examine this, as well as other factors which may be associated with increased risk of CNS or systemic recurrence in these patients. Methods: A database search at a single institution identified 178 patients with brain metastases (BM) from breast cancer out of which 45 patients had BO-MBC between 2007-2020. We collected demographic, clinical, radiographic and other treatment data. Leptomeningeal disease (LMD) was diagnosed by cerebrospinal fluid (CSF) cytology, neuroimaging, or both. We used the Brookmeyer and Crowley method. Results: The patients were followed for a median of 17.9 months; 36 out of 45 patients (80%) received local treatment for BM (surgery/radiation/both) and HER2 directed antibodies or tyrosine kinase inhibitors and/or anti-estrogen treatment, whereas 9 out of 45 patients (20%) received systemic chemotherapy in addition. There were 22 out of 45 (49%) HER2 +, 5 out of 45 (11%) HR + and 18 out of 45 (40%) triple negative breast cancer (TNBC) patients. There were 17 out of 45 patients (38%) who were deemed to have low burden of BM (defined as one to three BM and largest being ≤3 cm) whereas there were 24 out of 45 patients (53%) who had high burden of BM (defined as four or more BM or largest being &gt; 3 cm). Conclusions: Patients with BO-MBC represent a distinct entity. Despite having better survival than patients with BM and extra CNS disease these patients have a high risk of developing LMD, CNS and systemic recurrences. The addition of chemotherapy to targeted therapy and/or anti-estrogens does not decrease the rates of systemic or CNS recurrence. The ER+ subset have a lower rate of development of systemic disease, as expected due to their relatively indolent biology. The CNS and systemic recurrence seem to be higher in patients with HER2+ cancers and counterintuitively even in those with low burden of BM; albeit these were statistically insignificant.[Table: see text]

Cemiplimab monotherapy as first-line (1L) treatment of patients with brain metastases from advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥ 50%: EMPOWER-Lung 1 subgroup analysis.

9085 Background: In the Phase 3, EMPOWER-Lung 1 study, cemiplimab monotherapy provided significant survival benefit and an acceptable safety profile vs chemotherapy in patients with advanced NSCLC and PD-L1 ≥50%. EMPOWER-Lung 1 included patients with brain metastases at baseline who are typically underrepresented in clinical trials. Other published exploratory analyses in single-cohort studies suggest benefit from immunotherapy in this patient population. Here, we present subgroup analysis of patients with brain metastasis from EMPOWER-Lung 1. Methods: Patients were randomized 1:1 to cemiplimab 350 mg IV every 3 weeks or investigator’s choice of chemotherapy (NCT03088540). Patients with treated, clinically stable brain metastases (radiological stability not required) were eligible to enroll and are the focus of this subgroup analysis from the PD-L1 ≥50% population (n=563) of the EMPOWER-Lung 1 study. Results: A total of 68 of 563 (12.1%) cases had treated stable brain metastases at time of randomization. Patients were evenly distributed between cemiplimab (n=34) and chemotherapy (n=34), with similar median duration of follow-up (Table). Baseline characteristics were generally similar; median (range) age: 60.0 (45–76 ) vs 62.0 (48–77); male: 97.1% vs 85.3%; and non-squamous histology: 85.3% vs 76.5%; between cemiplimab vs chemotherapy, respectively. Per independent review committee, median overall survival (OS, 18.7 vs 11.7 months), median progression-free survival (PFS, 10.4 vs 5.3 months), and objective response rate (ORR, 41.2% vs 8.8%) were superior with cemiplimab vs chemotherapy (Table). After baseline, central nervous system (CNS) disease progression occurred in 2 (5.9%) patients with cemiplimab vs 4 (11.8%) patients with chemotherapy; extra-CNS disease progression occurred in 9 (26.5%) patients with cemiplimab vs 15 (44.1%) patients with chemotherapy. Conclusions: 1L cemiplimab monotherapy improved OS, PFS, and ORR vs chemotherapy, in patients with advanced NSCLC with PD-L1 ≥50%, and clinically stable brain metastases at baseline. Cemiplimab monotherapy represents a suitable option for this subgroup of patients. Clinical trial information: NCT03088540. [Table: see text]

CTNI-02. TBCRC049: A PHASE II STUDY TO ASSESS THE SAFETY AND EFFICACY OF THE COMBINATION OF TUCATINIB, TRASTUZUMAB AND CAPECITABINE FOR THE TREATMENT OF LEPTOMENINGEAL METASTASIS IN HER2 POSITIVE BR1AST CANCER

Abstract Treatment options for patients with leptomeningeal metastasis (LM) from HER2-positive breast cancer (HER2+ BC) are limited and prognosis is poor. Tucatinib is an oral, potent, HER2 specific tyrosine kinase inhibitor with good tolerability and combinatory anti-tumor activity, including partial responses in heavily treated patients and those with brain metastases (BM). This is a phase 2 single-arm study to evaluate the efficacy of tucatinib, trastuzumab and capecitabine in HER2+ BC with newly-diagnosed LM. CNS disease will be evaluated at screening and every 6 weeks by neuroaxis MRI, CSF cytology, and neurological assessments per RANO-LMD (adapted) and RANO-BM criteria. Extra-CNS disease will be evaluated at screening and every 12 weeks by CT scan per RECIST criteria. All patients will be followed for survival. Symptom burden and quality of life assessments, as well as correlative blood and CSF samples, will be collected. Eligible patients include adults with HER2+ BC, KPS &amp;gt; 50, and newly-diagnosed, untreated LM (defined as positive CSF cytology and/or radiographic evidence of LM, plus clinical signs/symptoms). Patients with treated or concurrent/new BM are allowed. Patients treated with capecitabine within the last 12 months are excluded. This study has a Gehan-like design with an interim futility analysis and overall intent to estimate OS. For the interim analysis, success is defined as CNS PFS for 12 weeks. Enrollment will end if fewer than two successes are observed in the first 15 patients. Secondary endpoints include safety, CNS PFS at 12 weeks, RR in CNS and extra-CNS, and symptom burden/quality of life. The regimen will be considered worthy of future study if the median OS is &amp;gt; 4.4 months. Fourteen of 30 patients have accrued thus far. The study is active at multiple Translational Breast Cancer Research Consortium sites around the country.

Craniospinal irradiation(CSI) in patients with leptomeningeal metastases: risk-benefit-profile and development of a prognostic score for decision making in the palliative setting

BackgroundThe aim of our study was to assess the feasibility and oncologic outcomes in patients treated with spinal (SI) or craniospinal irradiation (CSI) in patients with leptomeningeal metastases (LM) and to suggest a prognostic score as to which patients are most likely to benefit from this treatment.MethodsNineteen patients treated with CSI at our institution were eligible for the study. Demographic data, primary tumor characteristics, outcome and toxicity were assessed retrospectively. The extent of extra-CNS disease was defined by staging CT-scans before the initiation of CSI. Based on outcome parameters a prognostic score was developed for stratification based on patient performance status and tumor staging.ResultsMedian follow-up and overall survival (OS) for the whole group was 3.4 months (range 0.5–61.5 months). The median overall survival (OS) for patients with LM from breast cancer was 4.7 months and from NSCLC 3.3 months. The median OS was 7.3 months, 3.3 months and 1.5 months for patients with 0, 1 and 2 risk factors according to the proposed prognostic score (KPS < 70 and the presence of extra-CNS disease) respectively. Nonhematologic toxicities were mild.ConclusionCSI demonstrated clinically meaningful survival that is comparable to the reported outcome of intrathecal chemotherapy. A simple scoring system could be used to better select patients for treatment with CSI in this palliative setting. In our opinion, the feasibility of performing CSI with modern radiotherapy techniques with better sparing of healthy tissue gives a further rationale for its use also in the palliative setting.

Enteroviral and herpes simplex virus central nervous system infections in infants

BackgroundThe relative contribution of viruses to central nervous system (CNS) infections in young infants is not clear. For viral CNS infections, there are limited data on features that suggest HSV etiology or on predictors of unfavorable outcome.MethodsIn this cross-sectional retrospective study, seven centers from the Pediatric Investigators Collaborative Network on Infections in Canada identified infants < 90 days of age with CNS infection proven to be due to enterovirus (EV) or herpes simplex virus (HSV) January 1, 2013 through December 31, 2014.ResultsOf 174 CNS infections with a proven etiology, EV accounted for 103 (59%) and HSV for 7 (4%). All HSV cases and 41 (40%) EV cases presented before 21 days of age. Four HSV cases (57%) and 5 EV cases (5%) had seizures. Three (43%) HSV and 23 (23%) EV cases lacked cerebrospinal fluid (CSF) pleocytosis. HSV cases were more likely to require ICU admission (p = 0.010), present with seizures (p = 0.031) and have extra-CNS disease (p < 0.001). Unfavorable outcome occurred in 12 cases (11% of all EV and HSV infections) but was more likely following HSV than EV infection (4 (57%) versus 8 (8%); p = 0.002).ConclusionsViruses accounted for approximately two-thirds of proven CNS infections in the first 90 days of life. Empiric therapy for HSV should be considered in suspected CNS infections in the first 21 days even in the absence of CSF pleocytosis unless CSF parameters are suggestive of bacterial meningitis. Neurodevelopmental follow-up should be considered in infants whose course of illness is complicated by seizures.

Abstract OT2-01-02: TBCRC049: A phase II non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab and capecitabine for treatment of leptomeningeal metastases in HER2 positive breast cancer TBCRC049: A phase II non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab and capecitabine for treatment of leptomeningeal metastases in

Abstract Background: Treatment options for patients with leptomeningeal disease (LMD) from HER2-positive breast cancer (HER2+ BC) are limited, and the prognosis is poor. Tucatinib is an oral, potent, HER2 specific tyrosine kinase inhibitor with good tolerability and notable early combinatory anti-tumor activity, including partial responses in heavily treated patients and those with parenchymal brain metastases (BM). Trial Design: This is a phase 2 single arm study to evaluate the efficacy of the combination of tucatinib plus trastuzumab (T) and capecitabine(C) in patients with HER2+ BC and newly diagnosed LMD. CNS disease will be evaluated at screening and every six weeks by MRI, CSF cytology, and neurological assessments according to RANO-LMD (adapted) and RANO-BM criteria. CT scans/PET-CT will evaluate extracranial disease according to RECIST criteria at screening and every 12 weeks. All patients will be followed for survival from the date of the last dose until death, lost to follow-up, or consent withdrawal. Symptom burden and quality of life assessments are conducted throughout the study. Blood and CSF sample collections occur at each cycle for the planned correlative analyses. Eligibility Criteria: Eligible patients are adults (&amp;gt;18 years old) with HER2+ BC, ECOG status&amp;lt;3/KPS&amp;gt;50, and newly diagnosed untreated LMD (defined as positive CSF cytology and/or radiographic evidence of LMD, plus clinical signs/symptoms. Patients with a history of treated BM or concurrent/new BM are allowed. Patients previously treated with tucatinib or capecitabine (within the last 12 months) are excluded. Specific Aims: The primary endpoint is OS. Secondary endpoints include safety, CNS PFS at 12 weeks, RR and CBR in CNS and extra-CNS disease, and symptom burden/quality of life. Statistical methods: This study has a Gehan-like design with an interim futility analysis and overall intent to estimate OS. For the interim analysis, we define success to be CNS PFS for 12 weeks. An event will be considered to be either CNS progression or death from any cause before 12 weeks.We will stop enrollment if there are fewer than two successes in the first 15 patients. If the trial continues to completion, the regimen will be considered worthy of future study if the median overall survival is &amp;gt; 4.4 months. Study Accrual: The target accrual is 30 patients. The study is currently active at UAB and MDACC. Other TBCRC sites throughout the country are to be activated this year. Citation Format: Rashmi K Murthy, Barbara J O'Brien, Ken R Hess, Nick Navin, Jason Johnson, Maria Gule-Monroe, Jose P Leone, Jennifer Specht, Michelle Melisko, Aki Morikawa, Anna M Storniolo, Adam Brufsky, Paula R Pohlmann, Deric M Park, Ben H Park, Ian Krop, Nancy U Lin, Antonio Wolff, Andres Forerro-Torres, Erica Stringer-Reasor. TBCRC049: A phase II non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab and capecitabine for treatment of leptomeningeal metastases in HER2 positive breast cancer TBCRC049: A phase II non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab and capecitabine for treatment of leptomeningeal metastases in HER2 positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-01-02.

Circulating Tumor DNA Analysis for Patients with Oncogene-Addicted NSCLC With Isolated Central Nervous System Progression.

In patients with oncogene-addicted NSCLC and isolated central nervous system progression (iCNS), tissue biopsy is challenging, and the clinical utility of plasma liquid biopsy (i.e., circulating tumor DNA [ctDNA]) is unknown. Patients with advanced NSCLC with known baseline genomic alteration (GA) (EGFR, ALK, BRAF, KRAS, HER2, ROS1, MET, PIK3CA, STK11, TP53) on tissue were divided into three groups on the basis of their disease progression pattern: iCNS, extra-CNS only (noCNS), or both (cCNS). All patients with available plasma ctDNA were included and were analyzed by next-generation sequencing InVisionFirst-Lung. ctDNA was considered positive if at least one GA was detected. Cell-free tumor DNA was analyzed in cerebrospinal fluid when available. Out of 517 patients screened, 247 were included: 54 had iCNS, 99 had noCNS, and 94 had cCNS progressive disease (64, 128, and 110 ctDNA samples, respectively). CtDNA was positive in 52% iCNS versus 84% in noCNS and 92% in cCNS (p < 0.00001), with lower detection of driver (37% versus 77% and 73%, respectively) and resistance alterations (6% versus 45% and 44%). Patients with iCNS and positive ctDNA were more at risk of extra-CNS progression (32% versus 7%, p= 0.026). In 12 patients with iCNS, ctDNA was positive in six (50%) plasma and in 10 (83%) paired cerebrospinal fluid (p= 0.193). Although tagged amplicon-based next-generation sequencing has high detection rates of GA in plasma ctDNA in patients with NSCLC with extra-CNS disease, detection rate of GAs (52%) is lower in the subset of patients with iCNS disease. Complementary tests such as cerebrospinal fluid cell-free DNA may be useful. Further evidence would be beneficial to understand the genomic landscape in patients with NSCLC and iCNS.

Sequential Matrix-RICE Therapy Followed By Autologous Stem Cell Transplant in Patients with Diffuse Large B-Cell Lymphoma and Secondary Central Nervous System Involvement: The International Extranodal Lymphoma Study Group-42 Phase II (MARIETTA) Trial

Sequential Matrix-RICE Therapy Followed By Autologous Stem Cell Transplant in Patients with Diffuse Large B-Cell Lymphoma and Secondary Central Nervous System Involvement: The International Extranodal Lymphoma Study Group-42 Phase II (MARIETTA) Trial

LPTO-08. INTRATHECAL TRASTUZUMAB PLUS/MINUS IT TOPOTECAN FOR PATIENTS WITH HER2+ BREAST CANCER AND LEPTOMENINGEAL METASTASIS

BACKGROUND: Leptomeningeal metastasis (LM) is an aggressive complication of cancer. No standard therapies exist, although at our institution we commonly use IT topotecan in good-risk patients. We report our experience in patients with HER2+ breast cancer (BC) LM treated with intrathecal (IT) trastuzumab +/- IT topotecan. METHODS: We retrospectively reviewed records of patients managed with IT trastuzumab at MD Anderson Cancer Center from 2016–2019. Demographics, clinical course, and outcomes data (Kaplan-Meier) were collected and analyzed. RESULTS: 14 female patients (median age 49, range 33–67) with HER2+ BC (29% hormone receptor (HR) positive, 71% negative) were treated with IT trastuzumab (titrated to 40 mg -100 mg/week); 8 (57%) received concurrent IT topotecan. LM diagnosis was made in 64% by MRI alone, and 36% by both MRI and CSF cytology; 79% had brain metastases (BM), and of those, 55% (6/11) had active BM at LM diagnosis; 57% received WBRT prior to initiation of IT therapy. Median KPS was 90 (range, 60–100). Of those with initially positive cytology, 50% (4/8) converted to negative during treatment. MRI findings improved in 79%; 79% were symptomatic at diagnosis (most commonly ataxia, cranial neuropathy, headache); 70% (7/10) had symptom improvement on IT therapy. The only IT-associated symptom reported was mild nausea that occurred in 29%. Median time from diagnosis of metastatic BC was 10.7 mos. (range 0–83 mos); 36% had active extra-CNS disease and 86% received concurrent systemic therapy; 57% underwent change in systemic therapy during IT treatment; 91% were progression-free at 6 months, 32% at 24 months. Median overall survival from LM diagnosis was 24.7 months (95% CI 10.7, NR). CONCLUSIONS: IT trastuzumab is a safe and promising therapy for patients with HER2+ BC and LM. Dual IT therapy with trastuzumab and topotecan was well-tolerated and warrants further investigation in a larger study.

2342. Treatment Implications of Herpes Simplex Virus Central Nervous System Infection in Canadian Infants &lt;90 Days Old: A Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) Study

BackgroundIn the pre-acyclovir era, HSV CNS infection was associated with very high morbidity and mortality. Since antiviral drugs recommended for therapy and long-term prophylaxis improve outcomes, clinicians need to be able to clinically detect young infants most likely to have HSV to facilitate early initiation of therapy. Limited data exist on outcomes of infants who require prolonged therapy and those completing prophylaxis. The objective of this study was to identify clinical and laboratory features associated with HSV CNS disease and describe outcomes following antiviral therapy and prophylaxis.MethodsInfants <90 days old with a discharge diagnosis of meningitis or encephalitis from whom a virus was identified from cerebrospinal fluid (CSF) were included. These were identified using PICNICs retrospective database of microbiologically confirmed CNS infections detected January 2013 to December 2014. Clinical features and outcomes of HSV and non-HSV infection were compared.ResultsOf the 112 cases of viral infections, HSV accounted for 8 (7%) and enterovirus for 103 (92%). Eight (100%) HSV cases and 45 (43%) non-HSV cases presented at <21 days. Four (50%) HSV cases had no pleocytosis. HSV cases were more likely to require ICU admission (P = 0.016), present with seizures (P < 0.001) and have extra-CNS disease (P < 0.001). Among infants <3 weeks of age, seizures were more likely in HSV than non-HSV cases (4 (50%) vs. 4 (8%); P = 0.013). All HSV cases received acyclovir for a median of 23 days. Two (25%) remained PCR-positive at 21 days; these were treated for 51 and 42 days, respectively, until PCR negative or death (acyclovir resistance was confirmed postmortem). Four infants received suppressive acyclovir until 6 months, one of whom developed virologically proven CNS recurrence and subsequent infantile spasms. Neurodevelopmental morbidity (4 (57%) vs. 7 (7%)) was more likely in HSV than non-HSV (P = 0.003).ConclusionHigh levels of suspicion for viral infections must be maintained for young infants presenting with seizures in the first 3 weeks of life. CSF pleocytosis may often be absent. Resistance testing should be considered if PCR remains positive beyond 21 days. CNS recurrences may still occur beyond the recommended period of prophylaxis.Disclosures All authors: No reported disclosures.

Abstract P1-17-04: Clinical presentation and outcome of leptomeningeal metastasis in patients with breast cancer in relation to histology and tumor subtypes

Abstract Background: Among solid tumors, breast cancer (BC) is one of the most common cause of leptomeningeal metastases. Leptomeningeal disease (LMD) typically carries a devastating prognosis; however, disease presentation and prognostic factors are still uncertain. The aim of this study was to characterize clinical features of LMD in relation to BC histology and subtypes. Patients and Methods:104 patients (pts) with LMD from BC diagnosed between 2002 and 2017 at two European institutions were included. LMD diagnosis was based on the presence of neoplastic cells on cerebrospinal fluid examination and/or radiological evidence of LMD. Patients' characteristics and their associations with time from LMD to death or last follow up were evaluated by the Kaplan-Meier method, log-rank tests, and Cox proportional hazard models. Results: Median age at LMD diagnosis was 56 yrs (range 26-75). Tumor histology (n=102) was ductal in 72 pts (70.6%), lobular in 22 (21.6%) and other histology in 8 (7.8%, including mixed ductal and lobular tumors). Tumor phenotype distribution was as follows: hormone receptor (HR)+/HER2- 54.8%, triple-negative (TN) 14.4%, HR+/HER2+ 12.5%, HR-/HER2+ 6.7% and unknown 11.5%. LMD diagnosis was cytologically proven (n=64, 62.7%) and/or radiologically proven (n=88, 85.4%). At time of LMD diagnosis, 63 pts (58.9%) had an ECOG performance status (PS) ≤ 2. 91 pts (87.5%) had extra-CNS disease localizations and 20 (18.7%) had a history of known BC brain metastasis (BM) (predating LMD diagnosis of more than 30 days). In lobular BC, LMD diagnosis was more frequently made in the absence of a known history of BM compared with ductal BC (95.5% vs 73.3%, Fisher test p=0.036). A majority of pts was treated with intrathecal (n=59, 55.1%) or systemic treatment (n=73, 68.2%) after LMD diagnosis, while only a minority underwent radiotherapy (n=28, 26.2%) or surgical derivation procedures (n=14, 13%). Median overall survival (OS) from LMD diagnosis was 3.2 months (95% CI, 1.9-4.4 months). No significant difference was observed across tumor phenotypes, with HER2+ subgroups experiencing better outcomes (median OS: 2.9, 1.6, 6.6 and 12.9 months in HR+HER2-, TN, HR+HER2+ and HR-HER2+ subgroups; p=0.54). In univariate analysis, ECOG PS ≤ 2 at LMD diagnosis, intrathecal treatment and systemic treatment after LDM diagnosis were significantly associated with an improved OS (see table). Multivariate analysis showed that only ECOG PS ≤ 2 and systemic treatment after LMD diagnosis were independent factors associated with OS (see table). Updated results on an extended cohort of about 150 patients total will be presented at the meeting. UnivariateMultivariatePrognostic factorsMedian OS in months (95%CI)HR (95%CI)pHR (95%CI)pECOG PS 0-25.9 (2.1-9.7)0.43 (0.27-0.66)0.0010.64 (0.4-1.0)0.06≥31.7 (1.2-2.3)ref ref Intrathecal treatment Yes5.3 (1.9-8.7)0.65 (0.43-0.98)0.0370.89 (0.57-1.38)0.6No1.9 (0.5-3.3)ref ref Systemic treatment Yes7.3 (4.7-9.8)0.13 (0.08-0.22)&amp;lt;0.0010.16 (0.09-0.29)&amp;lt;0.001No1.0 (0.6-1.3)ref ref Conclusions: LMD carries a dismal prognosis. The results of this series highlight that patient-related features and treatments (in particular the use of systemic treatment) contribute to modulate the prognosis of BC pts with LMD. Citation Format: Griguolo G, Pouderoux S, Dieci MV, Jacot W, Bourgier C, Miglietta F, Firmin N, Conte P, Viala M, Guarneri V, Darlix A. Clinical presentation and outcome of leptomeningeal metastasis in patients with breast cancer in relation to histology and tumor subtypes [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 P1-17-04.

Genotyping tumour DNA in cerebrospinal fluid and plasma of a HER2-positive breast cancer patient with brain metastases

BackgroundCentral nervous system (CNS) involvement contributes to significant morbidity and mortality in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) and represents a major challenge for clinicians. Liquid biopsy of cerebrospinal fluid (CSF)-derived circulating tumour DNA (ctDNA) harbours clinically relevant genomic alterations in patients with CNS metastases and could be effective in tracking tumour evolution.MethodsIn a HER2-positive mBC patient with brain metastases, we applied droplet digital PCR (ddPCR) and next-generation whole exome sequencing (WES) analysis to measure ctDNA dynamic changes in CSF and plasma collected during treatment.ResultsBaseline CSF-derived ctDNA analysis revealed TP53 and PIK3CA mutations as well as ERBB2 and cMYC amplification. Post-treatment ctDNA analysis showed decreased markers level in plasma, consistent with extra-CNS disease control, while increased in the CSF, confirming poor treatment benefit in the CNS.DiscussionAnalysis of ctDNA in the CSF of HER2-positive mBC is feasible and could represent a useful companion for clinical management of brain metastases.

Afatinib alone or afatinib plus vinorelbine versus investigator's choice of treatment for HER2-positive breast cancer with progressive brain metastases after trastuzumab, lapatinib, or both (LUX-Breast 3): a randomised, open-label, multicentre, phase 2 trial

Patients with advanced HER2-positive breast cancer frequently develop CNS metastases. The metastases that progress after brain radiotherapy and HER2-targeted systemic therapy are a difficult therapeutic challenge. We aimed to assess the efficacy and safety of afatinib, an irreversible blocker of the ErbB protein family, alone or combined with vinorelbine, compared with treatment of the investigator's choice in women with HER2-positive breast cancer with progressive brain metastases during or after treatment with trastuzumab, lapatinib, or both. We did this randomised, open-label, multicentre, phase 2 trial in 40 hospitals in Canada, Finland, France, Germany, Italy, Spain, South Korea, and the USA. Women older than 18 years with histologically confirmed HER2-overexpressing breast cancer and CNS recurrence or progression as determined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) during or after treatment with trastuzumab, lapatinib, or both, were eligible. We randomly assigned patients (1:1:1) centrally to afatinib 40 mg orally once per day, afatinib 40 mg per day plus intravenous vinorelbine 25 mg/m(2) once per week, or investigator's choice of treatment in cycles of 3 weeks until disease progression, patient withdrawal, or unacceptable toxicity. Treatment assignment was not masked for clinicians or patients, but the trial team was masked until database lock to reduce bias. The primary endpoint, assessed in the intention-to-treat population, was patient benefit at 12 weeks, defined by an absence of CNS or extra-CNS disease progression, no tumour-related worsening of neurological signs or symptoms, and no increase in corticosteroid dose. Safety was assessed in all patients who received at least one dose of a study drug. This completed trial is registered with ClinicalTrials.gov, number NCT01441596. Between Dec 22, 2011, and Feb 12, 2013, we screened 132 patients, of whom 121 were eligible and randomly assigned to treatment: 40 to afatinib alone, 38 to afatinib plus vinorelbine, and 43 to investigator's choice. All patients discontinued study treatment before the data collection cutoff on Oct 16, 2014. Patient benefit was achieved in 12 (30·0%; 95% CI 16·6-46·5) patients given afatinib alone (difference vs investigator's choice: -11·9% [95% CI -32·9 to 9·7], p=0·37), 13 (34·2%; 19·6-51·4) given afatinib plus vinorelbine (difference vs investigator's choice: -7·6% [-28·9 to 14·2], p=0·63), and 18 (41·9%; 27·0-57·9) given investigator's choice. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (seven [18%] of 40 patients in the afatinib only group vs nine [24%] of 37 patients in the afatinib plus vinorelbine group vs two [5%] of 42 patients in the investigator's choice group) and neutropenia (none vs 14 [38%] vs four [10%]). Patient benefit with afatinib-containing treatments was not different from that in patients given investigator's choice of treatments; however, adverse events were frequent and afatinib-containing treatments seemed to be less well tolerated. No further development of afatinib for HER2-positive breast cancer is currently planned. Boehringer Ingelheim.

Abstract P5-19-07: Randomized Phase II trial of afatinib alone or with vinorelbine versus investigator's choice of treatment in patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and/or lapatinib-based therapy: LUX-Breast 3

Abstract Background: Over one-third of patients (pts) with HER2-positive (+) advanced breast cancer (BC) develop brain metastases (BM), which often leads to short survival. Afatinib (A), an irreversible ErbB family blocker, demonstrated activity in pts with heavily pretreated, HER2+ metastatic BC (MBC) progressing after trastuzumab (T) therapy, with partial responses (PR) in 10% and clinical benefit in 46% of pts (Lin 2012a). We evaluated the activity of A alone or in combination with vinorelbine (V), versus investigator’s choice of therapy for MBC (IC), in pts with HER2+ BC with BM after prior T and/or lapatinib (L) therapy. Methods: Eligible pts had at least one measurable and progressive lesion in the central nervous system (CNS; ≥10 mm on magnetic resonance imaging) after prior systemic and/or radiation therapy. Pts were randomized to receive A (40 mg/day oral), AV (40 mg/day oral + 25 mg/m2/week i.v.) or IC in 3-week cycles. Stratification factors were: ECOG performance status (PS, 0–1 vs 2), number of BM (≤3 vs &amp;gt;3) and prior exposure to L (yes/no). The primary endpoint was pt benefit at 12 weeks (i.e. absence of CNS and extra-CNS disease progression per RECIST 1.1, and no tumor-related worsening of neurological signs/symptoms or increase in steroid dosage). Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) in CNS/extra-CNS lesions, and safety. Results: 121 pts were randomized (2 were not treated): median age, 53 years; ECOG PS 0–1, 83%; &amp;gt;3 BM, 59%; prior L therapy, 78.5%. The IC treatment consisted of: T+ chemotherapy (CT) (22 pts); T+L+CT (3 pts); L+CT (10 pts); L alone (1 pt); or CT alone (6 pts). Results for efficacy endpoints are shown (Table). A (n=40)AV1 (n=38)IC1 (n=43)Pt benefit rates at 12 weeks, n (%)12 (30)13 (34)18 (42)Median PFS, weeks11.912.318.4Median OS, weeks57.737.352.1ORR (PR), n (%): CNS lesions03 (8)6 (14)Extra CNS lesions03 (8)2 (5)Disease control, n (%): CNS lesions27(68)27 (71)31 (72)Non CNS lesions17 (43)19 (50)26 (61)1One pt randomized but not treated In the treated set (n=119), the most frequent treatment-related adverse events (AEs) in the A and AV arms were diarrhea (90% and 84%) and rash (38% and 54%); neutropenia (51%) was also common in the AV arm. Diarrhea (33%), neutropenia (21%) and asthenia (21%) were the most frequent related AEs in the IC arm. Grade (G) 3/4 treatment-related AEs were observed in 50%/3% (A), 57%/24% (AV; G4 AEs were mainly neutropenias) and 14%/7% (IC) of pts; there were no treatment-related G5 events. Conclusions: Approximately one third of pts with HER2+ MBC benefited from the assigned treatments and two thirds had CNS lesions controlled per RECIST in each group. Objective response in CNS was infrequent (0 to 14%) with all treatments. Overall, AEs were manageable in this heavily pretreated pt population. aLin et al. Breast Cancer Res Treat 2012;133:1057–1065. Citation Format: Javier Cortés, Veronique Dieras, Jungsil Ro, Jérôme Barriere, Thomas Bachelot, Sara Hurvitz, Emilie Le Rhun, Marc Espie, Sung-Bae Kim, Andreas Schneeweiss, Joo Hyuk Sohn, Jean-Marc Nabholtz, Pirkko-Liisa Kellokumpu-Lehtinen, Julie Taguchi, Federico Piacentini, Eva Ciruelos, Petri Bono, Mahmoud Ould-Kaci, Flavien Roux, Heikki Joensuu. Randomized Phase II trial of afatinib alone or with vinorelbine versus investigator's choice of treatment in patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and/or lapatinib-based therapy: LUX-Breast 3 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-07.

Outcomes of gamma knife radiosurgery, bi-modality & tri-modality treatment regimens for patients with one or multiple brain metastases: the Columbia University Medical Center experience.

Optimal treatment of brain metastases (BMs) is debatable. However, surgery or gamma knife radiosurgery (GKRS) improves survival when combined with whole brain radiotherapy (WBRT) versus WBRT alone. We retrospectively reviewed an institutional database of patients treated with GKRS for BMs from 1998 to 2013 to explore effects of single or multi-modality therapies on survival. There were 528 patients with median age 62 years. Histologies included 257 lung, 102 breast, 62 melanoma, 40 renal cell, 29 gastrointestinal, and 38 other primary cancers. Treatments included: 206 GKRS alone, 111 GKRS plus WBRT, 109 GKRS plus neurosurgical resection (NSG), and 102 all three modalities. Median overall survival (mOS) was 16.6 months. mOS among patients with one versus multiple metastasis was 17.2 versus 16.0 months respectively (p = 0.825). For patients with one BM, mOS following GKRS alone, GKRS plus WBRT, GKRS plus NSG, and all three modalities was 9.0, 19.1, 25.5, and 25.0 months, respectively, and for patients with multiple BMs, mOS was 8.6, 20.4, 20.7, 24.5 months for the respective groups. Among all patients, multivariate analysis confirmed that tri-modality group had the longest survival (HR 0.467; 95 % CI 0.350-0.623; p < 0.001) compared to GKRS alone; however, this was not significantly different than bi-modality approaches. Uncontrolled primary extra-CNS disease, age and KPS were also independent predictors of survival. Patients treated with GKRS plus NSG, GKRS plus WBRT, or all three modalities had improved OS versus GKRS alone. In our analysis, resection and GKRS allowed avoidance of WBRT without shortening survival.

High Doses of Antimetabolites Followed By High-Dose Sequential Chemoimmunotherapy and Autologous Stem Cell Transplant in Patients with Systemic B-Cell Lymphoma and Secondary Central Nervous System Involvement: Final Results of a Multicenter Phase II Trial

Abstract INTRODUCTION: Secondary central nervous system (CNS) dissemination is a lethal event in patients (pts) with aggressive lymphomas. A few studies focused on the treatment of this condition are available, confirming the dismal prognosis and the high rate of severe neurotoxicity in pts managed with radiotherapy-based induction. Thus, the most effective treatment for secondary CNS lymphoma remains an important, unmet clinical need. Herein, we report the final results of a multicenter phase II trial addressing a new treatment in pts with aggressive B-cell lymphoma and CNS involvement (NCT00801216). Experimental treatment is based on the encouraging experiences with high doses of antimetabolites in pts with primary CNS lymphoma (Ferreri et al. Lancet 2009), and with high-dose sequential chemotherapy combined with rituximab (R-HDS) and supported by autologous stem cell transplant (ASCT) in pts with relapsed aggressive B-cell lymphoma (Tarella et al. JCO 2008). METHODS: Selection criteria were: 1) histological diagnosis of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma blastoid variant (MCLb) or grade-3 follicular lymphoma (FL); 2) secondary CNS involvement at diagnosis or relapse; 3) age 18-70 years; 4) ECOG PS ≤3; 5) absence of HIV infection; 6) adequate organ functions. Pts with primary CNS lymphoma (exclusive CNS disease at diagnosis) were excluded. Experimental treatment consisted of an induction phase with 2 courses of methotrexate 3.5 g/m2 d1 + cytarabine 2 g/m2 x2/d d2-3, followed by an intensification phase with R-HDS (cyclophosphamide 7 g/m2 d1; cytarabine 2 g/m2 x2/d d22-25; pts with residual extra-CNS disease received also etoposide 2 g/m2 d43) and a consolidation phase with BCNU-thiotepa conditioning + ASCT (figure). Treatment included 8 doses of rituximab and 4 of intrathecal liposomal cytarabine. The primary endpoint was 2-year PFS; the planned accrual was 38 pts. RESULTS: 39 pts were registered (age 32-70 ys, median 59; M/F ratio 1.5): 33 had DLBCL, 3 MCLb, 3 FL. CNS disease (brain 21, meninges 5, spinal cord 2, multiple 11) was detected at diagnosis in 16 pts (all with extra-CNS disease) and at relapse in 23 (8 with extra-CNS disease). The median TTP from the previous treatment line was 3 months (range 0-77 months). Thirty-four pts completed the induction phase; 73 (93%) of 78 planned courses were actually delivered; G4 neutropenia, thrombocytopenia and anemia were recorded in 77%, 63% and 5% of courses, G3-4 febrile neutropenia in 16%, CMV reactivation in 3 pts. Transient G4 transaminases increase (3% of courses) was the only G4 non-hematological toxicity. Drugs dose reduction was indicated in 3 pts. Response after induction phase was complete in 11 pts and partial in 19 (ORR= 77%; 95%CI=64-90%). Thirty pts were referred to intensification phase (figure); 58 (97%) of 60 planned courses were actually delivered; G4 neutropenia, thrombocytopenia and anemia were recorded in 67%, 60% and 7% of courses, G3-4 febrile neutropenia in 22%, G4 sepsis in 8%. CMV reactivation was diagnosed in 4 pts, pulmonary aspergillosis in 1. No cases of G4 extra-hematological toxicity were recorded. Response after intensification phase (before conditioning) was complete in 22 pts and partial in 2 (ORR= 62%; 95%CI=47-77%). ASCs were collected in 21/22 (95%) pts (median 9.5 x 106/kg; range 6-19); 20 pts underwent ASCT. Response at the end of the whole program was complete in 23 pts and partial in 1 (ORR= 62%, 95%CI= 47-77%), 1 pt had SD, 10 experienced PD (all in the CNS), and 4 died of toxicity (sepsis 2, stroke, acute tracheal obstruction). Importantly, no pt was irradiated to the brain to achieve lymphoma remission, and no evidence of neurotoxicity was recorded in pts with a survival longer than 3 years. One pt was referred to sibling-donor transplant due to sMDS, and is alive and NED at 91 months of follow-up. At a median follow-up of 42 months, 16 pts remain relapse-free, with a 2-yr PFS of 42±8%. Sixteen pts are alive, with a 2-yr OS of 42±8%; 2-yr OS of transplanted pts was 72±11%. Extra-CNS and/or meningeal disease did not affect outcome, and survival was similar in both pts treated at presentation or at relapse. CONCLUSION: This radiotherapy-free combination of high doses of antimetabolites, R-HDS and ASCT is feasible and effective in pts ≤70 ys with secondary CNS lymphoma. Toxicity is usually haematological and manageable. Survival benefit is attainable also in pts with meningeal and/or concomitant extra-CNS disease. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.