Leptomeningeal Metastases Research Articles

Abstract PS11-05: Trastuzumab Deruxtecan in patients with HER2[+] or HER2-Low Advanced Breast Cancer and Pathologically Confirmed Leptomeningeal Carcinomatosis: Results from Cohort 5 of the DEBBRAH Study

Abstract Background: Leptomeningeal carcinomatosis (LMC) occurs in approximately 5-15% of patients (pts) with advanced breast cancer (ABC) and is associated with poor survival and a significant reduction in quality of life. The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has shown remarkable intracranial and extracranial activity, leading to its widespread clinical use. DEBBRAH is evaluating the efficacy and safety of T-DXd in pts with HER2[+] and HER2-low ABC with a history of brain metastases (BM) and/or LMC. Here, we report results from cohort 5 that included pts with pathologically confirmed LMC. Methods: DEBBRAH (NCT04420598) is a single-arm, open-label, five-cohort, phase 2 study conducted across 18 sites in Spain and Portugal. A total of 39 pts aged ≥18 years with pretreated HER2[+] or HER2-low ABC with stable, progressing, or untreated BM and/or LMC were enrolled in 5 cohorts: (1) HER2[+] ABC with non-progressing BM after radiotherapy and/or surgery; (2) HER2[+] or HER2-low ABC with asymptomatic untreated BM; (3) HER2[+] ABC with progressing BM after local treatment; (4) HER2-low ABC with progressing BM after local treatment; (5) HER2[+] or HER2-low ABC and LMC with positive cerebrospinal fluid cytology. Pts received 5.4 mg/kg T-DXd intravenously once every 21 days until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint for cohort 5 was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response, clinical benefit rate (CBR) according to RANO-BM (intracranial lesions) and RECIST v.1.1 (extracranial and overall lesions); and safety and tolerability as per NCI-CTCAE v.5.0. OS was tested with the maximum likelihood exponential method (H0: median OS ≤2 months; H1: median OS≥6 months). We estimate that 7 pts are needed to attain an 80% power at the nominal level of one-sided α of 0.05. Results: Between Apr 14, 2021, and Apr 5, 2022, 7 pts were allocated into cohort 5. Median age was 57 (range, 42–69) years, 3 (42.9%) pts were HER2[+], 6 (85.7%) pts had synchronous extracranial metastases, 2 of whom (28.6%) also presented BM, and 3 (42.9%) pts had measurable disease. Median number of previous lines of therapy for advanced disease was 4 (range, 1-8) and no patient received prior local treatment for central nervous system involvement. At data cut-off (Apr 4, 2023), median follow-up was 12 months (range, 2.5-18.6). Median duration of treatment was 9.0 months (range, 2.1-18.6). Two (28.6%) pts remained on treatment: 1 HER2[+] and 1 HER2-low, after 18.6 and 12.0 months, respectively. Median OS rate was 13.3 months (95% CI, 5.7-NA, p< 0.001) meeting the primary endpoint. Among 5 pts with disease progression, none had intracranial progression. A total of 4 (57.1%) pts presented extracranial progression and 1 (14.3%) patient had clinical worsening. No objective responses were observed, but 5 out of 7 pts had prolonged stabilization (≥24 weeks) for an overall CBR of 71.4% (95% CI, 29.0-96.3) and a median PFS of 8.9 months (95% CI, 4.9-NA) according to RECIST v.1.1. The most common non-hematological treatment emergent adverse events (TEAEs) of any grade (G) were nausea (57.1%; 14.3% G3), fatigue (42.9%; 0% G3), vomiting (42.9%; 0% G3), headache (42.9%; 0% G3), and urinary tract infection (42.9%; 0% G3). Anemia (42.9%; 0% G3) and thrombocytopenia (28.6%; 14.3% G3) were the most frequent hematological TEAEs. No cases of interstitial lung disease/pneumonitis were reported. Serious unrelated TEAEs occurred in 4 (57.1%) of 7 pts, and 1 patient experienced a related serious TEAE (nausea G3). No treatment-related deaths were reported. Conclusions: T-DXd showed promising activity with no new safety concerns in HER2[+] and HER2-low pts with previously untreated, pathologically confirmed LMC. These encouraging data warrant further investigation to address the unmet need in this difficult-to-treat condition. Citation Format: Marta Vaz Batista, José Manuel Pérez-García, Laia Garrigós, José Ángel García-Sáenz, Patricia Cortez-Castedo, Fabriccio Racca, Salvador Blanch, Manuel Ruíz - Borrego, Adela Fernández, María Fernández-Abad, Vega Iranzo, Maria Gion, Griselda Martrat, Daniel Alcalá-López, Jhudit Pérez-Escuredo, Miguel Sampayo-Cordero, Antonio Llombart-Cussac, Sofía Braga, Javier Cortés. Trastuzumab Deruxtecan in patients with HER2[+] or HER2-Low Advanced Breast Cancer and Pathologically Confirmed Leptomeningeal Carcinomatosis: Results from Cohort 5 of the DEBBRAH Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS11-05.

Ventriculovesical Shunting in a Patient with Leptomeningeal Carcinomatosis: An Alternative to VP Shunts. A Technique Report

AbstractLeptomeningeal carcinomatosis (LC) is a rare but serious complication when cancer cells infiltrate the meninges. It is most commonly associated with breast cancer, but only 5% of breast cancer patients develop it. Leptomeningeal carcinomatosis typically presents with headaches, mainly due to hydrocephalus, and the diagnosis involves a cytological analysis of cerebrospinal fluid (CSF) and/or magnetic resonance imaging (MRI) scans. The treatment of LC consists of a combination of intra-CSF chemotherapy, systemic therapy, radiation therapy, and/or supportive care, including CSF drainage. In the case herein reported, a technique known as ventriculovesical shunting was performed on a female patient with LC and breast cancer who had hydrocephalus due to this condition. This procedure is not as common as ventriculoperitoneal shunts, which can lead, in this case, to serious complications such as peritoneal carcinomatosis.

Abstract PO5-20-02: Secondary BRain metastases prevention after Isolated intracranial progression on trastuzumab/pertuzumab or T-DM1 in pts with aDvanced human epidermal Growth factor receptor 2+ brEast cancer with addition of Tucatinib (BRIDGET)

Abstract Background: Despite treatment with trastuzumab-based therapy, up to half of patients with HER2+ advanced/metastatic breast cancer (MBC) will develop brain metastases (BrM). First-line therapy for advanced HER2+ MBC remains a taxane, trastuzumab, pertuzumab (TP) which demonstrates poor brain permeability. Isolated brain relapse with stable or absent extracranial disease remains a clinical problem in both the adjuvant (Untch et al., ESMO 2019 Congress) and metastatic settings (Noteware et al., Breast Cancer Res Treat. 2023). Current guidelines recommend continuing current systemic therapy in the setting of first isolated brain relapse following local therapy. Tucatinib, a brain-penetrable HER2-targeting tyrosine kinase inhibitor, when added to trastuzumab and capecitabine improves intracranial progression free survival (PFS) and overall survival (OS) in patients with stable or active HER2+ BrMs. We hypothesize that adding tucatinib to TP or T-DM1 in patients with HER2+ MBC with isolated brain relapse or progression could delay or prevent the development of further intracranial lesions and improve OS. Methods: BRIDGET (NCT05323955) is a single arm, phase II, multicenter study of tucatinib added to TP or T-DM1 after local therapy in patients with isolated brain relapse or progression. A total of 48 patients at 9 U.S. sites as part of the Hoosier Cancer Research Network (HCRN) with metastatic HER2+ breast cancer will be enrolled after 1st or 2nd BrM relapse or progression within 8 weeks of local therapy. Patients must currently be receiving standard of care treatment with TP or T-DM1 in the metastatic setting, or adjuvant trastuzumab-based or T-DM1 therapy with isolated brain recurrence. Extracranial disease must be stable per RECISTv1.1 or absent. Patients may not have leptomeningeal disease or untreated brain lesions over 5 mm. Patients will receive continuous tucatinib added to their current therapy (TP or T-DM1). The primary objective is intracranial PFS compared to a historical control (H0: PFS < 5 months (mos), HA: PFS > 8 mos) of the HER2CLIMB clinical trial where patients could continue on trial with isolated brain progression. In these patients, median time from brain progression to second progression or death was 7.6 mos (95% CI, 3.9 to 11.3 mos) in the tucatinib arm versus 3.1 mos (95% CI, 1.2 to 4.1 mos) in the control arm (Lin et al., J Clin Onc 2020). Secondary endpoints include PFS by RECISTv1.1, PFS of extracranial disease, locally treated versus new distant intracranial metastasis PFS, site of first progression (brain versus non-brain), OS, and toxicity in patients with BrM. Collection of correlative specimens including archival tissue, cerebrospinal fluid (optional), whole blood for ctDNA are planned. Patient-reported outcomes surveyed utilizing the FACT-BR and FACIT-Fatigue questionnaires are also included for future analyses. As of 7/06/23, accrual is 5 patients of the anticipated 48 patients overall, across 5 sites (Duke University, Dana Farber Cancer Institute, Ohio State University, Providence Portland Medical Center, and Washington University in St. Louis) currently open. An additional 4 sites are pending opening. Those interested in this trial can reach out to the study Principal Investigators, Carey Anders, MD (carey.anders@duke.edu) or Sarah Sammons, MD (sarahl_sammons@dfci.harvard.edu). Citation Format: Sarah Sammons, Amanda Van Swearingen, Laura Noteware, Nusayba Bagegni, Kelly Moulton, Stevie Threatt, Denise Jaggers, Shannon Shea, Eric Lipp, Erin Riley, Sin-Ho Jung, Gloria Broadwater, Masey Ross, Kimberly Strickland, Sasha Beyer, Alison Conlin, Aki Morikawa, Rashmi Murthy, Carey Anders. Secondary BRain metastases prevention after Isolated intracranial progression on trastuzumab/pertuzumab or T-DM1 in pts with aDvanced human epidermal Growth factor receptor 2+ brEast cancer with addition of Tucatinib (BRIDGET) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-20-02.

Abstract PO4-20-11: Excellent Response to Trastuzumab Deruxtecan in “HER-2 Low” Leptomeningeal Breast Cancer and Diagnostic and Monitoring Utility of CNSide Assay

Abstract A 72-year-old female presented to the emergency department with sudden onset of imbalance and cognitive decline. Two years ago, she was diagnosed with stage III estrogen receptor (ER) positive, progesterone receptor (PR) negative and human epidermal growth factor receptor 2 (HER2) negative (immunohistochemistry score: 0) invasive breast cancer. She subsequently underwent lumpectomy, adjuvant radiation and chemotherapy. She had been taking adjuvant letrozole at the time of presentation. Magnetic resonance imaging (MRI) of the brain showed obstructive hydrocephalus without any parenchymal lesion or leptomeningeal enhancement. MRI of spine, computerized tomography of chest/abdomen/pelvis and bone scan were unrevealing except a left adrenal mass which was equivocal for metastasis. Cerebrospinal fluid (CSF) analysis showed rare malignant cells. Based on the morphology of malignant cells and the patient’s prior history of breast cancer, the diagnosis of leptomeningeal disease with breast primary was made. There were insufficient cells for additional studies. CNSide, a microfluidic platform that uses antibody capture method to detect CSF tumor cells, showed 4678 tumor cells per milliliter (ml) of CSF. Immunocytochemistry of these cells showed that the cells were ER negative (criterion: < 2.6% ER positive cells) and programmed cell death ligand 1 (PD-L1) negative (criterion: < 3.4% PD-L1 positive cells). Fluorescence in situ hybridization (FISH) testing showed 22% of tumor cells with HER2 amplification (either HER2 to CEP17 ratio >/= 2.0 or HER2 copy number >/= 6). She underwent ventriculoperitoneal (VP) shunt placement with complete recovery of her neurological symptoms. Five weeks later, she was started on trastuzumab deruxtecan (T-DXd) mainly because of the HER2 FISH results from CNSide. She did not receive central nervous system(CNS) irradiation due to complete resolution of neurological symptoms with VP shunt placement. After two cycles of T-DXd, MRI brain showed mild leptomeningeal enhancement along bilateral superior cerebellar sulci. Positron emission tomography/computed tomography(PET/CT) scan showed a new sclerotic rib focus, thought to represent treatment response. It also showed decrease in size of the adrenal mass. The adrenal mass was hypermetabolic on PET, consistent with malignancy. CSF cytology was negative, while CSF tumor cell count significantly reduced to 6.72 cells/ml using CNSide. There were no new neurological symptoms. Despite MRI brain findings, she was continued on T-DXd given overall favorable clinical, radiological and CSF data. After 7th cycle of T-DXd, repeat CSF cytology continued to remain negative, CNSide CSF tumor cell count decreased further to 6.27 cells/ml, MRI brain showed interval resolution of prior leptomeningeal enhancement, CT scan showed further decrease in size of the adrenal mass (baseline 5.4cm to 3cm), stable rib sclerotic lesion and no additional metastatic lesion. To date, she has undergone eight cycles of T-DXd which has effectively controlled her disease for a period of seven months. She has not needed VP shunt revision and continues to do well. To our knowledge, this is the first case demonstrating the activity of T-DXd against CSF tumor cells where a small subset exhibited HER2 amplification. This case also highlights the benefits of using advanced and highly sensitive CSF assays to diagnose and surveil leptomeningeal disease and to assess HER2 signaling. This case is well-timed especially in the era of next-generation, CNS penetrating, potent HER2-directed antibody-drug conjugate like T-DXd which can mount antitumor activity even with minimal HER2 expression in tumors. Citation Format: Sarah Stanford, Zeni Kharel, Lauryn Hemminger, Tyler Schmidt, Sara Hardy, Jason Zittel, Nimish Mohile, Ajay Dhakal. Excellent Response to Trastuzumab Deruxtecan in “HER-2 Low” Leptomeningeal Breast Cancer and Diagnostic and Monitoring Utility of CNSide Assay [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-20-11.

Abstract PS08-02: Efficacy of Sacituzumab-Govitecan (SG) post Trastuzumab-deruxtecan (T-DXd) and vice versa for HER2low advanced or metastatic breast cancer (MBC): a French multicentre retrospective study

Abstract Background: Based on ASCENT, TROPICS-02 and DESTINY-Breast04 trials, SG and T-DXd recently became approved for HER2low MBC. Since the payloads of both SG and T-DXd belong to the same cytotoxic class (topoisomerase-1 inhibitor), cross-resistance is a potential concern. However, no data is available on the efficacy of one antibody drug conjugate (ADC) after another and the best therapeutic sequence has not been evaluated yet. Methods: We conducted a retrospective study in 19 French comprehensive cancer centres. All patients (pts) with HR+ or HR- and HER2low MBC treated with SG followed, immediately or not, by T-DXd (or vice versa) were included. HR expression was defined on the last available tumor sample. The study primary objective was to report the second ADC (ADC2) progression-free survival (PFS) in the whole population. Secondary objectives included first ADC (ADC1) progression-free interval (PFI) and overall survival (OS) in the whole population and subgroup analyses by HR status. Results: The individual data of 126 eligible women were obtained from 19 participating centres. Median age was 54.5 years (range: 30-80y). N=110 (87.3%) pts had invasive carcinoma of not special type, N=12 (9.5%) invasive lobular carcinoma and 4 (3.2%) other histological subtype. N=87 (69%) and 39 (31%) had HR+/HER2low and HR-/HER2low MBC, respectively. N=16 patients were germline mutation carriers (BRCA1 N=7; BRCA2 N=6; other genes on HBOC panel N=3). ADC1 was given as a median of third (range: 1-10) line of chemotherapy and ADC2 as fifth (range: 2-12) line. A large majority (N=94, 74.6%) of pts received SG as ADC1 (N=82 with HR- and N=12 with HR+ MBC) while N=32 (25.4%) received T-DXd as ADC1 (N=27 with HR+ and n=5 with HR- MBC). 53.2% (N=67) received ADC1 immediately followed by ADC2 while 46.8% (N=59) received ADC2 after 1 (N=40) or 2 (N=12) or ≥ 3 (N=6) other lines of chemotherapy. N=19 (15.07%) and N=26 (20.63%) had a meningeal and/or cerebral metastasis at the time of the initiation of ADC1 and ADC2 respectively. After a median follow-up of 3 months, ADC2 was discontinued in 63 pts of which 51 (82.3%) for progression disease and 4 (6.5%) for toxicity due to T-DXd. Importantly, 50% of pts (N=63) were still under ADC2 at the time of this first analysis. The observed median PFS for ADC2 and median PFI for ADC1 are presented in the Table below: Median OS was not reached independently of the sub-populations of pts. Population and sequential regimen Median (mo) PFI ADC1 Median (mo) PFS ADC2 Whole population (N=126) SG → T-DXd (N=94) T-DXd→SG (N=32) 4.5 (95%CI [3.4-5.1]) 2.7 (95%CI [2.1-3.3] HR-/HER2low (N=82) having received SG as ADC1 then T-DXd as ADC2 4.8 (95%CI [3.8-5.1]) 3.3 (95%CI [2.5-3.7]) HR+/HER2low (n=27) having received T-DXd as ADC1 then SG as ADC2 2.7 (95%CI [2.0-3.2]) 2.0 (95%CI [1.6-NR]) Conclusion: To the best of our knowledge, this is the largest cohort evaluating the efficacy of subsequent ADCs administration in HER2low MBC. In these heavily pre-treated pts, subsequent use of ADCs seem to be associated with shortened PFS in both HR+/HR- subgroups, independently of their administration order. Data will be updated and completed for the meeting. Moreover, the number of eligible pts will be increased. Table 1: median TPP and PFS2 in whole population and HR subgroups Citation Format: François Poumeaud, Mathilde Morisseau, Luc Cabel, Anthony Gonçalves, Charlène Rivier, Olivier Trédan, Elsa Volant, Jean Sebastien FRENEL, Sylvain Ladoire, William Jacot, Mathieu Jamelot, Hervé Fokatichoue, Luis Teixeira, Francois-Clement Bidard, Delphine Loirat, Christelle Levy, Bastien Cabarrou, Antoine Deleuze, Elise Deluche, Thomas Grellety, Frédéric Fiteni, Hervé Bischoff, Roman Vion, Stéphanie Becourt, Thibaut Reverdy, Alexandre de Nonneville, Florence Dalenc. Efficacy of Sacituzumab-Govitecan (SG) post Trastuzumab-deruxtecan (T-DXd) and vice versa for HER2low advanced or metastatic breast cancer (MBC): a French multicentre retrospective study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-02.

Abstract PO1-20-10: Wernicke Encephalopathy Syndrome in Metastatic Breast Cancer – A Diagnostic Dilemma or An Underdiagnosed Entity

Abstract Wernicke encephalopathy (WE) is an acute medical syndrome that manifests as a clinical triad of encephalopathy, gait ataxia, and oculomotor dysfunction, requiring urgent treatment. Early recognition and treatment can prevent severe neurological morbidity and the chronic neurological consequence of WE, known as Korsakoff syndrome. Thiamine (vitamin B1) deficiency is the root cause of WE, which can occur due to several underlying conditions, including chronic alcoholism, hyperemesis of pregnancy, malnutrition, prolonged fasting, and malignancy. In cases of malignancy, WE is often undiagnosed or misdiagnosed because the presenting symptoms can be confused with several other complications of malignancy. We present the case of a 47-year-old woman with no significant medical history who was diagnosed with triple negative metastatic breast cancer and admitted to the hospital with confusion, memory loss, and progressive lower extremity weakness. During her breast cancer treatments, she experienced significant nausea and vomiting, leading to a prolonged state of nutritional imbalance. Patient underwent extensive infectious and neurological workup for encephalopathy including lumbar puncture which was negative for leptomeningeal disease or infection. MRI brain did not show any new metastatic lesions however revealed enhancement of mammillary bodies bilaterally. Mammillary body enhancement can be seen in WE but not always present on imaging. She was treated for WE with high dose of thiamine infusion for five days, resulting in an improvement of her neurological symptoms. Diagnosing WE in cancer patients is challenging, as there are various factors to consider, such as cerebral metastasis, infection, chemotherapy treatment, and electrolyte imbalances, that can cause neurological symptoms. Cancer patients are at high risk for development of WE due to chemotherapy or whole brain radiation induced nausea and vomiting that can lead to chronic malnutrition. The typical triad of symptoms is not present in many cases and presenting symptoms can be nonspecific which makes the diagnosis challenging. As a result, WE is often underdiagnosed in such patients, making it essential to educate the physician community about this acute neurological manifestation that can be easily treated. A high index of suspicion is necessary for early recognition, and prompt treatment can prevent Korsakoff syndrome, thereby enhancing the overall quality of life of patients with malignancy. Citation Format: Archit Patel, Arya Mariam Roy, Ronald Alberico, Shipra Gandhi. Wernicke Encephalopathy Syndrome in Metastatic Breast Cancer – A Diagnostic Dilemma or An Underdiagnosed Entity [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-10.

Incidence and outcome of brain and/or leptomeningeal metastases in HER2-low metastatic breast cancer in the French ESME cohort

Breast cancer (BC) is the second most common cancer that metastasizes to the brain. Particularly up to half of patients with human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (mBC) may develop brain metastases over the course of the disease. Nevertheless, little is known about the prevalence and the outcome of brain and leptomeningeal metastases (BLMM) in HER2-low BC. We compared the cumulative incidence of BLMM and associated outcomes among patients with HER2-low, HER2-negative (HER2-) and HER2+ mBC. This cohort study was conducted from the Epidemiological Strategy and Medical Economics (ESME) mBC database and included patients treated for mBC between 2012 and 2020 across 18 French comprehensive cancer centers and with known HER2 and hormone receptor (HR) status. The cumulative incidence of BLMM after metastatic diagnosis was estimated using a competing risk methodology with death defined as a competing event. 19 585 patients were included with 6118 (31.2%), 9943 (50.8%) and 3524 (18.0%) being HER2-low, HER2- and HER2+ mBC, respectively. After a median follow-up of 48.6 months [95% confidence interval (CI) 47.7-49.3 months], BLMM were reported in 4727 patients: 1192 (25.2%) were diagnosed with BLMM at first metastatic diagnosis and 3535 (74.8%) after metastatic diagnosis. Multivariable analysis adjusted for age, histological grade, metastases-free interval and HR status showed that the risk of BLMM at metastatic diagnosis was similar in patients with HER2- compared to HER2-low mBC [odds ratio (OR) (95% CI) 1.00 (0.86-1.17)] and higher in those with HER2+ compared to HER2-low [OR (95% CI) 2.23 (1.87-2.66)]. Similar results were found after metastatic diagnosis; the risk of BLMM was similar in HER2- compared to HER2-low [subdistribution hazard ratio (sHR) (95% CI) 1.07 (0.98-1.16)] and higher in the HER2+ group [sHR (95% CI) 1.56 (1.41-1.73)]. The prevalence and evolution of BLMM in HER2-low mBC are similar to those in patients with HER2- tumors. In contrast to patients with HER2+ mBC, the prognosis of BLMM remains dismal in this population.

Preoperative stereotactic radiosurgery for cerebral metastases: safe, effective, and decreases steroid dependency.

Preoperative stereotactic radiosurgery (SRS) is emerging as a viable alternative to standard postoperative SRS. Studies have suggested that preoperative SRS provides comparable tumor control and overall survival (OS) and may reduce the incidence of leptomeningeal disease (LMD) and adverse radiation effects (AREs). It is unknown, however, if preoperative SRS remains effective in cohorts including large brain metastases (> 14 cm3) or if preoperative SRS affects steroid taper/immunotherapy. Here, the authors report the results of a phase 2 single-arm trial assessing a prospectively acquired series of 26 patients who underwent preoperative SRS, without a volumetric cutoff, compared with a propensity score-matched concurrent cohort of 30 patients who underwent postoperative SRS to address these salient questions. Demographics, oncological history, surgical details, and outcomes were collected from the medical records. Coprimary endpoints were local tumor control (LTC) and a composite outcome of LTC, ARE, and LMD. Additional outcomes were OS, steroid taper details, and immunotherapy resumption. For survival analyses, cohorts were propensity score matched. Preoperative and postoperative SRS patients were comparable in terms of age, sex, Karnofsky Performance Status score, oncological history, and operative details. Gross tumor volume (GTV) was significantly higher in the preoperative group (median 12.2 vs 5.3 cm3, p < 0.001). One-year LTC (preoperative SRS: 77.2% vs postoperative SRS: 82.5%, p = 0.61) and composite outcome (68.3% vs 72.7%, p = 0.38) were not significantly different between the groups. In multivariable analysis, preoperative SRS did not have a significant effect on LTC (HR 1.57 [95% CI 0.38-6.49], p = 0.536) or the composite outcome (HR 1.18 [95% CI 0.38-3.72], p = 0.771), although the confidence intervals were large. The median OS (preoperative SRS: 17.0 vs postoperative SRS: 14.0 months, p = 0.61) was not significantly different. Rates of LMD were nonsignificantly lower in the preoperative SRS group (3.8% vs 16.7%, p = 0.200). Greater GTV volume was associated with prolonged (> 10 days) steroid taper (OR 1.24 [95% CI 1.04-1.55], p = 0.032). However, in multivariable analysis, preoperative SRS markedly reduced the steroid taper length (OR 0.13 [95% CI 0.02-0.61], p = 0.016). Time to immunotherapy was shorter in the preoperative SRS group (36 [IQR 26, 76] vs OR 228 [IQR 129, 436] days, p = 0.02). Compared with postoperative SRS, preoperative SRS is a safe and effective strategy in the management of cerebral metastases of all sizes and provides comparable tumor control without increased adverse effects. Notably, preoperative SRS enabled rapid steroid taper, even in larger tumors. Future studies should specifically examine the interaction of preoperative SRS with steroid usage and resumption of systemic therapies and the subsequent effects on systemic progression and OS.

Discussion of ABC7 Consensus and German Recommendations.

The rationale behind the "International Consensus Conference for Advanced Breast Cancer" (ABC) is to standardize the treatment of patients with advanced or metastatic breast cancer worldwide using an evidence-based approach. The aim is also to ensure that patients in all countries receive adequate treatment based on current treatment recommendations and standards. The 7th International Consensus Conference on Advanced Breast Cancer (ABC7) took place from November 9 to 12, 2023 in Lisbon/Portugal. ABC7 focused on metastatic disease as well as on locally advanced and inflammatory breast cancer. Special topics included the treatment of oligometastatic patients, leptomeningeal disease, treatment of brain metastases, and pregnant women with ABC. As in previous years, patient advocates from all over the world participated in the consensus conference and were involved in decision making.

The importance of CSF neoplastic cell recognition in the diagnosis of leptomeningeal carcinomatosis

The importance of CSF neoplastic cell recognition in the diagnosis of leptomeningeal carcinomatosis

Development and validation of a nomogram to predict leptomeningeal metastases in lung adenocarcinoma: Cervical lymph node metastasis is an important association factor.

The goal of this study was to create a nomogram using routine parameters to predict leptomeningeal metastases (LMs) in advanced lung adenocarcinoma (LAC) patients to prevent needless exams or lumbar punctures and to assist in accurately diagnosing LMs. Two hundred and seventy-three patients with LMs and brain metastases were retrospectively reviewed and divided into derivation (n = 191) and validation (n = 82) cohorts using a 3:7 random allocation. All LAC patients with LMs had positive cerebrospinal fluid cytology results and brain metastases confirmed by magnetic resonance imaging. Binary logistic regression with backward stepwise selection was used to identify significant characteristics. A predictive nomogram based on the logistic model was assessed through receiver operating characteristic curves. The validation cohort and Hosmer-Lemeshow test were used for internal validation of the nomogram. Five clinicopathological parameters, namely, gene mutations, surgery at the primary lung cancer site, clinical symptoms of the head, N stage, and therapeutic strategy, were used as predictors of LMs. The area under the curve was 0.946 (95% CI 0.912-0.979) for the training cohort and 0.861 (95% CI 0.761-0.961) for the internal validation cohort. There was no significant difference in performance between the two cohorts (p = 0.116). In the internal validation, calibration plots revealed that the nomogram predictions were well suited to the actual outcomes. We created a user-friendly nomogram to predict LMs in advanced lung cancer patients, which could help guide treatment decisions and reduce unnecessary lumbar punctures.

Patients with Leptomeningeal Carcinomatosis and Hydrocephalus-Feasibility of Combined Ventriculoperitoneal Shunt and Reservoir Insertion for Intrathecal Chemotherapy.

Therapeutic management of patients with leptomeningeal carcinomatosis (LC) may require treatment of concomitant hydrocephalus (HC) in addition to intrathecal chemotherapy (ITC). Ventriculoperitoneal shunts (VPS) equipped with a valve for manual deactivation of shunt function and a concomitant reservoir for application of ITC pose an elegant solution to both problems. The present study evaluates indication, feasibility, and safety of such a modified shunt/reservoir design (mS/R). All patients with LC aged ≥ 18 years who had undergone mS/R implantation between 2013 and 2020 at the authors' institution were further analyzed. ITC was indicated following the recommendation of the neuro-oncological tumor board and performed according to a standardized protocol. Sixteen patients with LC underwent mS/R implantation for subsequent ITC and concomitant treatment of HC. Regarding HC-related clinical symptoms, 69% of patients preoperatively exhibited lethargy, 38% cognitive impairment, and 38% (additional) visual disturbances. Postoperatively, 86% of patients achieved subjective improvement of HC-related symptoms. Overall, postoperative complications occurred in three patients (19%). No patient encountered cancer treatment-related complications. The present study describes a combination procedure consisting of a standard VPS-system and a standard reservoir for patients suffering from LC and HC. No cancer treatment-related complications occurred, indicating straightforward handling and thus safety.

Phase I trial of dose escalation for preoperative stereotactic radiosurgery for patients with large brain metastases.

Single-session stereotactic radiosurgery (SRS) or surgical resection alone for brain metastases larger than 2 cm results in unsatisfactory local control. We conducted a phase I trial for brain metastases(>2 cm) to determine the safety of preoperative SRS at escalating doses. Radiosurgery dose was escalated at 3 Gy increments for 3 cohorts based on maximum tumor dimension starting at: 18 Gy for >2-3 cm, 15 Gy for >3-4 cm, and 12 Gy for >4-6 cm. Dose-limiting toxicity was defined as grade III or greater acute toxicity. A total of 35 patients/36 lesions were enrolled. For tumor size >2-3 cm, patients were enrolled up to the second dose level (21 Gy); for >3-4 cm and >4-6 cm cohorts the third dose level (21 and 18 Gy, respectively) was reached. There were 2 DLTs in the >3-4 cm arm at 21 Gy. The maximum tolerated dose of SRS for >2-3 cm was not reached; and was 18 Gy for both >3-4 cm arm and >4-6 cm arm. With a median follow-up of 64.0 months, the 6- and 12-month local control rates were 85.9% and 76.6%, respectively. One patient developed grade 3 radiation necrosis at 5 months. The 2-year rate of leptomeningeal disease (LMD) was 0%. Preoperative SRS with dose escalation followed by surgical resection for brain metastases greater than 2 cm in size demonstrates acceptable acute toxicity. The phase II portion of the trial will be conducted at the maximum tolerated SRS doses.

PROTAC EZH2 degrader-1 overcomes the resistance of podophyllotoxin derivatives in refractory small cell lung cancer with leptomeningeal metastasis

BackgroundLeptomeningeal metastasis (LM) of small cell lung cancer (SCLC) is a highly detrimental occurrence associated with severe neurological disorders, lacking effective treatment currently. Proteolysis-targeting chimeric molecules (PROTACs) may provide new therapeutic avenues for treatment of podophyllotoxin derivatives-resistant SCLC with LM, warranting further exploration.MethodsThe SCLC cell line H128 expressing luciferase were mutated by MNNG to generate H128-Mut cell line. After subcutaneous inoculation of H128-Mut into nude mice, H128-LM and H128-BPM (brain parenchymal metastasis) cell lines were primarily cultured from LM and BPM tissues individually, and employed to in vitro drug testing. The SCLC-LM mouse model was established by inoculating H128-LM into nude mice via carotid artery and subjected to in vivo drug testing. RNA-seq and immunoblotting were conducted to uncover the molecular targets for LM.ResultsThe SCLC-LM mouse model was successfully established, confirmed by in vivo live imaging and histological examination. The upregulated genes included EZH2, SLC44A4, VEGFA, etc. in both BPM and LM cells, while SLC44A4 was particularly upregulated in LM cells. When combined with PROTAC EZH2 degrader-1, the drug sensitivity of cisplatin, etoposide (VP16), and teniposide (VM26) for H128-LM was significantly increased in vitro. The in vivo drug trials with SCLC-LM mouse model demonstrated that PROTAC EZH2 degrader-1 plus VM26 or cisplatin/ VP16 inhibited H128-LM tumour significantly compared to VM26 or cisplatin/ VP16 alone (P < 0.01).ConclusionThe SCLC-LM model effectively simulates the pathophysiological process of SCLC metastasis to the leptomeninges. PROTAC EZH2 degrader-1 overcomes chemoresistance in SCLC, suggesting its potential therapeutic value for SCLC LM.

Fractionated stereotactic radiotherapy of intracranial postoperative cavities after resection of brain metastases – Clinical outcome and prognostic factors

Background and PurposeAfter surgical resection of brain metastases (BM), radiotherapy (RT) is indicated. Postoperative stereotactic radiosurgery (SRS) reduces the risk of local progression and neurocognitive decline compared to whole brain radiotherapy (WBRT). Aside from the optimal dose and fractionation, little is known about the combination of systemic therapy and postoperative fractionated stereotactic radiotherapy (fSRT), especially regarding tumour control and toxicity. MethodsIn this study, 105 patients receiving postoperative fSRT with 35 Gy in 7 fractions performed with Cyberknife were retrospectively reviewed. Overall survival (OS), local control (LC) and total intracranial brain control (TIBC) were analysed via Kaplan-Meier method. Cox proportional hazards models were used to identify prognostic factors. ResultsMedian follow-up was 20.8 months. One-year TIBC was 61.6% and one-year LC was 98.6%. Median OS was 28.7 (95%-CI: 16.9–40.5) months. In total, local progression (median time not reached) occurred in 2.0% and in 20.4% radiation-induced contrast enhancements (RICE) of the cavity (after median of 14.3 months) were diagnosed. Absence of extracranial metastases was identified as an independent prognostic factor for superior OS (p = <0.001) in multivariate analyses, while a higher Karnofsky performance score (KPS) was predictive for longer OS in univariate analysis (p = 0.041). Leptomeningeal disease (LMD) developed in 13% of patients. ConclusionFSRT after surgical resection of BM is an effective and safe treatment approach with excellent local control and acceptable toxicity. Further prospective randomized trials are needed to establish standardized therapeutic guidelines.

Clinical Outcomes of Patients with Non-Small Cell Lung Cancer Leptomeningeal Disease Following Receipt of EGFR-Targeted Therapy, Immune-Checkpoint Blockade, Intrathecal Chemotherapy, or Radiation Therapy Alone

BackgroundEGFR-targeted therapy (ETT) and immune-checkpoint blockade (ICB) have shown promising results in treating NSCLC brain metastases (BM). However, little is known of their effect in treating leptomeningeal disease (LMD). Patients and MethodsThis is a retrospective review of 80 patients diagnosed with NSCLC LMD from January 2014 to March 2021. Patients were grouped based on initial LMD treatment: radiotherapy (RT) alone, ETT, ICB, and intrathecal chemotherapy (ITC). ResultsEGFR mutation was present in 22 patients (28%). Twenty patients had positive cytology in cerebrospinal fluid, while 60 patients were diagnosed based on MRI with clinical correlation. The RT alone group consisted primarily of whole brain radiation (n = 20; 77%), stereotactic radiation (n = 3; 12%), and palliative spine radiation (n = 2; 7%). There were no significant differences amongst the treatment groups in age, performance status, or neurologic symptoms. Overall, the 6-month overall survival (OS) and craniospinal progression free survival (CS-PFS) were 35% and 24%, respectively. The 6-month OS for the ETT, ICB, ITC, and RT alone groups was 64%, 33%, 57%, and 29% respectively (log-rank P = .026). The 6-month CS-PFS for the ETT, ICB, ITC, and RT alone groups was 43%, 33%, 29%, and 19% respectively (log-rank P = .049). Upon univariate analysis, receipt of ETT compared to RT alone reached significance for OS (HR 0.35, P = .006) and CS-PFS (HR 0.39, P = .013). ConclusionsThe prognosis for patients with NSCLC LMD remains poor overall. However, the receipt of ETT for patients with EGFR-positive disease was associated with improved outcomes.

Successful treatment of pediatric patients with high-grade gliomas featuring leptomeningeal metastases by targeting BRAF V600E mutations with dabrafenib plus trametinib: two illustrative cases.

A combination of BRAF and MEK inhibitors is reported to be effective for gliomas with the BRAF V600E mutation; however, its efficacy in gliomas with leptomeningeal metastases (LMM) is still unknown. In this report, we describe two pediatric patients with high-grade glioma featuring the BRAF V600E mutation who were treated with dabrafenib and trametinib for LMM. Both 2 cases underwent craniotomy for primary intracranial lesions and were diagnosed as a high-grade glioma with BRAF V600E mutation; one case was consistent with anaplastic pleomorphic xanthoastorocytoma, the other was epithelioid glioblastoma. They received standard treatment for the lesions but subsequently were found to have new lesions including multiple spinal dissemination. We started administering dabrafenib and trametinib. Within a few days of starting treatment, the symptoms improved dramatically and MRI performed one month after the prescription of the two drugs demonstrated remission of both brain and spinal lesions. This report shows that dabrafenib and trametinib are effective not only for recurrent lesions but also for LMM in pediatric patients.

Cryptococcal Meningitis Misdiagnosed as Leptomeningeal Disease (LMD): A Case Series (P6-5.031)

Cryptococcal Meningitis Misdiagnosed as Leptomeningeal Disease (LMD): A Case Series (P6-5.031)

Rapidly Progressive Dementia and Extrapyramidal Symptoms Associated with Froin’s Syndrome due to Leptomeningeal Carcinomatosis (P6-5.027)

Rapidly Progressive Dementia and Extrapyramidal Symptoms Associated with Froin’s Syndrome due to Leptomeningeal Carcinomatosis (P6-5.027)

Proton Craniospinal Irradiation for Treatment of Leptomeningeal Metastasis in Patients with Solid Malignancy: The MD Anderson Cancer Center Experience (S27.006)

Proton Craniospinal Irradiation for Treatment of Leptomeningeal Metastasis in Patients with Solid Malignancy: The MD Anderson Cancer Center Experience (S27.006)