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Background Brain metastases (BM) are common among HER2+ breast cancer (BC) and prognostic stratification is crucial for optimal management. BC-GPA score and subsequent refinements (modified-GPA, updated-GPA) recapitulate prognostic factors. Since none of these indexes includes extracranial disease control, we evaluated its prognostic value in HER2+ BCBM. Methods Patients diagnosed with HER2+ BCBM at Istituto Oncologico Veneto-Padova (2002–2021) and Montpellier Cancer Institute (2001–2015) were included as exploratory and validation cohorts, respectively. Extracranial disease control at BM diagnosis (no disease/stable disease/response vs. progressive disease) was evaluated. Results In the exploratory cohort of 113 patients (median OS 12.2 months), extracranial control (n = 65, 57.5%) was significantly associated with better OS at univariate (median OS 17.7 vs. 8.7 months, p = 0.005) and multivariate analysis after adjustment for BC-GPA (HR 0.61, 95% CI 0.39–0.94), modified-GPA (HR 0.64, 95% CI 0.42–0.98) and updated-GPA (HR 0.63, 95% CI 0.41–0.98). The prognostic impact of extracranial disease control (n = 66, 56.4%) was then confirmed in the validation cohort (n = 117) at univariate (median OS 20.2 vs. 9.1 months, p Conclusions Extracranial disease control provides independent prognostic information in HER2+ BCBM beyond commonly used prognostic scores.

Background: Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. Methods: European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumours, prognostic factors were analysed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich. Results: At the database lock of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 incompletely characterised) had been registered. In the IDH wildtype population, median age was 56 years (range 24–78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumours with O 6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Median overall survival was 9.9 years (95% confidence interval [95% CI] 7.9–11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p < 0.001) and had a high rate (48.8%) of MGMT promoter-unmethylated tumours. Conclusions: Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Patients without relapse often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma.

International audience; In patients with metastatic breast cancer (MBC), brain metastases (BM) are associated with high morbidity and mortality. However, there is no validated serum biomarker that accurately predicts BM occurrence in these patients, and the role of serum biomarkers for prognosis remains unclear. Here, we evaluated the association of neurofilament light chain (NfL), ubiquitin C-terminal hydrolase L1 (UCHL1), glial fibrillary acidic protein (GFAP) and tau serum levels with BM presence and prognosis in patients with MBC. In serum samples from patients with MBC with (n = 100) and without BM (n = 47), we measured the biomarker serum levels using single molecule array (Simoa) technology (Neurology-4-Plex assay). To evaluate their accuracy to identify patients with BM, we determined the receiver operating characteristic curve and the area under the curve (AUC) for each biomarker and calculated their sensitivity and specificity. The median serum levels of NfL, UCHL1, tau and GFAP were significantly higher in patients with BM. The AUC for GFAP (0.82, 95% confidence interval [CI] 0.75-0.88) was significantly higher than those of the other biomarkers considered independently. Using the medians as cutoff values, elevated serum levels of NfL, UCHL1, tau and GFAP were associated with BM in univariate analysis, but only high GFAP levels in multivariate analysis (odd ratio 23.4, 95% CI 6.8-80.5, P

Background The diagnosis of breast cancer (BC)-related leptomeningeal metastases (LM) relies on the detection of tumor cells in cerebrospinal fluid (CSF) using conventional cytology (gold standard). However, the sensitivity of this technique is low. Our goal was to evaluate whether circulating tumor cell (CTC) detection in CSF using the CellSearch® system could be used for LM diagnosis. Methods This prospective, monocentric study included adult patients with suspected BC-related LM. The clinical sensitivity and specificity of CTC detection in CSF for LM diagnosis were calculated relative to conventional CSF cytology. Results Forty-nine eligible patients were included and 40 were evaluable (CTC detection technical failure: n = 8, eligibility criteria failure: n = 1). Cytology was positive in 18/40 patients. CTCs were detected in these 18 patients (median: 5824 CTC, range: 93 to 45052) and in 5/22 patients with negative cytology (median: 2 CTC, range: 1 to 44). The detection of ≥1 CSF CTC was associated with a clinical sensitivity of 100% (95% CI, 82.4–100) and a specificity of 77.3% (95% CI, 64.3–90.3) for LM diagnosis. HER2+ CTCs were detected in the CSF of 40.6% of patients with HER2− BC (median: 500 CTC, range: 13 to 28 320). Conclusions The clinical sensitivity of CTC detection in CSF with the CellSearch® system for LM diagnosis is higher than that of CSF cytology. CTC detection in patients with negative cytology, however, must be further investigated. The finding of HER2+ CTCs in patients with HER2− BC suggests that the HER2 status of LM should be evaluated to increase the treatment opportunities for these patients.

In patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer, leptomeningeal metastases (LM) are a rare but often a fatal clinical scenario. In this multicentric study, clinical and pathologic characteristics of patients with HER2+ breast cancer developing LM were described, as well as survival outcomes. Data were gathered retrospectively from medical records of 82 patients with advanced HER2+ breast cancer and LM treated between August 2005 and July 2020. Following LM diagnosis, 79 (96.3%) patients received at least one line of anti-HER2 therapy, 25 (30.5%) patients received intrathecal therapy and 58 (70.7%) patients received radiotherapy. Overall survival (OS) was 8.3 months (95% confidence interval [CI] 5.7-11), 1-year OS was 42%, and 2-year OS was 21%. At univariate analysis, patients who were treated after 2010, had better Karnofsky performance status, were free of neurological symptoms, had better prognostic, received chemotherapy (OS difference 9.4 months, P = .024), or monoclonal antibodies (trastuzumab ± pertuzumab; OS difference 6.1 months; P = .013) after LM diagnosis, had a statistically significantly longer OS. Presence of neurological symptoms (hazard ratio 3.32, 95% CI 1.26-8.73; P = .015) and not having received radiotherapy (hazard ratio 2.02, 95% CI 1.09-3.72; P = .024) were all associated with poorer OS at multivariate analysis. To summarize, not having neurological symptoms and receiving RT at LM diagnosis were associated with prolonged OS in our cohort. Survival seemed to be prolonged with multimodality treatment, which included targeted therapy, chemotherapy, and RT to the LM sites.

Riassunto I gliomi diffusi di basso grado, o gliomi di grado II secondo l’Organizzazione Mondiale della Sanita (OMS), rappresentano un sottogruppo di tumori cerebrali primari rari ed eterogenei, che colpiscono, il piu delle volte, pazienti giovani che conducono una vita normale fino alla comparsa di una crisi epilettica inaugurale. In risonanza magnetica convenzionale, questi tumori appaiono come una massa scarsamente delimitata, generalmente piuttosto omogenea, che coinvolge la sostanza bianca e la sostanza grigia, in iposegnale sulle sequenze T1 e ipersegnale sulle sequenze T2. Varie alterazioni molecolari identificate nel corso degli ultimi 20 anni, in particolare la mutazione del gene dell’isocitrato deidrogenasi e la codelezione 1p19q (associata agli oligodendrogliomi), sono state integrate nel 2016 nella nuova classificazione dell’OMS. La migliore conoscenza della storia naturale di questi gliomi, vale a dire la crescita continua, l’infiltrazione lungo i fasci di sostanza bianca e l’inevitabile evoluzione verso un glioma maligno, minacciando, cosi, la prognosi funzionale e vitale, associata a una riduzione del rischio di effetti secondari legati ai trattamenti (in particolare alla chirurgia), ha trasformato la strategia astensionistica “tradizionale” in un atteggiamento risolutamente terapeutico. L’obiettivo e, d’ora in poi, tendere all’elaborazione di una gestione dinamica e adattata a ciascun paziente, ovvero determinare l’ordine e il momento di ogni trattamento (exeresi chirurgica primaria o exeresi multiple quanto piu ampie possibile, linee di chemioterapia primaria o linee multiple, radioterapia) in base all’evoluzione del tumore (misurata sulle risonanze magnetiche regolari di controllo), allo stato clinico e neuropsicologico del paziente, alla biologia del tumore, nonche all’anatomia funzionale cerebrale individuale (studiata con metodi di mappatura e suscettibile di rimodellarsi grazie ai meccanismi di neuroplasticita), al fine di evitare la trasformazione maligna il piu a lungo possibile, preservando, al tempo stesso, la qualita di vita. Un tale approccio multidisciplinare nel contesto di questa malattia cerebrale cronica consente di offrire un vero e proprio futuro ai pazienti portatori di gliomi diffusi di basso grado, con la possibilita di concepire progetti a lungo termine a livello socioprofessionale o familiare.

The study investigated the prospective memory (PM) functioning among patients with brain metastases (BM), eligible for neurosurgy/radiosurgery, and its relationships with depression and quality of life (QoL). This case-healthy-control, cross-sectional study, comprised 160 participants, including 49 patients with BM from various cancers treated with neurosurgery or radiosurgery. They were compared with 111 matched controls on a set of neuropsychological tests, including the MoCA global cognitive test and an experimental PM task ‘PROMESSE’. Participants also completed a depression scale (BDI-II), a generic (SF-12) and a specific (QLQ-C30) QoL instrument for cancer patients. Multivariate analyses were conducted on various PM outcomes, in particular on event-based (EBPM) and time-based (TBPM) PM performances. After adjusting for age and socio-cultural level, patients with BM performed worse than the control on the PM task (p

Background Primary central nervous system tumors (PCNST) among adolescents and young adults (AYA, 15–39 y) have rarely been reported. We present a nationwide report of PCNST histologically confirmed in the French AYA population between 2008 and 2013. Methods Patients were identified through the French Brain Tumor Database (FBTDB), a national dataset that includes prospectively all histologically confirmed cases of PCNST in France. Patients aged 15 to 39 years with histologically confirmed PCNST diagnosed between 2008 and 2013 were included. For each of the 143 histological subtypes of PCNST, crude rates, sex, surgery, and age distribution were provided. To enable international comparisons, age-standardized incidence rates were adjusted to the world-standard, European, and USA populations. Results For 6 years, 9661 PCNST (males/females: 4701/4960) were histologically confirmed in the French AYA population. The overall crude rate was 8.15 per 100 000 person-years. Overall, age-standardized incidence rates were (per 100 000 person-years, population of reference: world/Europe/USA): 7.64/8.07/8.21, respectively. Among patients aged 15–24 years, the crude rate was 5.13 per 100 000. Among patients aged 25–39 years, the crude rate was 10.10 per 100 000. Age-standardized incidence rates were reported for each of the 143 histological subtypes. Moreover, for each histological subtype, data were detailed by sex, age, type of surgery (surgical resection or biopsy), and cryopreserved samples. Conclusion These data represent an exhaustive report of all histologically confirmed cases of PCNST with their frequency and distribution in the French AYA population in 2008–2013. For the first time in this age group, complete histological subtypes and rare tumor identification are detailed.

Background Metastatic breast cancer (MBC) behaviour differs depending on hormone receptors (HR) and human epidermal growth factor receptor (HER2) statuses. Methods The kinetics of central nervous system (CNS) metastases (CNS metastasis-free survival, CNSM-FS) and subsequent patient’s prognosis (overall survival, OS) according to the molecular subtype were retrospectively assessed in 16703 MBC patients of the ESME nationwide multicentre MBC database (Kaplan–Meier method). Results CNS metastases occurred in 4118 patients (24.6%) (7.2% at MBC diagnosis and 17.5% later during follow-up). Tumours were HER2−/HR+ (45.3%), HER2+/HR+ (14.5%), HER2+/HR− (14.9%) and triple negative (25.4%). Median age at CNS metastasis diagnosis was 58.1 years (range: 22.8–92.0). The median CNSM-FS was 10.8 months (95% CI: 16.5–17.9) among patients who developed CNS metastases. Molecular subtype was independently associated with CNSM-FS (HR = 3.45, 95% CI: 3.18–3.75, triple-negative and HER2−/HR+ tumours). After a 30-month follow-up, median OS after CNS metastasis diagnosis was 7.9 months (95% CI: 7.2–8.4). OS was independently associated with subtypes: median OS was 18.9 months (HR = 0.57, 95% CI: 0.50–0.64) for HER2+/HR+ , 13.1 months (HR = 0.72, 95% CI: 0.65–0.81) for HER2+/HR−, 4.4 months (HR = 1.55, 95% CI: 1.42–1.69) for triple-negative and 7.1 months for HER2−/HR+ patients (p Conclusions Tumour molecular subtypes strongly impact incidence, kinetics and prognosis of CNS metastases in MBC patients. Clinical trial registration NCT03275311.

BACKGROUND Breast cancer (BC) is the most frequent cause of leptomeningeal metastases (LM). LM diagnosis is confirmed by the detection of tumor cells in the cerebrospinal fluid (CSF) using conventional cytology (gold standard). However, even with optimal CSF sample volume and time to the analysis, the sensitivity of this technique is low, demanding repeated samples. Here, we aimed to evaluate the value of circulating tumor cell (CTC) detection in CSF using the CellSearch® system for LM diagnosis. MATERIAL AND METHODS This prospective, monocentric study included adult BC patients with suspected LM (clinical and/or radiological signs). CSF samples from 1–3 lumbar puncture(s) were analyzed: protein level, conventional cytology (60 drops), and CTC detection with the CellSearch® system (60 drops, first lumbar puncture only). Sensitivity (Se) and specificity (Sp) were calculated, using the results of the conventional cytology as the gold-standard. RESULTS Forty-nine eligible patients were included (Jan 2017-Jan 2020): median age 51.8, 95.9% women, 20.4% HER2+ BC, 93.8% previously diagnosed with metastatic BC, 89.8% with clinical symptoms. Among them, 40 were evaluable (CTC detection failure: n=8, eligibility criteria failure: n=1). Median sample volume was 3.0 mL for conventional cytology samples (median time to analysis: 22min) and 3.3 mL for CTC samples. Of the 40 evaluable patients, 18 had a positive cytology (on CSF sample n=°1/n°2: n=16/n=2) and were therefore diagnosed with LM using the gold-standard method. Protein level was elevated in 88.2% of these patients, compared with 45.1% of patients with negative CSF cytology (p=0.005). CTCs were detected in these 18 patients (median 5824 CTCs, range 93-45052). CTCs were also detected in 5/22 patients with a negative cytology (median 2 CTCs, range 1–44). Among them, one patient (44 CTCs) was diagnosed with a cytologically-proven LM 9 months later, while there was no further argument for LM in the other 4 patients’ history (1–3 CTC), who died of the extra-cerebral disease after a median time of 5.2 months (range 0.9–25.9). The detection of at least one CTC in CSF was associated with a Se of 100.0% (IC95% 82.4–100) and a Spe of 77.3% (IC95% 64.3–90.3) for the diagnosis of LM. CONCLUSION CTCs were detected with the CellSearch® system in all patients diagnosed with a cytologically-proven LM, as well as in a few patients without a cytological confirmation of LM. The prognosis of these patients with CSF cytology-/CTCs+ needs to be further investigated in a larger cohort.

Background Glioblastoma is the most frequent primary malignant brain tumor. In daily practice and at whole country level, oncological care management for glioblastoma patients is not completely known. Objectives To describe oncological patterns of care, prognostic factors, and survival for all patients in France with newly-diagnosed and histologically confirmed glioblastoma, and evaluate the impact of extended temozolomide use at the population level. Methods Nationwide population-based cohort study including all patients with newly-diagnosed and histologically confirmed glioblastoma in France in 2008 and followed until 2015. Results Data from 2053 glioblastoma patients were analyzed (male/female ratio 1.5, median age 64 years). Median overall survival (OS) was 11.2 [95% confidence interval (CI) 10.7–11.9] months. The first-line therapy and corresponding median survival (MS, in months) were: 13% did not receive any oncological treatment (biopsy only) (MS = 1.8, 95% CI 1.6–2.1), 27% received treatment without the combination of radiotherapy (RT)–temozolomide (MS = 5.9, 95% CI 5.5–6.6), 60% received treatment including the initiation of the concomitant phase of RT–temozolomide (MS = 16.4, 95% CI 15.2–17.4) whom 44% of patients initiated the temozolomide adjuvant phase (MS = 18.9, 95% CI 18.0–19.8). Only 22% patients received 6 cycles or more of adjuvant temozolomide (MS = 25.5, 95% CI 24.0–28.3). The multivariate analysis showed that the risk of mortality was significantly higher for the non-progressive patients who stopped at 6 cycles (standard protocol) than those who continued the treatment, hazard ratio = 1.5 (95% CI 1.2–1.9). Conclusion In non-progressive patients, prolonging the adjuvant temozolomide beyond 6 cycles may improve OS. Electronic supplementary material The online version of this article (10.1007/s11060-018-03065-z) contains supplementary material, which is available to authorized users.

Background Diffuse low-grade gliomas (DLGGs) are rare and incurable tumors. Whereas maximal safe, functional-based surgical resection is the first-line treatment, the timing and choice of further treatments (chemotherapy, radiation therapy, or combined treatments) remain controversial. Methods An online survey on the management of DLGG patients was sent to 28 expert centers from the European Low-Grade Glioma Network (ELGGN) in May 2015. It contained 40 specific questions addressing the modalities of use of chemotherapy in these patients. Results The survey demonstrated a significant heterogeneity in practice regarding the initial management of DLGG patients and the use of chemotherapy. Interestingly, radiation therapy combined with the procarbazine, CCNU (lomustine), and vincristine regimen has not imposed itself as the gold-standard treatment after surgery, despite the results of the Radiation Therapy Oncology Group 9802 study. Temozolomide is largely used as first-line treatment after surgical resection for high-risk DLGG patients, or at progression. Conclusions The heterogeneity in the management of patients with DLGG demonstrates that many questions regarding the postoperative strategy and the use of chemotherapy remain unanswered. Our survey reveals a high recruitment potential within the ELGGN for retrospective or prospective studies to generate new data regarding these issues.

Diffuse grade II IDH−mutant gliomas are slow−growing brain tumors that progress into high−grade gliomas. They present intratumoral cell heterogeneity, and no reliable markers are available to distinguish the different cell subtypes. The molecular mechanisms underlying the formation of this cell diversity is also ill−defined. Here, we report that SOX9 and OLIG1 transcription factors, which specifically label astrocytes and oligodendrocytes in the normal brain, revealed the presence of two largely nonoverlapping tumoral populations in IDH1−mutant oligodendrogliomas and astrocytomas. Astrocyte−like SOX9+ cells additionally stained for APOE, CRYAB, ID4, KCNN3, while oligodendrocyte−like OLIG1+ cells stained for ASCL1, EGFR, IDH1, PDGFRA, PTPRZ1, SOX4, and SOX8. GPR17, an oligodendrocytic marker, was expressed by both cells. These two subpopulations appear to have distinct BMP, NOTCH1, and MAPK active pathways as stainings for BMP4, HEY1, HEY2, p−SMAD1/5 and p−ERK were higher in SOX9+ cells. We used primary cultures and a new cell line to explore the influence of NOTCH1 activation and BMP treatment on the IDH1−mutant glioma cell phenotype. This revealed that NOTCH1 globally reduced oligodendrocytic markers and IDH1 expression while upregulating APOE, CRYAB, HEY1/2, and an electrophysiologically−active Ca2+−activated apamin−sensitive K+ channel (KCNN3/SK3). This was accompanied by a reduction in proliferation. Similar effects of NOTCH1 activation were observed in nontumoral human oligodendrocytic cells, which additionally induced strong SOX9 expression. BMP treatment reduced OLIG1/2 expression and strongly upregulated CRYAB and NOGGIN, a negative regulator of BMP. The presence of astrocyte−like SOX9+ and oligodendrocyte−like OLIG1+ cells in grade II IDH1−mutant gliomas raises new questions about their role in the pathology.

Background Leptomeningeal metastasis (LM) is a rare complication of metastatic breast cancer (MBC), with high morbidity/mortality rates. Our study aimed to describe the largest-to-date real-life population of MBC patients treated with intrathecal (IT) therapy and to evaluate prognostic models. Methods The Epidemiological Strategy and Medical Economics (ESME) MBC database (NCT03275311) includes all consecutive patients who have initiated treatment for MBC since 2008. Overall survival (OS) of patients treated with IT therapy was estimated using the Kaplan–Meier method. Prognostic models were constructed using Cox proportional hazards models. Performance was evaluated using C-index and calibration plots. Results Of the 22 266 patients included in the database between 2008 and 2016, 312 received IT therapy and were selected for our analysis. Compared with non-IT-treated patients, IT-treated patients were younger at MBC relapse (median age: 52 years versus 61 years) and more often had lobular histology (23.4% versus 12.7%) or triple-negative subtype (24.7% versus 13.3%) (all P < 0.001). Median OS was 4.5 months [95% confidence interval (CI) 3.8-5.6] and 1-year survival rate was 25.6%. Significant prognostic factors associated with poorer outcome on multivariable analysis were triple-negative subtype (hazard ratio 1.81, 95% CI 1.32-2.47), treatment line ≥3 (hazard ratio 1.88, 95% CI 1.30-2.73), ≥3 other metastatic sites (hazard ratio 1.33, 95% CI 1.01-1.74) and IT cytarabine or thiotepa versus methotrexate (hazard ratio 1.68, 95% CI 1.28-2.22), while concomitant systemic therapy was associated with better OS (hazard ratio 0.47, 95% CI 0.35-0.62) (all P < 0.001). We validated two previously published prognostic scores, the Curie score and the Breast-graded prognostic assessment, both with C-index of 0.57. Conclusions MBC patients with LM treated with IT therapy have a poor prognosis. We could identify a subgroup of patients with better prognosis, when concomitant systemic therapy and IT methotrexate were used., Highlights • The outcome of BC patients with IT-treated LM is poor, with a median OS of 4.5 months. • Concomitant systemic therapy may improve the outcome in IT-treated patients. • Patients treated with IT methotrexate had better outcome than those treated with IT cytarabine/thiotepa. • The Curie and Breast-graded prognostic assessment scores were prognostic for IT-treated patients.

Simple Summary Diffuse grade II IDH-mutant gliomas are rare brain tumors mainly affecting young patients. These tumors are composed of different populations of tumoral cells. Little is known of these cells and how they are generated. These different cells may show different sensitivity to treatments, so our aim was to study them in detail by directly using patient resections. We identified two clearly distinct tumoral populations and defined reliable markers for them. We also uncovered part of the molecular mechanisms that generate them. Finally, we found that the two cell types have different electrical activity. This article provides unique data and new issues on these rare tumors, which need to be further investigated to develop innovative treatments. Abstract Diffuse grade II IDH-mutant gliomas are slow-growing brain tumors that progress into high-grade gliomas. They present intratumoral cell heterogeneity, and no reliable markers are available to distinguish the different cell subtypes. The molecular mechanisms underlying the formation of this cell diversity is also ill-defined. Here, we report that SOX9 and OLIG1 transcription factors, which specifically label astrocytes and oligodendrocytes in the normal brain, revealed the presence of two largely nonoverlapping tumoral populations in IDH1-mutant oligodendrogliomas and astrocytomas. Astrocyte-like SOX9+ cells additionally stained for APOE, CRYAB, ID4, KCNN3, while oligodendrocyte-like OLIG1+ cells stained for ASCL1, EGFR, IDH1, PDGFRA, PTPRZ1, SOX4, and SOX8. GPR17, an oligodendrocytic marker, was expressed by both cells. These two subpopulations appear to have distinct BMP, NOTCH1, and MAPK active pathways as stainings for BMP4, HEY1, HEY2, p-SMAD1/5 and p-ERK were higher in SOX9+ cells. We used primary cultures and a new cell line to explore the influence of NOTCH1 activation and BMP treatment on the IDH1-mutant glioma cell phenotype. This revealed that NOTCH1 globally reduced oligodendrocytic markers and IDH1 expression while upregulating APOE, CRYAB, HEY1/2, and an electrophysiologically-active Ca2+-activated apamin-sensitive K+ channel (KCNN3/SK3). This was accompanied by a reduction in proliferation. Similar effects of NOTCH1 activation were observed in nontumoral human oligodendrocytic cells, which additionally induced strong SOX9 expression. BMP treatment reduced OLIG1/2 expression and strongly upregulated CRYAB and NOGGIN, a negative regulator of BMP. The presence of astrocyte-like SOX9+ and oligodendrocyte-like OLIG1+ cells in grade II IDH1-mutant gliomas raises new questions about their role in the pathology.

Background Breast cancer (BC) is the most frequent cause of leptomeningeal metastases (LM). LM diagnosis is confirmed by the detection of tumor cells in the cerebrospinal fluid (CSF) using conventional cytology (gold standard). However, even with optimal CSF sample volume and time to the analysis, the sensitivity of this technique is low, demanding repeated samples. Here, we aimed to evaluate the value of circulating tumor cell (CTC) detection in CSF using the CellSearch® system for LM diagnosis. Materials and Methods This prospective, monocentric study included adult BC patients with suspected LM (clinical and/or radiological signs). CSF samples from 1-3 lumbar puncture(s) were analyzed: protein level, conventional cytology (60 drops), and CTC detection with the CellSearch® system (60 drops, first lumbar puncture only). Sensitivity (Se) and specificity (Sp) were calculated, using the results of the conventional cytology as the gold-standard. Results Forty-nine eligible patients were included (Jan 2017-Jan 2020): median age 51.8, 95.9% women, 20.4% HER2+ BC, 93.8% previously diagnosed with metastatic BC, 89.8% with clinical symptoms. Among them, 40 were evaluable (CTC detection failure: n=8, eligibility criteria failure: n=1). Median sample volume was 3.0 mL for conventional cytology samples (median time to analysis: 22min) and 3.3 mL for CTC samples. Of the 40 evaluable patients, 18 had a positive cytology (on CSF sample n=°1/n°2: n=16/n=2) and were therefore diagnosed with LM using the gold-standard method. Protein level was elevated in 88.2% of these patients, compared with 45.1% of patients with negative CSF cytology (p=0.005). CTCs were detected in these 18 patients (median 5824 CTCs, range 93-45052). CTCs were also detected in 5/22 patients with a negative cytology (median 2 CTCs, range 1-44). Among them, one patient (44 CTCs) was diagnosed with a cytologically-proven LM 9 months later, while there was no further argument for LM in the other 4 patients’ history (1-3 CTC), who died of the extra-cerebral disease after a median time of 5.2 months (range 0.9-25.9). The detection of at least one CTC in CSF was associated with a Se of 100.0% (IC95% 82.4-100) and a Spe of 77.3% (IC95% 64.3-90.3) for the diagnosis of LM. Considering the number of CTC as a quantitative value, we determined the cut-off maximizing the Youden index using the ROC analysis (93 CTC). The detection of at least 93 CTC in CSF was associated with a Se and a Spe of 100.0% for the diagnosis of LM (area under the curve [AUC]: 1.0). Conclusion CTCs were detected with the CellSearch® system in all patients diagnosed with a cytologically-proven LM, as well as in a few patients without a cytological confirmation of LM. The prognosis of these patients with CSF cytology-/CTCs+ needs to be further investigated in a larger cohort. Citation Format: Amélie Darlix, Stéphane Pouderoux, Simon Thezenas, Alexis Bievelez, William Jacot, Laure Cayrefourcq, Nicolas Menjot-de-Champfleur, Cristina Leaha, Catherine Alix-Panabières. Detection of circulating tumor cells in cerebrospinal fluid for patients with suspected breast cancer leptomeningeal metastases: A prospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-01-12.

Introduction: Leptomeningeal metastasis (LM) is a severe complication of many solid tumors generally associated with dismal prognosis. Limited therapeutic options are available in this setting and assessment of response to treatment currently lacks validated tools. In 2017, the Response Assessment in Neuro-Oncology (RANO) LM Working Group proposed a standardized scorecard to aid in the evaluation of MRI findings in LM, which was revised and simplified in a subsequent 2019 version. To date, the prognostic impact of response to treatment evaluated according to these criteria has not been assessed in breast cancer (BC). In this study, we aim to validate this tool in a multicentric cohort of BC patients (pts) diagnosed with LM.Methods: Pts with LM from BC diagnosed at Istituto Oncologico Veneto (Padova, Italy) and Montpellier Regional Cancer Institute (Montpellier, France) between December 2005 and June 2018 were identified. Clinicopathological characteristics were collected from medical charts. Baseline and follow-up MRI scans were centrally reviewed by a dedicated radiologist and response assessment was evaluated according to the 2019 revised RANO LM response criteria (Le Rhun E. et al., Neuro-Oncology 2019).Results: A total of 225 pts diagnosed with BC-related LM were identified; among these, 142 had an available baseline brain MRI imaging and were included in the present study. Among these 142 pts, 78 had a positive cerebrospinal fluid (CSF) cytology and were classified as type I according to EANO-ESMO classification (41 type IA, 9 type IB, 28 type IC); for 64 pts CSF cytology was negative (N=25) or not performed (N=39), and were classified as type II (28 type IIA, 4 type IIB, 32 type IIC). At the time of last follow-up, 138 out of 142 pts had died and median overall survival (OS) from baseline MRI was 5.0 months (95% CI 3.4-6.7). Presence/absence of positive CSF cytology did not impact OS (median OS 5.3 versus 5.2 months, log-rank p=0.406). A total of 60 pts (positive/negative/not done CSF cytology: N=36/9/15) had an evaluable follow-up MRI imaging, with drop-off mainly due to deteriorating performance status or death. In this selected subgroup of pts, a longer OS was observed (median OS 15.2 months; 95% CI 9.5-21.0). Treatment administered for BC-related LM was heterogeneous and several pts received more than one treatment modality: systemic chemotherapy (N=44), endocrine therapy (N=27), HER2-targeted treatment (N=16), intrathecal chemotherapy (N=37) and radiotherapy (N=24). Response to treatment at time of first disease re-evaluation by brain MRI imaging was as follows: complete response for 2 pts, partial response for 12 pts, stable disease for 33 pts, and progression of disease for 13 pts. Response according to 2019 RANO criteria was significantly associated with OS (p=0.029, Table 1). Conclusions: Response assessment in pts with LM is challenging. In our study, the 2019 RANO revised response score was associated with OS in patients with LM from BC, thus validating these criteria in a real-world cohort. Response according to 2019 RANO LM criteriaMedian OS (months)OS 95% CI (months)Univariate Cox Hazard RatioUnivariate Cox Hazard Ratio 95% CIp-valueComplete Response31.1NE-NE0.100.01-0.780.028Partial Response16.10.0-37.40.410.17-0.970.043Stable Disease17.98.3-27.50.450.22-0.910.026Progression of Disease9.55.9-13.1Ref.Ref.Ref. Citation Format: Gaia Griguolo, Vittoria Aldegheri, Michele Bottosso, Francesca Caumo, Stéphane Pouderoux, Federica Miglietta, William Jacot, Maria Vittoria Dieci, Amélie Darlix, Valentina Guarneri. Response according to revised RANO criteria is associated with overall survival in breast cancer patients with leptomeningeal metastasis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-01.

Background Neurosurgical resection represents an important treatment option in the modern, multimodal therapy approach of brain metastases (BM). Guidelines for perioperative imaging exist for primary brain tumors to guide postsurgical treatment. Optimal perioperative imaging of BM patients is so far a matter of debate as no structured guidelines exist. Methods A comprehensive questionnaire about perioperative imaging was designed by the European Association of Neuro-Oncology (EANO) Youngsters Committee. The survey was distributed to physicians via the EANO network to perform a descriptive overview on the current habits and their variability on perioperative imaging. Chi square test was used for dichotomous variables. Results One hundred twenty physicians worldwide responded to the survey. MRI was the preferred preoperative imaging method (93.3%). Overall 106/120 (88.3%) physicians performed postsurgical imaging routinely including MRI alone (62/120 [51.7%]), postoperative CT (29/120 [24.2%]) and MRI + CT (15/120 [12.5%]). No correlation of postsurgical MRI utilization in academic vs. non-academic hospitals (58/89 [65.2%] vs. 19/31 [61.3%], p = 0.698) was found. Early postoperative MRI within ≤72 h after resection is obtained by 60.8% of the participants. The most frequent reason for postsurgical imaging was to evaluate the extent of tumor resection (73/120 [60.8%]). In case of residual tumor, 32/120 (26.7%) participants indicated to adjust radiotherapy, 34/120 (28.3%) to consider re-surgery to achieve complete resection and 8/120 (6.7%) to evaluate both. Conclusions MRI was the preferred imaging method in the preoperative setting. In the postoperative course, imaging modalities and timing showed high variability. International guidelines for perioperative imaging with special focus on postoperative MRI to assess residual tumor are warranted to optimize standardized management and adjuvant treatment decisions for BM patients.

The aims of the present study were to describe treatment patterns and survival outcomes in patients with central nervous system metastases (CNSM) selected among metastatic breast cancer (MBC) patients included in a retrospective study from the Epidemiological Strategy and Medical Economics (ESME) MBC cohort.Neurological progression-free survival (NPFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Significant contributors to NPFS were determined using a multivariate Cox proportional hazards model.After a median follow-up of 42.8 months, of 16 701 patients included in the ESME MBC database, CNSM were diagnosed in 24.6% of patients. The most frequent treatments after diagnosis of CNSM were whole-brain radiotherapy (WBRT) (45.2%) and systemic treatment (59.3%). Median OS and NPFS were 7.9 months (95% CI: 7.2-8.4) and 5.5 months (95% CI: 5.2-5.8), respectively. In multivariate analysis, age70 years (vs50 years; HR = 1.40; 95% CI: 1.24-1.57), triple-negative tumours (vs HER2-/HR+; HR = 1.87; 95% CI: 1.71-2.06), HER2+/HR-tumours (vs HER2-/HR+; HR = 1.14; 95% CI: 1.02-1.27), ≥3 metastatic sites (vs 3; HR = 1.32; 95% CI: 1.21-1.43) and ≥3 previous treatment lines (vs 3; HR = 1.75; 95% CI: 1.56-1.96) were detrimental for NPFS. A time interval between selection and CNSM diagnosis superior to 18 months (vs9 months; HR = 0.88; 95% CI: 0.78-0.98) was associated with longer NPFS.This study describes current treatment patterns of MBC patients in a "real life" setting. Despite advances in stereotactic radiation therapy, most of the patients still received WBRT. More research is warranted to identify patient subsets for tailored treatment strategies.

Background Breast cancer (BC) is one of the solid tumors most commonly associated with leptomeningeal disease (LMD). LMD carries a devastating prognosis; however, disease presentation and prognostic factors are uncertain. Subjects, Materials, and Methods In order to describe patient characteristics, treatment patterns, and factors associated with survival in a contemporary multicentric cohort, 153 consecutive BC patients diagnosed with LMD at two European institutions (2002–2017) were included. Time to LMD and overall survival (OS) after LMD diagnosis were evaluated using the Kaplan-Meier method and Cox proportional hazards models. Results Median age at LMD diagnosis was 58 years (25–84). Tumor phenotype distribution was as follows: hormone receptor (HR) positive (HR+)/human epidermal growth receptor 2 (HER2) negative 51.0%, triple-negative 15.0%, HR+/HER2 positive (HER2+) 13.1% and HR negative/HER2+ 7.2%. Most patients received active anticancer treatments (radiation therapy [RT] n = 42, systemic therapy n = 110, intrathecal treatment n = 103). Median OS was 3.9 months (95% confidence interval [CI] 2.4–5.5). Eastern Cooperative Oncology Group performance status (ECOG PS) >2, high white blood cells count, low glucose, and high protein in cerebrospinal fluid (CSF) were poor prognostic factors. Having received RT or systemic treatment was associated with better prognosis. In multivariate analysis, ECOG PS (hazard ratio 2.22, 95% CI 1.25–3.94), CSF glucose levels (hazard ratio 1.74, 95% CI 1.05–2.88), and having received systemic treatment (hazard ratio 0.17, 95% CI 0.09–0.32) were confirmed as independent prognostic factors. In HER2+ BC patients, having received systemic HER2-targeted therapy was the only factor maintaining independent prognostication (hazard ratio 0.12, 95% CI 0.02–0.67) in multivariate analysis. Conclusion Despite being limited by their retrospective nature, these results highlight the need for clinical trials in BC LMD, stratified on tumor biology. Implications for Practice Leptomeningeal disease (LMD) is a devastating complication of breast cancer (BC), and its optimal therapy is still not defined. Here, patient characteristics, treatment patterns, and prognostic factors from a contemporary cohort of 153 BC-related LMD patients are reported. In multivariate analysis, Eastern Cooperative Oncology Group performance status, cerebrospinal fluid glucose levels, and having received systemic treatment were confirmed as independent prognostic factors in the overall population, whereas in human epidermal growth receptor 2 (HER2) positive BC patients, having received systemic HER2-targeted therapy was the only factor maintaining independent prognostication in multivariate analysis. These results highlight the need to consider stratification on tumor biology in the treatment of BC LMD.

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) 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.

International audience; BACKGROUND:Several prognostic scores have been developed to estimate survival of breast cancer (BC) patients with brain metastases (BM). Modified Breast Graded Prognostic Assessment (GPA), based on a single-institution cohort of 1552 patients, has been proposed as refinement of Breast-GPA. In addition to age, tumour subtype and KPS, Modified Breast-GPA comprises number of BM. This study was designed to validate Modified Breast-GPA.PATIENTS AND METHODS:Clinical data of 668 BC patients diagnosed with BM at four institutions between 1996 and 2016 were reviewed. Patients were classified by Breast-GPA and Modified Breast-GPA. Overall survival (OS) was calculated from time of BM diagnosis to death or last follow-up. Cox proportional models were used to calculate hazard-ratios and their 95% CI. The performances of Breast-GPA and Modified Breast-GPA were compared using Harrell's concordance index.RESULTS:Median age at BM diagnosis was 56 years (range 24-85). At last follow-up, 632 patients (94.6%) had died. Median OS was 8.1 months (95% CI 6.9-9.4). The number of BM (1-3 vs. >3) was significantly associated with OS in univariate analysis (p < 0.001) and having >3 BM was identified as a negative prognostic factor in multivariate analysis. Both Breast-GPA and Modified Breast-GPA accurately predicted OS (p < 0.001 for both scores). Performance of Modified Breast-GPA was better: concordance indices were 0.6390 (95% CI, 0.6381 to 0.6399) and 0.6647 (95% CI, 0.6639 to 0.6655) for Breast-GPA and Modified Breast-GPA, respectively (p < 0.001).CONCLUSIONS:This work provides the first external independent validation of Modified Breast-GPA and confirms its better performance as compared to Breast-GPA.

BACKGROUND There is a need to develop new treatments in IDH-mutant high-grade gliomas recurring after radiotherapy and chemotherapy. Based on preclinical studies showing that IDH-mutant tumors could be vulnerable to PARP inhibition we launched a phase II study to test the efficacy of olaparib (Lynparza) monotherapy in this population. METHODS Adults with recurrent high-grade IDH-mutant gliomas after radiotherapy and at least one line of alkylating chemotherapy (PCV or TMZ), KPS > 60, normal organ function were enrolled. The primary endpoint was 6 months PFS according to RANO criteria. Patients were treated with olaparib 300 mg twice daily. We used a single-stage Fleming design with p0 = 30%, p1 = 50%, a type I unilateral error rate of 5% and a power of 80%. RESULTS 35 patients with recurrent IDH-mutant gliomas (IDH1R132H-mutant n = 32, other IDH mutation n = 3, 1p/19 codeleted n = 16, 1p/19q non-codeleted n = 14) were enrolled (malignantly transformed low-grade gliomas n = 21, anaplastic gliomas n = 8, glioblastomas n = 6). Median time since diagnosis was 7.4 years (1–22 years), median time since radiotherapy was 2.8 years (0.6–18 years), median number of previous chemotherapy lines was 2 (1–5). With a median follow-up of 11 months, 30 patients had stopped treatment due to tumor progression and 2 patients were still on treatment 16 to 18 months after treatment start. At 6 months, 11/35 patients were progression-free (31 %). According to RANO criteria, based on local investigator analysis, 2 patients (5%) had a partial response and 14 patients a stable disease (37%) with a median duration of response of 9 months (4–18+). Median PFS and OS were 2.3 and 15.9 months and were similar in 1p/19q codeleted and non-codeleted patients. A grade 3 olaparib-related adverse event was observed in 5 patients (14%, lymphopenia n = 3, fatigue n = 2, diarrhea n = 1) and a grade 2 in 15 patients (43%), most frequently consisting in fatigue (23%), gastrointestinal disorders (20%) and lymphopenia (20%). No patient definitively stopped olaparib due to side effects. CONCLUSIONS In this heavily pre-treated population of recurrent IDH-mutant gliomas, olaparib monotherapy was well tolerated and resulted in some activity supporting its evaluation in association with alkylating chemotherapy in recurrent IDH-mutant gliomas in future studies.

Diffuse low-grade glioma form a rare entity affecting young people. Despite advances in surgery, chemotherapy, and radiation therapy, diffuse low-grade glioma are still incurable. According to current guidelines, maximum safe resection, when feasible, is the first line of treatment. Apart from surgery, all other treatment modalities (temozolomide, procarbazine-CCNU-vincristine regimen, and radiation therapy) are handled very differently among different teams, and this in spite of recent results of several phase 3 studies. Based on a European survey, this paper aimed to get a picture of this heterogeneity in diffuse low-grade glioma management, to identify clinically relevant questions raised by this heterogeneity of practice, and to propose new methodological frameworks to address these questions.

BACKGROUND Diffuse low-grade gliomas (DLGG) are defined by a continuous growth and an unavoidable malignant transformation. Foci of malignant transformation may be found within DLGG samples obtained from surgical resections. As the medical management is classically based on the higher tumor grade, an immediate adjuvant treatment is usually proposed (radiotherapy [RT] with Temozolomide or PCV), whatever the extent of resection. Yet, early RT has no impact on overall survival compared with late RT, and is associated with cognitive toxicity. An alternative approach consists in postponing the medical treatment in selected patients. MATERIAL AND METHODS We conducted a monocentric retrospective analysis of a consecutive series of patients managed with this conservative approach. Inclusion criteria were: DLGG (WHO 2016 grade II) with at least one focus of malignant transformation (grade III-IV); no previous chemotherapy or RT; no less than a subtotal resection of the FLAIR tumor volume; no intention of treating with immediate adjuvant therapy; at least two years of postoperative follow-up. The time interval to the next medical treatment (chemotherapy and/or radiotherapy) was assessed, as well as the functional and survival results. RESULTS Forty-five DLGG patients, of median age 36.5 years, were included in the analysis (median time interval from diagnosis: 7.3 months). The histo-molecular diagnosis was diffuse astrocytoma, IDH mutant in 46.7% of cases, astrocytoma, IDH wild-type in 13.3% and oligodendroglioma, IDH mutant and 1p/19q codeleted in 40.0%. Ten tumors presented with grade IV foci. The quality of resection was subtotal (FLAIR tumor residue ≤15 cm3) in 73.3%, total (no FLAIR tumor residue) in 24.4% and supratotal in 2.2%. After surgery, patients were managed with regular clinical and radiological follow-up. With a median postoperative follow-up of 6.3 years, 75.5% of patients received a subsequent medical treatment, after a median time interval of 3.7 years. The first treatment after surgery consisted of repeated surgery in 11 patients, Temozolomide in 28 patients, RT in one patient. At the time of analysis, 19 patients (42.2%) had been treated with RT, after a median time interval of 9.5 years. Nine patients (20.0%) had died (median overall survival not reached, 5-years and 7-years survival rates: 95.2% and 67.0%). Most surviving patients were still active professionally (69.4%), with a median Karnofsky performance status of 90, and no or rare seizures. CONCLUSION In this series, total or subtotal resection of DLGG with a least one focus of grade III-IV glioma radically changed the natural history of these tumors and allowed delaying the following medical treatment by several years. This strategy is feasible in selected patients and should be considered on a case-by-case basis in patients with foci of malignant transformation following total or subtotal resection.

ObjectiveDiffuse low-grade gliomas (DLGG) are defined by continuous growth and an almost unavoidable malignant transformation. Foci of malignant glioma can be found within DLGG samples obtained from surgical resections. As the medical management of patients is classically based on the higher tumor grade, an immediate adjuvant treatment is usually proposed. To determine whether postponing the medical treatment in selected patients is feasible, we conducted a single-center retrospective study.MethodsThis was a single-center retrospective analysis of a consecutive series of DLGG managed with this conservative strategy. Inclusion criteria were at least 1 focus of malignant tumor (grade III–IV, WHO 2016), no previous chemotherapy or radiotherapy, no less than a subtotal resection of the fluid-attenuated inversion recovery tumor volume, no intention of treating with immediate adjuvant therapy, and minimum 2 years of follow-up. The time interval to the following oncologic medical treatment was analyzed, as well as the functional and survival results.ResultsForty-four patients met the inclusion criteria (median age 36, median time interval from diagnosis 7 months). Most tumors (88%) were IDH-mutant and 1p19q intact (59%); 9 presented with grade IV foci. With a median follow-up of 6.7 years, 75% of patients received a subsequent medical treatment, after a median time of 3.4 years since surgery. At the time of analysis, 9 patients (20.0%) had died (5- and 7-year survival rates: 95% and 67.0%). Most surviving patients were still active professionally, without seizures.ConclusionsPostponing the medical treatment in DLGG with foci of malignant tumor following total or subtotal resection should be considered in selected patients.

International audience; Diffuse low-grade gliomas (DLGG) are brain tumors of young adults. They affect the quality of life of the inflicted patients and, if untreated, they evolve into higher grade tumors where the patient's life is at risk. Therapeutic management of DLGGs includes chemotherapy, and tumor diameter is particularly important for the follow-up of DLGG evolution. In fact, the main clinical basis for deciding whether to continue chemotherapy is tumor diameter growth rate. In order to reliably assist the doctors in selecting the most appropriate time to stop treatment, we propose a novel clinical decision support system. Based on two mathematical models, one linear and one exponential, we are able to predict the evolution of tumor diameter under Temozolomide chemotherapy as a first treatment and thus offer a prognosis on when to end it. We present the results of an implementation of these models on a database of 42 patients from Nancy and Montpellier University Hospitals. In this database, 38 patients followed the linear model and four patients followed the exponential model. From a training data set of a minimal size of five, we are able to predict the next tumor diameter with high accuracy. Thanks to the corresponding prediction interval, it is possible to check if the new observation corresponds to the predicted diameter. If the observed diameter is within the prediction interval, the clinician is notified that the trend is within a normal range. Otherwise, the practitioner is alerted of a significant change in tumor diameter.

BACKGROUND: Neurosurgical resection is an important treatment option in the multimodal therapy of brain metastases (BM). Perioperative imaging is established in primary brain tumors to assess the extent of resection. However, structured guidelines on the use of perioperative imaging for BM patients are so far missing. METHODS: The European Association of Neuro-Oncology (EANO) Youngsters committee designed a comprehensive questionnaire on the use of perioperative imaging. The survey was distributed to physicians with neuro-oncologic focus via the EANO and the European Association of Neurosurgical Societies (EANS) network. RESULTS: 120 physicians from non-European countries and European countries responded to the survey. 76/120 neurosurgeons, 18/120 radiation oncologists and 17/120 neurologists participated. 89/120 participants worked at academic hospitals and 39/40 participants worked in high patient volume centers as defined by >50 BM cases per year. Local standard operating procedures for perioperative imaging were applied by 94/120 physicians. The preferred preoperative imaging method represented MRI for 112/120 (93.3%) participants. Postsurgical imaging was routinely performed by 106/120 physicians. 77/120 participants indicated MRI as the preferred postoperative imaging method, however, only 71/120 performed postoperative MRI imaging within 72 hours after resection. No correlation of postsurgical MRI and localization at an academic hospital (58/79 [73.4%] vs. 19/27 [70.4%], p>0.05) or patient volume (49/71 [69%] vs 25/40 [62.5%], p>0.05) was evident. The most frequently indicated reason for postsurgical imaging was the assessment of extent of resection as participants indicated to adjust the radiotherapy plan or even considered re-surgery to achieve complete resection. CONCLUSIONS: This EANO survey indicates that preoperative MRI is the preferred imaging technique for the majority of physicians, whereas a high variability of postoperative neuroimaging routines including CT and MRI was observed. International guidelines for perioperative imaging with special focus on postoperative MRI are warranted in order to optimize perioperative treatment modalities for BM patients.

International audience; Few data are currently available regarding the efficacy and safety of T-DM1 in breast cancer (BC) patients with unselected brain metastases (BM), since most clinical trials have excluded BM patients or have only included highly selected patients. HER2 + BC patients with BM treated with T-DM1 in 5 French centers were included in this retrospective study. Clinical management was performed according to the product guidelines. Efficacy was evaluated recording tumor response rates, progression-free (PFS) and overall survival, treatment compliance, and safety. Thirty nine patients received T-DM1, among whom 82 % presented with concomitant extra-cerebral disease. Median number of previous metastatic chemotherapy and HER2-directed targeted therapy regimens was 2 (range 0-8) and 1 (0-7), respectively. Thirty six patients had received BM loco-regional treatment (72 % whole-brain radiation therapy). After a median follow-up of 8.1 months (1.4-39.6), 24 patients had progressed (first site of progression: brain 14; meningeal 2; outside of the central nervous system 5; both intra- and extra-cerebral 3), 12 patients had died (disease progression), and 27 patients were still alive. Median number of T-DM1 cycles was 8 (1-43). There were 17 partial responses (44 %) and 6 patients achieved disease stabilization (59 % clinical benefit rate). Median PFS was 6.1 months (95 %CI 5.2-18.3), with one- and two-year PFS rates of 33 and 17 %, respectively. Treatment was well tolerated, without unexpected toxicities, treatment delay, or dose reduction. In this retrospective study, T-DM1 appeared to be an effective and well-tolerated therapeutic option in unselected HER2 + BC patients with BM. These findings require a prospective validation.

2527 Background: Isolated central nervous system (CNS) progression on first-line systemic therapy with Trastuzumab (T) and Pertuzumab (P) for HER2-positive metastatic breast cancer (MBC) is a therapeutic challenge. Our aim was to describe the clinical outcome and current treatment strategies for such patients in a large retrospective cohort. Methods: Patients (pts) were selected among all MBC pts included in the French Epidemiological Strategy and Medical Economics (ESME) database involving 18 specialized cancer centers (NCT03275311). CNS progression-free survival (CNS-PFS), progression-free survival (PFS) and overall survival (OS) from diagnostic of brain metastases (BM) were estimated using the Kaplan-Meier method. Results: Between January 2008 and December 2016, 995 pts were treated with first-line T and P for their HER2-positive MBC. They were 55 years old in median, with tumors expressing hormone-receptors in 62%. A total of 132 pts (13%) experienced isolated CNS progression on T and P, with a median time from metastatic diagnosis to CNS progression of 12 months. It was the first CNS progression for 108 pts (82%) while 24 (18%) already had BM at time of metastatic relapse. After CNS progression, T and P were continued for 58% of pts (n = 73). The remaining 47 pts were switched to another HER2-directed therapy (T-DM1 for 57%, T alone or combined with chemotherapy for 36% and lapatinib for 21%). Among those 132 pts, 37% received whole-brain radiotherapy, 18% stereotactic radiation therapy, and 11% surgery. Systemic treatment was combined with CNS-directed therapy for 50% of pts. Median follow-up is 21 months (95%CI: 14.9-25.5) from the diagnosis of CNS metastases. Median OS (mOS) of the 132 pts is 35 months (95%CI: 29.2-53,6), and median PFS 7 months (95%CI: 6.3- 9.2). A total of 77 pts (58.3%) experienced a new CNS progression with a median CNS-PFS of 9 months (95%CI: 7.6-12,0). Patient who stayed on T and P had a significantly better OS in comparison to pts who were switched to another systemic HER2-directed therapy (mOS not evaluable vs23 months), whereas PFS and CNS-PFS were similar between groups. Conclusions: In this real life setting, isolated CNS progression occurred among 13% of pts with HER2+ MBC on first-line treatment with T and P, after a median time of 12 months. Following current ASCO recommendations, continuation of T and P after CNS-directed therapy, seemed to be adequate. Nevertheless, time to subsequent progression is short and better therapeutic options are needed.

2526 Background: Despite clinical implications, the complexity of brain metastases (BM) immune microenvironment in breast cancer (BC) patients is poorly understood. Multiplex immunofluorescence (mIF), a novel imaging technique allowing simultaneous visualization and quantification of several IF labeled proteins while maintaining spatial information, holds promise to comprehensively describe BCBM immune microenvironment, potentially providing valuable information to improve treatment. Methods: Clinical data and archival BM samples were collected for 60 BC patients undergoing neurosurgery (2003-2018) at three institutions. BM immune contexture was characterized using a custom mIF panel, including cell subtyping (CD4, CD8, FOXP3, CD68), activation (Granzyme B) and localization (keratin for tumor recognition) markers. Mean immune cell density (cells/mm2) for each sample was determined by digital image analysis and classified in tumor and stroma areas. Associations between immune subpopulations, BC subtype and overall survival from BM diagnosis (OS) were studied. Results: Up to date, 30 BCBM samples have been analyzed; 33% HR+/HER2-, 20% HR-/HER2+, 10% HR+/HER2+, 37% HR-/HER2-. At a median follow-up of 46 months, BC subtype was the only clinical variable associated with OS (longest for HER2+ and shortest for HR-/HER2-, log-rank p = 0.002). In the total sample area, no significant difference in immune cell densities was observed according to BC subtype. In the tumor area, HR+/HER2- tumors showed higher densities of CD8+ and CD68+ cells compared to other subtypes (p = 0.036 and p = 0.016, respectively). In stroma, HR-/HER2- tumors presented numerically higher densities of CD4+ and FOXP3+ cells and higher ratio of CD4/CD8 and FOXP3/CD8 ratio (not statistically significant). Higher CD4/CD8 and FOXP3/CD8 ratio in the stroma was significantly associated with worse OS, even after correction by BC subtype (Table). Conclusions: In BCBM, immune infiltrate differs according to BC subtype. Preliminary results suggest that a more tolerogenic immune microenvironment is associated with worse OS and might represent a target for optimization of immunotherapy for these patients. Updated results for all 60 patients will be presented. [Table: see text]

BACKGROUND: The main objective of this study was to explore the patterns of alternative therapy use, in parallel to the standard treatment, in glioma patients in France. MATERIAL AND METHODS: Questionnaires were distributed during visits at hospital and filled in and returned anonymously by adult patients with histologically confirmed glioma and with an ECOG performance score of 0–2. The protocol was approved by the French authorities on April 13th, 2016. Descriptive analyses of the population as well as correlation analysis according to gender, age, WHO grade IV versus other, recurrent disease as declared by the patients versus none, were conducted. RESULTS: Two hundred questionnaires were collected. Patients were male in 65% of the cases. Median age was 46 (range 18–85). Forty-six patients had glioblastoma, 83 patients declared having recurrent disease. Patients declared taking a complementary treatment in 46.5% (mainly vitamins and other food supplements), having modified their diet (ketogenic diet, Servent-Schreiber diet, addition of curcuma) in 48%, and using another alternative medicine approach (mainly magnetism, acupuncture, sophrology), in 34%. In total, 69% of the patients declared using at least one of these approaches. No difference was observed according to gender, age or occurrence of a recurrence, however, glioblastoma patients used significantly more often at least one approach (p

BACKGROUND Diffuse low-grade gliomas (DLGG) are characterized by a continuous growth and an unavoidable anaplastic transformation. IDH mutation and 1p19q codeletion have been integrated to the 2016 WHO classification to define the oligodendroglioma entity. Whenever feasible, neurosurgical resection is the first treatment option. At recurrence, a second surgical resection is proposed in selected cases. The consistency of molecular patterns (IDH mutation, 1p19q codeletion) at recurrence has been poorly studied in DLGG. MATERIAL AND METHODS We conducted a retrospective study on consecutive DLGG patients treated at our institution with repeated surgery (2006–2017). Clinical and biological data were collected for both the initial and subsequent surgery. Additional immunohistochemistry (including tumor morphology, ATRX and p53) and genetic analyses (TERT promoter mutation, CIC mutation, CGHa) were also performed on tumors with joint loss of IDH mutation and of 1p19q codeletion at recurrence. RESULTS A total of 71 patients were identified. Analyses were carried out on 56 patients (molecular data missing: n=15). Nine patients (16.1%) presented with a loss of their IDH mutation at second surgery. Five of them (8.9%) had an additional loss of their 1p19q codeletion. These five cases (3 men, median age 36.6 years) were all treated with surgery as the first oncological treatment. The first surgery revealed in all cases tumors with morphological oligodendroglial features, IDH mutation and 1p19q codeletion. Further molecular analysis strengthened the diagnosis of oligodendroglioma (TERT promoter and CIC mutations, no ATRX loss, no expression of p53). Four patients were followed-up after the first surgery; one patient received Temozolomide 14 months later due to FLAIR tumor volume growth. Because of the regrowth of the residual FLAIR tumor volume, a second surgery was performed in all patients, after a median time of 38.9 months. The morphological oligodendroglial features were lost, and the genetic analyses revealed in all cases no IDH mutation, no 1p19q codeletion, no ATRX loss and no expression of p53. No evidence of anaplasia was found histologically or by CGHa analysis in these recurrent tumors. CONCLUSION We describe five DLGG patients with a shared histo-molecular evolution characterized by the loss of the initial IDH mutation and of oligodendroglial features at second surgery. While rare, this possible evolution must be acknowledged as it can impact the subsequent therapeutic strategy. This observation is the first of a loss of founder alterations in DLGG genesis (i.e. IDH mutation and 1p19q codeletion); the involved mechanism likely differs from the previously described oligoclonal selection caused by spontaneous tumor genetic drift and/or pressure of chemotherapy, and could be linked with the Darwinian selection of a subpopulation of tumor cells after the first surgery.

International audience; Background The European Low-Grade Glioma network indicated a need to better understand common practices regarding the managing of diffuse low-grade gliomas. This area has experienced great advances in recent years. Method A general survey on the managing of diffuse lowgrade gliomas was answered by 21 centres in 11 European countries. Here we focused on specific questions regarding perioperative and intraoperative cognitive assessments. Results More centres referred to the same speech and language therapist and/or neuropsychologist across all assessments; a core of assessment tools was routinely used across centres; fluency tasks were commonly used in the perioperative stages, and object naming during surgery; tasks that tapped on attention, executive functions, visuospatial awareness, calculation and emotions were sparsely administered; preoperative assessments were performed 1 month or 1 week before surgery; timing for postoperative assessments varied; finally, more centres recommended early rehabilitation, whenever needed. Conclusions There is an emerging trend towards following similar practices for the management of low-grade gliomas in Europe. Our results are descriptive and formalise current discussions in our group. Also, they contribute towards the development of a European assessment protocol.

International audience; Diffuse low-grade gliomas (DLGG) prognosis is variable, depending on several factors, including the isocitrate dehydrogenase (IDH) mutation and the 1p19q codeletion. A few studies suggested associations between these parameters and tumor radiological characteristics including topography. Our aim was analyzing the correlations between the IDH and 1p19q statuses and the tumor intracerebral distribution (at the lobar and voxel levels), volume, and borders. We conducted a retrospective, monocentric study on a consecutive series of 198 DLGG patients. The IDH and 1p19q statuses were recorded. The pre-treatment magnetic resonance FLAIR imagings were reviewed for determination of lobar topography, tumor volume, and characterisation of tumor borders (sharp or indistinct). We conducted a voxel-based lesion-symptom mapping analysis to investigate the correlations between the IDH and 1p19q statuses and topography at the voxel level. The IDH mutation and 1p19q statuses were correlated with the tumor topography defined using lobar anatomy (p \textless 0.001 and p = 0.004, respectively). Frontal tumors were more frequently IDH-mutant (87.1 vs. 57.4%) and 1p19q codeleted (45.2 vs. 17.0%) than temporo-insular lesions. At the voxel level, these associations were not found. Tumors with sharp borders were more frequently IDH-mutant (p = 0.001) while tumors with indistinct borders were more frequently IDH wild-type and 1p19q non-codeleted (p \textless 0.001). Larger tumors at diagnosis (possibly linked to a slower growth rate) were more frequently IDH-mutant (p \textless 0.001). IDH wild-type, 1p19q non-codeleted temporo-insular tumors are distinct from IDH-mutant, 1p19q codeleted frontal tumors. Further studies are needed to determine whether the therapeutic strategy should be adapted to each pattern.

International audience; Primary central nervous system tumors (PCNST) are rare tumors responsible for high mortality and morbidity. Their epidemiology is poorly known, and clinical data are scarcely analyzed at a national level. In this study, we aimed at providing descriptive epidemiological data and incidence rates for all histological subtypes of PCNST according to the WHO classification. We conducted a nationwide population-based study of all newly diagnosed and histologically confirmed PCNST in France, between 2006 and 2011. A total of 57,816 patients were included: male 46.4%, median age at diagnosis 56 years old (range 0-99). For all newly diagnosed PCNST with histological confirmation the crude incidence rate was 15.5/105 per 100,000 person-years. To enable international comparisons, standardized rates were calculated: 14.1/105 (population of reference: USA), 14.5/105 (population of reference: Europe), and 12.0/105 (population of reference: world). 23.4% of samples were cryopreserved. Resection was performed in 79.1% of cases. Results are detailed (incidence rate, sex ratio, median age at diagnosis, number of cryopreserved samples, and type of surgery) for each of the 143 histological subtypes of PCNST, including all rare tumors. For example, incidence rates (population of reference: USA) were 0.018/105 for anaplastic gangliogliomas, 0.054/105 for malignant meningiomas, and 0.036/105 for hemangiopericytomas. Our study is the first to describe incidence rates and epidemiological data for all histological subtypes of PCNST, including rare tumors, at a national level. Its methodology ensures the exhaustiveness of the data collection for histologically-proven cases. Histological population-based studies have many perspectives in the field of clinical epidemiology and research.

International audience

International audience; The origins of diffuse low-grade gliomas (DLGG) are unknown. Beyond some limited data on their temporal and cellular origins, the mechanisms and risk factors involved are poorly known. First, based on strong relationships between DLGG development and the eloquence of brain regions frequently invaded by these tumors, we propose a "functional theory" to explain the origin of DLGG. Second, the biological pathways involved in DLGG genesis may differ according to tumor location (anatomo-molecular correlations). The cellular and molecular mechanisms of such "molecular theory" will be reviewed. Third, the geographical distribution of diffuse WHO grade II-III gliomas within populations is heterogeneous, suggesting possible environmental risk factors. We will discuss this "environmental theory". Finally, we will summarize the current knowledge on genetic susceptibility in gliomas ("genetic predisposition theory"). These crucial issues illustrate the close relationships between the pathophysiology of gliomagenesis, the anatomo-functional organization of the brain, and personalized management of DLGG patients.

The improved understanding of the natural course of diffuse low-grade gliomas (DLGG) has allowed a paradigmatic shift in their management, from a “wait-and-see” attitude to an early, individualized and dynamic therapeutic strategy. However, optimization of this management requires a better understanding the origins of DLGG. To date, the origins and etiologic factors of DLGG are mostly unknown. Beyond some data, yet limited, regarding the temporal and the cellular origins of DLGG, the mechanisms and risk factors involved in DLGG are poorly known. A way to better understand the mechanisms involved in the genesis of DLGG is to study their spatial distribution, both within the brain and at the geographical level. Indeed, some hypotheses regarding the mechanisms involved may be speculated from these distributions. It is interesting to note that DLGG have preferential locations within the brain, mostly within the so-called “functional areas”. On the basis of strong relationships between DLGG development and the eloquence of brain regions frequently invaded by these tumors, we propose a “functional theory” to explain the origin of DLGG. In addition, it can be hypothesized that the biological pathways involved in the genesis of DLGG may differ according to the tumor location, as anatomo-molecular studies showed significant correlations between the DLGG locations and tumor genetics, with a higher rate of IDH mutation and 1p19q codeletion in frontal tumors. The cellular and molecular mechanisms of such “molecular theory” will be reviewed in the present chapter. It is also interesting to note that the geographical distribution of diffuse WHO grade II and grade III gliomas is heterogeneous at the international and national levels, suggesting possible environmental risk factors. We will thus also discuss this “environmental theory". Finally, we will briefly summarize the current knowledge on genetic susceptibility in gliomas. All of these crucial issues very well illustrate the close relationships between the pathophysiology of gliomagenesis, the anatomo-functional organization of the brain, and personalized management of DLGG patients.