Development of a prognostic score for meningeal carcinomatosis in patients with advanced breast cancer

Development of a prognostic score for meningeal carcinomatosis in patients with advanced breast cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Development of a prognostic score for meningeal carcinomatosis in patients with advanced breast cancer Grégoire Narjoux, Juliette Mainguené, Marie-Noëlle Guilhaume, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3979871/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Meningeal carcinomatosis carries a dismal prognosis in patients with breast cancer, and requires invasive therapies. The aim of the present retrospective study was to elaborate a prognostic score of overall survival in patients with breast cancer related meningeal carcinomatosis (MC). Methods 109 patients with proven breast cancer MC, treated by at least one intrathecal (IT) injection of methotrexate or thiotepa at Institut Curie were retrospectively recorded from 2011 to 2019. We developed prognostic clinical scores for overall survival and 24-weeks survival. Results Diagnosis and evaluation of meningeal carcinomatosis appears based on a combination of clinical, imaging and laboratory studies. Three significant Overall Survival (OS) prognostic factors were identified. Clinical response or stabilization at one month of intrathecal therapy had a favorable independent prognostic value for both overall and 24-weeks survival. Additionally, baseline CSF Cyfra 21 − 1 level lower than 79 ng/mL in the cerebrospinal fluid and absence of 1-month cerebrospinal fluid (CSF) malignant cells carried a borderline favorable independent prognostic value for overall and 24-weeks survival, respectively. We constructed 2-class and 3-class prognostic scores for each outcome, identifying a very poor prognosis population. Conclusions To our knowledge it is the first study to develop a response-based prognosis score in patients with breast cancer related MC. This one month prognostic score may help to decide which patient could actually benefit from the prolongation of intrathecal therapy. Meningeal carcinomatosis breast cancer prognostic score Cyfra 21 − 1 Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Meningeal carcinomatosis (MC) is defined as leptomeningeal infiltration by tumor cells, including the pia mater, arachnoid and subarachnoid spaces, from a primary malignant tumor. Breast cancer is the most common etiology of MC among solid tumors, and MC occurs in approximately 5% of patients with metastatic breast cancer[ 1 , 2 ], who then carry an extremely poor prognosis [ 3 , 4 ]. The gold standard for the diagnosis of MC remains the CSF (cerebrospinal fluid) cytology, but with a poor sensitivity[ 5 ]. Imaging (MRI mostly) and elevated proteins in the CSF strongly suggest diagnosis without being acknowledged standards [ 6 ], and there is either not validated assessment tool during the course of MC [ 7 ]. Our group had suggested that elevated Cyfra 21 − 1 in the cerebrospinal fluid is associated with an MC diagnosis, with a potential prognostic value[ 3 ]. There is also no consensus about treatment, and treatment effectiveness is low[ 8 ]. In our Institution, patients with breast cancer MC are generally treated by a dose-dense IT (intra-thecal) methotrexate regimen, in combination with other systemic treatment whenever possible[ 3 ]. There are no general accepted criteria defining patient subgroups who might benefit from intrathecal therapy[ 8 ], and patients have often been heavily pretreated with various systemic drugs with few remaining therapeutic options. We report here our updated experience in patients with advanced breast cancer (BC) and MC. We had previously developed a poorly validated 4-parameter prognostic score solely based on baseline clinical features, which did not take into account the early clinical evolution in treated patients[ 8 , 9 ]. The aim of the present retrospective study was to elaborate a prognostic score of overall survival in patients with BC related MC and initially considered amenable to intrathecal therapy , in order to provide a relevant tool to help clinicians to decide who might benefit from the continuation of invasive treatment regimens. PATIENTS and METHODS We retrospectively recorded all patients with proven BC related MC and who were treated at least once with intrathecal chemotherapy from 2011 to 2019. Key eligibility criteria were: histologically proven breast carcinoma; meningeal carcinomatosis as defined either by tumor cells in the CSF, or the combination of neurological symptoms and/or compatible radiology results (CT scanner or MRI) and/or elevated total protein or Cyfra 21 − 1 level in the CSF; treatment by at least one IT injection of methotrexate or thiotepa. Patients who received IT therapy were identified using a systematic search in the electronic records of the chemotherapy database of the hospital. All electronic medical records of identified patients were manually analyzed and details on MC diagnosis, treatment and clinical course were collected, including CSF Cyfra 21 − 1 level, CSF protein count, CSF malignant cells that were collected at diagnosis and after one month of IT treatment. Statistics The principal objective of the study was to elaborate a prognostic score of overall survival in patients with newly diagnosed MC, and considered amenable to intrathecal therapy. Conventional descriptive statistics were used. Overall survival (OS) was defined as the time elapsed from MC diagnosis until death from any cause. Overall survival prediction curves were constructed with the Kaplan-Meier proportional hazard model. Multivariate analyses were performed with Cox-proportional hazards regression, with death as endpoint and using a forward variable selection procedure, based on the results of the univariate analyses. Final estimates were retained with a p value (Wald) < 0.05. Due to the very poor prognosis of MC, we refined the analyses by focusing on 24-weeks overall survival. We considered the following variables of interest in building the univariate and multivariate analyses: pathological subtype (triple negative vs other), clinical presentation (visceral metastases, neurological symptoms), previous therapies, cerebrospinal fluid (CSF) protein level (abnormal vs normal), CSF Cyfra 21 − 1 levels with various exploratory threshold values. Based on our previous reports[ 9 ], we also included in the analyses clinical response (worsening at 1 month vs no) and CSF malignant cells at 1 month (yes vs no). In order to build the prognostic scores, points were attributed to the final independent prognostic variables from the global OS and 24-weeks survival Cox models. Global scores were derived for each patient and 2 or 3 risk categories were defined (i.e. low and high risk, or low, intermediate and high risk). The statistical analyses were performed with the MedCalc® Statistical Software version 20.008 (MedCalc Software Ltd, Ostend, Belgium; https://www.medcalc.org ; 2021) The study was approved by the French national data protection authority and our Institutional Review Board. This study followed the precepts of the Declaration of Helsinki and French laws concerning biomedical research. Per current French regulations, no written informed consent was required. RESULTS Population The characteristics of the 109 patients population at diagnosis of MC are depicted in Supplementary Table 1. Briefly, 81 patients had a HR (hormone receptor) positive, HER2 negative breast carcinoma (74.3%), while 10 out of 109 had a Her 2 + cancer (9.2%) and 18 out of 109 (16.5%) had triple negative (TN) cancer. Most tumors were of non-specific subtype (NST, 66.5%) and 32 out of 109 were infiltrating lobular carcinomas (29.4%). At MC diagnosis, 44 patients out of 109 (40.4%) had at least one prior or concurrent brain metastasis and among them 32 (72.7%) had already undergone brain radiation therapy. Visceral metastases were present in 67 patients (61.5%). The median number of systemic treatments lines before MC diagnosis was 2 (0–7). Time between initial BC diagnosis and MC diagnosis was significantly longer in HR + than in HR- patients (median time 7 years vs 2 years, p < 0.0001) as was time between metastasis diagnosis and MC diagnosis (median : 2 years vs 1 year, p = 0.004). Her2 + status did not affect time between diagnosis of metastasis and MC (median time: 1.8 years vs 1.8 years, p = 0.76, when compared to HR + patients). TN status shortened time between diagnosis of metastasis and MC (median time to MC metastases: 11 vs 25 months, p = 0.001, when compared to HR + patients). Diagnosis of meningeal carcinomatosis Most patients (n = 102, 93.6%) initially presented miscellaneous neurological symptoms that triggered further investigation (Table 1 and Fig. 1 a). Brain and/or spinal MRI were initially performed in 92 patients out of 109 (84%). MRI was abnormal in 54 out of 92 (59%) and 47 patients out of 54 (87%) with an abnormal MRI also reported MC-related clinical symptoms. Conversely, 38 patients out of 92 (41%) had a normal MRI while presenting MC symptoms. Seven patients were diagnosed with MRI only. Malignant cells were observed in 85 out of 108 (78%) CSF baseline samples. CSF protein count was abnormal for 101 out of 108 (92.8%) CSF samples (median value: 1.02 g/mL – normal value < 1 g/mL). We performed CSF dosing of Cyfra 21 − 1 at diagnosis [ 9 ] (Fig. 1 b). The Cyfra 21 − 1 level (normal value ≤ 1 ng/mL) was elevated in 86 patients out of 95 (90.5%), with a median value of 18 ng/mL (IQR 25–75: 2.8–79). No patient had Cyfra 21 − 1 elevation as sole diagnostic feature (Fig. 1 a). Table 1 Diagnosis of meningeal carcinomatosis n % MC* symptoms N = 109 symptomatic 102 93.6% asymptomatic 7 6.4% Most frequent MC symptoms N = 98 Dizziness 28 20.3% Headache (and no Intra-cranial hypertension syndrome) 27 19.5% Intra-cranial hypertension syndrome (Nausea. vomiting. headache) 24 17.4% Cranial nerve dysfunction 17 12.3% Confusion 15 10.9% Motor paralysis 11 8% Sensory symptoms 11 8% Meningeal syndrome (headache + neck stiffness + phono or photophobia) 5 3.6% CSF** level of CYFRA 21 − 1 at baseline N = 95 Normal 9 9.5% Elevated 86 95.5% Total 95 100.0% *MC : meningeal carcinomatosis ; **CSF : cerebrospinal fluid ; We next analyzed the relationship between the clinical, radiological and biological diagnostic features (Fig. 1 a) showing that only 23 patients (29.1% of 79 patients evaluable with all modalities) had a comprehensive MC diagnostic presentation. When looking at the relationship between MRI and CSF data, it was observed that 2 patients out of 92 (2.2%) had a diagnosis based on symptoms associated with either elevated CSF protein or Cyfra 21 − 1 levels, but with no CSF malignant cells and normal MRI, while 35 patients out of 71 (49.3%) with CSF malignant cells had a concordant abnormal MRI and 36 patients out of 71 (50.7%) with CSF malignant cells had a concurrent normal MRI (p = 0.0016, Fisher’s exact Test). Overall, 35 patients out of 53 (66.1%) with an abnormal MRI had CSF malignant cells. Finally, 36 patients out of 38 (94.7%) with a negative MRI had CSF malignant cells and 18 patients out of 20 (90%) with no CFS malignant cells had an abnormal MRI. Secondly, exploring the relationship between CSF malignant cells and CSF protein count suggested a correlation trend: 91 patients had elevated CSF proteins, and 73 patients out of 91 (80.2%) had CSF malignant cells (p = 0.24, Chi-squared test). Of note, 10 patients out of 15 (66.7%) with a normal CSF protein count had CSF malignant cells. Furthermore, among the 23 patients with no CSF malignant cells, 18 (78.2%) had an elevated CSF protein count. Interestingly, no significant difference was observed between the presence CSF malignant cells and a baseline elevated CSF protein count (p = 0.31, Fisher exact test). Finally, we explored the relationship between baseline Cyfra 21 − 1 CSF level and baseline CSF cellularity and CSF protein count. Of 74 patients with baseline CSF malignant cells, 69 (93.2%) had also an elevated CSF Cyfra 21 − 1. Similarly, among 21 patients with no baseline malignant cells, 17 (81%) had an elevated CSF Cyfra 21 − 1 (p = 0.10, Fisher exact test). Likewise, no significant difference was observed between Cyfra 21 − 1 and proteins baseline CSF elevation (p = 0.15, Fisher exact test). Treatments We used intrathecal treatments in combination with systemic therapies according to the underlying breast cancer subtype: 88 patients (80.7%) had systemic chemotherapy associated with IT treatment, 26 patients (23.8%) received endocrine therapy including 10 with a CDK4/6 inhibitor. In the 10 HER2 positive patients, 8 were administered HER2 blocking agents. In 38 patients (out of 44 with concurrent brain metastases, 86.4%), radiation therapy had been previously used to treat brain metastases. Methotrexate was commonly used as first IT therapy (Supplementary Table 2). IT Thiotepa was used as a second line in case of progressive MC, or methotrexate related toxicity, or when radiotherapy involving Central Nervous System (CNS) was indicated [ 3 ]. The treatment protocols were established as previously reported [ 3 ]. Changing IT treatment decision was made based on clinical worsening and/or imaging (MRI or scan) progressive disease. Discontinuation of IT therapies was decided according to clinical worsening when both methotrexate and thiotepa had been used, or according to individual quality of life considerations. Malignant CSF cells detection during IT was taken into account to change or stop IT treatment if concordant with clinical evolution but was not used alone to conclude. Overall, 103 patients received IT methotrexate, including 97 out of 109 (88.9%) as a first line of IT therapy. The median number of IT cycles in the overall population was 6 (1–47). IT thiotepa was administered in 42 patients (37.6%), including 12 as a first line and 29 as a second line of IT therapy (Supplementary Table 2). Response at one month We considered response to IT therapy at 1 month by examining neurological clinical evaluation and CSF biology. Clinically, neurological improvement, stability, and worsening were observed in 49 (44.9%), 32 (29.4%) and 28 patients (25.7%), respectively (Fig. 2 a). One-month CSF cytology was evaluable in 87 patients, and almost half of them (n = 43, 49.5%) had no detectable tumor cells in the CSF at 1 month, including 28 patients with baseline CSF tumor cells. In the 17 patients with no CSF malignant cells at baseline, 2 had detectable cells at one month (Fig. 2 b). There was no correlation between clinical and cellular responses (p = 0.723; Fisher exact test). We observed a significant decrease in the median Cyfra 21 − 1 CSF level at one month (2.55 ng/mL vs 18 ng/mL, p < 0.0001; Wilcoxon rank sum test, Fig. 2 c). We again found no relation between Cyfra 21 − 1 level decrease and clinical response (p = 0.856; ANOVA and Chi-squared test). Progression free and overall survival Median follow up was 57.5 months (45 – ongoing). Five years survival rate was 1.8%. Median OS was 32.4 weeks (range 2.6–230). By univariate analysis (Supplementary Table 3), 1-month clinical response was the only parameter associated with overall survival, whether considered as a two-class (worsening vs no) or three-class (worsening, stability, improvement) variable. Triple negative subtype and a baseline CSF Cyfra 21 − 1 threshold value > 79 ng/mL attained borderline significance (p < 0.1) and were therefore retained in the multivariate analyses. Due to the very dismal prognosis of meningeal carcinomatosis, we also examined the 24-weeks survival. Besides 1-month clinical response which was also associated with 24-weeks survival, the number of previous lines of therapy, a baseline CSF Cyfra 21 − 1 value below the median (18 ng/mL) and the absence of tumor cells at 1 month in the cerebrospinal fluid also attained borderline significance (p 79 ng/ml were independently associated with overall survival. Clinical response at 1 month and absence of tumor cells in the CSF at 1 month were associated with 24-weeks survival. Table 2 Results of the Cox proportional-hazards regression analyses Categories HR (95% CI) P value Overall Survival Clinical response A* + B** C*** 1 § 2.00 (1.23–3.28) 0.006 Baseline CSF Cyfra 21 − 1 value ≤ 79 ng/mL > 79 ng/mL 1 1.73 (1.07–2.80) 0.025 24-weeks survival Clinical response A* + B** C*** 1 5.96 (3.05–11.37) < 0.0001 1-month CSF tumor cells No Yes 1 2.28 (1.16–4.50) 0.017 *A : improvement; **B : stability; ***C: worsening. HR: hazard ratio. 95% CI: 95% confidence interval. §1 denotes the reference category. In addition, we looked at progression free survival (Supplementary Table 3). Median PFS was 27.1 weeks (range 1.6–174.0). No clinical nor baseline parameter was significantly associated with PFS. We did not evaluate the relationship between PFS and response–related parameters. We also did not look at the duration of response, a surrogate of progression-free survival, due to the overall poor prognosis of leptomeningeal carcinomatosis. Prognostic score In order to deliver a clinically actionable prognostic tool, we built different scores based on the results of the Cox models (Table 2 ). For each outcome (overall or 24-weeks survival), we were able to construct 2 or 3 groups of patients with distinct prognoses. The 2-class scores were constructed as follows. Patients were classified in the “good prognosis” group when both variables were favorable (0 point), and alternatively they were classified in the “poor prognosis” group (1 or 2 points). To construct the 3-class scores, patients were classified in the “good prognosis” group when both variables were favorable (0 point), in the “poor prognosis” group when both variables were unfavorable (2 points), and an “intermediate prognosis” group when either variable was favorable (1 point). Results are depicted in Fig. 3 and Supplementary Fig. 1. Regarding overall survival, the 3-class score based on 1-month clinical response and baseline CSF Cyfra 21 − 1 identified clinically and statistically meaningful different survival, notably for the patients of poor prognosis who were all deceased at 24 weeks, and had a median survival of about 8 weeks (Fig. 3 a). The median overall survival of each group is detailed in Table 2 . We specifically looked at the 81 patients with luminal breast cancer, with very similar results (supplementary Fig. 2). These results prompted us to specifically look at the 24-weeks survival, a reasonable clinical endpoint in this clinical setting. The short-term survival was closely related to 1-month response parameters combining clinical and biological evaluation. Both the 3-class (supplementary Fig. 1a) and 2-class (supplementary Fig. 1b) groups were very significantly associated with short term survival. It is noteworthy that all 17 patients with both unfavorable response variables at 1 month (clinical response and CSF malignant cells) were deceased at 18 weeks. DISCUSSION We report here important observations about diagnosis, treatment and prognosis of meningeal carcinomatosis in patients with advanced breast cancer. Our cohort appears representative of this clinical setting, with an important proportion of patients with very advanced breast cancer, as well as lobular carcinoma or triple-negative cancer subtypes, as already reported [ 1 , 8 , 10 ]. Meningeal carcinomatosis may frequently be clinically misleading. We describe here how a multidimensional approach may be necessary to confirm the diagnosis of meningeal carcinomatosis. A combination of MRI and biological analyses of the cerebrospinal fluid has been suggested as being the best approach [ 6 ], and almost all our patients underwent both procedures. Our observations are similar to the literature, with elevated protein levels in the CSF (> 50 mg/dl) in 56%-91% of patients (5). Diagnostic relevance of Cyfra 21 − 1 is confirmed, as elevated CSF levels of Cyfra 21 − 1 are associated with all other diagnosis features. This result is similar to several studies on MC from other primitive solid tumor, such as lung cancer [ 11 ], or head and neck cancer [ 12 ]. Abnormal baseline Cyfra 21 − 1 did not reach statistically significant prognostic value, although evidence suggests that after the start of IT treatment, elevated CSF Cyfra 21 − 1 is an independent adverse prognosis factor [ 3 ]. Statistical significance was reached for a baseline CSF Cyfra 21 − 1 value greater than 79 ng/mL, corresponding to patients in the upper quartile, which we used in our score. Strikingly, we overall show that less of 25% of patients had comprehensive features of meningeal carcinomatosis (Fig. 1 a). Taken together, these results suggest that the formal diagnosis of meningeal carcinomatosis should rely on a combinatorial but not exclusive approach, harnessing clinical, biological and radiological methods. We used widely described therapies for patients with advanced breast cancer, including intrathecal therapy [ 1 , 3 , 6 , 9 ]. We focused the present analysis on early response to IT therapy, then on overall survival prognosis, in order to identify which patients could potentially benefit from extended intrathecal therapy. After one month of IT treatment, almost all patients experienced either an improvement in clinical symptoms which triggered early clinical evaluation as a potential prognostic factor, or a decrease in the presence of tumor cells in the CSF or in the Cyfra 21 − 1 CSF level, with any relevant correlation, in line with the current limitations in evaluating response in leptomeningeal disease [ 7 ]. Only 15 patients had a comprehensive response, none evaluable with magnetic resonance imaging. It is noteworthy that so far no standardized MRI evaluation of leptomeningeal disease has been developed, due to a very low interobserver agreement[ 7 ]. Based on these results, we constructed the prognostic univariate and multivariate analyses on individual response criteria. Median overall survival was 32.4 weeks (range 2.6–230), consistent with recent large scale studies[ 8 ]. Most interestingly, clinical evaluation at one month was the most statistically significant factor associated with overall and 24-weeks survival. Clinical response at one month retained its powerful prognostic value in all multivariate models. Specifically treating patients with intrathecal chemotherapy has been demonstrated to improve progression free survival and reduce the number of MC-related death events [ 4 ]. Other biologically sound parameters also attained borderline significance, such as triple negative subtype (which therefore was not retrieved from the analyses), CSF Cyfra 21 − 1 levels or presence of tumor cells, and were retained in the multivariate models. None of the features associated with the cancer history or burden of disease showed significant prognostic value, as opposed to previous studies which did not consider neither the early clinical evolution nor key MC specific biological parameters [ 1 , 9 , 13 ]. Several scores have been already proposed, including in very recent studies, to refine the prognostic evaluation of meningeal carcinomatosis, however with very limited discriminating properties [ 8 ]. We introduce here two important novelties to build four original prognostic scores. First, we based the scores on a combination of clinical evaluation and biological response criteria specific to meningeal carcinomatosis. Second, we considered both overall survival and the landmark 24-weeks survival, because of the poor prognosis of BC MC and for clinical relevance purposes. Regarding overall survival, the 3 classes score based on 1-month clinical response and baseline Cyfra 21 − 1 (in the upper quartile) identified a very poor prognosis subset of patients. Regrouping the poor and intermediate prognosis groups confirmed a clear identification of two different prognostic subgroups. The 24-weeks OS prognostic score also described very well a very poor prognosis population. This result appears clinically relevant and applicable, as it is based on two variables easily measurable in daily practice: clinical response and 1-month CSF tumor cells, whereas Cyfra 21 − 1 is not always part of the usual biological analyses. The present report has several limitations. It is an observational, retrospective and monocentric work. Due to our very specific approach combining evaluation of the neurological clinical response by the same trained clinical team and original biological CSF analyses, it has not been possible to build a validation cohort. Of note, our population consisted exclusively of patients treated with intrathecal chemotherapy. This can be a recruitment bias, by selecting only patients fit enough to be treated at the onset of meningeal carcinomatosis, thus not representing the entirety of patients with advanced breast cancer and meningeal carcinomatosis. In summary, and to the best of our knowledge, this report is the first to propose comprehensive prognostic scores for both long- and short-term overall survival in patients with advanced breast cancer and meningeal carcinomatosis, considered treatable by intrathecal chemotherapy. As there is still no standard of care for such patients, we suggest that simple features such as clinical evaluation and presence of tumor cells in the cerebrospinal fluid after one month of treatment, and baseline CSF level of Cyfra 21 − 1 could be used in order to adequately decide which patient will potentially benefit from a prolongation of intrathecal therapy. DECLARATIONS Funding No specific funding was required for this institutional review Competing Interests The authors declare no conflict of interest Authorship Conception of the work: GN, PC Acquisition of data: all authors Analysis and interpretation of the data: GN, PC Drafting the manuscript: GN, PC Final approval: all authors Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: all authors Data Availability The data will be made available upon reasonable request to the corresponding author. REFERENCES Franzoi MA, Hortobagyi GN (2019) Leptomeningeal carcinomatosis in patients with breast cancer. 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Cancer Biomark Sect Dis Markers 13:123–130. https://doi.org/10.3233/CBM-130338 Liu L, Xie W, Xue P, Wei Z, Liang X, Chen N (2019) Diagnostic accuracy and prognostic applications of CYFRA 21-1 in head and neck cancer: A systematic review and meta-analysis. PloS One 14:e0216561. https://doi.org/10.1371/journal.pone.0216561 Le Rhun E, Massin F, Tu Q, Bonneterre J, Bittencourt MDC, Faure GC (2012) Development of a new method for identification and quantification in cerebrospinal fluid of malignant cells from breast carcinoma leptomeningeal metastasis. BMC Clin Pathol 12:21. https://doi.org/10.1186/1472-6890-12-21 Additional Declarations No competing interests reported. Supplementary Files CottuSupplementarydatajno.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3979871","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":274380422,"identity":"aae7c645-8732-473f-94ad-98e7dcd7d642","order_by":0,"name":"Grégoire Narjoux","email":"","orcid":"","institution":"Institut Curie","correspondingAuthor":false,"prefix":"","firstName":"Grégoire","middleName":"","lastName":"Narjoux","suffix":""},{"id":274380423,"identity":"839f78bc-a14e-477d-9b3f-84f4595420e0","order_by":1,"name":"Juliette Mainguené","email":"","orcid":"","institution":"Institut Curie","correspondingAuthor":false,"prefix":"","firstName":"Juliette","middleName":"","lastName":"Mainguené","suffix":""},{"id":274380424,"identity":"83598122-43d5-4622-a6a9-2724fce587f3","order_by":2,"name":"Marie-Noëlle Guilhaume","email":"","orcid":"","institution":"Institut Curie","correspondingAuthor":false,"prefix":"","firstName":"Marie-Noëlle","middleName":"","lastName":"Guilhaume","suffix":""},{"id":274380425,"identity":"4766ee12-a409-4957-98f9-904532baea72","order_by":3,"name":"Olivier Brenet","email":"","orcid":"","institution":"Institut Curie","correspondingAuthor":false,"prefix":"","firstName":"Olivier","middleName":"","lastName":"Brenet","suffix":""},{"id":274380426,"identity":"29b4b541-363e-4d27-b2ec-772ec56f6cab","order_by":4,"name":"Edith Borcoman","email":"","orcid":"","institution":"Institut Curie","correspondingAuthor":false,"prefix":"","firstName":"Edith","middleName":"","lastName":"Borcoman","suffix":""},{"id":274380427,"identity":"69c711c1-0c2b-41ef-9e65-2ba2a5d42b45","order_by":5,"name":"Laurence Escalup","email":"","orcid":"","institution":"Institut Curie","correspondingAuthor":false,"prefix":"","firstName":"Laurence","middleName":"","lastName":"Escalup","suffix":""},{"id":274380428,"identity":"6306236f-c4b3-4a5e-ac17-7b5d1b69f570","order_by":6,"name":"Hélène Salaun","email":"","orcid":"","institution":"Institut Curie","correspondingAuthor":false,"prefix":"","firstName":"Hélène","middleName":"","lastName":"Salaun","suffix":""},{"id":274380429,"identity":"7e1fc515-8f1e-442f-abba-6baed88e714c","order_by":7,"name":"Pauline Moreau","email":"","orcid":"","institution":"Institut Curie","correspondingAuthor":false,"prefix":"","firstName":"Pauline","middleName":"","lastName":"Moreau","suffix":""},{"id":274380430,"identity":"9aea25a9-6b5a-4e1f-a739-40f300a6db4f","order_by":8,"name":"Anne-Sophie Bouyer","email":"","orcid":"","institution":"Institut Curie","correspondingAuthor":false,"prefix":"","firstName":"Anne-Sophie","middleName":"","lastName":"Bouyer","suffix":""},{"id":274380431,"identity":"00530c69-8a31-4be9-b64c-a7549d847dbd","order_by":9,"name":"Paul Cottu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYHACxgMQmhlES0BpAgCslIeBLQGiBUwTp4XHAMIlpMWc/YzBAYYamzp7iZyPn3n3WMgxsPE+wKvFsicHqOVYmgSPRO5maZ5nEsYMbOwGeLUYHABqYWw4DNKyjZnngERig3wbfocZnH8D05LzDKSlvoGNjYCWG3BbcthAWhIYCGmxnPGs4EDCsTTJnjPPjCXnHJAwbCOkxZw/eeODDzU2/OztyQ8/vDlQJ89P0GEgIgFZhIAGqJZRMApGwSgYBXgBAGriO6NX/6DTAAAAAElFTkSuQmCC","orcid":"","institution":"Institut Curie","correspondingAuthor":true,"prefix":"","firstName":"Paul","middleName":"","lastName":"Cottu","suffix":""}],"badges":[],"createdAt":"2024-02-22 21:35:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3979871/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3979871/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51565344,"identity":"ce78a93b-2933-4ef7-bef9-0dd290b745b4","added_by":"auto","created_at":"2024-02-23 19:00:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":130889,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDiagnostic features of meningeal carcinomatosis in patients with breast cancer\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003ea. Venn diagram illustrating the variability of diagnostic features of meningeal carcinomatosis, and how each patient may differ from one another. Each shape represents a specific diagnostic parameter: \u003cem\u003egreen\u003c/em\u003e, clinical symptoms; \u003cem\u003elight blue\u003c/em\u003e: presence of tumor cells in the cerebrospinal fluid; \u003cem\u003elight red\u003c/em\u003e: magnetic resonance imaging showing leptomeningeal involvement; \u003cem\u003edark blue\u003c/em\u003e: elevated proteins in the cerebrospinal fluid; \u003cem\u003eorange\u003c/em\u003e: elevated Cyfra 21-1 in the cerebrospinal fluid. The figures indicate the number of patients sharing the same diagnostic characteristics.\u003c/p\u003e\n\u003cp\u003eb. Cyfra 21-1 concentration in the cerebrospinal fluid at diagnosis. \u003cem\u003eLeft, in red\u003c/em\u003e: distribution of all individual values. The blue bar indicates the upper quartile (values\u0026gt;79ng/mL). \u003cem\u003eRight, in blue\u003c/em\u003e: detail of the Cyfra 21-1 concentration values distribution in the first three quartiles.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-3979871/v1/e97cc6f69917b6b2d74c4412.png"},{"id":51565345,"identity":"a23d85f4-929b-4b25-a88c-ce88b4a8248b","added_by":"auto","created_at":"2024-02-23 19:00:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":65672,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eResponse evaluation after one month of intrathecal therapy.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ea. Clinical response at one month\u003c/p\u003e\n\u003cp\u003eb. Variation of tumor cells in the cerebrospinal fluid between baseline (X axis) and 1-month (Y axis)\u003c/p\u003e\n\u003cp\u003ec. Variation of Cyfra 21-1 concentration in the cerebrospinal fluid between baseline (red dots, each indicating an individual patient) and 1-month (green dots, each indicating an individual patient).\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-3979871/v1/070a4ef658cdf91fe5316427.png"},{"id":51565343,"identity":"b29ccdc5-b27d-4aa8-a2e9-2a2bd85c5cef","added_by":"auto","created_at":"2024-02-23 19:00:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":50358,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOverall survival\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ea. Overall survival according to a 3-class prognostic score\u003c/p\u003e\n\u003cp\u003eb. Overall survival according to a 2-class prognostic score\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-3979871/v1/126d360a371f9b7d3cc28894.png"},{"id":52147919,"identity":"df931f8f-850a-4eed-836f-b26ba19e5768","added_by":"auto","created_at":"2024-03-07 13:16:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":725302,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3979871/v1/0aabc991-beaa-4593-aeae-eb4be5bb6fb6.pdf"},{"id":51565346,"identity":"90043ff6-0fe7-4407-878d-105193390cec","added_by":"auto","created_at":"2024-02-23 19:00:43","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":106161,"visible":true,"origin":"","legend":"","description":"","filename":"CottuSupplementarydatajno.docx","url":"https://assets-eu.researchsquare.com/files/rs-3979871/v1/89f999f85856e1b81963d414.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Development of a prognostic score for meningeal carcinomatosis in patients with advanced breast cancer","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eMeningeal carcinomatosis (MC) is defined as leptomeningeal infiltration by tumor cells, including the pia mater, arachnoid and subarachnoid spaces, from a primary malignant tumor. Breast cancer is the most common etiology of MC among solid tumors, and MC occurs in approximately 5% of patients with metastatic breast cancer[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], who then carry an extremely poor prognosis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe gold standard for the diagnosis of MC remains the CSF (cerebrospinal fluid) cytology, but with a poor sensitivity[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Imaging (MRI mostly) and elevated proteins in the CSF strongly suggest diagnosis without being acknowledged standards [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], and there is either not validated assessment tool during the course of MC [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Our group had suggested that elevated Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 in the cerebrospinal fluid is associated with an MC diagnosis, with a potential prognostic value[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. There is also no consensus about treatment, and treatment effectiveness is low[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In our Institution, patients with breast cancer MC are generally treated by a dose-dense IT (intra-thecal) methotrexate regimen, in combination with other systemic treatment whenever possible[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. There are no general accepted criteria defining patient subgroups who might benefit from intrathecal therapy[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], and patients have often been heavily pretreated with various systemic drugs with few remaining therapeutic options.\u003c/p\u003e \u003cp\u003eWe report here our updated experience in patients with advanced breast cancer (BC) and MC. We had previously developed a poorly validated 4-parameter prognostic score solely based on baseline clinical features, which did not take into account the early clinical evolution in treated patients[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The aim of the present retrospective study was to elaborate a prognostic score of overall survival \u003cem\u003ein patients with BC related MC and initially considered amenable to intrathecal therapy\u003c/em\u003e, in order to provide a relevant tool to help clinicians to decide who might benefit from the continuation of invasive treatment regimens.\u003c/p\u003e"},{"header":"PATIENTS and METHODS","content":"\u003cp\u003eWe retrospectively recorded all patients with proven BC related MC and who were treated at least once with intrathecal chemotherapy from 2011 to 2019. Key eligibility criteria were: histologically proven breast carcinoma; meningeal carcinomatosis as defined either by tumor cells in the CSF, or the combination of neurological symptoms and/or compatible radiology results (CT scanner or MRI) and/or elevated total protein or Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 level in the CSF; treatment by at least one IT injection of methotrexate or thiotepa. Patients who received IT therapy were identified using a systematic search in the electronic records of the chemotherapy database of the hospital. All electronic medical records of identified patients were manually analyzed and details on MC diagnosis, treatment and clinical course were collected, including CSF Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 level, CSF protein count, CSF malignant cells that were collected at diagnosis and after one month of IT treatment.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistics\u003c/h2\u003e \u003cp\u003eThe principal objective of the study was to elaborate a prognostic score of overall survival in patients with newly diagnosed MC, and considered amenable to intrathecal therapy. Conventional descriptive statistics were used. Overall survival (OS) was defined as the time elapsed from MC diagnosis until death from any cause. Overall survival prediction curves were constructed with the Kaplan-Meier proportional hazard model. Multivariate analyses were performed with Cox-proportional hazards regression, with death as endpoint and using a forward variable selection procedure, based on the results of the univariate analyses. Final estimates were retained with a p value (Wald)\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Due to the very poor prognosis of MC, we refined the analyses by focusing on 24-weeks overall survival. We considered the following variables of interest in building the univariate and multivariate analyses: pathological subtype (triple negative vs other), clinical presentation (visceral metastases, neurological symptoms), previous therapies, cerebrospinal fluid (CSF) protein level (abnormal vs normal), CSF Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 levels with various exploratory threshold values. Based on our previous reports[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], we also included in the analyses clinical response (worsening at 1 month vs no) and CSF malignant cells at 1 month (yes vs no).\u003c/p\u003e \u003cp\u003eIn order to build the prognostic scores, points were attributed to the final independent prognostic variables from the global OS and 24-weeks survival Cox models. Global scores were derived for each patient and 2 or 3 risk categories were defined (i.e. low and high risk, or low, intermediate and high risk). The statistical analyses were performed with the MedCalc\u0026reg; Statistical Software version 20.008 (MedCalc Software Ltd, Ostend, Belgium; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.medcalc.org\u003c/span\u003e\u003cspan address=\"https://www.medcalc.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e; 2021)\u003c/p\u003e \u003cp\u003e The study was approved by the French national data protection authority and our Institutional Review Board. This study followed the precepts of the Declaration of Helsinki and French laws concerning biomedical research. Per current French regulations, no written informed consent was required.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003ePopulation\u003c/h2\u003e\n\u003cp\u003eThe characteristics of the 109 patients population at diagnosis of MC are depicted in Supplementary Table\u0026nbsp;1. Briefly, 81 patients had a HR (hormone receptor) positive, HER2 negative breast carcinoma (74.3%), while 10 out of 109 had a Her 2\u0026thinsp;+\u0026thinsp;cancer (9.2%) and 18 out of 109 (16.5%) had triple negative (TN) cancer. Most tumors were of non-specific subtype (NST, 66.5%) and 32 out of 109 were infiltrating lobular carcinomas (29.4%).\u003c/p\u003e\n\u003cp\u003eAt MC diagnosis, 44 patients out of 109 (40.4%) had at least one prior or concurrent brain metastasis and among them 32 (72.7%) had already undergone brain radiation therapy. Visceral metastases were present in 67 patients (61.5%). The median number of systemic treatments lines before MC diagnosis was 2 (0\u0026ndash;7). Time between initial BC diagnosis and MC diagnosis was significantly longer in HR\u0026thinsp;+\u0026thinsp;than in HR- patients (median time 7 years vs 2 years, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) as was time between metastasis diagnosis and MC diagnosis (median : 2 years vs 1 year, p\u0026thinsp;=\u0026thinsp;0.004). Her2\u0026thinsp;+\u0026thinsp;status did not affect time between diagnosis of metastasis and MC (median time: 1.8 years vs 1.8 years, p\u0026thinsp;=\u0026thinsp;0.76, when compared to HR\u0026thinsp;+\u0026thinsp;patients). TN status shortened time between diagnosis of metastasis and MC (median time to MC metastases: 11 vs 25 months, p\u0026thinsp;=\u0026thinsp;0.001, when compared to HR\u0026thinsp;+\u0026thinsp;patients).\u003c/p\u003e\n\u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\n\u003ch2\u003eDiagnosis of meningeal carcinomatosis\u003c/h2\u003e\n\u003cp\u003eMost patients (n\u0026thinsp;=\u0026thinsp;102, 93.6%) initially presented miscellaneous neurological symptoms that triggered further investigation (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea). Brain and/or spinal MRI were initially performed in 92 patients out of 109 (84%). MRI was abnormal in 54 out of 92 (59%) and 47 patients out of 54 (87%) with an abnormal MRI also reported MC-related clinical symptoms. Conversely, 38 patients out of 92 (41%) had a normal MRI while presenting MC symptoms. Seven patients were diagnosed with MRI only. Malignant cells were observed in 85 out of 108 (78%) CSF baseline samples. CSF protein count was abnormal for 101 out of 108 (92.8%) CSF samples (median value: 1.02 g/mL \u0026ndash; normal value\u0026thinsp;\u0026lt;\u0026thinsp;1 g/mL). We performed CSF dosing of Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 at diagnosis [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e] (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eb). The Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 level (normal value\u0026thinsp;\u0026le;\u0026thinsp;1 ng/mL) was elevated in 86 patients out of 95 (90.5%), with a median value of 18 ng/mL (IQR 25\u0026ndash;75: 2.8\u0026ndash;79). No patient had Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 elevation as sole diagnostic feature (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eDiagnosis of meningeal carcinomatosis\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMC* symptoms\u003c/p\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;109\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003esymptomatic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e102\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e93.6%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003easymptomatic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.4%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMost frequent MC symptoms\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;98\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDizziness\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20.3%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHeadache (and no Intra-cranial hypertension syndrome)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19.5%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIntra-cranial hypertension syndrome (Nausea. vomiting. headache)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.4%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCranial nerve dysfunction\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12.3%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eConfusion\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.9%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMotor paralysis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSensory symptoms\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMeningeal syndrome (headache\u0026thinsp;+\u0026thinsp;neck stiffness\u0026thinsp;+\u0026thinsp;phono or photophobia)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.6%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCSF** level of CYFRA 21\u0026thinsp;\u0026minus;\u0026thinsp;1 at baseline\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eN\u0026thinsp;=\u0026thinsp;95\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.5%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eElevated\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e86\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95.5%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTotal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e95\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100.0%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\"\u003e\u003cem\u003e*MC : meningeal carcinomatosis ; **CSF : cerebrospinal fluid ;\u003c/em\u003e\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eWe next analyzed the relationship between the clinical, radiological and biological diagnostic features (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea) showing that only 23 patients (29.1% of 79 patients evaluable with all modalities) had a comprehensive MC diagnostic presentation. When looking at the relationship between MRI and CSF data, it was observed that 2 patients out of 92 (2.2%) had a diagnosis based on symptoms associated with either elevated CSF protein or Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 levels, but with no CSF malignant cells and normal MRI, while 35 patients out of 71 (49.3%) with CSF malignant cells had a concordant abnormal MRI and 36 patients out of 71 (50.7%) with CSF malignant cells had a concurrent normal MRI (p\u0026thinsp;=\u0026thinsp;0.0016, Fisher\u0026rsquo;s exact Test). Overall, 35 patients out of 53 (66.1%) with an abnormal MRI had CSF malignant cells. Finally, 36 patients out of 38 (94.7%) with a negative MRI had CSF malignant cells and 18 patients out of 20 (90%) with no CFS malignant cells had an abnormal MRI. Secondly, exploring the relationship between CSF malignant cells and CSF protein count suggested a correlation trend: 91 patients had elevated CSF proteins, and 73 patients out of 91 (80.2%) had CSF malignant cells (p\u0026thinsp;=\u0026thinsp;0.24, Chi-squared test). Of note, 10 patients out of 15 (66.7%) with a normal CSF protein count had CSF malignant cells. Furthermore, among the 23 patients with no CSF malignant cells, 18 (78.2%) had an elevated CSF protein count. Interestingly, no significant difference was observed between the presence CSF malignant cells and a baseline elevated CSF protein count (p\u0026thinsp;=\u0026thinsp;0.31, Fisher exact test). Finally, we explored the relationship between baseline Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 CSF level and baseline CSF cellularity and CSF protein count. Of 74 patients with baseline CSF malignant cells, 69 (93.2%) had also an elevated CSF Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1. Similarly, among 21 patients with no baseline malignant cells, 17 (81%) had an elevated CSF Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 (p\u0026thinsp;=\u0026thinsp;0.10, Fisher exact test). Likewise, no significant difference was observed between Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 and proteins baseline CSF elevation (p\u0026thinsp;=\u0026thinsp;0.15, Fisher exact test).\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eTreatments\u003c/h2\u003e\n\u003cp\u003eWe used intrathecal treatments in combination with systemic therapies according to the underlying breast cancer subtype: 88 patients (80.7%) had systemic chemotherapy associated with IT treatment, 26 patients (23.8%) received endocrine therapy including 10 with a CDK4/6 inhibitor. In the 10 HER2 positive patients, 8 were administered HER2 blocking agents. In 38 patients (out of 44 with concurrent brain metastases, 86.4%), radiation therapy had been previously used to treat brain metastases.\u003c/p\u003e\n\u003cp\u003eMethotrexate was commonly used as first IT therapy (Supplementary Table\u0026nbsp;2). IT Thiotepa was used as a second line in case of progressive MC, or methotrexate related toxicity, or when radiotherapy involving Central Nervous System (CNS) was indicated [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]. The treatment protocols were established as previously reported [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]. Changing IT treatment decision was made based on clinical worsening and/or imaging (MRI or scan) progressive disease. Discontinuation of IT therapies was decided according to clinical worsening when both methotrexate and thiotepa had been used, or according to individual quality of life considerations. Malignant CSF cells detection during IT was taken into account to change or stop IT treatment if concordant with clinical evolution but was not used alone to conclude.\u003c/p\u003e\n\u003cp\u003eOverall, 103 patients received IT methotrexate, including 97 out of 109 (88.9%) as a first line of IT therapy. The median number of IT cycles in the overall population was 6 (1\u0026ndash;47). IT thiotepa was administered in 42 patients (37.6%), including 12 as a first line and 29 as a second line of IT therapy (Supplementary Table\u0026nbsp;2).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eResponse at one month\u003c/h2\u003e\n\u003cp\u003eWe considered response to IT therapy at 1 month by examining neurological clinical evaluation and CSF biology. Clinically, neurological improvement, stability, and worsening were observed in 49 (44.9%), 32 (29.4%) and 28 patients (25.7%), respectively (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea). One-month CSF cytology was evaluable in 87 patients, and almost half of them (n\u0026thinsp;=\u0026thinsp;43, 49.5%) had no detectable tumor cells in the CSF at 1 month, including 28 patients with baseline CSF tumor cells. In the 17 patients with no CSF malignant cells at baseline, 2 had detectable cells at one month (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb). There was no correlation between clinical and cellular responses (p\u0026thinsp;=\u0026thinsp;0.723; Fisher exact test). We observed a significant decrease in the median Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 CSF level at one month (2.55 ng/mL vs 18 ng/mL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; Wilcoxon rank sum test, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ec). We again found no relation between Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 level decrease and clinical response (p\u0026thinsp;=\u0026thinsp;0.856; ANOVA and Chi-squared test).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003eProgression free and overall survival\u003c/h2\u003e\n\u003cp\u003eMedian follow up was 57.5 months (45 \u0026ndash; ongoing). Five years survival rate was 1.8%. Median OS was 32.4 weeks (range 2.6\u0026ndash;230). By univariate analysis (Supplementary Table\u0026nbsp;3), 1-month clinical response was the only parameter associated with overall survival, whether considered as a two-class (worsening vs no) or three-class (worsening, stability, improvement) variable. Triple negative subtype and a baseline CSF Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 threshold value\u0026thinsp;\u0026gt;\u0026thinsp;79 ng/mL attained borderline significance (p\u0026thinsp;\u0026lt;\u0026thinsp;0.1) and were therefore retained in the multivariate analyses. Due to the very dismal prognosis of meningeal carcinomatosis, we also examined the 24-weeks survival. Besides 1-month clinical response which was also associated with 24-weeks survival, the number of previous lines of therapy, a baseline CSF Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 value below the median (18 ng/mL) and the absence of tumor cells at 1 month in the cerebrospinal fluid also attained borderline significance (p\u0026thinsp;\u0026lt;\u0026thinsp;0.1) and were retained in the multivariate analyses. We developed two Cox proportional-hazards regression analyses (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Clinical response at 1 month and a baseline CSF Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 value\u0026thinsp;\u0026gt;\u0026thinsp;79 ng/ml were independently associated with overall survival. Clinical response at 1 month and absence of tumor cells in the CSF at 1 month were associated with 24-weeks survival.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eResults of the Cox proportional-hazards regression analyses\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCategories\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eHR (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOverall Survival\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eClinical response\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eA* + B**\u003c/p\u003e\n\u003cp\u003eC***\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e2.00 (1.23\u0026ndash;3.28)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.006\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline CSF\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 value\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026le;\u0026thinsp;79 ng/mL\u003c/p\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;79 ng/mL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003cp\u003e1.73 (1.07\u0026ndash;2.80)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.025\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e24-weeks survival\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eClinical response\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eA* + B**\u003c/p\u003e\n\u003cp\u003eC***\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003cp\u003e5.96 (3.05\u0026ndash;11.37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e1-month CSF\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003etumor cells\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003cp\u003e2.28 (1.16\u0026ndash;4.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.017\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cem\u003e*A : improvement; **B : stability; ***C: worsening. HR: hazard ratio. 95% CI: 95% confidence interval.\u003c/em\u003e \u003csup\u003e\u003cem\u003e\u0026sect;1\u003c/em\u003e\u003c/sup\u003e \u003cem\u003edenotes the reference category.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn addition, we looked at progression free survival (Supplementary Table\u0026nbsp;3). Median PFS was 27.1 weeks (range 1.6\u0026ndash;174.0). No clinical nor baseline parameter was significantly associated with PFS. We did not evaluate the relationship between PFS and response\u0026ndash;related parameters. We also did not look at the duration of response, a surrogate of progression-free survival, due to the overall poor prognosis of leptomeningeal carcinomatosis.\u003c/p\u003e\n\u003cdiv id=\"Sec10\" class=\"Section3\"\u003e\n\u003ch2\u003ePrognostic score\u003c/h2\u003e\n\u003cp\u003eIn order to deliver a clinically actionable prognostic tool, we built different scores based on the results of the Cox models (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). For each outcome (overall or 24-weeks survival), we were able to construct 2 or 3 groups of patients with distinct prognoses. The 2-class scores were constructed as follows. Patients were classified in the \u0026ldquo;good prognosis\u0026rdquo; group when both variables were favorable (0 point), and alternatively they were classified in the \u0026ldquo;poor prognosis\u0026rdquo; group (1 or 2 points). To construct the 3-class scores, patients were classified in the \u0026ldquo;good prognosis\u0026rdquo; group when both variables were favorable (0 point), in the \u0026ldquo;poor prognosis\u0026rdquo; group when both variables were unfavorable (2 points), and an \u0026ldquo;intermediate prognosis\u0026rdquo; group when either variable was favorable (1 point). Results are depicted in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e and Supplementary Fig.\u0026nbsp;1. Regarding overall survival, the 3-class score based on 1-month clinical response and baseline CSF Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 identified clinically and statistically meaningful different survival, notably for the patients of poor prognosis who were all deceased at 24 weeks, and had a median survival of about 8 weeks (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ea). The median overall survival of each group is detailed in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. We specifically looked at the 81 patients with luminal breast cancer, with very similar results (supplementary Fig.\u0026nbsp;2).\u003c/p\u003e\n\u003cp\u003eThese results prompted us to specifically look at the 24-weeks survival, a reasonable clinical endpoint in this clinical setting. The short-term survival was closely related to 1-month response parameters combining clinical and biological evaluation. Both the 3-class (supplementary Fig.\u0026nbsp;1a) and 2-class (supplementary Fig.\u0026nbsp;1b) groups were very significantly associated with short term survival. It is noteworthy that all 17 patients with both unfavorable response variables at 1 month (clinical response and CSF malignant cells) were deceased at 18 weeks.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eWe report here important observations about diagnosis, treatment and prognosis of meningeal carcinomatosis in patients with advanced breast cancer. Our cohort appears representative of this clinical setting, with an important proportion of patients with very advanced breast cancer, as well as lobular carcinoma or triple-negative cancer subtypes, as already reported [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMeningeal carcinomatosis may frequently be clinically misleading. We describe here how a multidimensional approach may be necessary to confirm the diagnosis of meningeal carcinomatosis. A combination of MRI and biological analyses of the cerebrospinal fluid has been suggested as being the best approach [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], and almost all our patients underwent both procedures. Our observations are similar to the literature, with elevated protein levels in the CSF (\u0026gt;\u0026thinsp;50 mg/dl) in 56%-91% of patients (5). Diagnostic relevance of Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 is confirmed, as elevated CSF levels of Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 are associated with all other diagnosis features. This result is similar to several studies on MC from other primitive solid tumor, such as lung cancer [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], or head and neck cancer [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Abnormal baseline Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 did not reach statistically significant prognostic value, although evidence suggests that after the start of IT treatment, elevated CSF Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 is an independent adverse prognosis factor [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Statistical significance was reached for a baseline CSF Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 value greater than 79 ng/mL, corresponding to patients in the upper quartile, which we used in our score. Strikingly, we overall show that less of 25% of patients had comprehensive features of meningeal carcinomatosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Taken together, these results suggest that the formal diagnosis of meningeal carcinomatosis should rely on a combinatorial but not exclusive approach, harnessing clinical, biological and radiological methods.\u003c/p\u003e \u003cp\u003eWe used widely described therapies for patients with advanced breast cancer, including intrathecal therapy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. We focused the present analysis on early response to IT therapy, then on overall survival prognosis, in order to identify which patients could potentially benefit from extended intrathecal therapy. After one month of IT treatment, almost all patients experienced either an improvement in clinical symptoms which triggered early clinical evaluation as a potential prognostic factor, or a decrease in the presence of tumor cells in the CSF or in the Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 CSF level, with any relevant correlation, in line with the current limitations in evaluating response in leptomeningeal disease [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Only 15 patients had a comprehensive response, none evaluable with magnetic resonance imaging. It is noteworthy that so far no standardized MRI evaluation of leptomeningeal disease has been developed, due to a very low interobserver agreement[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBased on these results, we constructed the prognostic univariate and multivariate analyses on individual response criteria. Median overall survival was 32.4 weeks (range 2.6\u0026ndash;230), consistent with recent large scale studies[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Most interestingly, clinical evaluation at one month was the most statistically significant factor associated with overall and 24-weeks survival. Clinical response at one month retained its powerful prognostic value in all multivariate models. Specifically treating patients with intrathecal chemotherapy has been demonstrated to improve progression free survival and reduce the number of MC-related death events [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Other biologically sound parameters also attained borderline significance, such as triple negative subtype (which therefore was not retrieved from the analyses), CSF Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 levels or presence of tumor cells, and were retained in the multivariate models. None of the features associated with the cancer history or burden of disease showed significant prognostic value, as opposed to previous studies which did not consider neither the early clinical evolution nor key MC specific biological parameters [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral scores have been already proposed, including in very recent studies, to refine the prognostic evaluation of meningeal carcinomatosis, however with very limited discriminating properties [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. We introduce here two important novelties to build four original prognostic scores. First, we based the scores on a combination of clinical evaluation and biological response criteria specific to meningeal carcinomatosis. Second, we considered both overall survival and the landmark 24-weeks survival, because of the poor prognosis of BC MC and for clinical relevance purposes. Regarding overall survival, the 3 classes score based on 1-month clinical response and baseline Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 (in the upper quartile) identified a very poor prognosis subset of patients. Regrouping the poor and intermediate prognosis groups confirmed a clear identification of two different prognostic subgroups. The 24-weeks OS prognostic score also described very well a very poor prognosis population. This result appears clinically relevant and applicable, as it is based on two variables easily measurable in daily practice: clinical response and 1-month CSF tumor cells, whereas Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 is not always part of the usual biological analyses.\u003c/p\u003e \u003cp\u003eThe present report has several limitations. It is an observational, retrospective and monocentric work. Due to our very specific approach combining evaluation of the neurological clinical response by the same trained clinical team and original biological CSF analyses, it has not been possible to build a validation cohort. Of note, our population consisted exclusively of patients treated with intrathecal chemotherapy. This can be a recruitment bias, by selecting only patients fit enough to be treated at the onset of meningeal carcinomatosis, thus not representing the entirety of patients with advanced breast cancer and meningeal carcinomatosis.\u003c/p\u003e \u003cp\u003eIn summary, and to the best of our knowledge, this report is the first to propose comprehensive prognostic scores for both long- and short-term overall survival in patients with advanced breast cancer and meningeal carcinomatosis, considered treatable by intrathecal chemotherapy. As there is still no standard of care for such patients, we suggest that simple features such as clinical evaluation and presence of tumor cells in the cerebrospinal fluid after one month of treatment, and baseline CSF level of Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 could be used in order to adequately decide which patient will potentially benefit from a prolongation of intrathecal therapy.\u003c/p\u003e"},{"header":"DECLARATIONS","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo specific funding was required for this institutional review\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception of the work: GN, PC\u003c/p\u003e\n\u003cp\u003eAcquisition of data: all authors\u003c/p\u003e\n\u003cp\u003eAnalysis and interpretation of the data: GN, PC\u003c/p\u003e\n\u003cp\u003eDrafting the manuscript: GN, PC\u003c/p\u003e\n\u003cp\u003eFinal approval: all authors\u003c/p\u003e\n\u003cp\u003eAgreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: all authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data will be made available upon reasonable request to the corresponding author.\u003c/p\u003e"},{"header":"REFERENCES","content":"\u003col\u003e\n\u003cli\u003eFranzoi MA, Hortobagyi GN (2019) Leptomeningeal carcinomatosis in patients with breast cancer. Crit Rev Oncol Hematol 135:85\u0026ndash;94. https://doi.org/10.1016/j.critrevonc.2019.01.020\u003c/li\u003e\n\u003cli\u003eLamba N, Cagney DN, Catalano PJ, Elhalawani H, Haas-Kogan DA, Wen PY, Wagle N, Lin NU, Aizer AA, Tanguturi S (2023) Incidence proportion and prognosis of leptomeningeal disease among patients with breast vs. non-breast primaries. Neuro-Oncol 25:973\u0026ndash;983. https://doi.org/10.1093/neuonc/noac249\u003c/li\u003e\n\u003cli\u003eComte A, Jdid W, Guilhaume MN, Kriegel I, Piperno-Neumann S, Dieras V, Dorval T, Pierga JY, Cottu PH, Mignot L, Bidard FC (2013) Survival of breast cancer patients with meningeal carcinomatosis treated by intrathecal thiotepa. J Neurooncol 115:445\u0026ndash;452. https://doi.org/10.1007/s11060-013-1244-x\u003c/li\u003e\n\u003cli\u003eLe Rhun E, Wallet J, Mailliez A, Le Deley MC, Rodrigues I, Boulanger T, Lorgis V, Barri\u0026egrave;re J, Robin YM, Weller M, Bonneterre J (2020) Intrathecal liposomal cytarabine plus systemic therapy versus systemic chemotherapy alone for newly diagnosed leptomeningeal metastasis from breast cancer. Neuro-Oncol 22:524\u0026ndash;538. https://doi.org/10.1093/neuonc/noz201\u003c/li\u003e\n\u003cli\u003eZhang Z, Tian C, Shi Q, Hao J, Zhao N, Liu Z (2017) Diagnostic Value of CYFRA 21-1 in the Cerebrospinal Fluid for Leptomeningeal Metastasis. Dis Markers 2017:2467870. https://doi.org/10.1155/2017/2467870\u003c/li\u003e\n\u003cli\u003eLe Rhun E, Guckenberger M, Smits M, Dummer R, Bachelot T, Sahm F, Galldiks N, de Azambuja E, Berghoff AS, Metellus P, Peters S, Hong Y-K, Winkler F, Schadendorf D, van den Bent M, Seoane J, Stahel R, Minniti G, Wesseling P, Weller M, Preusser M (2021) EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours. Ann Oncol Off J Eur Soc Med Oncol 32:1332\u0026ndash;1347. https://doi.org/10.1016/j.annonc.2021.07.016\u003c/li\u003e\n\u003cli\u003eLe Rhun E, Devos P, Boulanger T, Smits M, Brandsma D, Rud\u0026agrave; R, Furtner J, Hempel J-M, Postma TJ, Roth P, Snijders TJ, Winkler F, Winklhofer S, Castellano A, Hattingen E, Capellades J, Gorlia T, Van den Bent M, Wen PY, Bendszus M, Weller M (2019) The RANO Leptomeningeal Metastasis Group proposal to assess response to treatment: lack of feasibility and clinical utility and a revised proposal. Neuro-Oncol 21:648\u0026ndash;658. https://doi.org/10.1093/neuonc/noz024\u003c/li\u003e\n\u003cli\u003eCarausu M, Carton M, Darlix A, Pasquier D, Leheurteur M, Debled M, Mouret-Reynier MA, Goncalves A, Dalenc F, Verret B, Campone M, Augereau P, Ferrero JM, Levy C, Fumet J-D, Lefeuvre-Plesse C, Petit T, Uwer L, Jouannaud C, Larrouquere L, Chevrot M, Courtinard C, Cabel L (2021) Breast cancer patients treated with intrathecal therapy for leptomeningeal metastases in a large real-life database. ESMO Open 6:100150. https://doi.org/10.1016/j.esmoop.2021.100150\u003c/li\u003e\n\u003cli\u003eGauthier H, Guilhaume MN, Bidard FC, Pierga JY, Girre V, Cottu PH, Laurence V, Livartowski A, Mignot L, Di\u0026eacute;ras V (2010) Survival of breast cancer patients with meningeal carcinomatosis. Ann Oncol Off J Eur Soc Med Oncol 21:2183\u0026ndash;2187. https://doi.org/10.1093/annonc/mdq232\u003c/li\u003e\n\u003cli\u003eFigura NB, Rizk VT, Armaghani AJ, Arrington JA, Etame AB, Han HS, Czerniecki BJ, Forsyth PA, Ahmed KA (2019) Breast leptomeningeal disease: a review of current practices and updates on management. Breast Cancer Res Treat 177:277\u0026ndash;294. https://doi.org/10.1007/s10549-019-05317-6\u003c/li\u003e\n\u003cli\u003eWang P, Piao Y, Zhang X, Li W, Hao X (2013) The concentration of CYFRA 21-1, NSE and CEA in cerebro-spinal fluid can be useful indicators for diagnosis of meningeal carcinomatosis of lung cancer. Cancer Biomark Sect Dis Markers 13:123\u0026ndash;130. https://doi.org/10.3233/CBM-130338\u003c/li\u003e\n\u003cli\u003eLiu L, Xie W, Xue P, Wei Z, Liang X, Chen N (2019) Diagnostic accuracy and prognostic applications of CYFRA 21-1 in head and neck cancer: A systematic review and meta-analysis. PloS One 14:e0216561. https://doi.org/10.1371/journal.pone.0216561\u003c/li\u003e\n\u003cli\u003eLe Rhun E, Massin F, Tu Q, Bonneterre J, Bittencourt MDC, Faure GC (2012) Development of a new method for identification and quantification in cerebrospinal fluid of malignant cells from breast carcinoma leptomeningeal metastasis. BMC Clin Pathol 12:21. https://doi.org/10.1186/1472-6890-12-21\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Meningeal carcinomatosis, breast cancer, prognostic score, Cyfra 21 − 1","lastPublishedDoi":"10.21203/rs.3.rs-3979871/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3979871/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eMeningeal carcinomatosis carries a dismal prognosis in patients with breast cancer, and requires invasive therapies. The aim of the present retrospective study was to elaborate a prognostic score of overall survival in patients with breast cancer related meningeal carcinomatosis (MC).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e109 patients with proven breast cancer MC, treated by at least one intrathecal (IT) injection of methotrexate or thiotepa at Institut Curie were retrospectively recorded from 2011 to 2019. We developed prognostic clinical scores for overall survival and 24-weeks survival.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eDiagnosis and evaluation of meningeal carcinomatosis appears based on a combination of clinical, imaging and laboratory studies. Three significant Overall Survival (OS) prognostic factors were identified. Clinical response or stabilization at one month of intrathecal therapy had a favorable independent prognostic value for both overall and 24-weeks survival. Additionally, baseline CSF Cyfra 21\u0026thinsp;\u0026minus;\u0026thinsp;1 level lower than 79 ng/mL in the cerebrospinal fluid and absence of 1-month cerebrospinal fluid (CSF) malignant cells carried a borderline favorable independent prognostic value for overall and 24-weeks survival, respectively. We constructed 2-class and 3-class prognostic scores for each outcome, identifying a very poor prognosis population.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eTo our knowledge it is the first study to develop a response-based prognosis score in patients with breast cancer related MC. This one month prognostic score may help to decide which patient could actually benefit from the prolongation of intrathecal therapy.\u003c/p\u003e","manuscriptTitle":"Development of a prognostic score for meningeal carcinomatosis in patients with advanced breast cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-23 19:00:38","doi":"10.21203/rs.3.rs-3979871/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"94e3e041-ca5d-4eaf-aafc-9e07ff70a5a5","owner":[],"postedDate":"February 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-07T13:15:55+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-23 19:00:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3979871","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3979871","identity":"rs-3979871","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}