LMD-18. Detection and serial monitoring of CSF ctDNA in breast cancer leptomeningeal disease (BCLM)

Abstract Background CSF cytology is the gold standard diagnostic test for BCLM, but is hampered by a low sensitivity, often necessitating repeated lumbar puncture to confirm or refute the diagnosis. Furthermore, during the treatment of BCLM, there is no robust quantitative response tool to guide treatment decisions. Material and Methods cfDNA was obtained from CSF and plasma in patients with breast cancer undergoing investigation for BCLM (n = 28) and during subsequent intrathecal treatment (n = 13). Ultra low pass whole genome sequencing (ulpWGS) and estimation of the ctDNA fraction was performed. Results were validated by mutation-specific digital droplet PCR (ddPCR). Results 22/28 cases had confirmed BCLM by positive MRI and/or CSF cytology. The remaining 6/28 had suspected but non-confirmed BCLM, and at median 20 months follow up, these patients were BCLM-free. CSF ctDNA fraction was significantly elevated (median 57.5, IQR 38.3 - 84.9%) in confirmed BCLM compared to 6 non-confirmed BCLM (median 5.0, IQR 0.0 - 6.7%) (p <0.0001). ctDNA fraction was detected in BCLM confirmed cases regardless of negative cytology or MRI. Plasma ctDNA fraction was only detected in extra-cranial disease progression. ctDNA fraction was concordant with mutant allele fraction measured by ddPCR (n = 118 samples). Serial CSF ctDNA fraction during intrathecal treatment showed dynamic changes, while CSF cytology and MRI were often unchanged or equivocal. Early reduction in CSF ctDNA fraction was associated with longer responses to intrathecal therapy. Further, rising ctDNA fraction during intrathecal chemotherapy could be detected up to 6 weeks before relapse in neurological symptoms, cytology or MRI. Conclusion Measuring CSF ctDNA fraction is a sensitive diagnostic test for BCLM and could lead to more timely and accurate diagnosis. During intrathecal chemotherapy, CSF ctDNA also provides a quantitative response biomarker to help guide clinical management in this difficult treatment scenario.

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Leptomeningeal disease and breast cancer: Relationship of outcome and subtype.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.601 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 601-601

Author(s):

Sausan Abouharb ◽

Joe Ensor ◽

Monica Elena Loghin ◽

Ruth Katz ◽

Ana M. Gonzalez-Angulo ◽

...

Keyword(s):

Breast Cancer ◽

Proportional Hazards ◽

Treatment Strategies ◽

Continuous Variable ◽

Cox Proportional Hazards ◽

Intrathecal Therapy ◽

Leptomeningeal Disease ◽

Tumor Subtype ◽

Dismal Prognosis ◽

Significant Difference

601 Background: Breast cancer (BC) is one of the most common tumors to involve the leptomeninges. Outcome of leptomeningeal disease (LMD) across BC subtypes is not well documented. We aimed to characterize clinical features and outcomes of LMD based on BC subtypes. Methods: We retrospectively reviewed medical records of patients diagnosed with LMD from BC (1997 to 2012). All patients had BC. Cases of LMD were based on the presence of neoplastic cells on cerebrospinal fluid examination and/or evidence of LMD by imaging studies. Survival was estimated by the Kaplan-Meier method and significant differences in survival were determined by Cox proportional hazards or log-rank tests. Results: 232 patients were included, 189 of them had available tumor subtype classified as: hormone receptor positive (HR+) BC N=67 (35.5%), human epidermal growth factor receptor 2 positive (HER2+) N=55 (29%), and 67 (35.5%) triple-negative BC (TNBC). Median age at diagnosis of LMD was 49.7 years. (Range 24-89). Median overall survival (OS) from LMD diagnosis across all subtypes was 3.1 months (95% CI, 2.5 to 3.7). Median OS correlated with BC subtype: 3.7 months (95% CI: 2.4, 6.0) in HR+, 4.0 months (95% CI: 2.6, 6.9) in HER2+, and 2.2 months (95% CI: 1.5, 3.0) in TNBC, (p=0.0002). There was an 11.4% chance a patient diagnosed with LMD would survive 1 year and the chance of surviving at least 3 years was 1.3%. When age was used as a continuous variable, older age was associated with worse outcome (p<0.0001). Patients with HER2+ BC and LMD were more likely to have received systemic therapy (ST) (70%), compared to HR+ (41%) and TNBC (41%) (p=0.002). 38% of patients with HER2+ BC received HER2 directed therapy. There was no difference in the use of intrathecal therapy (IT) (52%) across subtypes (p=0.3). Use of IT therapy (p<0.0001) and ST (p<0.0001) were both associated with improved age-adjusted OS. After adjusting for age, ST, there was no difference in OS between patients with HR+ and HER2+ BC (p =0.14), but a significant difference remained between TNBC and HER2+ BC (p < 0.0001). Conclusions: LMD carries a dismal prognosis. Our data shows that OS correlates with tumor subtype. Patients with TNBC had a significantly shorter OS compared to patients with HER2+ BC. New treatment strategies are needed.

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BIOM-05. CASE SERIES OF MULTI-INSTITUTIONAL UTILITY OF CNSide TO MANAGE LEPTOMENINGEAL DISEASE IN PATIENTS WITH METASTATIC BREAST CANCER

Neuro-Oncology ◽

10.1093/neuonc/noab196.036 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi10-vi10

Author(s):

Priya Kumthekar ◽

Barbara Blouw ◽

Julie Mayer ◽

Deanna Fisher ◽

Michael Dugan ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Tumor Cells ◽

Case Series ◽

Metastatic Breast ◽

Ommaya Reservoir ◽

Leptomeningeal Disease ◽

Cell Detection ◽

Breast Cancer Patients ◽

Intrathecal Treatment

Abstract INTRODUCTION Leptomeningeal Disease (LMD) occurs in 5% of breast cancer patients. Diagnosing LMD remains challenging. Current standard of care has limited sensitivity and is inadequate for monitoring treatment response. Biocept’s CNSide™ is a proprietary assay utilizing a 10-antibody capture cocktail with microfluidic chamber that quantitatively detects tumor cells in the cerebrospinal fluid (CSF). We present a case series using CNSide to manage LMD of 4 unique breast cancer patients treated at three different institutions and demonstrate its impact on clinical management. METHODS Patients were treated at Smilow Cancer Hospital at Yale-New Haven (1 patient), Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute (1 patient) and Barrow Neurological Institute (2 patients). All patients received intrathecal treatment (IT) via an Ommaya Reservoir. CSF tumor cells were detected via cytology and CNSide at diagnosis (3 patients) and throughout treatment (4 patients). RESULTS At diagnosis, CNSide detected tumor cells in 3/3 patients, vs 2/3 patients for cytology. The fourth patient was diagnosed with LMD before CNSide was available. CNSide detected CSF tumor cells in 9/9 (100%) of measurements, vs 4/9 (44%) for cytology for samples analyzed in parallel. Throughout treatment, CNSide was able to track the quantitative LMD response and showed a decrease in CSF tumor cells in all four patients, ranging from 99.7% (from 773 to 2 cells, 1 patient) to 100% (from 4447 to 0 cells; and from 33 to 0 cells, 2 patients). CONCLUSION Intrathecal treatment of LMD via Ommaya reservoir is not widely adopted across the US. Our experience suggests that using CNSide for quantitative CSF tumor cell detection may aid in diagnosing LMD, as well as in quantifying response to treatment particularly in the setting of intrathecal therapy. However, larger prospective clinical trials are needed to establish the role of CNSide in the diagnosis and management of LMD.

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LMD-09. Outcomes and symptom benefit from palliative radiotherapy for leptomeningeal disease in breast cancer patients

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab071.034 ◽

2021 ◽

Vol 3 (Supplement_3) ◽

pp. iii9-iii9

Author(s):

Jamie Takayesu ◽

Eli Sapir ◽

Jiaheng Xie ◽

Yilun Sun ◽

Aki Morikawa ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Hormone Receptor ◽

Multivariate Logistic Regression Model ◽

Her2 Status ◽

Symptom Improvement ◽

Intrathecal Therapy ◽

Leptomeningeal Disease ◽

Breast Cancer Patients ◽

Improvement Rate

Abstract Objective The benefit of radiotherapy (RT) in patients with leptomeningeal disease (LMD) is poorly characterized. This study assessed the overall survival (OS) and clinical improvement of a largely symptomatic cohort of breast cancer patients with LMD, to identify patient subsets most likely to benefit from palliative RT. Methods Patients with breast cancer-related classic radiographic LMD (36% cytology-confirmed) were treated with palliative whole brain and/or partial spine RT between 2000–2020 at a single academic institution in this retrospective analysis. OS was calculated from date of LMD diagnosis using the Kaplan-Meier method. A multivariate logistic regression model incorporating ER/PR status, HER2 status, ECOG and steroid use was developed to identify factors associated with symptom benefit, which was ascertained retrospectively by chart review. Results Among 64 patients, the radiographic distribution of LMD was in the brain (58%), spine (22%), or both (20%). A total of 63% had brain metastases, and 57% of patients had ER+ and/or PR+, 22% HER2+, and 38% triple-negative disease. Of the symptomatic patients (94%), primary symptom domains included cranial nerve deficits (34%), sensory/motor deficits from intracranial disease (25%) or spinal disease (27%), and headaches/nausea (14%), with 42% of patients reporting >1 symptom domain. Two-thirds of patients were on steroids prior to RT, and 13% of patients received intrathecal therapy. OS was 3.75 months. Following a median dose of 30Gy in 10 fractions, 59% of symptomatic patients experienced symptom improvement, with similar improvement rate across domains (12%, 15%, 19%, 14%, respectively); 21% of patients had improvement in >1 symptom domain. Hormone receptor positivity was independently associated with symptom improvement following RT (OR 3.5, 95% CI 1.2–11, p=0.029). Conclusions In this poor-prognosis cohort of breast cancer patients with LMD, palliative RT yielded symptomatic improvement, and may be particularly beneficial among better-prognosis patients with hormone receptor-positive disease.

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Survival differences in patients with brain metastases according to breast cancer subtypes

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.11507 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 11507-11507

Author(s):

B. Nam ◽

K. Lee ◽

T. Kim ◽

J. Ro

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Triple Negative ◽

Multivariate Analyses ◽

Metastatic Breast ◽

Intrathecal Therapy ◽

Leptomeningeal Disease ◽

Receptor Subtypes ◽

Significant Variable ◽

Trastuzumab Therapy

11507 Background: Brain metastases (BM) occur in as many as one-third of patients with metastatic breast cancer (MBC). Incidences and prognoses by triple receptor subtypes in BM have not been well delineated. Methods: Retrospectively, prognoses were assessed according to clinical characteristics, triple receptor subtypes, and receipt of trastuzumab therapy by univariate and multivariate analyses. ER/PR/HER2 were tested by IHC with HER2 FISH for IHC 2+ and for all 118 consecutive primary BC. Results: Between 8/2001 and 4/2006, 138 of 805 pts (17.1%) with MBC presented with BM at NCC Korea. More pts with triple negative and HER2+ tumors developed BM (see table ). The median age was 47 years. They were single (9%), multiple (80%), or leptomeningeal disease with or without multiple BM (11%). As initial therapy, 104 pts received WBRT, 8, intrathecal therapy (IT), 9, WBRT with IT, and 17 others. Of 56 HER2+ pts, 45 received trastuzumab either before (n=25) or after (n=13), or continuously before and after BM diagnosed (n=7). By 10/2006, 117 pts died with a median survival of 4.5 months. Multivariate analyses indicated age, tumor receptor subtypes, leptomeningeal presentation and number of extracranial disease sites as significant factors. Receipt of trastuzumab therapy after BM was a significant variable for survival in HER2+ diseases (3.8 vs. 13.4 mo, p=0.0000). Pts with triple negative subtype lived shortest compared with other types (p=0.0035). Conclusions: More pts with triple negative and HER2+ disease developed BM. HER2+ disease gained a significant survival benefit by trastuzumab therapy. Supported by NCC Grant 0610240 and 0510520. [Table: see text] No significant financial relationships to disclose.

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Concordant HER2 status between malignant CSF cells and primary breast carcinoma tissue

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.1104 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 1104-1104

Author(s):

Y. Kwon ◽

J. Ro ◽

K. S. Lee ◽

I. H. Park

Keyword(s):

Breast Carcinoma ◽

Cancer Center ◽

Her2 Status ◽

Intrathecal Therapy ◽

Leptomeningeal Disease ◽

Csf Cytology ◽

Her2 Positive ◽

Carcinoma Tissue ◽

Csf Cells ◽

Cytology Specimen

1104 Background: Leptomeningeal diseases (LMD) from breast cancer are detected in up to 19% of patients with brain metastasis and their prognosis is extremely poor. Diagnosis of leptomeningeal disease requires positive cerebrospinal fluid (CSF) cytology. However, it is not known whether HER2 status of malignant CSF cells coincides with that of original breast carcinoma cells. We intended to determine whether CSF cytology specimen is suitable for evaluating HER2 status by fluorescence in situ hybridization (FISH) in LMD to provide the basis for HER2 targeted intrathecal therapy. Methods: Both formalin-fixed paraffin-embedded (FFPE) breast carcinoma tissue and liquid based CSF cytology specimen were tested for HER2 status in 16 patients who developed LMD at National Cancer Center between Dec 2004 and Jul 2008. We evaluated HER2 gene amplification by FISH on destained CSF cytology slides which contained minimum 20 malignant cells per slide, and compared with HER2 status by immunohistochemistry (IHC) in FFPE breast carcinoma tissue. HER2 was determined positive when FISH ratio > 2.2 or IHC 3+ according to ASCO/CAP guideline. Results: Concordance rate of HER2 status between CSF cytology by FISH and FFPE tissue by IHC was 100% as shown in the table. Conclusions: When CSF cytology specimen was appropriately prepared yielding adequate cellularity without dry artifact, CSF cytology was suitable for evaluating HER2 status by FISH in LMD. Intrathecal HER2 targeted therapy could be attempted when FFPE breast carcinoma tissue is HER2 positive in view of highly concordant HER2 status by our data. Supported by NCC Grant No 0610240- 3. [Table: see text] No significant financial relationships to disclose.

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Gene Expression Assay in the Management of Early Breast Cancer

Current Medicinal Chemistry ◽

10.2174/0929867326666191205163329 ◽

2020 ◽

Vol 27 (17) ◽

pp. 2826-2839 ◽

Cited By ~ 2

Author(s):

Roberta Caputo ◽

Daniela Cianniello ◽

Antonio Giordano ◽

Michela Piezzo ◽

Maria Riemma ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Decision Making ◽

Adjuvant Chemotherapy ◽

Early Breast Cancer ◽

Treatment Decision ◽

Endocrine Treatment ◽

Expression Ratio ◽

Treatment Decision Making ◽

Low Sensitivity

The addition of adjuvant chemotherapy to hormonal therapy is often considered questionable in patients with estrogen receptor-positive early breast cancer. Low risk of disease relapse after endocrine treatment alone and/or a low sensitivity to chemotherapy are reasons behind not all patients benefit from chemotherapy. Most of the patients could be exposed to unnecessary treatment- related adverse events and health care costs when treatment decision-making is based only on classical clinical histological features. Gene expression profile has been developed to refine physician’s decision-making process and to tailor personalized treatment to patients. In particular, these tests are designed to spare patients the side effects of unnecessary treatment, and ensure that adjuvant chemotherapy is correctly recommended to patients with early breast cancer. In this review, we will discuss the main diagnostic tests and their potential clinical applications (Oncotype DX, MammaPrint, PAM50/Prosigna, EndoPredict, MapQuant Dx, IHC4, and Theros-Breast Cancer Gene Expression Ratio Assay).

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High-dose intravenous methotrexate in the management of breast cancer with leptomeningeal disease: Case series and review of the literature

Hematology/Oncology and Stem Cell Therapy ◽

10.1016/j.hemonc.2019.08.008 ◽

2019 ◽

Vol 12 (4) ◽

pp. 189-193 ◽

Cited By ~ 3

Author(s):

Jonathan T. Kapke ◽

Robert J. Schneidewend ◽

Zeeshan A. Jawa ◽

Chiang-Ching Huang ◽

Jennifer M. Connelly ◽

...

Keyword(s):

Breast Cancer ◽

Case Series ◽

Leptomeningeal Disease ◽

High Dose ◽

Review Of The Literature ◽

Disease Case

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Dissemination of health technologies: Trends in the use of diagnostic test in breast cancer screening

Journal of Healthcare Quality Research ◽

10.1016/j.jhqr.2019.02.007 ◽

2019 ◽

Vol 34 (4) ◽

pp. 177-184

Author(s):

C. Natal ◽

A. Fernandez-Somoano ◽

I. Torá-Rocamora ◽

C. Vidal ◽

X. Castells ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Screening ◽

Breast Cancer Screening ◽

Diagnostic Test ◽

Health Technologies

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A prospective study of an AI-based breast cancer screening solution for resource-constrained settings.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e13586 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e13586-e13586

Author(s):

Richa Bansal ◽

Bharat Aggarwal ◽

Lakshmi Krishnan

Keyword(s):

Breast Cancer ◽

Cancer Screening ◽

Breast Cancer Screening ◽

Sensitivity And Specificity ◽

Breast Tissue ◽

Dense Breast ◽

Resource Constrained ◽

Dense Breast Tissue ◽

Dense Breasts ◽

Low Sensitivity

e13586 Background: Screening mammography is often found to have low sensitivity in women with high density breast tissues. Alternate modalities of breast USG and MRI require high-quality expensive equipment making the regular screening with these modalities less affordable and accessible, particularly in resource-constrained settings This study evaluates the clinical performance of an AI-based test (Thermalytix) that uses machine learning on breast thermal images which could potentially be a low-cost solution for breast screening in low- and middle-income countries (LMICs). Methods: The prospective comparative study conducted from December 2018 to January 2020 evaluated the performance of Thermalytix in women with dense and non-dense breast tissue who presented for a health check-up at a hospital. All women underwent Thermalytix and mammography. Further investigations were recommended for participants who were reported as positive on either test. Sensitivity and specificity of Thermalytix were evaluated across age-groups, menopausal status, and breast densities. Results: Among the 687 women recruited for the study, 459 women who satisfied the inclusion criteria were included in the analysis. 168 women had ACR categories ‘c’ or ‘d’ dense breasts, of which 37 women had an inconclusive mammography report (BI-RADS 0). Overall, 21 women were detected with breast cancer in the study. Thermalytix demonstrated an overall sensitivity of 95.2% (95% CI, 76.1-99·9) and a specificity of 88.6% (95% CI, 85.2-91.4). Among women with dense breast tissue (n=168), Thermalytix showed a sensitivity of 100% (95% CI, 69.2-100) and a specificity of 81.7% (95% CI, 74.7-87.4). In women with ACR categories ‘c’ and ‘d’ dense breasts, mammography reported 22% of them as inconclusive (BI-RAD 0), while in the same sub-set of the population Thermalytix demonstrated a sensitivity of 100%. Conclusions: The AI-based Thermalytix demonstrated high sensitivity and specificity in the study cohort. It also fared well in women younger than 50 years and pre-menopausal women where routine mammography screening yields low sensitivity. Overall, this study introduces Thermalytix, a promising radiation-free, automated, and privacy-aware test that can supplement mammography for routine screening of women, especially in women with dense breast tissue, and has the potential to influence the clinical practice in LMICs by making breast cancer screening portable and affordable. Performance of Thermalytix and mammography in women with high breast densities (ACR categories ‘c’ and ‘d’ breasts). Clinical trial information: NCT04688086. [Table: see text]

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