Leptomeningeal metastasis in breast cancer - a systematic review

Scott, Brian J.; Oberheim-Bush, Nancy Ann; Kesari, Santosh

doi:10.18632/oncotarget.5911

Cited by 98 publications

(119 citation statements)

References 38 publications

(49 reference statements)

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“…In our models, i.c.v. delivery of HER2-BBz CAR T cells demonstrated robust antitumor activity against multifocal disease and leptomeningeal spread, which is clinically relevant to CNS-metastatic breast cancer where leptomeningeal disease is associated with shorter survival (24). Our findings will ultimately inform the design of our upcoming phase I trial in which HER2-BBz CAR T cells will be delivered i.c.v.…”

Section: Discussionmentioning

confidence: 66%

Regional Delivery of Chimeric Antigen Receptor–Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain

Priceman

Tilakawardane

Jeang

et al. 2018

Clinical Cancer Research

240

185

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Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease. Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T-cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain. Results: Here, we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo antitumor activity in orthotopic xenograft models. Importantly, we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease. Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. Clin Cancer Res; 24(1); 95–105. ©2017 AACR.

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Section: Discussionmentioning

confidence: 66%

Regional Delivery of Chimeric Antigen Receptor–Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain

Priceman

Tilakawardane

Jeang

et al. 2018

Clinical Cancer Research

240

185

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“…To our knowledge, lots of previous studies enrolled patients with various solid tumors2, 17, 24, 29, 30, 31, 32 despite the prognosis of LM from breast cancer was satisfactory 33. Therefore, patients with different primaries were enrolled in this study.…”

Section: Discussionmentioning

confidence: 99%

Concurrent radiotherapy and intrathecal methotrexate for treating leptomeningeal metastasis from solid tumors with adverse prognostic factors: A prospective and single‐arm study

Pan

Yang

et al. 2016

Intl Journal of Cancer

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The prognosis of leptomeningeal metastasis (LM) from solid tumors is extremely poor, especially for patients with adverse prognostic factors. In this phase II clinical trial, we evaluated the efficacy and safety of intrathecal chemotherapy (IC) combined with concomitant involved‐field radiotherapy (IF‐RT) for treating LM from solid tumors with adverse prognostic factors. Fifty‐nine patients with LM from various solid tumors were enrolled between May 2010 and December 2014. Concurrent therapy consisted of concomitant IC (methotrexate 12.5–15 mg and dexamethasone 5 mg, weekly) and IF‐RT (whole brain and/or spinal canal RT, 40 Gy/20f). For patients with low Karnofsky performance status (KPS) score and radiotherapy intolerance, induction IC (1–3 times) was given before concurrent therapy. Thirty‐eight patients (64.4%) received subsequent treatments. All patients were followed up at least 6 months after LM diagnosis or until death. Primary endpoint evaluated was clinical response rate. Secondary endpoints were overall survival (OS) and safety. The pathological types included lung cancer (n = 42), breast cancer (n = 11) and others (n = 6). Median KPS score was 40 (range 20–70). Fifty‐one patients (86.4%) completed concurrent therapy. The overall response rate was 86.4% (51/59). OS ranged from 0.4 to 36.7 months (median 6.5 months), and 1‐year‐survival rate was 21.3%. Treatment‐related adverse events mainly included acute meningitis, chronic‐delayed encephalopathy, radiculitis, myelosuppression and mucositis. Twelve patients (20.3%) had grade III–V toxic reactions. We concluded that IC combined with concomitant IF‐RT, with significant efficacy and acceptable toxicity, may be an optimal therapeutic option for treatment of LM from solid tumors with adverse prognostic factors. LM, in which cancer cells spread to membranes enveloping the brain and spinal cord, is a devastating complication of solid cancers. Existing LM therapies center on IC. In this prospective clinical study, the authors combined intrathecal methotrexate with involved‐field radiotherapy in a concomitant regimen, showing that the approach can potentially improve quality of life for patients with adverse prognostic factors. Concurrent radiotherapy‐bolstered IC by contributing to prolonged remission of neurological symptoms and increasing OS. The findings suggest that the concomitant regimen could be an optimal treatment option for LM.

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“…Traditional regimens such as cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), anthracycline-based regimens have reported efficacy in case series. 35,36 Leptomeningeal disease occurs in 3%-5% of patients with metastatic breast cancer, and although there is no standard of care for leptomeningeal disease, radiation therapy and chemotherapy may be considered. Depending on the functional status of the patient, the healthcare provider may consider IV chemotherapy with high-dose methotrexate, intrathecal chemotherapy with liposomal cytarabine, methotrexate or thiotepa.…”

Section: A N U S C R I P Tmentioning

confidence: 99%

“…Depending on the functional status of the patient, the healthcare provider may consider IV chemotherapy with high-dose methotrexate, intrathecal chemotherapy with liposomal cytarabine, methotrexate or thiotepa. 35 educate patients about the incidence, presentation, related symptoms, treatment strategies, and prognosis. The advanced practice nurse should assess and manage the side effects of treatment, as well as monitor treatment effectiveness.…”

Section: A N U S C R I P Tmentioning

confidence: 99%

“…Agents such as tyrosine kinase inhibitors, inhibitors of intracellular signaling pathways, angiogenesis inhibitors, poly (ADP-ribose) polymerase inhibitors for BRCSdeficient tumors, rapamycin analogs, and agents that interfere with DNA repair have shown remarkable clinical activity. 6,[19][20][21][22][23][24][25][27][28][29][30][31][32][33][34][35][36] Several of these agents are already a part of standard of care for patients with breast cancer, and others are being further investigated due to indications of clinical response in early clinical trials. As a result of these targeted therapies health care providers will have the ability to match each patient with the right therapy.…”

Section: Future Directionsmentioning

confidence: 99%

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