Leptomeningeal Carcinomatosis: 'A Catastrophic Complication of Breast Cancer'

Kate M. O'Rourke

Disclosures

May 05, 2020

Extending the lifespans of patients with breast cancer with novel therapeutic interventions comes with a downside: It has made patients more susceptible to leptomeningeal carcinomatosis (LC), an increasingly prevalent secondary disease. Estimated to occur in up to 16% of patients with breast cancer, LC carries severe consequences.

"Leptomeningeal metastases are a catastrophic complication of breast cancer and lead to death in an average of 3.5 to 6 months, despite treatment," said Adrienne Boire, MD, PhD, a neuro-oncologist at Memorial Sloan Kettering Cancer Center in New York City.

Recent research efforts are aiming to bring this disease, which Boire described as relatively understudied compared with other sites of central nervous system (CNS) metastases, out of the shadows. LC occurs when cancer cells invade the leptomeninges, or spinal fluid–filled compartments that surround the brain and spinal cord, either with or without parenchymal brain metastases.

"At present, the therapies we are using are based on creative reapplication of strategies from other sites of disease, and it is for this reason that there is a real push to understand the biology of leptomeningeal metastases," Boire said.

The risk for leptomeningeal disease varies. Compared with ductal carcinoma, lobular carcinomas are more likely to metastasize to the meninges. Other factors further amplify a patient's risk of developing LC.  

"The risk for leptomeningeal carcinomatosis is greater with more aggressive tumors, such as triple-negative and HER2-positive [tumors], and it is also greater for patients who have very extensive bone metastases," said Fatima Cardoso, MD, director of the breast unit of the Champalimaud Clinical Centre in Lisbon, Portugal.

Most patients with LC also have solid brain metastases. Research has demonstrated that patients who undergo resection of brain metastases are at an increased risk of leptomeningeal disease. One study showed that patients who underwent surgical resection of brain metastases before stereotactic radiosurgery were 6.5 times more likely to develop LC compared with those who underwent stereotactic radiosurgery alone.

The timing in which LC develops is also variable, ranging from a late-stage complication of gradual disease progression to something observed immediately upon the cancer becoming metastatic. Diagnosing LC is also a challenging endeavor because patients often have nonspecific symptoms, such as headaches, cognitive disorders, and potential signs of progressive focal lesions.

Much-Needed Guidance Being Offered

Oncology societies have gradually started to provide guidance to physicians on the diagnosis and treatment of LC.

The first European guidelines on LC were published in 2017 by the European Association of Neuro-Oncology and the European Society for Medical Oncology. The National Comprehensive Cancer Network includes a small section on LC in their guidelines for CNS cancers. The Society for Neuro-Oncology held its first conference on brain metastases in 2019.  

Patients with suspected LC should undergo MRI of the brain and the spinal cord, interpreted by a specialist in neuro-oncology, and undergo biological analysis of the cerebrospinal fluid (CSF). A diagnosis of LC can be confirmed if neoplastic cells are present.

Current management of LC may include a combination of intra-CSF chemotherapy, usually with methotrexate, systemic therapy, radiotherapy, or best supportive care. Prolonged survival has been observed in patients with LC who are treated with systematic administration of high-dose methotrexate (3.5-8 g/m2), and combining methotrexate with intrathecal liposomal cytarabine has also shown promising efficacy with decent tolerability in clinical trials. However, Boire noted that, to date, very few patients actually receive intrathecal chemotherapy.

Radiotherapy is used for relieving obstruction points on CSF-outflow channels due to ependymal nodules, tumor deposits, or bulky disease, and it can provide symptom palliation. Ventriculoperitoneal or lumboperitoneal shunt surgery can improve symptoms and prolong survival in patients with hydrocephalus from LC. Clinical trials are currently testing targeted therapies and immunotherapy strategies for LC.

"Selection of the appropriate treatment for leptomeningeal disease in an individual patient depends on the volume and location of the disease in the central nervous system, prior treatments, the presence and volume of extracranial metastases, and more importantly, performance status," said Joseph Bovi, MD, associate professor of radiation oncology at the Medical College of Wisconsin.

Changes to Clinical Trials May Improve LC Research

Prospective trials on LC are limited and many studies are underpowered, according to Priscilla Brastianos, MD, director of the Central Nervous System Metastasis Program at the Massachusetts General Hospital Cancer Center, who presented on leptomeningeal disease at this year's American Society of Clinical Oncology meeting. According to Brastianos, deaths from progression of systemic disease can prevent assessment of the effect on intracranial disease. Few systematic studies of LC in patients with breast cancer exist.

But that may be changing. In 2019, the US Food and Drug Administration (FDA) and the National Brain Tumor Society sponsored a brain metastases workshop to strategize how to include more patients with brain metastases in clinical trials. Traditionally, researchers have excluded patients with brain metastases from clinical trials because this population may have unknown side effects that may impact trial results. In a paradigm shift, the FDA has decided not to necessarily approve clinical research proposals that exclude patients with CNS metastases, stating that this group of patients should be included in the protocol design and perhaps studied as a separate cohort.

New research may lead to better treatments for LC. In Boire's laboratory, researchers are studying how cancer cells enter the spinal fluid and how they live and grow once they arrive, with the hope of understanding ways to target this process. They have found that cancer cells circulating in the blood enter the brain through the choroid plexus, a structure in the ventricles that generates spinal fluid. In preclinical models, they have also shown that pharmacologic interference with complement C3a signaling is beneficial in suppressing leptomeningeal metastasis.

Boire said cancer cells make use of the innate immune system and co-opt the complement cascade, which loosens the connections on the blood-CSF barrier, making it leaky. This alters the composition of the spinal fluid, which is typically without much protein or metabolic intermediates, to support cell growth.

"However, with this leakier CSF barrier, the spinal fluid is enriched and able to support cancer cell growth," Boire said. "We have found that interrupting this process will inhibit the ability of cancer cells to grow in the spinal fluid."

Boire said she envisions a therapeutic strategy for LC that targets the microenvironmental interactions by interrupting C3a in addition to delivering a chemotherapy directed at the cancer cell itself.

"You would end up targeting the ability of cancer cells to grow in this space and then also targeting the cancer cell itself, really giving it a one-two punch, which is what we try to do in oncology, target multiple pathways at once," she said. "There are a number of C3a antagonists that have been used commercially for asthma but failed to alter outcomes. However, we repurposed them in mouse models and found they worked beautifully to prevent cancer cell growth."

Future work will test these strategies in humans. Boire added that although there is currently no means of preventing LC, this has not lessened her hopes of changing the paradigm in this deadly disease.

"My dream is to identify an at-risk population for leptomeningeal carcinomatosis and provide a [preventive] treatment."

Drs Boire, Bovi, and Cardoso have no relevant disclosures. Dr Brastianos disclosed honoraria from Angiochem, Genentech, Merck; consulting/advisory with Angiochem, Genentech, Roche, Lilly, Tesaro, and research funding from Bristol-Myers Squibb, Merck, and Pfizer.

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