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SABCS Studies Shed Light on Targetable Mutations, Enhertu Efficacy in Leptomeningeal Disease

NEW YORK – Researchers at the San Antonio Breast Cancer Symposium last week reported that breast cancer patients whose disease has spread to the tissues surrounding the brain and spinal cord may have therapeutically targetable mutations in the cerebral spinal fluid.

They further highlighted the potential of one targeted agent, AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan), to treat this rare and otherwise difficult-to-treat disease.

In 5 percent to 15 percent of metastatic breast cancer patients, cancer cells from their breast will migrate to their CSF. This fluid, which shuttles nutrients to the brain and spinal cord, can also ferry cancer cells to areas of the brain and spinal cord where they can take hold and grow. This type of cancer, called leptomeningeal disease, is typically treated with surgery, radiation, and chemotherapy, but patients have poor outcomes. Patients typically live between two and four months with treatment following diagnosis of leptomeningeal disease.

Researchers led by Laura Huppert, a breast cancer oncologist at the University of California, San Francisco, wanted to assess whether patients with this disease have therapeutically targetable mutations in CSF, and compare those mutations with mutations found in their central nervous system tumor tissue and peripheral blood. Since "analysis of CSF for actionable mutations is not routinely done," Huppert said, "the frequency and concordance of actionable mutations in the CNS versus peripherally is not well characterized."

Leptomeningeal disease is difficult to diagnose. Currently, oncologists need positive CSF cytology for a confirmed diagnosis, but when cytology tests are negative, they can draw on imaging tests. "Sometimes you need to do multiple CSF taps, and there are even cases where … the CSF is negative, and I do clinically think they have leptomeningeal disease," Huppert said.

At UCSF, Huppert's group prospectively collected CSF, blood, and archival tumor samples from patients with metastatic breast cancer who were known or suspected to have leptomeningeal disease. They analyzed these samples using different next-generation sequencing tests: Biocept's CNSide test on CSF; CNSide, Foundation Medicine's FoundationOne Liquid CDx, and Guardant Health's Guardant360 on blood; and NGS panels from Strata Oncology, Caris Life Sciences, and UCSF on tumor tissue.

Researchers collected CSF samples from seven patients with metastatic hormone receptor (HR)-positive, HER2-negative metastatic breast cancer with leptomeningeal disease, and found mutations that can be targeted with currently available drugs in four: two had a PIK3CA E542K mutation; one patient had both a PIK3CA E542K mutation and an ERBB amplification; and one patient had an ESR1 Y537S mutation. When researchers compared actionable mutations detected in the CSF with results from tumor tissue and blood testing, they found the same PIK3CA E542K mutation from CSF samples in the two patients' tumor samples; in one patient they detected an ESR1 mutation systemically that they didn't see in CSF; and in another patient they found a different type of ESR1 mutation in tumor tissue than they did in the CSF.

They also analyzed samples from six patients with metastatic triple-negative breast cancer and found an actionable PIK3CA E542K mutation in the CSF of one patient. When they compared the mutational profiles of four patients' blood and tissue samples, they similarly reported discordant and concordant mutations by sample type.

In one patient without a confirmed diagnosis of leptomeningeal disease but with a brain metastasis, the researchers found a TP53 mutation in both the CSF and blood. While there aren't any commercially available drugs specifically indicated for TP53-mutated cancers, when these mutations are found in circulating tumor DNA, they have been informative for diagnosing other types of cancers.

As such, "detection of a [TP53] mutation in the CSF in the absence of confirmed leptomeningeal disease was intriguing," Huppert said. She concluded that her team's findings demonstrate the need for further studies to pin down the clinical utility of detecting targetable mutations in leptomeningeal disease patients, particularly now that CNS-penetrant targeted agents are becoming available.

Although Huppert's group focused on leptomeningeal disease in HR-positive, HER2-negative and triple-negative breast cancer, in another study led by Marta Vaz Batista, a medical oncologist at the Hospital Professor Doutor Fernando Fonseca in Portugal, researchers focused on HER2-positive and HER2-low metastatic breast cancer patients with leptomeningeal disease. At SABCS, Batista shared preliminary data on the activity of one targeted agent, Enhertu, which is already approved for HER2-positive and -low metastatic breast cancer and is known to have CNS activity.

In a cohort of the DEBBRAH study, researchers enrolled seven heavily pretreated patients, all of whom had their leptomeningeal disease diagnosis confirmed by a positive cytology test. None had prior treatment for CNS diseases.

With two patients still on treatment at data cutoff, median overall survival with Enhertu was 13.3 months and median progression-free survival was 8.9 months. One patient with an intracranial brain lesion saw it completely resolve and two patients had stable disease for at least 24 weeks. Batista reported a clinical benefit rate of 71 percent, and noted that activity was seen in patients with HER2-positive and HER2-low tumors. Researchers didn't see any new side effects with Enhertu in this population.

Despite the study's limited size, "it adds some knowledge to what we have today," Batista said, but noted that the activity of Enhertu warrants more investigation in larger cohorts of patients with leptomeningeal disease.