For a long time, women with advanced HER2+ breast cancer, when the disease reached the coverings of the brain, found themselves almost without a solution. These
leptomeningeal metastasesrare but serious, often lead to rapid neurological deterioration.
A team from MD Anderson Cancer Center evaluated a combination of three treatments in 17 women with leptomeningeal metastases from metastatic HER2+ breast cancer. The first results are intriguing in their scale.
HER2+ breast cancer when it reaches the meninges
Leptomeningeal metastases correspond to tumor cells which disperse in the cerebrospinal fluid and line the meninges, these thin membranes which surround the brain and spinal cord. Unlike a tumor “ball” in the brain, the disease is diffuse. It can cause headaches, balance disorders, partial paralysis or epileptic seizures.
Treating this form remains complicated because the blood-brain barrier blocks many drugs before they reach the cerebrospinal fluid. The options were mainly limited to radiotherapy or intrathecal injections (directly into the spinal cord). Tucatinib, a small molecule targeting HER2, had already shown an effect on brain metastases, and the researchers found it in this fluid at levels close to the free fraction in the blood.
A combination treatment that prolongs survival in leptomeningeal metastases
In the TBCRC049, non-randomized phase II trial, 17 women aged at least 18 years, with newly diagnosed HER2+ metastatic breast cancer and leptomeningeal metastases, received 21-day cycles: tucatinib twice daily, oral capecitabine 14 days a day (oral chemotherapy – Xeloda), and trastuzumab infusion every three weeks (conventional cancer treatment HER2+ breast cancer, the best known of which is herceptin). Fifteen patients already presented neurological symptoms.
Median overall survival reached 10 months, more than double the 4.4 months observed in historical series, and 41% of women were still alive at 18 months. “The combination provided a clinically meaningful improvement in overall survival compared to historical controls“said Rashmi Murthy, associate professor of breast medical oncology and lead author of the study. “For these patients, who often face limited treatment options, our results represent a step forward, offering new hope in how we treat and manage leptomeningeal metastases.“.
Fewer neurological symptoms and tolerance considered acceptable
In 13 evaluable patients, 5 presented an objective response from leptomeningeal metastases, and 7 of the 12 women followed for neurological deficit saw their disorders improve. “In addition to the encouraging results on survival, throughout the study we observed improvements in neurological symptoms.“, says Barbara O’Brien, associate professor of neuro-oncology and co-senior author of the study. “Treatments for leptomeningeal metastases from breast cancer have historically focused on stabilizing the disease rather than improving symptoms, making these results particularly significant and encouraging.“, according to the MD Anderson Cancer Center. The main side effects – diarrhea, nausea, vomiting, hand-foot syndrome and increased liver enzymes – were considered generally manageable in this trial limited to 17 patients.
The study has some limitations (an early interruption due to the slow pace of recruitment, a low volume of data due to the rarity of leptomeningeal metastases, etc.), nevertheless, it offers a first hope for women whose prognosis is currently very poor.