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Drug treatment based on precision medicine has shown unprecedented results in the therapy of a rare type of brain tumor, papillary craniopharyngiomas (PCP), which may mean a paradigm shift in the approach to this type of tumor, which accounts for between 1.2-4.6% of intracranial tumors

The study, which has just been published in The New England Journal of Medicine, has been carried out by researchers at the Mass General Cancer Center, part of the Mass General Brigham health care system. This is a phase II trial, in which 15 patients have been included. One of the most striking results is that 94% of patients showed a response to therapy.

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They manage to gain time to advance one of the most malignant brain tumors thanks to a new drug

  • Editor: PILAR PÉREZ Chicago

They manage to gain time to advance one of the most malignant brain tumors thanks to a new drug

Papillary craniopharyngiomas are a rare type of brain tumor that causes significant morbidity to patients. While surgery and radiation are often used to treat these tumors, incomplete removal of the tumor and radiation toxicity can leave patients with lifelong health problems after treatment, including neuroendocrine dysfunction or loss of vision or memory, the study authors explain.

"The tumor is located in a delicate area, close to the hypothalamus and pituitary, very enervated and the action on it to try to eliminate the tumor with radiotherapy and surgery carries significant risks," explains Pablo Santamarina, doctor in Biomedicine from the University of Oviedo and member of the Cancer Epigenetics group, in his assessment of the study. attached to the Health Research Institute of the Principality of Asturias, the CSIC and the IUOPA.

Therapeutic repositioning

Researchers at the Mass General Cancer Center have directed the first multicenter treatment protocol in this tumor considered rare because of its frequency.

The study built on findings from General Brigham Laboratory, whose researchers studied the genetic drivers of PCP growth and found that existing cancer drugs can directly interfere with proteins involved in PCPs to halt their progression and dramatically reduce their size.

Based on this breakthrough, researchers treated 15 patients with a BRAF/MEK inhibitor as part of this phase II clinical trial and found that tumors shrank by an average of 91 percent.

High response rate in brain tumors

"All patients who completed one or more cycles of therapy responded to treatment, which is the highest response rate to date of any medical therapy for brain tumors," said Priscilla Brastianos, M.D., director of the Center for Nervous System Metastasis at Central Mass General Cancer Center and first author of the study.

These unprecedented results signal "a paradigm shift to attack brain tumors," she said, because they show that "with the right target and drugs, precision medicine can have a dramatic impact on brain tumors."

Pablo Santamarina considers the results relevant because of the changes experienced in tumor growth, the high disease-free survival and the improvement in the quality of life of patients who present this primary brain tumor of the pituitary-hypothalamus axis.

Prior to this study, the laboratories of Brastianos and Sandro Santagata, of the Department of Pathology at Brigham and Women's Hospital, showed that approximately 95% of PCPs have a type of mutation in the BRAF gene, known as the BRAF V600E mutation, that drives their cancerous activity. This type of mutation is also present in some forms of melanoma. Treatment already approved in melanoma

Recently, therapies that inhibit BRAF and a related gene, MEK, have been approved by the U.S. FDA to treat melanoma and some other cancers, leading researchers to hypothesize that a BRAF/MEK inhibitor, namely vemurafenib/cobimetinib, might also be effective for treating PCP.

This protein regulates a signaling pathway in cells related to cell division and, therefore, tumor proliferation. "The overactivation of the protein induces greater tumor growth," explains Pablo Santamarina.

In this phase II multicenter trial, conducted by the Alliance for Clinical Trials in Oncology Network, funded by the National Cancer Institute, researchers first screened PCP patients across the country for BRAF V600E mutations to identify candidates for the study.

Sixteen patients at nine centers were enrolled in the study and 15 eventually completed at least a 28-day course of therapy. Over the course of four cycles, the median reduction in tumor size was 91%, with a range of 68 to 99%.

Seven patients received no other treatment after discontinuing vemurafenib/cobimetinib and six demonstrated no evidence of tumor progression at a median follow-up of nearly two years.

No tumor progressed

No patient's tumor progressed while taking vemurafenib/cobimetinib and no deaths were reported.

In terms of adverse reactions, three patients discontinued treatment due to the occurrence of any such effect, and one patient discontinued therapy after eight days due to anaphylaxis and acute kidney injury.

The most common secondary events were rashes, reported by six patients. Still, many patients tolerated the drugs well and chose to continue therapy beyond the prescribed four cycles as a result of their positive response, the study authors explain.

Optimal number of cycles

Future research may determine the optimal number of cycles of vemurafenib/cobimetinib for patients with PCP. Researchers are also advancing additional precision medicine clinical trials for patients with meningiomas and brain metastases.

Both apply precision medicine approaches similar to the one used in this trial to screen patients for biomarkers that indicate their cancers can be treated with existing therapies.

"This study has shown that national biomarker-based trials are feasible for patients with brain tumors," Brastianos said. "Advancing the treatment of rare brain tumors really requires a multidisciplinary, multi-institutional effort, and we were able to highlight this through our research."

  • cancer
  • Neurology

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