The Role of Molecular Testing in H3 K27M-mutant Diffuse Midline Glioma Management

H3 K27M-mutant diffuse midline glioma is a rare brain tumor characterized by a genetic mutation in one of the genes encoding the histone H3 protein, which regulates global gene expression. The presence of this mutation, termed H3 K27M due to its effect on the H3 protein structure, results in the development of a highly aggressive glial tumor, which has historically few treatment options. While front-line radiotherapy remains the standard of care and can provide temporary symptom relief for some patients, it has no effect on disease progression and no systemic therapies have shown meaningful clinical benefit to date. As a result, this tumor remains the number one cancer killer in children, and has a devastating effect on adults as well. Undoubtedly, there is an urgent need for new and more effective molecular-targeted treatment options for this aggressive brain tumor.

There are unique characteristics of H3 K27M-mutant glioma that make it particularly difficult to treat. 

• They most commonly occur deep within the anatomical middle of the central nervous system, including the thalamus or brainstem, typically precluding safe surgical removal. In addition, when located in the midline or hemispheric locations, its diffuse rather than focal nature makes gross total surgical resection nearly impossible.
• Given that complete surgical removal is not a feasible treatment option, hundreds of trials over the past 45 years have investigated the potential benefit of chemotherapeutic agents for this cancer. However, as with other brain tumors, the presence of the blood-brain barrier (a protective layer of cells surrounding blood vessels in the brain), precludes effective entry of most treatments to the tumor site, making systemic chemotherapy ineffective.
• Lastly, and perhaps most importantly, the H3 K27M somatic mutation causes tumor cells to grow rapidly and exhibit greater conventional treatment resistance, leading to an even poorer prognosis than tumors without this mutation.

Because of the complex and distinct anatomic, molecular and clinical features of these tumors, early identification of the presence of the H3 K27M mutation is critically important to help determine the correct diagnosis and treatment course, including potential eligibility for targeted therapy or clinical trials.

Increasing access to testing

While significant progress was made in recent years to elucidate the biology and tumorigenesis of H3 K27M-mutant glioma, unfortunately barriers that limit knowledge of and access to the necessary diagnostic molecular testing for these patients still persist. Because of the critical impact H3 K27M mutation detection has on molecular tumor diagnosis and patient eligibility for more effective, targeted treatments, greater awareness of the critical impact of H3 K27M mutation testing on patient clinical outcomes, as well as early access to molecular testing, is needed for both patients and their clinicians.

Hope for H3 K27M mutant glioma treatment

Recent research advancements have led to new insights into the biology of these complex tumors, providing hope for patients and their families as we look to the future. “We are increasingly understanding these tumors at an astonishing level of detail,” said Joshua E. Allen, Ph.D., Chief Scientific Officer, Chimerix, part of Jazz Pharmaceuticals. “The confluence of patients donating tumor tissue for study, including the increased availability of fresh tumor tissue that has resulted from improved surgical techniques enabling safe tissue biopsy, as well as advancements in molecular profiling technologies has dramatically accelerated our knowledge and understanding of this disease. The hope is that this knowledge will allow us to better address the specific drivers of this disease and identify vulnerabilities that can be attacked with new treatments.”

Despite this exciting progress, there is still more work to be done, particularly as it relates to raising awareness among health care professionals about the role of molecular diagnosis for H3 K27M and other prevalent mutations that inform treatment for glioma patients. As research progresses, molecular testing represents a critical opportunity to help ensure patients are pointed to the right treatments early on in their journey.

Read more about how Jazz is redefining what’s possible in H3 K27M-mutant diffuse midline glioma.