June 10, 2016 1:00 PM

Expanding Targeted Therapies to Rare Eye, Orbit Cancer

Researchers examined the DNA of lymphomas that occur in and around the eye, and found several mutations for which targeted therapies are being tested in other cancer types.

Thanks to advanced techniques for sequencing tumors, researchers are now identifying potential opportunities to treat rare cancers with new targeted therapies.

The latest example involves orbital and ocular adnexal lymphomas.

Current treatments for these rare tumors in and around the eye include radiation therapy and chemotherapy — treatments that can cause severe and sometimes vision-threatening side effects, including glaucoma and retinopathy. A new study aims to combat these issues.

“Precision medicine is taking off in cancer. Yet this technology has not been applied to orbital or ocular adnexal diseases,” explains Rajesh C. Rao, M.D., assistant professor of ophthalmology and visual sciences and of pathology at the University of Michigan.

Rao and his collaborator, pathologist Scott A. Tomlins, M.D., Ph.D., used next-generation sequencing techniques for the first time with orbital and ocular adnexal lymphomas. The researchers looked at 38 tissue samples from patients with this type of tumor, and potentially identified a future pathway for new targeted treatments.

“We found a distinctive set of genetic mutations that may distinguish these lymphomas from those that occur elsewhere in the body,” Rao says. The research is published in Modern Pathology.

The U-M team not only found several common gene mutations, but it also discovered that many of these mutations already have targeted therapies that are FDA-approved or in clinical trials.

"These targeted drugs could one day be another option to radiation and chemotherapy."
Rajesh C. Rao, M.D.

Sequencing archived tissue samples

The researchers tested the samples against a panel called the Oncomine Comprehensive Assay, which identifies alterations in more than 100 cancer-related genes. Unlike other sequencing techniques that require a fresh biopsy sample, the panel can be used with archived tissue samples, even those that are decades old. This allows researchers to obtain enough samples rapidly — no easy task for a rare disease.

The panel targets alterations in genes for which targeted treatments have been approved or are being tested in clinical trials. A version of this panel is being used in the National Cancer Institute’s MATCH precision medicine clinical trial.

Orbital or ocular adnexal lymphomas occur in about 1,500 Americans each year. They can cause loss of vision and disfigurement and can be deadly. Current therapies effectively control the more common, low-grade forms of the disease but can be associated with vision-threatening side effects. High-grade forms of the cancer often relapse after chemotherapy and radiotherapy and can be lethal.

In this study, researchers uncovered actionable alterations in 53 percent of the samples. The most common was MYD88, which was altered in 71 percent of diffuse large B-cell orbital lymphomas and 21 percent of marginal zone lymphomas. MYD88 mutations in these forms of orbital and ocular adnexal lymphomas appear more commonly than similar mutations in types of lymphoma that occur in other parts of the body.

Additional mutations were found in ARID1A, EZH2, PTEN, TP53, HRAS and NRAS. EZH2 dysregulation was recently found to play a role in the most common cancer, the skin cancer cutaneous basal cell carcinoma.

The future of this research

Clinical trials are testing potential targeted therapies against many of these mutations in several other types of cancers, including lymphomas outside the orbital and ocular adnexal region that carry these genetic alterations. Researchers plan to explore whether patients with orbital and ocular adnexal lymphomas could be eligible for these clinical trials.

“We need to find new treatments that have fewer toxic effects for this disease,” Rao says.  “We’re seeing a unique set of mutations that distinguish lymphomas found in the orbital and ocular adnexal area.

“Even more exciting is that we found mutations that may, in the near future, allow some patients to enroll in a clinical trial evaluating targeted agents tailored to the unique genetic profile of the tumor,” he adds. “These targeted drugs could one day be another option to radiation and chemotherapy.”