OS ANGELES — Retinoblastoma was one of the first cancers to have its genetic origins identified in the late 1980s — a finding that helped launch the current era of personalized treatments that have transformed treatment of breast, lung, and prostate cancer.
But the children who develop these rare tumors in their retinas have never benefited from that wave of precision diagnostics and therapies. That’s largely because doctors haven’t been able to biopsy the tumors for genetic information that could guide treatment, without removing the very eyes clinicians are trying so hard to save.
Now, because a young oncologist at Children’s Hospital Los Angeles followed a hunch, there may be a safe, non-invasive way to biopsy retinoblastoma tumors — using fluid that’s removed from the eye during chemotherapy and typically discarded. A small study published Thursday in JAMA Ophthalmology showed that DNA found in the fluid matched the DNA found in tumors — a discovery that could lead to a new liquid biopsy.
Dr. Jesse Berry, 36, has long been frustrated by not being able to tell the parents of her young retinoblastoma patients what to expect. Even in cases that look identical, some patients quickly respond to standard chemotherapy, while others don’t respond after years of difficult treatments. In other cancers, biopsies can guide oncologists toward the best treatment options. But biopsying tumors in the retina, the thin layer of nerve cells in the back of the eye, risks spreading cancer by unleashing tumor particles into the rest of the body and the brain.
“It’s ironic. The retinoblastoma gene … opened up a huge, huge area of research that benefited so many cancer patients,” Berry said. “But not retinoblastoma patients.”
A few years ago, Berry was performing a routine chemotherapy injection into the eye of a retinoblastoma patient that required her to first withdraw a tiny amount of fluid. “I discarded the fluid and syringe and just had a thought — maybe there’s something in the fluid,” said Berry, a pediatric ocular oncologist at CHLA and assistant professor at the University of Southern California’s Roski Eye Institute. “I started writing my research proposal that night.”
Retinoblastoma is one of the most common childhood cancers, but it’s still rare. It affects about 300 children in the U.S. each year, most of them under 5. In many developing countries where tumors can progress until they literally burst out of eyes, retinoblastoma remains an often fatal diagnosis. In the U.S., the survival rate has climbed to 98 percent.
But many children with aggressive tumors — like 4-year-old Damian Salgado, who Berry treated in 2015 — still lose eyes. In Damian’s case, the eye he lost became pivotal to the new research.
He was born in June 2013 with a chromosomal deletion and was developmentally delayed. But in 2015, Damian’s mother Kati (pronounced Kathy) Parra noticed something strange about her son’s eye. “It had a glare,” she said. “A glow.”
She and her husband went from their son’s pediatrician in Las Vegas to an ophthalmologist and then to a retinal specialist and finally to the LA children’s hospital, which is one of just a handful in North America that specialize in retinoblastoma treatment.
An MRI showed that the cancer had thankfully not spread to Damian’s brain. But the tumor was so large and advanced, Damian’s right eye had to be immediately removed. Damian also underwent six rounds of chemotherapy to make sure all the cancer was gone. On Tuesday, he was declared cured; he’s been cancer-free for two years, is now in preschool, and is obsessed, as 4-year-olds can be, with fire trucks, police cars, and the games on his dad’s cellphone.
Parra said she decided to allow Damian’s eye and eye fluid to be used in Berry’s proof-of concept study (he was one of three patients involved) because she hates to think of other parents going through what she did. There are practical matters — like whether his aversion to riding bikes is due to a lack of depth perception. And there is grief, still, as she continues to mourn the loss of her son’s eye.
“We live through it every day,” she said. “We take his prosthetic out and clean it and live through it every day.”
Few people thought the team would be able to find tumor DNA in the fluid of the eye, or aqueous humor, Berry said. The fluid sits in a different chamber of the eye where tumor cells cannot migrate. And they knew that even if any DNA from the tumor had made it to the fluid, it would only be in tiny fragments that are difficult to detect.
Working with James Hicks, a biologist at USC, the team was able to detect tumor DNA in tiny fragments that had likely been loosed as tumor cells died and broke up.
The new liquid biopsy technique could be the first step toward offering more personalized, genetic-based cancer treatments to retinoblastoma patients from the very start, potentially saving more eyes and vision. In the case of very aggressive tumors, it could allow doctors to advise quickly removing eyes to spare children from years of needless chemotherapy when eyes are unlikely to be salvageable.
“It can be devastating as a doctor to make that call,” Berry said. “You’ve fought for three years to save the eye.”
Outside retinoblastoma experts say they’re excited about the finding because they’ve never been able to grab samples of the tumors they treat without removing the eye. But they warn that any new treatments are many years away.
“It won’t cure children on its own, but it is a step toward saving eyes,” said Dr. Brenda Gallie, an expert on the genetics of retinoblastoma at the Hospital for Sick Children in Toronto.
About 50 percent to 70 percent of patients with aggressive tumors do not respond to standard chemotherapy and suffer recurring tumors, Berry said.
“A major issue is that our therapies are not targeted,” said Dr. Jonathan Kim, who directs the retinoblastoma program at CHLA and the ocular oncology service at USC’s Roski Eye Institute and was part of the research team. Standard chemotherapy agents don’t work specifically on blocking retinoblastoma tumors but instead broadly inhibit DNA replication. That means lots of side effects, such as anemia, infections, lost hair, and damage to bone marrow.
“Children often get sick on chemotherapy for retinoblastoma. It’s considered fairly toxic,” Kim said.
For children who don’t respond to chemotherapy, there is cryotherapy and laser treatment and radiation available — and of course removal of the affected eye. But what Kim and Berry really want in their arsenal are precision treatments that target specific pathways in the retinoblastoma tumor, as well as information on which tumors might be resistant to chemotherapy.
While there is no genetic diagnostic test yet available based on their findings, Kim and Berry said it is relatively simple for an ophthalmologist to remove eye fluid that could then be analyzed at a genetic lab with the proper expertise.
Since completing the initial paper published Thursday, the team has analyzed 50 more samples from eye fluid of retinoblastoma patients, including those with less aggressive tumors whose eyes were saved, to get a start on determining what factors might be at play in tumor progression. (That paper is expected to be published soon.)
Berry plans to spend the next decade immersed in the data trying to develop diagnostic tests and better treatments based on the genetic material that now appears easy to obtain. “It’s a very fertile area,” said Kim. “It will take her career.”