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Monday, December 22, 2014         

NEW YORK TIMES


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Genetic test changes game in cancer prognosis

By Gina Kolata

New York Times

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In May 2011, Cassandra Caton, an 18-year-old with honey-colored hair and the soft features of a child, suddenly went blind in her right eye. Five months later, an ophthalmologist noticed something disturbing. A large growth in the back of her eye had ripped her retina, destroying her vision.

He sent her to Washington University in St. Louis, a three-hour drive from her sparsely furnished apartment in the working-class town of Sedalia, Mo.

And there, Caton, mother of a 2-year-old daughter, wife of a chicken factory worker, got almost incomprehensibly bad news. The growth was cancer, a melanoma, and it was so huge it filled her eyeball.

“Am I going to die?” Caton asked. “Is my baby going to have a mommy in five years?”

It is a question that plagues cancer patients. Doctors try to give survival odds based on a tumor’s appearance and size, but often that is just an educated guess.

But Caton had a new option, something that became possible only in this new genetic age. She could have a genetic test of her tumor that could reveal her prognosis with uncanny precision. The test identifies one of two gene patterns in eye melanomas. Almost everyone in Class 1 — roughly half of patients — is cured when the tumor is removed. As for those in Class 2, 80 to 90 percent will die within five years. Their cancers will re-emerge as growths in the liver. For them, there is no cure and no way to slow the disease.

No test has ever been so accurate in predicting cancer outcomes, researchers said.

The data from studies of the test are “unbelievably impressive,” said Dr. Michael Birrer, an ovarian cancer specialist at Massachusetts General Hospital. “I would die to have something like that in ovarian cancer.”

While for now the ocular melanoma test is in a class by itself, cancer researchers say it is a taste of what may be coming as they continue to investigate the genes of cancer cells. Similar tests, not always as definitive but nonetheless able to give prognostic information, are under development or starting to be used for other cancers, like cancers of the blood.

Having a prognosis allows people to plan their lives, but most do not want to know if they have a gene for an incurable, fatal illness, like Huntington’s disease or early onset Alzheimer’s.

The eye test raises a similar choice, with an added twist. This is not a test offered to healthy people but to patients who have just gotten the news that they have cancer. The results will either give them reassurance that they will survive the cancer — or near certainty that they will die from it.

Can patients in the throes of getting this terrifying news really make an informed choice about whether they want the test? Are they able to understand at such a fraught time that, for now at least, there is nothing that can save them if they get the bad prognosis?

Some doctors do not offer the test, reasoning that there is little to be gained.

But other doctors, including J. William Harbour of Washington University, who developed the test (but does not profit from its use), encourage patients to have it. And probably because of the way he describes it, Harbour says his patients almost always want it.

Caton was no exception. Without the test, doctors would have had to guess her outcome based on the size of her tumor. And the conventional wisdom is that people with growths as large as hers have a slim chance of surviving. But perhaps, her doctors hoped, the genetic test would come up with a different answer.

HERALDING THE FUTURE

Harbour, a genial and burly man with salt-and-pepper hair, has a way about him that relaxes patients, makes them feel everything will be OK.

“I give them as much information as I think they can handle,” Harbour says.

And he’s an optimist. The ocular melanoma test is just the beginning, he believes, of a new understanding of that cancer — and perhaps other cancers as well — and why they spread.

About 2,000 people a year, or about 5 percent of melanoma patients, have ocular melanoma, a tumor of the dark brown melanocytes that forms a sheet much like a photographer’s backdrop behind the retina. Those with very large tumors are most likely to have a bad prognosis, but patients with small tumors also can have the deadly type.

Often there are no symptoms; the tumor may be discovered by an ophthalmologist during a routine exam. Other patients, though, lose vision or see flashing lights or a sea of floaters in an eye, all signs of damage to the retina as the tumor encroaches.

Most get radiation, a highly radioactive disc placed on the surface of the eye that destroys the tumor in a few days and then is taken out. But those with huge tumors, like Caton, must have their eye removed.

Ocular melanoma specialists had long noticed that some patients did well and the rest did not, but Harbour wanted to know why.

Then he saw an opportunity. Ever since he came to Washington University in 1996, Harbour had been storing bits of tumors from ocular melanoma patients and keeping track of what happened to the patients. Working with his colleagues at the genome center, Harbour looked for genetic differences in tumors that spread and those that did not.

The genes themselves were no different. But a group of several hundred genes that looked the same in cells from patients in Class 1 and Class 2 were acting differently in the patients who did poorly. The genes were churning out many more proteins in the cells of patients in Class 2. Harbour found that he could look at the activity of 12 of those genes and predict how well a patient would do.

After a rigorous study to confirm that the test worked, the university licensed it to a small company, Castle Biosciences. They bill more than $6,000, with the price depending on the quality of the sample. But the company has programs to make sure that the poor or uninsured can receive the test, said Derek Maetzold, the company’s president and chief executive.

Some cancer specialists ask what is to be gained by using the test.

When it comes to dividing patients into two prognostic groups, “the data are really astonishing,” said Dr. Keith Flaherty, a melanoma researcher at Massachusetts General. Yet, he added, “There is no treatment yet that will alter the natural history of the disease.”

“Why would you want that information when we don’t have anything we can do for you?” Flaherty asked. “That is the fundamental question that has caused people to pause.”

Nothing has been shown to prolong the lives of Class 2 patients, said Evangelos S. Gragoudas, an ocular oncologist at Massachusetts Eye and Ear Infirmary. Not more frequent monitoring of the liver, not more aggressive or earlier chemotherapy. Nothing.

Gragoudas tells patients that the ocular melanoma test is available. Then, he said, “I tell them that I do not do it at the present time. But if you want it, there are people who will do it.”

“I had only one patient tell me, 'I want to know,'” Gragoudas said.

Harbour has a different view and conveys it to his patients. He tells them that if they are Class 2 he will monitor them closely, doing liver scans every six months and blood tests in between, and will treat metastases with chemotherapy, delivered to the site of the cancer’s spread, as they occur.

Patients sometimes think that means they can be cured, Harbour confesses, adding that he makes a point of repeating the information about what the test results mean on several different visits to be sure it sinks in.

Harbour says he believes that frequent monitoring and prompt treatment of the cancer may be extending some patients’ lives, although that has not been rigorously established. Gragoudas says a study he did found that early treatment made no difference.

Before the gene test was developed, patients would not know their cancer had spread until they were at the end stages of their disease. Then they would suddenly shed weight, lose their appetite, fall ill and their skin would turn yellow from liver failure. Within a few months they would be dead.

Now, by finding the cancer as soon as it spreads to the liver, it often can be controlled, at least for a while. The cancer then tends to spread to the lung or bones, where it can also be controlled. Death still tends to be from cancer in the liver, but even if it occurs at the same time, it may be less painful, Harbour says.

“Would you want a horrible death that is relatively short,” he asks, “or a death that is slower?”

‘PRAYING FOR A MIRACLE’

Cassie Caton and an older man came in for their biopsy and treatment on a frigid morning in early December. Both would have to have their eyes removed — their tumors were too large for radiation.

First was Joe Ritter, age 70.

“We are praying for a miracle,” his wife, Judy, said that morning, as Ritter sat silently in his bed, waiting to be wheeled into the operating room.

At 11:30 that morning, Caton’s surgery began. Harbour looked at her dilated eye. There, visible behind her blue pupil, was a brown halo, the melanoma.

He began to work, carefully and efficiently, preserving and pinning back the muscles that control her eye’s movement.

About an hour into the surgery, Harbour removed Caton’s eyeball, cutting the optic nerve with a scissors. Her eye looked like a white marble with a blue pupil on top and a little white wicklike stalk on the end, the stub of the optic nerve.

He took the eyeball to a metal table and cut it open. It was filled with what looked like slices of brown olives, the melanoma. A fluid squirted out, the vitreous. Normally it would be clear and jellylike. But cancer had made it liquid and the color of weak tea.

Some of that cancer tissue would go to Castle Biosciences for analysis. The rest would be stored for future research.

Then Harbour covered a plastic ball about the size of Caton’s eyeball with the outer layer from a cadaver’s eyeball, and put it into her eye socket so the ball would move like her eye. Finally, he carefully sewed the controlling muscles in place. In about six weeks, an artist would paint a thick contact lens to match Caton’s remaining eye, giving her a prosthesis that would be all but indistinguishable from her healthy eye.

Ritter would also end up with a prosthetic eye that would look and move just like his healthy one.

After the tumors were removed, both Caton and Ritter would return in about a month to find out if they were Class 1 or Class 2. On Jan. 9, they arrived to hear their verdicts. Ritter went first, bringing his wife with him into the small windowless room.

After a few pleasantries, Harbour delivered the news.

“Based on what we found from your biopsy result, it was Class 2,” he said.

Judy Ritter looked stricken, her eyes filled with tears. She crossed the room and hugged her husband. Joe Ritter grinned nervously while Harbour explained how he would like to monitor him. And, he said, he planned to start some clinical trials to see if he could slow the cancer in Class 2 patients. Perhaps Joe Ritter could join one.

Then Harbour stepped out of the room, allowing the Ritters to compose themselves.

Joe Ritter reflected on how the news about his eye had steadily worsened.

“I started out thinking it was a cold in my eye,” he said. “Then I thought it was a cataract. Then they told me it was a torn retina. That turned into a tumor. Now it’s a Class 2.”

Judy Ritter tried to be positive.

“Maybe we caught it in time,” she said. “We’ve got a lot of prayers coming our way.”

Caton and her stepfather came in next. He had driven three hours from his home in Kansas City and picked her up in Sedalia. The two had arrived in St. Louis the night before.

She had been too nervous to sleep.

With few preliminaries, Harbour told her what the test showed.

“Your test result,” he said, “was very good.”

Her tumor was not only Class 1 but was a subset of Class 1 that had an even better prognosis than Class 1 in general. It was Class 1a.

“That is very, very good news,” Harbour said.

“In the old days, the size of a tumor was the best indicator,” he told Caton. “People would have told you, you were at very high risk. Your tumor was almost an inch in its largest dimension. Pathologists’ eyes widened when they saw it. But molecular testing trumps all of that.”

“If you did not have this test you would have walked away being told you have a bad prognosis when you actually have a good prognosis,” he added.

Caton could not stop smiling. Then, still grinning, the 18-year-old asked her next question.

“When can I wear eye makeup again?”






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