Targeting cancer with genomic tests

BY CRAIG SAILOR | csailor@thenewstribune.com | See Original Here

A Gig Harbor mother of three and former President Jimmy Carter have new shots at life from advances in genetic testing that is keeping their cancer at bay.

Local oncologists say the advances in understanding the genetics of cancer is leading a new wave in research and treatment.

Cancer claims more than half a million Americans a year. For decades, chemotherapy has been the backbone of advanced treatment.

Now, the building blocks of tumors — their genetic code — is being unraveled to find the mutations and defects that cause cancer to grow. In turn, genetic researchers are creating drugs that target the specific mechanisms of those aberrant genes.

The medical field uses various terms for the new wave of cancer treatment: personalized oncology, targeted therapy and genomic directed therapy are some.

But all mean roughly the same thing: personally tailored health care.

Cancer researchers say the key to more advances is a better understanding of how an individual tumor’s genetic blueprint corresponds to the bigger picture of what’s known about cancer’s genetic origins.

Once more data are collected and trials are conducted, patterns can be ascertained.

“It’s truly personalized medicine,” said Dr. Eric Holland of the Fred Hutchinson Cancer Research Center in Seattle. “You can look at your tumor and compare it to a gigantic data set of other tumors.”

The Pacific Northwest could be the epicenter of that sort of research.

“The ability to use big data like that and to visualize big data sets is something that the Northwest is really good at,” Holland said. “It’s got Amazon and Microsoft and all these people that think about big data.”

MARIE’S STORY

Marie Dougil was just 30 when she was diagnosed with stage three breast cancer in 1997. The youngest of the Gig Harbor woman’s three daughters had just turned 1.

“I was healthy,” Dougil said. “I didn’t smoke. I didn’t drink. I exercised. There was no history of any cancer in my family.”

She had a mastectomy to remove her breast and started chemotherapy followed by radiation. Like many chemo patients she suffered through months of on-and-off nausea and other side effects.

Chemotherapy refers to a class of about 100 drugs that use various methods to slow or kill tumors. Oncologists use them in various combinations and strengths.

Chemotherapy choices are based on the type of cancer being treated — the organ of origin as it’s known.

If cancer that started in the breast moves into a patient’s liver, it’s still breast cancer. Melanoma that moves into the brain, as in Carter’s case, for example, is still melanoma and is treated as such.

Chemotherapy doesn’t help everyone but it has saved and prolonged countless lives, even in advanced cases such as cyclist Lance Armstrong. Still, it’s a one-size-fits-all approach.

“Most anti-cancer drugs or chemotherapy in the classic sense are rather broad spectrum. They are toxic to cells,” said Dr. John Keech of MultiCare’s Regional Cancer Center in Gig Harbor.

“One takes advantage of the fact that the cancer cells can’t recover from the effects of chemotherapy and normal cells can to some degree.”

Aside from nausea and hair loss, chemotherapy also can cause heart damage and be a cause of cancer itself later in life.

In Dougil’s case, the treatment worked. By 2007, “I was considered cured because I had reached the 10-year mark,” she said.

Breast cancer, if detected early, has one of the highest remission rates. The downside is that it can recur years, even decades later.

In 2010, concerned she might have a hernia, Dougil went to see her doctor. Instead of a hernia, cancer was found in her liver.

Dougil knew what that probably meant. When cancer metastasizes beyond the organ in which it originated it’s considered to be in the final stage (four) and usually terminal.

“I just asked him, ‘How long do you think I have?’ ” Dougil recalled.

Two years, she was told.

Shortly thereafter Dougil was introduced to genetic testing.

According to the Mayo Clinic, about one in five patients with breast cancer has a gene mutation that causes an excess of a protein called human epidermal growth factor receptor 2 (HER2). The protein promotes the growth of cancer cells.

Since the discovery of the mutation, drugs — the most well know being Herceptin — have been developed to target the overproduction of HER2.

When Dougil tested negative for HER2, she began standard chemotherapy in 2012. The nausea wasn’t as bad as before but she experienced extreme fatigue and what’s colloquially called “chemo brain” — thinking and memory problems.

At the time she was working in the payroll department at Lighthouse Christian School in Gig Harbor. She started to make errors.

“I had to quit,” she said. “I couldn’t keep going like this. Even though the chemo is killing the tumors in your body it’s wreaking havoc.”

At first it appeared the cancer had gone into remission. But three months after she finished chemo Dougil learned the cancer had metastasized into her bones and lungs.

“The chemotherapy was shrinking the tumors in some areas but in other areas it was still growing,” she said.

She figured she had about six months to live.

“That was the low point for me.”

TARGETED ONCOLOGY

What Dougil didn’t know was that the pace of genetic testing and its use in fighting cancer was about to pick up exponentially.

“It’s been a complete shift,” said Keech, Dougil’s current oncologist.

“It’s not new,” he said. “It’s just that over the last 20 years the tools have evolved dramatically. Over the last two or three years explosively.”

The first step in the shift was a better understanding of the basic building blocks of life: deoxyribonucleic acid or DNA.

Most cancers are caused by damaged DNA.

There are several types of damaged or defective genes that can lead to cancer. One type, inherited genes, predispose people to the disease.

Actress Angelina Jolie became a poster child for this type when she tested positive for a mutation of the BRCA1 gene — associated with breast cancer. She had no sign of cancer but because her mother, grandmother and aunt had died of cancer, and she had a double mastectomy in 2013.

Another type of gene defect, called driver mutations, probably have a variety of causes, including well established links such as smoking and lung cancer.

As medical researchers better understood how these genes caused cancer, they realized tests could find the genes or the end results of those genes, such as proteins that foster cancer growth.

That, it turn, led to drugs developed to target the effects of the genes.

“For guys like me who have been doing this for 30 years, it’s a challenge to get our arms around this because it’s a completely different way of looking at what makes up a cancer and how to treat it,” Keech said.

The move beyond standard chemotherapy began in the late 1980s and early 1990s, when doctors began to test breast cancers for the presence or absence of sensitivity to estrogen. That allowed estrogen-targeted therapies to be developed specifically for the women who would benefit from them.

“That was a huge advancement in the treatment of breast cancer,” Keech said.

In 1998, the drug Rituximab was developed. The biologically engineered molecule disrupts the multiplication of lymphoma in patients who have a specific gene mutation.

“It changed the nature of treatment for many lymphomas and many leukemias,” Keech said.

Later Herceptin (Trastuzumab) came online for breast cancer.

“HER2-expressed cancers are very aggressive and before were very difficult to treat and had a poor prognosis,” Keech said. “The advent of Trastuzumab…flipped the prognosis of that gene around completely.”

In the mid-2000s, hundreds of what are called small molecules drugs were developed. They block the growth of cancer cells and are effective in treating kidney cancer and some forms of lung cancer, leukemia and skin cancers.

“It’s been a dramatic evolution,” Keech said.

Within the last three years, technology advanced to allow what the medical community calls next generation deep gene sequence analysis. The process creates a genetic profile of an individual tumor. The goal is to find specific driver mutations in a patient’s cancer so it can be treated.

New drugs now come on the market almost daily, Keech said.

“This is where precision oncology is today,” he said. “It’s finding a genetic driver that’s uniquely identified to that individual’s cancer and then finding a drug that matches that target.”

And that is making all the difference for Dougil.

By summer 2014, she and Keech had exhausted all options of hormonal and chemotherapies.

“It seemed like we had nothing further to offer until, as luck would have it, the technology to test cancer cells for next generation deep gene sequence analysis became available,” Keech said.

He had Dougil’s cancer cells tested by Foundation Medicine.

“We got a ‘hit,’ meaning that her cancer has a genetic mutation which we felt could be a mutation driving her cancer,” Keech said.

He settled on two oral medications that could target that mutation — Exemestane and Everolimus.

In August 2014, Dougil began taking the drugs. By the end of the year she was in complete remission.

SHOWING RESTRAINT

Cancer is just one of many diseases caused by genes or their mutations. As the mysteries of the human genome are unraveled more tests are developed to find rogue genes. Those, in turn, lead to more drugs.

Is that a good thing?

“This is a hot-button topic,” said Fred Hutch’s Holland.

“(Medical institutions) are using these phrases (personalized oncology, etc.) as justification for going to their hospital,” he said. “I’m not saying it’s the wrong thing to do. But (the hospitals) are using it for advertising.”

The federal Food and Drug Administration urges restraint.

In a Nov. 16 report to Congress, the FDA said inaccurate and unreliable laboratory-developed tests are adding to unnecessary costs and, more worrisome, unnecessary medical procedures that put Americans at risk.

The FDA cited several instances in which testing led to over-treatment.

OvaCheck, a test that creates a genetic profile of markers displayed by ovarian cancer cells, had trouble predicting or detecting the cancer and had inflated accuracy claims from its manufacturer, the FDA said.

OvaCheck and similar products led to false-positive results — when a test wrongly indicates a disease is present in the patient. That, in turn, led to unnecessary removal of ovaries in some patients. OvaCheck was never brought to market in the United States.

In the recent report, the FDA said it did not enforce the regulation of genomic testing products. The Obama administration has indicated it wants to increase the regulation and oversight of the products.

Big Pharma is on board with personalized medicine in a big way but has resisted more regulation. Companies such as Genentech, Genomic Health and Foundation Medicine assess cancer genes and create drugs to combat them.

The new drugs are extremely expensive. Herceptin costs $54,000 a year. Gleevec, a “wonder drug” that is effective against leukemia, costs $106,000 a year. Keytruda, the drug that has probably put Carter’s cancer into remission, costs $150,000 a year.

One area where prices are improving is testing.

“The price is falling and the ability is increasing at an alarming rate,” Holland said. “Things you could not have imagined doing several years ago are quite doable now.”

Still, insurance companies that might pay for a specific mutation test are balking at the complete testing of a tumor, he said.

But the bigger issue to Holland is the efficacy of targeted therapies.

“Some of those mutations are clearly drivers of cancer behavior and blocking their function is a good idea,” he said. “With others the data is not as good.”

Even if a mutation is found that has a corresponding drug, “Not everybody who has that mutation responds to that drug,” Holland said. “In fact, many don’t.”

Cases such as Dougil’s and Carter’s are encouraging but still are in the anecdotal stage of research.

“You always get those stories,” Holland said. “They’re rare but it happens. The response is almost always from the drug. But what you don’t know is why that patient who had mutation X who is given drug Y got such an amazing response and other people don’t.”

Genetic-based treatments for cancer are not pushing aside chemotherapy, radiation and other standard treatments, doctors said.

“When the tumor becomes a distant metastasis it is still treatable but no (longer) curable,” said Dr. Nehal Masood, an oncologist at MultiCare Regional Cancer Center at Tacoma General Hospital who specializes in treating breast cancer. “You can spend billions of dollars but at the end of the day the disease will take over. It’s true for most cancer.”

The five-year survival rate for stage one breast cancer is 100 percent and drops to 22 percent for stage four, according the American Cancer Society.

Tumors need to be roughly one-fourth the size of a dried pea before they can be seen in imaging, Masood said. The exception is in mammograms, which can detect cancer when it’s much smaller.

“That’s why mammograms are still a very important tool to detect and treat breast cancer in an early stage,” Masood said. “You can pick it up much earlier before it becomes palpable or can be picked up by CT scans. Just with screening we have been able to save so many lives.”

The day is coming when cancer, instead of being cured, might be treated like kidney failure is treated by dialysis, he said.

“The modern oncology is people living with and dying peacefully from cancer,” Masood said. “It’s becoming a chronic disease rather than a death verdict.”

He considers genetic testing and the therapies it suggests part of his tool kit.

“I would use it whenever I need it,” he said. “I would not compromise standard-of-care options for treatment based solely on genetic mutations until it has proven quite effective on many advanced cancers such lung and colon.”

Holland is just as cautionary but believes that eventually the data will add up to solid conclusions and proven therapies.

“There’s going to be vast amounts of information that are collectively going to be used to predict who is going to respond and who is not going to respond (to targeted therapies),” Holland said.

The key is evidence-based medicine, Masood said.

“All of these exciting and novel drugs need to be tested in a comparative trials against the standard care (chemotherapy, radiation, etc.),” he said “It’s only time that’s gong to tell regarding their long-term toxicity and success.”

Holland, like all the medical professionals interviewed for this story, said genetic-based oncology is where cancer is headed.

“It is the future,” he said. “There’s no question. It’s just a matter of how quickly we get there.”

MARIE’S FUTURE

Oncologists rarely use the word “cure” when talking about individual cases. Cancer is a wile foe. It moves, goes into remission and recurs.

Cancer lay dormant in Dougil’s body for more than a decade before returning with a vengeance. She currently has no signs of cancer. But testing has its limits.

Dougil continues to take the medication and will do so, “Until it stops working,” she said.

Though genetic testing can help only some cancer patients Dougil is bullish on the approach.

“It buys you time if it works,” she said.

For Dougil, time — and how she spends it — is what’s important.

“Before the 2010 diagnosis,” she said, “I was living like everyone else was — just trying to make the day pass with doing all the things you have to with the things on your plate.”

She still works at Lighthouse and lives with husband Matt and their youngest daughter in Gig Harbor. Their oldest two daughters have graduated from college.

“It’s so important to surround yourself with people who care about you,” she said. “Do away with the fluff and live your life and live it in a meaningful life.”

Craig Sailor: 253-597-8541, @crsailor

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