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Genetic testing - New Technology pinpoints cancer's code


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Genetic Testing

New technology pinpoints cancer’s code

By Laura Putre

When Heidi Henn, a mother of two and a program manager for the U.S. Navy, started having trouble breathing in October 2011, she thought it might be heart problems. Heart disease ran in her family, after all. But when a surgeon at George Washington University Hospital in Washington, D.C., did a biopsy, he found that Henn’s lungs, not her heart, were causing her problems.

A nonsmoker all her life, Henn was stunned to find out she had stage 3 lung cancer. She quickly started chemotherapy, but the treatment didn’t help. The cancer was still spreading, and the chemo gave her nausea and fatigue that left her bedridden and miserable.

Because Henn was only 48—young for a cancer patient—and had never smoked, her oncologist wondered whether her cancer might be linked to a genetic mutation and could be treated with a new generation of cancer drugs called targeted therapies. That’s when he had her tumor samples sent off for a pair of genetic tests that look for common mutations linked to certain types of lung cancer. Patients with such mutations sometimes improve when treated with targeted therapies, which work on specific molecules in the body to block cancer growth.

Taking aim

Targeted therapies are different from chemotherapy in that they are tailored to reach the cells that cause tumors to grow and spread. Chemotherapy, on the other hand, can harm normal cells along with cancer-causing cells—but can also be especially effective in combating certain cancers, like testicular cancer. Targeted therapies are sometimes used alone, sometimes in combination with other targeted therapies, and sometimes with chemotherapy.

Henn’s doctor’s instincts were right. Henn tested positive for a mutation that causes overactivity of the enzyme ALK, and in February 2012 she was started on a targeted therapy called crizotinib, a pill that the FDA had approved just six months before. The drug worked initially, and when it stopped working her oncologist suggested trying chemo again. But Henn, who lives in southern Maryland, had done her research and found a clinical trial at Fox Chase for an experimental targeted therapy called LDK378.

“When it’s a matter of life and death, you get smart any way you can,” Henn says of her quest to find the best treatment, even if it meant traveling outside the state. “My daughter is 18 and my son is 15. I definitely want to be around for my kids.”

“The biggest challenge is getting this technology and this sort of knowledge—these new tools for cancer care—from the laboratory to the patient.”

– Jeff Boyd, executive director, Cancer Genome Institute

In January, with the cancer spreading to Henn’s brain, doctors at Fox Chase began treating her with the experimental drug, which is designed to decrease the activity of the defective gene linked to the cancer’s spread. Within two weeks, Henn started feeling better. Her next scan, on February 15, showed a dramatic reduction in the size of her lung tumors. Three of four of her brain lesions were no longer measurable, and the remaining one had shrunk by half.

Though it’s too early to tell whether the drug will work in the long term, “I’m thrilled it seems to be successful in crossing to the brain,” Henn says. “It’s very rare that chemo drugs do that.” The drug has since eradicated the cancer in her lymph nodes and a lesion on her liver, and even the largest brain tumor can no longer be measured.

Henn is exercising again and has gone back to work part-time. “I’m feeling almost normal,” she says. “My quality of life is incredible.”

A changing landscape

Cancer treatment has been changing rapidly since the FDA approved the first targeted cancer therapy, tamoxifen, for the treatment of breast cancer more than 30 years ago.

In 1992, the National Institutes of Health began mapping the human genome—sequencing all 3 billion base pairs in human DNA. That project, completed in 2003, has so far led to the discovery of more than 1,800 genes linked to various diseases, according to the NIH, and opened wide the development of therapies that target them. It’s given scientists a detailed map of the makeup of human DNA. Instead of having the sole option of traditional chemotherapy—which may act more like a bludgeon than a scalpel—today’s cancer patients may be able to take a specialized pill or injection to either eradicate their cancer or keep it under control. That’s the case for those with chronic myeloid leukemia, or CML; a medication called Gleevec®, which was introduced in 2000 and targets an abnormal protein present in most CML sufferers, has extended patients’ survival rates from a few months to indefinitely. The drug may benefit patients with other diseases as well.

Photo: Jessica Hui

One Fox Chase patient with melanoma is living proof of the difference that targeted treatments can make. Before the man, now 73, started targeted treatment, “he had an expected survival rate measured in months,” says his doctor, Anthony Olszanski, a Fox Chase oncologist and drug-development researcher. “I started him on Gleevec, and he had a complete response. We cannot find his disease. He’s been on therapy for over two years, and he’s capable of doing the things he wants to do.”

‘Where the excitement is’

The latest advances in gene sequencing allow doctors to test for many genetic alterations at once, in patients with many different types of cancer. At Fox Chase’s new Cancer Genome Institute, a single tissue sample can be tested for 50 genes and hundreds of genetic mutations related to cancer. Not all of the mutations have therapies available, but the hope is that eventually, they will.

The multidisciplinary Institute provides the 50-gene test using new technology referred to as “next-generation DNA sequencing” to help guide the treatment of patients with advanced cancers and, when appropriate, match them with the latest trials of targeted drugs. The genetic information collected from the test goes into patients’ medical records with their other personal health information. With informed consent from the patient, the data is also included in an institutional review board-approved data registry without the patient’s name or other identifying information (such as address or social security number). Researchers can access the data and patient characteristics like race, ethnicity, and age to see how certain types of patients are responding to clinical trials.

The Cancer Genome Institute provides a 50-gene test to help guide the treatment of patients with advanced cancers and match them with approved or experimental drugs.

Such multiple-gene testing “is where the excitement is,” says Olszanski, the Institute’s senior medical advisor. “We know about this one gene that’s important in colon cancer, but we do not know about many other genes that may be important. And we think that if we study a number of patients with colon cancer, for example, we will find other important changes in DNA that will allow us to treat them more effectively.”

Formally launched in January, the Institute strives to promote precision medicine—or medicine specifically tailored to each patient at the molecular level—in oncology through patient care, prevention research, partnerships, and education. The Institute brings together doctors, scientists, and pathologists from various disciplines at Fox Chase who not only are up on the latest research and have the best technology at their disposal, but also can bring those advances to the patient in a meaningful way—interpreting and explaining test results in ways patients can understand, enrolling them in clinical trials for experimental therapies, and monitoring their progress on a long-term basis.

“The biggest challenges aren’t the technology or the bioinformatics that go along with interpreting the data,” says Jeff Boyd, the Institute’s executive director and an expert in the genetics of breast, ovarian, and endometrial cancer. “The biggest challenge is getting this technology and this sort of knowledge—these new tools for cancer care—from the laboratory to the patient.” Which is what the Institute is doing.

On trial

With the help of $2.9 million in funding from Temple University, the Institute is offering its services through a series of clinical trials in which certain patients are eligible to participate. Boyd calls the funding from Temple “tremendous,” adding, “It allows us to undertake exciting and important clinical research, the goals of which are to generate useful scientific findings and advance clinical care.”

Igor Astsaturov, a Fox Chase medical oncologist and researcher who works closely with the Institute, says 30 or 40 of his patients already have undergone genetic testing at Fox Chase or other institutions as part of their treatment. Binders on his desk are filled with their tumorgenetic profiles, information that helps him determine the best treatment options.

In the case of one of Astsaturov’s patients with a rare type of gastrointestinal tumor called neuroendocrine carcinoma, unexpectedly finding a mutation of the C-KIT gene resulted in starting the patient on a targeted therapy that in four months substantially reduced the size of the person’s tumors.

In the coming months, the Institute plans to enroll about 200 patients in five clinical trials of genetic testing related to lung, colorectal, rectal, and neuroendocrine cancers, as well as of the efficacy of using genetic sequencing to guide therapy. Which patients will qualify for the free testing is not yet clear.

“We won’t discourage the testing based on cancer type,” Olszanski says, noting that the various targeted therapies have had an effect on a “pretty wide range” of cancers. “But we sometimes will discourage it based on when the patient was diagnosed. If they’ve not yet received the standard of care, we generally tell them that we think the test will be better for them later.”

Just the start

Fox Chase has long been a pioneer in the field of cancer genetics. The first link between cancer and a genetic abnormality was discovered in 1960 by David Hungerford of Fox Chase’s Institute for Cancer Research and Peter Nowell from the University of Pennsylvania School of Medicine. Their discovery of the Philadelphia chromosome, a chromosomal abnormality in patients with chronic myeloid leukemia, paved the way for the eventual development of Gleevec.

As a National Cancer Institute-designated comprehensive cancer center, Fox Chase has an obligation “to move the field of personalized medicine forward,” Boyd says.

Charis Eng, director of the Genomic Medicine Institute at Cleveland Clinic, agrees. Eng says that every cancer center “worth its salt” is either testing for genetic alterations in cancerous tumors or will soon be doing so. With dozens of targeted therapies already approved or in clinical trials, he says, “this is the time that if you find certain types of alterations, you can say, ‘Yes, let’s choose this type of treatment and yes, the tumor will respond.’”

With more than 25,000 genes in a single human (though not all are linked to disease), the Institute’s 50-gene test captures just a fraction of the potential for genetic testing.

Plans call for testing even more genes.

“The more we learn about certain cancers and genes and drugs—which is just a matter of time and experience—then the number of patients we can help will obviously increase,” Boyd says.

Questions and quandaries

Even as it opens the door to new hope and knowledge, genetic testing also raises fresh issues and questions. One concerns cost: the test is expensive to provide, running institutions up to more than a thousand dollars per tumor—and whether insurance companies will reimburse that cost remains an open question.

Genetic test results are kept private under HIPAA laws, which prevent the sharing of medical information without a patient’s consent. Photo: Jessica Hui

Olszanski predicts the answer to that question will be “yes” and that within the next year, insurance companies will begin to cover the cost of providing the test. “I think they will have no choice,” he says. “They already cover other tests that have clinical validity.” Insurance companies look at data on positive outcomes, he reasons, and there will be more such data available as more patients undergo genetic testing and targeted therapies.

Privacy is another concern for those who undergo testing. Is anyone’s genetic information completely confidential? In January, a researcher publishing in the journal Science was able to uncover the identity of five people and 45 of their family members using “blind” genetic data posted online, as well as information that anyone can access on genealogy websites.

Theoretically, someone with access to a genetic database could identify people through that data, Boyd says. But they could not use the information in any meaningful way. Federal law prohibits health insurance companies from using genetic information to raise rates or deny coverage.

At Fox Chase, genetic test results are placed into a patient’s electronic medical record like any blood test or CAT scan would be. The information is kept private under HIPAA laws, which prevent the sharing of medical information without a patient’s consent. “It is not available to insurance companies, and it is not available to employers,” Olszanski says.

The test results are also entered into an institutional review board-approved research registry at Fox Chase that may include the patient’s age, characteristics of the tumor, and type of follow-up treatment. Identifying information such as the patient’s name, location, and social security number are not included. Boyd says the registry is “vitally important” to advancing research and providing data to show whether genetic sequencing provides a path to better cancer care.

Another issue arises in about 1 percent of cases, according to the American College of Medical Genetics and Genomics, when genetic testing reveals information that the patient wasn’t looking for—like a gene for a disease other than the one being tested for, or maybe that their paternity was different from what they thought.

“You have to be ready to handle that as part of informed consent,” says Arthur L. Caplan, head of the Division of Bioethics at New York University Langone Medical Center. If the test might reveal something unexpected, he suggests the test provider explain, “‘We may find out certain things that you may or may not want to know, so you have to tell us how you want us to handle these things as we find them.’”

Incidental findings are rare but can happen, Olszanski acknowledges. Fox Chase is working with its clinical genetics group to come up with a policy on how to reach out to patients if they do find something they weren’t looking for. To a great degree, he says, the patient would have a right to refuse to be informed of unexpected information.

Scratching the surface

So what could the future hold for genetics and cancer treatment? Thanks to genetic testing, Olszanski looks forward to a day when cancers that cannot be cured can be treated as a chronic disease with targeted therapies—that just like patients with diabetes or heart disease, cancer patients will be able to live full lives while taking medications to control their cancer.

“We’re just beginning to scratch the surface,” he says. “I think the future will have us testing more genes and discovering new drugs with the hope of helping more patients with cancer.”

Laura Putre is a Cleveland freelance writer whose work has explored the mysteries of Vitamin B12, genetic research on the Hutterite colony in South Dakota, and using computer modeling to develop tropical disease vaccines. Her work has been published in The Root, Pacific-Standard, and O: The Oprah Magazine.

FAQs: Genetic testing and targeted therapies

with Anthony Olszanski, senior medical advisor, Cancer Genome Institute

Who can benefit most from genetic testing?

I see a number of patients with late-stage disease where we are, unfortunately, running out of standard treatment options. And that’s where I think that genetic testing really makes sense. Then we can possibly identify targets that we can inhibit with new targeted drugs, most often on clinical trials, which may make a difference for patients who are running out of options.

How do targeted medications work in cancer treatment?

Many of them are given as tablets or pills; others need to be given as intravenous medications. They work by different mechanisms to block the growth of cancer cells. Some of them target receptors on the cell surface, and some attack signaling pathways inside the cells. One interesting approach is to combine a targeted therapy with a chemotherapy drug. These combinations are called antibody-drug conjugates. The goal of these drugs is to use the targeted portion to seek out tumor cells. It’s like the Trojan horse. The tumor cells ingest or engulf the antibody-drug conjugate, and the toxic therapy is released inside the tumor cells and specifically kills those cells, sparing most healthy cells.

Are certain types of cancer more appropriate than others for genetic testing and targeted therapy?

That’s part of what we’re trying to figure out. We do know that some types of cancer harbor more genetic mutations than others, but we do not know the mutation status on some cancers.

Photo: Joe Hurley

For example, we know that lung cancer, breast cancer, and colon cancer have high mutation rates. But there’s not a lot of data out there to tell us about the mutation rate in neuroendocrine tumors, for example. Part of the reason we’re doing these studies is to try to learn the details about how many mutations occur in each type of cancer, how often we can find a targeted therapy for an individual patient, and how often that therapy actually works.


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