Susan Jenks

With many anti-cancer drugs taken orally, it’s up to patients to comply with prescribed regimens — but what happens if they don’t?

Technically, K. Eric Perrin takes his cancer medicine as prescribed. But, the 67-year-old retired pastor admits, he bends his daily regimen to fit “what works best for me.”

Twice a day, the Strasburg, Pa., resident takes the powerful targeted drug Nexavar (sorafenib) to keep his liver cancer at bay. But he takes the pills when it’s convenient for him — starting the day’s dosing at 3 a.m., when he’s typically sleepless, rather than an hour before breakfast, as his doctor ordered.

Perrin’s treatment illustrates a growing trend: As the number of oral anti-cancer medications grows, many cancer patients are in charge of administering their own treatments. And many don’t stick faithfully to the dosing schedules they’ve been given.

Despite his tweaks to the timing of his doses, Perrin is adhering to his treatment plan more faithfully than many others in his shoes. Some patients with cancer deviate more radically from their prescribed oral treatment regimens due to side effects, complexity or cost — and the trend is raising concern among cancer care experts.

K. ERIC PERRIN, pictured at home with his wife, sticks to his oral drug regimen but adjusts the timing of doses for convenience.

The World Health Organization estimates that only half of patients across all diseases adhere to prescribed medication, diets and/or lifestyle changes. In the oncology arena, oral therapies such as chemotherapies and targeted treatments comprise an estimated 25 percent of all drugs designed to control disease or prevent its recurrence, but that number is expected to climb to 50 percent or more in the future, making the issue of treatment adherence a key concern in the cancer community.

“It’s a tsunami of a problem we’re seeing come down the road,” says Ann O’Mara, head of palliative care research in the division of cancer prevention at the National Cancer Institute, “and our clinicians are not yet prepared.”

According to a national study by Harris Interactive, of the one fourth of all cancer patients who take oral drugs to manage their disease or side effects, a third admitted to not always following their doctors’ directions and half reported having forgotten to take their medicine. While adherence is strictly overseen in clinical trials, some non-adherence is built into expectations when drugs are used in real-world situations; often, adherence is defined as complying with regimens at a rate of 80 percent or better. Yet, out in the field, experts on cancer care say adherence rates can vary widely, with estimates running the gamut from 20 to 100 percent.

Unpleasant side effects are a major reason for non-compliance. Other factors, O’Mara says, may include language barriers, patient misperceptions about how well oral agents work, and a lack of available alternative treatments if a patient experiences a high burden of side effects related to initial targeted therapy.

Studies have shown that people who have social support, lower out-of-pocket costs and particularly those who are taking aromatase inhibitors are more likely to comply. Those who take several medications, are depressed, or are very young or very old are less likely to adhere to their prescribed regimens.

While “data on adherence are scattered,” rates of adherence do seem to span “a wide range,” concedes Christine

Lombardi, an oncology nursing professional at the Hospital of the University of Pennsylvania in Philadelphia and author of “Patient Adherence to Oral Cancer Therapies: A Nursing Resource Guide.” Lombardi says patients adhere to oral drug therapies more successfully in some cancers than in others. In gastrointestinal malignancies, for example, because the targeted anticancer agents generate few side effects, patients generally do well in following clinicians’ advice. But other drugs, like Nexavar (sorafenib), which blocks kinase proteins that contribute to the growth of liver, kidney and thyroid cancers, can generate difficult side effects — nausea, vomiting and diarrhea &mdash; leading some patients to stop using them.

“Adherence can be really hard,” she says. “We’re asking them to fight all these side effects at the same time they’re fighting cancer.”

For Andrew Schorr, adhering to his regimen of the targeted drug Jakafi (ruxolitinib) as a treatment for his myelofibrosis — a bone marrow neoplasm &mdash; has been easy, because the drug has eased more discomfort than it has caused.

The twice-a-day treatment, he says, relieves the extreme fatigue, anemia, itching and enlarged liver and spleen caused by the disease.

“I’m terrified of missing a dose. Within two weeks of taking it, all my symptoms went away,” the North Carolina resident says.

Not so for Perrin, who has struggled to stick with his regimen of Nexavar because of the side effects it has brought. When the now 67-year-old first began taking the drug about 30 months ago, he started with a single daily pill, gradually upping the dosage to two pills. The severity of his early side effects filled him with dread about going to the prescribed higher dose, and although his body eventually adapted to the single pill, the increase took its expected toll.

That was when the “side effects really kicked in,” he recalls. Not only did he have diarrhea, but the exhaustion surprised him. “The fatigue was amazing,” he says. “I’m a person of boundless energy, but I could barely get through the day.”

Perrin became so exhausted, in fact, that he decided to step down as senior pastor of the Covenant Presbyterian Church in Cherry Hill, N.J., moving to Pennsylvania in mid-2014.

“Anybody who doesn’t have a strong will would have trouble adhering to these drugs,” he suggests. In his case, Perrin found that his strong religious faith helped him “tough it out.”

In addition to harsh side effects, high cost may be a deterrent to adherence, as many newer targeted agents are extremely expensive, sometimes costing as much as $8,000 to $12,000 a month, O’Mara says.

Schorr recognizes that his treatment, Jakafi, is expensive at $8,000 each month. He considers himself lucky that his insurer, Blue Cross, covers that cost, but knows that some other patients face high co-payments or deductibles.

In fact, a recent study showed that higher out-of-pocket costs for one particular cancer medication increased the chances that patients would skip doses or stop taking the drug altogether. According to the findings, patients in employer- sponsored health plans who had higher co-payments for Gleevec (imatinib), an oral drug for chronic myeloid leukemia, were 70 percent more likely to stop taking it and 42 percent more likely to skip doses. Co-payments ranged from nothing to more than $4,500 for a one-month supply.

While prices for Gleevec could drop this year after the drug goes off patent, the cost of many other cancer treatments may actually go up as regimens become more advanced. Given cancer’s Darwinian nature, some regimens, such as those used to treat melanoma and breast cancer, now include two or three targeted therapies given together, each honing in on a different pathway a tumor might use, and more combination therapies are expected to emerge.

“You can’t discount cost,” stresses Helen Chew, a professor of medicine in the Division of Hematology/Oncology at the University of California, Davis. “These drugs are relatively new and lack generics, making them more expensive.”

Medicare patients, in particular, might get into financial trouble when they fall into the “doughnut hole” each year and federal insurance coverage runs out, Chew adds, leaving these seniors to absorb the remaining cost.

Still another level of complexity involves specialty pharmacies, according to Pamela Ginex, a nurse researcher at Memorial Sloan Kettering Cancer Center in New York. Most of these newer targeted agents are unavailable at chain-store or local pharmacies, or even at the hospital, she says, so patients often receive their pills through the mail. That means they have to remember to order their prescriptions on time to prevent gaps in treatment.

And then there are the problems posed by complicated regimens.

“One of our biggest concerns is unintentional non-adherence,” says Ginex. “In most cases, patients want to take their drugs as prescribed.” But some may forget to take their pills, or else forget to stop when they should — particularly because some oral medicines are not taken every day, or are taken for a week or two with a break and then restarted. For instance, Xeloda (capecitabine), approved for Dukes’ stage C colon cancer, is given twice a day for 14 days, but then stopped for seven days; Ibrance (palbociclib), recently approved for breast cancer, is given daily for 21 days out of every 28 day cycle, while the hormonal therapy that accompanies it is given daily for all 28 days. Furthermore, some patients with cancer may need to remember to take different medication doses in the morning and at night, or to take drugs with or without food.

Chew also distinguishes between anti-cancer pills that patients take for a few months and those that must be taken for many years. “It’s far harder, in terms of compliance,” to stick with longterm therapy, she says.

That’s the situation in which Perrin finds himself. As with many targeted therapies under development today, Perrin’s Nexavar pills work by controlling active disease, and must be taken indefinitely.

“I asked my oncologist how long that might be,” he says, “and she said, ‘As long as they are effective.’ I understood that to mean I would outgrow it (the medicine) or it would outgrow me.”

Typically, the most aggressive cancers require a combination of intravenous chemotherapy and oral medicines, Lombardi and other experts say. As long as patients show up for their infusions, they’ll get their chemotherapy. But when it comes to oral regimens, patients are on their own. And if they stop complying, researchers aren’t sure what will happen.

“What is the demarcation between having enough drug (for benefit and tolerability), and what leads to a bad outcome?” O’Mara asks. “It’s a fuzzy area, still, and we should be researching it.”

Intuitively, it makes sense that severe complications can result when patients fail to take their oral drugs as directed in more aggressive cancers. Lombardi says the data are scant, but that some exist in specific cancers, showing that when patients take only half of what’s prescribed, progression and worsening disease can be anticipated. Without proper doses, she says, oral therapies can’t fully succeed in their mission: to precisely target the molecules involved in cancer cell growth and survival while sparing normal cells.

Most of the available data on treatment adherence, Chew says, exist on the prevention side, around drugs like aromatase inhibitors in breast cancer, which doctors prescribe after breast cancer surgery to prevent recurrences or further spread of disease.

One 2013 study of adherence to such hormonal therapies — in which patients took five years of either tamoxifen or aromatase inhibitors, or combinations of both &mdash; found that those with low rates of adherence (less than 80 percent of all prescribed doses taken) faced a nearly 20 percent higher risk of death. The study also showed that adhering well for the whole five years, compared with less than three years, decreased the risk of death.

“The best data I know are in breast cancer,” Chew says, “but we don’t always have data on how much of an oral drug you have to take in order for it to be effective. For instance, prior studies of chemotherapy after early breast cancer show that, if a patient took at least 85 percent of the intended dose, she got the intended benefit. But these results don’t necessarily translate to oral agents. If a patient takes a (targeted oral anti-cancer) drug 90 percent of the time, studies aren’t clear on the benefit.”

Some clarity was provided by a small, phase 3 study published in 2007, which demonstrated that an interruption in treatment with Gleevec for advanced gastrointestinal stromal tumors resulted in rapid disease progression for most patients. In the interrupted group, 26 of 32 patients experienced disease progression, compared with eight of 26 patients in the continuous therapy group.

“There’s not one solution” when it comes to medication adherence, Ginex concludes. The patient with breast cancer on (maintenance) tamoxifen, she points out, has a different experience, and different concerns, than someone taking oral treatment for metastatic pancreatic cancer.

With Laura Fennimore, director of clinical programs at the University of Pittsburgh Medical Center Health Plan, Ginex presented a report at an Oncology Nursing Society meeting in 2014 on lessons learned from HIV about treatment adherence that can be applied to cancer patients.

There are many studies addressing the issue of medication adherence in patients who have HIV, she says, and there are marked similarities between treating AIDS and cancer, including a grave diagnosis and complicated treatment regimens that patients are asked to follow. Not surprisingly, Ginex says, researchers have highlighted a need for “good communication, not only for patients, but to help support the medical team.”

Indeed, for health care providers, the shift to oral medications has created a new treatment paradigm. “We need to rethink how to follow patients, and we’re in the process of doing so now,” she says. “Although nurses tend to ask patients about adherence, getting back a ‘yes’ or ‘no’ answer is insufficient. Nurses need to say to the patient, ‘Tell me what you’re taking every day, and when.’ That way we can identify patients who might be having difficulties.”

Some supports for patients that have demonstrated success include medication reminders sent by text and the use of electronic pill dispensers that can monitor whether drugs have been taken and signal patients that they are due for a scheduled dose.

Meanwhile, a variety of new options designed to encourage adherence are sprouting up within the health care system. They include hospital-based medication adherence support programs, as well as ideas for minimizing the side effects of medications.

For Danette Kienstra, forgetting had nothing to do with her decision to cut back on one of her breast cancer drugs, despite a busy life as a mother of three and a longtime piano teacher.

“I had a huge weight gain,” she says, on two hormonal therapies, tamoxifen and Arimidex (anastrozole), adding that the regimen “took away all of my estrogen, making me very tired.”

Diagnosed with invasive breast cancer in 2004, Kienstra, then age 45 and a resident of Indian Harbour Beach, Fla., underwent three surgeries in the midst of back-to-back hurricanes barreling down the state’s east coast near her home.

Once she had completed four months of chemotherapy and six weeks of radiation, Kienstra went on tamoxifen for three years, then was prescribed Arimidex for two more years — all as adjuvant, or preventive, therapy. Although she took tamoxifen religiously, she says, when doctors put her on the aromatase inhibitor, she grew more lax. She never experienced the severe joint pain commonly associated with these drugs, but she was depressed by her weight gain, and therefore did not regularly take her Arimidex.

DANETTE KIENSTRA, pictured with her husband and sons, stopped taking hormonal therapy prescribed after initial breast cancer treatment because of side effects.

“I wasn’t worried” about harmful consequences, she says.

“But several times I missed a week or so, and that’s when I started bleeding,” raising doctors’ concerns. However, tests showed no signs of cancer, and Kienstra has been cancer-free ever since. Also, she lost all the extra weight, which she attributes not to diet, but to her excitement about being in a local musical.

Looking back, Kienstra says, given the chance, she would have been non-adherent even to her intravenous chemotherapy.

“After all the surgery I went through, I felt I was done,” she says. “I felt I was cured.”

On the website of the Dr. Susan Love Research Foundation, Love, a breast cancer specialist, writes that it’s not uncommon for women to stop their long-term maintenance hormone therapy before they’ve reached the five-year treatment mark, due to side effects. And for some women, that might be OK based on their specific situations.

“I think one of the most important pieces of information that may get lost…is that the additional five years of therapy only offers a ‘modest’ benefit in survival,” so women should talk to their doctors about whether they need an entire five-year maintenance course, Love writes.

She recommends that patients work with their doctors to determine their risk of dying from breast cancer at the time of diagnosis, and how much surgery and chemotherapy are expected to reduce that risk — possibly getting those numbers by using a special online calculator. “If your chance of dying was 5 percent and it goes to 2.5 percent, that is different than if your risk of dying or recurrence (was) 30 percent and it goes to 15 percent,” she writes.

Based on that risk assessment and other information, Love concludes, “a woman will…have to decide whether staying on treatment longer is the best option for her.”

Articles

With many anti-cancer drugs taken orally, it's up to patients to comply with prescribed regimens &mdash; but what happens if they don't?

The Best Laid Plans

Her doctor calls her his “miracle child,” even though she’s over 60, the mother of two adult sons and a grandmother of three. But Vera Lynn Coe, or “just Lynn” as she prefers, has survived advanced breast cancer for nearly a dozen years—a medical milestone few reach.

The Cocoa, Fla., resident says she has always maintained a positive attitude, even when refusing to limit her options to palliative care after learning her breast cancer had spread to her liver. Instead, she chose to undergo chemotherapy while she continued working. After surgery, she took Herceptin (trastuzumab), a drug that targets HER2, a protein in her cancer cells that fuels rapid growth. Within a few months, her cancer went into remission.

“It locks the gates on my tumor cells,” Coe says of Herceptin, describing how it prevents tumors that produce too much of the HER2 receptor to gain a survival edge. Because she tested positive for this molecular biomarker, her physician knew immediately that she had a particularly aggressive cancer and that her cancer would likely respond well to this targeted therapy.

The biomarker that guided Coe’s treatment is one of several dozen cancer-associated biomarkers considered “actionable” by clinicians. Some biomarkers, such as HER2, are predictive, meaning they can be used to predict how a patient will respond to treatment. Others are prognostic, meaning they can be used to estimate how a disease will progress. Still others are diagnostic—they can be used to confirm a diagnosis even in its earliest stages. Broadly defined, biomarkers refer to an array of biological molecules in the body, which take many forms&mdash;genes, their protein products and the organic chemicals inside cells&mdash;that can be objectively measured and evaluated, in the blood, urine, other bodily fluids or tissues, to distinguish normal from abnormal processes and indicate the presence or severity of disease. Biomarkers can be inherited, such as certain genetic mutations, or acquired, such as damage to DNA that occurs from certain exposures.

In cancer, these biological substances are playing an increasingly important role in helping doctors “personalize” medicine, tailoring treatment to each individual’s genetic fingerprint. Molecular mutations inside tumor tissues can help predict responses to certain therapies, as in Coe’s case, or flag differences between aggressive and indolent disease, allowing some patients to avoid or delay chemotherapy. With the aid of other tests, biomarkers can also confirm the early presence of disease or monitor treatment for a risk of recurrence. In blood tests, biomarkers can reveal an inherited vulnerability to certain cancers, including breast and ovarian cancer and a familial type of colon cancer.

As a screening tool in an asymptomatic general population, the bar is high for finding biomarkers unique enough to detect cancer at its earliest, most curable stages while at the same time resulting in the fewest possible false alarms, making it an intensive research goal.

Cancers are Darwinian. The cancer may get better for short periods of time, but then it returns.

Since mapping the entire human genome more than a decade ago, scientists have generated thousands of candidate biomarkers, using advances in technologies to pinpoint genetic errors that may signal disease. Although international teams are sifting through this dense molecular landscape for clues to many illnesses, the early focus has been largely on cancers and how they alter normal cellular processes to promote explosive and uncontrolled cell growth.

In no cancer is that process clearer than in chronic myeloid leukemia (CML), a “disease defined by its biomarker,” the Philadelphia chromosome, according to Mikkael A. Sekeres, director of the leukemia program at the Cleveland Clinic in Cleveland and chairman of the Food and Drug Administration’s (FDA) oncologic drugs advisory committee. Individuals with chronic phase CML carry this genetic abnormality in their leukemia cells, and this “fusion gene” encodes a protein called BCR-ABL, which tells leukemia cells to “grow, grow, grow,” he says, crowding out healthy blood cells and damaging bone marrow.

Named for the city in which it was discovered, the Philadelphia chromosome “is the first genetic abnormality linked to a cancer,” Sekeres says. With the approval in 2001 of the targeted therapy Gleevec (imatinib), which directly inhibits the activity of the BCR-ABL protein, it became “the first real success we’ve had in biomarker monitoring and molecular therapy,” he adds.

Richard Levine, president and founder of Space Coast Cancer Center in Brevard County, Fla., and Coe’s oncologist, describes the success seen in treating CML as the standard bearer for treating other cancers. “You can have patients in complete remission,” he says, “but they do have to take it [the targeted drug] forever, or the cancer recurs. It’s a new concept—the idea of turning cancer into a chronic disease,” similar to hypertension or diabetes, which can be contained for many years.

“Of course, not everybody responds to targeted therapy, and there is relapse,” Levine adds, saying cancer is a complex disease and molecular differences can be seen even within the same cancer.

Biomarkers have a relatively short history in medicine, starting in the mid-19th century when an English scientist identified the first potential cancer marker in the urine of a patient with multiple myeloma. A century later, however, the discovery of DNA’s double helix laid the groundwork for unraveling the genetic code, leading to a burst of biomedical activity. The first protein biomarker targeted by a cancer drug—the estrogen receptor in breast cancer&mdash;emerged in 1977, and the prostate-specific antigen (PSA) became the first biomarker for early detection in the early 1980s.

Biomarkers that hold the greatest promise for patients are those seen in the cancerous process itself, such as the Philadelphia chromosome. However, many candidate biomarkers are also found in normal cells or cellular functions, such as cell death. Finding biomarkers elevated only in cancer has proven challenging. Moreover, once a key molecular pathway is shut down, tumors employ “work-arounds,” allowing them to bypass that pathway and continue to grow.

“Cancers are Darwinian,” says Sekeres, referring to the 19th-century English naturalist Charles Darwin, who theorized that nature evolves by selecting for those most adaptable to environmental forces. For example, even though researchers have identified genetic abnormalities in 75 percent of patients with types of leukemia other than CML, drug-targeting efforts have failed. “The cancer may get better for short periods of time, but then it returns,” he says.

Right now, I think we're in the early days of molecular discovery. We're just nibbling at the edges. But there's still a lot more we need to learn about cancer.

Another hurdle: the sheer number of biomarkers discovered over the past decade through “omic” technologies, such as genomics, proteomics and metabolomics. These terms refer to different functional groups of proteins that give us windows into the cancer cell’s behavior. Despite the massive volume of molecular information generated through these large-scale efforts, comparatively few biomarkers have been validated for clinical usefulness, affordability or whether they can be independently reproduced or replicated, says  Sudhir Srivastava, chief of the cancer biomarkers research group in the division of cancer prevention at the National Cancer Institute (NCI). “We still want discovery done,” he says, “but driven by clinical usefulness.”

[Questions to ask your healthcare team about biomarker testing]

In 2000, the National Institutes of Health formed the Early Detection Research Network, a consortium of more than 300 investigators and 40 private or academic institutions, for just that purpose—to move the discovery and development of biomarkers from a disorganized, piecemeal effort into a collaborative, highly structured endeavor.

The multitiered process, establishing both a scientific standard and a road map, takes a biomarker from discovery and analysis to large validation studies in tumor specimens and patients, and ultimately, to the FDA. The consortium focuses on early detection markers in populations at high risk for developing cancer, Srivastava says, with the hope of identifying the earliest possible molecular shifts in cells as they march toward malignancy.

So far, just five network-supported biomarkers have moved forward to clinical trials, illustrating the sustained, long-term effort required to reach the clinic. Once a biomarker makes it to the FDA, the agency treats it as neither a device nor a drug, says Susan Laine, an FDA spokeswoman, but as a companion test for “pharmaceutical and diagnostic partners who are developing products that detect and target the molecular drivers of cancer.”

Of the five consortium-validated biomarkers, all but one can be measured in blood. Two of those five seek to refine screening for PSA.

Because the PSA cannot distinguish between aggressive and indolent cancers, it is a somewhat problematic biomarker, Srivastava says, “yet it is so widely used around the world, we wanted to increase its performance.” One new biomarker, proPSA, may reduce the number of unnecessary initial biopsies during screening, he says, as aggressive prostate cancers preferentially make this PSA by-product. The other, prostate cancer gene 3, or PCA3, measurable in urine, would be used to see whether men at risk for the disease require repeat biopsies.

From his perspective, James D. Brooks, chief of urologic oncology at Stanford University Medical Center in Palo Alto, Calif., sees PSA screening as a cautionary tale about how biomarkers can fail and lead to overtreatment.

“We have to be careful,” Brooks says. “We learned a lot from PSA screening about detecting stuff that might not be life-threatening,” yet can lead to invasive and unnecessary procedures. Also, PSA testing “falls apart in patients with metastatic disease,” he says, because biomarker expression can change during the course of disease.

Still, Brooks says he’s both an optimist and a realist about the pace of biomarker research today and its potential for improving patient care in the future. To reduce the risk of overtreatment, for example, he says, investigators could couple a cancer-detection biomarker with one that delivers prognostic information about how rapidly a cancer may grow.

“Right now, I think we’re in the early days of molecular discovery,” identifying certain genetic mutations that can bring “stunning results to small groups of patients—5 percent here, 2 percent there,” he says. “We’re just nibbling at the edges. But, there’s still a lot more we need to learn about cancer.”

Coe takes Herceptin every three weeks and will do so for the rest of her life until her cancer progresses, and then she will probably move on to another targeted agent based on her biomarker information. Other than losing her hair from chemotherapy, which is often given with Herceptin, she’s suffered few ill effects. “I’m alive, I keep my spirits up, and I keep wearing my wig,” she says with characteristic grit.

Biomarker research paves the way to precision cancer medicine.

Personalized Medicine Revolution Gains Momentum

People with cancer rarely ask about molecular testing for biomarkers, but they need to be better informed about what these tests offer and what they don’t.

Right now, doctors might ask patients if they would like to have a particular biomarker test, “but such tests are not part of the standard of care,” says Sudhir Srivastava, chief of the cancer biomarker research group in the division of cancer prevention at the National Cancer Institute.

Moreover, tests for every cancer are not yet available. Those that are can provide vital information that might mean the difference between effective and ineffective treatments, or suggest how aggressive treatments must be to keep a cancer in check. Molecular testing for genetic errors also can assess an individual’s personal risk when certain cancers run in families.

Cancer tests that are available can provide vital information that might mean the difference between effective and ineffective treatments, or how aggressive treatments must be to keep a cancer in check.

Sometimes, though, such tests can result in overtreatment and even harm, Srivastava and two co-authors warned in a recent editorial in the 

. As the “crude screening tools of the past” are replaced by increasingly sensitive tests, they wrote, slow-growing and even completely nonlethal lesions are being detected and overtreated. Examples of cancer screening tests that can be “misleading, of questionable value, or none at all,” include cancer antigen 125 (CA-125) and transvaginal ultrasound for ovarian cancer; prostate-specific antigen (PSA) screening for prostate cancer; and chest radiography for lung cancer, according to the authors.

[Read more on how biomarkers are changing cancer treatment]

So what should patients ask a doctor when faced with a cancer diagnosis or fearful about their personal cancer risk? A partial list of questions follows:

•	Is there a molecular test for my particular cancer? 

•	Does the test require a biopsy of my tumor or can it detect molecular changes in the blood or other bodily fluids? 

•	Is this test approved for use in my case and covered by insurance? 

•	How will it help diagnose or treat my cancer? 

•	How reliable and accurate is this test? Does it pick up indolent cancers or nonlethal lesions that may never cause health problems? 

•	How will the results be used to make a treatment decision? 

•	How does carrying a specific genetic mutation increase my risk for cancer and by how much?

People with cancer should ask questions about what biomarker tests are offered for their cancer type, what those tests offer and what they don't.

What You Need to Know About Biomarker Testing

	A new Food and Drug Administration (FDA) method for speeding drug development holds promise primarily for therapies that carry early and striking benefits for patients whose diseases lack adequate treatments or have none at all, investigators say.

	“It‘s really for drugs that appear to be lifesaving,” says Wyndham Wilson, head of the National Cancer Institute’s lymphoma therapeutics section, referring to the “breakthrough therapy“ designation. The designation was signed into law as part of the Food and Drug Administration Safety and Innovation Act in July 2012.

	As the name implies, this act reflects the federal agency’s recognition that some treatments offer such obvious benefits to patients early in development that there might be no need for traditional, large-scale clinical trials. As scientists continue unraveling the molecular underpinnings of disease, drugs can also be approved in advance, pending the results from larger trials. Key to the new designation, however, is frequent, “hands-on” interaction between the FDA and drug developers to ensure patient safety as a drug moves closer to possible approval.

	Such intense guidance during the drug approval process distinguishes breakthrough therapy status from other FDA avenues for streamlining approval of important drugs, according to Wilson. “Breakthrough therapy designation has more to do with how the FDA engages a company rather than different mechanisms,” he says, with the agency helping, for example, to design smaller, more efficient studies to validate—or not&mdash;a dramatic, early finding.

	Other mechanisms include fast-track designation, accelerated approval and priority review—all designed to shorten the standard drug review process. The fast-track designation also speeds drug development for serious or life-threatening diseases while the accelerated approval process allows drugs to gain approval based on preliminary data, pending completion of confirmatory studies. Priority review can shorten review time from 10 months to six.

	Wilson predicts limited use of this newest designation, however. So far, the FDA has granted breakthrough therapy designation to 31 novel agents out of 92 requests made by the industry, with two approvals so far. (See 

 items about Gazyva [obinutuzumab] and Imbruvica [ibrutinib].) Sometimes the FDA requires follow-up confirmation trials.

	Otis W. Brawley, chief medical officer of the American Cancer Society, predicts the breakthrough therapy designation will be reserved primarily for drugs that exhibit a “Lazarus effect.” That’s when seriously ill patients who’ve exhausted treatment options “suddenly get out of bed” after receiving a new drug.

	The rapid emergence of molecular markers is credited, in part, with driving creation of the breakthrough therapy designation. But, another important factor, Brawley says, is the difficulty in accruing sufficient numbers of patients with rare diseases or uncommon genetic markers for large clinical trials.

	“With targeted therapies, we are seeing unprecedented effects very early in development,” says Jeff Allen, a molecular biologist and executive director of Friends of Cancer Research, an advocacy group in Washington, D.C., that pushed for the breakthrough therapy designation. “But how much time might be shaved off (the development process) must be looked at on a case-by-case basis.”

	Similarly, the magnitude of an effect seen early on will vary by disease type with no “set bar” at this point, Allen says.

	“What we’re hoping for with this designation is there will be early collaboration with FDA, not just for clinical trials but all facets of drug development,” he says. “The designation is to start that conversation.”

A new law hopes to speed drug development for therapies in the age of biomarker-driven treatment.

Susan Jenks

The Best Laid Plans

Personalized Medicine Revolution Gains Momentum

What You Need to Know About Biomarker Testing

FDA's Breakthrough Therapy Designation Aims to Speed Drug Approvals

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