August 2008
Feature Story

Anne Paxton

There’s no question that targeting therapies based on biomarker tests is becoming common practice. Mara G. Aspinall, past president of Genzyme Genetics, Westborough, Mass., calls this new practice of personalized medicine a tremendous opportunity for pathologists. Speaking at the CAP Future­scape conference in Chicago in June, Aspinall said she prefers the term “specific medicine” because it underscores the critical role of precise diagnosis in treating patients effectively.

In hematologic malignancies, for example, “five-year survival has gone from zero to 70 percent, because we have the ability to do not just morphology but fundamental molecular work to get an expanded characterization and to get that very specific diagnosis,” she pointed out.

This “specific medicine” should be a friend, not a foe to pathology, Aspinall said. But pathologists may have to meet its challenges by forging a new integrative role in medicine.

The returns from personalized medicine are well known, and Aspinall shared additional analyses that highlight the savings. The EGFR-inhibitor Erbitux (cetu­xi­mab), for instance, significantly reduces the average-patient cost of treating colon cancer cases. “With this drug you can treat 10 patients and get three successes. But with personalized medicine, you can now test for those who will not respond and eliminate drug treatment from that subset. You then have six patients to be treated instead of 10. You still end up with three successes, but you’re avoiding the toxicity of unnecessary treatment for four patients.

“With this type of testing,” Aspinall said, referring to KRAS mutation tests, “you will determine who will not respond to Erbitux, and your average treatment costs drop from $28,000 if you treated everyone, down to $22,000.”

She has analyzed these data not only according to cost-per-person but also on the basis of cost-per-success. “If you compare a 30 percent rate of colon cancer patients that are going to be successful with Erbitux versus a 50 percent success rate, you see a huge difference—cost of $100,000 versus $156,000. This is how we’re proving that personalized medicine and accurate diagnosis not only save lives but also save money.”

An important factor that sometimes gets short shrift in cancer treatment, Aspinall noted, is that cancer patients don’t have time for trial-and-error medicine. “Patients may have good or bad insurance, access to physicians, and tremendous wealth, but the one thing they don’t have is time. So if you’re trying to practice trial-and-error medicine, and you let your lung cancer patients try chemotherapy and you don’t try an EGFR test first, you’re only dealing with 40 percent of them at the end of the year. With colorectal cancer, you’ve lost a quarter of them before you’ve targeted that treatment.” This has been dramatized by chronic myeloid leukemia, which before the drug Gleevec had a one-year survival rate of 63 percent; the post-Gleevec survival rate is 93 percent.

The explosion in all the “omics” sciences—not just proteomics but also cardiogenomics, cryobionomics, fluxomics, and dozens more— is one of the fruits of the Human Genome Project, she said. “But what it’s really about is diagnostics. If you look at diagnostic technology in the past, you had disease diagnosis solely based on the organ in which the tumor was found. Now, diagnosis formerly based on macro level analysis is based on the DNA of the tumor. So the future will bring us much more predictive testing on multiple technology platforms, and that creates the need for an integrative role of the pathologist.”

As this testing unfolds, multiple gene signatures will be explored—not just a single gene that has all the answers, but multiple genes, tested through new sample types, not only tissue and blood but also perhaps urine and saliva. “And that will not solely be based on laboratory testing,” she added. “I believe imaging will become increasingly relevant to all of our testing in the future.”

Meanwhile, the government’s role in regulating genomics is expanding. “The FDA has issued draft guidelines on IVDMIAs [in vitro diagnostic multivariate index assays], the most complex gene signatures, and they’ve said that is a high priority for them.” Aspinall, who is a member of the Secretary’s Advisory Committee on Genetics, Health and Society, noted that a key finding of the committee’s recent report on genetic testing oversight is the need to close gaps in the regulation of tests. “The government is taking notice on the increased role and importance of diagnostic testing.”

Aspinall is now on what she describes as a “working sabbatical,” at Harvard Medical School and Dana Farber Cancer Institute, the focus of which is understanding and integrating personalized medicine into physician education and practice. For any technology, she said, there is a three-step adoption process. The first stage is fear: “No matter how good the technology is, there is a tremendous amount of fear about its meaning and how it will change the physician’s role.” The second stage is value: how the technology can improve the value of the product and help patients and physicians. “Only after that can it go into acceptance,” she said. Typically, the adoption process for technologies, from Pap tests to vaccines, takes about 15 to 20 years.

Personalized medicine is moving out of the fear stage into the proving value stage. Payers are asking: What action will change as a result of this test? This is an important point, she noted. Until recently, there have been large numbers of prescriptions written concurrent with the ordering of a HER2/neu test, which says the doctor is going to prescribe Herceptin either way.

“Physicians, on the other hand, are saying, ‘This is great, but don’t tell me what to do. I need to use the art as well as the science of medicine to go forward. Give me enough flexibility to think it through myself,’” she said.

Everyone is enthusiastic about personalized medicine, but the flip side of that is the drugs that aren’t given, Aspinall pointed out. “Try telling a 30-year-old breast cancer patient that we have nothing more to do and you’re HER2/neu negative. It’s difficult to say personalized medicine says you can’t get the drug, so we have not seen many of the patient organizations coming out aggressively for personalized medicine. We have a mindset—and a reimbursement system—that says action is not always better than nonaction, but it’s more nuanced than that.”

The regulatory aspects are also complex. “If we want to put tests on drug labels, how does the FDA do that if they don’t approve the test? And if they do want to approve it, do they need to create a whole new set of guidelines as to how they will analyze a test in order to actually put on the label?” There are 121 drugs with labels saying their use is determined by pharmacogenomics, but only two name the actual test, she said. “Six have a recommended test and 16 mention the test for information only. So 100 drugs tell the physician, yes, this has a pharmacogenomic impact, but they don’t say what to do about it.” This will change, she predicts, in the new era of personalized medicine.

The fear of the pharmaceutical industry has several components, Aspinall said. First, spending on research and development is going up while drug approvals are not. “That’s been a consistent pattern for the last seven or eight years. There are 105 blockbuster drugs today with over $200 billion in sales, but seven out of 10 of the top launches last year were generics. And by 2012, many believe 85 percent of all prescriptions written will be for generics.”

But generics hit pharmaceutical companies’ profitability. “Eighty percent of a drug’s sales will go away in the first 80 days post-generic introduction.”

Several studies have demonstrated one fact that really drives personalized medicine, she said: “If you look at all drugs across all classes, the average efficacy is 50 percent, not because they’re bad drugs but because they’re not given to the right people at the right time. And it’s most dramatic in oncology where only 25 percent show clinical efficacy in patients who take them.”

Adverse events are another factor the pharmaceutical companies have to consider. They cause 100,000 deaths each year. These events remind us that “we don’t know enough about how drugs are metabolized person by person,” she said. And finally, the “dirty little secret” in pharmacology: “If you look at compliance, only 25 percent of prescriptions are truly filled and taken as prescribed.” If personalized medicine can supply a drug that truly works and thereby an incentive for patients to take it as prescribed, “then I don’t believe it will shrink the market for any individual pharmaceutical. If it works, it will increase the market,” Aspinall said.

Sharing the risk on the performance of a drug might be a shocking concept in the United States, but in Europe it is beginning to happen because of personalized medicine, Aspinall said. In the U.K. and France, for example, the drug manufacturer offers a full refund if the therapy that a multiple myeloma patient receives is not successful. Under the protocol, the serum M protein, a biomarker for tumor load, is looked at through a blood or urine test before therapy and again after four cycles of the Johnson & Johnson drug Velcade (bortezomib).

“The biomarker is clearly linked to efficacy and then to payment,” she said. “If there’s a complete response—i.e., no serum M protein—the company is paid. It’s also paid if there’s a partial response with a reduction of 50 percent or more. But if there is a minor or minimal response, the company is not paid for the drug.” This trend could accelerate personalized medicine even more, in her view. “This says: Integrate the use of a biomarker up front, if that is the only way to get paid.”

Pathology has its own reasons for being fearful of personalized medicine, she said. Potentially new sample types such as molecular blood tests, breath tests for H. pylori, and urine tests as a noninvasive procedure are one reason. Another is the steady replacement of traditional tests with new microarrays. “Work at the National Cancer Institute says Burkitt lymphoma is misdiagnosed 17 percent of the time using morphology,” Aspinall said. “But if you use gene-expression technology in addition to or in place of morphology, you get a very clear picture and no misdiagnosis between Burkitt and diffuse large B-cell lymphoma.”

Traditional diagnostic tests have changed only incrementally over the past 20 years, and “there are less than a dozen IVDMIAS on the market today, depending on how you define it,” she said. But with more than 200 U.S. companies now developing IVDMIAs, she foresees a phase of unprecedented growth moving forward. “Let’s say only half of them succeed in the next 10 years. This is still an influx of new tests that’s never happened before in diagnostics.” On top of that, she added, “it looks like 2008 may be another record year for venture capital investment in diagnostic companies.”

This surge of new molecular tests is coinciding with an Internet age that creates demand for immediate answers. And industry is reacting by putting more and more diagnostics into IVD kits that physicians can use in their offices. In answer to the trend, pathologists need to “own” personalized medicine, Aspinall said.

Especially with the advent of new tests that focus on very targeted patient populations, “the pathologist needs to be the source of expertise on all tests, whether they happen in their laboratory or not. Pathologists need to be the interpreter and consolidator of results, and most importantly, the educator of other physicians on diagnosis—so they don’t believe they can do it without a core pathologist bringing all those together.”

Eighty-five percent of patients are treated in communities, not academic centers, so “that’s where this change will happen,” she said. The CAP and the American Society of Clinical Oncology need to continue developing practice guidelines, as they have done already with HER2/neu.

Pathologists must also continue their leadership in developing the electronic medical record, of which 70 percent is already laboratory data, to make it truly representative of the diagnosis of the patient, Aspinall urged. “And pathologists must develop data for ourselves, for our colleagues, to be able to say that personalized medicine works. The diagnostic company may have a great new test, but the providers have the outcome data and the payers have the system costs and benefits. It’s great to relate anecdotes about personalized medicine, but as an industry we need to work together to show it with data.”

As for policy, Aspinall said pathologists should push to shape reimbursement to reward value, not activity. “We need pay-for-performance guidelines to include diagnosis, which they do not today. And we need regulatory options that embrace personalized medicine drugs and tests.”

Pathologists’ concerted action on these fronts will help move the industry from fear to acceptance, she predicts. “When you put this together, the pathologist, I believe, needs to and can lead these efforts.”

As they embrace the new “Era of Diagnostics,” pathologists will expand their scope of practice to be the institutional knowledge coordinators, the holders of cutting-edge expertise. “And ‘personalized medicine’ as a term will no longer be something we have special conferences on, it will just be medicine,” she concluded.

“This is what I believe the future is—and we need to drive it.”