Mon, Jan 9 2012
By Ivan Oransky, MD
NEW YORK (Reuters Health) – In a reminder of how much a once-heralded area of lung cancer research has crumbled, a former Duke oncologist and his colleagues issued their eighth study retraction late last week.
On Friday, Dr. Anil Potti and his co-authors formally withdrew a 2008 study in the Journal of the American Medical Association (JAMA) that purported to offer a “genetic signature” that would show which patients with breast cancer would respond to a particular treatment.
The authors write in a statement on the JAMA website — available at bit.ly/AeIufY — that they are retracting the paper because it was based on a method they now believe is unreliable. That approach — which no one has been able to reproduce — was described in a now-withdrawn paper in the journal Nature Medicine in 2006.
The case is yet another example of researchers — some of whom had financial interests in the method — being overly enthusiastic about findings that held great promise for very sick patients, but that did not hold up to scrutiny.
The retraction is the eighth of what Duke officials said this past summer would be about a dozen, along with another dozen corrections and partial retractions. The Duke team had published about 40 papers, many of which have been cited hundreds of times by other scientists, according to Thomson Scientific’s Web of Knowledge.
The now-retracted JAMA study garnered a fair amount of media coverage, too, including a story by Reuters Health on April 1, 2008.
Journals and universities began subjecting the work to intense scrutiny, however, after it emerged that Potti had claimed awards and scholarships that he never received, in biographical sketches for grant applications.
The whole episode has been a “huge setback,” said Dr. Otis Brawley, chief medical officer of the American Cancer Society.
“What happened at Duke is that you have a whole bunch of folks worried that this genomic information is just too complicated, making it too easy for someone to basically create fraudulent science,” Brawley told Reuters Health.
UNDONE BY RESUME ‘INACCURACIES’
Keith Baggerly, who studies genomics at the M.D. Anderson Cancer Center in Houston, has been looking into the Duke team’s data since shortly after the Nature Medicine report came out. A colleague approached him and Kevin Coombes excitedly at the time, hoping he could use the work to improve the treatment of patients at M.D. Anderson.
But Baggerly and Coombes found numerous problems in the research, including mislabeling of data. He began asking the Duke team for their data, but they were slow to provide it. Eventually, some journals began publishing his critiques, often alongside defenses of the work by Potti and his colleagues. Meanwhile, clinical trials making use of the genetic signature continued at Duke.
Baggerly’s questions went largely unheeded until July 2010, when The Cancer Letter, a trade publication, reported that Potti had falsely claimed to be a Rhodes Scholar on an American Cancer Society grant application. Within months, the trials were halted, and Duke returned $729,000 to the cancer organization.
Potti resigned from Duke in November 2010, and has since joined a private oncology practice with offices in North Carolina and South Carolina. He and his colleagues, along with Duke, face two lawsuits from nine patients who took part in the trials. Eleven other such cases have already been settled for at least $75,000 each, according to the North Carolina Medical Board, which reprimanded Potti for the “inaccuracies” on his biographical sketch and CV.
According to the JAMA retraction notice, Potti works at the Myrtle Beach, South Carolina office of Coastal Cancer Center. But a person answering the phone there said he did not work in that office and was unavailable because he was in clinic.
For plaintiffs’ attorneys, proving that patients were actually harmed by being in the trials will be difficult, said Brawley.
“I don’t myself think that patients were harmed by being steered to a particular chemotherapy, at one level,” he said. The choices in the trial were widely accepted therapies that their own doctors would have likely given them.
That wasn’t the only risk, however.
“I’m a little bit concerned that some of the patients may have gone back and had new biopsies, for new analysis in the laboratory,” Brawley said. “If that was purely for this trial, those were unnecessary procedures, with risks. I hope no one was harmed by that.”
MOVING FORWARD
The episode is fueling soul-searching at Federal agencies.
There are “some positive things coming out of this whole mess,” Baggerly said. One potential move being considered as part of a review of cancer genomics studies by the U.S. Institute of Medicine (IOM), for example, is to require genetic tools such as the one the Duke team used to go through the same approvals that a medical device would go through at the Food and Drug Administration.
The IOM’s report is expected out in the next few months, and there are similar changes being considered at the National Cancer Institute — which funded some of the Duke team’s work — and the Food and Drug Administration. Duke itself has created a team to establish new safeguards as genetic research moves into the clinic.
But the dark lessons remain.
“To a certain extent, what I’m worried about is that this may show aspects of how it is becoming increasingly difficult to check the scientific literature and how that difficulty stems at least in part from lack of immediate access to data but also lack of code and documentation,” Baggerly told Reuters Health.
Given the highly technical nature of the work, it’s not surprising that the flaws in the papers weren’t caught before they were published, according to Baggerly.
“That’s actually OK,” he said. “It’s not OK that it took so long for the challenges to be accepted once the research was questioned.”
“The other thing that is not OK is the fact that it made it into guiding clinical trials,” Baggerly added.
Brawley said the story “is a tragedy in a number of different ways.”
“I’m actually more concerned right now with the systemic issue across the country that it’s up to universities to police their researchers,” he said. “But as science progresses, those universities are more and more interested in how many patents they have, and how many licenses they have for those patents.”
“The universities that are responsible for assuring academic integrity actually have a conflict of interest,” said Brawley, pointing out that Duke had an ownership stake in CancerGuide Diagnostics (formerly Oncogenomics, Inc.).
CancerGuide, which cut ties with Potti in July 2010 after the Rhodes misrepresentation came to light, had licensed technology based on Potti’s work from Duke, the student newspaper The Duke Chronicle reported in 2010. Duke has since divested from the company.
‘A 21ST CENTURY DEFINITION OF CANCER’
Despite the setback, cancer treatment will continue to make more and more use of genetic information, Brawley said. Oncologists already use tools such as the OncotypeDX genetic test to tailor treatments for breast cancer and colon cancer.
“Since the 1840s, we’ve been using a light microscope to define cancer,” he said. “Now with all the other advances we have, even the needle biopsy, we often find a one-centimeter tumor, and we’re saying ‘this looks like cancer,’ according to a 19th-century definition. What we need is a 21st century definition of cancer.”
“We’ve got these new tools, and people are very excited about using them,” Baggerly said. “Some of these genetic level screw-ups are indeed what cause the disease, so there is the potential there. That said, some of the initial claims about how quickly we’re going to be able to turn these (findings) into clinically useful assays have been overoptimistic.”
“We’re going to get there, but a number of the early studies thought this would be an easy problem,” he said. “The biology turns out to be quite complex.”
(This story corrects the date in paragraph 12 and adds Kevin Coombes’ name to paragraphs 10 and 11.)
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