Recently in Oncology Category
This time from the NEJM.
Multiple authors, lead by disgraced, former Duke geneticist Anil Potti, retracted their 2006 article, "A Genomic Strategy to Refine Prognosis in Early-Stage Non–Small-Cell Lung Cancer." (For background, start here.) The authors (all of them) wrote in a nearly inconspicuous letter to the editor that they had "tried and failed to reproduce results supporting the validation of the lung metagene model described in the article." Deep regret was expressed for "the effect of this action on the work of other investigators," but regret for any patients who enrolled in clinical trials on the basis of the unreproducible work was not mentioned.
This is now the fourth Potti-authored article to be retracted since the veracity of Potti's work was called into serious question last year in The Cancer Letter.
- A 2007 article in the Journal of Oncology was retracted in December of last year.
- A 2006 Nature Medicine article was pulled in January.
- And, on the basis of this action, a 2007 article in the Lancet Oncology was retracted, also in January.
The Duke Chronicle reports that the NEJM retraction is "somewhat unexpected," because a journal spokesperson told the web site Retraction Watch in January that there were no plans to pull the article.
Today's PubMed search reveals that "A Potti" is coauthor on 128 returned articles, beginning in 2000, and first author on 33 articles—including 2 of the 4 retracted articles. The Potti-authored articles include a self-promoting piece in an April 2010 issue of Science Translational Medicine, in which Potti (along with Richard Schilsky of the University of Chicago and Joseph Nevins, Potti's Duke mentor) wrote "that it is now imperative that future clinical trials be designed with a plan to incorporate biomarker development."
Photo of Anil Potti, formerly from Duke's ISGP web site.
Today's Duke Chronicle reports the retraction of yet another article by geneticist Anil Potti. (For important story background, go here, here, and here.) On Friday, editors of The Lancet Oncology and the article's European coauthors justified their retraction of "Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy," expressing "concern over the validity of the results."
They continued:
The chemotherapy sensitivity predictions reported in the Article were based on an approach described by Anil Potti and colleagues in Nature Medicine. Re-examination of the validation datasets used for the Nature Medicine study has uncovered errors in the labeling of the clinical response in some of the datasets. Reanalysis of the predictive accuracy with correctly labeled data has shown that in two instances the reported signatures do not predict the response of the validation samples to chemotherapy.
In other words, the article was retracted because the results were founded on the flawed (ie, mislabeled) data from another retracted article by Potti et al (in Nature Medicine). An investigation into the validity of the Lancet Oncology article was begun last October, when editor David Collingridge relayed an "expression of concern" from 15 European investigators who were coauthors with Potti and 3 other Duke researchers. After a damning report in July from biostatisticians at M. D. Anderson about data-labeling errors in another article by Potti et al, the Lancet Oncology coauthors repeatedly attempted to contact their Duke colleagues, but they were ignored, wrote Collingridge.
This is the third article by Potti to be retracted since his work was called into serious question last year. A 2007 article in the Journal of Oncology was retracted in December, and the Nature Medicine article was pulled this month. In October, Collingridge also revealed that "a large group of scientists" wrote to NCI director Harold Varmus on July 19th, expressing their concerns about the validity of a) Potti's cancer-treatment prediction models and b) 3 clinical trials that were based on these prediction models.
On a related note, Friday's The Cancer Letter (subscription required), by way of The Great Beyond Blog, reveals that FDA auditors have visited Duke to determine if the university obtained proper approval for 3 cancer trials, which were based on the demonstrably flawed work of geneticist Anil Potti. At issue, from the agency's standpoint, is whether Duke obtained an Investigational Device Exemption (IDE), which was necessary because genomic chips were used to identify genetic biomarkers on which treatments was based.* There was evidently some confusion at Duke about whether an IDE was needed.
* The trials used Potti's (mislabeled) data to determine what anticancer drugs or combination of drugs cancer patients would receive on the basis of genetic biomarkers.
We made the decision because the drug has a marginal effect on tumor growth in breast cancer and in light of Avastin's severe side effects, the risks outweigh the limited benefit.
Pazdur cited "issues" and "problems" with a pivotal study, E2100, which showed that Avastin (with paclitaxel) delays the growth of advanced breast cancer for 5 months. Not surprisingly, drugmaker Genentech, a subsidiary of Roche, rejects the FDA's view of the controversial study and its results. But follow-up studies failed to confirm the favorable results of E2100, reports the WSJ. Some insurance companies, acting independently of the FDA, have already denied coverage for the use of Avastin in metastatic breast cancer.
Blogs and traditional sources are abuzz with the news that the FDA is considering the withdrawal of Avastin's indication for breast cancer. The agency, in what may be a harsh, but necessary decision, concluded that Roche's monoclonal antibody—which is otherwise approved for the treatment of colon cancer, non-small cell lung cancer, glioblastoma, and metastatic kidney cancer—"has not been shown to be safe and effective for [breast cancer]."
The FDA based its looming rescission on the postmarketing results of 4 clinical studies, which showed that Avastin does not prolong overall survival or slow disease progression to an extent that outweighs drug-related risks (like hemorrhage, organ perforation, and MI). The agency evidently reached its conclusion after agreeing with input from an oncology advisory committee (which voted, 12-1, in July of this year to pull the breast-cancer indication).*
For now, Genentech (Roche's subsidiary) has not agreed to voluntarily pull the drug. Confusing the US regulatory decision is the fact that the European Medicines Agency affirmed the utility of Avastin in metastatic breast cancer (with paclitaxel). Genentech will evidently accept the FDA's invitation for a Notice of Opportunity for a [Public] Hearing, according to a company press release. In the meantime, the drug will retain its breast-cancer indication in the United States.
There are others who also oppose the FDA's decision on Avastin, including patient advocates, US breast-cancer experts (who observe that subgroups of patients clearly respond remarkably to the drug), and House Republicans. The political charge is that the FDA is considering cost—not merely efficacy and safety—in its decision to withdraw Avastin for breast cancer. Two statements jump out in a joint press release.
Reps. Gingrey, Myrick, Pitts and Upton are gravely concerned that the FDA is putting economics ahead of proper courses of treatment and that today's announcement is the first step towards government rationing of health care.
And
Allowing the FDA to factor in the cost of a drug when determining whether that drug should be approved is the first big step towards government rationing.
If this is true (that the FDA considered the cost of Avastin in its approval process),** the government would be overstepping its legislated bounds. It's not the FDA's legal job or purview to consider what the free market can or should bear (despite the rising costs of health care). That issue should be left up to the free market. Perhaps House Republicans are creating a diverting issue by raising drug cost in the case of Avastin withdrawal, but it is an issue worth exploring (by further probing the FDA's review process of Avastin).
According to the AP and other sources, Avastin costs about $8000 a month, but Roche caps the annual price at $57,000. The drug brings in about $1 billion from use in breast-cancer patients (which is a fraction of overall Avastin revenue). According to the NY Post (I know), agency officials deny that their decision is based on cost.
Of course, individuals with breast cancer could still receive Avastin off-label, if the FDA's withdrawal sticks; however, insurance coverage for the indication may be jeopardized as a consequence. That's the point and fear of Avastin advocates and patients.
* In a July analyst call, Avastin director Stefan Frings reportedly complained openly about the biased makeup of the advisory panel and the FDA's statistical methods.
** Although I've found no evidence that the FDA considered the cost of Avastin in the process of making its latest decision.
Specifics are lacking, but geneticist and physician Anil Potti now takes "full responsibility for a series of anomalies in data handling, analysis and management that have come under scrutiny in the past months." Potti's mea culpa and resignation from Duke University is delivered by way of Hunt Willard, director of the university's Institute for Genome Sciences and Policy, through today's Duke Chronicle (what I remember as being a-not-so-terrible college newspaper).
In Friday's e-mail to the IGSP staff, Willard asked faculty members to "remember, especially at this time of year, all that Anil has done to positively influence the lives of many of his colleagues, trainees, friends and patients. The loss of any member of our family is difficult, and I ask you to keep that in your thoughts today." It's an overly gracious good-will sentiment generally and an insulting slap specifically to those researchers whose professional lives have been tarnished by proxy—not to mention the hopeful cancer patients who enrolled in clinical trials that were based on Potti's dubious work.
Potti had been on administrative leave from Duke since July, shortly after The Cancer Letter charged that he had seriously fudged his resume by falsely claiming to be a Rhodes scholar or "finalist." More important, Potti was facing allegations of research misconduct on the basis of a 2009 examination of his work by M. D. Anderson biostatisticians. Back-and-forth external and internal investigations ultimately led to the termination of several clinical trials, on which Potti's work was based, and the retraction of several published articles. The most recent literary casualty is a report cowritten by Potti that was published in Nature Medicine, reveals The Great Beyond Blog (presumably this article, published in 2006).
For its part in the Potti scandal, the Duke leadership (ie, President Richard Brodhead) has received sharp criticism from the blogging team (at least I think they're a team) at Duke.Fact.Checker ("Inside the Potti Mess: A Fact Checker Special Report"). The excoriation:
We do not find that Uncle Dick has taken any profile at all, that is to say exhibited any leadership. In particular, he has not expressed appropriate concern for the patients.
His only important comment came just after The Cancer Letter reported Potti's fake claim of a Rhodes Scholarship and the Rhodes Trust confirmed there was no award. With other credential issues looming at the time, Brodhead cautioned the editorial board of the [Durham] Herald-Sun not to reach rapid conclusions of truth or lie, for there could also be "intermediate explanation."
Pathetic. Dick, just pathetic.
Photo of Anil Potti, formerly from the ISGP web site.
A big HT to the WSJ Health Blog for showcasing this intriguing study in Health Affairs. Against the otherwise commonsensical preference for screening colonoscopy (to prevent and detect colorectal cancer), researchers at RTI International showed that yearly testing for fecal occult-blood leads to more life years saved. The result held even when adherence to CRC screening guidelines dropped to 40% and follow-up compliance was only 65%.
The context of the study was a fixed budget for a CRC-screening program ($1 million), and the assumed costs for guaiac testing and colonoscopy were $23 and $699, respectively. (Although the Healthcare Blue Book price for colonoscopy [no biopsy] is much higher, at $1658.) Consequently fecal occult-blood tests allowed the hypothetical program to screen more individuals and lead to a greater number of life-years gained.
The authors warned that the study only assessed life-years gained, not quality-adjusted life years (QALY), and that the test selection was made in the context of a fixed budget. "If there were no budget constraints," they wrote, "a different screening test might be preferable."
But really: When are there no budget constraints?
Addendum: At the WSJ Health Blog, one commenter raised the issue that the authors only assessed a hypothetical population-based screening program. The results do not necessarily indicate that fecal occult-blood tests are preferable screening tools for individuals who are at high risk for CRC (eg, people with Crohn disease or a family history of CRC).
Photo of Olympus standard video colonoscope: price, $3500. (Avoiding Olympus standard video colonoscope: priceless.)
Just as an astronomical white count is not an entity unto itself but a marker of a serious underlying disorder, like leukemia, so a big lie on a CV is an indicator of a grave underlying problem, like sociopathy.
Faculty members at the Duke Institute for Genome Sciences and Policy are learning this lesson the hard way thanks to the failure of someone at Duke to perform the basic HR duty of vetting Anil Potti's curriculum vitae 7 years ago. Potti, who was hired in 2003 as a physician-researcher by Duke, falsely claimed that he was a Rhodes Scholar on scientific grant proposals, according to a recent expose by Paul Goldberg in The Cancer Letter. That's a big lie and one suggesting that other big lies are possible, if not probable. Taking this very cue, Goldberg then questioned the integrity of Potti's research at Duke and found that 2 biostatisticians at M. D. Anderson discovered "a series of errors," including mislabeling errors, in a seminal article by Potti and others.
Consequently the biggest victim of Duke's remote HR lapse: cancer patients who enrolled in clinical trials, which were based on Potti's questionable work. According to the NYT, these trials have now been suspended (after stuttering efforts by Duke officials to reopen them, reported Goldberg). News coverage can also be found at NPR's Shots blog.
For yucks or groans, I performed a quick PubMed search: "A Potti" is the coauthor of 48 articles that were published within the last 5 years. Potti's articles appeared in, for example, PNAS, JAMA, JCO, PLoS One, Lancet Oncology, Nature Medicine, and the NEJM.
Photo of Anil Potti from Duke Institute for Genome Sciences and Policy.
10/24/10 addendum: As the AP reported yesterday, Lancet Oncology editor David Collingridge relayed an "expression of concern" from 15 European investigators who were coauthors with Potti and 3 other Duke researchers on a 2007 article in the journal. (The article validated the use of gene signatures to predict the response of breast cancers to neoadjuvant [perioperative] chemotherapy.) After the damning report from biostatisticians at M. D. Anderson about Potti's alleged errors in another article, the Lancet Oncology coauthors repeatedly attempted to contact their Duke colleagues, but they were ignored, wrote Collingridge.
The editor also revealed that "a large group of scientists" wrote to NCI director Harold Varmus on July 19th, expressing their concerns about the validity of a) Potti's cancer-treatment prediction models and b) 3 clinical trials that were based on these prediction models. Collingridge expressed his own concerns about the Lancet Oncology article given recent developments surrounding Potti. The journal has contacted the Duke coauthors—Anil Potti, Chaitanya Acharya, Sayan Mukherjee, and Joseph Nevins—and awaits their responses.
Dr. George Lundberg, MedPage's Editor at Large, is really excited about an article that was published in March in the Journal of Clinical Investigation. And he predicts big things for the article's authors, like a Nobel Prize.
The article, by California academicians and an employee at AntiCancer, Inc., describes how vasculogenesis* of irradiated tumors can be inhibited by an already approved drug, AMD3100, in a mouse model of glioblastoma multiforme—the deadliest of brain cancers.
AMD3100 is also known as plerixafor or Mozobil, which is owned by Genzyme. The injectable drug is currently indicated, in combination with G-CSF, to mobilize hematopoietic stem cells for autologous transplantation in patients with non-Hodgkin lymphoma or multiple myeloma. So human trials of the drug and uncontrolled case studies can begin, Lundberg argues, more or less immediately.
G-CSF = granulocyte-colony stimulating factor (eg, filgrastim [Neupogen; Amgen]).
* Which is distinguished from angiogenesis or "the sprouting and proliferation of endothelial cell from local vessels. The authors posit that tumor recurrence after radiation is largely mediated by vasculogenesis, the "colonization of circulating endothelial or other cells primarily from the bone marrow."
Photo of Ted Kennedy, who died last year of glioblastoma: Biographical Directory of the United States Congress.
A first-of-its-kind investigational vaccine prevents breast cancer in mice, according to a press release from Cleveland Clinic researchers. Results of their preclinical studies, which were published online Saturday in the journal Nature, lay the foundation for clinical development of the vaccine in women.
The new vaccine differs from the most notable cancer-preventing vaccine, Merck's Gardasil, in that it targets an autoantigen, alpha-lactalbumin, not a cancer-associated virus, like HPV. Alpha-lactalbumin is a breast-specific protein that is overexpressed in most breast cancers and during lactation, but not in normal breast tissue of nonlactating women. In transgenic mouse models of breast cancer, disease was prevented in all inoculated animals, while unvaccinated mice developed cancer. The vaccine also stymied the growth of existing tumors.
The excitement of the study's lead investigator, Vincent Tuohy, PhD, is palpable: "If it works in humans the way it works in mice, this will be monumental. We could eliminate breast cancer," he says in the press release. Tuohy proposes that the vaccine would be appropriate for women older than 40, when pregnancy (and lactation) is less likely and the risk of breast cancer rises.
Human trials of the vaccine may begin within the year, reports the Clinic.
HPV = human papillomavirus.
Mass screening or rational design? Malcolm Gladwell, the 10,000-hours guy with Leo Sayer's hair, examines the monumental barriers to finding effective treatments for cancer in the upcoming issue of the New Yorker.
Given the oppressive anti-pharma mood generated by mainstream media and Marcia Angell, it's refreshing to have Gladwell remind us—in a really entertaining way, no less—just how "boinking" hard it is to bring an effective and safe cancer therapy to market.
