TIME TO DISCOVER NEW CANCER BIOMARKERS

August 17, 2010 — Not a single new "major cancer biomarker" has been approved for clinical use in the past 2 decades, despite large amounts of funding and plenty of public-relations hype, according to an essay published online August 12 in the Journal of the National Cancer Institute.

"A major biomarker is one that is used widely at the international level, has been FDA [US Food and Drug Administration]-approved, and is recommended by experts for use in clinical practice in professional practice guidelines, such as the ones issued by the American Society of Clinical Oncology," the essay author, Eleftherios P. Diamandis, MD, PhD, told Medscape Medical News.

The absence of a new major cancer biomarker has not been the result of "either a shortage of funds or lack of effort," writes Dr. Diamandis, who is professor of pathology and laboratory medicine at Mount Sinai Hospital in Toronto, Ontario.

In the United States, one federal government program alone, the Early Detection Research Network, which is devoted to finding diagnostic cancer biomarkers, has spent "hundreds of millions" of dollars in a 10-year period but has yet to yield a single FDA-approved marker, writes Dr. Diamandis.

The overall futility is obscured by the fact that there have been multiple "breakthrough" cancer biomarkers that are highly publicized. However, long after the press releases are issued and news conferences are over, the markers are still not validated and quietly turn into failures, says Dr. Diamandis.

Repeatedly, biomarker studies have had "deficiencies" in design and analysis, writes Dr. Diamandis, who cites 7 notable examples in his essay, including early prostate cancer antigen-2 (EPCA-2) for prostate cancer detection.

Nevertheless, "experienced authors, reviewers, and editors" publish data and "overlook" the deficiencies, he says.

Has the disciplined world of science gone awry? Yes and no, suggested Dr. Diamandis during an interview.

The scientific literature is full of deficiencies and inaccuracies, he said. "But nobody checks it unless it has profound scientific value."

Cancer biomarkers have such value and eventually get checked as part of the validation process, he explained.

But other "conflicting" and powerful "driving forces" are also at work, said Dr. Diamandis.

"There is a great hunger and desire to find very good markers in cancer like those in other diseases, such as myocardial infarction," he said about the humanitarian impulses of scientists.

"We all have the dream of finding the ultimate cancer biomarker," he said. But the dream is also fuelled by the promise of riches.

"A good biomarker for, say, breast cancer could be worth hundreds of millions of dollars annually," he said.

The disarray that has characterized cancer biomarker discovery is partly the result of the scramble to hit it big, he suggested.

"Extremely Difficult"

Dr. Diamandis defines a biomarker as "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention."

The last time a cancer biomarker was approved by the FDA was in 2009. However, that marker, the HE4 protein for ovarian cancer, was only approved for monitoring recurrence and is thus an example of a "minor" biomarker, he said.

Major cancer biomarkers that have gotten FDA approval in the last 15 to 25 years include prostate-specific antigen (PSA) for prostate cancer, CA125 for ovarian cancer, CA19-9 for pancreatic cancer, and CA 15.3 for breast cancer, Dr. Diamandis said.

Currently, there are only a "handful" of cancer biomarkers used clinically, he points out, and those are mainly for monitoring treatment response in patients with advanced disease.

Furthermore, most cancer biomarkers in clinical use are "not suitable for population screening or for early diagnosis," says Dr. Diamandis. One of the markers that is used that way — PSA for prostate cancer screening — is "still controversial," he adds.

"It has proven extremely difficult to find and validate a cancer biomarker," said Dr. Diamandis.

The challenges are manifold. For instance, for a molecule to be effective in early diagnosis, "it must be released into circulation in appreciable (and easily detectable) amounts by a small asymptomatic tumor (or its microenvironment), a requirement that could be considered an oxymoron."

The process of analyzing a biomarker candidate is complex and full of pitfalls. Dr. Diamandis offers the example of tissue-sample analysis. "It is important to examine whether various individual characteristics (e.g., patient age, diet, sex, ethnicity, lifestyle, drugs, or exercise) and/or storage of tissue samples could independently affect biomarker levels," he notes.

Validation is especially challenging and requires sophisticated quantitative skills, suggests Dr. Diamandis.

"Part of the problem is that many scientists, including even Nobel Prize winners in basic sciences, have embarked on biomarker discovery and validation with experiences from qualitative fields of science," he writes.

Caution is needed in describing cancer biomarker candidates, given all of the failures, says Dr. Diamandis. "It may be appropriate, in the future, not to call a molecule a biomarker until it passes at least one independent validation study," he writes.

In short, the discovery and validation process clearly needs improving, he summarizes in the essay.

Agreed, said another cancer biomarker expert.

"There is no satisfactory process in cancer biomarker development," said Samir Khleif, MD, who was approached by Medscape Medical News for comment.

Dr. Khleif is chief of the cancer vaccine section of the National Cancer Institute (NCI). He wears another hat as the cochair of the Cancer Biomarkers Collaborative (CBC), a joint effort from the American Association of Cancer Research, the FDA, and the NCI.

Time to Get Organized

"The biological science has developed so fast that the process as it currently exists is not equipped to carry it to fruition in an efficient way," Dr. Khleif said in an interview.

The CBC aims to change that. The group was formally created in 2007 but its roots go back a year earlier when its trio of organizers, along with the Pharmaceutical Research and Manufacturers Association, convened a workshop.

The workshop focused on the use of biomarkers in oncologic drug development. Since then, the group has published a report on advancing the use of biomarkers in cancer drug development (Clin Cancer Res. 2010;16:3299-3318). CBC committees have put forward 27 recommendations and associated action plans to address "barriers" to cancer biomarker development.

The process of biomarker development is "multifaceted," said Dr. Khleif. It includes not just the nitty gritty of developing assays, but also science policy, regulatory and legislative issues, and, with regard to drug development, clinical trial design.

Clinical trial design is being turned upside down by biomarkers and personalized medicine, he noted.

The predominant current clinical trial design is "from the 1960s" and is the "antithesis" of what is now needed, Dr. Khleif said.

"The current design that we follow for drug development is structured to control for bias and the impact of random variability. However, this variability is at the heart of personalized medicine. What determines this variability is biomarkers."

For example, in the past, patients in lung cancer trials did not require any kind of molecular testing to participate. Now, patients are tested to determine the status of EGFR and the mutation of RAS, he said.

"Clinical trial design must accommodate biomarker development," he said.

Among other innovations, the CBC details their goals for developing best practices for "adaptive" clinical trial designs, which allow for changes in a study based on interim results.

Dr. Diamandis and Dr. Khleif have disclosed no relevant financial relationships.

J Natl Cancer Inst. Published online August 12, 2010. Abstract