In 1974 a Thomas Jefferson Medical College professor asked my medical school class: “Who would like to admit to having a genetic disorder?” Of course, none of this group of over 200 of the best and brightest would ever chance to raise a hand. The professor went on to order every one of us to raise a hand. For even in the mid 1970s he knew that every human genome on the planet had the basis of some medical condition, even if no technology available at that time could hope to find it.
President Reagan’s 1987 budget included a funding request for the Human Genome Project (HGP) that led the way to the official start of this massive endeavor in 1990. Compared to the United States’ goal of putting a man on the moon, the decade-long HGP will most assuredly exceed that historic accomplishment in helping mankind.
Directly as a result of the knowledge gained through the HGP, a relatively silent revolution is taking place in oncology offices around the country. Many cancer patients will be faced with the opportunity to know exactly what genes are the actual “deviant” genes that have led to this dreaded and once mysterious diagnosis.
As eloquently described in the landmark article by Douglas Hanahan from the University of California–San Francisco and Robert Weinberg from the Massachusetts Institute of Technology, “The Hallmarks of Cancer,” in the Jan. 7, 2000 issue of Cell, cancer is largely an acquired genetic disease. Their single statement, “Cancer cells have defects in regulatory circuits that govern normal cell proliferation and homeostasis,” has done more for the typical physician’s understanding of the etiology of cancer than virtually any other sentence. Hanahan and Weinberg went on to define “six essential alterations in cell physiology that collectively dictate malignant growth.”
Although other experts have suggested adding to these six, they remain the foundational hallmarks of cancer. The six are:
- Self-sufficiency in growth signals
- Insensitivity to growth-inhibitory (antigrowth) signals
- Evasion of programmed cell death (apoptosis)
- Limitless replicative potential
- Sustained angiogenesis
- Tissue invasion and metastasis
Most current oncology drug development is focused on these “targets” leading to revolutionary changes in the hope for those with a diagnosis of cancers containing “targets” for existing or research drugs.
Although not yet the norm, a corollary to the development of targeted drugs is the development of “companion diagnostics”; a biomarker test associated with tumors that reflect the presence of a genomic change of the cancer cell that is also the target for the associated drug.
But testing for genetic changes in tumors is not isolated to trying to prove the presence of the handful of tumor markers that have associated targeted treatments. Oncologists around the country are now able to identify virtually all tumor-derived genetic alterations. And these tests can be done serially.
Tumors reproduce sloppily
It seems that the genetic make-up of tumors is dynamic. Tumors basically reproduce sloppily, and in fact accumulate genetic change over time and partly in response to treatment. This trait makes it desirable to test tumors chronologically.
In addition, the genetic content of tumor cells can often be found in free circulating plasma allowing oncologists to identify tumor-derived genetic alterations with a “simple” blood test, and thereby gain a better understanding of a patient’s tumor characteristics not dependent on ability to obtain a biopsy. The testing is designed to detect alterations in actual chromosomal copies, rearrangements of chromosomes, and amplification of the actual cancer driver genes with an alphabet soup list of names such as: HER2, EGFR, BRAF, ERBB2, CDK6, KRAS, PIK, PTEN, NOTCH 1–4 and others.
A few of the 100+ genetic deviants have associated drugs that target the defect, but most currently do not. The actual testing result becomes a treasure trove to those researching treatment for cancer.
This approach to better understanding tumor biology is the result of large scale DNA sequencing termed “Next Generation” or “Next Gen” sequencing that allows for extremely rapid analysis of DNA to actually sequence the genetic code of more than 20,000 human genes in a matter of days, not decades.
Only a relatively small percentage of all genetic material has to be analyzed, significantly simplifying the task. Thus, companies involved in genome cancer screening are not attempting to actually create the library of the entire genome for a given patient. They are only identifying the actual gene coding sequences of the cancer DNA that are called exomes (although this is still an enormous feat!).
There are basically two approaches; whole exome assay which captures all 20,000 plus genes, or a more selective approach that looks at those 100+ genes that reflect the Hallmarks of Cancer”approach. These genes reflect those cellular activities that have deviated from normal and are the actual trigger for malignancy in most tumors. Reports back to the physician include the actual base substitutions, insertions, deletions, rearrangements, and copy number alterations.
With this information, physicians can search for relevant clinical trials focusing on studying drugs for the specific mutations if no drug currently exists. Although numerous academic institutions are offering these services, the leading commercial companies involved in this service are Personal Genome Diagnostics, a company created by the researchers from Johns Hopkins University who were the first to sequence the entire cancer genome, and Foundation Medicine, a collaborative effort of MIT, Harvard Medical School, and Google Ventures among others. (Of note, Google’s interest is not random; these efforts require enormous computing power!)
But, as exciting as this approach is to oncologists and patients, health plans have a far different opinion on the utility of this approach. Health plans are clear in their policies that they do not pay for this “shotgun” testing in the absence of clinical evidence supporting not only the test but any resultant treatment. Because there are only a literal handful of genetic changes associated with FDA approved therapies, health plans see Next Gen testing as potentially leading physicians to approach cancer from a biomarker perspective instead of a clinical trial proven, tissue-based approach.
For instance in the clinical trial approach, a drug approval for a given mutation is based on improved outcome for a specific type and stage of cancer based on site of origin (e.g., lung or breast or skin) along with the proven presence of the receptor.
But Next Gen testing opens up a totally different list of questions. What if the same mutation is found on a far different tumor where no FDA approval (or even completed research) is available? Health plans fear physicians will attempt to “throw in the kitchen sink” to treat a genetic marker with a targeted therapy that has not been studied in that particular type or stage of tumor. They are also concerned that patients will demand access to these speculative drugs to gain hope.
Does it work?
Despite the conflict, the likes of Foundation Medicine, Personal Genome Diagnostics and others will continue to push Tomorrow’s Medicine to the limits, testing not only the tissue and plasma samples, but also the technology committees of health plans in the process!
The author is a director in the value-based health department at Genentech. He has had no other industry affiliations in the past three years. The views expressed in Tomorrow’s Medicine are the author’s alone.