Redefining the word "cancer"


Debu Tripathy blog image

Can a simple act of a few individuals change how we think about cancer?

Well, not a few, anymore, but a growing choir of voices are now redefining the term "cancer." We have known for a long time that there is a continuum from benign to cancerous growth. We even have names for some of these, such as borderline malignancy of the ovary. In the case of ductal carcinoma in situ of the breast (DCIS), the survival of patients is equal to the general population, but it is often treated with surgery, radiation and tamoxifen.

The Institute of Medicine has called for not just a redefinition of names, but a realignment of the cancer culture of "detect and eradicate." A recent article (Overdiagnosis and Overtreatment in Cancer: An Opportunity for Improvement) in the Journal of the American Medical Association highlights this problem in cancer screening, where the knee-jerk reaction for any cancer is to treat low- and high-risk cancer with many of the same treatment, therefore exposing everyone to side effects and complications while many derive no benefit--because their chance of dying or having their life affect by their "cancer" was minimal.

Solutions proposed in this article include getting rid of the word "cancer" and using terms like "indolent lesions of epithelial origin"--this may alter behavior both on side of the medical team and the patient. Of course, one cannot just declare a new system into existence.

The medical system must provide safeguards that truly dangerous cancers will be diagnosed and treated appropriately. Even some cases of DCIS can recur as invasive cancer, which can then potentially spread and lead to death. This means more research on prognostic tests – a huge ongoing needed in oncology that involves molecular/biological assays and large follow-up studies to validate these tests. We have a long way to go on redefining cancer, but perhaps starting with labeling changes is at least a symbolic start – but hopefully will be followed by both a scientific and cultural shift.


Whose genome is it anyway?


Debu Tripathy blog image
It may confuse most of us how our DNA, a product of nature that defines our identity and personal traits, could have been patented in the first place. Some claim that patent protection for years of hard work is needed to continue our efforts to isolate and identify genes in order to help develop diagnostic tests and therapies for the good of the general public. [Nature: Myriad ruling causes confusion]

Myriad, the gene diagnostic company that has been in the cross hairs of the recent Supreme Court to invalidate key portions of their patent on the breast and ovarian susceptibility genes BRCA1 and 2, should be credited for their diligent work. They have helped thousands of patients know their cancer risk and act accordingly, and have allowed the medical community to better understand which mutations are actually harmful – something that requires access to large amounts of pooled information.

However, the prices commanded for testing no longer reflect the state of the art of gene sequencing that has dropped precipitously with newer "next generation" sequencing technology. [CURE: Can a Human Gene Be Patented?] Furthermore, the discovery of the BRCA genes were not made in isolation but rather grew out of earlier work to pinpoint the general location of these genes dating back nearly two decades earlier.

Nimble and efficient gene diagnostic companies are popping up like Internet start-up companies of the 1990s. Their day has now arrived as they find new freedom to operate.

The Supreme Court's decision is not fully sweeping and its effects will not be seen overnight [New York Times: Justices, 9-0, Bar Patenting Human Genes]. Larger companies like Myriad still retain significant intellectual property and will probably switch over to offering more complex gene panels tests and tissue assays that go beyond the effect of single gene mutation, but rather the biological impact on tissues. This too, will move the field forward. But will competition in the free market lower prices of testing at the cost of reciprocal stifling of investment and innovation? Only time will tell, but history seems to be on the side of healthy completion equaling continual improvements in both quality and value in most other areas.

We hope the same will pertain to the matter of our genes.


Affordable Cancer Act upheld by Supreme Court


It was a complicated decision – so complicated that a couple of the major news outlets reported incorrectly that the sweeping health care reform law enacted by Congress in 2010 have been struck down by the Supreme Court.

In fact, most of this law, with the exception of the Federal government's ability to withhold states' Medicaid funding, was upheld. Despite calls by some for this law to be dismantled, it is unlikely that the more popular measures of significant impact to cancer patients will go away. These include the outlawing of limitations of insurance coverage for pre-existing medical conditions or exceeding lifetime caps. It also means that 30-plus million individuals will join the ranks of the insured – entitled to health care screening and prevention, earlier cancer diagnosis and treatment and appropriate cancer follow-up. Reams of data show worse cancer outcomes among the uninsured. The consequences on care costs and improved productivity are also projected to be positive by most experts.

So this is a big deal (in Joe Biden's words – BFD) not only for cancer patients, but also for the whole country that shares the burden of cancer both in human and financial terms. While the law will certainly be amended by Congress and Executive actions over time, a new era in health care will emerge as the new law of the land is enacted.

Cancer patients and their advocates must stay on guard to understand and participate in this process and new initiatives that affect cancer care and research. Regardless of one's opinion in the whole matter, we must exercise our inherent rights bestowed by our government system – a time-tested model that still works in today's partisan environment.


Choosing wisely


In an unusual move, several professional societies jointly released a set of principles entitled "Choosing Wisely" (see – five tests and treatments for each of several specialties that physicians and patients should question. Things that eventually cause more harm than good and also tend to drive up healthcare costs. The ones that are listed for cancer are available at:

While these recommendations will need to be tailored to individual situations, they have the common theme that these tests that are done for "reassurance" or early detection of recurrence or metastasis of cancer when the chances of having a positive test are low, even lower than the chances of "false-positive" results that commonly lead to further testing or even harmful procedures. Also, there are two recommendations to avoid medical treatments (white blood count boosting drugs and chemotherapy for advanced cancers) in situations where there is no proven benefit. However, there is certainly going to be vocal opposition and there are already some who are criticizing this as some type of healthcare rationing. In particular, the recommendation to withhold chemotherapy in patients who have almost no chance of being helped by such treatment will be hard for many to accept.

This illustrates one of the key dilemmas of medical care and one of the reasons that our healthcare costs are the highest in the world whereas our health outcomes are clearly not the best. In the U.S., doctors and patients are quick to request tests and procedures that on the average may yield a very small chance of benefit and a greater chance of unnecessary treatment. But if you happen to be one of the rare patients that is helped by one of these tests, your viewpoint may be different. At the moment, the public (and most lawmakers who are elected by the public) have no appetite for advocating any restrictions on what a doctor and patient feel is the best course of care. But as patients are burdened with more costs of insurance and co-pays, they are starting to "self-ration" care.

In the last couple of years, more patients are opting to defer test and even cancer treatments mostly because of cost. Despite the controversy this movement will stir, it is clear that patients and physicians need to have information available to prioritize what test and treatments can be omitted without any (or minimal) change in outcome. But will our society be willing to accept these statistics and forgo the long shot?


Drug approvals: Are we in a new age yet?


With all the news of cancer drug shortages and the FDA's controversial decision to withdraw approval of Avastin (bevacizumab) for breast cancer, we are also getting some positive developments.

Just recently (on Aug. 26), the FDA granted accelerated approval to Xalkori (crizotinib), the newest member of an emerging generation of "niche" drugs. These are drugs that work in very defined subsets of patients, based on certain biological characteristics.

In the case of Xalkori, this is confined to the approximately 3 to 9 percent of patients with non-small cell lung cancer (NSCLC) who carry a chromosomal translocation that results in overexpression of the ALK protein (anaplastic lymphoma kinase). In fact, the approval of this drug is accompanied by the approval of a gene-based test to detect this translocation in tumor tissue. This approval comes on the heels of the approval of Zelboraf (vemurafenib) just eight days earlier for advanced melanoma, and again, only for the subset who harbor a mutation in the BRAF gene, and also approved with a diagnostic kit called the cobas 4800 BRAF V600 Mutation Test. In this case, the mutation is more common, seen in about half of all melanomas.

The big question is whether these two approvals herald the new age of personalized drugs. The now old story of Herceptin that many regard as one of the first targeted therapies, was spread out over 17 years from discovery of the gene to drug approval (or 11 years if you go from the discovery of HER2 amplification in breast cancer).

The new generation of drugs is being developed in a just a few years based on our exponentially growing body of data on mutations carried in cancers and new clinical trial designs that rapidly test drugs and verify biomarkers that predict response. Moreover, they seem to be quite effective with a higher percentage of patients responding, but not to the point that permanent cures are expected.

One can only hope that we are truly in the new era – and there are several indicators that this is the case. The Cancer Genome Atlas (TCGA) program is one of several worldwide that is collaboratively sequencing tumor genomes. Drug companies are investing more effort into biomarker analyses and integrating them earlier in the clinical trial process. Healthcare reform is demanding that drugs have a larger impact and that they not be used indiscriminately. Finally, the public's expectations are rising – they want more information about their cancers and access to clinical trials.

While it is possible that the initial wave of "low-hanging fruit" of "druggable" gene targets will soon be exhausted, it is more likely that we will have more targets and drugs than we can test. The bottleneck will really be in the patient clinical trials and how quickly and widely they can be deployed and fully enrolled. There will still be negative trials and other disappointments, but perhaps we are entering a new era where the bar of success is being raised.


Do the FDA Avastin hearings mark the end of an era?


The Avastin public hearings, which were organized by the FDA, began yesterday as part of Genentech's appeal to reverse the FDA's plan to withdraw the drug's accelerated approval.

This temporary approval, which was pending more data, was granted back in 2008. The approval came despite a recommendation for disapproval by the Oncologic Drugs Advisory Committee, which cited a lack of survival benefit. Although there was nearly a doubling of progression-free survival, it came with significant, albeit infrequent, serious toxicities and even excess treatment-related deaths. We have previously covered the background and controversies surrounding this topic in Hurdles on the Faster Track.

Now as two more trials have been analyzed -- neither showing a survival benefit -- the FDA stated that in the balance, the benefit did not outweigh the harm. The public hearing has taken on a circus-like atmosphere despite the seriousness of the topic and the emotional testimonies of patients whose disease has improved or been stable on Avastin.

On the other hand, several patients and advocacy groups have lobbied against approval, saying that giving this drug the nod despite the lack of scientific evidence of benefit is counterproductive to the whole field -- attention must be focused on developing survival-enhancing therapies.

How can such divergence in opinions exist? Actually, both sides of the argument have some merit. There probably are individuals who are clearly benefitting from Avastin. However, we do not know how to identify them, so the impact from the small number of "super-responders" is diluted.

The average effects in large trials then look rather small or nonexistent. This is probably true of many drugs we use today. We could probably get more dramatic effects, but only if we treat that fraction of patients who would benefit--if only we had tests to guide these decisions.

Avastin affects a complicated process -- angiogenesis, which involves tumor blood vessel formation that includes numerous receptors, enzymes and biological pathways. So called "predictive biomarkers" have been particularly elusive for Avastin.

There is no right answer to this wrenching issue that has dominated the headlines this week. Many patients and doctors want "freedom to operate" and the ability to do what they believe is best for their patients. Others don't want health care dollars (and in some cases, patient safety) expended for the kind of benefit seen in the trials so far.

The process of testing new cancer agents has forever changed because of this. It is now necessary to define predictive factors at the same time a drug is initially being developed. Not only is FDA approval in jeopardy, but drug companies can no longer afford the cost of huge trials to show a tiny difference in outcomes. The FDA hearings mark a milestone in this turn - the end the old era of cancer drug development.


A preview of ASCO – The new way of doing clinical trials


For decades, we have used the same system of testing and ultimately approving new treatments for cancer. The starting point of new drugs has become sexier--by targeting genetic lesions and avoiding some of the poisonous effects of older drugs. But the rest of the sequence of trials toward the road to approval is stale. It still starts by demonstrating safety (phase 1 trials), then some sense of effectiveness in shrinking tumors (phase 2) and ultimately a large trial comparing it with "standard" treatment or to adding the new drug to standard treatment (phase 3). Drug companies are focused on meeting the metrics by the FDA for approval--usually improving survival or time to recurrence or delaying progression. This used to mean showing a statistically significant improvement in a large number of eligible patients, even if the overall improvement was small--just a couple of months of extra survival.

This model is no longer working well because as we discover that cancer is broken down into small subsets that are biologically distinct, with only some subsets responding to targeted drugs. Given the side effects and spiraling costs of newer drugs, what might work for a cheaper and safer hypertension drug will certainly not apply for cancer therapies. Having to treat hundreds of patients for only a few to benefit is not sustainable, especially when newer technology is available to improve the situation. This year at ASCO, you will read our blogs about exciting updates on the cancer front, and a common theme will emerge. A much greater effort is being made to understand what subset of patients might respond even before a new agent is ready for human testing. Sometimes it is not clear what tissue tests should best qualify a clinical trial subject, so even in phase 1 testing, analysis of tissue is not built into the study in hopes of refining eligibility criteria for future trials.

Another innovative trial design we use when we do not know what patient population might best respond is called a "randomized discontinuation trial." It is based on the notion that only a small fraction of patients might respond. A large number of patients are initially tested (after basic safety is established). A very small number of patients might actually have shrinkage of tumor and they stay on treatment, while those who progress are taken off the study. However, those who have neither growth nor shrinkage after a defined period of time (termed "stable disease") are randomized to either continue or discontinue therapy. If those who stop therapy exhibit tumor growth after some time more so than those who continue, it proves that the drug is effective and may even shed some light on the tumor characteristics that predict response in the small fraction of cases. Of course, the trial can be designed to allow the "randomized discontinuation" group to restart therapy with the assumption that they might derive a benefit.

Another approach is called "adaptive trial design" where the results of the trial are analyzed in real time, and the randomization scheme (the fraction of patients randomized to standard vs. experiment treatment) changes over time to maximize the efficiency of the trial. While these ideas are not exactly new, they are being applied more often, especially for biologically targeted drugs since we have tools newly made available, such as rapid whole genome sequencing that can be feasibly done for at least part of the genome and are standardized to the point that they can be used for both pilot and large definitive trials. This will no doubt be a part of the major overhaul of the clinical research process currently under way in the government and drug industry sectors--the transformation of cancer clinical trials has just begun.


Chemotherapy shortage: A symptom of a bigger problem


You may have heard about the chemotherapy shortage over the past few weeks whereby the supply of certain drugs is limited and even causing some infusion centers to reschedule appointments or change treatment plans.

While this is not a major disaster and will be fixed shortly, it is emblematic of our country's whole medical system. We really don't have a shortage of drugs as a looming problem – it is more a matter of supply temporarily not meeting demand due to production, transport and inventory. But the bigger problem is coordination. Because our health care is decentralized and insurance coverage is spotty, you will get a wide spectrum of opinions about our nation's health care – from "best in the world" to "bloated, expensive, inefficient and unfair."

I see incredible wastage of resources in my everyday practice of medicine – tests that are repeated because earlier results are unavailable or not felt to be reliable. Treatments or diagnostics that are "long shots" and made by both doctors and patients in haste without much reflection. State-of-the-art facilities and equipment that are not used to capacity.

There is much talk about electronic medical records (EMRs) as the savior for all of these problems, although the verdict so far is that these systems have not really made much of an impact on quality or efficiency of care. However, we are really only on "version 1.0" of EMRs, and further integration and standardization of these systems do hold the potential to improve many aspect of medical care, particularly the coordination of care and other activities (like chemotherapy availability) that are essential in the very complicated arena of cancer management. I believe that the public needs to be very engaged in the debate regarding EMRs and coordination of care because quality and affordability, especially in oncology, is at stake.

An informed and vocal public can steer the health care debate from the rancorous halls of Washington to a discourse with the public and ultimately the enactment and adoption of a coordinated information network, including patient portals and a seamless transfer of information across medical practices and hospitals. These advances have had huge effects in commerce, banking, entertainment and even social networking and dating, so why is medicine being left behind?


A disquieting moment: Two steps backwards?


Just about all of us attending the San Antonio Breast Cancer Symposium were disappointed and puzzled by two negative studies that went counter to all the early clinical data and biological theories in two important areas. While we recognize that this can sometimes be the normal course of science, it is never what we expect when we attend a meeting amid all the buzz about the latest news.

The first was in the area of personalized medicine--more specifically, the field called pharmacogenomics, which refers to the analysis of gene variants in drug metabolism enzymes to customize recommendations for specific drugs and doses. We all inherit different versions of the gene that encodes an enzyme called CYP2D6, which metabolizes the hormonal therapy tamoxifen into a more active form called endoxifen.

While preliminary studies showed that those who inherit a low activity version of this gene might have a higher risk of recurrence or progression on tamoxifen, it appeared that a new method to steer patients to the right therapy might be emerging. However, these early results were on smaller groups of patients.

More recent and much larger updates presented on Thursday showed no difference at all based on CYP2D6 genotype, even though tests are already commercially available and used by some oncologists. The consensus from the presenters, including the commentator, Dr. Matthew Goetz from Mayo Clinic, (one of the original investigators to observe differences in clinical outcomes), is that for now, doctors should discuss the controversy with patients, but not use CYP2D6 testing routinely to make decisions about tamoxifen. However, it is still recommended that drugs that inhibit CYP2D6, notably certain anti-depressants, should be avoided in patients taking tamoxifen. This is not really a big step backwards for patients because it doesn't necessarily take any benefits or options away. But it is an unexpected turn in the road where all the pieces of the puzzle were starting to fall together, only to be contradicted for the moment.

Another negative confirmation, however, was really a setback. Every indication was that bisphosphonates (a class of drugs used to protect the bone from both osteoporosis and bone metastases) might also prevent metastases. Several studies had suggested this earlier. In a smaller study of premenopausal patients receiving hormonal therapy, the drug Zometa had already been shown to lower the risk of recurrence. The supposition was that it made the bone a less fertile ground for breast cancer cells to colonize and use it as a springboard to metastasize elsewhere. But after a long anticipated wait, a much larger study yielded absolutely no difference in patients who received Zometa compared with those who did not. A secondary analysis hinted that in postmenopausal patients, there might be a benefit, but this was not statistically significant and no recommendations can be made at this time to use Zometa as a way to further reduce recurrence risk above what chemotherapy and hormonal therapy can achieve.

A large North American study was recently completed, but the results of this one are not expected for several years. The good news is that these studies took longer to analyze because fewer women are recurring after early-stage breast cancer than ever before. Still, we would like to get this down to zero and still have a ways to go. Progress is just never linear, but even negative data helps us create better experiments and trials for the future.


Finding the Perfect Prevention Drug


Using drugs to prevent cancer has long been sought, as many clues from the laboratory and observational population studies have pointed to several clues and candidate drugs. Testing these in the clinic requires huge numbers of subjects (well over 10,000) that have to be randomized to placebo or the active drug and then followed for many years, an expense that few companies or the government will take on. The first prevention drug, tamoxifen was approved in 1998 to lower the risk of getting breast cancer (lowered the rate from about 2% to 1% over 5 years). However, this drug is rarely used, in part because of bothersome side effects, but also more serious ones like an elevated risk of uterine cancer and blood clots.

A cousin of tamoxifen, raloxifene (Evista), with a lower risk of both these side effects was approved in 2007. This class of drugs, known as selective estrogen receptor modulators (SERMs), also improves bone mineral density--Evista is actually approved for osteoporosis. Since the estrogen receptor pathway mediates many different physiological processes ranging from breast cancer to clotting to bone density, SERMs have been engineered, through slight chemical alterations in their structures, to be the perfect women's health drug--with the potential to lower cancer risk and to improve bone and cardiac health.

Evista was designed to not produce stimulation of uterine cells as to avoid a known complication of tamoxifen--an increased risk of uterine cancer. While it did achieve that goal, its breast cancer risk-attenuating activity is not as good as tamoxifen's, and it still raises the risk of blood clots. Another SERM called lasofoxifene has come a little closer, with a recent update of a large randomized trial now showing a lowering of breast cancer rates by nearly 80%--that is from 1 in every 114 women to 1 in every 550 women over 5 years. It also lowered the bone fracture rate and even the stroke rate without increasing endometrial cancer risk. However, it did increase blood clotting--the one SERM side effect that we cannot seem to "engineer out." Still, the FDA earlier rejected lasofoxifene as a preventive drug because the overall death rate (from non-cancer causes) was higher in the low-dose arm compared to placebo even though it was not in the high-dose arm. This turn of events reflects the frustration by all parties--doctors, patients, researchers and the FDA itself.

We have prevention drugs that can lower cancer risk with side effects that are much lower in number than the cancers prevented. So far, no drug is free of rare but serious side effects--and coupled with the less dangerous but still bothersome side effects, such as hot flashes and a myriad of less characterized symptoms, it is understandable why only a fraction of eligible patients opt for FDA-approved breast cancer prevention drugs. Also, there is no statistical difference in the overall death rate in prevention studies, in part because they were not designed to be large enough to detect them, but it may also be that we are preventing the less dangerous estrogen receptor-positive breast cancers.

The field of cancer prevention is still very active but could use a shot in the arm. While the science behind it is very elegant, it appears that, like many other things in life, it comes down to a popularity contest. Doctors and patients will vote with their feet--with prescribing and compliance hinging on both a better side effect profile, and a bigger impact on saving lives, not just lowering the number of cancer cases.


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