To put this into perspective – virtually no intervention in the advanced disease setting provides a survival advantage. The best we can usually do once the disease is established is an improvement in time to progression. When we do observe a true survival advantage it is usually in the range of a few percentage points and never of this magnitude. How might we explain this astonishingly positive result?

One way to view this finding is to reexamine the biology of cancer. One of the leading experts in the field, Bert Vogelstein, MD, from Johns Hopkins, explained colon carcinogenesis as a pattern of gene perturbations starting at atypia, progressing to carcinoma in situ and ending with invasive, metastatic disease. According to Dr. Vogelstein, the average colon cancer found in a patient at the time of colonoscopy has been present in that person’s colon for 27 years. From there it is only a hop, skip and a jump from one-centimeter adenomatous polyp to metastatic (lethal) disease, all playing out over the last three years in the natural history of the disease. Thus, cancer truly is a disease that doesn’t grow too much, but dies too little and interrupting this process while it is still slumbering can, it would seem, lead to cures.

What I find surprising is the success of the strategy. Since it is now well established that cancer can metastasize when it has achieved the rather diminutive proportions of 0.125 cubic centimeters or less and the average polyp can only be detected at one or more cubic centimeters, it is our good fortune that so many cancers chose not to (or could not) metastasize prior to detection. Reading between the lines, those 12 patients who died of colon cancer as opposed to the expected 25.4 are presumably those with early metastasizing disease. The next frontier will be the detection of these cancers when they are teenagers and not 20-somethings. It may be that proteomic analyses will provide an avenue for earlier detection in the future.

The second article is a European study (Quintero, E et al; Colonoscopy versus Fecal Immunohistochemical Testing in Colorectal-Cancer Screening) that compared colonoscopy with fecal blood testing in a large cohort of patients. While the rates of detection for colorectal cancer were similar, the rates of detecting both advanced and early adenomas, favored colonoscopy (p < .001). This study represents an interesting adjunct to the American study described above. Specifically, if the early detection (and removal) of adenomas can confer a survival advantage then it could be argued that colonoscopy by its virtue of it’s higher detection rate of these precancerous adenomas, is the preferred “screening” modality. With over 50,000 deaths attributed to colorectal cancer in the U.S. each year, the public health benefit of colonoscopies becomes an intersecting point of discussion. Until now, fecal occult blood testing yearly or sigmoidoscopies every several years has been considered equivalent to colonoscopies every 10 years starting at age 50. Do we need to move colonoscopies to the front of the line?

What is most interesting about both these reports is the low-tech nature of the study modalities – and the astonishing efficacy of their application. Colonoscopies have been conducted for decades. They are comparatively simple, do not require affymetrix chips, and yet provide demonstrable benefit that appears to exceed anything offered, to date, by the “genomic revolution.” Perhaps we should all keep an open mind about other comparatively low-tech methodologies that can provide survival advantages.

Using molecular profiling, Dr. Poti and his collaborators, reported their capacity to distinguish responding and non-responding cancer patients, providing survival curves that were nothing short of astonishing. I recall attending the original lectures given by these investigators at the American Association of Cancer Research meeting several years ago.

As an investigator in the field of drug response prediction, working in lung cancer I had a particular interest in their platform and I was extremely impressed by the outcomes they reported. At the time, I wondered how the static measurement of gene profiles could possibly characterize the nuances of human biology, to encompass the epigenetic, siRNA, pseudogene, non-coding DNA and protein kinetics that ultimately characterize the human phenotype. Nonetheless, with such compelling data I was prepared to be convinced.

That is until a relatively unheralded report in the Cancer Letter raised concerns by several biostatisticians regarding the reproducibility of Dr. Poti’s findings. And then more comments were followed by a full NIH investigation. A panel of biostatisticians was convened and a formal report provided the explanation for Dr. Poti’s excellent results.

They had been invented. The clinical outcomes were not real results. The findings had been retrofitted to match the patient responses and this was the subject of the 60 Minutes report.

What the 60 Minutes report did not address however, was the real problem. That being the inability of contemporary genetic profiling to truly define human biology. For all the reasons enumerated above, siRNA, non-coding DNA, etc., the simple measurement of gene sequences cannot accurately predict biological behavior. This is what the 60 Minutes reporters and the physicians they interviewed, never discussed. The problem at hand is not an errant investigator but an errant scientific community. Our love affair with the gene that began in 1953 (Watson and Crick) has now been confronted by a most heartbreaking example of infidelity (pun intended).

Genes do not make us what we are; they only (sometimes) permit us to become what we are, with the vagaries of transcription and translation lying between.

This leads us to the reasons I find this so critically important:

1. I cannot stress strongly enough that this is NOT what I do. Genomic analysis (their work) and functional analysis (our work) are distinctly different platforms.
2. I strenuously resist any attempt on the part of anyone to tar me or my work with this brush.
3. It is precisely because genomic analysis cannot accurately predict cancer patient outcomes, that these investigators found it necessary to invent their data.
4. Despite this, functional analyses can and do provide these types of predictive results in lung cancers and other diseases as we have reported in numerous publications.
5. Finally, while imitation is the sincerest form of flattery, this is one instance in which I would prefer to decline the compliment.

These encouraging results have been touted as evidence of success in the war on cancer. The war on cancer itself began in December 1971, when then president Richard Nixon established a national priority to conquer this disease. Since that time, we have dedicated more than $200,000,000,000 to this effort and published literally millions of articles on the topic. Despite these efforts and tremendous resource allocations, the focus of this research effort, i.e. treatment of advanced malignancies, has provided limited successes.

If we drill down onto the ACS statistics we find that most of the survival changes reflect earlier detection and the successful application of cancer screening. Mammograms, colonoscopies, the use of PSA and the growing application of screening CT scans for lung cancer detection have, and will continue to have, a favorable impact on cancer statistics.

This is the good news. The bad news is that our success in treating advanced disease is almost non-existent. While there have been slow migrations in a favorable direction for the five-year survival rates in some malignancies, the big killers like lung and GI, have shown extremely limited progress. There are many reasons why cancer cures remain out of reach, but several changes could be implemented immediately to increase our rate of success.

First, we need to incorporate systems biology into cancer research. As opposed to analyte-based approaches like genomics that unravel one finding at a time, the field of biosystematics examines human cancer through the lens of interacting networks.

Second, we need to redouble our efforts in the study of basic metabolism and the growing field of metabolomics.

Third, we need to revamp the clinical trial process. Were investigators incentivized to achieve greater clinical successes, there were be fewer failed Phase II and Phase III trials. Contrary to the business world where success is rewarded, academic physicians today receive the same compensation for every patient treated, whether the intervention is successful or not. This has the unintended consequence of encouraging physicians to accrue patients to clinical trials with no focus on effective therapies. While it may be gratifying to the trialists to have successes, they receive the same compensation for their failures. Clinical investigators need skin in the game.

Finally, the regulatory environment is currently over-restrictive. The process should allow investigator-initiated efforts with more lenient review processes. The current environment that punishes dedicated physicians for stepping out of the established guideline therapies is thwarting progress and frightening dedicated investigators out of the field. Good faith efforts on the part of physicians using new drugs and combinations that document successes and failures, could unleash an army of clever physicians to utilize novel approaches to advance new therapies with little additional cost.

Lethal diseases, like advanced cancer, pose hurdles that require novel trial designs and less stringent controls. Patients confronting these illnesses should be allowed to receive therapies and should be granted the dignity to determine their own risk-benefit ratios when they confront life and death decisions. Simple consent forms could make available effective treatments while pharmaceutical corporations should be encouraged to provide drugs under the auspices of these patient-driven developmental trials.

While we applaud the discoveries of our colleagues in the field of genomics, and their analyte-driven platforms, we forget at our peril that medicine and most of its discoveries have been observational.

Dr. Ames has distinguished himself as a pioneer in the study of aging, degenerative disease and cancer and I have read many of his papers since then. You can imagine my delight when I received a phone call some months ago and found that my interlocutor was none other than Bruce Ames, inviting me to speak at his research institute.

On Tuesday, January 31, I traveled to Oakland to present a symposium. Dr. Ames arranged for me to meet many of his colleagues. The topics ranged from neuraminic acid residues expressed as neoantigens on dividing cancer cells, to antifungal agents as anti-cancer drugs. One discussion of particular interest surrounded sphingomyelin metabolism as an important mediator of tumor cell progression. A subject about which I knew little prior to this discussion but will certainly now examine with interest.

It is my hope that I might forge collaborations with some of these investigators. But, there is little that could have prepared me for the pleasure I experienced when sitting across the table from Dr. Ames, while sipping a freshly brewed espresso (deftly prepared by Dr. Ames himself), while we discussed Bruce’s six decades of extraordinary discoveries. Everywhere I looked was an award or a textbook that he had authored. Despite his many accomplishments he was humble, engaging and very witty.

My symposium that afternoon introduced the attendees to human tumor primary culture studies as predictors of response to cancer therapy. I then moved through the accumulated data supporting the clinical outcomes and finally examined our developmental work, finishing with our published collaboration with investigators at NYU and Cornell on the study of a novel class of Wnt inhibitors. Lively discussion ensued.

Among the attendees was Bengt Mannervik, who asked several good questions. I note his presence for he is one of the leading experts in the field of glutathione metabolism and a scientist who I had met several times before. As one of the fathers of glutathione s-transferase chemistry, Bengt’s work had influenced my earlier studies. It was an unexpected honor to have him in the audience, as a visiting professor on sabbatical from Uppsala.

As I have noted before, the reception from the scientists in these fora improves as they examine the data on its own merit, unaffected by the clinical dogma and politicking that contaminates so much discourse in medical oncology today. There was no agenda, just scientific interest and open discussion. It was a refreshing departure and a welcome opportunity to interact with open-minded investigators.

In the audience was Dr. Ames’ wife, Giovanna, a former professor of biochemistry at Berkeley, and a scientist whose work included the earliest discovery of the ABC transporters, now recognized as the basis for the human p-glycoprotein drug resistance mechanisms. At the end of the lecture, Giovanna Ames, impressed by the data, raised her hand and asked, “If what you need is a small portion of each patient’s tumor to conduct these studies, what do we have to do to be sure that every doctor sends you a piece of tumor?” While I’m not sure I that have the answer to her question, I am very sure that I like the way she thinks.

The presumptive mechanism of cancer causation seems to revolve around the presence of nitrates in these cured meats. Nitrates are added to meats as preservatives. Preservatives function to inhibit bacterial growth responsible for food spoilage. Nitrates under the acid conditions in the stomach, are converted to nitrites. And it is these nitrites, primarily in the form of nitrosamines, which may be the culprits.

When we exam these findings several issues must be considered. First, however nefarious the consuming public may think the meat packing industry, I for one am fully convinced that these companies do not add nitrates to cause cancer. Quite the contrary. The most dangerous organisms found in foodstuffs, through spoilage and lethal food toxins, are the anaerobic organisms. The most frightening of all is clostridium botulinum, which produces the fatal condition known as botulism. Nitrates converted to nitrites are potent inhibitors of clostridia.

In the grand scheme of things, it is highly likely, in fact certain, that many, many more people have been saved from nitrites in food than would ever die from pancreatic cancer. These risk-benefit ratios are the subjects that keep epidemiologists up at night.

Nitrates in food are not the only possible man-made exposures that we encounter on a daily basis. Take for example chlorinated water. The “chlorine” in water is, for all intents and purposes, bleach. That’s right every time you drink tap water you are being exposed to tiny quantities of bleach. It is probably unnecessary for me to explain to the average reader, the risks and hazards of common household bleach, which is a solution of hypochlorite. And, however toxic that bottle under your sink may seem, remember that is only a 5 percent solution.

Another example is fluoride. While the benefits of fluoridation of water are numerous, including bone density and improved hardness of the enamel of teeth, demonstrably reducing tooth decay, fluorine itself is not, at least theoretically, free of risk. We know that sodium fluoride is an inhibitor of phosphodiesterase, an enzyme responsible for regulating cyclic AMP and cyclic GMP levels in the cell. These protein kinase A signals events may be tonically affected by changing levels of fluoride in the cell, to what end it is hard to say.

Like chlorination or fluoridation of water, nitrates in food represent risks that we as a society have accepted, based upon what we deem as acceptable benefit-risk ratios.

It is possible, that the increased incidence of food-borne illness and enteric infections, increased dental caries associated with the elimination of all these risks, may far exceed the hazards associated with these exposures.

The human species evolved over millennia in an environment exploding with free radical activity, fortunately we have developed defenses, superoxide dismutase, glutathione, peroxidase, catalase, etc., that counteract the toxic effects of these chemical compounds. Whether the man-made exposure substantively changed the balance will be a topic of discussion for years to come.

This symposium organized by David Carbone and Roy Herbst, brought together a broad spectrum of sophisticated scientists and international investigators, as well as community members and fundraising organizations who had the opportunity to present a special session on patient advocacy.

The meeting began with a keynote address examining microRNAs and lung cancer presented by Frank Slack from Yale University. He examined the growing recognition that lung cancer arises not only from gene mutations but also from small fragments of RNA that can up- or down-regulate normal genes in abnormal ways. This was the topic of discussion for many subsequent presentations.

As an aside, many of the readers will know that I am generally underwhelmed by genomic analyses for the prediction of cancer response. The fact that normal genes can function abnormally under the control of these small RNA sequences is just one more example of the genotype–phenotype dichotomy that cannot be adequately examined on static contemporary genomic platforms.

Many presentations examined the molecular biology of lung cancer with important distinctions being drawn between adenocarcinoma and squamous cell carcinomas. While adenocarcinomas reveal a growing number of targets – EGFR, ALK, ROS, RAS, and others – all the subject of small molecule inhibitors; squamous cell carcinomas provide fewer opportunities for the use of these classes of drugs.

One of the interesting discussions was the frequent mutation of LKB1 in lung cancers. Work going back several years by John Minna, a pioneer in this field, identified changes in this metabolic regulator as a common finding in lung malignancies.

Additional presentations examined chemoprevention, molecular pathology, new mechanisms to categorize lung cancer subtypes, and a very interesting discussion of field cancerization. In a particularly interesting analysis, Ignacio Wistuba from M.D. Anderson, showed that molecular changes in the surface epithelium of the lung bronchioles recapitulated the molecular biology of the final tumor in a step-wise manner, inversely related to the distance to the tumor. That is, starting at the main bronchi, one or two mutational changes were detected. Moving closer to the site of the tumor, additional mutations were accumulated. Finally arriving at the site of the established malignancy, all of the constituent mutations associated with this particular cancer became manifest; a saltatory slide into cancer presumably associated with exposure to carcinogens.

Among the other exciting presentations were updates on redox-based approaches to cancer presented by Kenneth Tew and Garth Powis.

Jeff Engelman presented an update on a new class of agents that target the RAS pathway. This is ongoing work that he and his group have reported on over the last several years. We have been engaged in related work using an MEK/ERK inhibitor similar to the compound that Dr. Englemen reported on at this meeting. It is exciting indeed to see early clinical results with this class of compounds, for we have identified many patients who might benefit from this pathways’ inhibition. We wait with great anticipation for FDA approval of these compounds so that our patients currently being identified as candidates in the laboratory may soon receive these treatments.

This is one of many reports associating vitamin D levels with disease. Indeed, so many reports on this topic have been published that vitamin D consumption in the U.S. has exploded. While some physicians have made careers promoting the concept, the science of vitamin D is indeed credible and very interesting.

What is vitamin D? Well, although we refer to it as a vitamin, it is, in fact, a hormone. It is obtained from the diet or from exposure to sun. The most potent form of vitamin D is that associated with sunlight exposure. Once in the body, vitamin D interacts with cells at very specific receptors. The term receptor reflects the role of these “landing sites” contained within the cell’s nucleus. As the vitamin D molecule traverses the cell membrane and enters the cell nucleus, it binds with the vitamin D receptor, which connects to the chromosome at a hormone response element and drives the cell machinery forward.

The vitamin D receptor is part of a large collection of genes called the steroid super gene family. These include receptors for estrogen, progesterone, testosterone, and, yes, vitamin D.

What makes the field so interesting is the interaction between these factors. Inside the nucleus are a large variety of receptors. Vitamin D and the other molecules are known as ligands. When the ligands enter the nucleus, they must compete for receptors. This leads to a complicated collection of down-stream events that are unique to the individual. If, for example, your nucleus has a number of orphan receptors (receptors with unclear ligand associations) and these orphan receptors have some binding affinity for the vitamin D, then the down-stream signaling will reflect this new biology.

Many studies have associated vitamin D levels with disease. Prostate cancer, colon cancer, even blood-born tumors may, in part, arise in vitamin D deficient states. But, the most compelling evidence in several analyses supports its protective effect against colon cancer. In one study there was a 15 percent risk reduction for every 10 ug/ml increase in circulating blood levels of calciferol (Gandini S, Int J Cancer. March 11, 2011). What is interesting about the report from the University of Rochester is that it was the most aggressive forms of breast cancer that were found to be associated with Vitamin D deficiency. To date, the correlations with the more common forms of breast cancer have been less positive.

Cardiovascular disease and musculoskeletal diseases are also associated with vitamin D levels. So critical is vitamin D to the well-being of the human that mankind could not easily migrate far north from the equator until he found a source of vitamin D unrelated to the skin synthesis. This source proved to be fish and animals that survived by eating fish. Older readers will remember cod liver oil as a remedy doled out by grandparents. It is ironic that cod liver oil is an excellent source of vitamin D.

While deficiencies of vitamin D are likely to be deleterious, substantially exceeding the normal levels of 30 micrograms/ml have not been shown to further enhance health. It is prudent for patients to monitor their vitamin D levels and highly appropriate for physicians to recommend replacement. Interestingly, a scientific colleague recently commented that sun exposure, by providing active vitamin D, is greatly under appreciated as a healthful activity. He wondered whether the broad use of sunscreens would ultimately save or cost more lives when the aggregate impact of vitamin D levels upon cancer and health is finally understood.

First, we needed our space measured. The big box store contracted with a group who did their flooring measurements. Second, we needed to purchase the material. This was done through the large concern acting as our purchasing agent. Finally, after the several weeks delay for the “special order materials,” our flooring material was delivered to yet a third party, the flooring installation experts.

Despite the delays, everything was moving along reasonably well. And then came the problem. Our contractor had needed to resurface a section of our entranceway. This left a gap from the bare wood up to the existing surface that was about to be recovered by the installation staff. We contacted the installation group the night before their scheduled   arrival to explain that they would need to match the new surface level with that of the old one. And then the wheels came off.

“We can’t do this job for a fear that there could be a need for asbestos remediation.”

“What asbestos?” I responded.

Their response, “We don’t know, but it’s a possibility.”

“Well then, come out and take a look.”

“Oh, no, we can’t do that, it will be at least a week.”

I felt stymied. Our carefully scheduled flooring, followed by appliance replacement, followed by painting, followed by cabinetry installation was now on indefinite hold. Luckily, I had a personal contact with a privately-owned flooring company who provided their own installers. They arrived the next day, examined the situation and explained that there was no asbestos risk whatsoever. They neatly matched the floor levels using a plywood sheet and proceeded to perfectly complete the flooring job.

After all was said and done, I suddenly realized that I had almost double the flooring material I actually needed. After much discussion, we convinced the big box store to accept the excess material in return and to compensate us for the difference.

So what’s this got to do with medicine? Quite a lot I would suggest.

Like the big box stores, American medicine is migrating towards generic care with each function contracted out to a different entity. The internist who diagnoses the problem is then forced to refer the patient to an outside contracted diagnostic service provider (i.e. radiology, CT, MRI). Results then slowly percolate back to the primary care physician who, one or two weeks later, recognizes the problem and recommends hospital admission. At this point a contracted hospitalist starts all over again, examining the patient and taking a detailed history in an attempt to uncover that, which the internist already knew. With the best data the hospitalist can accumulate, he then turns again to a contracted provider for a final intervention. The patient all the while has waited weeks, undergone numerous  interventions and investigations and more often than not gets more, or in some circumstance less, than what they really needed.

As we continue to undervalue the abilities and expertise of individual private physicians functioning as quarterbacks in patient management, we abdicate the management of a patient’s delicate problems to the intersecting tectonic plates of medical systems: HMO, PPO, VHA, Medicare, HHS, AARP, etc., etc., etc.

Like the big box stores that adequately meet the average needs of the average customer with an average problem, these medical behemoths lack the insight to meet individual patient needs. Duplication of services and inefficiency are the inevitable result. In retrospect I would gladly have paid a slightly higher fee for a privately owned concern to have measured, purchased and installed my kitchen floor. The savings associated with big box stores, are like those associated with HMO care . . . nonexistent.

So long as you are 42 ½ years old, have a viral respiratory infection and don’t have any allergies or prior medical history, HMOs provide great care. For everyone else,  Caveat Emptor!

Christopher Hitches died at age 62 from cancer of the esophagus. Although unapologetic for his use of alcoholic beverages and tobacco products, his lifestyle may have contributed to his diagnosis. What saddens me most is the possibility that he could have done better. And didn’t.

Like so many celebrities when they are diagnosed with cancer, Hitchens entered a realm that I call, “social medicine.” Not to be confused with socialized medicine and related political issues, social medicine is the process whereby the rich and famous receive care from the “right” doctors. These luminaries, through their channels and connections, are hand carried to the most famous physicians in the country. Their prominent and widely published ivory tower investigators then provide the best care money can buy. Yet, more often than not it is exactly the same therapy that they would have received from their home-town oncologists, who read the same journals, attend the same meetings and adhere to the same NCCN guidelines as the “best and the brightest” academics. We then conveniently chalk these patient’s failures up to the biology of the disease and the patient’s drug resistance rather than examining the more discomforting reality that protocol therapy doesn’t work for famous patients any better than it does is for anyone else.

But what if these patients just got the wrong treatment? What if the drugs these doctors chose were the very best for many, but not right for them? What if the right treatment was just right around the corner, but these prominent academics couldn’t see it? What if these patients had submitted a tumor sample for an EVA-PCD® assay and knew which drug or combinations would kill their cancer cells?

It isn’t that Christopher Hitchens or Steven Jobs are more important than any other patient. Their collective suffering and the losses to their families are no greater than any other cancer patient who confronts this illness. It’s just that they are famous and we know about it from the beginning to the end. We watch as these patients suffer through the toxicities and side effects of randomly administered therapies. And, in the case of Hitchens we are provided a blow-by-blow description in his writings. Unlike other patients who seek their care outside of the limelight, these celebrities are above the fray, protected by their handlers, PR agents and managers – they are unapproachable. With Jobs or Hitchens I would have relished the opportunity to offer any assistance possible, and through contacts at Apple I actually tried, but to no avail.

These individuals suffer and die in the public eye. Like salt in a wound, investigators like my colleagues and myself who are engaged in the pursuit of better, more intelligently delivered therapies, suffer with them. No, they are not more important, but it just seems so when you watch it every day on television, online, or in the print media, you clearly see an “in your face” example of a failing paradigm of cancer therapeutics.

Into this mix comes an interesting concept apparently floated by Roche’s European affiliates. Described in a brief press release was the suggestion that Roche might be prepared to attach Avastin reimbursement to its efficacy. That is – Roche would only demand payment from patients and third party payers if the treated patient revealed objective evidence of response. This is an interesting idea!

The concept of conditional reimbursement is extremely intriguing. Contrary to contemporary reimbursement policy, the purveyors of therapy would only receive compensation if they could prove benefit, not mind you, benefit in the broad brush Phase III tiny statistically significant result (e.g. the FDA approval of erlotinib plus gemcitabine in pancreatic cancer for a median survival advantage of 10.6 days!), but instead very real benefit on a patient-by-patient basis.

We use erlotinib plus gemcitabine, as well as Avastin combinations, to great benefit for many of our patients and applaud the availability of these drugs and combinations. But we never, just give them. Were the federal government, major payers or HMOs to be prepared to reimburse novel therapies predicated on their efficacy, we might envisage a meaningful advance in cancer therapeutics.

Today, few small laboratories, start-up companies and early stage biotech firms have the resources to marshal multi-million dollar clinical trials to test new therapies. This may in part be why advances in cancer therapy are moving so slowly forward.  The barriers to entry are insurmountable, causing many good ideas to fall by the wayside for lack of the hundreds of millions of dollars required to achieve FDA approval and Medicare reimbursement. But what if on an individual basis, reimbursement policies reflected the most meaningful of all endpoints – individual patient response and survival. Even the largest pharmaceutical companies are now coming to realize that despite their clout they too are suffering under the guidelines forced upon drug developers in this era of ever increasing regulation.

This is a concept worth pursuing. Let’s see where it goes.