What Goes Around Comes Around

On a recent morning, I found myself listening to an analysis of the public defender program in America. It seems that defendants who are provided with publically funded lawyers are almost uniformly advised to submit pleas. Regardless of the strength of their cases or their apparent innocence, plea bargains have become the preferred legal defense.

As I listened, the reason became increasingly apparent. It seems that in many states, legal fees paid to public defenders are bundled into a single, one-time payment. Lawyers are provided the same amount of money whether the client is convicted or found innocent. If the lawyers choose to vigorously defend their clients and prove their innocence, they receive precisely the same amount of money that they would receive if the accused pleaded guilty on the spot. It has not taken long for the legal community to figure out that plea bargains are good for business.

As a physician, I found this analysis of more than passing interest. After all, the movement toward managed care and the DRG (diagnosis-related groups) system make lump sum payments for medical care the norm. Using arbitrary metrics like per member/per month, physicians receive the same amount of the money whether they save your life or not. The defenders of this approach explain that it was designed to limit the profit motive and curtail physician avarice. What it has succeeded in doing however, is to incentivize physicians to give up. If there is no return on investment, then there will be no investment of time, energy, skill or ability. If physicians receive no more payment, accolades, or recognition for good outcomes than for bad ones, how long can we realistically expect good outcomes to continue?

The district attorneys, who were interviewed for the piece on public defenders, pointed out, in their defense, that this has succeeded in “clearing the dockets” of backlogged court cases. However, if we were to extend that line of reasoning into the realm of medical care delivery, we would need to confront a number of distinctly unappealing ramifications.

The corporatization of medicine, expanding regulation, creation and promotion of the HMO model, and recent legislation are all the products of legal minds. While NCCN cancer therapy guidelines are increasingly employed, not as guidelines, but instead as dictates to limit the ability of well-trained, sophisticated oncologists to practice their art; a recent article in the New England Journal of Medicine on bending the healthcare curve had the “underutilization” of hospice care as a principal focus. It is interesting to observe how lawyers, faced with “lump sum” payments, are responding. Is the reported deterioration of legal representation, especially for the under privileged in America, the jurisprudence counterpart to policies already underway in the medical system? Will the same disincentives in place for physicians now come home to roost for lawyers?

Of Helicobacter, Cancer and the Medical Establishment

The 2005 Nobel Prize in physiology was awarded to Barry Marshall and Robin Warren. These two practicing physicians made the discovery that peptic ulcer disease resulted, not from excess acid production, the prevailing theory, but instead from infection with an enteric pathogen – helicobacter pylori. In 1982, Marshall and Warren identified this organism in the stomach of an ulcer patient. When they proposed the causative relationship with ulcers they were virtually laughed off the stage. First, no organism could withstand the high concentration of acid found in the stomach. Second, excess acid, not infections caused ulcers.

These investigators wrote letters to the Lancet describing their early findings, while they continued to accumulate supporting documentation that correlated the presence of these spiral shaped organisms with gastric ulceration. This led other gastroenterologists and pathologists to more closely inspect gastric biopsy specimens for the presence of these pathogens.

What seemed so obvious to Warren and Marshall met with enormous resistance. After all, the acid causation theory had been in place for almost a century. The treatment of peptic ulcer disease had spawned an industry. From Maalox to Mylanta to Tums, sodium bicarbonate and even to Coca Cola and dairy products, soothing patient’s gastric symptoms had become a cause celebré for Western medicine. Ulcer surgery in the form of the vagotomy and pyloroplasties (V&P), Bilroth1 and Bilroth2, even gastrectomies, had come to constitute the most widely practiced surgical procedures in the United States. Gastric ulcers were good for business and no one from the pharmaceutical industry, to the hospitals, or the operating surgeons, were very interested in changing that.

Frustrated by their lack of traction amongst their colleagues, Marshall consumed a flask filled with helicobacter, thereby inflicting himself with an ulcer that was confirmed at the time of an endoscopy 10 days later. Treating the ulcer successfully with antibiotics still left little impact on his doubting Thomas colleagues. But clearly some were listening. By 1987, the first triple therapy cocktail had been developed. The success of this medical treatment became increasingly irrefutable. Slowly, but surely, these two unsung heroes were recognized for their fundamental and practice-altering observations.

These two physicians represent the very best of medical scientists. They began with an observation and painstakingly worked back to an etiology. This is how most medical discoveries are made. Yet, this is not the model for today’s oncologic investigation wherein, scientists conceive of novel theories and then demand that physicians test them, rarely to good effect. These Australian physicians were not highly acclaimed academics, or senior professors. Instead, they practiced their art and unceremoniously made important observations. . Confronting immense inertia in an entrenched medical community, they stood their ground and ultimately carried the day. Aided by the invention of the fiber-optic gastroscope, they were able to prove correlations, repeat experiments and ultimately confirm their results. It took 20 years, but the Nobel committee finally recognized their contribution.

Cancer research today is inhabited by these same entrenched forces, which are convinced of certain principles and unwilling to reconsider their positions. Like the environment in which Warren and Marshall found themselves 30 years ago, the academic community eschew any idea that disrupts their hegemony However, similar paradigm shifts are occurring today in oncology: Yesterday’s gastric acid theory is akin to today’s cell proliferation model. The development of the fiberoptic endoscope in the 1980s is the equivalent of today’s advance in primary culture laboratory platforms. Marshall and Warren changed  medical history. Do we really need to wait another 30 years to do the same for cancer patients?

Do We Already Have the Tools We Need to Cure Cancer?

The rapid-fire sequence of the annual American Association of Cancer Research (AACR) meeting, held in May, followed by the annual American Society of Cllinical Oncology (ASCO) meeting, held in June, provides the opportunity to put scientific discoveries into perspective as they find their way from theoretical to practical.

Members of AACR, the basic science organization, ponder deep biological questions. Their spin-offs arrive in the hands of members of ASCO as Phase I and Phase II trials, some of which are then reported at ASCO meetings.

Many of the small molecules my laboratory has studied over the years are now slowly making their way from “Gee Whiz” to clinical therapy. At the ASCO meeting I attended many of the Phase I sessions, where alphabet soup compounds had their first “in-human” trials. As most of these compounds are familiar to me, I was very interested in these early, though highly preliminary, results.

Departing from one Developmental Therapy (Phase I) session, with visions of signal transduction pathways in my head, I attended a poster discussion on triple negative breast cancer. For those of you unfamiliar with the term, it refers to an increasingly common form of breast cancer that doesn’t mark for the usual estrogen, progesterone, or HER-2 features. Often occurring in younger patients, this form of breast cancer can be aggressive and unresponsive to some forms of therapy. Much work has gone into defining sub-types of this disease and slow progress is being made.

As I examined the posters, one caught my eye, “Clinical Characteristics and Chemotherapy Options of Triple Negative Breast Cancer: Role of Classic CMF regimen. (Herr, MH et al, abstract #1053, ASCO 2012.) What these investigators showed in a series of 826 breast cancer patients was that those treated with the oldest drug combination for breast cancer (CMF) did better than those who received the more modern and more intensive anthracycline or taxane-based regimens. CMF, originally developed by Italian investigators in the 1970s, was the principal therapy for this disease for two decades before it was replaced, first by anthracycline and later by taxane-based treatments. What struck me was the unexpected superiority of this old regimen over its more modern, toxic and expensive brethren.

I began to wonder about other modern therapies and their real impact upon cancer outcomes. One study in HER-2 positive patients revealed relative equivalency between weekly taxol, every three-week Taxotere and Abraxane-based therapy. Once again, the cheaper, older, less toxic Taxol regimen proved superior. While most of the attendees at the ASCO meeting were considering how the newest VEGF inhibitor Regorafenib, or the addition of aflibercept, might impact their practices, I was somewhat underwhelmed by the results of these statistically significant, but clinically marginal survival advantages, all associated with great expense.

As I pondered the implications of the CMF results in triple negatives and those of the taxol results in HER-2 positives, I considered other old-fashioned therapies with newfound potential. Among them, losartan, the angiotensin antagonist that influences tumor stroma or the results of an earlier published study that identified intraconazole (a widely available anti-fungal therapy), as an inhibitor of the hedgehog pathway. While the pharmaceutical industry promotes the use of vismodegib, a hedgehog inhibitor for basal cell skin cancer, and dozens of trials examine VEGF and FGF inhibitors, I wondered whether losartan or intraconazole or other simple compounds and combinations might not already provide many of the tools we need. Is it possible that effective treatments for cancer are at hand?

Lacking the tools to decipher the signals and combine the agents to greatest effect, are we destined to continue to blindly administer increasingly expensive, toxic, yet arguably no more effective therapies? With the myriad of drugs and combinations available today, might it be that we “can’t see the forest for the trees.”

Tumor Ecology, Not Tumor Biology

During the first years of this millennium as the newly discovered field of anti-angiogenesis was reaching a fevered pitch, I had the opportunity to attend an AACR Special Symposium, held at Whistler Resort in British Columbia. While there I attended a symposium by Dr. Rakesh Jain. Dr. Jain a long-time colleague of Judah Folkman, MD,  at Harvard University presented his observations on tumor vascularity and its implications for therapy. Despite the prevailing belief that tumor angiogenesis was a linear phenomenon, from cessation of blood supply – and thereby nutrients and oxygen – to the death of cancer, Dr. Jain provided compelling evidence to the contrary.

Every so often I read an article, hear a lecture, or attend a symposium that changes the way I think. Dr. Jain’s presentation that year was just that type of lecture. In the span of an hour he described the dynamics of blood flow through the network of disorganized tumor blood vessels. He showed that anti-angiogenic factors actually “pruned” the blood supply and returned normal flow. He went on to point out that most of the experiments being reported at that time by other investigators had short windows of observation during which the effects of Bevacizumab could be captured, photomicrographed and published to great acclaim in the most prestigious journals. But there was a fly in the ointment. Bevacizumab by itself had a miniscule response rate. Indeed, in the absence of chemotherapy, it was single digits.

Jain, an engineer by training, developed a novel tissue “window” method that enabled him to explore the temporal sequence of cellular response to VEGF therapy. He found that it all wasn’t as simple or tidy as it had seemed. The short-term control of vasculature was followed by revascularization. Cells deprived of oxygen and nutrients devolved into more stem cell-like phenotypes. Therapies based on an incomplete understanding of angiogenesis might, in his opinion, be adding to the problem.

As the years have gone on I’ve carried the insights from that lecture with me. At a subsequent AACR presentation by Napoleon Ferrara, PhD, many years later, Dr. Ferrara, who developed Bevacizumab, reminded his audience that VEGF was originally known as VPF (vascular permeability factor). Perhaps this aspect of the VEGF effects were responsible for its minimal single agent activity, yet profound combinatorial effect.

With this as a backdrop, I sat among 15,000 medical oncologists at the plenary session lecture where Dr Jain presented his work and I delighted in the possibility (however slight) that his message of experimental analysis and systems biology would sink in.

Cancer is not a cell, it is a system. Tumor cells are but a small portion of the process. Carcinogenesis may represent a response to cellular stress, some of which, we as “therapists” may inflict. The indiscriminate use of cytotoxic agents and antivascular drugs may, in some circumstances, be more harmful than helpful to our patients.

What is the appropriate dose of Bevacizumab? How should it be given? In what sequence with radiation or chemotherapy? With what drugs or targeted agents? Are low doses better than high doses? Is the effect of VGEF inhibition a driver of response or an epiphenomenon? What about the fibroblast matrix, lymphatic vessels, infiltrating monocytes, T-cells, B-cells and neutrophils? Dr. Jain elegantly outlined the complexities of the human tumor microenvironment.

It was with more than a small amount of satisfaction, that I realized how quite correct our approach to this disease has been over the years. It is not just the cancer cell that is important, but the tumor as a whole. Cancer cells are just part of the problem. Using native state microspheroids replete with vasculature, cytokines, stromal elements and tumor cells; we feel that we are now poised to advance the growing use of effective targeted therapies in ever-expanding ways.

Venture Capital Goes Genomic

During the 1960s, 70s and into the 90s, a field of investigation arose that examined buyer’s practices when it came to the consumption of goods and services. Algorithms were developed to interrogate consumer choice. One such treatise was reported in 1994 (Carson, RT et al, Experimental Analysis of Choice, Marketing Letters 1994). What these researchers explored were the motivations and forces that drove consumption. When choices are offered, decisions are driven by such factors as complexity and utility. Complexity demands personal expertise or failing that, input from experts, while utility places a value on the good or service.

A recent report from a small biotechnology company called Foundation Medicine has brought this field of endeavor to mind. It seems that this group will be offering DNA sequencing to select chemotherapy drugs. This service, currently priced at $5,800, will focus upon a small cassette of genes that they described as “key” in tumor growth. Based on their technology they have already raised $33.5 million from the likes of Third Rock, Google and Kleiner Perkins Caulfield & Byers, venture capital sources. The CEO of Foundation substantiates the approach by pointing out that fully 150 people have already used their services. One hundred and fifty!

It seems from this report that our colleagues in the field of molecular profiling have studied the dictates of “Experimental Analysis of Choice” to a “T.” What we have is the perfect storm of medical marketing.

First, the technology is so complex as to be beyond the ken of both patients and physicians alike. Thus, expertise is required and that expertise is provided by those engaged in the field. Second, the utility of drug selection is beyond reproach. Who in their right mind wouldn’t want to receive a drug with a higher likelihood of a response when we consider the toxicities and costs, as well as the consequences of the wrong treatment? Dazzled by the prospect of curative outcomes, patients will, no doubt, be lining up around the block.

But, let’s deconstruct what this report is actually telling us. First, a scientifically interesting technology has been brought to the market. Second, it exists to meet an unmet need. So far, so good. What is lacking, however, is evidence. Not necessarily evidence in the rarefied Cochrane sense of idealized survival curves, nor even Level II evidence, but any evidence at all. Like whirling dervishes, patients and their physicians are drawn into a trancelike state, when terms like NextGen sequencing, SNP analysis and splice variants are bandied about.

Despite the enthusiastic reception by investors, I fear a lack of competent due diligence. To wit, a recent article in Biotechniques, “Will the Real Cancer Cell Please Stand Up,” comes to mind. It seems that cancer cells are not individual entities but networks. A harmonic oscillation develops between tumor, stroma, vasculature and cytokines. In this mix, the cancer cell is but one piece of the puzzle.

Indeed, according to recent work from Baylor, some of the tumor promotion signals in the form of small interfering RNAs, may arise not from the cancer cells, but instead from the surrounding stroma. How then, will even the most punctiliously perfect genomic analyses of a cancer cells play out in the real world of human tumor biology and clinical response prediction? Not very well I fear. But then again such a discussion would require data on the predictive validity of the method, something that appears to be sorely lacking.

Will today’s gene profile companies prove to be the biotech Facebook IPOs of tomorrow?