Future (Cancer) Shock

Two related clinical trials were reported in the last several months describing the use of heat shock protein 90 (HSP90) inhibitors in lung cancer. Both trials fell short of their pre-specified endpoints casting a pall upon these drugs. However, the study of HSP90 inhibitors should not be abandoned based on these finding, as this is a fertile area of investigation and offers opportunities for the future.

Human cells marshal many defenses against stress. Thermal injury can damage basic cellular functions by denaturing (inactivating) proteins. The machinery of cells is largely comprised of protein enzymes. Excessive heat coagulates proteins much the way the albumin of an egg turns white during cooking. The loss of fluidity and function ultimately results in cell death. The heat shock proteins come to the rescue by shepherding these proteins away from injury and protecting them from denaturation.

220px-Hsp90There are many different heat shock proteins found in human cells, but one of the most abundant and active in cancer cells is known as HSP90 for its molecular weight in the range of 90-kilodaltons. Over the last two decades investigators have explored the use of small molecules to inhibit these important proteins. Among the first compounds to be isolated and applied were derivatives of geldenamycin. Although geldenamycin itself is a poison that causes severe liver damage, its derivative 17-AAG, also known as tanespimycin, has successfully entered clinical trials.

The current studies examined two other HSP90 inhibitors. One retaspimycin, has been developed by Infinity Pharmaceuticals. This clinical trial combined retaspimycin with docetaxel and compared results with docetaxel alone in 226 patients with recurrent lung cancer. None of the patients had received docetaxel prior to the trial. Drugs were administered every three weeks and the efficacy endpoint was survival with a subset analysis focused on those with squamous cell cancer. The trial fell short of its pre-designated endpoint. Interestingly, the study failed to provide benefit even in patients who were specifically targeted by their tumor’s expression of the K-Ras, p53 or by elevated blood levels of HSP90, the putative biomarkers for response.

The second trial examined a different HSP90 inhibitor developed by Synta Pharmaceuticals. The drug ganetespib was combined with docetaxel and the combination was compared with docetaxel alone. The results just reported indicate that the combination provided a median survival of 10.7 months, while docetaxel alone provided a median survival of 7.4 month. Although this represented a three month improvement, it did not meet the pre-specified target.

Taken together, these results could dampen enthusiasm for these agents. This would be unfortunate, for this class of drugs is active in a number of human tumors. We observed favorable activity and synergy for the HSP90 inhibitor geldenamycin and its derivative 17-AAG as we reported (Nagourney RA et al Proc. AACR, 2005). More importantly, 17-AAG (tanespimycin) provided objective responses in 22% and clinical benefit in 59% of patients with recurrent HER2 positive breast cancer after these patients had failed therapy with Herceptin. This clearly supports the role of HSP90 inhibition in breast cancer and would suggest that other more carefully selected target diseases could benefit as well.

The function of HSP90 is not completely understood as it influences the intracellular trafficking of dozens ofHsp90cycle proteins. One of the complexities of this class of drugs is that they protect and enhance the function of both good and bad proteins. After all, the HSP90 protein doesn’t know which proteins we, as cancer doctors, would like it to protect.

When we apply the EVA-PCD analysis to these and related classes of compounds we focus our attention upon the downstream effects, namely the loss of cell survival. That is, whatever proteins are influenced, the important question remains “did that effect cause the cells to die?” Classes of compounds with nonspecific targets like the HSP90 inhibitors will surely be the most difficult to characterize at a genomic or proteomic level: What protein? What gene?

Functional platforms like the EVA-PCD offer unique opportunities to study these classes of agents. We are convinced that the HSP90 inhibitors have a role in cancer therapy. It would be unfortunate if these setbacks led us to “throw the baby out with the (hot) bathwater,” thus slowing or preventing their use in cancer treatment.

A Tribute to Loretta Stamos 1939 – 2014

RAN & Loretta cropped lo res

Dr. Nagourney and Loretta Stamos

On Monday, September 22, 2014, we lost a great ally and a better friend.

Loretta Stamos lost her own fight with cancer, the very disease that she had worked so tirelessly to defeat. I first met Loretta in 1995 when her brother Jake was diagnosed with advanced lung cancer. His physicians didn’t offer much hope. At our meeting, I explained my approach to cancer therapy using each patient’s cells to select drugs (EVA-PCD functional profile).

“Let’s do it,” said Loretta.

“Now?” I asked.

“Why not?” she replied. As I would come to know over our 20 year friendship, Loretta didn’t mince words and was not one to take no for an answer.

A simple two drug combination was recommended for Jake, but his physicians declined. Loretta asked if I would assume his care. As I was out-of-network for his HMO, each time we treated her brother, Loretta generously covered the chemotherapy costs. After two cycles of treatment, the pleural fluid stopped accumulating. Jake gained weight and returned to some of his normal activities.

The in-network physicians began to realize that they were on the wrong side of this equation and suddenly offered to continue the treatments at their facility. Jake’s cancer ultimately progressed. His extensive metastatic disease involving his lung and bones was too aggressive for even the best chemotherapy to cure. Despite the sad loss, we had succeeded in showing that every patient deserved the chance to get better regardless of their insurance or finances.

Loretta wondered what would have happened if she had not been there to help. I explainRAN_LS_JS2 lo resed that the laboratory analyses were too costly for me to donate. Though they came in at a fraction of the price of a single dose of chemotherapy, many insurers refused to cover them. Loretta said, “I’m going to make sure that people who need these tests will never be denied.” And the Vanguard Cancer Foundation (VCF) was born.

Months of work, committee meetings and planning sessions culminated in a “A Night in Brazil,” a gala benefit that raised $100,000. John Stamos, Dave Coulier and Bob Saget turned in stellar performances as the MCs and a great time was had by all. More importantly, for the first time we could to say to patients, “We can find the treatment that’s right for you and if you can’t afford it, we’ll give it to you.” With each passing year the fund grew as did the number of patients we could help.

John and Loretta Stamos w-Sarah AmentoWhat a luxury to never turn a patient away. What an opportunity to help uninsured and younger patients. What a pleasure to see the good responses, even in some patients considered previously “untreatable.” I was overwhelmed by Loretta’s dedication and the kindness that she and the VCF members showed to patients in need. Every year we would recognize Loretta and her family for their hard work and generous contributions, and every year Loretta would say that she did this because “I made her brother smile.”

There is a silver lining to even the darkest cloud. It was Loretta who put it most poignantly when she defined the mission of the Vanguard Cancer Foundation as providing lifesaving care to “persons of worth but not of means.” The most fitting tribute of all for this noble soul is the more than 400 patients who can thank Loretta Stamos for a second chance at life.

New Diagnostic Test for the Early Detection of Lung Cancer

I was invited to discuss a new diagnostic test for the early detection of lung cancer by Gerri Willis of Fox Business News’ Willis Report.
An Italian clinical study presented at the September 2014 European Respiratory Society described 82 patients with abnormal chest x-rays. Patients breathed into a machine that measured the temperature of the exhaled air. Forty of the patients ultimately proved to have cancer and 42 did not, as confirmed by subsequent biopsy. They found a correlation between the temperature of the exhaled breath and presence of lung cancer. They also found that long term smokers had higher breath temperatures, as did those with higher stage disease.

For a variety of reasons, a test as simple as breath temperature seems unlikely to be highly specific. After all, the temperature of the exhaled breath could reflect infection, inflammation, or even activity level, as vigorous exercise can raise the body’s core temperature. Nonetheless, the fact that there is any correlation at all is of interest.

PET scan lung cancerWhat might underlie these findings? Accepting the shortfalls of this small study, it is an interesting point of discussion. First, cancer is a hyper metabolic state. Cancers consume increased quantities of glucose, proteins, and lipids. PET scans measure these phenomena every day. Second, cancer is associated with hyper vascularity. Up-regulation of VEGF could cause hyperemia (increased capillary blood flow) in the airways of lung cancer patients, resulting in the finding. Finally, cancer, in and of itself, is an inflammatory state. Inflammation reflects increased metabolic activity that could manifest as a whole body change in basal temperature.

Lung cancer is the leading cause of cancer death in the US, constituting 27% of all cancer deaths. Despite the over 224,000 new diagnoses and 160,000 deaths, the five-year survival for lung cancer today at 17% has not changed in several decades. Nonetheless patients who are detected early (Stage I) have a greater than 50% five-year survival.

We know from the National Lung Cancer Screening Trial published in 2010, that early detection by CT scans can reduce mortality from this disease by 20%. In the cancer literature, that is huge. The problem is that screening CTs are comparatively expensive, inconvenient, expose patients to radiation and are themselves fraught with false positives and false negatives. Furthermore, it is estimated that that broad application of spiral CT’s could cost over $9 billion a year. Thus, simple, non-invasive screening techniques are sorely needed.

The use of exhaled breath to diagnose cancers has been under in development for decades. Recently, investigators from The Cleveland Clinic and others from Israel have reported good results with a microchip that measures the concentration of volatile organic compounds in the breath and provides a colorimetric score. With several hundred patients the receiver-operating curves (ROC, a technique that gauges the sensitivity and specificity of a test) in the range of 0.85 (1.0 is perfect) are quite favorable. Although these techniques have not yet gained broad application, they are extremely interesting from the standpoint of what it is they are actually measuring.

For decades, the principal focus of scientific exploration in cancer has been genomic. Investigators at Boston University and others at MD Anderson in Texas have used genomic and methylation status of oro-and naso-pharyngeal swabs to identify the earliest hallmarks of malignant transformation. To the contrary, the breath tests described above measure phenomena that fall more in the realm of metabolomics. After all, these are measures of cellular biochemical reactions and identify the transformed state at a metabolic level.

Though still in its infancy, metabolomics reflects the most appealing of all cancer analyses. Examining cancer for what it is, rather than how it came to be, uses biochemistry, enzymology and quantitative analyses. These profile the tumor at the level of cellular function. Like the platforms that I utilize (EVA-PCD), these metabolic analyses examine the tumor phenotype.

I applaud these Italian investigators for using a functional approach to cancer biology. This is a highly productive direction and fertile ground for future research. Will breath temperature measurement prove sensitive and specific enough to diagnose cancer at early stage? It is much too early to say, but at least for now, I wouldn’t hold my breath.

Expert Advice – Another Wrinkle

Few dictates of modern medicine could be considered more sacrosanct than the prohibition of excess salt intake in our daily diets. For more then five decades every medical student has had the principle of dietary salt reduction drummed into his or her heads. Salt was the bane of human health, the poison that created hypertension, congestive heart failure, stroke, renal failure and contributed to the death of untold millions of people in the western society. At least so it seemed.

Three articles in the 08/14/2014 New England Journal of Medicine raise serious questions about the validity of that heretofore established principle of medical therapeutics.

Two of the articles utilized urinary sodium and potassium excretion as a surrogate for dietary intake to examine impact on blood pressure, mortality and cardiovascular events overall. A third article applied a Bayesian epidemiologic modeling technique to assess the impact of sodium intake on cardiovascular mortality.

salt shaker-nihThe first two articles were unequivocal. Low sodium intake, that is, below 1.5 to 2 grams per day was associated with an increase in mortality. High sodium intake that is, greater than 6 grams per day, was also associated with an increase in mortality; but the middle ground, that which reflects the usual intake of sodium in most western cultures did not pose a risk. Thus, the sodium intake associated with the western diet was safe. What is troubling however is the fact that very low sodium diets, those promulgated by the most established authorities in the field, are in fact hazardous to our health.

It seems that every day we are confronted with a new finding that refutes an established dogma of modern medicine. I have previously written blogs on the intake of whole milk or consumption of nuts, both of which were eschewed by the medical community for decades before being resurrected as healthy foodstuffs in the new millennium. One by one these pillars of western medicine have fallen by the wayside. To this collection, we must now add the low-salt diet.

Thomas Kuhn in his 1962 book, The Structure of Scientific Revolutions, stated that a new paradigm would only succeed if a new one arises that can replace it. Perhaps these large meta-analyses will serve that purpose for sodium intake and health. One can only wonder what other medical sacred cows should now be included in these types of inquiries?

As a researcher in the field of human tumor biology and purveyor of the EVA-PCD platform for prediction of chemotherapy drug response and oncologic discovery, I am intrigued but also encouraged, by the scientific community’s growing ability to reconsider its most established principles as new data forces a re-examination of long held beliefs. It may only be a matter of time before more members of the oncologic community re-examine the vast data supporting the predictive validity of these Ex Vivo Analyses and come to embrace these important human tumor phenotypic platforms. At least we can hope so.

Toward A 100% Response Rate in Human Cancer

Oncologists confront numerous hurdles as they attempt to apply the new cancer prognostic and predictive tests. Among them are the complexities of gene arrays that introduce practicing physicians to an entirely new lexicon of terms like “splice variant, gene-rearrangement, amplification and SNP.”

Althougcancer for dummiesh these phrases may roll of the tongue of the average molecular biologists (mostly PhDs), they are foreign and opaque to the average oncologist (mostly MDs). To address this communication shortfall laboratory service providers provide written addenda (some quite verbose) to clarify and illuminate the material. Some institutions have taken to convening “molecular tumor boards” where physicians most adept at genomics serve as “translators.” Increasingly, organizations like ASCO offer symposia on modern gene science to the rank and file, a sort of Cancer Genomics for Dummies. If we continue down this path, oncologists may soon know more but understand less than any other medical sub-specialists.

However well intended these educational efforts may be, none of them are prepared to address the more fundamental question: How well do genomic profiles actually predict response? This broader issue lays bare our tendency to confuse data with results and big data with big results. To wit, we must remember that our DNA, originally provided to each of us in the form of a single cell (the fertilized ovum) carries all of the genetic information that makes us, us. From the hair follicles on our heads to the acid secreting cells in our stomach, every cell in our body carries exactly the same genetic data neatly scripted onto our nuclear hard-drives.
What makes this all work, however, isn’t the DNA on the hard drive, but instead the software that judiciously extracts exactly what it needs, exactly when it needs it. It’s this next level of complexity that makes us who we are. While it is true that you can’t grow hair or secrete stomach acid without the requisite DNA, simply having that DNA does not mean you will grow hair or make acid. Our growing reliance upon informatics has created a “forest for the trees” scenario, focusing our gaze upon nearby details at the expense of larger trends and insights.

What is desperately needed is a better approximation of the next level of complexity. In biology that moves us from the genotype (informatics) to the phenotype (function). To achieve this, our group now regularly combines genomic, transcriptomic or proteomic information with functional analyses. This enables us to interrogate whether the presence or absence of a gene, transcript or protein will actually confer that behavior or response at the system level.

I firmly believe that the future of cancer therapeutics will combine genomic, transcriptomic and/or proteomic analyses with functional (phenotypic) analyses.

Recent experiences come to mind. A charming patient in her 50s underwent a genomic analysis that identified a PI3K mutation. She sought an opinion. We conducted an EVA-PCD assay on biopsied tissue that confirmed sensitivity to the drugs that target PI3K. Armed with this information, we administered Everolimus at a fraction of the normal dose. The response was prompt and dramatic with resolution of liver function abnormalities, normalization of her performance status and a quick return to normal activities. A related case occurred in a young man with metastatic colorectal cancer. He had received conventional chemotherapies but at approximately two years out, his disease again began to progress.

A biopsy revealed that despite prior exposure to Cetuximab (the antibody against EGFR) there was persistent activity for the small molecule inhibitor, Erlotinib. Consistent with prior work that we had reported years earlier, we combined Cetuximab with Erlotinib, and the patient responded immediately.

Each of these patients reflects the intelligent application of available technologies. Rather than treat individuals based on the presence of a target, we can now treat based on the presence of a response. The identification of targets and confirmation of response has the potential to achieve ever higher levels of clinical benefit. It may ultimately be possible to find effective treatments for every patient if we employ multi-dimensional analyses that incorporate the results of both genomic and phenotypic platforms.

Cancer Centers and Advertising: The Truth Be Told

Screen shot 2014-08-06 at 5.08.23 PMSome of the most interesting literature on cancer comes from journals that are not directly involved in the field. I was reminded of this by an article that appeared in the June 17, 2014 Annals of Internal Medicine entitled “What Are Cancer Centers Advertising to the Public?”

The authors examined the types of clinical services that are promoted by commercial advertising. They reviewed advertisements that appeared in the top media markets during the year 2012, including both television and magazine ads. They excluded duplicates, public service announcements, fund raising and research subject recruitment. Of 1,427 total advertisements, 409 were considered to be unique ads that promoted clinical programs at 102 different cancer centers.

Screen shot 2014-08-06 at 5.13.29 PMTo analyze the content, the investigators developed a “code book” that included four domains; the types of clinical services, information provided, the use of emotional advertising appeals and the use of patient testimonials. Among the centers analyzed, 59% were for profit and the same percent were accredited by the Commission on Cancer. Sixteen percent were NCI designated centers. Advertising was also characterized by region of the United States. The results are interesting and instructive.

Of the 409 unique clinical advertisements, 88% promoted treatment. This was demonstrably higher than the percentage promoting cancer screening at 18% or supportive services at only 13%. While the benefits of therapies were described in 27% of the ads, the risks were only mentioned in 2%. Emotional appeals were frequent with 85% of the ads evoking hope for survival. Cancer was often described as a fight or battle, and the use of fear (of death, etc.) was found in fully 30% of the advertisements.

Screen shot 2014-08-06 at 5.15.28 PMIn their discussion, the authors pointed out several interesting findings. Among them, the “frequent use of emotional appeals and scarce mention of risk of services or quantification of benefit.” They also found “that NCI designated centers more frequently used emotional appeals related to survival or potential for cure.” These same centers “omitted information about risks, benefits and alternatives with similar frequency as non-NCI designated centers.” They concluded that “emotional appeals coupled with incomplete information are being widely used to promote services even among the nation’s most prestigious cancer centers.” Interestingly while only 5% of cancer centers in the United States are NCI designated, fully 16% of the clinical cancer advertising in 2012 was conducted by NCI-designated centers, a three-fold higher use.

What are we to gather from this analysis? First a journal like the Annals of Internal Medicine, removed from the direct delivery of cancer care, has the gravity to review processes that would rarely be reported in the oncology literature. Second, NCI designated (academic) cancer centers, who claim to eschew dissemination of unsScreen shot 2014-08-06 at 5.23.56 PMubstantiated information, appear to be the very centers that engage in such promotion. As the authors note, “clinical advertisements that use emotional appeal uncoupled with information about indications, benefits, risks, or alternatives may lead patients to pursue care that is either unnecessary or unsupported by scientific evidence.”

We applaud the authors of this Annals of Internal Medicine article for their unbiased and informative analysis. We must all strive to provide patients practical and actionable information about cancer and its treatment. It appears from this study that the practice of self-promotion crosses all lines of cancer care delivery from the most august academic institutions to the for-profit cancer centers. As with all activities in life, cancer patients are to be reminded of the ancient Roman admonition “Caveat Emptor” (Buyer Beware!).

With an EVA-PCD Assay, It Can Be That Simple

Shortly after I left the university and joined a medical oncology group, one of the junior members of the practice asked if I would cover for him during his summer vacation. Among the patients he signed over to me was a gentleman in his 60s with what he described as “end-stage” chronic lymphocytic leukemia (CLL). As the patient had already received the standard therapies, second line regimens and experimental drugs available at the time, the physician had run out of options. My charge was to keep him comfortable. I asked if it would be all right for me to study his cells in my lab and the doctor agreed.

CLL 130611.06I met the patient the next day. He was a very pleasant tall, slender black man lying in bed. He had lost a great deal of weight making the already enlarged lymph nodes in his neck appear that much more prominent. As I was engaged in the study of CLL as my principal tumor model, I asked if I might examine his circulating CLL cells as part of our IRB-approved protocol. He graciously obliged and I obtained a few ccs of blood. We were deeply ensconced in tumor biology analyses and his cells were used to explore membrane potentials, DNA degradation and glutathione metabolism as correlates with drug response profiles by EVA-PCD analysis. A large number of those studies have since been published.

What struck me about the patient’s EVA-PCD profile was the exquisite sensitivity to corticosteroids. Corticosteroids in the form of prednisone, Medrol, Solu-Medrol and Decadron are the mainstays of therapy for lymphoid malignancies like CLL. Everyone receives them. Indeed this patient had received them repeatedly including his first line chlorambucil plus prednisone, his second-line CHOP and his third line ESHAP. It was only after he had failed all of these increasingly intensive regimens that he finally moved on to an experimental agent, homoharringtonine, a drug that finally received FDA approval in 2012, after almost 40 years of clinical development. Unfortunately for him homoharringtonine did not work and it seemed we were well beyond conventional therapies, or were we?

I pondered the corticosteroid sensitivity finding and decided to start the patient on oral prednisone. It would be another two weeks before his physician returned and there really weren’t many options. The patient responded overnight. The lymph nodes melted away. The spleen diminished. He began to eat and gained weight. Within a few days he felt well enough to go home. I discharged the patient and remember writing his prednisone prescription, 40 mg by mouth each morning.

A week later, my colleague returned from his retreat in the Adirondacks. He inquired about his patients and surmised that this gentleman, no longer in the hospital, had died. I explained that he had been discharged.

“Discharged . . . how?” he asked. I described the findings of our EVA-PCD study, the sensitivity to steroids and the patient’s miraculous clinical response to this, the simplest of all possible treatments. The physician then turned to me and said “Prednisone . . . hmmm . . . I could have done that.”

I am reminded of this story almost daily. It is emblematic of our work and of those who choose not to use it. Good outcomes in cancer do not occur by chance. They also do not require blockbuster new drugs or brilliant doctors. They require individualized attention to the needs of each patient.

A recurring theme, exemplified by this patient among others, is that cancer cells can only defend themselves in a limited number of ways. Once a selection pressure, in a Darwinian sense, is removed (e.g. corticosteroids were not used during the homoharringtonine treatments) the surviving cells, sensitive to steroids, re-emerge to be identified and captured in our laboratory platform.

It is remarkable how often heavily pretreated patients with ovarian cancer are found sensitive to Taxol after they had received it years earlier, but not since; or breast cancer patients who fail every new agent only to prove responsive to CMF, the earliest of all of the breast cancer drug combinations developed in the 1970s. Our job as oncologists is to find those chinks in armor of cancer cells and exploit them. The EVA-PCD platform, in the eyes of some, may not be groundbreaking . . . it just happens to work!


The Changing Landscape in Non-small Cell Lung Cancer (NSCLC)

In October 2012, we published a study of patients with metastatic NSCLC whose treatment was guided by EVA-PCD laboratory analysis. The trial selected drugs from FDA approved, compendium listed chemotherapies and every patient underwent a surgical biopsy under an IRB-approved protocol to provide tissue for analysis.

The EVA-PCD patients achieved an objective response rate of 64.5 percent (2-fold higher than national average, P < 0.0015) and median overall survival of 21.3 months (nearly 2-fold longer than the national average of 12.5 months).

Non-small cell lung cancer

Non-small cell lung cancer

The concept of conducting biopsies in patients with metastatic NSCLC was not only novel in 2004, it was downright heretical. Physicians argued forcefully that surgical procedures should not be undertaken in metastatic disease fearing risks and morbidity. Other physicians were convinced that drug selection could not possibly improve outcomes over those achieved with well-established NCCN guidelines. One oncologist went so far as to demand a formal inquiry. When the hospital was forced to convene an investigation, it was the co-investigators on the IRB approved protocol and the successfully treated patients who ultimately rebuffed this physician’s attempt to stifle our work.

With the publication of our statistically superior results and many of our patients surviving more than 5 years, we felt vindicated but remain a bit battle scarred.

I was amused when one of my study co-authors (RS) recently forwarded a paper authored at the University of California at Davis about surgical biopsies and tumor molecular profiling published by The Journal of Thoracic and Cardiovascular Surgery. This single institution study of twenty-five patients with metastatic NSCLC reported their experience-taking patients with metastatic disease to surgical biopsy for the express purpose of selecting therapy. Sixty four percent were video assisted thoracic (VATS) wedge biopsies, 16 percent pleural biopsies, 8 percent mediastinoscopies, 12 percent supraclavicular biopsies and 8 percent rib/chest wall resections. Tissues were submitted to a commercial laboratory in Los Angeles for genomic profiling.

The authors enthusiastically described their success conducting surgical procedures to procure tissue for laboratory analysis. Gone was the anxiety surrounding the risk of surgical morbidity. Gone were the concerns regarding departure from “standard” treatment. In their place were compelling arguments that recapitulated the very points that we had articulated ten years earlier in our protocol study. While the platforms may differ, the intent, purpose and surgical techniques applied for tissue procurement were exactly the same.

What the Cooke study did not describe was the response rate for patients who received “directed therapy.” Instead they provide the percent of patients with “potentially targetable” findings (76 percent) and the percent that had a “change in strategy” (56 percent) as well as those that qualified for therapeutic trials (40 percent). Though, laudable, changing strategies and qualifying for studies does not equal clinical responsiveness. One need only examine the number of people who are “potential winners” at Black Jack or those who “change their strategies” (by changing tables/dealers for example) or, for that matter, those who qualify for “high roller status” to understand the limited practical utility of these characterizations.

Nonetheless, the publication of this study from UC Davis provides a landmark in personalized NSCLC care. It is no longer possible for oncologists to decry the use of surgical biopsies for the identification of active treatments.

As none of the patients in this study signed informed consents for biopsy, we can only conclude that the most august institutions in the US now view such procedures as appropriate for the greater good of their patients. Thus, we are witness to the establishment of a new paradigm in cancer medicine. Surgical biopsies in the service of better treatment are warranted, supported and recommended. Whatever platform, functional or genomic, patient-directed therapy is the new normal and the landscape of lung cancer management has changed for the better.

With Cancer, Don’t Ask the Experts

I was recently provided a video link to a December 2013 TEDx conference presentation entitled, “Big Data Meets Cancer” by Neil Hunt, product manager for Netflix. Mr. Hunt’s background has nothing to do with cancer or cancer research. His expertise is in technology, product development, leadership and strategy and has personally shepherded Netflix to its current market dominance. With his background and lack of expertise in cancer, he is an ideal person to examine cancer research from a fresh perspective.

The Long Tail of CancerMr. Hunt begins with a (admittedly) simplistic look at cancer research today. Because he is a data guy, naïve to all of the reasons why cancer cannot be cured, he can look anew at how it might be cured. Using a graphic, he defines cancer as “a long-tail disease” made up of outliers. He points out that most 20th century medical successes have been in the common diseases that fall close to the thick end of the curve. As one moves to the less common illnesses data becomes more scant. Echoing a new conceptual thinking, he points out that cancer is not a single disease but many, possibly thousands.  His concept is to accumulate all of the individual patient data to allow investigators to explore patterns and trends: a bottom up model of cancer biology. Many of his points bear consideration.

For those of you who have read these blogs, you know that I am an adherent to the concept of personalized cancer care. I have articulated repeatedly that cancer patients must be treated as individuals. Each tumor must be profiled using available platforms so that time and resources will not be wasted. We have used the same term “N-of-1” (a clinical trial for one patient) that Mr. Hunt uses in his discussion. He provides two anecdotes regarding patients who benefitted dramatically from unexpected treatment choices. His rallying cry is that contemporary clinical trials are failing. Again, this is an issue that I have addressed many times. He then describes broad-brush clinical protocols as the “tyranny of the average.”

The remainder of the discussion focuses upon possible solutions. Among the obvious hurdles:
1.    Cancer centers are hesitant to share data.
2.    The publication process is slow.
3.    Few are willing to publish negative trials.

To counter these challenges, he points out that small organizations are more incentivized to share and that successes in long-tail diseases can resurrect failed drugs, thereby repaying the costs. Several points were particularly resonant as he pointed out that early adopters face outsized resistance but their perseverance against adversity ultimately evolves the field. He sees this as a win-win-win scenario with patients receiving better care, physicians witnessing better outcomes, and pharmaceutical companies gaining more rapid approval of drugs.

As I watched, it occurred to me that Mr. Hunt was articulating many points that we have raised for over the last decade. As an outsider, he can see, only too clearly, the shortcomings of current methods. His clear perceptions reflect the luxury of distance from the field he is describing. Mr. Hunt’s grasp of cancer research is direct and open-minded. Many problems need fresh eyes. Indeed as we confront problems as complex as cancer it may be best not to ask the experts.

Truly Personalized Cancer Care

In the mid 1980s, it became apparent to me that cancer did not result from uncontrolled cell proliferation, but instead from the lack of cell death. Yet, cancer research labored for almost a century under the erroneous belief that cancer represented dysregulation of cell proliferation. Today, we confront another falsehood: the complexities and redundancies of human tumor biology can be easily characterized based on genomic analyses.

The process of carcinogenesis reflects the accumulation of cellular changes that provide a selective survival advantage to transformed cells.  However, the intricate circuitry that provide these survival advantages, reflect harmonic osolations between DNA, RNA and protein. Put simply, Genotype does not equal Phenotype. It is the phenotype that determines biological behavior and clinical response in cancer. Thus, it is overly simplistic to imagine that a DNA profile by itself can provide more than a fraction of the information required to make individual patient treatment decisions.

Colon cancer

Colon cancer

When therapies are based on genomic analysis, only a portion of the patient’s profile is taken into consideration. These analyses disregard the environmental, epigenetic and proteomic factors that make each of us individuals. Though useful prognostically and applicable in select circumstances where a unique genetic perturbation leads to a clinical response (c-ABL and Imatinib response in CML), genomic analyses provide only a veneer of information.

The Rational Therapeutics Ex Vivo Analysis – Programmed Cell Death™ (EVA-PCD) assay focuses upon the complexity of human tumors by measuring cell death, the end result of all cellular mechanisms of response and resistance acting in concert. By incorporating cell-cell, vascular, stromal and inflammatory elements into the tumor response assessment, the EVA-PCD platform provides a robust surrogate for human tumor response. While much of modern cancer research pursues the question of “Why” cancer arises, the clinical oncologist must confront the more practical question of “How” the best outcome can be achieved.

Assay-directed therapy is truly personalized cancer care providing treatments unique to the individual.


Reblogged from February 2010.


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