Cancer Patients Who Get Better, Get Better

JCO coverA study published in the October 20 Journal of Clinical Oncology (Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with Cetuximab, Piessevaux H. et al, 31:3764-3775,2013) described “early tumor shrinkage” as a predictor of long-term survival in patients with metastatic colorectal cancer. These Belgian and German investigators re-analyzed two large clinical trials in colon cancer, CRYSTAL and OPUS, to evaluate the impact of early tumor shrinkage at eight weeks of therapy. Both studies were in patients with wild type (non-mutated) KRAS colon cancer who received chemotherapy with or without the monoclonal antibody Cetuximab.

They used a cutoff of 20 percent tumor shrinkage at eight weeks to separate “early responders” from “non-responders.” Early responders were found to have a significantly better survival. The accompanying editorial by Jeffrey Oxnard and Lawrence Schwartz (Response phenotype as a predictive biomarker to guide treatment with targeted therapies, J Clin Oncol 31:3739-3741, 2013) examined the implications of this study.

The measurement of tumor response has been a lynchpin of cancer therapeutics for decades. This was later refined under what is known as RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Despite this, there remained controversy regarding the impact of early response on long term survival. The current Piessevaux trial however, is only the most recent addition to a long history of studies that established the correlation between tumor shrinkage and survival. Earlier studies in colorectal, kidney, esophagus and lung cancers have all shown that early response correlates with superior outcomes.

What is gratifying in the accompanying editorial is the discussion of the “response phenotype” as a predictor of survival. Phenotype, defined as “the set of observable characteristics of an individual resulting from the interaction of its genotype with the environment” reflects the totality of human biology not just its informatics (genotype). This renewed appreciation of tumor phenotype in oncology is important for it re-focuses on tumor biology over tumor genetics.

The  ex-vivo analysis of programmed cell death (EVA-PCD) that we utilize, is itself a phenotypic platform that measures actual cellular behavior, not gene profiles, to gauge drug sensitivity. We have previously shown that the measurement of chemotherapy effect on human tumor tissue predicts response, time to progression and survival. The current study used clinical response (early tumor shrinkage) to successfully measure the same.

This analysis of early response by Piessevaux is bringing our most sophisticated investigators back to what they should have known all along.
1. Responding patients do better than non-responding patients.
2. Early measurement of response is predictive of long term outcome.
3. These measurements can and should be done in the laboratory.

Taken together, the current study supports early tumor shrinkage and by inference, ex vivo analyses, as important predictors of patient response and survival.

Personalized Cancer Care: N-of-1

The New York Yankees catcher Yogi Berra famous quote, “Déjà vu all over again,” reminds me of the growing focus on the concept of “N- of-1.” For those of you unfamiliar with the catchphrase, it refers to a clinical trial of one subject.

In clinical research, studies are deemed reportable when they achieve statistical significance. The so-called power analysis is the purview of the biostatistician who examines the desired outcome and explores the number of patients (subjects) required to achieve significance. The term “N” is this number. The most famous clinical trials are those large, cooperative group studies that, when successful, are considered practice-changing. That is, a new paradigm for a disease is described. To achieve this level of significance it is generally necessary to accrue hundreds, even thousands of patients. This is the “N” that satisfies the power analysis and fulfills the investigators expectations.

So what about an N-of-1? This disrupts every tenet of cancer research, upends every power analysis, and completely rewrites the book of developmental therapeutics. Every patient is his or her own control. Their good outcome reflects the success or failure of “the trial.” There is no power analysis. It is an “N” of 1.

This “breakthrough” concept however, has been the underpinning of the work of investigators like Drs. Larry Weisenthal, Andrew Bosanquet, Ian Cree, myself and all the other dedicated researchers who pioneered the concept of advancing cancer outcomes one patient at a time. These intrepid scientists described the use of each patient’s tissue to guide therapy selection. They wrote papers, conducted trials and reported their successful results in the peer-reviewed literature. These results I might add have provided statistically significant improvements in clinical responses, times to progression, even survival. By incorporating the contribution of the cellular milieu into clinical response prediction, these functional platforms have consistently outperformed their genomic counterparts in therapy selection So why, one might ask, have the efforts of these dedicated investigators fallen on deaf ears?

I think that the explanation lies in the fact that we live in a technocracy. In this environment, science has replaced religion and medical doctors have abdicated control of clinical development to the basic scientists and basic scientists love genomics. It is no longer enough to have good results; you have to get the results the right way. And so, meaningful advances in therapeutics based on functional platforms have been passed over in favor of marginal advances based on genomic platforms.

There is nothing new about N-of-1. It has been the subject of these investigators compelling observations for more than two decades. Though functional platforms (such as our EVA-PCD®) are not perfect, they provide a 2.04 (1.62 to 2.57, P < 0.001) fold improvement in clinical response for virtually all forms of cancer – as we will be reporting (Apfel C, et al Proc ASCO, 2013).

It seems that in the field of cancer therapeutics “perfect is the enemy of good.” By this reasoning, good tests should not be used until perfect tests are available. Unfortunately, for the thousands of Americans who confront cancer each day there are no perfect tests. Perhaps we should be more willing to use good ones while we await the arrival of perfect ones. After all, it was Yogi Berra who said, “If the world was perfect, it wouldn’t be.”

A “Clinical Trial” Too Far

An interesting paper was published in the January 10 NEJM (Abiraterone in Metastatic Prostate Cancer with Previous Chemotherapy, Ryan et al). The study randomized 1,088 hormone-refractory prostate cancer patients to receive abiraterone plus prednisone, or placebo plus prednisone.

Abiraterone works by blocking the syntheses of testosterone (the critical survival factor for prostate cancer cells), both in the adrenal glands and within the tumor cells themselves. The drug had previously been approved for patients who had failed hormone therapy, but was only approved for those who had also failed Taxotere chemotherapy.

The results were so strongly positive in favor of the treatment arm, revealing a significant progression-free survival 16.5 versus 8.3 months (p < .001) and overall survival hazard ratio 0.75 (p = .01) that the monitoring committee invoked early stoppage rules. Virtually all of the other markers of disease also strongly favored the treatment arm. All of this speaks for an effective therapy in hormone-refractory prostate cancer and we applaud their success.

The question remains: Did we really need to conduct this study?

On a biochemical level, abiraterone represents an effective mechanism for androgen ablation. The drug has been established to work well in patients who have failed prior hormone and Taxotere chemotherapy. In that prior exposure to Taxotere would not be expected to substantively influence abiraterone efficacy, the wisdom of committing 1,088 hormone-refractory patients to a “placebo controlled” randomized trial to prove its efficacy in the Taxotere naive population seems questionable.

Prostate cancer generally afflicts older men. While most patients respond to hormonal ablation, hormone-refractory disease develops in virtually all patients over time. A comparatively mild oral therapy like abiraterone represents a demonstrably superior alternative to a comparatively toxic alternative intravenous cytotoxic drug like taxotere. Did we need to marshal a multi-million dollar trial to prove that abiraterone worked in people who had not received Taxotere, when there was absolutely no reason to believe that it wouldn’t?

The reason that this trial was conducted was to meet an increasingly onerous regulatory environment that demands that every use of every drug in every situation be proven with a large and enormously expensive clinical trial.

Registration trials cost between $10,000 and $20,000 per accrued patient. Using these figures, we can guess that this clinical trial cost between $10,000,000 and $20,000,000 to conduct. Those costs must now be recouped from patients and insurers. Thus, the very agency whose purpose is to protect patients and limit the inappropriate use of drugs has created an environment that adds to those expenses and it can be argued, prevents the appropriate use of drugs.

To put this into perspective, let’s examine the female counterpart – breast cancer. Once aromatase inhibitors showed activity in postmenopausal women, they were rapidly incorporated into clinical therapeutics. Dovetailing nicely with the established antiestrogen tamoxifen, these drugs became second line hormonal therapies. While these drugs naturally assumed their roles in hormonal management of breast cancer, no one would ever demand that a breast cancer patient with ER positive cancer first receive chemotherapy before being allowed to use the well-established aromatase inhibitors. Had the FDA demanded that no one could receive anastrozole, letrozole or Aromasin until they had had Adriamycin, there would have been a march on Washington to reverse the policy. It was obvious to all those engaged in the field that these drugs worked and that they would work at different points in hormonal management of the disease.

The physiology of and clinical experience in breast cancer management allowed smart scientists with the approval of the regulatory agencies to “crosswalk” the application of these important agents. It is time for the American public to demand that clinical trials be conducted (and resources allocated) when the questions they address can only be answered through the expenditure of these vast financial and human resources.

Looking Beyond Translation

An article in the May 3, 2012, New England Journal of Medicine, (NEJM) from the Mount Sinai School of Medicine and Mayo Clinic, examined the concept of translational research and its largely unfulfilled mission.  (Gelijns AC, Gabriel SC. Looking Beyond Translation – Integrating Clinical Research with Medical Practice. NEJM 2012; 366:1659–1661).  These investigators reviewed many of the precepts of clinical research and described mechanisms by which outcomes could be improved. Among the points they raised is the need to integrate clinical research with clinical practice to create “patient-centered, science-driven healthcare.”

Despite their academic credentials, Drs. Gelijns and Gabriel recognized that academic medical settings are not always conducive to conducting clinical research. They also describe the lack of incentives for clinical physicians to undertake research studies.  They go on to examine the need to refocus medical education onto a science of healthcare delivery. Finally, they decry the performance metrics by which clinical physicians are gauged (tests performed and numbers of patients seen) and contrast that with the equally unsatisfactory metrics for academicians (grants received and papers published). We couldn’t agree more.

While many of the points raised are worthwhile, these authors fail to grasp the fundamental problem at hand. Falling back on the age-old adage that pediatric malignancies have been cured through the clinical trial process, they criticize the adult oncology physicians for their lack of accrual. Their focus on participation in clinical trials as the highest accomplishment to which a medical oncologist might aspire is misguided and misleading. Grinding patients through ill-conceived clinical trials is no way to cure cancer. What are needed are intelligent solutions to complex problems. Complexity by its nature precludes the use of linear reasoning in the solution of problems. So complex is the cancer problem that investigators long since abdicated insights for statistical significance hoping that by throwing enough patients onto protocols, discernible patterns will emerge.

Childhood cancers have not been cured by protocols. They have been cured because they are curable. The average pediatric malignancy manifests a small number of mutational changes. Founder clones identified within these tumors can be eradicated even with the blunt instrument of contemporary chemotherapy. It is not an accident that childhood leukemia is curable, but instead a manifestation of the cells of origin.  Childhood ALL, the most common pediatric malignancy is a prime example. Hematopoietic elements by nature are good at dying. Chemotherapy just helps them along.

As we move from pediatric oncology to adult oncology however, we encounter a horse of a different color. There are the common adult tumors like colon and lung that have accumulated a myriad of perturbations over a lifetime of exposures and genetic errors. The pathway back to normality is fraught with hazards and the founder clones are often numerous and diverse.

To meaningfully advance cancer therapeutics we need wholly new conceptual frameworks that connect complex systems to available solutions. Analytic platforms that can reproduce human tumor biology in the laboratory will provide clinicians the targets for treatment, the results they seek and the incentive to participate in clinical trials.

The Unfulfilled Promise of Genomic Analysis

In the March 8 issue of the New England Journal of Medicine, investigators from London, England, reported disturbing news regarding the predictive validity and clinical applicability of human tumor genomic analysis for the selection of chemotherapeutic agents.

As part of an ongoing clinical trial in patients with metastatic renal cell carcinoma (the E-PREDICT) these investigators had the opportunity to conduct biopsies upon metastatic lesions and then compare their genomic profiles with those of the primary tumors. Their findings are highly instructive, though not terribly unexpected. Using exon-capture they identified numerous mutations, insertions and deletions. Sanger sequencing was used to validate mutations. When they compared biopsy specimens taken from the kidney they found significant heterogeneity from one region to the next.

Similar degrees of heterogeneity were observed when they compared these primary lesions with the metastatic sites of spread. The investigators inferred a branched evolution where tumors evolved into clones, some spreading to distant sites, while others manifested different features within the primary tumor themselves. Interestingly, when primary sites were matched with metastases that arose from that site, there was greater consanguinity between the primary and met than between one primary site and another primary site in the same kidney. Another way of looking at this is that your grandchildren look more like you, than your neighbor.

Tracking additional mutations, these investigators found unexpected changes that involved histone methyltransferase, histone d-methyltransferase and the phosphatase and tensin homolog (PTEN). These findings were perhaps among the most interesting of the entire paper for they support the principal of phenotypic convergence, whereby similar genomic changes arise by Darwinian selection. This, despite the observed phenotypes arising from precursors with different genomic heritages. This fundamental observation suggests that cancers do not arise from genetic mutation, but instead select advantageous mutations for their survival and success.

The accompanying editorial by Dr. Dan Longo makes several points worth noting.  First he states that “DNA is not the whole story.” This should be familiar to those who follow my blogs, as I have said the same on many occasions.  In his discussion, Dr Longo then references Albert Einstein, who said “Things should be made as simple as possible, but not simpler.” Touché.

I appreciate and applaud Dr. Longo’s comments for they echo our sentiments completely. This article is only the most recent example of a growing litany of observations that call into question molecular biologist’s preternatural fixation on genomic analyses. Human biology is not simple and malignantly transformed cells more complex still. Investigators who insist upon using genomic platforms to force disorderly cells into artificially ordered sub-categories, have once again been forced to admit that these oversimplifications fail to provide the needed insights for the advancement of cancer therapeutics. Those laboratories and corporations that offer “high price” genomic analyses for the selection of chemotherapy drugs should read this and related articles carefully as these reports portend a troubling future for their current business model.

Cancer Survivorship

Some of you may have read the January report from the American Cancer Society (ACS) that described a decline in U.S. cancer death rates by 1.8 percent per year in men and 1.6 percent per year in women during the period between 2004 to 2008.

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.

The TEDx Experience

On Saturday July 16, I had the opportunity to present at the TEDxSoCal conference held here in Long Beach. The overall theme for this event was “thriving,” and appropriately, I presented in the afternoon session called, “well-being.” My lecture was entitled “The Future of Cancer Research Lies Behind Us.”

I chose this topic in light of the growing recognition that genomic analyses are not providing the therapeutic insights that our patients so desperately need. As I have written before in this blog, the Duke University lung cancer gene program, which has received much attention recently, is emblematic of the hubris associated with contemporary genomic analytic platforms.

I reviewed the contemporary experience in clinical trials, examined the potential pitfalls of gene-based analysis, and described the brilliant work conducted by biochemists and cell biologists, like Hans Krebs and Otto Warburg, who published their seminal observations decades before the discovery of the double helix structure of DNA.

I described insights gained using our ex-vivo analytic platform, that lead to treatments used today around the world, all of which were initially discovered using cell-based studies. More interesting still will be the opportunity to use these platforms to explore the next generation of cancer therapies – those treatments that influence the cell at its most fundamental level – its metabolism.

Many attendees stopped me after my lecture to thank and congratulate me for my presentation. Fearing that my topic might have been too esoteric, I was delighted by the reception and more convinced than ever that there are many enlightened individuals who thirst for new approaches to cancer treatment. It is these people who will forge the next generation of therapy.

The Avastin Saga Continues

We previously wrote about bevacizumab (Avastin) and its approval for breast cancer. The early clinical trials revealed evidence of improved time to disease progression. This surrogate measure for survival benefit had, over recent years, gained popularity, as time to disease progression is a measure of the impact of a given treatment upon the patient’s response durability. It was hoped and believed that time to progression would be an early measure of survival.

Unfortunately, the survival advantage for the Avastin-based therapies in breast cancer has not met statistical significance. As such, careful review by the oncology drug committee of the FDA lead to a unanimous decision to remove Avastin’s indication in breast cancer. Avastin has not been removed from the market, but instead, cannot be promoted or advertised, nor do insurers necessarily reimburse it. This decision, however, will have a very big impact on Medicare patients and many others who are in managed care programs (HMOs).

There are no villains here. Instead, dedicated physicians empowered to scrutinize the best data could not prove beyond any doubt that the drug improved survival. The time to progression data was favorable and the survival data also trended in a favorable direction. But, the final arbiter of clinical approval — statistically significant survival — was not met.

The physicians who want to provide this for the patients, the company that produces the drug and the patients who believe it offers benefit all have legitimate positions. As Jerome Groopman, MD, once said, in a similar situation with regard to the FDA approval of interleukin 2 (a biological agent with profound activity in a small minority of melanoma and renal cell cancer patients), “I am confronted with a dilemma of biblical proportions, how to help the few at the expense of the many.”

The Avastin saga is but one example of what will occur repeatedly. The one-size-fits-all paradigm is crumbling as individual patients with unique biological features confront the results of the blunt instrument of randomized clinical trials. Our laboratory has been deeply involved in these stories for 20 years. When we first observed synergy for purine analogs (2CDA and fludarabine) with cytoxan, and then recommended and used this doublet in advanced hematologic malignancies (highly successfully, we might add) we were a lone voice in the woods. Eventually, clinical trials conducted at M.D. Anderson and other centers confirmed the activity establishing these treatments as the standards of care for CLL and low-grade lymphoma.

The exact same experience occurred in our solid tumor work when we combined cisplatin plus gemcitabine in pancreatic, ovarian, breast, bladder, lung and other cancers. While our first patient (presumably the first patient in the world) received cisplatin plus gemcitabine for drug-resistant recurrent ovarian cancer in 1995 — providing her an additional five years of life — it wasn’t until 2006 that the FDA approved the closely related carboplatin plus gemcitabine for this indication.

We now confront an even greater hurdle. With our discoveries, using novel combinations of targeted agents, we are years (perhaps decades) ahead of the clinical trial process. We know that patients evaluated in our laboratory with favorable profiles can respond to some of the newest drugs, many of which have already completed Phase I of clinical trials. It is our fervent belief that we could accelerate the drug development process if we could join with the pharmaceutical companies and the FDA to put these hypotheses to a formal test.

Again, there are no villains here. Patients want, and should, receive active drugs. Doctors should be allowed to give them. The drug companies want to sell their agents and the FDA wants to see good therapies go forward.

The rancor that surrounds these emotionally charged issues will best be resolved when we introduce techniques that match patients to active therapies. We believe that the primary culture platform used in our laboratory, and a small number of dedicated investigators like us, may be the answer to this dilemma.

We will redouble our efforts to apply these methods for our patients and encourage our patients to lobby their health care insurers and representatives to sponsor these approaches. To date, we have been unsuccessful in convincing any cooperative group to test the predictive ability of these selection methodologies. In response, I reiterate that I will gladly participate and, to the best of my ability, support at least the laboratory component of any fair test of our primary culture methodologies.

We stand at the ready for the challenge.

Targeted Therapies — The Next Chapter

Within this blog, we have intermittently reviewed the concept of targeted therapies. To reiterate, these are classes of drugs that target specific pathways considered tumorigenic. Among the pathways initially targeted were the epidermal growth factor receptor and the closely related HER2. Shortly after the introduction of EGFr and HER2 directed therapies came the development of drugs that target another critical pathway, mTOR.

Hundreds of compounds are now under development intended to more accurately hone in on the pathways of interest in patients’ tumors. Regrettably, the medical community continues to apply old clinical trial methods to this newest era of drugs. While the selective application of drugs like: Tarceva for EGFR mutants, Herceptin for HER2 over-expressers, and Crizotinib for EML4-ALK mutants, are much more effective in patients with these gene expressions, these are a select few examples of linear thinking that bore fruit.

That is, this gene is associated with this disease state and can be treated with this drug.

Many, if not most cancers will prove to be demonstrably more complicated. Genomic trials can only succeed if we first know the gene of interest and second know that its (over) expression alone is pathogenetic for the disease entity. Even meeting these conditions is likely to result in comparatively brief partial responses due to the crosstalk, redundancy and complexity of human tumor signaling pathways — the “targets” of these new drugs.

To address these complexities, functional analytic platforms that examine outcomes, not targets, are needed. This bottom-up approach has now enabled my team to explore the activity of novel compounds. When investigators develop interesting “small molecules,” we examine the disease specificity, combinatorial potential and sequence dependence of these compounds in short-term cultures to provide meaningful insights that can then be addressed on genomic and proteomic platforms. This reduces the time required to take these new agents from bench to bedside. We cannot solve tomorrow’s questions using yesterday’s mindsets

The I-SPY 2 Clinical Trial

For those of you who read the Wall Street Journal, an article appeared in the Friday, October 1 issue that described the I-SPY 2 (investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2) clinical trial. This is an adaptive phase II trial designed to facilitate the introduction of new forms of therapy into clinical practice.

The reporter presents the trial as a dramatic advance, suggesting that the era of “personalized care” is finally upon us. I applaud the intent of a trial to apply “window therapy” (i.e. using the window of time before definitive intervention to introduce and test new therapies) to facilitate drug introduction. However, despite the author’s enthusiasm, the design and application of this trial is demonstrably less than meets the eye.

I-SPY2 uses several molecular markers and established prognostics in conjunction with a new molecular profile (mammaprint) to subgroup candidates prior to randomization. The randomization then allows patients to receive either a standard treatment, or one of five investigational drugs combined with standard agents. Sophisticated imaging technologies are used as surrogates for clinical response, while additional biopsies will provide insights into genomic events.

What this trial does not do is utilize molecular markers (beyond those already available to most clinicians) to select patients for therapy. As such, despite the WSJ author’s glowing review, the trial is, at its core, a randomized selection of candidates. While it may enable the investigators to interrogate the tissue biopsies to answer scientific questions of interest, it does so with no immediate benefit to the patients who participate. Indeed, patients who gain benefit (after being randomized to the investigational arm and then receiving a new combination that actually works) receive said benefit by what could best be described as blind luck. The suggestion that this is “personalized care” falls flat when one realizes that a good outcome is nothing more than a chance event!

Truly personalized care represents the application of validated predictive models to select candidates for specific therapies. Good outcomes can then be ascribed to the intelligent selection and application of effective treatments. The cancer research community’s single-minded focus on genomic platforms, to the exclusion of functional platforms, forces patients to continue to participate in “randomized” trials to test hypotheses of interest to the investigators, largely at the expense of the patients in need. These types of advances could be more rapidly made utilizing functional profiles, such as the one offered at Rational Therapeutics.

What these genomic investigators are expecting their patients to say to them is “You may not be able to treat me any better, but I like the way you think.” What informed patients should be saying instead is, “I don’t care how you think. I want you to treat me better!”