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As always, the goal of medicine is to discover the cause and remedy of disease so as to cure, control, or minimize its adverse impact against our quality of life and survival. Though we have known for some time that cancer is fundamentally a disease of genes that control growth, maturation, and senescence, recent breakthroughs in molecular diagnosis pertaining to next generation DNA sequencing (NGS) are providing an unprecedented look at the drivers or oncogenes that activate abnormal cell growth in the clinic.

Decoding Cancer: From Genetic Variations to Precision Medicine

The genetic code forms the template instructions for synthesizing proteins that regulate all the biological activities in our cells. Variations in the spelling of the genetic code in the form of mutations, deletions, insertions, or altered gene expression can either activate oncogenes in a way that causes cancer; or inactivate tumor suppressor genes thereby removing the brakes that prevents the malignant process from occurring. Molecular diagnosis identifies the unique elements causing the malignant phenotype.

Precision medicine refers to specific strategies to address those problems, namely to target the proteins involved as drivers or the pathways that are causing resistance. Reaching beyond the basics of diagnosis and prognosis, theranosis refers to the use of biomarkers to determine which drugs or supplements have the greatest likelihood of working based on identifying their targets and the signaling pathways involved in drug resistance.

Cancer is characterized as a collection of aberrations involving 10 hallmarks[1] of cell biology, leading to:

  • uncontrolled proliferation, or self-sufficient growth
  • blockade of apoptosis, or the interruption of normal cell death
  • unlimited replicative capacity, or immortalization and blockade of sensecence
  • failure to respond to inhibitory growth signals, or tumor suppressors
  • angiogenesis, or the capacity to grow new blood vessels
  • invasion and metastatic spread in the body
  • inflammation promoting tumor growth
  • genome instability and mutation
  • deregulation of cellular energy, or the metabolic switch to burning glucose under aerobic conditions
  • evasion of the immune response

Unveiling the Therapeutic Landscape: From Molecular Diagnostics to Personalized Immunotherapy

Dr. Michael Castro, MD

In the next hallmark iteration, we might expect to see epigentic dysregulation of gene expression, and susceptibility to cytotoxic agents. At the same time, there are about 12 - 13 pathways that generate the elements of the malignant phenotype. In the genomic revelation of disease, that’s all there is. Cancer is no more and no less. Molecular diagnostics informs us precisely which genes in which pathways that govern cellular behavior have gone awry. Armed with this knowledge, physicians can determine what tools in the therapeutic armamentarium are most likely to have an impact against an individual’s cancer. While oncology still lacks drugs for many genetic abnormalities, the mechanisms driving a particular type of cancer are now understood in ways that make drug development a rational undertaking. On the other hand, for individual patients, oncologists can often see exactly what must be done to treat their patients’ diseases- no more guesswork. For example, the recent elucidation of NTRK fusions driving cancer has led to the development of drugs with exceptional efficacy for patients with these subtypes of disease. Accordingly, there is a new a therapeutic imperative to check for whether any given patient’s cancer is being caused by one of these fusions. In another example, we can now understand which cancers will respond to immunotherapy, why a cancer stops responding, and we are able to dissect the mechanisms of immune tolerance of cancer. As such, the emerging field of immunomics will be indispensable for identifying which strategy will overcome the barrier to successful immunotherapy. Moreover, unique mutational signatures from individual cancer's may soon lead to personalized neo-epitope vaccines that will elicit long lasting, potentially permanent anti-tumor responses based on immunizing the patient against their cancer.

Beyond Body Parts: Genomic Insights Transform Cancer Classification

With the revolution in understanding malignancy supplied by genomic insight, cancer acquires another level of classification, not so much by what part of the body it starts in, but by the molecular mechanism driving the cancer. Perhaps the biggest revelation of genomic medicine is that diseases like colon, stomach, or breast cancer (to name but a few) once thought to represent one disease have many underlying subtypes that respond to different therapies.

Therefore, the one-size-fits-all approach to treatment appears to have been based on an incredibly naive assumption: that for the sake of treatment everyone has the same disease. The truth turns out to be far different. The former view that “Nothing matters much, few things matter at all in cancer” turns out to be a falsehood based in ignorance, chiefly the historical ignorance that until a decade ago there were no clinically or commercially available genomic tests beyond individual markers.

Now we have an explosion of diagnostic options in the clinic fostered by rapid commercialization and the falling cost of the technology. In 2017, whole genome sequencing (WGS) in oncology may emerge for a few thousand dollars. And while not every patient needs WGS, the costs of smaller panels are a small fraction of the cost of the drugs used to treat cancer.

Revolutionizing Cancer Treatment

Often capitalizing on the differences between one cancer and the next has provided the greatest strides achieved against certain cancers. The paradigm successes of modern oncology are built on the bedrock of defining these differences and the genomic technologies that allows us to do so. In the old controversy between the lumpers and the splitters, the splitters have it. The lumpers who prefer simplicity and reductionist approaches to disease are ill-suited for careers in oncology, and the lumpers in practice are for the most part unhappy and overwhelmed by the explosive growth of genomic insights, and the ever-greater complexity of patient management. But there is no stopping the Niagra - previously unknown drivers create new therapeutic possibilities for patients and lead to historically unprecedented outcomes in controlling cancer and improving survival.

Mechanisms that cause resistance to one strategy can be identified and in principle overcome. Ignorance of genomics may cost the patient their life. Not only will certain drugs that may cure one patient have no activity at all for another person with the same cancer, but there are many circumstances where medicine can shorten the survival of a patient when given to the wrong patient - one man’s medicine may be another's poison.

For the most part, it is not an exaggeration that if a patient has not gotten a molecular diagnosis of their cancer, that patient has not received the most important part of the evaluation, and the correct treatment might well be forfeited in the process.

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Challenges and Opportunities in Oncology's Genomic Evolution

The heterogeneity among patients with a given cancer poses steep new challenges to the study and treatment of the disease. For example, the uncommon subtypes of a common disease such as lung cancer amounts to a group of many rare or uncommon conditions. This makes it harder to test new treatment hypotheses. Even more challengingly, mutations in one part of a gene may confer responsiveness to a given drug, but in another part of the same gene, a different mutation generates no benefit at all. The explosion of new insights also creates new challenges for physicians to remain abreast in the field. Not least, the old business model of giving everyone the same drugs to generate huge profits for the pharmaceutical industry is also in need of change to a business model where profits can be developed from developing drugs in a group of smaller but far more numerous niche markets. No less, the regulatory hurdle of drug approval is still chained to the past and could evolve much more quickly into approving molecular indications rather than disease site indications. Just as the laws of physics are the same everywhere, pathway aberrations across multiple cancers tend to be pathogenic wherever they are found with relatively few caveats. Is it really cost effective to test the same treatment hypothesis in 40 different disease types once the drug is on the market? Not least of all, the refusal of the insurance industry to pay for molecular diagnostics and off-label drug use for agents identified in the course of profiling a patient’s cancer is not only a tragedy of denying access to lifesaving treatments for the patient, but one of the great recalcitrant, shortsighted, and inefficient (shall we stay bluntly - stupid) uses of resources of our time. It is not that precision medicine will only add to the cost of care; it will eliminate an enormous amount of ineffective and outrageously expensive drugs in patients that cannot benefit from them. All these challenges create terrific resistance to and inertia for the development of precision medicine.

To those who resist the genomic evolution of oncology, two points deserve consideration. First we cannot return to the naïve assumption that cancer is a single disease for which there will be one best treatment. The clinical trials that are so intent on proclaiming a winner and a loser are guilty of simpleton errors.

  • Simpleton error #1: drugs (the winners) will be given to patients for whom they offer no benefit and only toxicity and waste of health resources,
  • Simpleton error #2: drugs (the losers) that work for the minority are discarded because of poor trial design and patients who would have been helped never get access to the drugs that make a profound difference, representing incredible lost opportunities.

Second point to the naysayers: the achievements in oncology in the pre-genomic era plateaued with such incrementally small improvements, no one can deny that the treatment of cancer remains woefully inadequate. To meet the challenge of tumor heterogeneity now means that we master the differences between patients, and capitalize on those in our approach to therapeutics. As a field, we have enormous potential to improve cure rates by bringing molecular diagnosis and precision medicine to the adjuvant setting. The longer we resist doing this, the longer we go on failing our patients, employing decades old approaches with still impressive failure rates. It is not that the existing standards of care of accomplished nothing, but that so much of the remaining chasm can now be conquered. Measure everything, discover something, make a difference. It's sounds like an elevator pitch for precision medicine, but it is also our obvious mandate.

Embracing Molecular Diversity in Cancer Treatment

In the process, cancer treatment furthers its departure from the hit and miss approach where patients were assumed to be the same and only minimal improvements in survival were identified. In oncology, the difference between cancers have turned out to be more important than the similarities. Even now when a breast cancer patient is classified as having HER2 positive disease, further studies of the genomic changes tell us why some patients respond fabulously well to Herceptin, while others barely at all. Now armed with insight into Herceptin resistance, we can strategize in specific ways what remedies are most likely to work for a given patient.

A few commentators have cautioned against thinking of precision medicine as a panacea. There is some truth in those critiques. After all, the field has only just begun to explore the genomic underpinnings of cancer. The diagnostic tools employed in this approach are also developing at a terrific rate. Yesterday's FDA-approved companion diagnostic test may already be antiquated for finding all the variants that respond to a given drug. Yesterday, we had only genome (DNA), today we have the transcriptome (RNA) as well, and it may take years for transcriptomic insights to mature. On the other hand, we don’t yet have all the targeted drugs we need, as some molecular drivers remain un-drugable for the moment. Finally, we will need dedicated study, better agents, innovative trial design, and lots of patience to learn how to treat multiply aberrant pathways effectively and with tolerable side effects.

Shedding Light on Oncology: Embracing Molecular Precision

Nevertheless, the time has emerged, when we can peer into a particular cancer’s molecular underpinnings and see precisely what is going on. The standard of care in oncology if not all of medicine is an evolving historical process, informed by discovery and treatment breakthroughs, but never beyond critique of its intrinsic limitations.

In oncology, the standard of care has been based mostly on marginal improvements evolved with a molecular blindfold. We now have the option to embrace the historical moment with every patient we see to identify the molecular Achilles heel lurking in their cancer, or the resistance pathway we may be able to do something about.

With the continued development of molecular insight, oncology has finally arrived at the starting line, the point of working with the lights on, and no longer in the dark, blindly trying the next thing to see what works. To borrow the quote from Mal Pancoast, “The odds of hitting your target go up dramatically when you aim at it.” Genomic medicine removes the blindfold. As a result, the ability to take aim and the promise of curing cancer has never been more within reach. Precision medicine is not just an option, but the new theranostic imperative.

[1] Hanahan A and Weinberg RA. The Hallmarks of Cancer: The Next Generation. Cell 2011, 144(5):646-74.

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