A brief reflection on death and resurrection

If there is one universal truth about all life, from the gigantic dinosaurs to the microscopic DNA strands making up a virus, is that it will all eventually die. Death lurks over life as a constant shadow. In fact, the “dying process”, a process of increasing entropy, starts the moment life itself begins. However, no living creature other than humans has to endure their life with this deep-rooted and primal anxiety that life is evanescent, a brief candle of individual conscious awareness with dark voids of nothingness extending to the remote past and infinite future.

Of course, most of us, in the service of sanity, don’t fixate on our inevitable death. We go about the world focused on worldly concerns. We accept the inevitable and direct our energies to the mundane chores of living. Yet the recognition that our time is finite is always lurking deep within each of us, helping to shape the choices we make, the stories we tell ourselves and the physical and the spiritual monuments we create as a species.

From artistic exploration to scientific discovery to religion, pursuits that truly separate us, humans, from all other species are our attempts to turn our ephemeral life into personal and collective immortality. Jean-Paul Sartre once noted, “life itself is drained of meaning when you have lost the illusion of being eternal.”  So, it is no surprise that across cultures and through the ages, we have placed such a significant value on permanence.

Our dichotomy of an incredibly nimble mind in a fragile body has been beautifully captured by Ernest Becker who suggested “we humans live under constant existential tension, pulled toward the sky by a consciousness that can soar to the heights of Shakespeare, Beethoven, and Einstein but tethered to earth by a physical form that will decay to dust; Man is literally split in two: he has an awareness of his own splendid uniqueness in that he sticks out of nature with a towering majesty, and yet he lives with an awareness that one day he will go back into the ground to rot to nothingness.” 

According to Becker, we are compelled by such awareness to deny death the capacity to permanently erase us. We soothe the existential yearning through a commitment to family, a team, a movement, a religion, a nation—constructs that will outlast the individual’s allotted time on earth. Others leave behind creative expressions, artifacts that extend the duration of their presence symbolically. “We fly to Beauty,” said Emerson, “as an asylum from the terrors of finite nature.” Once the domain of the Pharaohs who could afford to build pyramids or the supremely gifted who could conjure timeless art or everlasting equations, now even ordinary mortals like us could attempt at this "virtual immortality" thanks to modern technology. 

Across the millennia, one consequence of our mortality awareness has been a widespread fascination with all things, real or imagined, that touch on the timeless. From prophecies of an afterlife to teachings of reincarnation, we have developed strategies to contend with knowledge of our impermanence and, offer hope for permanence.

What’s unique now in our age is the remarkable power of science to tell a lucid story not only of the past, back to the Big Bang but also of the far future. What is also unique is that unlike our pre-scientific ancestors who thought of the universe – the sun, the planets, and the distant stars - as eternal, modern physics have taught us that even such heavenly bodies – from planets to stars, solar systems to galaxies, black holes to swirling nebulae share with us in their impermanence. While for us humans the time allotted is measured in decades, for stars and planets they are in the billions of years, yet they also perish as surely as we humans do. In fact, the basic stuff that makes up matter itself would disintegrate once the decay of the proton starts, which is calculated to happen in 10³⁵ years, a duration so long, it is meaningless for us humans, but this puts an upper bound on how long intelligent life could exist in the universe, even theoretically.  Moreover, even space-time could disintegrate in the very far future. The fact that even those majestic and heavenly bodies, even matter and space-time itself share our impermanence is at once comforting, and terrifying. 

One of the more uplifting stories from the Hebrew Bible is that of the resurrection of Jesus, being celebrated today throughout the world as Easter. The power of the story of life triumphing over death is immense and timeless and often repeated throughout human history and across various cultures. And this year, we are also going through a global pandemic that is sowing death and destruction around the world. So the resurrection story is an especially powerful reminder this year and takes on an added significance on how the human mind, when faced with existential threats, still could come up with such a hopeful and uplifting narrative to give meaning to existence.

References

1) Being and Nothingness: Jean-Paul Sartre
2) The Denial of Death: Ernest Becker
3) Ode to Beauty: Ralph Waldo Emerson
4) The Greatest Story Ever Told: Lawrence M. Krauss

Update on Cancer Immunotherapy and Immuno Oncology

The past several years have been a particularly optimistic period for immuno-oncology. The first approval of modern cancer immunotherapy was interferon-alpha in 1986 for hairy cell leukemia, and later for chronic myelogenous leukemia, follicular non-Hodgkin lymphoma, melanoma, and AIDS-related Kaposi’s sarcoma (1) Several other agents have been approved since then, but a transformation in the landscape of Immuno Oncology (IO) started with the approval of ipilimumab—a checkpoint inhibitor targeting cytotoxic T-lymphocyte antigen 4 (CTLA- 4) for advanced melanoma in 2011(2) 

Since then there has been an explosion of agents that work by enhancing body’s immune response to cancer. As of this writing there has been 26 immunotherapies approved in various cancers, and 17 types of cancer have at least one approved immunotherapy as a treatment option. 

Image 1: Approved Immuno Oncology agents against cancer. (Courtesy: Annals of Oncology)

In the past 3 years alone, five new checkpoint inhibitors (targeting PD-1 or PD-L1), two new cell therapies (targeting CD19), and one new CD3-targeted bispecific antibody (also targeting CD19) have been approved (3-6). Below is a brief summary of the clinical and scientific update on these exciting new class of molecules which has shown remarkable activity across a wide array of cancer types. 

Checkpoint inhibitors 

Immune cells navigate the body looking for anything that does not belong—bacteria, viruses, and even cancer cells. They do so by using their molecular receptors to scan for foreign molecules that intruder cells display on their surface. Once an intruder is detected, a class of immune cells, known as cytotoxic T cells, move in to eliminate it. Unfortunately, cancers have a number of ways to hide from immune cells and avoid their attack. One of the most successful classes of Immuno Oncology uses drugs that are known as immune checkpoint inhibitors.

“Check points” are certain proteins that down regulate the immune system, acting as a “break” and examples include the protein PD-1 (programmed cell death protein 1), PD-L1 (programmed death-ligand 1), PD-L2 (programmed death-ligand 2), and CTLA-4 (cytotoxic T-lymphocyte antigen 4 (CTLA-4). Why do our body need these “check points” that down regulate our immune system? Because body has to work hard to suppress its own immune reactions most of the time. The immune system has enough arsenal that it can kill us faster than whatever ails us, and in healthy individuals, these immune checkpoints prevent autoimmunity. 

Many Cancers have unfortunately learned to exploit this check point pathways so it will be spared from destruction by the immune cells. The immune check point inhibitors are monoclonal antibodies against these “check points”, which work by taking “the brakes off” the immune system. Checkpoint-blockade immunotherapy has hence been the most exciting advance made in cancer treatment in recent years and has now become a new arsenal in the fight against several cancers, often showing dramatic response even in advanced stages.

The science behind Immune Oncology:

It has been known for decades that immune surveillance is critical against the development of various malignancies and patients with impaired immune system are at high risk for the development of cancer. It has also been known for more than 50 years that the human immune system has the potential to be a very powerful anticancer therapy. Part of the rationale for doing bone marrow transplantations was to give the patient a new immune system, which could help fight the patient’s cancer, with the so called graft versus leukemia / lymphoma effect, and that’s where so much interest in cellular immunotherapy originated.

In many cancers, oncogenesis is accompanied by the accumulation of mutations, which can provide a selective advantage to populations of cancer cells by increasing their degree of genetic diversity and accelerating their evolutionary fitness. Yet this diversity comes at a cost to the cancer cell: the further a cancer cell diverges from a normal cell, the more likely it is to be recognized as foreign by the immune system. Although long considered a possibility, it has been demonstrated only in the past five years that the mutational burden of tumors contributes to immune recognition of cancer and that it may, at least partly, determine a person’s response to cancer immunotherapy (7)

The role of the immune system in cancer remained unappreciated for many decades because tumors effectively suppress immune responses by activating negative regulatory pathways (above described checkpoints) that are associated with immune homeostasis or by adopting features that enable them to actively escape detection (8) Two such checkpoints, cytotoxic T-lymphocyte protein 4 (CTLA4) and programmed cell death protein 1 (PD-1), are the most studied so far. 

CTLA4 is a negative regulator of T cells, essentially acting as a break on T-cell activation.  The cell-surface receptor PD-1 is expressed by T cells on activation during priming or expansion and binds to one of two ligands, PD-L1 and PD-L2. Many types of cells can express PD-L1, including tumor cells and immune cells after exposure to cytokines such as interferon (IFN)-γ; however, PD-L2 is expressed mainly on dendritic cells in normal tissues. Binding of PD-L1 or PD-L2 to PD-1 generates an inhibitory signal that attenuates the activity of T cells. 

Both CTLA4 and the PD-1/PD-L system thus acts as “immune check points”, or “breaks” in the host immune response. Although it was found that blocking these check points can elicit antitumor response in mice as early as 1996 (9) it has been only in the last couple of years its role and significance found in humans. But once this flood gate has been opened, the development has been swift, and more marked than the development of any dug class against cancer. And response have been observed across a wide variety of cancer types, unlike traditional targeted therapies where the effect is often limited to a small subset of patients. (10) 

Even more importantly, the responses are often durable, lasting years or indefinitely, and occur without causing serious toxicity in most people. These results suggest that many people with cancer have pre-existing T-cell mediated immunity that is restrained by the PD-L1/PD-1-induced suppression of T cells. They also emphasize the role of immunosuppression as a main impediment to the series of steps that is required for effective anticancer responses — the cancer–immunity cycle (11) 

Figure 2: Cancer Immune Phenotype (Image Courtesy: Nature)

Anticancer immunity in humans can be segregated into three main phenotypes: the immune-desert phenotype (brown), the immune–excluded phenotype (blue) and the inflamed phenotype (red). Each is associated with specific underlying biological mechanisms that may prevent the host’s immune response from eradicating the cancer. A tumor that is characterized as an immune desert can be the result of immunological ignorance, the induction of tolerance or a lack of appropriate T-cell priming or activation. Immune-excluded tumors may reflect a specific chemokine state, the presence of particular vascular factors or barriers, or specific stromal-based inhibition. 

Inflamed tumors can demonstrate infiltration by a number of subtypes of immune cells, including immune-inhibitory regulatory T cells, myeloid-derived suppressor cells, suppressor B cells and cancer-associated fibroblasts. Tumor-infiltrating lymphocytes that express CD8 may also demonstrate a dysfunctional state such as hyper exhaustion. Tumor cells in inflamed tumors can also express inhibitory factors, down regulating MHC class I molecule expression or other pathways that de-sensitize them to anticancer immunity. 

The profile that responds best to immunotherapy are the so called immune-inflamed phenotype (Figure 2 above), which is characterized by the presence in the tumor parenchyma of both CD4- and CD8-expressing T cells, often accompanied by myeloid cells and monocytic cells; the immune cells are positioned in proximity to the tumor cells. (12) This profile suggests the presence of a pre-existing antitumor immune response that was arrested — probably by immunosuppression in the tumor bed. 

The second profile is the immune-excluded phenotype, which is also characterized by the presence of abundant immune cells. However, the immune cells do not penetrate the parenchyma of these tumors but instead are retained in the stroma that surrounds nests of tumor cells. The stroma may be limited to the tumor capsule or might penetrate the tumor itself, making it seem that the immune cells are actually inside the tumor. After treatment with anti-PD-L1/ PD-1 agents, stroma-associated T cells can show evidence of activation and proliferation but not infiltration, and clinical responses are uncommon. These features suggest that a pre-existing antitumor response might have been present but was rendered ineffective by a block in tumor penetration through the stroma or by the retention of immune cells in the stroma. T-cell migration through the tumor stroma is therefore the rate-limiting step in the cancer–immunity cycle for this phenotype. (13)

The third profile, the immune-desert phenotype, is characterized by a paucity of T cells in either the parenchyma or the stroma of the tumor. Although myeloid cells may be present, the general feature of this profile is the presence of a non-inflamed tumor microenvironment with few or no CD8-carrying T cells. Unsurprisingly, such tumors rarely respond to anti-PD-L1/PD-1 therapy. This phenotype probably reflects the absence of pre-existing antitumor immunity, which suggests that the generation of tumor-specific T cells is the rate limiting step. The immune-desert phenotype and the immune-excluded phenotype can both be considered as non-inflamed tumors.

Predicting response to immunotherapy:

The immune-inflamed phenotype correlates generally with higher response rates to anti-PD-L1/PD-1 therapy, which suggests that biomarkers could be used as predictive tools. Most attention has been paid to PD-L1, which is thought to reflect the activity of effector T cells because it can be adaptively expressed by most cell types following exposure to IFN-γ6, (14). In an increasingly large clinical data set, it is becoming clear that the expression of PD-L1 in pretreatment biopsies facilitates enrichment with people who are most likely to respond to antibodies against PD-L1 or PD-1. PD-L1 expression also correlates strongly with various markers of active cellular immunity, including IFN-γ, granzymes, CXCL9 and CXCL10. The presence of these biomarkers or others such as T cells that carry the CD3 antigen or tumor mutational burden may also enrich for responders. When used in combination with PD-L1 expression, these biomarkers may enhance predictive power (15)

As described previously, it is probable that the mutation burden of a given tumor will contribute to its immune profile with clearest association demonstrated between response and overall mutational burden. The greater the number of mutations in a given tumor, the more probable it is that some of the mutations will be immunogenic, providing targets for T-cell attack (16). Mutations that arise early in oncogenesis and are shared by almost all of the cancer cells in an individual (known as truncal mutations) may generate more effective anticancer T-cell responses than mutations that arise later on and are limited to only a subpopulation of cancer cells (known as branch mutations)

The importance of the cancer–immune set point

The cancer–immune set point is the threshold that must be overcome to generate effective cancer immunity. The set point can be understood as a balance between the stimulatory factors (Fstim) minus the inhibitory factors (Finhib), which together must be equal to or greater than 1, over the summation of all T-cell antigen receptor (TCR) signals for tumor antigens. The cancer–immune set point is shown as: 

∫ (Fstim) − ∫ (Finhib) ≥ 1 ∕ ∑ n=1, y (TCRaffinity × frequency)   (17)

It is probable that –immune set point of a particular person is already determined by the time of clinical presentation, driven by the inherent immunogenicity of the tumor and by the responsiveness of the individual’s immune system. Although it is reasonable to assume that various lines of cancer therapy or changes in environmental factors might alter Fstim and Finhib, such changes might only be transient. 

Often, the set point that is identified using pretreatment biopsies is similar to the set point determined by biomarker profiling from biopsies taken on progression after therapy. Likewise, despite the continued accumulation of mutations in a tumor as a function of time, primary and metastatic lesions can exhibit similar immune profiles. The features that determine the set point may therefore reflect genetic factors that are specific to a given tumor, the genetics of the person with cancer, or the extent to which antitumor immunity had developed initially. 

Although largely conceptual, the idea of a set point provides a framework to help organize the torrent of clinical and biomarker data that will emerge over the coming months and years. The number of targets that could prove effective for cancer immunotherapy is great; the number of potential combinations of therapeutic agents that are directed against these targets (or combinations of such agents with conventional standard-of-care agents) is even greater. The development of some cancer therapies may be largely empirical, but it can be guided by considering, even in general terms, the elements that comprise cancer immunity.

Adoptive cellular Immunotherapy:

Apart from immune check point inhibitors, another area of rapid development in immune oncology has been the use of CAR-T cells.  Adoptive cell immunotherapy boosts the body’s immune defenses against cancer in a completely different way—by genetically re-engineering a patient’s own immune T cells. It was Dr. Carl June and team from University of Pennsylvania who was the first to experiment with genetically reprogramming T cells, now known as CAR T cells. (18)

CAR T cells are custom made to work against the cancer in each individual patient. To create these cells, researchers collect immune T cells from the patient and insert an artificial gene into the cells. The gene is designed to endow T cells with chimeric antigen receptors that can detect unique molecules on cancer cells after CAR T cells are multiplied in the laboratory and injected back into the patient. In essence, CAR T-cell therapy is both a gene therapy and an immunotherapy.

When the CAR T-cell receptor attaches to a molecule on a cancer cell, it sends a signal to turn on the destruction machinery of the T cell. Unlike traditional cancer treatments, this living therapy needs to be given to the patient only once, because CAR T cells continue to multiply in the patient’s body. As a result, the anticancer effects of CAR T cells can persist and even increase over time.

Challenges

Immuno Oncology brings its own unique set of challenges. Selecting the appropriate patients for the highly expensive therapies are still not completely well defined. While markers like PD-L1 expression can act as a good predictor of response, the predictive value varies between various tumor types. While the response to these drugs could be dramatic some time even in terminally ill patients, the exorbitant cost prevents its use more widely in deserving patients. Not all patients respond to these medications, and in a sub group of patients the cancer cells could become resistant after a period of initial response. The mechanisms of resistance remains an active area of intense research but as of this writing clinical options for patients who progress on immunotherapy remains limited. (19)

Immunotherapy drugs also come with a unique set of side effects, and clinicians should familiarize with these often unusual side effects so that it could be recognized early, as some of the side effects could be serious, even fatal (20) 

Another challenge for future drug development is the identification of the appropriate targets on cancer cells.  The problem with many cancers is that they are too close to self and there aren’t easily identifiable target antigens that allow you to apply immune therapy without off-target toxicity. It is quite possible that over the next 5 to 10 years, some of the biggest advances will come from identifying new targets for various kinds of cancers and then applying vaccine therapy, antibody therapy, and cellular therapy against these specific targets. This will be done through extensive studies of cancer cell biology, DNA sequencing, and other techniques that will allow this type of immunotherapy to become increasingly personalized to a patient’s specific tumor and the tumor’s specific targets. 

It’s going to be a long time before chemotherapy is obsolete. Some chemotherapy may actually have a role concurrently with immunotherapy and may function to modulate the immune interactions. There will also be instances where we use multimodality therapy, including chemotherapy, radiation therapy, and immunotherapy.

Curing Cancer

Even the most successful targeted therapies like imatinib for chronic myeloid leukemia are rarely curative, and once the therapy is withdrawn the cancer could come back. Immunotherapy however could be curative even in some advanced malignancies. Going back to the example of bone marrow transplantation, there are circumstances when patients with leukemia or lymphoma relapse after allogeneic transplant and can be cured with infusions of normal T cells from their original transplant donor (donor lymphocyte infusion). There has been cases of patients with advanced malignancies who had received check point inhibitors or CAR-T cell therapy who have been cured and remains disease free despite not receiving any ongoing therapy. 

Immune therapies are the new frontier in cancer therapy, and the field is in its infancy. As of this writing, there were 940 IO agents in clinical development, with another 1064 in preclinical phase, with over 3000 interventional active clinical trials evaluating these clinical-stage immunotherapies with a target of enrolling over half a million patients across the world. So it can be anticipated that the application of immunotherapy in the treatment of cancer will grow dramatically over the next decade.

References:

1) Talpaz M, Kantarjian HM, McCredie K et al. Hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha A in chronic myelogenous leukemia. N Engl J Med 1986; 314(17): 1065–1069.).

2) Hodi FS, O’Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8): 711–723.) . 

3) Topalian SL, Hodi FS, Brahmer JR et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366(26); 2443–2454.

4) Grupp SA, Kalos M, Barrett D et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013; 368(16): 1509–1518.

5) Locke FL, Neelapu SS, Bartlett NL et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther 2017; 25(1): 285–295.

6) Topp MS, Kufer P, Gokbuget N et al. Targeted therapy with the T-cellengaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol 2011; 29: 2493–2498.

7) Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015). 

8) Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480–489 (2011). 

9) Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996)

10) Zou, W., Wolchok, J. D. & Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci. Transl. Med. 8, 328rv4 (2016).

11) Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).

12) Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014)

13) Salmon, H. et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J. Clin. Invest. 122, 899–910 (2012)

14) Gajewski, T. F. The next hurdle in cancer immunotherapy: overcoming the nonT-cell-inflamed tumor microenvironment. Semin. Oncol. 42, 663–671 (2015)

15) Taube, J. M. et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 20, 5064–5074 (2014)

16) McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016)

17) Cho, J. H. & Feldman, M. Heterogeneity of autoimmune diseases: pathophysiologic insights from genetics and implications for new therapies. Nature Med. 21, 730–738 (2015)

18) Rosenbaum, L. Tragedy, Perseverance, and Chance — The Story of CAR-T Therapy. N Engl J Med 2017; 377:1313-1315 (2017)

19) Russell, W.J. Mechanisms of resistance to immune checkpoint inhibitors. British Journal of Cancer 118, 9–16 (2018)

20) Postow, M. et al. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade N Engl J Med 2018; 378:158-168 (2018)

Spontaneous Regression of Cancer

Cancer is one of the scariest words in the English language and when we are afraid we tend to become irrational – even otherwise intelligent people. That is why there are more quackery around cancer treatments than any other disease.  Cancer is likely second only to death itself in terms of stuff that frighten people. And just like there are myths and charlatans exploiting our fear of death, there is an entire voodoo industry to exploit the fear of patients with cancer.

While complimentary and alternative therapy for cancer is a universal phenomenon (I often see patients who also take some form of alternative medicine for cancer here in USA too), it is of a completely different and dangerous magnitude in India. I have seen this first hand as I frequently get medical records of cancer patients for second opinion from India, and it is very troubling to see the number of poor patients who continues to be exploited by peddlers of alternative medicine in India.

As a recent example, from my visit to Kerala in November 2017, one of the patients who came to see me for a second opinion was someone I knew all the way from my childhood days who was unfortunately diagnosed with bladder cancer around 6 months ago. He saw an Oncologist and a Urologist at a highly reputed hospital in Kozhikode, who both appropriately advised immediate surgery to take care of his early stage bladder cancer, which could have been curative. Instead he decided to forego Modern Medicine and sought treatment from an alternative medicine provider who claimed he could cure this cancer with some “lehyam” and other quackery. As symptoms continued to worsen patient went back to his original doctors, who repeated a CT scan. He brought with him his CT scans, and I reviewed his old and new scans, and unfortunately his disease had now progressed significantly and had become inoperable. And sadly, patient also had gone in to renal failure due to the enlarging tumor blocking his ureters. While we are constantly bombarded in social media on the extremely rare instances of advanced cancers “being cured” with alternative medicine, one never sees the much common occurrences like the case above, where relying on alternative medicine and delaying modern medical treatment become deadly.

The number of claims of medical miracles and magic diets for cancer is astounding. As discussed above, the more frightening an issue is, the more willing people will be to believe in fairy tales and subscribe to magical thinking. What is unfortunate is that, unlike in the past, effective cancer treatments are now widely available and cancer death rate down. However, the key to a good out come still remains early treatment. And many a time as in the case above, the delay in early treatment while patient tries out various unproven alternative medicines could change an early treatable disease to an advanced and incurable death sentence.

Quacks and promoters of alternative medicine comes in various forms. Some are “professional peddlers” who promote their wares with benign sounding words (like “organic”, “plant derived” and so on. A brief note here - just because some thing is derived from plant does not make it automatically healthy – nicotine, the commonest cancer-causing agent in the world, is an “absolutely organic and plant derived” product!) These professional peddlers are very adept at marketing and experts at using social media. Unfortunately, people are much keener on reading and disseminating extra ordinary claims and conspiracy theories than what is truly scientific and rational, so these charlatans have become very successful with the wide spread use of social media.

Another and even more effective form of peddlers are those who have been the very fortunate quacks who happened to come across a case of spontaneous regression of cancer. These quacks have other people, often cancer patients or relatives, vouching for their remarkable recovery. Many of these are again totally fabricated stories, but some time these could be real patients and real stories. So how would one explain those remarkable stories, assuming the story is real? Can a patient with advanced cancer who have failed all therapies can suddenly become cancer free?

Here is how to explain this – as briefly noted, there is a well-known entity in cancer biology called “spontaneous regression of cancer”. This is the disappearance of cancer without a satisfactory explanation. There is an entire body of literature on this rare but well described topic. And with a better understanding of cancer biology, especially with advances in cancer immunology, this is no longer a “mysterious” or “miraculous” subject but come totally within the realm of known cancer biology.

The patron saint of cancer patients is St Peregrine, OSM (1265-1345), a 14th century priest whose cancerous leg became ulcerated and festered for years and was, according to Christian legend, healed by Divine intervention the night before he was scheduled to undergo amputation.^1,2 Case reports like this fits the general rubric of “spontaneous regression.”³

Discounting these unique events may be the easiest course of action but it is unscientific, as medical historian and hematologist Dr Jocalyn Duffin noted in an analysis of Vatican archives in her book, “Medical Miracles: Doctors, Saints, and Healing in the Modern World”.⁴ Her interest in this subject started when Dr Duffin was sent pathology slides for interpretation from the Vatican regarding a patient diagnosed with acute myeloblastic leukemia, who was supposed to have been cured “miraculously”. The source of the slides was unknown to her at first, though more than 30 years later the patient is alive after initially failing standard therapy.^4,5

Critical analysis of cases of spontaneous regression by sober and scientific observers dates back more than a century to physicians like Dr William Coley, Dr G.L. Rohdenburg in 1918, landmark studies by Drs J.J. and J.H. Morton in 1953, and the widely cited review by Drs T. Everson and W. Cole in 1956.^6-8 The latter study defined the modern version of spontaneous regression of cancer as: “the partial or complete disappearance of a malignant tumor in the absence of all treatment, or in the presence of therapy which is considered inadequate to exert a significant influence on neoplastic disease.”

Medical literature is now filled with observations of biopsy-confirmed malignancies with computerized tomography (CT) scans or magnetic resonance images (MRIs) showing widespread disease that spontaneously regresses, which encompasses nearly every cancer type and histology. Examples include: acute myelocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, breast cancer, non–small cell and small cell lung cancer, testicular cancer, prostate cancer, cervical cancer, hepatocellular cancer, colon cancer, Merkel cell carcinoma, sarcoma, melanoma, neuroblastoma, astrocytoma, and renal cell carcinoma.^9-26

The mechanisms most-often implicated in driving the spontaneous regression of cancer are thought to be mediated by immune system activation (or reactivation). Sometimes the driving force is an acute intercurrent bacterial or viral infection. Initiated by the work of Dr Lloyd Old, the founder of modern cancer immunology, the US Food and Drug Administration (FDA) in 1990 approved the first bacterial immunotherapy, Bacillus Calmette-Guerin (BCG), for in situ bladder cancer. More recently the FDA approved T-Vec [talimogene laherparepvec], a viral vaccine used to evoke an immune response in patients with advanced melanoma.^27-29

The development of other viral and bacterial vectors is an active area of new drug development, with further success anticipated.^30,31 The recent approval of checkpoint inhibitors against an array of cancers and chimeric antigen receptor (CAR)-Tcell therapy are testimonies to the power of the immune system, when it awakes from its slumber, to simulate a process historically regarded as “miraculous.”^32,33

The immuno-editing theory proposed by Drs Robert Schreiber, Mark Smyth, and Lloyd Old has helped to refine medical understanding of spontaneous regression, which may be seen as the interplay of cancer undergoing incomplete elimination, equilibrium, and escape.³⁴ Under ideal conditions the innate and adaptive elements of the immune system work in concert to eliminate the cancer (often imperfectly) with regulatory (CD4+) and cytotoxic (CD8+) T cells, dendritic (or antigen presenting cells), natural killer (NK) cells, and macrophages along with a host of immune-activating secreted proteins such as interferon gamma, interleukin 12, and tumor necrosis factor (TNF) all working in harmony. Spontaneous regression may in some cases be a manifestation of this dynamic process, and immunoediting fits well into observations that some cancers that undergo spontaneous regression recur, sometimes years later.

Another example of this phenomenon can be seen with the so-called abscopal (or out-of-field) effects of radiation therapy, which causes the immune system to mount a systemic response to distant metastases.³⁵

I expect that in the future, as our understanding of cancer immunity matures, the fascinating phenomenon of spontaneous regression will help guide us towards developing safer and even more effective drugs. What is remarkable is that, these rare cases of “spontaneous regression of cancer”, once ascribed to miraculous intervention or unproven “herbal” and other remedies, now have a very scientific explanation. Unfortunately, how this plays out in the real world currently is however different; a patient with an advanced malignancy who was fortunate to have such a case of spontaneous remission may end up with a lucky quack, who claims full credit for this rare natural phenomenon; and the news spread like wild fire in the social media jungle; prompting a deluge of desperate patients flocking to get this “magical herb”, while the herb had nothing to do with the spontaneous remission. And while a sole case of spontaneous remission is broadcast through out the world, millions of more lives are cut short trying these voodoo "treatments" from alternative medicine practitioners. And with the Indian Government's proposed recent legislation that could allow a back door entry for alternative medical practitioners to practice Modern Medicine, public will have even more trouble in the future to distinguish between real Medicine and quackery in India.   

References:

1.       Pack GT. St. Peregrine, O.S.M.--the patron saint of cancer patients. CA Cancer J Clin. 1967;17(4):181-2.

2.       Jackson R. Saint Peregrine, O.S.M.--the patron saint of cancer patients. Can Med Assoc J. 1974; 111(8):824-7.

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Death and Dying - Some Reflections

Read the deeply affecting "When Breath Becomes Air" by the late Dr. Paul Kalanithi recently; it is a small yet powerful book, not just because the book appears like a deeply thoughtful and smart man talking to you from beyond the grave, but the contents are especially affecting for us doctors who has to deal with death and dying on a daily basis. As an Oncologist I could empathize with his Oncologist, whom he trusts and adores, but could see through her at times - times when the relationship is no longer just a bland and emotionless "Doctor-Patient relationship", but as he wrote beautifully "it is the relationship of two people huddled together, with one of them facing the abyss" and how he forgives his Oncologist's sunny - and eventually wrong - prognostications with the saying "some time Doctors needs hope too". 

With his deep and vast knowledge including a PhD in English Literature, formal training in Philosophy, a stint at History of Medicine, Neuroscience and of course as a promising Neurosurgeon, all at some of the world’s best institutions, even without his untimely death and this book, it is fairly certain he would have become famous, a future Oliver Sachs. Or may be like many doctors, his profession would have swallowed him whole and the wider world would never have heard of him. Medicine is indeed like a possessive wife, often causing other passions to die. So in one way, even though he died at age 37, he has become now immortalized by his book, which I suspect could become a "required reading material" for many future students of Medicine. I often tell patients with terminal cancers "to live one day at a time" which is really a cop-out - as Dr. Paul Kalanithi writes "I would like to know; because if I have only few months I want to write a book; if I have few years I want to pursue Neuroscience". But nothing is harder than prognostication, especially with newer treatments for previously incurable cancers. It is easier in some cases, but often it is not. Anyway I would strongly recommend this remarkable book; short book which can be finished in one sitting yet powerful. 

So the book, an examination of death, reminded me of something I read couple of years back and wanted to share this with readers. This is a remarkable idea on death and afterlife that most people have not heard of. The two traditional and competing theories of afterlife are 1) An Eternal Heaven/Hell 2) Nothingness. But there is a third alternative: The term for this is "Near Death Experience leading to Never Ending Dream" or NDE to NED. NDEs are well documented phenomenon and reported across various cultures. In many NDEs, individuals describe intense dreams of being drawn through a tunnel toward a bright light into a celestial realm and of feeling wonder, love, and contentment.  The NED theory of heaven suggests that NDEs provide evidence of a “natural afterlife” and thus perhaps a heaven which exist in the person's mind; etched forever in the brain of the dying person. The NED theory suggests those describing NDE are indeed experiencing "heaven". But then they awake and return to consciousness. That is, the NDE doesn’t become their NED and natural afterlife, though it very well could have.

To better grasp this, imagine what it’s like to never wake up from a dream, something none of us have experienced. You’re having your NDE. Effectively, you’re in heaven. But then you die, and so you never become consciously aware that your dream ends. It’s not like the dream screen displays "The End" or even goes blank! Thus, as far as you know, you’re in heaven forever. And reality is what ever our brain makes of this world. So to an out side observer you are dead; but as far as the dead person is concerned, his last experience is the vivid dreams of a Near Death Experience - which thus becoming a Never Ending Dream as the person never wakes up from this dream. 

Most people would find it hard to swallow, as we are chained by our ideas of time. So the first question when some one hears of NED is "what happens when the person dies"? This question forgets the intensively subjective nature of time as well as consciousness and sense of self. But what is time anyway? Time may be only a human illusion. It’s relative to perceived events and when we begin to perceive none—e.g., when falling into a dreamless sleep or passing out under general anesthesia (or in dying!)—our self, or our spirit (or soul?), doesn’t cease but time ceases and we simply enter a timeless state. The universe itself may be fundamentally timeless as Einstein himself believed.

The concept of time here is like that which we have “experienced” before-life, i.e., before we were born. Timeless! Billions of years pass by in no time at all, literally. The big difference, however, is that our “afterlife” begins at death enjoyably immersed in a glorious dream. While this dream physically ends, from our mind’s perspective it is now an NED. After a billion years have passed by, for instance, we are still unaware that we are dead.

Why this third way, the so called “Never Ending Dream” could be true? Because of the following three features 

1) Our ability to dream—specifically, to have an NDE, there are so many well documented evidence of this across varying cultures; there is an excellent book written by Neurosurgeon Dr. Eben Alexander who almost died from a severe case of meningitis (“Proof of Heaven”); All these NDEs are very similar, and some as in Dr. Eben Alexander’s case could be extremely elaborate 

2) Our perception of time as a perceived ordering of events is illusory 

3) Our inability to realize the moment of death, i.e., our imperceptible death.

Based on research, some scientists believe that common NDE features may be induced, possibly as a defense mechanism, by psychological and physiological processes occurring in the brain as it senses doom or shuts down. For instance, chemicals are released as a protective mechanism when the brain is traumatized. These chemicals have been shown to trigger intense hallucinations with features like those of NDEs. While such science is used to explain NDEs as just natural phenomena mistaken for a supernatural heaven, it also shows the natural ability and propensity of the brain to trigger vivid NEDs.

More support for the NED theory comes from our dreaming experiences. I for one believe that despite numerous studies and publications about dreaming, it hasn’t been given the prominence it deserves. When inside our dreams, we can’t distinguish them from real-life. Also, when dreams are pleasant, real-life worries are left behind, as in heaven. Our dreams are truly another dimension of being, like another universe.

And why do we possess this amazing ability to dream? Some scientists believe that dreaming evolved to better prepare us to face life’s crises, though this theory seems to apply only to nightmares and doesn’t seem to explain most of my dreams. The NED theory provides another purpose: a potentially satisfying, evolved and/or God-given, afterlife experience.

And who or what controls our dreams? I certainly don’t control mine. Some scientists speculate they’re brain-controlled processes that assimilate and store recently accrued knowledge. However, many of my dreams are weird, unrelated to recent experience, and so don’t appear to fit this explanation at all. Dreaming seems a realm within our universe yet out of this universe.

The NED theory facilitates a distributive heaven rather than a centralized one. So, heaven could be whatever one believes and dreams. Suppose one doesn’t believe in heaven? Then maybe there’s no NED and one’s afterlife will be just like one’s before-life.

Can an NED be "hell"? Studies based on NDE reports vary much but show that on average about 15% of NDEs are reported as hellish experiences. So yes, I guess NED could be like a nightmare that never ends.

Will someone be denied an NED if they are “blown to bits” in an instant? As indicated before, the brain can likely paint a heavenly landscape almost instantaneously. Also, if the brain can, as reported, make life flash before one’s eyes in the moments before pending disaster, maybe it can execute an NED in nanoseconds before shutting down.

Why this is important? Whether one agrees with the idea of NED or not, as far as I know, this idea of “Never Ending Dream” ties together lots of loose ends, and could answer one of the most fundamental questions humanity ever faced. I would even go on to say that, if there is even a tiny possibility of NED, then we should develop techniques and medications (like endogenous hallucinogen dimethyltryptamine) to help dying patients to have vivid and happy dreams; which would become his/her “Never Ending Dream”. While waiting for such technology to evolve, I guess the next best thing is to live a good life; from Dr. Kalanithi’s book, and the description of how he died surrounded by so much love, it is quite possible that Paul is now in a heavenly state of Never Ending Dream. Research also shows that what we dream can be influenced somewhat by heavy concentration on a topic just before falling asleep. So what is one’s final dream after fixating the mind on death and its meaning? A life well lived without too many regrets could indeed be the way to heaven; so one's Near Death Experience is a pleasant and even heavenly one. and if it indeed ends up as death, then one has the possibility of entering an eternal world of heavenly "Never Ending Dream" state.

The Paradigm of Cancer Care in the Era of Genomics, Proteomics and Immuno-oncology

The word “paradigm shift” is used fairly loosely in many contexts, but in the field of Oncology there has truly been a paradigm shift in both the understanding of cancer biology as well therapeutics in the last decade and the pace of change has accelerated even more so in the last couple of years. Those outside the fields of oncology and related fields are unaware of many of these seismic shifts taking place, and this blog is an attempt at briefly updating the reader on what is happening in the field of oncology.

Let me start by illustrating by the example of a current patient of mine; she is a 56 year old patient, non smoker, with stage IV adenocarcinoma of the lung with brain metastasis, diagnosed over 2 years ago. If some one asked me how to treat a patient like this when I was doing my Hematology-Oncology fellowship over 12 years ago, the appropriate answer would have been “any doublet chemotherapy containing a platinum compound”, along with brain radiation. Basically, it didn’t matter what kind of mutations the tumor itself possessed as we not only knew little about mutations withing lung cancer, we also had no specific or targeted therapy for individual mutations even if we found them then. So all lung cancers were treated as a single group, and given a pretty similar type of chemotherapy regimen. Some of the patients responded to this, and those who did not and those who progressed, there were few, if any viable options apart from palliative care.

What has changed in over 12 years? So many things. For once, we have now so many different sub types of lung cancers, based not just on histology but also based on molecular and genetic profiling. My particular patient was found to have a lung adenocarcinoma with a so called EGFR exon 19 mutation, which is very sensitive to an oral kinase inhibitor called Afatnib. My patient initially underwent so called “Cyber knife Radiation” for her brain metastasis – which is a highly focused form of radiation targeting the metastasis while sparing normal brain. After this she was started on afatinib. This is a pill taken once daily while she continued to work. A PET scan done after 3 months of this therapy showed she was in a PET negative remission. She continued the same medication for another 18 months but unfortunately progressed with a new bone lesion. At the time of progression, a new test which can test mutational status of any circulating tumor cells became available and was performed, and this showed she had now circulating tumor cells positive for a mutation called T790M. This is a classic mutation which makes the EGFR clones resistant to drugs like afatinib. These mutant cells are actually a bit less robust than cells without the T790M mutation, but in the presence of drugs like Afatnib the cells with the T790M mutation have a specific survival advantage.

At this point she was enrolled in a clinical trial looking at a so called third generation EGFR kinase inhibitors which works around the T790M mutation, being developed by Astra Zeneca. She responded nicely for about 5 months on this yet to be approved drug; then around 1 month ago she progressed again. A repeat cell free DNA testing now showed she has developed cells expressing so called BRAF V600E mutation, which was not present in the original tumor or on first progression – one of her cancer cells have now mutated to be now the “fittest” clone. We have now obtained a BRAF inhibitor and a MEK inhibitor on a compassionate use protocol (as these drugs are not yet approved for lung cancer but only for melanoma). We and the patient and her family are all keeping our fingers crossed to see what would happen. My guess is she will respond for few months, and then her cancer cells will find a way around that pathway also and then progress, but hopefully we will find another mutation which we can target by then, or she could get conventional chemotherapy which is yet to receive nearly 2 years after diagnosis. And during these nearly 2 years of ongoing therapy, patient continued to work and enjoy a fair quality of life allowing her to pursue her work and hobbies. 

The above case illustrates how from randomly treating all lung cancer patients with a generic “platinum doublet” 10 years ago, cancer treatment now involves sub dividing the cancers in to very specific molecular sub types and treating with appropriate medications. The case also illustrates how dynamic is the process of cancer; we spoke about targets in the past as if they were fixed (like "estrogen receptor positive breast cancer"). We still do so, but is realizing these targets change and mutates and cancers evolve over time. While vast majority of cancers still do not have "targetable mutations " like the patent's case above, we are at the cusp of some exciting new fronts in cancer care. What follows is a very short summary of cancer biology as well as how this is changing how cancer is treated now a days, along with a brief overview of future potentials and challenges.  

Cancer as an Evolutionary Process:

What we have learned is that the best way to look at the cancer is through a Darwinian lens. This so called micro evolution – or evolution at cellular levels and happening at warp speed can explain a whole lot of once mysterious things about cancer biology. In the past we used to look at cancer as a “monoclonal process”, a set of uniform cells competing against normal cells. This appears to be a very simplistic way to look at cancer – cancer is unfortunately a way more complex disease process than that.


What is meant by looking at cancer through Darwinian lens? Here is how: A body can be considered as an entire eco system –whose individual members are cells. These cells have ecological and classic Darwinian features like cell births, deaths, habitats, territorial limitations, and maintenance of population sizes. The one Darwinian rule that does not apply is however “natural selection” – there is no competition among somatic cells. The rules of somatic cells are instead self-sacrifice—as opposed to survival of the fittest. Ultimately, all somatic cells are committed to die; they dedicate their existence to support of the germ cells, which alone have a chance of survival and propagation. One could think of germ cells like the “queen bee” of an ant colony. There is no mystery in this, as the body is a clone, and the genome of the somatic cells is the same as that of the germ cells. By their self-sacrifice for the sake of the germ cells, the somatic cells help to propagate copies of their own genes.

To coordinate their highly cooperative behavior, cells send, receive, and interpret an elaborate set of signals that serve as social controls, telling each of them how to act, when to divide, when to die. As a result, each cell behaves in socially responsible manner, resting, dividing, differentiating, or dying as needed for the good of the organism. Molecular disturbances that upset this harmony mean trouble for a multi cellular society like our body. In a human body with more than 10^14 (or 100 Trillion) cells, billions of cells experience mutations every day, potentially disrupting the social controls. And an occasional mutation can give one cell a selective advantage, allowing it to divide more vigorously than its neighbors and to become a founder of a growing mutant clone, a “selfish” clone. Once cells learn to be “selfish” then the typical Darwinian “survival of fittest” rule applies within that clone– each subsequent cancer cell population gets “better” at resource utilization. And since mutational rates are higher among cancer cells, purely from random chance one of these cells would develop a special property (like more efficient anaerobic metabolism) - this cell then have a survival advantage over other normal and cancer cells. Note that by this time cancer cells are competing among themselves, and not against normal cells. Because cancer cells are way so advanced in their ability to divide and utilize resources, competing with normal cells is like Michael Jordan playing against a school kid. Their competition is mostly with other cancer cells.  Such repeated rounds of mutation, competition, and natural selection operating within the population of cancer cells cause matters to go from bad to worse, see the diagram below. 


For example: when a critical size is reached, the cancer cells may not get enough oxygen, then one of these cancer cells – who are all competing with each other like it is the great African Serengeti plains – would develop a mutation that allows it to utilize anaerobic pathways better, or attract blood vessels to grow in to it, or develop an ability to pump out chemotherapy drugs etc.  Several more cell divisions later another cell would find a way to get out of the resource poor primary site and goes and thrive in another, healthier and "less competitive" environment - what we call metastasis. See the diagram below to show how clonal evolution works:








This is why recurrent cancers are harder to treat and cure. Thus cancer is a disease in which individual mutant clones of cells begin by prospering at the expense of their neighbors, but soon their competition is among cancer cells themselves, each “out mutating” each other, eventually becoming such a remarkable , and almost immortal, dividing cells, who only dies in the end when they destroy the whole body. If those cells can be taken out and given perpetual nourishment, these cells can literally live forever (portrayed in the wonderful book “The Immortal Life of Henrietta Lacks). These advanced cancer cells have actually mastered what humans have been searching for all of history - immortality.

As noted a single mutation alone can rarely causes cancer. Genesis of a cancer typically requires that several independent, rare accidents occur in the lineage of one cell. If a single mutation were responsible, occurring with a fixed probability per year, the chance of developing cancer in any given year should be independent of age. In fact, for most types of cancer the incidence rises steeply with age—as would be expected if cancer is caused by a slow accumulation of numerous random mutations in a single line of cells. In fact if one lives long enough, it is almost a given that some type of cancer is bound to happen. A recent study from Sweden looked at whole genome sequencing of healthy adults, and found that over 12% of general population over age 65 had what we now call as ARCH (Age Related Clonal Hematopoiesis) in their blood – and they had 15 times risk for developing subsequent blood diseases like AML and MDS. (Interestingly those with ARCH in their blood also had higher cardio vascular and endocrine morbidity and mortality suggesting a possible common inflammatory pathway to both cancers and other common diseases)

Why are so many mutations needed for cancer? Because think of cell as a car; but instead of a single accelerator and a single break, cells have many many breaks and accelerators. A critical number of breaks have to be gone and a critical number of accelerators pressed before a cell truly becomes “cancerous”. (By the way those with familial cancer syndrome like Li Freumani already are born with some major breaks - like p53 - already gone, so it takes less mutation for them to get a cancer). Moreover, not all cancers are the same in terms of how "fast" they are. In fact we now routinely use a test called “Mammaprint” to decide which of the early stage breast cancer patients need treatment, and who does not. I explain to patients this test differentiates whether their cancer is an old car or a brand new Ferrari. And if they are lucky and if their cancer is a like an old car, we don’t give them chemo these days and treat them just with hormonal therapy.


Just to add some subtlety to this story – mutations alone can’t cause cancer – often many mutations are needed unless it is one of the “driver” mutations like 9-22 translocations in CML. An estimated 10^16 cell (100,00 Trillion) cell divisions take place in a normal human body in the course of a lifetime. (By the way these are truly cosmic numbers. For example an average human have 1000 times the number of stars in the Milky Way galaxy!)  Even in an environment that is free of mutagens, mutations will occur spontaneously at an estimated rate of about 1 in a million mutations per gene per cell divisions.—a value set by fundamental limitations on the accuracy of DNA replication and repair. Doing the math one can see that in a lifetime, every single gene is likely to have undergone mutation on about 10^10 (or 10 billion) separate occasions in any individual human being. Among the resulting mutant cells one might expect that there would be many that have disturbances in genes that regulate cell division and that consequently disobey the normal restrictions on cell proliferation. From this point of view, the problem of cancer seems to be not why it occurs but why it occurs so infrequently. I routinely get asked by patients – often who have done all the right things from their diet to exercise who gets cancer – why they got cancer. (Without elaborating the numbers what I tell them is this: That it is a miracle of our immune system that we don’t get a new cancer every day!) 

What is a Driver Mutations versus “Passenger” mutations:

Countless studies have shown that sequential acquisition of mutations results in gains in evolutionary fitness. Furthermore, tumor initiator clones (also often referred to as cancer stem cells) have been identified in a subset of cancers and highlight the potential for a genetically “simple” tumor cell progenitor to propagate disease relapse. There is perhaps no disease with greater evidence of this than CML.

The introduction of imatinib, a small molecule inhibitor of ABL family kinases including the BCR-ABL fusion gene, revolutionized the way that CML is managed and dramatically improved outcomes for these patients. An important factor contributing to the unusual success of imatinib is that it targets the initiating event in the clonal evolution of CML. This means that all daughter cells that evolve following this initial event (ie, every cell in the clonal pool) also carry the BCR-ABL trans location and are susceptible to the effects of imatinib. . The terms “driver mutation” and “passenger mutation” were coined to discriminate between (1) those mutations that play an active role in disease pathogenesis (ie, driver mutations) and (2) those mutations that do not contribute to disease pathogenesis but undergo clonal expansion alongside one that does (ie, passenger mutations). Also note that not all driver mutations are created equal but rather are acquired in an ordered hierarchy. That is, some driver mutations occur as early events during clonal evolution and play a role in disease genesis (early drivers), whereas others occur as later events during clonal evolution and play a role in disease progression (late drivers/accelerators). Early driver mutations that have a role in disease genesis, such as the BCR-ABL trans location, will therefore be present in every tumor cell, whereas late driver mutations may only be present within a subset of tumor cells (ie, in a subclone).


To further complicate understanding and measurement of the clonal origin of mutations, each driver mutation will confer a variable boost in evolutionary fitness, which will cause them to overtake less-fit clones at different rates. This means that some driver mutations, despite occurring as late events in disease evolution, may appear to be present in the majority of tumor cells because they provide a significant boost to clonal fitness.


Currently, we do have “actionable” mutations (mutations that are matched to targeted therapies) for a number of cancer types, but as of this writing we know of many more “mutations” than there are “actionable mutations”. However, the future of precision medicine is one in which we will have a much wider array of actionable mutations matched to suggested therapeutics or clinical trials. Understanding the hierarchical order in which somatic mutations are acquired in each cancer will become an important consideration in ranking therapeutic targets for drug development, but this is a complex scientific undertaking, to say the least, and would require significant computing and clinical resources. A future format of molecular genetic results should incorporate a measure of not just the presence or absence of a mutation, but also the clonal representation or allelic frequency for each mutation, so that oncologists can be more informed about the biology of the tumor they are treating.While cancer is primarily a disease of the genes and result from acquired mutations within somatic cells, there are additional layers of complexity involved in actual cancer. We have to consider many host factors affecting the development and propagation of cancer (like familial predisposition, immunologic factors and metabolic factors). Add to this fact that cancer cells are intimately linked to the host in multiple ways, briefly as shown in the diagram below; unlike in experimental models, cancer in vivo has complex interactions between various host factors as represented below:

The initiating event in CML is acquisition of the t(9;22)(q34;q11) translocation, which creates a fusion between the BCR and ABL1 genes. Secondary genetic alterations, such as mutations of TP53, RB1, and CDKN2A, can be acquired after the BCR-ABL translocation and may play a role in progression of CML from an early chronic phase to a more aggressive blast phase.

We also have to consider that not all genetic changes will lead to protein production, so will need to interrogate cancer cells at not only genomic level but also at the proteomic levels. But once we start looking at cancer in such a comprehensive way, oncology care wil change from one that relies primarily on trial-and-error treatment strategies based on the anatomy of the tumor to one that is more precisely based on the tumor’s molecular, proteomic, metabolic level and appropriate for the particular host, thus enabling many cancers to be turned into manageable chronic disease, and providing patients with long-term high quality of life.

Dr. Patrick Soon-Shiong, MD is one of the leaders of this new push for a paradigm shift in how to address cancer given all these current understanding in to the biology of cancer. He is the inventor of nab-paclitaxel (Abraxane), the first U.S. Food and Drug Administration (FDA)-approved nanotechnology-based chemotherapeutic agent. He is also the Founder and CEO of NantWorks and its subsidiary NantHealth, a cloud-based biomolecular medicine and bioinformatics company that uses high-frequency, high-throughput tumor genome sequencing to analyze the DNA, RNA, and protein levels of an individual patient’s cancer cells. Proud to say the our practice is one of the select few from the US South Central region who is collaborating with Dr. Soon-Shiong’s company in developing a global consortium of cancer providers and patients to advance this field of precision medicine.

A GPS for the Oncologist:

How do you navigate this “maze” of molecular genetics, protoemics and other data to come up with the best suited treatment for a particular patient? I think Dr. Soon-Shiong is a true visionary in this regard, as his aptly named GPS (genome/proteome sequencing) involves a next-generation sequencing technology to analyze genomic (DNA) and transcriptomic (RNA) sequencing data. This identify variants between somatic and germ line DNA. What was interesting, though not unexpected was that, after analyzing a cohort of 3,784 patients (on 19 anatomic tumor types), it was found that genetic mutations in gene panels do not always result in protein expression. Thus even the informed clinician who is up to date with the latest molecular genetic data could miss or over read these reports – as what truly matters is downstream protein expression and not just DNA alterations alone. And this signatures change with time. Luckily however this entire GPS Cancer can be run now on circulating tumor cells, avoiding the need for repeat biopsies, capturing cancer as it evolves, rather than considering cancer as a static process as was the orthodox - and flawed - view in the past.

Advancing the Next Paradigm of Cancer Care

As detailed above, cancer is no longer considered as a single clonal disease nor static in it's genetic make up. Cancer cells also show enormous inter- and intra patient tumor heterogeneity and cancer progression is driven not just by one genetic mutation, but in many instances driven by tens and even hundreds and perhaps thousands of mutations, rearrangements, and structural changes in the genome, dynamically changing across time and space.

What is the downside of this approach of interrogating cancer at a much deeper level? Basically from being a “common disease” cancer becomes a set of rare diseases. Each patient’s mutational, proteomic, immunologic signature is going to be unique, and hence treatment should be tailored to that individual patient. Even large institutions will not have enough patients of a “specific GPS signatures” so Dr.  Dr. Patrick Soon-Shiong is spearheading a large collaborative “omics” network—a muscularly sophisticated network of oncologists to share outcome data and create an “adaptive learning system.”  This will require an infrastructure for sharing of outcomes in real time as well as an infrastructure to receive an in-depth whole-genome, RNA, and proteome sequence analysis in a timely manner to take advantage of real-time knowledge that may better inform a clinical decision.

Cancer care in the not distant future:

How do we effectively attack this multi clonal disease that changes its gene expression over time and space? The best way is to explore ubiquitous pathways driving proliferation and metabolism of the cancer cell, to attack both the stem and metastatic cancer cells, to recognize that the biology and evolution of these two cell types differ, and to use multiple drugs focused on multiple points of attack, targeting the cell’s nucleus, DNA, cell signal pathways, and metabolism and micro environment all simultaneously while also enhancing host immune system. The field of immunotherapy for cancer is worth it’s own blog, but briefly this has been one of the most exciting areas in all of oncology in the year 2015, with several new medications approved across a variety of cancer types where the treatment work by stimulating patient’s own immune cells or by enhancing the anti tumor immunogenecity.

Is there going to be a “magic pill” for cancer:

If you are still asking this question after reading the above blog, I would strongly recommend reading it again! Cancer is an extremely heterogeneous disease, so unlikely we will have a “magic pill” that will work across cancer types. However by “intelligently and selectively” blocking the various metabolic and survival pathways of cancer cells, by going after the cancer stem cells as well as the metastatic cells, and by enhancing the patient’s immune system we have a chance of changing the paradigm of how we manage cancer patients. Eventually, by more deeply understanding the biology of the cancer stem cell, we will provide long-lasting remission and get closer to a functional cure for cancer.