Musings of a Cancer Doctor
Wide-ranging views and perspective from George W. Sledge, Jr., MD
Monday, February 02, 2015
I’ve had this conversation a hundred times. My patient, still stunned by her recent breast cancer diagnosis, asks the “why me?’ question. She doesn’t smoke, or drink to excess, and has lived a pretty unexceptionable life. Her family history is devoid of breast or ovarian cancer. And yet here she sits, her life forever altered by the Latinate-sounding words of a pathology report, and she has no idea why she is here.
I can’t help her, not in any meaningful sense. I explain that most women do not have a family history or an inherited predisposition. I explain that we have a number of risk factors related to the internal hormonal milieu, things like early menarche and late menopause and breast feeding and the number of childbirths, but I cannot mount any enthusiasm for these as personal risk factors for her. There are hundreds of women walking by my clinic every day with the same risk factors, and most will never get breast cancer.
When you get right down to it, I usually end up saying, it’s just bad luck.
I thought about these doctor-patient interactions while reading the recent paper in Science by Cristian Tomasetti and Bert Vogelstein of Johns Hopkins. The authors performed a fairly simple analysis, matching up the number of stem cell divisions in a given organ with the reported incidence of that organ’s cancer. They concluded that there was a clear and fairly strong relationship between the two: the more stem cell divisions, the greater the likelihood of cancer.
They concluded that only a third of the variation in cancer risk between different tissues was attributable to either the environment or an inherited predisposition. The majority is due to “bad luck.” “Bad luck” now enters the scientific literature as the cause of most human cancer.
The paper has already, in the month or so since its publication, elicited a striking range of responses—one would almost say, of emotions—in both lay and scientific circles. Google “bad luck and cancer” and you will see a mountain of references. The article induced an almost visceral response in readers, or at least in newspaper editors.
And among scientists, who have been quick to respond to the paper (for an elegant analysis read the recent Cancer Letter interview with Barnett Kramer). One unhappy cancer biologist told me “this just proves that they’ll publish anything in Science.”
Part of the reaction is based on the paper’s technical elements. Because of a paucity of data on stem cell divisions in breast and prostate cancer—two rather common human cancers—these were left out of the analysis. Also, the take-home message that two-thirds of variation in cancer risk is due to random mutations in normal stem cells has attracted attention. Two thirds of variation in risk is not the same thing as saying two-thirds of human cancer is due to “bad luck.” Not all tissues are created equal in terms of their cancer incidence, so a correlation coefficient between “all cancer types” is not the same as “all cancers.” The Science press release, interestingly, made this mistake.
But what rendered many apoplectic was the “lessons learned” aspect of the correlation. If most cancer is “bad luck,” then cancer primary prevention efforts will inevitably prove futile. And indeed, many news outlets drew exactly this message from the paper, and from interviews with the authors. The paper itself is much more nuanced, but nuance makes for bad headlines.
It is an unfortunate message. Lung cancer, the leading cause of cancer death in the United States, is largely preventable. Cervical cancer, a viral disease, is largely preventable, as is hepatocellular carcinoma. Large percentages of head and neck cancer, esophageal cancer, bladder cancer, and skin cancer (among others) are largely preventable. If the public views lung cancer as “bad luck,” why quit smoking? If cervical cancer is “bad luck,” why bother to vaccinate your twelve-year-old daughter? Why put on sunscreen if skin cancer is “bad luck”?
“Bad luck” absolves one of responsibility, and therefore of any need to live one’s life in a healthy way. If a man with a gambling addiction goes broke at the racetrack, “bad luck” is a useful excuse. If a two pack-a-day smoking habit, another addictive behavior, leads to small cell lung cancer, “bad luck” implies the smoker is not responsible.
The other problem with the paper is the very concept of “bad luck.” A public that believes in ghosts to a greater degree than evolution may take an essentially supernatural view of “bad luck.” “Bad luck” may not, in the universal hierarchy, be at quite the same as divine will or destiny or fate. But some of my patients believe that there is a degree of supernatural intent at work there, cancer as cosmic payback for a youthful indiscretion, or a family curse at work.
The world is full of superstitions, and many of these are medical: the belief, enshrined by generations of ER doctors, that the full moon floods the emergency room with crazies, or that Friday the 13th increases the trauma load. Statistically not the case, a PubMed search assures me, but I’ve heard it affirmed dozens of times. For what it’s worth, the only strong correlation I ever saw in the ER was with the Super Bowl or the World Series: heart attacks could wait until the end of the game.
In Ireland there is a common belief that a Saturday hospital discharge is bad luck, and associated with rapid readmission: “Saturday flit, short sit.” Some 13.7% of patients interviewed for a study published in the Irish Medical Journal would refuse a Saturday discharge, and 40% of doctors would humor them.
One thinks of Shakespeare’s lovely line in Hamlet: “There’s a special providence in the fall of a sparrow.” At some level we want our lives to have a special providence, even our personal catastrophes: “I got cancer because I was doomed to get cancer” may be more satisfying than what the authors of the Science paper actually meant: a stochastic process, a probabilistic event without any deeper meaning.
In short, we mean “bad luck” in the sense first described by Pascal in the seventeenth century. Pascal, attempting to understand games of chance, rendered the supernatural natural: you lost that card game because the odds were against you, not the gods. Kiss the dice for good luck all you want, but when they roll on the table randomness prevails.
Pascal was an essentially gloomy philosopher/mathematician: though religiously devout, his blinding mathematical brilliance had the effect of stripping the universe of mystery. He was also terrified by what he saw through the telescope: “Le silence éternel de ces espaces infinis m'effraie.” The eternal silence of these infinite spaces frightens me: he believed the universe to be essentially random, but did not like what it implied.
Nor was he the only great scientist who detested randomness, The great 20th century debate between Bohr and Einstein over quantum theory largely boiled down to the issue of randomness. “God does not play at dice,” Einstein famously said. Bohr supposedly responded “Albert, stop telling God what to do with his dice.”
But even Bohr allowed for the possibility of good luck, keeping a horseshoe above his door, as was then a common superstition in Denmark. Asked whether he really believed that it brought him good luck, he replied “Of course not…but I am told it works even if you don’t believe in it.”
It’s a principle that I can endorse. So, after a second opinion, as we shake hands and prepare to leave the room, my last words to the patient are always “best of luck to you.”
Monday, December 22, 2014
Breast cancer is not so much a disease as it is a universe: endlessly complex, huge, and continuously evolving. 2014 saw fascinating glimpses of where the new biology of breast cancer is taking us, as well as some important clinical advances.
Genetics and Biology
Let’s begin by looking at several fascinating stories involving biology and genetics. Physicians have, since the mid-1990’s, screened patients for mutations in BRCA1 and 2. Such testing was expensive, controlled by a single company, and occasionally confusing (the dreaded “Variant of Unknown Significance”).
The landscape of genetic testing is now in hyper-evolution. The Supreme Court’s invalidation of the Myriad patent has led to multiple new diagnostic companies entering the field, with a consequent fall in prices. At the same time, so-called “panel testing” has come to the fore, with broader sweeps of the human genome than just BRCA 1 and 2.
Kurian et al. (J Clin Oncol. 2014 Jul 1;32(19):2001-9) looked at panel testing in a population of women referred for genetic testing who proved to be BRCA-mutation-negative. Overall, 11.4 % of these women harbored another mutation associated with a human cancer (including ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4), though many of these were mutations not typically thought of as predisposing to breast cancer. Many of these were “actionable” mutations in that they would normally lead to some diagnostic or therapeutic intervention.
One mutation that drew particular scrutiny this year was PALB2. This somewhat low-frequency mutation had been known for some time to be associated with a higher rate of breast cancer, though until the paper by Antoniou in the NEJM (2014;371:497-506) the strength of this association had not been recognized. The authors estimated that a patient harboring a PALB2 mutation carries a risk of developing breast cancer of 35% by age 70. This makes PALB2 as being a heavy hitter in terms of breast cancer risk.
Tumor genomics, like host genomics, continues to excite. My favorite breast cancer genomics paper in 2014 was a Nature paper by Wang and colleagues at MD Anderson (Nature. 2014 Aug 14;512:155-60) looking at single cell genomics. The original genomics studies involved looking at populations of breast cancer cells within a tumor. The technology has now improved to the point that one can isolate single cancer cell nuclei and perform deep sequencing.
The world revealed by single cell sequencing is fascinating and frightening. Looking at ~50 cells per tumor, the authors stated “No two single tumor cells are genetically identical.” Heterogeneity reigns at the single cell level, and certainly goes a long way to explaining the ineffectiveness of current therapies for metastatic breast cancer: the whack-a-mole phenomenon of compensatory resistance is common when a cancer as a multitude of mutations. In one triple-negative breast cancer studied, 374 clonal mutations were seen across the cancer, with an additional 154 subclonal mutations, a quarter of which are predicted to affect protein function. Such studies suggest that there are hard limits to kinase-based approaches for many breast cancers.
One of my favorite papers this year, published in JAMA (312(9):902-14.), was a population-based study (189,734 women) of contralateral prophylactic mastectomy. Bilateral mastectomies have increased significantly in recent years (from 2.0% to 12.3% between 1998 and 2011 in California), particularly in younger women. This is the result of increased genetic testing, increased use of breast MRI’s, changes in plastic surgery techniques, and increased public awareness (the “Angelina Jolie effect”).
But does contralateral prophylactic mastectomy improve outcome? The answer, as the JAMA study clearly demonstrates, is no. When compared with lumpectomy and radiation therapy, 10-year overall survival is virtually identical. Interestingly, unilateral mastectomy is inferior to both bilateral mastectomy and lumpectomy plus radiation therapy, perhaps suggesting that patients with more aggressive cancers are more likely to undergo mastectomy than lumpectomy.
Breast Cancer Subtypes
Breast cancer, as we have realized for the past decade or more, is a collection of diseases, with distinctive biologies and (more-or-less) specific treatments. Describing breast cancer therapy necessarily requires an understanding of breast cancer subtypes. 2014 brought us interesting new information regarding the main subtypes.
In estrogen receptor positive disease, the field awaits the completion of large phase III metastatic trials (some of which may report out in 2015) for approaches involving CDK 4/6 inhibition and HDAC inhibition, both of which have had promising results is underpowered randomized Phase II trials.
While we hold our collective breaths awaiting such results, 2014 saw the presentation (at ASCO and San Antonio, and in a recent NEJM publication) of the SOFT and TEXT trials in premenopausal estrogen receptor positive breast cancer. These trials asked straightforward yet important questions: should tamoxifen continue as the standard of care for premenopausal ER-positive disease in the adjuvant setting, or should (as smaller, earlier studies suggested) we add ovarian suppression to the mix? And, if ovarian suppression adds something, should it be combined with tamoxifen or with an aromatase inhibitor?
SOFT (N Engl J Med. 2014 Dec 11. [Epub ahead of print]) randomized patients to tamoxifen alone, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. While ovarian suppression did add significant benefit or the overall group (which contained a substantial portion of low-risk, node-negative patients), planned subset analyses revealed a significant benefit for the more high-risk subgroup of women who had received chemotherapy and remained premenopausal. Here the rates of freedom from breast cancer at 5 years were, respectively, 78% (tamoxifen alone), 82.5% (tamoxifen plus ovarian suppression), and 85.7% (exemestane plus ovarian suppression).
The age breakdown in SOFT was also of interest. In women younger than 35, freedom from breast cancer at 5 years was 67.7% for tamoxifen alone, 78.9% for tamoxifen plus ovarian suppression, and 83.4% for exemestane plus ovarian suppression. This is an impressive difference, though the number of patients analyzed in this subset was small.
Ovarian suppression in premenopausal women is not without a price; premature menopause carries significant symptomatic burdens regarding hot flashes, sexuality and bone health. Understanding that, the data would certainly suggest that exemestane plus ovarian suppression should be part of the treatment discussion for high-risk premenopausal women (defined as women receiving chemotherapy and those under age 35 in the study).
2014 was a year both of triumph and disappointment in the HER2-positive world, as physicians tested novel combinations of HER2-targeting agents. On the disappointment side of the ledger, the long-awaited ALTTO trial, presented at the ASCO annual meeting’s plenary session, failed to demonstrate a significant benefit for the addition of lapatinib to adjuvant trastuzumab. In addition to representing the failure of a drug, the trial results called into question the suggestion that neoadjuvant trials would represent a valuable surrogate for adjuvant trial results, a hypothesis that had led to an FDA draft document for preoperative drug development.
What the ALTTO trial clearly did not do was put a damper on HER2 combinations. The CLEOPATRA trial, originally published in 2013, demonstrated a progression-free survival advantage for the addition of the monoclonal antibody pertuzumab to trastuzumab. This year’s European Society for Medical Oncology meeting updated the trial results, and the results were stunning. Front-line metastatic HER2-positive patients randomized to the combination of docetaxel, trastuzumab and pertuzumab lived a median of 56.5 months, versus the 40.8-month median for docetaxel and trastuzumab. This is a stunning result. In the past 15 years, survival for metastatic HER2 positive disease has almost tripled, and is now at least equivalent to, or perhaps superior to, that of ER-positive disease.
Pertuzumab has already entered the neoadjuvant setting as a result of an FDA approval, and more standard adjuvant trials (including combinations with T-DM1) are ongoing. If the results of these trials mimic those of CLEOPATRA, then HER2-positive disease may cease to be a major public health hazard. If so, this will represent a signal accomplishment for the breast cancer clinical trials community.
Along the lines of “science by press release,” we are told that there is a positive “late adjuvant” trial for the small molecule HER2 inhibitor neratinib, and that the MARIANNE trial has failed to show additional benefit for the addition of T-DM1 to pertuzumab in the metastatic setting. Both of these results should be presented more formally in coming months.
Triple-Negative Breast Cancer
With real advances in ER-positive and HER2-positive breast cancer (and even more within our short-term reach), triple-negative breast cancer remains stubbornly recalcitrant. For practical purposes, treatment remains confined to chemotherapy, and advances in the past decade (e.g., eribulin in the metastatic setting) have had only a minimal effect on overall outcome. Recent years have explained why this is the case: genomic studies have identified triple-negative breast cancer as a subtype dominated by genomic chaos. Combined with the lack of our favorite breast cancer targets (ER and HER2), this genomic instability dooms our treatment approaches to rapid failure in all too many cases.
Are we beginning to find our way out of this morass? Perhaps. Numerous drug targets have been identified based on subsetting of triple-negative breast cancer. This year’s San Antonio Breast Cancer Symposium saw two interesting triple-negative presentations that may point the way forward.
First, Andrew Tutt and colleagues presented the results of the TNT trial. TNT randomized front-line metastatic breast cancer patients to either docetaxel (100 mg/m2 every 3 weeks) or carboplatin (AUC of 6 every 3 weeks). Platinating agents have been around since the 1980’s, and taxanes since the 1990’s, but neither had been tested head-to-head prior to TNT.
This would have been a quite boring Toothpaste A vs. Toothpaste B chemotherapy trial were it not for the biologic correlates included by the investigators. While overall the trial was a wash, with no significant difference in progression-free or overall survival, in BRCA1/2 mutation carriers, carboplatin was the clear winner over docetaxel (68% vs 33% response rate, p =.03). And while carboplatin had a mediocre progression-free survival in BRCA wild-type patients (3.1 months), PFS was twice as long in BRCA 1/2 mutants (6.8 months). DNA damage repair clearly matters when one is using a DNA-damaging agent.
Secondly, while finding the right place for an old drug is clearly of value, we do need new approaches to triple-negative. Rita Nanda and colleagues offered us a glimpse of the future with their Phase Ib study of the checkpoint inhibitor pembrolizumab (an anti-PD-1 IgG4 monoclonal antibody) in triple-negative breast cancer. Using PD-L1 positivity as the trial’s gateway, an overall response rate of 18.5% was seen in a smallish (27 evaluable patient) cohort. Short follow-up and small numbers, but several robust and durable responses were seen.
Similar results, albeit with an even smaller Phase I study, were seen with another checkpoint inhibitor called MPDL3280A. Immuno-oncology appears poised to spill over from melanoma and lung cancer into triple-negative breast cancer: more to come, I am sure, but 2014 appears to be a transitional year between receptor-based approaches that have dominated the past decades and newer approaches that may bring us closer to a cure.
Wednesday, December 03, 2014
Case 75, an infant, presented to the Clinical Genomics Center at UCLA with a history of multifocal complex partial epilepsy and regression of developmental milestones. The child, as well as the two parents, underwent clinical exome sequencing (so-called trio-CES). You can imagine what it must have been like to be the parents of such a child, their desire to understand what caused such misery, and the hope that something beneficial might emerge from genomic analysis. Sequencing revealed that the child carried a previously undescribed missense variant in KCTN1, which encodes the KCa4.1 protein, a member of the calcium-activated potassium channel protein family.
When I was in training, and for many years thereafter, the description of such a case, and the identification of its etiology, warranted a paper in the New England Journal of Medicine or The Lancet. When the Human Genome Project opened its doors there were only some 25 well-delineated inherited diseases of metabolism. Now, according to the authors of a stunning recent JAMA paper on clinical whole-exome sequencing, the Online Mendelian Inheritance in Man website lists some 4000 disease-gene relationships. What was once impossible has become commonplace, even trivial.
At the UCLA center, 814 patients underwent whole exome sequencing, and 26% had a molecular diagnosis. Similar results were seen in 2000 patients studied at Baylor, where 25.2% had a diagnostic mutation detected. The Houston authors state that 58% of the diagnostic mutations were previously unreported. New diseases are raining down on us faster than any of us can possibly comprehend.
The genomic revolution continues to dazzle. I cannot imagine any more exciting time to be alive. Can there be any time in history when we have learned so much about human biology in so short a time? This seems the equivalent of that period early in the twentieth century when physics exploded, with atomic theory, special and general relativity and quantum mechanics all unrolled over a decade or two, the world utterly changed.
Some of it is cancer biology, and some just (just!) general biology. Starting with the human genome project, and continuing with The Cancer Genome Atlas project and its many relatives, we've seen a technological juggernaut roll through every aspect of human biology, indeed every aspect of biology. We've gone both deeper and wider, as the two JAMA papers suggest.
Leaving aside the "cool" factor of such work, this new look at human biology has profound implications for physicians and their patients.
When whole exome sequencing becomes cheap and ubiquitous, basically something you get on a newborn like Tay-Sachs testing, what do you do with the results? Do you tell the child's parents, their pediatrician (or geriatrician--some of these things may take a lifetime to emerge), or their insurance company?
And when you go looking, you frequently find something else, something unexpected. In the 2000 patients tested at Baylor, 92 patients (4.6%) had a medically actionable incidental finding. Looking over the list reported in the paper, I see old friends such as BRCA 1 and 2, PALB2, RAD51D and RET, among many others. Remember, they were not being tested for this: just incidental findings with the promise of future misery, or perhaps medical salvation.
What to Do with Results of Panel Testing?
One of the current debates going on in guideline committees involves what to do with the results of panel testing, and whether even to order panel testing. If I order a panel test because I suspect my patient has a BRCA mutation, and I find a gene predicting an increased risk of colorectal cancer, or (further afield) hypertrophic cardiomyopathy, what is my ethical and practical responsibility as a physician? What do I owe my patient, or my patient's children, or society (health economics rearing its ugly head almost immediately)?
My personal bias, for what it’s worth, is that such broad panel testing is inevitable technologic imperialism, like we see with just about every potentially useful diagnostic technology. There is part of me that wants to shout, just like when viewing some not very bright teenagers in a slasher movie, “Don’t look behind that door. There are monsters there.” But we always open that door. Always.
And how do the tests affect a patient sitting in the room with the doctor? How does knowledge of a KCTN1 missense variant help a baby with partial complex epilepsy? And if it does not, do we even want to know? We all know Francis Bacon's dictum that knowledge is power, but what happens when knowledge leaves the doctor powerless in the face of a previously undescribed disease?
O brave new world, that has such testing in it.
Most oncologists aren't cancer geneticists, at least not yet, though we may be forced into the role sometime soon. But the broader, deeper aspects of the genomic revolution are clearly affecting how we think about the cancer patients we see. When, a couple of years ago, the first decently sized genomic evaluations of human cancer began to come out, we were all impressed with the large number of mutations, and in particular the ubiquity of rare driver mutations seen across common human cancers.
These studies, it now seems obvious, seriously underestimated the problem for many cancers. The original TCGA work, for instance, tended to focus only on mutations occurring in more than 5% of a particular cancer's cells. This meant, as was recognized at the time, that we were missing many low frequency mutations buried within a cancer's genome. Now we are beginning to see what deep, dark waters there are in the genome's abyss.
Wang and colleagues (Nature, 2014; 512(7513):155-60) performed single cell whole genome sequencing on tumors from two breast cancer patients, one ER-positive and one triple-negative. In the first cancer genome studies, one chose an area with high tumor cellularity, ground it up, and took what was essentially a family portrait. If the family had eight adult brunettes and a runty blond baby sitting behind them, you only saw the brunettes. With single cell whole exome sequencing, if you sequence enough cells (the Nature paper sequenced about 50 per tumor), the rare family members pop out. Single cell sequencing allows a collection of individual portraits to complement the family group picture.
The first thing one discovers is the incredible variability of cancer cells. The authors state “No two single tumor cells are genetically identical,” which I find somewhat scary. The triple negative breast cancer they examined didn't even pretend to be a single cancer, having three distinct subtypes buried within the cancer and a myriad of private mutations.
For the past several years the emerging genomics have depressed me even as they have fascinated me. Hypervariation is obviously a bad thing if one is throwing kinase inhibitors at a cancer: the whack-a-mole problem of compensatory resistance mechanisms dooms monotherapy approaches to inevitable failure.
But the silver lining of genomic hypervariability is now beginning to be seen in the immune checkpoint field. Genomic hypervariability is associated with neoantigen diversity. A recent evaluation of melanoma patients treated with the checkpoint inhibitor ipilimumab demonstrates a link between genomic instability and tumor response: the more mutations per megabase, the better the response to Ipi.
Mutations per megabase is not a great way to select therapy (the same New England Journal of Medicine article presents a signature that is a better predictor of response), but I suspect the concept is sound. The current issue of Nature, as I write this blog, has five manuscripts devoted to cancer immunotherapy. Among them are some fascinating pieces of information: the emerging evidence that checkpoint inhibition immunotherapy will be useful in bladder cancer (a disease sorely in need of new therapies), and the importance of PD-L1 expression on tumor infiltrating lymphocytes as a marker of response.
But what really caught my eye was evidence, in two of the papers, that checkpoint inhibition would be particularly successful where there are specific tumor neoantigens. Much of the genome literature in recent years has distinguished “driver” and “passenger” mutations. One can imagine a driver mutation saying to a passenger “You’re just along for the ride. I’m the one that matters. I drive the cancer.” And this statement is no doubt true when one speaks of kinase inhibition for a cancer. It’s been the basis for drug discovery in the last decade: find the mutant growth factor, find a molecule to block it, treat.
But in the world of immunotherapy, the drivers are just chauffeurs; the important guys sit in back, like fat cat bankers in a black stretch limousine. The “passenger” mutations signal the immune system, unleashed by anti-PD1 antibody, to attack the cancer cell. So finding genomic hypervariabilty in a patient's cancer may lead, not to despair, but to a PD1 inhibitor.
Getting back to my earlier concern that knowledge is not always power, it is perhaps best to add a qualifier: "yet." Identifying the genomic disorder underlying a baby's seizures may not be actionable today, but if you believe that progress results from the progressive accumulation of facts, and our ability to weave those facts together into testable hypotheses and new therapeutic approaches, then some day that KCTN1 missense variant test result may be accompanied by a doctor telling the parents "but we've got a treatment for that" and a prescription. So what if there are 4000 gene-disease relationships in the online databases? Indeed, so what if it is 10,000 next year? So what if the cancer has a myriad of mutations? We have lots of assistant professors, and all the time in the world, to solve these problems. That's what we do.
Sunday, November 16, 2014
No birds sing on the island of Guam. Sometime in the 1940s the brown tree snake, native to Australia and New Zealand, arrived there, probably in the cargo hold of a passing ship. It had no natural predators, and was let loose on an island rich in wildlife. It proliferated madly, causing the extinction of numerous vertebrate species as it spread.
Something very similar is happening in Florida. The Burmese python, introduced by the pet trade, was first sighted in the Everglades in the 1980s. By 2000 or so there were well-established reproductive populations, and between 2000 and 2010 these grew exponentially. There are now estimated to be somewhere between 30,000 and 300,000 Burmese pythons in southern Florida, with effects on wildlife similar to those in Guam, writ large. These pythons are now genetically distinct from the pythons of Burma, but remarkable in their own lack of diversity: a clonal population run wild.
Or, if you appreciate unintended irony, take the case of Darwin’s frogs, the Chilean amphibian first described by the great evolutionary biologist during his voyage of discovery on HMS Beagle. Darwin’s frogs (Rhinoderma rufum is the proper scientific name) have likely gone extinct, the result of the introduction of a toxic fungal species, Batrachochytrium dendrobatidis.
Batrachochytrium dendrobatidis causes chytridiomycosis, a disease characterized by the inability to breathe, hydrate, osmoregualte, or thermoregulate correctly. It is sweeping around the globe, wiping out amphibian species wherever it lands: as many as 30 percent of amphibian species worldwide may be affected. Amphibians have been around for 365 million years, but their biodiversity is collapsing due to an invasive species.
The brown tree snake and the Burmese python and chytridiomycosis are part of a growing, and global problem: the spread, through human agency, of invasive species. These invasive species are an important part of what has been labeled “the sixth extinction.”
The previous five great extinctions (such as the meteor that wiped out the dinosaurs) were caused by cataclysmic natural events. The sixth extinction is on us: the species have spread sometimes through intent (the Burmese python) and sometimes by mistake (the brown tree snake), but always through human intervention.
The results have been devastating, with loss of biodiversity on a worldwide scale. They are also very expensive: one estimate puts the economic burden of the 6500 harmful invasive species in the United States at $100 billion per year. Not too different from the cost of cancer care in the U.S., I would guess, or at least the same order of magnitude.
Analogies are always dangerous, because biology is so particular and contextual, but the invasive species studied by wildlife ecologists seem, well, almost like cancer. They spread from their initial ecosystem, establish themselves at a distant site, proliferate madly, and push aside the normal hosts, in the process reconfiguring the microenvironment of the distant site. Uncontrolled, they eliminate their hosts.
This connection has not been lost on either ecologists or cancer researchers, both of whom now make use of each other’s scientific approaches. It is one of the delights of science that we can make important contributions through repurposing insights from one field to another, and the cancer-wildlife ecology connection is a good example of this phenomenon.
Take the Shannon index. Claude Shannon was one of the greatest, and least recognized, 20th century scientists. He is, for practical purposes, the father of information theory, and his work underlies much of the computer technology we take for granted. Shannon was interested in entropy (information loss) in strings of transmitted text, and his Shannon index was designed to measure the degree of that entropy.
Wildlife ecologists use the Shannon index to measure species biodiversity. A big issue surrounding the introduction of invasive species involves its effects on the overall biodiversity of an ecosystem. If the brown tree snake assassinates Guam’s birdlife, the biodiversity of the island diminishes, an impoverishment that ultimately affects us all. One can measure biodiversity using the Shannon index, the equation for which, for those who are interested, is as follows:
The Shannon index has been applied to cancer ecosystems as well. Intratumor diversity differs among cancers. For instance, among breast cancers, triple negative breast cancers are more genotypically diverse than luminal breast cancers, and their “biodiversity,” as measured by the Shannon Index, may predict patient survival. Distant metastatic deposits (the true “invasive species”) tend to have a greater degree of diversity than the primary tumor, perhaps a reflection of the treatments they have been exposed to. Vanessa Alemendro’s recent Cancer Research paper (Cancer Res; 74(5); 1338-48, 2014) is a nice starting point on this topic. Similar results have been seen in Barrett’s esophagus, where the Shannon index of a lesion predicts progression to frank esophageal cancer.
Evolutionary Imbalance Hypothesis
A colleague recently referred to Charles Darwin as “the first and best oncologist.” The Shannon index/biodiversity story is further evidence that this is true. Recently two evolutionary biologists, Dov Sax of Brown University and Jason Fridley of Syracuse University, have proposed what they call the Evolutionary Imbalance Hypothesis of invasive species.
The EIH goes something like this: species from regions with deep and diverse evolutionary histories are more likely to be successful invaders of regions with less deep, less diverse evolutionary histories.
Sax and Fridley have put EIH to the test through statistical analysis of multiple “host” and “recipient” ecosystems, looking both in the plant and animal kingdoms, and the hypothesis always appears to ring true. Humans have created several unintended experimental tests of EIH: digging the Suez and Panama canals exposed, in each case, a more evolutionarily diverse ecosystem to a less well-developed ecosystem. Guess who invaded whom?
EIH is nothing new, the authors point out: Darwin proposed it in 1859, saying that better tested species have "consequently been advanced through natural selection and competition to a higher stage of perfection or dominating power." When I think of a nice, well-behaved tubular breast cancer, each cell looking like its neighbor, each with a low mutational load, and compare it with a high-grade, genomically diverse basal breast cancer, and the subsequent fate of their hosts, I can only repeat, “Darwin was the first and best oncologist.”
Ken Pienta’s group at Hopkins has taken the connection even further, explicitly making the link between metastasizing cancers and invasive species. Invasive species, they point out in a recent paper (Journal of Cellular Biochemistry 115:1478–1485, 2014), are ecosystem engineers, reconfiguring their microenvironment “as they construct a niche that is favorable to their own survival.”
This niche construction results in ecologic inheritance, “the inheritance, via an external environment, of one or more natural selection pressures previously modified by niche-constructing organisms.” Pienta’s group has championed the use of mathematical approaches derived from the ecology literature (the Tilman equations for modeling the invasion of two species into a defined space) to describe bone marrow metastasis.
Tumors are great ecosystem engineers, through the secretion of cytokines and growth factors that permanently alter the neighborhood they live in, making life easier for their progeny. But whereas many invasive species eventually reach some sort of homeostasis with their new ecosystem, cancers rarely do so. Their ecosystem engineering, successful in the short term, ultimately results in environmental collapse, and the death of the host.
So are they “successful” invasive species, or not? It’s all a matter of perspective, and the duration of the perspective. They are successful invaders right up to the patient’s last breath.
And, at the need of the day, so what? Both of the groups mentioned above have suggested that we might use ecologic principles as part of a therapeutic attack on metastatic lesions. One wonders whether the recent immunologic approaches using checkpoint inhibitors (anti-PD1 and PDL-1) are a partial answer to the ecologic observations regarding tumor biodiversity: the more genomically and antigenically diverse a cancer (think melanoma and smoking-induce lung cancer), the more sensitive to immunotherapy? Is the Shannon index as a predictor of immunotherapy benefit? It’s a thought.
Wildlife ecologists are just beginning to draw on the cancer experience, if my cursory review of their literature is correct. While they regularly refer to invasive species as a form of ecosystem cancer, they are just beginning to think about what it takes to wipe out these “cancerous” species. A recent press release by the US Geological Survey pointed out that the cancer model of “prevention, early detection, diagnosis, treatment options and rehabilitation” made perfect sense, and this combined approach is being used to combat invasive American bullfrogs in the Yellowstone River of the Northern Rockies. I just hope invasive American bullfrogs are easier targets than triple negative breast cancer.
Humans are the ultimate invasive species, and the one that allowed all the others to spread. We’re responsible for the extinction (outside of 1.5% of our own genome) of our closest relatives, the Neanderthals, as well as the many other large mammalian and avian species that have disappeared since we conquered the world. We’ve provided the conduits for all the other invasive species that are performing ecosystem engineering on a global scale.
It would be easy to say that we are the ultimate cancer, the one doing its level best to foul its global environment. Indeed, many have said something like this. But if so, we are surely the first cancer with a conscience, and perhaps the only one ultimately capable of reining itself in before it kills its host.
Let’s hope that the fields of wildlife ecology and cancer biology continue to cross-fertilize, to the benefit of both planetary and human ecosystems. Let’s pray that we continue to be a “successful” invasive species.
Friday, September 19, 2014
Recently I was dining with friends, enjoying a pleasant Palo Alto evening on their porch. We noticed a family of quail walking on the ledge of the wooden fence that enclosed the yard, a mother and her brood of children. They hopped down into the yard. A peregrine falcon was sitting atop a tall tree, off in the distance. To me it was a thin smudge, featureless and motionless, perhaps a football field away. I suspect the falcon saw every minor blemish on my face. A falcon's vision is considerably better than that of an aging medical oncologist: they can see prey three kilometers away.
At some intellectual level I was aware that falcons were predators, capable of swift, violent action. My hostess even mentioned that she hoped the falcon had not seen the covey of quail. But we gave the falcon little thought until it fell from the sky, talons out, into the gathering of quail: a large, close blur, shocking in its suddenness, striking just feet from where we sat. I could have sworn I had seen it on that distant tree just seconds before, and that was in fact probably the case: falcons have been clocked at speeds as high as 242 miles per hour during their hunting stoop. They are, as I now know, the fastest animals on the planet.
One of the memes running through oncology right now is that of "cancer as a chronic disease." If you enter it as a search term in Google you get 54,100 hits. The idea taking hold is that we are entering a time when the average patient's cancer will be held in check through the judicious use of systemic targeted agents. Years will pass, the patient in generally good health.
I must admit that the phrase "chronic disease" always gives me pause when I hear it in relation to cancer. Historically, physicians separated acute illnesses such as pneumonia from chronic illnesses such as rheumatoid arthritis or diabetes. Prior to the advent of antibiotic therapies in the 1940's it was the acute illnesses that tended to kill; afterwards there was a progressive shift to chronic disease as a cause of death.
From a definitional standpoint, the standard definition of a "chronic disease" is “a long-lasting condition that can be controlled but not cured.” Most human solid tumors meet this definition, and are recognized as such by the CDC.
But I think that when we talk about "cancer as a chronic disease" we are usually thinking of something else: basically, the cancer goes into the stasis field of modern medicine and does not emerge to kill you. My patients certainly think in those terms.
There are, of course, some real candidates for what I might consider true chronic disease status, the oncoequivalent of "take your insulin and it won't kill you": chronic myelogenous leukemia, controlled with imatinib, or an ER-positive breast cancer held in check with an aromatase inhibitor for prolonged periods. Or, to a somewhat lesser degree, metastatic HER2-positive breast cancer, or metastatic colorectal cancer, or renal carcinoma, all diseases where survival has significantly improved through the application of targeted therapies.
Scientifically this rapidly brings us to the question of treatment duration. Here we are trapped in empiricism. Mother Nature selected a year of HER2-targeted adjuvant therapy with trastuzumab as optimum. Not six months, not two years, but the time it takes the earth to circle the sun. Or maybe not: adding a year of adjuvant neratinib to your year of trastuzumab may improve disease-free survival. Three years of adjuvant imatinib is better than one year for GIST tumors post-surgery. How about five?
For early stage ER-positive breast cancer, ten years of tamoxifen is better than five years is better than three years is better than one year: every time we have studied duration, longer is better. Though, of interest, the disease-free survival curves never quite plateau: are we are just delaying the inevitable?
And if so, is it really a chronic disease? If you stop treating rheumatoid arthritis and your joints get hot again, you may be miserable but you probably will not die, and have a good chance of going back into remission with the same old drug: joints don't mutate. If you have metastatic breast cancer you are walking around under the cloud of a death sentence, any temporary stay of execution provided by fulvestrant or T-DM1 notwithstanding. Part of my problem with "cancer as a chronic disease" is exactly this: I know few individuals who would trade RA for metastatic cancer. Equating them seems somehow disingenuous.
I keep thinking of that peregrine falcon and the quail family. I have had a number of patients who I have sheparded along for years, occasionally decades, with either estrogen receptor-targeted or HER2-targeted treatments. It is easy to contract and propagate the "cancer as a chronic disease" meme with such patients. The clinic visits become celebrations of the doctor's therapeutic virtuosity and the patient's family anniversaries, with drugs being switched in and out every now and then when the CAT scan demonstrates modest progression.
You can almost fool yourself into believing that the patient doesn't have a lethal disease. And then the falcon swoops in. “Chronic disease” can turn into “acute and lethal” in a shockingly brief period. One clinic visit you are discussing an upcoming high school graduation, and then the next you are having an end of life discussion.
I do not know why it is--perhaps because the patients have transitioned from being patients to old friends--but the death of a patient whom I have treated for a decade usually hits me harder than one who dies quickly. There is no intellectual reason for this: the death of a long-term survivor suggests I was actually doing my job, and I should be delighted that I have added many years of high quality life rather than just a few. But it always leaves a bitter taste in my mouth. I doubt it is an experience a rheumatologist deals with very often.
Like some old soldier looking over the parapets at a distant enemy, I have learned to respect my foe's endless ingenuity, its treachery, its patient evil, and its almost maniacal drive to escape the barriers I try and throw up around it. We have, again and again, seen the ultimate failure of kinase-based approaches that have dominated the last decade, the consequence of smart tumor’s ability to mutate and evade.
The real "chronic disease" possibilities may lie within the realm of immune checkpoint inhibitors, where some (though certainly not all) melanomas appear to go into stasis for years and years, the body's immune system unleashed to keep the wolves at bay. The idea of metastatic melanoma as a chronic disease still boggles the imagination, but it certainly looks to be a real possibility for many patients. Whether I want my T regulatory system ramped up for the next decade or two remains to be seen. I suspect we will be keeping the immunologists and rheumatologists very busy: more chronic disease.
Are there any other approaches that might turn human cancer into a true chronic disease?
I present for your edification the naked mole rat. These are probably the ugliest mammals on the planet, almost disgustingly so. They are also the longest-lived rodents we have, clocking in at 30 years, a good life if living in total darkness underground in what one leading student of the species has described as a “dictatorship” is your cup of tea.
But here is the really interesting thing: they never die of cancer. I don't mean rarely, I mean never.
It doesn't matter how hard you try, either. Pump them full of carcinogens, and they just go on their merry, repulsive way, burrowing through the earth as if nothing had ever happened. And why is this? It turns out that the naked mole rat produces generous amounts of a high molecular weight form of hyaluronic acid, an evolutionary adaption that changes their skin to something quite stretchy and allows them to easily traverse underground passages. This form of hyaluronic acid has the pleasant side effect of walling off individual cancer cells before they can gain mass or metastasize. The naked mole rat buries the cancer cell in concrete. This is a spectacular example of a microenvironmental approach to cancer.
Cancer cells live in neighborhoods, and for the past decade or so we have been enlisting the neighbors (blood vessels, T cells) in the neighborhood watch. These microenvironmental approaches have started to take off, and I suspect (based partly, but not entirely, on the naked mole rat story) that we just at the beginning of such interventions. Hopefully we will not end up looking like naked mole rats.
Naked mole rats also have exceptional transcriptional fidelity. This error-free life also protects them from cancer. So taken are laboratory researchers with the naked mole rat that Science magazine declared it the “Vertebrate of the Year” in 2013, and there has been an explosion of scientific articles plumbing the rodent’s exceptional longevity and freedom from cancer. And, of course, a naked mole rat genome project.
But back to the falcon and the quail. For a brief second after the falcon struck, we were unsure of the outcome. We couldn't see whether the falcon had succeeded in snatching one of the young covey. Then there was an explosion of quail, noisy, vectored in multiple contradictory directions, their panic reigning supreme. And then, much more quietly than the quail and more slowly than he had arrived, the falcon took off, talons empty: not today. Not today. Not today!