Musings of a Cancer Doctor
Wide-ranging views and perspective from George W. Sledge, Jr., MD
Thursday, June 11, 2015
I am no racing fanatic. I have never been to the track, know virtually nothing about horses, and can go years without seeing the Kentucky Derby on TV. I have never seen the Preakness, and the Belmont Stakes only rarely. I have never placed a bet in my life. While I find them quite beautiful, I am aware of the price these highly inbred animals pay for our amusement. But like many I was caught up in the recent Triple Crown mania and its protagonist, American Pharoah.
In the days leading up to the Belmont stakes I read an article saying that it was unlikely, indeed almost scientifically impossible, for American Pharoah to triumph, no matter how good a race he ran. The odds were stacked against him. The tight schedule of Kentucky Derby to Preakness to Belmont took too much out of even the best of horses. Other horses, having missed one or both of the other two races, simply had greater reserves, more stamina, and more stored glycogen to burn. It had been thirty-seven years since the last Triple Crown winner for a reason. In fact, the odds were against any horse winning the Triple Crown.
Certainly his trainer must have shared that concern, and the jockey that rode American Pharoah. They had been in the same situation before, winning the first two races only to lose the third. One might hope that this time things would be different this time, but what were the odds? Upsets weren't just common, they were ubiquitous.
As I sat in front of my television over the weekend, my mind drifted to the ASCO annual meeting I had just attended. As at every ASCO, I had caught up with old friends, attended talks, gone to innumerable side-meetings, and inhaled the Onco-zeitgeist.
Some years ASCO seems unalloyed triumph. Some years are years of consolidation. This was the latter, though "consolidation" barely seems to describe the forward progress of the checkpoint inhibitor juggernaut.
If a prize were given for "drug of the year" at ASCO, surely nivolumab would be the winner. The pride of the plenary session was Jedd Wolchok's presentation of the combination of nivolumab and ipilimumab for melanoma. The combination's median progression-free survival of 11.5 months easily beat out either single agent nivolumab (at 6.9 months) or ipilimumab (a piddling 2.9 months). Median overall survival for the combination has not yet been reached, but it was clear to all that we have passed an inflection point in the history of metastatic melanoma.
And not just melanoma. The Checkmate 057 nonsquamous non-small cell lung cancer trial (do we really have to say “nonsquamous non-small cell lung cancer” from here on out?) compared nivolumab with docetaxel in the second-line setting, and demonstrated a survival advantage, as well as the impressive "tail of the curve" effect we have seen repeatedly in immune checkpoint inhibitor trials. And there was nivolumab in hepatocellular carcinoma, with a 19% response rate, including complete responses: amazing for this disease. Nivolumab also looked like it might have a place in small cell lung cancer, a disease that has gone many a year since finding a new champion.
And not just nivolumab. Pembrolizumab is a star in Mismatch Repair (MMR) deficient colorectal cancer, with a 62% response rate (and inactive in MMR-proficient colorectal cancer, which makes for interesting biology). And pembro, like nivo, looked interesting in small cell lung cancer.
Recently a friend told me that he had called a major pharmaceutical company to speak to an individual involved in a trial he was opening. The voice at the other end of the phone asked: "Is he in Immuno-Oncology or Rest of Oncology?" Imagine having that conversation five years ago. Times have changed.
I think of the Annual Meeting's immune checkpoint story as the first leg of the Triple Crown, its Kentucky Derby, if you will. But what about the other two races in oncology's Triple Crown?
If I had to chose a topic for this year's Preakness race I would chose the word "value." Value kept coming up, both in the Plenary session, in other sessions I attended, and in conversations in the halls of the McCormick convention center.
Len Saltz gave his "Perspectives on Value" in the Plenary session, noting the astonishing cost of the new checkpoint inhibitors. The price of Ipi, for instance, is "approximately 4,000 times the cost of gold" on a weight for weight basis. Cancer drug prices bear little relationship to value, or to the cost of production, or even the cost of the research that goes into the making of the drugs. The prices are, quite simply, "what the seller thinks the market will bear."
These comments made their way to that altar of modern capitalism, the Wall Street Journal, whose well-insured readers no doubt considered Len's comments heretical. But the Value meme has taken hold in the oncology community, and I suspect will remain a concern and challenge for doctors and patients, just as it did for many speakers in many sessions. ASCO has taken some first awkward steps toward defining value, a difficult but necessary transition.
Defining value is tricky business, of course. I look at those first Ipilimumab patients in melanoma, some now a decade out and still in remission, and think "what a wonderful time to be an oncologist." Decades of research, the cynicism of most of us (about both melanoma and immunotherapeutic approaches), preceded this wonderful merger of science and clinical practice. I repeatedly find myself saying, "How cool is that?"
I love the basic science, the clinical-translational elements of the story, and the very real patient benefits, but I dread the financial consequences. A presentation that caught my eye was Aasthaa Bansal's study of the health effects of bankruptcy in cancer. It is quite simple: if you file for bankruptcy you are far more likely to die of your cancer. The adjusted hazard ratio for death was 1.79. Since health care costs are a leading cause of bankruptcy it is only a small stretch from the 4000-times-gold cost of a checkpoint inhibitor to, not just the poorhouse, but also the mortuary. Scary, but also an indictment of our dysfunctional American health care system.
"Value" too often ends up being about money, and rapidly devolves into sterile cost/benefit analyses. But what physicians value most is their time. While you can cost out time, doctors resent the unforgiving, irreplaceable, forever-gone nature of lost time. It is a major "value" issue. I saw this everywhere at this year's ASCO. There was a full education session devoted to the bureaucratic inefficiencies that waste our time. And, in the New Drugs in Oncology pre-meeting session, which I co-chaired, Tony Tolcher spoke eloquently of the ridiculous and unnecessary time burdens inflicted on clinical researchers.
These time-sucks are largely self-inflicted wounds. It is easy to blame the government, or the makers of electronic health records, or Pharma and the remora-like CROs attached to them, but we put up with this nonsense. If we are not quite losing the "Value" Preakness, we are certainly not winning it.
Which leads me to the Belmont Stakes, the third leg of the Triple Crown. I heard about this race mostly in side conversations with colleagues. The basic story was this: "I have no control over my life." Physicians in general, and oncologists in particular, have suffered a progressive loss of autonomy. They now feel firmly in the grasp of hospital bean counters who view them as interchangeable widgets, and information technology geeks who look on them as not very smart data entry specialists.
By chance, Dana Farber was transitioning from one electronic health record system to another while the Annual Meeting proceeded, and no one I met from Harvard thought it anything other than a massive waste of their time. Knowing the fate that awaited them I offered my condolences. The modern EHR is non-intuitive, treats doctors as secretaries, fails in its basic promise of inter-hospital connectivity, and is sold to hospitals for its billing benefits rather than for its timesaving characteristics. What's not to love?
I also heard from a young oncologist bullied by superiors over work RVUs. This doctor covered her salary, but that apparently was not enough: more was expected. She had gone into academic medicine in hope of a research career, and now she saw that career vanishing. The needs of the hospital corporation outweighed the needs of the individual. The time she needed to write protocols, produce papers, and perform research were considered unimportant. She was a widget, a part in the machine.
This is not just a complaint of the academics I met. All over the country the old private practice groups are disappearing, swallowed up by corporations. Few of the doctors I know are happy with these transitions. One I spoke to belonged to a practice that had been purchased by a large health care company, which then decided that the purchase had not met the corporate definition of a positive cost: benefit analysis. They had simply decided to stop paying physician salaries until the books balanced. The practice got out from under the corporation, at great cost, and now resides under the umbrella of an academic health organization, the lesser of two evils.
If the first leg of the Triple Crown was science, and the second value, let's call the third leg, for want of a better word, "happiness." Happiness is undervalued as a reason to come to work every day. Physicians burn out, or at least the ones I see leaving the profession, because they are no longer happy. By and large they still love their craft, adore their patients, and are thrilled by the scientific and clinical advances. The reasons they went into their profession are still there.
But I heard, over and over again, their unhappiness, and sometimes a feeling of desperation. I don't think I was projecting (really, I don't). These seem to be general stresses brought on by a change by medicine to something more corporate, more dollar-dominated. Perhaps more efficient as well; the old way of doing things was anything but efficient. But certainly we have arrived at a place where physician autonomy now resides in a very narrow space.
I saw bewildered-looking fellows navigating McCormick Place for the first time: enthusiastic, delighted to be in Chicago, a bit confused about what they had gotten themselves into. An old friend, standing next to me, turned and asked, "If you had to do it all over again would you still be an oncologist?"
I don't mean to leave this admittedly peculiar and particular view of the Annual Meeting on a down note. Nor do I mean to suggest that everyone is swigging Prozac cocktails, beating their collective chests, and wailing at the moon. They are not. But happy? Less so now than ever.
I do not think that there is anything inevitable in life, other than death and taxes, and I am not even sure about those. One of my favorite quotes is from Pericles of Athens’ famous funeral oration: "The secret to happiness is freedom, and the secret to freedom is courage." As a profession we need to find our courage, seize our freedom, and then we will, perhaps, find happiness.
American Pharoah won the Belmont stakes, blowing away the field. No one was even close when horse and jockey crossed the finish line: he led by more than five lengths. Courage and heart still mean something, and nothing is impossible. He joins War Admiral and Seattle Slew and Secretariat in horse racing's version of immortality.
Thursday, May 14, 2015
If you want to see what the future holds for us, let me suggest two recent articles. The first, published in the March 5th issue of the MIT Technology Review by Antonio Regalado, is called “Engineering the Perfect Baby.” The second, published in Nature just a week later by a group of concerned scientists, is called “Don’t Edit the Human Germ Line.” Both discuss recent advances that, for all practical purposes, turn science fiction into science. It’s an interesting story.
The story goes back three years to the development of CRISPR/Cas-9 technology for gene editing by Jennifer Doudna and Emmanuelle Charpentier. CRISPRs (short for Clustered Regularly Interspaced Short Palindromic Repeats) are short DNA segments in which segments of viral DNA are inserted, which are then transcribed to a form of RNA (cr-RNA). This viral-specific cr-RNA then directs the nuclease Cas9 to the invading complementary viral DNA, which is cleaved.
We do not think of bacteria as either needing or having an immune system, but CRISPR/Cas9 functions as one in the prokaryote/bacteriophage arms race. It is elegant and simple, a profoundly cool invention far down on the evolutionary tree that somehow failed to make it to mammals.
Doudna and Charpentier had the exceedingly clever, and in retrospect quite obvious, idea that this could be used to edit specific DNA sequences. I say “in retrospect quite obvious,” but it is the sort of retrospective obviousness that turns previously obscure professors working in equally obscure fields into Nobel laureates, as their 2012 Science CRISPR/Cas-9 paper certainly will.
Molecular biologists love this technology, and for good reason. With CRISPR/Cas-9 one can add or subtract genes almost at will. The technology, while not perfect (more on this later), is a straightforward, off-the-shelf tool kit that allows practically anyone to manipulate the genome of practically any cell. It is a game changer for laboratory research. The technology has launched an astonishing number of papers, several new biotech start-ups, and (already) the inevitable ugly patent lawsuits over who got there first.
Because bacterial DNA and human DNA are forged from the same base elements, what one can do in E. coli one can do in H. sapiens. Whether it is wise for H. sapiens to reproduce E. coli technology is the real question.
What Regaldo’s article suggests, and what the Nature article confirms, is that we are close to a tipping point in human history. It is easily conceivable that CRISPR tech can be used to edit the genes of human germ-line cells. We will, in the very near future, be able to alter a baby’s genome, with almost unimaginable consequences.
Is this a line we want to cross? Some, unsurprisingly, find this prospect disturbing. The authors of the Nature paper suggested a moratorium on gene editing of human stem cells until we can be work out all of the important practical and ethical issues. Let us slow down, they say, take a deep breath, think things through, and then proceed with caution.
A wonderful idea, but a bit too late, as it turns out. March was so last month. A group of Chinese investigators at the Sun Yat-Sen University in Guangzhou took human stem cells (defective leftovers from a fertility clinic) and used CASPR/Cas-9 to introduce the b-globin gene. b-globin mutations are responsible for beta thalassemia, which afflicts a significant population of patients.
The paper was published in the April 18 issue of Protein & Cell (a journal I had never heard of before), reportedly after having been rejected by Nature and Science on ethical grounds. It is rather like when Gregor Mendel published his article on the genetics of peas in Proceedings of the Natural History Society of Brünn, only now we have PubMed and the world is a very small place. I suspect Protein & Cell’s impact factor just took a quantum leap upwards.
The paper suggests we are not quite there yet: of the 86 embryos where the authors used CRISPR/Cas-9 to introduce the gene, only 4 “took”, and many had off-target mutational events, not a good thing if you are trying to eliminate a genetic defect. In other words, don’t expect this to be available at your local fertility clinic next week.
But if not next week, then maybe next year, or the year after: this field is moving at light speed, and the Chinese doctors were (or so a recent Science article suggests) using last year’s techniques. Lots of very smart people are piling into the field. This will soon be feasible, then eventually trivial, technology.
And as for a moratorium on gene editing of human stem cells? It might stick for a while, but I am not sanguine about its long-term prospects. I think it is a given that any moratorium will eventually fail.
To answer why this is the case, just look at the history of attempts to limit the use of new technologies:
First, the atomic bomb. In 1945, after the first nuclear explosion at Alamogordo, a group of Manhattan Project scientists, led by Leo Szilard (who famously first thought of the nuclear chain reaction that would occur once one split the uranium atom), petitioned the President to halt the use of the bomb. The petition, dated July 17, 1945, stated “the nation which sets the precedent of using these newly liberated forces of nature for purposes of destruction may have to bear the responsibility of opening the door to an era of devastation on an unimaginable
The powers that be were not amused. The US government had spent two billion 1945 dollars developing the A bomb as a war measure, it faced the likelihood of an invasion of Japan with untold potential casualties, and it had little sympathy for Japanese civilians. It also saw the bomb as a long-term source of political and military power. The niggling objections of the atomic scientists (and by no means all objected) were ignored, and literally within weeks Hiroshima and Nagasaki ushered in the Atomic Age, in all its frightful glory.
That decision tells you that technologies rapidly get out of control of those who create them. In the Atomic Age, one at least needed a well-heeled nation-state to back you if you wanted to build a bomb, a partial barrier (though only partial: impoverished Pakistan, two generations later, is capable of immolating its neighbors). And nation-states, since 1945, have thankfully not used these weapons on other nation-states, though nuclear proliferation sadly continues.
But in the Genome Era, just about any college biology graduate soon will be able to insert genes that eliminate defects or increase function. For practical purposes, Lichtenstein and Monaco could be the biologic equivalent of today’s nuclear powers five years from now. Unless the moratorium is worldwide, all you would need to do would be to fly somewhere that didn’t share the biomedical ethical stance of the Nature authors. And if I knew I carried a deadly genetic defect, I would do anything to save my children from the same fate.
By the way, you might say that comparing the atom bomb to CRISPR/Cas9 is a somewhat ridiculous comparison given the relative significance of the two. And you would be right, though perhaps not in the way you might first think: CRISPR/Cas9 is likely to be far more significant in the long run. A technology that allows a species to intentionally evolve new characteristics is far more important for the history of that species. Gills, anyone? Chlorophyll rather than melanin in your skin? All those pesky vitamins we don’t make ourselves? Edit them in.
The somewhat more pertinent analogy, and one commented on by many, is the Asilomar conference. After Cohen and Boyer performed the first recombinant DNA experiments, there was a similar terror of Dr. Frankenstein experiments by mad scientists. The city fathers of Cambridge, Massachusetts, appropriately frightened by the proximity of Harvard and MIT, passed a law banning the use of recombinant DNA technology within its city limits.
The then-small community of molecular biologists met at the Asilomar conference center (near San Francisco) in 1975 and voluntarily developed limits on certain types of genetic experiments until their safety could be determined. It was a highly moral stance by the leaders of a new biologic revolution, but also a highly practical one, as it decreased public opposition to recombinant DNA technology.
The moratorium turned out to a brief one (no one, to my knowledge, has ever been killed by recombinant DNA, at least not yet), and with its lifting the biotech industry was born, and we never gave those early qualms a second thought.
I’ve been to Asilomar several times: my Oncology division at Stanford holds its annual scientific retreat there. It is a lovely state park on the Pacific coast, and a great place to hold a conference: watching the sunset over the ocean at Asilomar is an awe-inspiring experience.
But Asilomar is just not the right model for what is happening today. Molecular biology is ubiquitous, a global enterprise carried on by tens or hundreds of thousands of scientists, not the small handful in the 1970s. A few academic scientists no longer drive it; big pharma and biotech call the shots, and can be expected to remain highly ethical just so long as no obscene profits can be made from a new technologic development.
Jennifer Doudna has suggested that we need an Asilomar equivalent for CRISPR/Cas9 gene editing of embryos, and indeed there has already been a preliminary meeting of scientists, lawyers, and bioethicists in Napa Valley’s Carneros Inn earlier this year. By the way, the Carneros Inn is even nicer than Asilomar: one should always hold scientific retreats at great resorts in wine country. It greatly improves the meeting outputs.
The Asilomar scientists had what were, in essence, short-term concerns: will recombinant DNA, let loose on the world, be the scientific equivalent of the Four Horsemen of the Apocalypse? Well, no, and we knew the answer quickly.
But CRISPR-Cas9 stem cell germ-line editing, once the technical wrinkles are worked out, is a technology whose medical and social implications will take generations to play out. The pressure to use it for medical purposes will be enormous. Edit out or fix a gene that causes some dreadful neurodegenerative disease (a Huntington’s chorea or its equivalent) and no one will notice the difference for forty or fifty years. These diseases will go away, and who will miss them? And who among my great-grandchildren will even care, it having been something they have always lived with?
Perhaps (one already knows the objections) we should not assign God-like powers over creation to ourselves, but how long will that dike hold when a Senator’s or a billionaire’s or a dictator’s misbegotten embryo needs genomic resuscitation?
And edit in something that makes one smarter or faster or—dare I say—cuter? Cosmetic editing will be popular the moment we figure out how to do it. Pretty much the first law of the consumer electronics industry is that every new technical advance (viz: VCR, CD-ROM, streaming video) is used almost immediately for pornography. I can only imagine what will happen with gene editing.
I simply do not trust us not to use CRISPR/Cas-9 germ-line editing. There is a certain technologic imperialism that renders it inevitable. We always want to play with the cool new toys, and this one will be really, really easy to play with. What will my descendants look like? Probably not like me. And there are those who would say that is a good thing.
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.