But in other ways this book is a massive disappointment -- because it leaves the reader with the sense that not much has changed in those several thousand years. Then, as now, we treat the symptoms of cancer, but against its ultimate cause, we are seemingly as helpless as the ancients.
Therapy
Here’s a nice summary of the therapeutic side of the equation.
Recall Atossa, the Persian queen who likely had breast cancer in 500 BC. Imagine her traveling through time -- appearing and reappearing in one age after the next. She is cancer’s Dorian Gray: as she moves through the arc of history, her tumor, frozen in its stage and behavior, remains the same. Atossa’s case allows us to recapitulate past advances in cancer therapy and to consider its future. How has her treatment and prognosis shifted in the last four thousand years, and what happens to Atossa later in the new millennium?
First, pitch Atossa backward in time to Imhotep’s clinic in Egypt in 2500 BC. Imhotep has a name for her illness, a hieroglyph that we cannot pronounce. He provides a diagnosis, but “there is no treatment,” he says humbly, closing the case.
In 500 BC, in her own court, Atossa self-prescribes the most primitive form of a mastectomy, which is performed by her Greek slave. Two hundred years later, in Thrace, Hippocrates identifies her tumor as a karkinos, thus giving her illness a name that will ring through its future. Claudius Galen, in AD 168, hypothesizes a universal cause: a systemic overdose of black bile -- trapped melancholia boiling out as a tumor.
A thousand years flash by; Atossa’s entrapped black bile is purged from her body, yet the tumor keeps growing, relapsing, invading, and metastasizing. Medieval surgeons understand little about Atossa’s disease, but they chisel away at her cancer with knives and scalpels. Some offer frog’s blood, lead plates, goat dung, holy water, crab paste, and caustic chemicals as treatments. In 1778, in John Hunter’s clinic in London, her cancer is assigned a stage -- early, localized breast cancer or late, advanced, invasive cancer. For the former, Hunter recommends a local operation; for the latter, “remote sympathy.”
When Atossa reemerges in the nineteenth century, she encounters a new world of surgery. In Halsted’s Baltimore clinic in 1890, Atossa’s breast cancer is treated with the boldest and most definitive therapy thus far -- radical mastectomy with a large excision of the tumor and removal of the deep chest muscles and lymph nodes under the armpit and the collarbone. In the early twentieth century, radiation oncologists try to obliterate the tumor locally using X-rays. By the 1950s, yet another generation of surgeons learns to combine the two strategies, although tempered by moderation. Atossa’s cancer is treated locally with a simple mastectomy, or a lumpectomy followed by radiation.
In the 1970s, new therapeutic strategies emerge. Atossa’s surgery is followed by adjuvant combination chemotherapy to diminish the chance of a relapse. Her tumor tests positive for the estrogen receptor. Tamoxifen, the antiestrogen, is also added to prevent a relapse. In 1986, her tumor is further discovered to be Her-2 amplified. In addition to surgery, radiation, adjuvant chemotherapy, and tamoxifen, she is treated with targeted therapy using Herceptin.
Much of this sounds strikingly similar to me. Herceptin may be more efficacious than goat dung, but they’re both intended to treat the cancer instead of the patient. But Mukherjee assures us that significant progress has been made.
It is impossible to enumerate the precise impact of these interventions on Atossa’s survival. The shifting landscape of trials does not allow a direct comparison between Atossa’s fate in 500 BC and her fate in 1989. But surgery, chemotherapy, radiation, hormonal therapy, and targeted therapy have likely added anywhere between seventeen and thirty years to her survival. Diagnosed at forty, say, Atossa can reasonably be expected to celebrate her sixtieth birthday.
And there is more to come -- although note Mukerjee’s use of the word “management.”
In the mid-1990s, the management of Atossa’s breast cancer takes another turn. Her diagnosis at an early age and her Achaemenid ancestry raise the question of whether she carries a mutation in BRCA-1 or BRCA-2. Atossa’s genome is sequenced, and indeed, a mutation is found. She enters an intensive screening program to detect the appearance of a tumor in her unaffected breast. Her two daughters are also tested. Found positive for BRCA-1, they are offered either intensive screening, prophylactic bilateral mastectomy, or tamoxifen to prevent the development of invasive breast cancer. For Atossa’s daughters, the impacts of screening and prophylaxis are dramatic. A breast MRI identifies a small lump in one daughter. It is found to be breast cancer and surgically removed in its early, preinvasive stage. The other daughter chooses to undergo a prophylactic bilateral mastectomy. Having excised her breasts preemptively, she will live out her life free of breast cancer.
Indeed, these are all “management” techniques. Ways to mitigate the impact of the disease, not ways to prevent it from happening, or to stop it from having its deadly effects. And when Mukerjee takes Atossa into the future, not much will change.
Move Atossa into the future now. In 2050, Atossa will arrive at her breast oncologist’s clinic with a thumb-size flash drive containing the entire sequence of her cancer’s genome, identifying every mutation in every gene. The mutations will be organized into key pathways. An algorithm might identify the pathways that are contributing to the growth and survival of her cancer. Therapies will be targeted against these pathways to prevent a relapse of the tumor after surgery. She will begin with one combination of targeted drugs, expect to switch to a second cocktail when her cancer mutates, and switch again when the cancer mutates again. She will likely take some form of medicine, whether to prevent, cure, or palliate her illness, for the rest of her life.
I’ll forgive Mukherjee’s use of the word “cure” in that last sentence -- coming in at the end like some kind of Hail Mary pass -- because the larger question is much more compelling. Why? Why is the future so much like the past, and why does that word “cure” seem so out of place?
Mukherjee is not oblivious to this painful reality. He concludes this summary with the following thoughts:
This, indubitably, is progress. But before we become too dazzled by Atossa’s survival, it is worthwhile putting it into perspective. Give Atossa metastatic pancreatic cancer in 500 BC and her prognosis is unlikely to change by more than a few months over twenty-five hundred years. If Atossa developed gallbladder cancer that is not amenable to surgery, her survival changes only marginally over centuries. Even breast cancer shows a marked heterogeneity in outcome. If Atossa’s tumor has metastasized, or is estrogen-receptor negative, Her-2 negative, and unresponsive to standard chemotherapy, then her chances of survival will have barely changed since the time of Hunter’s clinic. Give Atossa CML or Hodgkin’s disease, in contrast, and her life span may have increased by thirty or forty years.
Part of the unpredictability about the trajectory of cancer in the future is that we do not know the biological basis for this heterogeneity. We cannot yet fathom, for instance, what makes pancreatic cancer or gallbladder cancer so markedly different from CML or Atossa’s breast cancer. What is certain, however, is that even the knowledge of cancer’s biology is unlikely to eradicate cancer fully from our lives. As Doll suggests, and as Atossa epitomizes, we might as well focus on prolonging life rather than eliminating death. This War on Cancer may best be “won” by redefining victory.
It’s a fair point -- but one that became increasingly frustrating for me while I read this book. Mukherjee says we still do not understand the biological basis of cancer. To me, that means that, after several millennia, we still do not understand why cancer happens. We increasingly know what to do when we see it, and in some cases prevent it from appearing, but when it does appear, no one in Mukherjee’s long history, from Atossa to Doll, can definitively tell us why.
Etiology
The book will get us pretty close. When it gets down into the molecular and genetic nitty-gritty of what’s going on in an organism, one feels like we are getting tantalizingly close. But that final leap, from cause to effect, remains obscure.
By the early 1990s, cancer biologists could begin to model the genesis of cancer in terms of molecular changes in genes. To understand that model, let us begin with a normal cell, say a lung cell that resides in the left lung of a forty-year-old fire-safety-equipment installer. One morning in 1968, a minute sliver of asbestos from his equipment wafts through the air and lodges in the vicinity of that cell. His body reacts to the sliver with an inflammation. The cells around the sliver begin to divide furiously, like a miniscule wound trying to heal, and a small clump of cells derived from the original cell arises at the site.
There. That was it. Did you miss it? His body reacts to the sliver with an inflammation. That’s an example of how close cause will come to effect in this book, but it still doesn’t tell us what we really want to know. Why? Why does the body react to the sliver with an inflammation? Does the sliver cause the inflammation to occur? And if so, how? What does it actually do to make the inflammation occur?
We don’t know. But I’m going to relay the rest of Mukherjee’s story about this fire-safety-equipment installer -- one of Mukherjee’s actual patients -- not because it tells us any more whys or hows, but because it tells us a lot about the process that gives rise to cancer, and reveals how that process is surprisingly difficult and achingly random.
In one cell in that clump an accidental mutation occurs in the ras gene. The mutation creates an activated version of ras. The cell containing the mutant gene is driven to grow more swiftly than its neighbors and creates a clump within the original clump of cells. It is not yet a cancer cell, but a cell in which uncontrolled cell division has partly been unleashed -- cancer’s primordial ancestor.
A decade passes. The small collection of ras-mutant cells continues to proliferate, unnoticed, in the far periphery of the lung. The man smokes cigarettes, and a carcinogenic chemical in tar reaches the periphery of the lung and collides with the clump of ras-mutated cells. A cell in this clump acquires a second mutation in its genes, activating a second oncogene.
There. There it is again. A cell in this clump acquires a second mutation. From what? From its “collision” with a “carcinogenic chemical.” What does that mean? And how does that cause a cell to mutate?
Another decade passes. Yet another cell in that secondary mass of cells is caught in the path of an errant X-ray and acquires yet another mutation, this time inactivating a tumor suppressing gene. This mutation has little effect since the cell possesses a second copy of that gene. But in the next year, another mutation inactivates the second copy of the tumor suppressor gene, creating a cell that possesses two activated oncogenes and an inactive tumor suppressor gene.
Now a fatal march is on; an unraveling begins. The cells, now with four mutations, begin to outgrow their brethren. As the cells grow, they acquire additional mutations and they activate pathways, resulting in cells even further adapted for growth and survival. One mutation in the tumor allows it to incite blood vessels to grow; another mutation within this blood-nourished tumor allows the tumor to survive even in areas of the body with low oxygen.
Are you following this? We’re twenty-plus years in with six genetic mutations - each, evidently, an unlikely and random occurrence. And the man, now sixty-something, is still oblivious as to what is going on.
Mutant cells beget cells beget cells. A gene that increases the mobility of the cells is activated in a cell. This cell, having acquired motility, can migrate through the lung tissue and enter the bloodstream. A descendent of this mobile cancer cell acquires the capacity to survive in the bone. This cell, having migrated through the blood, reaches the outer edge of the pelvis, where it begins yet another cycle of survival, selection, and colonization. It represents the first metastasis of a tumor that originated in the lung.
The man is occasionally short of breath. He feels a tingle of pain in the periphery of his lung. Occasionally, he senses something moving under his rib cage when he walks. Another year passes, and the sensations accelerate. The man visits a physician and a CT scan is performed, revealing a rindlike mass wrapped around a bronchus in the lung. A biopsy reveals lung cancer. A surgeon examines the man and the CT scan of the chest and deems the cancer inoperable. Three weeks after that visit, the man returns to the medical clinic complaining of pain in his ribs and his hips. A bone scan revealed metastasis to the pelvis and the ribs.
You know what comes next. Time to treat those nasty symptoms.
Intravenous chemotherapy is initiated. The cells in the lung tumor respond. The man soldiers through a punishing regimen of multiple cell-killing drugs. But during the treatment, one cell in the tumor acquires yet another mutation that makes it resistant to the drug used to treat the cancer. Seven months after his initial diagnosis, the tumor relapses all over the body -- in the lungs, the bones, the liver. On the morning of October 17, 2004, deeply narcotized on opiates in a hospital bed in Boston and surrounded by his wife and his children, the man dies of metastatic lung cancer, a sliver of asbestos still lodged in the periphery of his lung. He is seventy-six years old.
Treat them, that is, until the patient dies. For many forms of cancer, that seems to be all that medicine can currently do.
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This post first appeared on Eric Lanke's blog, an association executive and author. You can follow him on Twitter @ericlanke or contact him at eric.lanke@gmail.com.
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