remember brian’s song?

maladies_coverHistorical records of cancer date to 2500 BC, when tumors were described in a medical compendium compiled by Imhotep. Under the heading Treatment, he states ominously “there is none.” That is where the recorded human history of cancer starts, and in three millennia it didn’t get much better: a 1760s text lists “remote” sympathy” as a treatment for cancer.

By the late 1800s, though, surgery became a viable treatment option. A premium had once been placed on the speed of surgery, to minimize the pain inflicted on conscious patients. The introduction of anesthetics and disinfectants meant surgeries could semi-humanely last for hours, and surgeons unsurprisingly found all manner of things that could suddenly be cured through application of the surgical touch. Cancer was chief among them.

Noting that cancers often recurred after mastectomies, treatment of breast cancer in the late 19th and 20th centuries turned into a sort of gruesome contest, with surgeons removing more and more tissue in hopes they would also remove all the cancer. In a horrifying game of one-upsmanship, surgeons began to perform radical mastectomies, removing not just the breasts, but chest muscle, lymph nodes, bones—as much as they could without killing the patient (with postural muscles gone, most survivors were left with a peculiar slouch and a gaunt, concave chest). That this happened was awful enough, but it’s made worse because such radical surgeries didn’t help. If the cancer had not yet metastasized to other locations, then even a “lumpectomy” (so named by its detractors and viewed as a trifle despite its effectiveness in treating localized tumors) was effective. If the cancer had metastasized, there was little chance of surgically removing all of the cancer-afflicted areas no matter how ‘radical’ the surgery. Surgery was not a panacea.

Some cancers have unexpected treatments. Because the prostate depends on testosterone, one way to treat prostate cancers is by castration (chemical or otherwise). Similarly, some breast cancers can be treated by removal of the ovaries (or, more generally, by blocking estrogen). Those two facts are pretty interesting on their own, but the first doctor who ever treated breast cancer by removing the ovaries did so a) before anyone had any good idea of what the ovaries did, 2) before estrogen had been discovered or isolated, and d) based on information he had received from Scottish farmers, who had noticed—in that peculiar folk-wisdom-passed-down-through-generations way—a relationship between cow ovary health and milk production.

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To understand how cancer might be cured, one has to recognize that cancer has a much more diffuse and amorphous cause than most diseases. We all have genes in our cells that are precursors to cancer. Occasionally, cell mutations cause these genes to be activated, potentially leading to the unchecked cell growth that is a hallmark of cancer. We also possess the converse: genes whose job it is to stop or slow tumor growth. Mutations sometimes cause these tumor suppressors to become inactive. So, what we call “cancer” is not some unitary thing; it’s really a heterogenous and idiosyncratic bundle of cell mutations, including mutations that cause unchecked cell growth and other mutations that prevent suppressors from stopping that growth. Generalized treatments for cancer are difficult to find in part because the clinical course in a given cancer case is the result of not one but many mutations accumulated from multiple rolls of the genetic dice.

Consider a hypothetical cancer case. It starts when an asbestos particle is inhaled, which causes localized inflammation and swelling. This leads to a mutation in a single cell in the lungs that, a decade later, causes unchecked cell growth. Because this hypothetical person smoked, a second mutation occurs elsewhere in the lungs. Later they have a few x-rays taken, causing a third mutation in different lung cells. Still later, another mutation occurs that allows for the mobility of the cells, and the cancer metastasizes throughout the body. Now it’s treated by chemotherapy, but one of the cells develops a mutation making it resistant to that particular chemical, and the cancer returns months or years later.

That last concept is counter to my intuition. I had generally assumed that when cancer recurred after seemingly being eliminated, it was because the drugs were not effective enough to completely clear all cancer cells from the body. This is true in one sense, but what I missed is that chemical-resistance mutations mean that even larger or stronger doses of a drug would never permanently remove the cancer. Thus, while it’s certainly true that a recurrence happens because there were cancerous cells left behind (even if only a few), those cells may have mutated to be resistant to the treatment. When we think of the importance of “identifying cancer early,” it’s not just because metastasized cancer is diffused throughout the body (making it more difficult to completely remove). It’s that by the time cancer metastasizes, there are likely so many layers of mutations built up that we can’t account for all of them in the treatment.

However, in some cases we actually can unravel those mutations: in some forms of cancer, the underlying genetic cause has been identified. With that information, even advanced and metastasized cancers can sometimes be reversed with a treatment targeted to their root causes. Probably the most important thing Mukherjee talks about is this point: in the future, cancer treatments will be individualized. We’ll genetically sequence each patient’s cancer to help identify the particular mutations, and thus the combination of treatments required to neutralize that specific “brand” of cancer—a combination of mutations, and therefore a treatment, that may be totally novel and never seen again.

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From the perspective of public health, “cures” alone do not solve epidemiological problems. Treatments for cholera and tuberculosis were discovered in the 20th century, but incidences of those diseases were already decreasing by the end of the 19th century, as preventative measures were implemented (either intentionally or not). But the causes of cancer are more indirect and delayed than the causes of cholera and tuberculosis. John Snow needed a few days of work to isolate the Broad Street pump as the source of the cholera epidemic; to figure out that smoking increases rates of lung cancer, we needed epidemiological statistics collected across decades.

Sometimes we can determine some very specific preventative measures: stop smoking or stop being a chimney sweep (one of the first people to identify carcinogens discovered that chimney sweeps had a high frequency of scrotal cancer, because soot would get buried deeply in their nether regions, where it would stay for weeks, months, or years, eventually causing a particular skin cancer). But carcinogens don’t really “cause” cancer in the same direct way that influenza viruses “cause” the flu. You might develop lung cancer decades after you inhale some asbestos particles, but in truth all those asbestos particles did is increase the likelihood of cell mutations leading to cancer, and it’s typical that multiple cell mutations are required for cancer to grow—that is, we need a mutation that unleashes cell growth to happen in concert with another mutation that deactivates genes that regulate tumor suppression. Did asbestos cause that hypothetical person’s cancer, if asbestos was responsible for only one of multiple mutations? This sort of diffusion (temporal and causal), I think, makes cancer hard to wrap your head around, in the same way we’re bad at intuiting the power of compound interest; it just doesn’t mesh with the timescales and 1:1 correspondence we intuitively can grasp the way we do with, say, the flu.

Side note: Many moons ago, tobacco industry scientists famously performed studies where tar from cigarette smoke was painted on the backs of mice. The mice developed some gnarly tumors. In the 1980s, when cigarette manufacturers were being sued, a corporate honcho claimed—in court and under oath—that millions of dollars had been spent on these studies to “try to reduce tumors on the backs of mice.”  Direct quote. The boldness of that is mind-boggling. If you are going to lie about something, I guess, go big or go home.

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