A New Perspective on the War against Cancer

 Myths and misconceptions about cancer abound. Oncologists are frequently criticized for torturing patients by burning, cutting and poisoning without making any real progress in the war against cancer. Siddhartha Mukherjee, an oncologist and cancer researcher, tries to set the record straight with his new book The Emperor of All Maladies: A Biography of Cancer.  

It is a unique combination of insightful history, cutting edge science reporting, and vivid stories about the individuals involved: the scientists, the activists, the doctors, and the patients. It is also the story of science itself: how the scientific method works and how it developed, how we learned to randomize, do controlled trials, get informed consent, use statistics appropriately, and how science can go wrong. It is so beautifully written and so informative that when I finished it I went back to page 1 and read the whole thing again to make sure I hadn’t missed anything. I enjoyed it just as much the second time.

 Mukherjee says

It will be a story of inventiveness, resilience, and perseverance against what one writer called the most “relentless and insidious enemy” among human diseases. But it will also be a story of hubris, arrogance, paternalism, misperception, false hope, and hype, all leveraged against an illness that was just three decades ago widely touted as being “curable” within a few years.

 In the early 1950s, a woman tried to place an ad for a breast cancer support group in the NY Times. She was told

I’m sorry, Ms. Rosenow, but the Times cannot publish the word breast or the word cancer  in its pages… Perhaps you could say there will be a meeting about diseases of the chest wall.

 The Pink Ribbon campaign has made public discourse about breast cancer not only acceptable, but popular. Before Pink Ribbons we had the Jimmy Fund, the March of Dimes, Mary and Albert Lasker, the American Cancer Society, and other efforts to fight cancer in general. Mukherjee describes the history of these efforts. There was a public outcry for a Manhattan Project to abolish cancer. Money was channeled into cancer research, but not enough and often not directed to where it would do the most good. Progress has been made, but it has been slow; and the idea of completely abolishing cancer with a massive Manhattan Project-like effort is unrealistic.

 Mukherjee’s book reads like a detective story with an exciting plot. In the effort to understand cancer, early clues led to both horrible failures and serendipitous successes. Early physicians attributed cancer to an excess of black bile. They didn’t have microscopes and didn’t know what a cell was, so they couldn’t recognize that cancer is uncontrollable pathological cell division. Later, they thought the white cell excess of leukemia was pus from an infection and were puzzled when they couldn’t find the focus of infection. Halsted’s famous radical mastectomy turned out to be a terrible, disfiguring, mutilating mistake: if the cancer had not spread, a simple lumpectomy would have been plenty; if microscopic foci of cancer were already present in other parts of the body, even the most extensive surgery had no chance of eradicating it. One early chemotherapy researcher made an outstanding breakthrough that permanently cured choriocarcinoma, but it resulted in his being fired!

 Little by little, our understanding grew. Cancer is not one disease but a whole collection of different diseases characterized by uncontrolled growth of cells. We have learned that it usually takes a whole series of mutations to cause cancer. We have learned about proto-oncogenes and oncogenes, some of which are present in our own chromosomes, but which can also (rarely) be introduced to our genome by a retrovirus. Cancer often results not from direct effects of a mutated gene itself, but by its activation or repression of a series of other genes that govern normal cell activities. We have learned about mutations of the cancer cell itself, about cancer stem cells, and about how cancer can change to evade once-effective therapy and achieve a relapse. The more we learn, the more complicated it gets. The simplistic idea of  “a cure for cancer” begins to look ridiculous.

 In 1900 the top four causes of death were TB, pneumonia, diarrhea and gastroenteritis; cancer was number seven. By 1940 the top cause of death was heart disease and cancer was second. Part of the reason was that between 1900 and 1940 the proportion of people older than 60 nearly doubled. Cancer is an age-related disease. People were living long enough to get cancer, plus diagnoses were being made earlier in the course of disease, and causes of death were being more reliably identified.

 Between 1970 and 1994, overall age-adjusted cancer mortality increased slightly. But by the measure of “years of life saved” there was definite improvement. The overall death rate statistics were misleading. Mortality had decreased in those under 55, but had increased in those over 55 by almost exactly the same amount. Death rates from several cancers (colon, breast, Hodgkins’s disease, testicular cancer) had plummeted. The lung cancer death rate for men had peaked and was dropping, but the rate for older women had increased by 400 percent as the effects of smoking caught up to them.

 Between 1990 and 2005, the cancer-specific death rate dropped by 15%, the breast cancer mortality by 24% (due about half to mammography and half to chemotherapy). Some cancers, especially childhood cancers, have become curable, while the death rates for others like pancreatic cancer have remained unchanged.

 We have learned that there are 6 essential alterations in cell physiology that collectively characterize malignant growth.

            1. Self –sufficiency in growth signals (accelerator pedals stuck “on”).

            2. Insensitivity to growth-inhibitory signals (brake pedals inactivated).

            3. Evasion of programmed cell death (apoptosis)

            4. Limitless replicative potential

            5. Sustained angiogenesis

            6. Tissue invasion and metastasis.

Many of the genes and pathways that enable these behaviors have now been identified. Cancer genomes are being mapped the same way the human genome was. Now a new kind of cancer medicine is possible, based on specific attributes of cancer cells. Once we know what the mutant genes are, we can start to investigate what the mutant genes do, and then we can search for targeted therapies.  

 Gleevec is the first of a new kind of cancer drugs; instead of nonspecifically killing all rapidly dividing cells, it targets a specific enzyme that is overactive in a specific type of cancer. Before 2000, we told patients with CML (chronic myelogenous leukemia)

…that they had a very bad disease, that their course was fatal, their prognosis was poor with a median survival of maybe 3 to 6 years, frontline therapy was allogeneic transplant… and there was no second-line treatment…

 Today we can tell them that

 …the disease is an indolent leukemia with an excellent prognosis, that they will usually live their functional life span provided they take an oral medicine, Gleevec, for the rest of their lives.   

Ironically, Gleevec is turning a once-rare disease into a fairly common one, because patients are surviving. The incidence has not changed, but the prevalence has.

James Watson, testifying before Congress, said

We shall soon know all the genetic changes that underlie the major cancers that plague us. We already know most, if not all, of the major pathways through which cancer-inducing signals move through cells. Some 20 signal-blocking drugs are now in clinical testing after first being shown to block cancer in mice. A few, such as Herceptin and Tarceva, have FDA approval and are in widespread use. 

The biology of cancer is deeply embedded in our genes. Oncogenes involve mutations in genes that are essential to normal cell growth and repair mechanisms. The processes of cancer are the same processes that govern aging, regeneration, healing, and reproduction. Cancer cells grow faster and adapt better; they exploit the very features that make us successful as a species or an organism. They could be considered more perfect versions of ourselves. To quote Pogo: 

We have met the enemy and he is us.

It may be unrealistic to hope that we can abolish this emperor of all maladies. Carcinogens in the environment cause some mutations; other mutations arise from random copying errors when cells divide; the latter might not be preventable. Instead of curing cancer, we may only be able to control cancer and postpone deaths to an advanced age. Cancer may become a chronic disease that requires many of us to take regular medication. We may have to redefine what constitutes victory in the war against cancer.

Posted in: Book & movie reviews, Cancer, History

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