The Emperor of All Maladies: A Biography of Cancer

Before the 1980s, cancer therapies targeted two of the disease’s Achilles heels, or weaknesses—local growth before cancer spreads and rapid cell division that doctors can stop through drugs. After discoveries about how cancer developed, three new Achilles heels presented themselves. The first was targeting “hyperactive” mutated genes while sparing others. The second was using the vulnerability of a cancer cell’s dependence on activated signaling pathways. The third was the vulnerability of a cancer cell’s reliance on other properties, such as its ability to avoid cell death and to create its own blood supply, among others.

In the 1980s, the first developed drugs built on these weaknesses. A team of researchers in China led by Zhen Yi Wang worked with Laurent Degos in France to use trans-retinoic acid to cause the maturity of cells in APL, a form of leukemia in which cells are frozen in an immature state. Cancer cells that matured died, and then the patients in their study received chemotherapy, resulting in a cure rate of 75%. Weinberg’s team in Boston isolated an oncogene called neu, but he and his assistant never got around to finding an antibody.

In 1984, a group of researchers at the company Genentech, working with Weinberg, found the human homolog of the neu gene and called it Her-2. Genentech, based in San Francisco, had used recombinant DNA technology to synthesize human proteins to make insulin, growth hormones, and other treatments.

Axel Ulrich, a scientist at Genentech, was looking for a use for Her-2, and Dennis Slamon, a UCLA oncologist who heard Ulrich speak, said he would test Her-2 on the cancer cells he had in his lab. Slamon found that Her-2 amplified in aggressive, metastatic breast cancer samples. When he treated these cancer cells with a Her-2 antibody, the cells died. The drug, Herceptin, combined an oncogene, a cancer that activated that oncogene, and a drug that targeted it. In 1992, a woman named Barbara Bradfield with a recurrence of breast cancer visited Slamon’s lab at UCLA. She and 14 other women enrolled in the first trial of Herceptin. The women watched as the tumor on Bradfield’s neck softened and shrank over time, and Bradfield survived (and was still alive at the time the book was written).

When news about Herceptin spread, activists pounded on Genentech’s doors for access to Herceptin for women with Her-2 positive breast cancer. They argued, even though the drug had not yet fully been tested, that it should be released for “compassionate use” (423). A woman named Marti Nelson, a gynecologist in California, died while awaiting approval from Genentech to take Herceptin. After her death, activists stormed the Genentech campus, and company executives met with representatives from the National Breast Cancer Coalition to create an expanded access program through which doctors could treat patients who were not in clinical trials. Genentech started Phase III trials to test Herceptin.

In 1998, Slamon released the results of the trials. Women who took Herceptin had response rates to chemotherapy that climbed by 150%, and patients who did not respond to traditional chemotherapy showed increased response rate of nearly 50%, a rate that was unheard of. In 2003, the combined results of studies showed that women who took Herceptin increased their survival rats by an incredible 33%—a rate that was unprecedented in Her-2 positive cancer.

Janet Rowley noted that all the leukemia cells in CML had a unique chromosomal aberration in which the head of chromosome 22 was joined to the tail of chromosome 9 to create a new gene. One team isolated the chromosome 9 gene, called abl, while another found the chromosome 22 gene, called Bcr. A team of chemists at Ciba-Geigy, a Swiss pharmaceutical company, developed drugs that could inhibit kinases, which act as “master switches” in the cell, activating some pathways and turning off others. A team of Nick Lydon and Brian Druker, who left Dana-Farber and founded his own laboratory in Oregon, used a kinase inhibitor on CML cells. Overnight, the cells died, as they did in mice, and Druker believed the drug could work on Bcr-abl positive leukemia. After begging Novartis for more kinase inhibitors, Druker would have a limited shot at trying the drug on CML patients with other physicians.

The drug became Gleevec, and the author first heard of it in 2002 when an intern called him about a man with a history of CML who presented with a rash. This man was in deep remission, and Druker and his team had experienced a number of these remissions. Gleevec has now become the standard treatment for patients with CML. While CML is rare, Druker’s treatment is a milestone in oncology, as it showed that non-toxic, targeted treatment was possible. 

In 2000, Jerry Mayfield, a Louisiana policeman diagnosed with CML, began treatment with Gleevec. However, his cells had become resistant to it, and Charles Sawyers and his team developed another kinase inhibitor to target Bcr-abl that was resistant to Gleevec. It worked, showing that targeted therapy was at times also a “cat-and-mouse game” (443) that required constant re-invention. In the decade since Gleevec’s development, the NCI has listed 24 targeted therapies for cancer. Some inactivate oncogenes, while others target oncogene-activated pathways. Such drugs have been effective against multiple myeloma, among other cancers.

However, the battle against cancer is like the “Red Queen Race” (444)—moving all the time to stay in place. Using the Framingham study, which started with a cohort of 5,000 people in this Massachusetts town, Harvard epidemiologists Nicholas Christakis and James Fowler determined that “circles of relationships” (445) predicted cigarette smoking more than any other factor. Circles of relationships explains why networks that promote cancer can turn off and turn on so quickly. In addition, carcinogens are constantly changing, though fears that cell phones cause gliomas, a fatal brain cancer, were unfounded. What experts call the “social challenge” (447) of preventing cancer is still very real, as it involves changing our customs and behaviors. 

In 2009, five years after Carla first received her diagnosis, the author visited her at her house. Although Carla had survived, Mukherjee found that she still connected to him as her doctor. She told him that being sick became her new normal.

After the Human Genome Project completed in 2003, a map of all cancer and cancer genes, called the Cancer Genome Atlas, began. One of the groups involved in its development was Bert Vogelstein’s team at Johns Hopkins. Some cancers, such as ALL, have relatively few genetic mutations, while others, such as breast and colon cancer, involve 50 to 80 mutations. Some cancers are “bedlams” (452), with mutations upon mutations. However, researchers can sort the “mountains” in the cancer genome—those genes that are most often mutated in a form of cancer—into key pathways. In a cancer cell, typically about 11 to 15 pathways are aberrant. Therefore, in the bedlam of a cancer cell, there is organization. The fact that researchers can implicate about 13 pathways in cancer cells could provide optimism, as it is a finite number.

The understanding of the functional biology of cancer provides three new routes for cancer treatments. Once scientists discover a mutation, then they can look for targeted therapies. The discovery of mutations can also help us prevent cancer, without resorting to large human studies or lab work to find carcinogens. For example, the Million Women Study in the UK recently identified progesterone and estrogen used in hormone replacement therapy as risk factors in estrogen-positive breast cancer. Therefore, scientists can use molecular biology to reshape epidemiology. The molecular understanding of cancer can help doctors better screen for cancer. For example, today, doctors screen women for the BRCA gene for breast cancer as part of prevention. The third direction for cancer research is to use an understanding of mutated genes and pathways to develop an understanding of cancer’s behavior. 

Cancer is part of our genome. It is a form of death that is part of ourselves. We might be, the author believes, forever joined to cancer, but we can try to stretch out treatment to prevent death before old age. It would be, Mukherjee writes, “a victory over our genomes” (463).

Mukherjee imagines what the treatment of Atossa, the Persian queen who probably had breast cancer in 500 BCE, would have been like through time. In Imhotep’s time, there was no treatment, and over time, physicians might have treated her with a mastectomy or regarded her as having too much black bile. In later eras, her treatment might have been radical surgery, radiation, or chemotherapy—before tamoxifen treatments in the 1980s and then later Herceptin. Doctors also might have screened her for BRCA-1 or BRCA-2 genes. Although she would have fared much better today, she would not have fared much better if she had a disease such as pancreatic cancer.

Mukherjee writes that it’s difficult to predict the future of cancer. New technologies might dramatically shift the landscape of cancer treatment, but there is unlikely to be a definitive cure in sight. He concludes the book with the story of Germaine Berne, a psychologist diagnosed with a rare gastrointestinal cancer called GIST. Treated with Gleevec, she survived for six years, time she had used well. The cancer returned, and she resigned to her death. She was like Lewis Carroll’s Red Queen, dodging one bullet only to be hit by another. She had, in a way, captured something of the 4,000-year-old war against cancer: It required constant reinvention.