The Exceptional: What Miraculous Recoveries Can Teach Us About Beating Cancer
When only a couple of people out of a hundred respond to a cancer drug, that drug is often shelved as a failure. But what if you're one of those two people?
After a cancer patient loses the battle, when the funeral has ended and the mourners have returned home, the cancer remains. It doesn't go where the body goes, to the funeral home or the crematorium. The hospital doesn't throw it away. Usually a pathologist freezes a piece of a tumor, or bathes it in an embalming fluid called formalin and sends it out to be fixed in a paraffin block. Then he seals it in a clear biohazard bag, puts it on dry ice, and adds it to a stockpile of other samples, their identities stripped to random sequences of numbers and letters, all awaiting a journey to a biorepository, a tissue bank for samples such as these. There the cancer will wait among thousands of other samples, until a doctor somewhere thinks of a reason to want it.
These warehouses are catalogs of the difficulties inherent in treating the disease oncologist Siddhartha Mukherjee famously called the emperor of all maladies: Of the hundreds of drugs that move into development annually to treat cancer, only a few are safe and effective enough to receive Food and Drug Administration approval. Despite advances in chemotherapy, proton therapy, and immunotherapy, techniques that employ drugs, radiation, and the immune system, respectively, to shrink tumors, more than 585,000 people succumb to the disease every year. Their tumors, fresh, frozen, or fixed in wax, build up in the tissue bank.
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Oncologist–researchers, the united human front line against cancer, are accustomed to disappointment. They tend to be driven by the conviction that cancer can be beaten, in spite of the massive trove of evidence to the contrary. David Solit, an athletic forty-six-year-old with eyes as blue as a work shirt, is a perfect example. In medical school he chose oncology because his aunt had died of breast cancer. "I wanted to find better treatments for people who had incurable tumors," he says. He is not intimidated by the word incurable.
Back in 2010 Solit was in a meeting on the fourth floor of the Kimmel Center, a treatment space for prostate, bladder, and related cancers at Memorial Sloan Kettering Cancer Center in New York City, where he works. In a windowless conference space, some fifteen doctors, researchers, and nurses sat around a U-shaped table in white coats, discussing the hospital's clinical drug trials. The meeting was a weekly status update for a drug called everolimus, which blocks a protein called mTOR that makes cells grow and divide. Forty-five bladder cancer patients had received everolimus. Nearly all of them—forty-three—had no response at all.
The doctors considered scrapping the drug entirely. But then Solit asked a critical question: What happened to the other two? One patient had had a partial response. But the other had gone into complete remission. She had remained cancer-free for two years. "I knew from that one patient that enough of the drug got into her tumor for it to work," Solit says. "For me, that meant it was a good drug. We just didn't know who to give it to."
The patient was exceptional, and Solit intended to find out why.
Cancer is not a single disease. In concept it is the growth of abnormal cells that spread around the body, overwhelming its systems like a weed in a garden. But what kind of weed it is and how fast it spreads are different in each case. Pancreatic cancer will kill you much faster, on average, than breast cancer. A type of lung cancer that is caused by a mutation in the gene for a protein called KRAS is far more lethal than the same type of lung cancer caused by a mutation in the gene for EGFR. What makes cancer so difficult to beat is that the mechanisms are unique to each person and, indeed, to each cancer. A drug that causes remission in one case may do nothing in another.
Because a tumor's genetic background can direct potential treatments, researchers have been keen to genetically map tumors since the technology became possible in 2000. If oncologists could map a tumor's entire genome, goes the theory, they could compare it with a reference sequence made up of normal DNA. Mismatches might explain what caused the tumor to grow. Correcting the mismatch could cure the cancer.
And so Solit will be the first to tell you that discovering the genetic target of the drug everolimus was partly due to luck. In 2010 whole-genome sequencing, the technique that would eventually allow Solit to sequence the tumor from the woman who had the exceptional response, was on the cusp of availability. At first he and more than a dozen of his colleagues tried to study the tumor "the old-fashioned way"—one gene at a time. Tumor cells have approximately twenty thousand genes, the same as in a normal human cell, which made this an inefficient, and not particularly promising, undertaking.
Then came the luck: Illumina, a San Diego–based biotech company, engineered a digital DNA sequencing machine, a sleek tabletop lab–computer complex that could analyze the sequence of bases—A, G, C, and T—in millions of fragments of DNA, then reconstruct the fragments to show a tumor's entire raw genetic code. The cost of the experiment Solit dreamed of doing, sequencing the full genome, dropped from millions of dollars to just $20,000. (As computer power accelerates, the cost continues to drop: The same experiment today would cost only $2,000.)
With the lower cost option available, the hospital contracted the sequencing out to Illumina, and, when the results returned, Solit and his colleagues began to sort through more than three billion base pairs' worth of data to figure out which one was relevant to the cancer. This is like trying to find a single misspelling in a book with six billion letters. It took six computational biologists five months to solve the puzzle. The exceptional patient had a mutation in two genes, called TSC1 and NF2. Through a complex metabolic pathway, the mutations allowed mTOR, the protein affected by everolimus, to run wild, creating new, malignant cells all over. There it was—sense made out of a blind mess of human suffering. A protein that told cells to grow and divide like crazy. The drug that shut it off.
"It was incredibly exciting," says Solit.
After undergoing the peer-review process, Solit's finding appeared in the journal Science in 2012. It wasn't exactly the cure for cancer, but it did point in the cure's direction, and other leaders in oncology noticed. At the National Cancer Institute, a part of the National Institutes of Health in Rockville, Maryland, oncologist and developmental therapeutics researcher Barbara Conley thought Solit's work could help her streamline testing for cancer drugs. In standard clinical trials for these types of drugs, patients are grouped according to the origin site of their cancer—prostate, breast, liver, brain. Then, depending on how the entire group responds during the test, a drug is either abandoned by the pharmaceutical company, or it's pursued through three phases of FDA trials until it is finally allowed on the market. Solit's work made Conley think patients could be grouped according to genetics instead.
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