September 4, 2017


Cancer's Invasion Equation : We can detect tumors earlier than ever before. Can we predict whether they're going to be dangerous? (Siddhartha Mukherjee, 9/11/17, The New Yorker)

Mets go to the brain." He punctuated the air with his fingers at each verb, his face flushed with excitement. "And--yes, yes--going is important, because we need to find what allows cells to break away from the tumor and enter the blood and the lymph nodes. But if primary human tumors shed cells continually, and if every cell is capable of forming visible metastasis, then every patient should have countless visible metastatic deposits all over his or her body." Anna Guzello's breast tumor should have stippled her brain, bones, and liver with mets. Why, then, did she have no visible evidence of disease anywhere else in her body? The real conundrum wasn't why metastases occur in some cancer patients but why metastases don't occur in all of them.

"The only way I could explain the scarcity of metastasis," Massagué said, "was to imagine that an enormous wave of cellular death or cellular dormancy must restrict metastasis. Either the cells shed by the tumor are killed, or they stop dividing, becoming dormant. When tumor cells enter the circulation, they must perish almost immediately, and in vast numbers. Only a few reach their destination organ, such as the brain or the bone." Once they do, they face the additional problem of surviving in unfamiliar and possibly hostile terrain. Massagué inferred that those few survivors must lie in a state of dormancy. "A visible, clinical metastasis--the kind that we can detect with cat scans or MRIs--must only occur once a dormant cell has been reactivated and begins to divide," he said. Malignancy wasn't simply about cells spreading; it was also about staying--and flourishing--once they had done so.

In the spring of 2012, while Massagué and others were searching for sleeper cells, Gilbert Welch, an epidemiologist at Dartmouth, was preoccupied with a different problem: the unfulfilled promise of early detection. Early-detection programs aimed to catch and eliminate cancers that were otherwise destined to become metastatic, but a huge ramp-up in screenings for certain cancers hadn't yielded comparable benefits in the mortality statistics. Welch was trained as a statistician as well as a physician, and when he recites numbers and equations his voice rises to a booming pitch, as if he were a televangelist moonlighting as a math teacher. To illustrate an extreme version of the problem, Welch told me the story of an epidemic-that-wasn't. In South Korea, starting about fifteen years ago, doctors began to screen aggressively for thyroid cancer. Primary-care offices in Seoul were outfitted with small ultrasound devices, and doctors retrained themselves to catch the earliest signs of the disease. When a suspicious-looking nodule was found, it was biopsied. If the pathology report was positive, the patient's thyroid gland was surgically removed.

The official incidence of thyroid cancer--in particular, a subtype termed papillary thyroid cancer--began to soar across the nation. By 2014, thyroid-cancer incidence was fifteen times what it was in 1993, making it the most commonly diagnosed cancer in the country. It was as if a "tsunami of thyroid cancer," in the words of one researcher, had suddenly hit. Billions of Korean wons were poured into treatment; tens of thousands of resected thyroids ended up in surgical buckets. Yet the rate at which people died from thyroid cancer remained unchanged.

What happened? It wasn't medical error: observed under the microscope, the questionable nodules met the criteria for thyroid cancer. Rather, what the pathologists were finding wasn't particularly pathological--these thyroid cancers had little propensity to cause illness. The patients had been not misdiagnosed but overdiagnosed; that is, cancers were identified that would never have produced clinical symptoms.

In 1985, pathologists in Finland assembled a group of a hundred and one men and women who had died of unrelated causes--car accidents or heart attacks, say--and performed autopsies to determine how many harbored papillary thyroid cancer. They cut the thyroid glands into razor-thin sections, as if carving a hock of ham into prosciutto slices, and peered at the sections under a microscope. Astonishingly, they found thyroid cancer in more than a third of the glands inspected. A similar study regarding breast cancer--comparing breast cancer incidentally detectable at autopsy with the lifetime risk of dying of breast cancer--suggests that a hyperzealous early-detection program might overdiagnose breast cancer with startling frequency, leading to needless interventions. Surveying the results of prostate-cancer screening, Welch calculated that thirty to a hundred men would have to undergo unnecessary treatment--typically, surgery or radiation--for every life saved.

"The early detection of breast cancer via mammography saves women's lives, although the benefit is modest," Daniel Hayes told me. But equally important is the question of what to do with the tumor we've detected: can we learn how to identify those cancers which need to be treated systemically with chemotherapy or other interventions? "It's not just early detection that we want to achieve," Hayes went on. "It's early prediction."

For Welch, the fact that diagnoses of thyroid cancer or prostate cancer could soar without a corresponding effect on mortality rates was a warning: a little knowledge had turned out to be a dangerous thing. Cancer-screening campaigns had expanded the known reservoir of disease without telling us if, in any particular case, treatment was necessary. Early detection helped us with when and what but not with whether. And there was an element of mystery. Why did some cancers spread and kill patients, while many remained docile?

One day in March, 2012, Welch flew to Washington to attend a conference on cancer metastasis. It was a gusty, gray morning--"the hotel was nondescript, the food unremarkable"--and Welch, dangling the requisite nametag on a forlorn lanyard, found himself in a room full of cancer biologists, feeling like an alien species. "I study patterns and trends in cancer in human populations," he told me. "I take the one-hundred-thousand-foot view of cancer. This meeting was full of metastasis biologists looking at cancer cells under the microscope. I couldn't tell what any of this had to do with population trends in human cancer--or, for that matter, why I'd even come to this meeting."

Then, coffee jolting in his hand, he saw a slide on the screen that made him sit up and take notice. It depicted the infestation of mussels in Lake Michigan. The speaker, Kenneth Pienta, an oncologist from the University of Michigan (and now at Johns Hopkins), had heard about the quagga crisis, and been struck by the seeming parallels with cancer. Rather than viewing invasiveness as a quality intrinsic to a cancer, researchers needed to consider invasiveness as a pathological relationship between an organism and an environment. "Together, cancer cells and host cells form an ecosystem," Pienta reminded the audience. "Initially, the cancer cells are an invasive species to a new niche or environment. Eventually, the cancer-cell-host-cell interactions create a new environment." Ask not just what the cancer is doing to you, Pienta was saying. Ask what you are doing to the cancer.

By talking about cancer in ecological terms, Pienta was, in the tradition of Paget and Fidler, urging his colleagues to pay more attention to the soil. A woman with a primary tumor in her breast was caught in a pitched but silent battle. Oncologists had spent generations studying one possible outcome of that battle: when the woman lost, she succumbed to metastasis. But what happened when cancer lost the battle? Perhaps cancer cells tried to invade new niches, but mainly perished en route, as a result of the resistance mounted by her immune system and other physiological challenges; perhaps the select few that, singly or in clusters, survived the expedition ended up languishing in forbidding tissue terrain, like seeds landing on a salt flat.

Welch was captivated. We had to be alert to the differences between the rampaging quagga mussel and the endangered purple-cat's-paw mussel--but what about the differences between the Great Lakes and the Dnieper? Evidence suggested, for example, that most men with prostate cancer would never experience metastasis. What made others susceptible? The usual approach, Welch knew, would be to look for markers in their cancer cells--to find patterns of gene activation, say, that made some of them dangerous. And the characteristics of those cells were plainly crucial. Pienta was arguing, though, that this approach was far too narrow. At least part of the answer might lie in the ecological relationship between a cancer and its host--between seed and soil.

Posted by at September 4, 2017 6:09 AM