Ten years ago, Dr. Kimryn Rathmell, a kidney oncologist who was then at Vanderbilt University, noticed a startling trend: Many younger patients were coming to her with kidney cancer, including an 18-year-old with metastatic disease, which Dr. Rathmell had never seen in someone so young.
She assumed these patients had been disproportionately referred to big cancer centers like hers. But this spring, when researchers at the National Cancer Institute published a report showing that, between 2010 and 2019, rates of 14 cancers increased among people under 50 in the United States, the significance of her experience came into focus.
“I realized that what I was seeing was a trend that was happening everywhere,” said Dr. Rathmell, a former director of the N.C.I. who now leads the cancer program at Ohio State. The data were striking.
“It makes me think differently even about a cancer I’ve studied for decades,” she said.
For years, studies and news articles have noted rising rates of “early-onset” cancers, generally defined as those occurring in adults under 50 years old. But the breadth of the trend over time and place, and across more than a dozen cancer types — including breast, colorectal, kidney, pancreatic, stomach, testicular and uterine cancer — is finally becoming clear.
Early-onset cancers remain rare. But data show that their global incidence has risen since 1990, amounting to thousands more new cases each year. For example, in 2019, there were 4,800 more early-onset breast cancer cases in the United States than would have been expected had 2010 rates persisted.
More screening and better detection probably explain some of the rise. But scientists say there are signs that something else, something more, is going on. Increasingly, they are marshaling their efforts to discover what that is.
Lifestyle changes that began decades ago may play a role.
Cancer researchers often point to a historical inflection point: the 1950s.
People born in or around that decade started experiencing higher rates of early-onset cancer in the 1990s. The risk increased with each successive group: Those born in 1990, for example, have a two- to threefold increased risk of certain cancers compared with those born in 1955.
This type of “birth-cohort effect” suggests that environmental and lifestyle exposures that have become more common in recent decades may be behind the increase in early-onset cancer, scientists said.
Much about our environment and daily life changed starting in the postwar boom years, especially in high-income countries, said Dr. Shuji Ogino, a professor of epidemiology at the Harvard T.H. Chan School of Public Health. We are less physically active. We consume more processed foods and sugar. We encounter plastics and forever chemicals everywhere we turn. We’re even sleeping less, according to some data.
Any of these factors may have something to do with early-onset cancer, but it’s still too early to tell which, if any, of them is responsible, said Yin Cao, an associate professor of surgery at the Alvin J. Siteman Cancer Center at Washington University in St. Louis and a leader of a global study on early-onset colorectal cancer.
“Identifying novel risk factors for cancer is a really challenging task,” Dr. Cao said. Historically, it has taken a long time and a large body of evidence to establish such a connection, as it did to prove that smoking caused lung cancer.
Still, the evidence linking obesity, alcohol use and poor diet to early-onset cancer is quite strong, Dr. Cao said. These are population-level trends that reflect our collective environment and exposures.
How obesity increases the risk is not clear, but scientists believe it could be related to overall metabolic dysregulation, insulin resistance, changes to the gut microbiome and chronic inflammation. Alcohol can damage DNA and increase estrogen levels, which fuels some types of breast cancer. Research shows that our drinking patterns have changed, with women making up an increasing share of heavy drinkers over time.
A review of nearly 15 million U.S. cancer cases found that the incidence of six out of 12 obesity-related cancers rose in young adults between 1995 and 2014, with steeper rises in successively younger generations. Colorectal cancer is one of the most common and well-studied types of early-onset cancer. In a 2018 paper, Dr. Cao and her colleagues looked at data on 85,000 female nurses over 20 years. They found that women who were obese were nearly twice as likely as those who had a healthy body weight to develop early-onset colorectal cancer.
Studies have also linked a western diet, which is generally low in fruits and vegetables and high in red and processed meats, sugary drinks and ultraprocessed foods, to early-onset colorectal cancer.
But whether the culprit is the whole pattern or a specific component remains to be determined, Dr. Cao said.
Reproductive shifts are significant for breast cancer.
Women are disproportionately affected by early-onset cancer, in part because breast cancer is one of the most common types.
Girls in the United States now get their periods around age 11 or 12 — slightly earlier than those born in the 1950s did. And the average age at first pregnancy is now 27½, up from the early 20s in the 1950s. This longer gap may be one reason breast cancer rates are rising in younger adults, scientists said.
With every menstrual cycle, a woman’s hormone levels rise and fall, and breast cells expand, proliferate and contract, said Dr. Sherene Loi, a professor of oncology at the Peter MacCallum Cancer Center in Melbourne, Australia. These repeated cycles of cell division offer opportunities for mutations to arise, Dr. Loi said.
During the interval between first period and first pregnancy, cells are also particularly susceptible to harmful exposures, for example from radiation, alcohol or metabolic disruption, said Dr. Graham Colditz, an epidemiologist and associate director for prevention and control at the Siteman Cancer Center.
During pregnancy and breastfeeding, research suggests, the number of immune cells increases in the breast, offering protection against potentially cancerous cells, said Camila dos Santos, an associate professor at Cold Spring Harbor Laboratory in New York. After a baby weans, the mother’s milk cells die and get cleared by the immune system, leaving fewer mutated cells behind. The cells that remain spend more time repairing DNA.
“That whole process changes the breast in a favorable way,” Dr. Loi said.
But with societal shifts to later first pregnancies and fewer babies, women are subject to the harms of this natural process for longer — and get fewer of the protective benefits. DNA damages that accumulate in their 20s are particularly dangerous “because you’ve got a whole lifetime to add on top of them” to get to cancer, Dr. Colditz said.
Changes to the genome may create a “fast track to cancer.”
Emerging research suggests that certain exposures — probably early in life or even in the womb — may change our genetic code and alter which parts of that code get turned on or off, accelerating the path to cancer.
In the gut, for example, cells switch back and forth between more and less developed states, a feature known as plasticity, said Dr. Karuna Ganesh, a medical oncologist and researcher at the Memorial Sloan Kettering Cancer Center in New York City.
In young people, when gut cells are confronted with a stressor like inflammation, they revert into a less developed state, she said. (In older people, the gut cells simply die off.) These cells behave aggressively and, with the right mutation, can lead to cancer, Dr. Ganesh said.
Studies of cancer genomes have also shown that a pattern of mutations associated with a bacterial toxin called colibactin are more common in early-onset colorectal cancer patients than in older patients. Some strains of E. coli and other bacteria carry an extra set of genes that enable them to produce this toxin, which mutates DNA in healthy colon cells.
Ludmil Alexandrov, a professor of bioengineering and cellular and molecular medicine at the University of California, San Diego, said his data suggest the cancer-causing E. coli infection typically occurs in the first two to three years of life, when the microbiome and immune system are immature. The mutations create a “first hit” to the genome, he said, potentially putting children who get the infection “on the fast track to cancer.”
Scientists believe the toxin-producing bacteria could be a result of industrialization — the food we eat, perhaps, or the antibiotics we take. Though they haven’t studied the toxin’s presence over time, scientists have found that genes for it are present in up to 40 percent of children’s stool samples in industrialized nations like the United States and France, but virtually absent in nonindustrialized areas like Africa or rural India, Dr. Alexandrov said. The prevalence of the genes closely correlates to the rate of early-onset colorectal cancer.
The interplay between environment, immunity and gene expression is apparent in other cancers, too. Dr. dos Santos has shown in mice that urinary tract infections — which are increasing in women over time — cause changes that make breast tissue more dense, allowing precancerous cells to flourish.
All of this points to a somewhat new way of thinking about cancer biology: Mutations alone are not sufficient to drive cancer. The genomes of healthy people, even babies, have mutations in cancer-causing genes, Dr. Ogino said. But it takes decades for tumors to develop.
That’s a big window of opportunity, he said. Some 40 percent of cancer risk can be cut through lifestyle changes, such as quitting smoking, limiting alcohol intake and maintaining a healthy weight.
“We can intervene over decades,” Dr. Ogino said. “It’s a good thing.”