Prostate cancer diagnoses are rising even as treatments improve — and researchers still don’t know why. Uncovering the cause could transform prevention and care for millions.

The American Cancer Society recently reported a 3% rise in diagnoses per year from 2014 to 2021, following a 7-year decline. Screening actually fell from 2008 to 2020, so the increase isn’t explained by more testing.

“This is one of the most complex puzzles out there,” said Phillip J. Koo, MD, chief medical officer of the Prostate Cancer Foundation in Santa Monica, California. “Can it be solved? We don’t know, but we’re not going to stop trying, because we have to.”

More than 600 researchers gathered for the Prostate Cancer Foundation’s 32nd annual retreat in Southern California to share breakthroughs and address the central question: What causes prostate cancer, and how can it be stopped? In the coming months, these efforts will continue in Boston, San Francisco, Chicago, and Washington, DC, at a time when their work is more critical than ever.

Researchers are hunting for modifiable factors, such as diet or lifestyle.

So far, “the only established risk factors for prostate cancer are advancing age, African ancestry, and a family history of the disease,” said Tyler Kratzer, MPH, a surveillance researcher and author of the American Cancer Society’s report. “None of those three are modifiable.”

Understanding triggers and when cancer cells first develop could open prevention strategies and earlier interventions for the disease that kills nearly 36,000 American men each year.

“There are a lot of unknowns and a lot of hypotheses,” said Erin Van Blarigan, ScD, an associate professor of epidemiology, biostatistics, and urology at the University of California, San Francisco. “We don’t yet have one thing that I would say there’s any consensus around.”

Here are some of the questions researchers are trying to answer.

Why do some guys with genetic risk factors develop prostate cancer, while others don’t?

Up to 60% of prostate cancer risk is linked to inherited factors, suggests the National Cancer Institute. For example, men with BRCA2 mutations have double to quadruple the risk for prostate cancer compared with men without them.

Some men with inherited risk factors for prostate cancer never develop it. Why is that?

“We do understand a lot about the genetics of prostate cancer in terms of the genes that are involved once it’s triggered and some of the earliest alterations that occur,” said Arul Chinnaiyan, MD, PhD, professor of pathology and urology at the University of Michigan Medical School in Ann Arbor, Michigan. “But what then actually causes those genes to be altered in such ways is still a mystery, and a number of investigators are certainly trying to study that.”

Chinnaiyan’s team is trying to understand why cellular androgen receptors go rogue in prostate cancer. Androgen receptors regulate normal cell growth; in prostate cancer, they help cancer cells proliferate instead. His team found that proteins known as NSD1 and NSD2 rewire androgen receptors to drive cancer development. It’s not yet clear why this happens. However, if researchers could knock out NSD1 and NSD2, they might be able to stop cancer in its tracks.

Chinnaiyan envisions developing an NSD2/NSD1 inhibitor that could work alone or in combination with existing therapies that target androgen receptors. They would probably study it in patients with advanced prostate cancer first, he said.

Can a healthy diet reduce prostate cancer risk?

So far, the answer is a tentative yes. A recent study review published in European Urology found that men who ate diets high in nutrient-dense plant foods such as fruits, vegetables, and whole grains and low in added sugars, refined grains, and saturated fats had a lower risk for prostate cancer than men who ate less ideal diets. And among those who already have prostate cancer, there was an even stronger link between healthy eating and a reduced risk for disease progression and death.

Study author Pao-Hwa Lin, PhD, a professor of medicine and member of the Duke Cancer Institute in Durham, North Carolina, said a diet rich in whole foods might stave off inflammation and free radical damage that helps cancer cells develop and grow.

Specialized diets may help. Lin’s group has studied the impacts of low-carb diets on prostate cancer progression, which shows promising early signs. They’re also investigating how a 5-day low-calorie fasting-mimicking diet affects men with metastatic prostate cancer.

Studying men with prostate cancer could inform research into prevention strategies, she said.

If diet affects progression, it makes sense that it would affect risk, she said. “You would think that whatever impacts the progression, the mechanism between risk and progression shouldn’t be totally different.”

Could vitamin D help mitigate prostate cancer disparities?

Men of African descent have a 67% higher incidence of prostate cancer than White men and double the risk for dying from the disease, according to the American Cancer Society. The reasons might include a mix of genetic, social, and environmental factors. Researchers want to close the gap.

Jabril Johnson, PhD, an assistant professor of microbiology, biochemistry, and immunology at Morehouse School of Medicine in Atlanta, studies risk factors that affect cancer disparities in men of African descent. His research points to vitamin D deficiency as a promising target.

Vitamin D deficiency is common among men of African descent with darker skin pigmentation — melanin in the skin has been shown to inhibit vitamin D synthesis by blocking ultraviolet radiation from sunlight exposure. In 2014, research suggested that African American men with vitamin D deficiency were more likely to be diagnosed with prostate cancer than those without deficiency. Severe deficiency was associated with higher-grade tumors.

“Based on the data, we know that there’s an association with vitamin D deficiency and prostate cancer, but now we’re trying to decouple, understand, and elucidate how vitamin D supplementation could potentially impact these mechanisms that are underlying prostate carcinogenesis,” said Johnson.

His team is looking at vitamin D’s impact on a cellular level. In one study, his group treated a noncancerous prostate cell line derived from a man of African descent with a day’s worth of vitamin D. They found that vitamin D downregulated two genes, ANLN and ECT2, that are strongly associated with prostate cancer development, growth, and patient survival. ANLN and ECT2 work in concert to regulate the cell cycle and determine a cell’s fate, he said.

So there’s a chance that correcting vitamin D deficiency through supplementation could help reduce prostate cancer aggression and/or boost the effectiveness of prostate cancer treatment, especially in men of African descent, said Johnson.

“We’re looking to reintroduce vitamin D into the conversation to potentially utilize it in combinatory therapy with FDA-approved chemotherapeutic drugs,” said Johnson.

Does exposure to environmental contaminants increase prostate cancer risk?

Van Blarigan’s team was surprised to find increases in advanced prostate cancer in California’s Central Coast region from 2018 to 2021. Were people there just slow to get screened? Were there chemical exposures in this farming region? These are questions they hope to investigate.

A study in Cancer found that 22 agricultural pesticides showed consistent associations with prostate cancer incidence in the counties where they were used across the US. Four of the pesticides — trifluralin, cloransulam-methyl, diflufenzopyr, and thiamethoxam — were linked with elevated prostate cancer death rates.

Researchers hypothesize that compounds in pesticides might increase prostate cancer risk by interfering with sex hormones or even directly damaging DNA. More research is needed to determine causation or understand the mechanism.

Van Blarigan said “there’s a lot of interest” in environmental and food contaminants, including food additives and microplastics, but no conclusive evidence. “People are curious about whether these things are contributing, but it’s very difficult to study them and measure them. I think a lot of research is going to be invested in trying to figure those out, but there’s not really anything known yet.”