The path to precision screening for cancer

Hutch News

The path to precision screening for cancer

For now, early detection of breast and prostate cancer means mammograms and PSAs, but a more tailored approach is on the horizon

Sept. 29, 2017
Precision Land

Illustration by Kimberly Carney / Fred Hutch News Service

You might call it the cancer screening hokey pokey.

You put some body part in, based on screening recommendations. Then you take that body part out, based on new recommendations. Then you put it in again; then you take it out again; then you shake your head — and perhaps your fist at the sky — because it’s getting harder and harder to figure out what to do when it comes to early detection because the dang rules keep changing.

The ever-fluctuating landscape of cancer screening shifted again last month with the publication of a new prostate cancer screening study co-authored by biostatistician Dr. Ruth Etzioni of Fred Hutchinson Cancer Research Center. The study, a re-analysis of two major prostate trials, strengthened the evidence that prostate-specific antigen, or PSA, testing can actually reduce deaths, after all.

Early guidelines recommended a yearly PSA for average risk men 50 and over, but they’ve seesawed many times since. At present, men are counseled to talk with their doctor about their risk and reach a decision together.

Etzioni said she hopes the study, which may or may not change current screening guidelines (again), will clarify things for men, but recognizes it may also confuse them. Just as all the back-and-forth that happens with breast cancer screening guidelines confuses women. And she acknowledges that’s a problem.

“The public gets confused and then you start losing credibility,” she said. “Screening is a very high impact and high cost intervention. In recent years, there’s been a lot of second guessing about the screening endeavor.”

Dr. Ruth Etzioni

Fred Hutch biostatistician Dr. Ruth Etzioni

Photo by Robert Hood / Fred Hutch News Service

The biostatistician and longtime public health researcher, who serves on three national committees that create early cancer detection guidelines, believes there may be a better way.

“What we want ultimately is to figure out who needs screening and who doesn’t,” she said. “We need to know if you are at a higher risk so we can watch you and the people like you. And maybe large population screening isn’t the tool.”

What is? There are a few names for it — risk stratification, personalized screening strategies, tailored screening or even precision prevention, the early detection BFF of precision oncology. At the heart of it, it’s the notion that individual differences in our genes, environment and behavior shape our health in individualized ways, that neither our bodies nor our cancer risk is one-size-fits-all.   

In other words, we are all unicorns and need to be treated — and screened — as such.

One-size-fits … some?

Unfortunately, guidelines are not made for unicorns, particularly the ones designed for common cancers like breast and prostate.

They are, in fact, made for whole populations. In the U.S., this behemoth task is regularly tackled by the American Cancer Society, the U.S. Preventive Services Task Force and professional associations like the American Urological Association and the American College of Radiology. Their recommendations are based on scientific studies: new studies, old studies, sometimes hundreds of studies that are sorted and analyzed and basically graded by each organization’s panel of national experts who then synthesize that evidence into the best course of action. 

But because science is in a constant state of discovery, the best course of action can (and does) change — a lot. And because guidelines are designed for the masses, not the individual, there is constant back and forth on how to best balance out the benefits (saving lives!) with the harms (unnecessary tests, treatments and anxiety) of what essentially amounts to one-size-fits-some screenings.

Dr. Pete Nelson

Fred Hutch clinical researcher and prostate cancer oncologist, Dr. Pete Nelson

Photo by Robert Hood / Fred Hutch News Service

Dr. Pete Nelson, an oncologist and Hutch researcher who, among other things, is trying to find reliable biomarkers, or biological red flags, for early stage prostate cancer, gets the frustration.

“I sympathize with the public because they keep getting these pendulum-type back and forth messages and that’s really hard,” he said. “I think the important thing to explain to people is that the guidelines are always based on the best available evidence and we learn more all the time. We learn more about risk; we get better tests. We kind of expect things to change over time.”

As the saying goes, it’s complicated.

When you look at things from a macro viewpoint, mass screening is effective and worth it. When you zoom in and look at it from the individual viewpoint — say, someone who had an aggressive breast cancer turn up in the two years between recommended mammograms or went through a prostate cancer biopsy they didn’t need because of a misleading PSA — it may not be.

Where are we on the path to precision for breast and prostate cancer screening?

”We are on the way but we are not yet there,” said Dr. Janie Lee, director of breast imaging at Seattle Cancer Care Alliance, the Hutch’s clinical care partner, and an affiliate investigator with the Hutchinson Institute for Cancer Outcomes Research (HICOR).

We are slowly moving away from one-size-fits-all breast cancer screening and folding in risk factors not taken into consideration 15 years ago, she said. These include inherited mutations in the BRCA1/2 genes, among others, and family history without a known mutation. We’re also more knowledgeable about dense breast tissue, which can both bump cancer risk and thwart detection since both tumors and dense tissue appear white on mammograms. Finding cancer is like finding a snowball in a snowstorm.

At the breast imaging clinic, Lee uses a number of methods to look for early breast cancers in normal risk women, including digital breast tomosynthesis (or 3D mammography), ultrasound and MRI.  Higher risk women may get all of this and more, via SCCA’s Breast and Ovarian Cancer Prevention Program.

“We have guidelines for women who are very high risk now,” said Lee. “These women are not only advised to get screening mammograms, but also recommended to get supplemental MRIs.”

Dr. Janie Lee

Dr. Janie Lee, director of breast imaging at Seattle Cancer Care Alliance.

Photo by Robert Hood / Fred Hutch News Service

Making breast cancer screening more precise

Two new studies —a national trial that SCCA is participating in and another being conducted at University of California, San Francisco — both seek to fine-tune current breast cancer screening practices for these higher-risk “unicorns.”

The first trial, which is currently recruiting women, focuses on women whose main risk factor is dense breast tissue, comparing the effectiveness of 3D mammography with an abbreviated breast MRI, or AB-MR.

3D mammography has increasingly replaced standard 2D digital mammography because it is much better at eliminating the masking effect of dense tissue. But some women — and/or some providers — also request supplemental MRIs. The problem, Lee said, is that MRIs are time-consuming, costly and not accessible to everyone, either because they’re not covered by insurance or because they simply aren’t available in all areas of the country. They’re also not currently recommended for women whose only risk is dense tissue.

Researchers are hoping that a “fast MRI” may be a better option. The study, which aims to recruit nearly 1,500 women, will compare the two emerging technologies head-to-head, screening women with first one method, then the other, on the same day. A year later, the women will return for a second “two-fer” screening.

“We are taking a standard MRI exam and stripping it down and making it very fast,” Lee said. “If we can get women in and out faster and lower the cost while maintaining the ability to detect cancer, it could be a more viable test for women who have dense breasts as a risk factor.”

The WISDOM trial takes things a little further. True to its name (the acronym stands for Women Informed to Screen Depending On Measures of risk), the study’s aim is smarter screening. It will track 100,000 women following one of two separate screening protocols: a new risk-based screening or a standard-of-care screening based on existing guidelines.

Researchers will use family and medical history, breast density and genetic information to come up with a more tailored screening approach for those in the risk-based arm.  These women will be tested for a panel of nine genes related to breast cancer risk (BRCA1, BRCA2, ATM, CDH1, CHEK2, PALB2, PTEN, STK11 and TP53) as well as a panel of single nucleotide polymorphisms (SNPs) that influence breast cancer.

“This is a precision screening trial,” said Lee. “They’re looking at whether risk-based screening reduces mammogram usage without causing an increase in late stage breast cancer.”

Lee said she would also like to see risk models that do a better job of reflecting both our short-term and long-term risk for cancer. Cancer risk isn’t static, after all. It changes over time.

“We know that breast cancer risk changes with age,” she said. “Yet when you look at a single number that’s projected over your lifetime, it makes it seem like that risk is constant and we know it’s not. Risk models that predict a 5 to 10 year risk, rather than lifetime risk, might be more helpful. It might be better to have a snapshot of your risk that helps you make your screening decision right now.”

Prostate cancer screening advancing ‘very quickly’

As for prostate cancer, things are moving toward precision, but again, we’re not there yet.

“Right now, we don’t have a prostate cancer-specific biomarker,” said Fred Hutch’s Nelson, “whether it’s a blood-based marker, a urine-based marker or even an imaging marker. There’s nothing yet that is specific enough to be used on a routine basis.”

But we’re close. Nelson said research is “moving very quickly” toward finding better diagnostic tools.

“We’re probably a good three to five years away from doing that,” he said. Until then, we’re reliant on our best tool at hand: measuring men’s PSA which generally — but not always — increases in the presence of prostate cancer. As a result, there are PSA pitfalls: false negatives (tests that fail to detect disease) and false positives that can lead to anxiety, unnecessary biopsies, overdiagnosis and unneeded treatment. Not to mention years of back-and-forth debate regarding the test’s validity.

An age-adjusted PSA would be a more useful approach to screening, Nelson said, since normally, PSA levels gradually increase with age. In other words, a PSA level of 2 in a 50-year-old would be concerning; a PSA level of 2 in a 70-year-old, not so much. Another idea:  calculating the rate of PSA change over time: a big increase from a low baseline would raise an instant red flag.

But as with breast cancer, risk stratification based on our improved understanding of the genetic underpinnings of the disease is better yet.

For high-risk men, ‘key is awareness’

“The individuals at greatest risk for aggressive prostate cancer are the ones in families with an inherited risk for breast cancer and ovarian cancer,” said Nelson. This includes, but isn’t limited to, BRCA1/2 mutations.

“There’s a lot of prostate cancer we don’t want to detect,” Nelson said, referring to slow-growing cancers that will never do harm. “But we’ve really turned our attention to men at the highest risk, and there are strategies you can use in those individuals to identify early and intervene.”

The Prostate Cancer Genetics Clinic, which opened a year ago at SCCA, is specifically designed for men with metastatic disease or a family history of prostate, breast, ovarian or pancreatic cancers or lymphoma or leukemia. In addition to counseling and genetic testing, men with known mutations are eligible for more intense screening, earlier screening and prophylactic options. The clinic also works with SCCA’s Breast and Ovarian Cancer Prevention Program since many inherited mutations are linked with various cancers in men and women.

“That’s a key point,” he said. “If you identify a family with these mutations you want to get both the men and the women screened. Although if you inherit a mutation, it doesn’t mean you’ll get cancer. The likelihood is many-fold higher, but it’s not a certainty.”

Nelson called the clinic “a starting point” towards precision screening. And he’s poised to launch a study to demonstrate its worth.

“We’ve written a guideline on how to manage these men, and we’re just starting a study to find out if our approach is the best approach,” he said.

What advice do these researchers have for African-American men who are more susceptible to aggressive prostate cancers?

”Black men should probably begin the conversation about screening 5 to 10 years earlier than their white counterparts,” said Etzioni, referencing a study she published earlier this year showing prostate cancer to be more common and more deadly in black men.

Nelson agreed.

“Right now, the guidelines aren’t different for African American men but they are clearly at higher risk,” he said. “The key is awareness. They should be aware and recognize symptoms and they should talk to their physician. And one of the first things that should be discussed is his family history. Not just prostate cancer, but breast cancer, ovarian cancer, pancreatic cancer. These men are at a higher risk and should have screening, but it’s on the individual to make that call.”

Looking to the future

This advice holds true for anyone concerned about any cancer, all three researchers agree.

Know your cancer risk factors. Know your family’s entire cancer history (not just breast or prostate). Talk to your doctor about your cancer risk and the risks and benefits of screening. Then if screening is recommended, get screened. Cancers caught early have a higher likelihood of being squelched. If possible, work to reduce your risk by not smoking, limiting alcohol, exercising, eating your vegetables (seriously!) and maintaining a normal weight.

For now, screening for breast and prostate cancer involves mammograms, MRIs and PSAs, the best evidence-based tools available at this moment in time. But it won’t be this way forever. Every day, we hear more and more about whole genome sequencing, liquid biopsies, breath testing and other futuristic cancer screening tools. Bit by bit, we’re making our way down the convoluted path to Precision Land, that magical place where late-stage cancers have become as rare and unlikely as, well, unicorns.

“It’s a long road,” Etzioni said.  “And we’re not there yet. But we are making incremental progress. The hope keeps us moving.”

Diane Mapes is a staff writer at Fred Hutchinson Cancer Research Center. She has written extensively about health issues for NBC News, TODAY, CNN, MSN, Seattle Magazine and other publications. A breast cancer survivor, she blogs at doublewhammied.com and tweets @double_whammied. Email her at dmapes@fredhutch.org.

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