DNA and protein 'liquid biopsy' for early pancreatic cancer better than either alone

September 4, 2017
Axial CT image with i.v. contrast. Macrocystic adenocarcinoma of the pancreatic head. Credit: public domain

Johns Hopkins scientists say they have developed a blood test that spots tumor-specific DNA and protein biomarkers for early-stage pancreatic cancer. The combined "liquid biopsy" identified the markers in the blood of 221 patients with the early-stage disease. Their results, published online the week of Sept. 4 in the Proceedings of the National Academy of Sciences, show that detection of markers from both DNA and protein products of DNA was twice as accurate at identifying the disease as detection of DNA alone.

Such liquid biopsies aim to fish out DNA molecules specific for amid a wide sea of normal DNA circulating in the blood. Tumors tend to shed their mutated DNA into the bloodstream, making it possible for scientists to use genomic sequencing tools to sift through the blood and find such cancer-linked DNA.

Most early-stage pancreatic cancers are found incidentally during an imaging scan and generally cause no symptoms. But the disease is most often found late, when it's far advanced and resection, or surgery, is not the first treatment option, says Jin He, M.D., assistant professor of surgery at the Johns Hopkins University School of Medicine. "In the past 30 years, we haven't made much progress in identifying people with resectable cancers," says He. "If this test's performance is validated in larger studies, it could be used to identify patients with early, asymptomatic pancreatic cancer."

While their test is not ready to be used outside of a research setting, they say, mutated DNA of the type that is shed from tumors and found in blood is "exquisitely specific" for cancer. "If cancer-linked DNA can be found in the blood of an individual, it is very likely that person has cancer," says Bert Vogelstein, M.D., co-director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center. Studies by Vogelstein's team and others have shown that DNA can be identified in the blood of more than 85 percent of patients with advanced cancers. However, the sensitivity of detecting such small bits of DNA in the blood of patients with early cancers, without prior knowledge of the genetic status of the cancers, was unknown prior to this study, say the scientists.

In their new study, blood and tumor tissue samples were collected from 221 men and women, mostly Caucasians, with stage I and II pancreatic cancers who underwent surgery to remove their pancreas at hospitals in Australia, Korea, Indiana, Pittsburgh, the Mayo Clinic, Rochester, Memorial Sloan Kettering in New York and The Johns Hopkins Hospital. Another 182 people with no known history of cancer, autoimmune disease or chronic kidney disease donated their blood for the study.

The scientists were able to identify 66 of the 221 patients, or 30 percent, with early-stage pancreatic cancer by using their blood screening tool to sift for mutations in the DNA of the KRAS gene alone, an early marker of pancreatic cancer development.

Their goal, however, was to improve the 30 percent detection rate, find more early cancers and avoid false positives in people without the disease, says Joshua Cohen, an M.D.-Ph.D. postgraduate student in Vogelstein's lab who worked on the study.

So, they turned to protein biomarkers circulating in the blood. Such circulation protein markers already are used clinically to detect and monitor diseases like diabetes and heart muscle damage from heart attacks as well as to monitor patients with a prior history of cancers.

Of special interest to the researchers was the protein biomarker CA19-9. It's used to monitor patients with pancreatic cancer for recurrence. But the level of CA19-9 used for recurrence monitoring is low (37 units/mL), because physicians want to pinpoint regrowing cancers quickly.

Some people without cancer may also have low levels of the protein, such as those with gallstones. For screening purposes, the level of CA19-9 needed to be much higher (100 units/mL).

"A screening test needs to be highly reliable to spare people the worry and side effects of procedures following a positive test for cancer," says Kenneth W. Kinzler, Co-Director of the Ludwig Center at Johns Hopkins.

When the scientists looked only for CA19-9 in the blood of their study participants, they found it in 109 of the 221 patients (49 percent). However, when they combined detection of KRAS mutations, CA19-9 and three other protein biomarkers, the scientists correctly identified pancreatic cancer in 141 of the 221 patients (64 percent). In contrast, only one individual among their control group of 182 people without cancer had elevation of one of the five biomarkers.

"A single marker on its own won't identify early cancers in most people," says Anne Marie Lennon, M.D., Ph.D., associate professor of medicine at the Johns Hopkins University School of Medicine and director of the Multidisciplinary Pancreatic Cyst Program. "This study shows that it may be possible to use multiple markers to nail down the detection of early with a blood test, and treat those patients earlier and better."

Vogelstein's team used a system of molecular barcoding that they developed to ensure that each KRAS mutation they detected was real and not an artifact. For example, they showed that there was complete agreement between the mutations detected in the blood and the mutations detected in the tumors. They say the mutations they detected are also common in lung and colon cancers, and they're planning on using a similar approach, combining protein and DNA biomarkers, to identify early cancers of several types.

Nick Papadopoulos, professor of oncology at the Johns Hopkins Kimmel Cancer Center, estimates that the cost of a screening test based on the approach described in this study would be between that of mammography and colonoscopy, which are widely used tests for breast and colorectal cancers, respectively. Papadopoulos notes that "both DNA and protein markers can be analyzed from the same draw in each patient. The technologies required to implement such tests, involving protein biomarker tests and DNA sequencing, are already widely used in hospital and commercial laboratories.

Explore further: Scientists develop blood test that spots tumor-derived DNA in people with early-stage cancers

More information: Joshua D. Cohen el al., "Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers," PNAS (2017). www.pnas.org/cgi/doi/10.1073/pnas.1704961114

Related Stories

Scientists develop blood test that spots tumor-derived DNA in people with early-stage cancers

August 16, 2017
In a bid to detect cancers early and in a noninvasive way, scientists at the Johns Hopkins Kimmel Cancer Center report they have developed a test that spots tiny amounts of cancer-specific DNA in blood and have used it to ...

Blood test for early detection of pancreatic cancer headed to clinic

July 12, 2017
A newly identified biomarker panel could pave the way to earlier detection and better treatment for pancreatic cancer, according to new research from the Perelman School of Medicine at University of Pennsylvania. Currently ...

Blood test for pancreatic cancer shows early promise

May 24, 2017
Scientists say they've developed a new blood test for identifying pancreatic cancer—a step that might eventually allow earlier diagnosis.

Blood test to detect DNA fragments shed from colon cancers predicts disease recurrence

July 6, 2016
Scientists at the Johns Hopkins Kimmel Cancer Center and University of Melbourne report they have used a genetic test that spots bits of cancer-related DNA circulating in the blood to accurately predict the likelihood of ...

Study finds genes associated with improved survival for pancreatic cancer patients

August 20, 2015
A study by the Translational Genomics Research Institute (TGen) and other major research institutes, found a new set of genes that can indicate improved survival after surgery for patients with pancreatic cancer. The study ...

New biomarkers to spot pancreatic cancer early

February 5, 2015
Pancreatic cancer could be diagnosed up to two years earlier by screening for two tumour markers found in blood, according to research published in Clinical Cancer Research.

Recommended for you

Brain powered: Increased physical activity among breast cancer survivors boosts cognition

September 19, 2017
It is estimated that up to 75 percent of breast cancer survivors experience problems with cognitive difficulties following treatments, perhaps lasting years. Currently, few science-based options are available to help. In ...

Targeted antibiotic use may help cure chronic myeloid leukaemia

September 19, 2017
The antibiotic tigecycline, when used in combination with current treatment, may hold the key to eradicating chronic myeloid leukaemia (CML) cells, according to new research.

Researchers compose guidelines for handling CAR T cell side effects

September 19, 2017
Immune-cell based therapies opening a new frontier for cancer treatment carry unique, potentially lethal side effects that provide a new challenge for oncologists, one addressed by a team led by clinicians at The University ...

Bone marrow protein a 'magnet' for passing prostate cancer cells

September 19, 2017
Scientists at the University of York have shown that a protein in the bone marrow acts like a 'magnetic docking station' for prostate cancer cells, helping them grow and spread outside of the prostate.

Brain cancer breakthrough could provide better treatment

September 19, 2017
A new discovery about the most common type of childhood brain cancer could transform treatment for young patients by enabling doctors to give the most effective therapies.

A new paradigm for treating transcription factor-driven cancers

September 18, 2017
In the current issue of Proceedings of the National Academy of Sciences, researchers from Nationwide Children's Hospital describe a new paradigm for treating transcription factor-driven cancers. The study focuses on Ewing ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.