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Clinical Laboratories and Pathology Groups

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News, Analysis, Trends, Management Innovations for
Clinical Laboratories and Pathology Groups

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Prenatal Testing Incidentally Finds Cancer in Mothers, Becomes Focus of New National Institutes of Health Long-term Study

Discovery could lead to new clinical laboratory testing for cancer screening in new mothers

Any clinical laboratory test that returns unexpected results is worth looking into more deeply. Such was the case with a recent study conducted by the National Institutes of Health (NIH), which investigated cases of pregnant women who received “unusual” results to prenatal lab tests conducted at a dozen labs in North America.

Following cancer screening protocols that included rapid whole-body magnetic resonance imaging, NIH scientists discovered “previously undetected cancers in 48.6% of pregnant people who had abnormal results for prenatal cell-free DNA (cfDNA) testing used to screen for chromosomal disorders in the fetus,” according to an NIH news release.

“They looked like healthy young women, and they reported themselves as being healthy,” Diana Bianchi, MD, head of the Prenatal Genomics and Therapy Section for the Medical Genetics Branch at the NIH’s National Human Genetics Research Institute, and senior author of the government study, told the Associated Press (AP).

While cfDNA tests are not diagnostic, pathologists and clinical laboratory managers involved in genetic testing are likely familiar with them. The blood tests are used by expectant mothers to assess risk of a fetus with an abnormal number of chromosomes that could suggest disorders such as Down Syndrome, according to ARUP Laboratories.

Unexpected results from tests draw attention. This one seems to have a chance to get more traction with labs because the results point to a prenatal test having some success predicting cancer, even if incidentally.

The researchers published their findings in the New England Journal of Medicine (NEJM) titled, “Prenatal cfDNA Sequencing and Incidental Detection of Maternal Cancer.”

“[The study participants] and their care providers need to take the results seriously and have additional testing because in that population there is a 48% risk of cancer,” Diana Bianchi, MD, senior author of the NIH study, told the AP. (Photo copyright: National Institutes of Health.)

Cancer Found in about Half of Those with Abnormal cfDNA

The NIH researchers started a long-term study, called IDENTIFY, to learn more about abnormal cfDNA results that could suggest cancer. Study participants must be:

  • Pregnant or postpartum with no known cancer.
  • Recipients of “unusual clinical cfDNA-sequencing results or results that are non-reportable (fetal aneuploidy status could not be assessed) from one of 12 different commercial laboratories,” they wrote in NEJM.

For the study’s initial cohort of 107 participants, researchers repeated cfDNA sequencing testing and coordinated standard medical diagnostic tests (such as Pap smears) and whole-body magnetic resonance imaging.

As reported by Ars Technica:

  • 52 women (48.6%) were found to have “hidden cancers.”
  • 32 had blood cancers.
  • 20 had solid tumors in the breast, bile duct, colon, pancreas, lung, kidney, bone, and adrenal gland.
  • 13 of the 20 with solid tumors were able to access “potentially curative treatments.”
  • 55 women did not have cancer and may have obtained an unreliable cfDNA result.

“In this study, 48.6% of participants who received unusual or nonreportable clinical cfDNA-sequencing results had an occult cancer (cancer of unknown primary).

“Further study of DNA-sequencing patterns that are suggestive of occult cancer during prenatal screening is warranted,” the researchers wrote in NEJM.

Follow-Up Testing Needed

Cancers found in the study participants “included colorectal, breast, lung and pancreatic cancers, as well as lymphoma, cholangiocarcinoma and renal carcinoma. The screening test analyzes placental DNA fragments circulating in the maternal bloodstream to identify an extra chromosome or to determine the baby’s sex,” according to the NIH news release.

Bianchi told AP the study results also pointed to a “very chaotic” pattern in DNA-sequencing of women with cancer, and that more research is needed to find out who should be screened for cancer.

Clinical laboratories and pathologists who analyze cfDNA tests could take a leadership role in assessing current standards for the tests, determining how suspicious results are reported, and suggesting needed changes. 

—Donna Marie Pocius

Researchers at University of Michigan Rogel Cancer Center Develop Urine Test That Detects Head and Neck Cancer

Proof-of-concept study may eventually lead to new clinical laboratory urine tests for fast, non-invasive detection of cancer

Here is the latest example of researchers finding useful biomarkers in urine for diagnosing certain cancers. The discovery comes from the University of Michigan Health Rogel Cancer Center, where, in a proof-of-concept study, scientists developed a urine-based test that screens for circulating free DNA (cfDNA) fragments (aka, cell-free DNA) released by tumors in the head and neck. If they confirm these findings, it’s possible the technology could be adapted into a non-invasive clinical laboratory test for selected cancers.

One such cancer is human papillomavirus (HPV) which, though “widely recognized for causing cervical cancer” is “increasingly found to cause cancers in the mouth, throat, and other head and neck regions,” according to a U-M Medical School press release.

The U-M study findings could lead to an early, non-invasive test for the detection of cancer, as compared to traditional urine or blood-based liquid biopsy testing.

The researchers published their findings in the journal JCI Insight titled, “ctDNA Transiting into Urine is Ultrashort and Facilitates Noninvasive Liquid Biopsy of HPV+ Oropharyngeal Cancer.”

“In this study, we provide evidence to support the hypothesis that conventional assays do not detect ultrashort fragments found in urine since they are designed to support longer DNA fragments. Our team used an unconventional approach to develop a urine test for HPV-positive head and neck cancer ctDNA detection,” said Chandan Bhambhani, PhD (above), Research Lab Specialist Intermediate at University of Michigan and co-first author of the study, in a news release. Clinical laboratories may soon have a new urine-based test for detecting cancer. (Photo copyright: LinkedIn.)

Advantages, Challenges of Urine Testing

Key to their discovery was use of whole genome sequencing to find what conventional assays tend to miss: predominantly ultrashort (under 50 base pairs) of circulating urine transrenal cell-free tumor DNA (TR-ctDNA) fragments, according to the JCI Insight paper.

According to the researchers, benefits of urine testing include:

  • Testing with urine is convenient for people who may be unable to access healthcare and phlebotomy services.
  • Urine has low biohazard risk and may be easily collected in large amounts, compared with blood.
  • Ongoing collection of urine could make way for TR-ctDNA “kinetics to be used as a high time-resolution biomarker” to monitor patients’ response to treatment.

However, urine, the researchers cautioned, must be analyzed in a different manner if it is to be comparable in efficiency to blood-based ctDNA testing.

“There have been mixed reports on the efficiency of TR-ctDNA detection compared with that of blood ctDNA. A potentially crucial factor for the analysis of TR-ctDNA is knowing the length of TR-ctDNA fragments present in urine, because this affects assay design for optimal sensitivity in TR-ctDNA detection,” the researchers explained.

New Assay Detects Ultrashort DNA Fragments

To complete their study, the U-M researchers developed an ultrashort HPV droplet digital PCR (polymerase chain reaction) assay that enabled detection of TR-ctDNA from HPV-associated oropharyngeal squamous cell carcinoma (HPV OPSCC), BioTechniques reported.

The assay was made to target the HPV16 E6 (Human papillomavirus 16) gene and to measure TR-ctDNA in patients with HPV OPSCC, the JCI Insight paper noted.

“The HPV16 E6 gene represents a highly recurrent ctDNA target in the population of patients with HPV OPSCC,” the researchers wrote in JCI Insight, adding:

  • Targeting ultrashort fragments was essential “for robust TR-ctDNA detection.”
  • Results in urine with patients with HPV OPSCC was consistent with results from plasma ctDNA.

The test, still in the discovery phase, was mailed to patients who were being treated for the disease and who reside within 100 miles of Ann Arbor, Mich. They returned urine samples for testing at the U-M lab and to get insights into possible post-treatment needs.

“Using longitudinal urine samples from a small case series, we showed proof of concept for early detection of cancer recurrence. Thus, our results indicate that by targeting ultrashort DNA fragments, TR-ctDNA becomes a viable approach for HPV OPSCC detection and potentially for cancer recurrence monitoring after treatment,” the authors wrote.

Further Studies, Possible Test Expansion

HPV infection—and especially HPV type 16—is a growing risk factor for oropharyngeal cancers, according to the National Cancer Institute.

The U-M Rogel Cancer Center scientists plan more studies to leverage the information urine may carry about an individual’s health. The researchers intend to expand the scope of their new test to other cancers including breast cancer and acute myeloid leukemia.

“The test that has been developed has detected cancer far earlier than would typically happen based on clinical imaging. As such, these promising results have given us the confidence to broaden the scope of this study, seeking to expanding distribution even further,” said J. Chad Brenner, PhD, Associate Professor of Otolaryngology-Head and Neck Surgery, U-M Medicine, and co-senior author of the study, in the news release.

The University of Michigan Health study exemplifies scientists’ commitment to new categories of biomarkers that can be used for medical laboratory tests and prescription drugs. And by focusing on urine, the researchers made it possible for patients to collect specimens themselves and send them to the medical laboratory for analysis and reporting.  

—Donna Marie Pocius

Related Information:

University of Michigan Health Lab Researchers Discover Urine-based Test to Detect Head and Neck Cancer

ctDNA Transiting into Urine is Ultrashort and Facilitates Noninvasive Liquid Biopsy of HPV+ Oropharyngeal Cancer

Urine-based Test Detects Head and Neck Cancer

National Cancer Institute: Head and Neck Fact Cancers

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