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Clinical Laboratories and Pathology Groups

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Clinical Laboratories and Pathology Groups

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UW Medicine Researchers Identify Blood Cell Genetic Mutations That Can Disrupt Liquid Biopsy Results

The discovery is yet another factor that must be considered when developing a liquid biopsy test clinical laboratories can use to detect cancer

How often do disruptive elements present in Liquid biopsies result in misdiagnoses and unhelpful drug therapies for cancer? Researchers at the University of Washington School of Medicine (UW Medicine) in Seattle wanted to know. And the results of their study provide another useful insight for pathologists about the elements that circulate in human blood which must be understood so that liquid biopsy tests can be developed that are not affected by that factor.

Based on their case series study of 69 men with advanced prostate cancer, the UW Medicine researchers determined that 10% of men have a clonal hematopoiesis of indeterminate potential (CHIP) that can “interfere” with liquid biopsies and cause incorrect reports and unneeded prostate cancer treatment, according to their paper published in the journal JAMA Oncology.

The process of clonal hematopoiesis occurs when hematopoietic stem cells generate blood cells that mimic blood mutations in the same way as hematopoiesis, Labroots explained in “Potential Problems with Liquid Biopsies.” Hence, the word “clonal” in the description. 

The UW Medicine researchers advised testing for “variants in the cell-free DNA (cfDNA)” shed in blood plasma to enable appropriate treatment for people with already diagnosed prostate cancer, noted to a UW Medicine news release.

According to pathologist Colin Pritchard, MD, PhD, Associate Professor of Laboratory Medicine and Pathology at the UW Medicine, who led the research team, “clonal hematopoiesis can interfere with liquid biopsies. For example, mutations in the genes BRCA1, BRCA2, and ATM have been closely linked to cancer development.

“Unfortunately, these same genes are also commonly mutated as a result of clonal hematopoiesis,” he told Labroots. Pritchard is also Head of the Genetics Division of Laboratory Medicine at UW Medicine, Director of Clinical Diagnostics for the Brotman Baty Institute for Precision Medicine, and Co-Director of the Genetics and Solid Tumors Laboratory at the University of Washington Medical Center.

“The good news is that, by looking at the blood cellular compartment, you can tell with pretty good certainty whether something is cancer, or something is hematopoiesis,” he said in the news release.

What Does CHIP Interference Mean to a Clinical Laboratory Blood Test?

In their published study, the UW Medicine researchers stressed the “urgent need to understand cfDNA testing performance and sources of test interferences” in light of recent US Food and Drug Administration (FDA) clearance of two PARP inhibitors (PARPi) for prostate cancer:

“We found that a strikingly high proportion of DNA repair gene variants in the plasma of patients with advanced prostate cancer are attributable to CHIP,” the researchers wrote. “The CHIP variants were strongly correlated with increased age, and even higher than expected by age group.

“The high rate of CHIP may also be influenced by prior exposure to chemotherapy,” they added. “We are concerned that CHIP interference is causing false-positive cfDNA biomarker assessments that may result in patient harm from inappropriate treatment, and delays in delivering alternative effective treatment options.

“Without performing a whole-blood control, seven of 69 patients (10%) would have been misdiagnosed and incorrectly deemed eligible for PARP-inhibitor therapy based on CHIP interference in plasma. In fact, one patient in this series had a BRCA2 CHIP clone that had been previously reported by a commercial laboratory testing company with the recommendation to use a PARPi. To mitigate these risks, cfDNA results should be compared to results from whole-blood control or tumor tissue,” the researchers concluded.

To find the clinically relevant CHIP interference in prostate cancer cfDNA testing, researchers used the UW-OncoPlex assay (developed and clinically available at UW Medicine). The assay is a multiplexed next-generation sequencing panel aimed at detecting mutations in tumor tissues in more than 350 genes, according to the UW Medicine Laboratory and Pathology website. 

“To improve cfDNA assay performance, we developed an approach that simultaneously analyzes plasma and paired whole-blood control samples. Using this paired testing approach, we sought to determine to what degree CHIP interferes with the results of prostate cancer cfDNA testing,” the researchers wrote in JAMA Oncology

Men May Receive Unhelpful Prostate Cancer Drug Therapies

The research team studied test results from 69 men with advanced prostate cancer. They analyzed patients’ plasma cfDNA and whole-blood control samples.

Tumor sequencing enabled detection of germline (cells relating to preceding cells) variants from CHIP clones.

The UW Medicine study suggested CHIP variants “accounted for almost half of the somatic (non-germline) DNA repair mutations” detected by liquid biopsy, according to the news release.

Colin Pritchard, MD, PhD
“About half the time when the plasma is thought to contain a mutation that would guide therapy with these drugs, it actually contains CHIP variants, not prostate cancer DNA variants. That means that in about half of those tested, a patient could be told that he should be administered a drug that is not indicated to treat to his cancer,” said Colin Pritchard, MD, PhD, pathologist and Associate Professor of Laboratory Medicine and Pathology at UW Medicine in the new release. (Photo copyright: University of Washington School of Medicine.)

Other detailed findings of the UW Medicine Study:

  • CHIP variants of 2% or more were detected in cfDNA from 13 of 69 men.
  • Seven men, or 10%, having advanced prostate cancer “had CHIP variants in DNA repair genes used to determine PARPi candidacy.
  • CHIP variants rose with age: 0% in those 40 to 50; 12.5% in men 51 to 60; 6.3% in those 61 to 70; 20.8% in men 71 to 80; and 71% in men 81 to 90.
  • Whole-blood control made it possible to distinguish prostate cancer variants from CHIP interference variants.

“Men with prostate cancer are at high risk of being misdiagnosed as being eligible for PARPi therapy using current cfDNA tests; assays should use a whole-blood control sample to distinguish CHIP variants from prostate cancer,” the researchers wrote in JAMA Oncology.

Liquid Biopsies Are ‘Here to Stay’

Surgical oncologist William Cance, MD, Chief Medical and Scientific Officer, American Cancer Society (ACS) in Atlanta, recognizes the challenge of tumor biology to liquid biopsies. 

“Genetic abnormalities are only one piece of the puzzle. We need to look comprehensively at tumors for the best therapy, from their metabolic changes and protein signatures in the blood to the epigenetic modifications that may occur, as cancers take hold,” he told Oncology Times. “It’s not just shed DNA in the blood.”

The UW Medicine study demonstrates the importance of understanding how all elements in liquid biopsies interact to affect clinical laboratory test results.

“I think liquid biopsies are here to stay,” Cance told Oncology Times. “They’re all part of precision medicine, tailored to the individual.”

Donna Marie Pocius

Related Information:

Association of Clonal Hematopoiesis in DNA Repair Genes with Prostate Cancer Plasma Cell-free DNA Testing Interference

Potential Problems with Liquid Biopsies

Blood Cell Mutations Confound Prostate Cancer Liquid Biopsy

Pursing and Perfecting Use of Liquid Biopsies in Cancer Early Detection

Researchers at Harvard’s Massachusetts General Hospital Develop a Non-Invasive Liquid Biopsy Blood Test to Detect and Monitor Common Brain Tumors in Adults

Using Extracellular Vesicles, Researchers Highlight Viability of Liquid Biopsies for Cancer Biomarker Detection in Clinical Laboratories

New studies in UK and at Stanford University Show Lung Cancer Cells Circulating in Blood; Findings Could Make It Possible for Pathologists to Diagnose Cancer with ‘Liquid Biopsies’

Top Healthcare Trends Affecting Cancer Business in 2017 Impact Pathologists and Medical Laboratory Leaders Who Serve Oncologists and Patients

Many aspects of traditional clinical laboratory pathology testing remain rooted to cancer care even as the cancer care industry embraces precision medicine, and digital pathology testing and interpretation

There’s good news for anatomic pathologists worried about the future of the pathology profession. A recent survey of oncology program participants in the United States determined that Precision Medicine—and the need for precision diagnostics—will be one of the top trends that significantly reshape how cancers are diagnosed and treated in the US.

Some of these five trends indirectly impact clinical laboratories and pathology groups by directly affecting the healthcare practices of hospitals and private practice doctors who order medical laboratory tests for their cancer patients.

Lindsey Conway, Managing Director, Research and Insights Division, for The Advisory Board, covered five of the top trends she says will “shape the business of cancer care in 2017,” which MedCityNews reported. They include:

1.     Precision Medicine

2.     Healthcare Consumerism

3.     Telehealth Services

4.     Care Navigation

5.     Payment Reform

One of the trends involves increased use of specialized diagnostic tests that identify genetic mutations to help ensure cancer drugs and therapies are precisely targeted to a patient’s specific needs. This is a critical element of precision medicine.

Here are brief run-downs on each of the five trends:

Precision Medicine in Clinical Laboratory Cancer Care

The Association of Community Cancer Centers (ACCC) in partnership with Advisory Board’s Oncology Roundtable (AB) conducted the survey, which was funded by Pfizer Oncology, according to an ACCC press release.

The survey found precision medicine to be among the top trends impacting the cancer care business in 2017. This will be of particular interest to pathologists and clinical laboratory leaders who provide services to oncologists and cancer patients.

ACCC’s press release states: “By taking the pulse on issues such as program mergers and acquisitions, clinical pathways usage, and precision medicine and immunotherapy, ACCC can continue to provide needed resources to its members.”

The Advisory Board is a respected “think tank” that uses research, technology, and consulting to aid healthcare organizations. And, the ACCC is an advocacy and education organization for cancer care professionals.

“We are all betting big on the promise of precision medicine,” declared Conway, in the MedCityNews story. She noted, however, specific challenges related to precision medicine. They include:

·       Understanding developments;

·       Financing equipment purchases; and,

·       Educating others.

Dark Daily noted similar concerns with precision medicine in an e-briefing on research conducted at the University of Washington School of Medicine in Seattle, where two commercially available next-generation sequencing tests had widely different results for the same cancer patients studied. (See Dark Daily, “University of Washington School of Medicine Study Finds Two Different Next-Generation Genetic Tests Can Produce Widely Different Results in the Same Patient,” May 1, 2017.)

Patient Consumerism in Cancer Care

Drawing on the AB/ACCC findings, MedCityNews noted that about 69% of cancer care consumers who use the Internet in healthcare decision-making are likely to change providers who receive negative online reviews.

These findings are not lost on cancer center administrators and medical directors who, according to an Advisory Board news release announcing the results of a survey of 250 cancer program leaders, have “increased interest in cancer patient consumerism—mainly around how to identify patient priorities and market cancer program services directly to patients.”

Telehealth Takes Cancer Care Virtual

Telehealth (AKA, Telemedicine) involves telecommunications and information technologies (IT), such as video, audio, and Internet-based software, to bring healthcare services to resource strapped remote and rural environments. One example of telemedicine that is focused on cancer care is the Breast Cancer Ally mobile app.  Developed by Michael Sabel, MD, FACS, Associate Professor of Surgery and Chief of Surgical Oncology at the University of Michigan Medical School (U-M), Breast Cancer Ally is “an information and symptom management tool specially designed [to help] patients through every stage of breast cancer treatment.” The app is available for use by U-M Comprehensive Cancer Care Center patients.

“This is disease-specific technology that helps patients navigate the multiple facets of medical care by delivering information and tools based on the appropriate stage of treatment,” U-M noted in a statement.

Navigating the Care Continuum

Driven by a need to guide more cancer patients throughout their treatment, the University of Alabama at Birmingham (UAB) is taking its navigation program to a national level, according to a UAB statement.

UAB’s partner in the Patient Care Connect Program (PCCP) is Guideway Care, a resource for personal guidance in cancer treatment and recovery. Guideway Care offers communication protocols and technology for assisting people following a cancer diagnosis.

According to UAB results, compared to non-navigated cancer patients the PCCP participants experienced:

·       55% less hospitalizations;

·       29% fewer emergency room visits;

·       60% less intensive care unit admissions; and,

·       45% reduction in Medicare costs.

“The PCCP is a model of navigation that supports patients throughout the cancer care continuum and may be a mechanism to extend palliative and support care more fully into the community,” wrote UAB-affiliated authors in a JAMA Oncology article.

“Overall, cost reductions were driven by substantial declines in hospitalizations and clinic-based services,” they concluded.

Ramona Colvin (standing) and Myeisha Hutchinson, patient navigators with UAB’s Patient Care Connect program, work together to help patients through their cancer journey. (Photo and caption copyright: UAB News.)

Healthcare Reimbursement and Reform

Insurance company programs intended to lower cancer care costs that operate concurrent with congressional lawmakers’ healthcare reform efforts are receiving increased scrutiny.

One relevant example of a payer plan aimed at increasing value is Anthem’s Cancer Care Quality Program. It enables participating oncologists to compare cancer care pathways and become eligible for additional $350 a month in reimbursements for each patient being treated.

“Private payers have been on the forefront of designing value-driven ways to pay for cancer care, but we’re not going to arrive at a satisfying payment solution any time soon,” stated Conway in the MedCityNews article.

Trends Can Guide Medical Laboratory Leaders

The findings of the AB/ACCC study affirm the important role that pathologists will have as precision medicine transforms cancer care. After all, it is pathologists who diagnose the primary cancer, and it is pathologists who conduct specialized testing to identify genetic mutations that would make a patient’s cancer vulnerable to a specific drug or therapy. Pathologists also have a role in monitoring the cancer patient’s treatment.

Thus, it is important for clinical laboratory leaders to acknowledge what their cancer care colleagues perceive as trends and topics of interest. Pathologists and medical laboratory leaders who provide services to oncologists and cancer patients should note these trends and related programs and research. Healthcare navigation and telemedicine applications, for example, could be ways for pathologists to collaborate with oncologists in outreach to cancer patients.

—Donna Marie Pocius

Related Information:

Five Healthcare Trends Impacting Cancer Care

ACCC Collaborates with Advisory Board to Conduct Eight Annual Trends in Cancer Care Survey

UAB Expands Cancer Navigation Program Nationally with Guideway Care

Resource Use and Medicare Costs During Lay Navigation for Geriatric Patients with Cancer

U-M Breast Cancer Ally Providing Patients with Effective Disease Management

Advisory Board Research for 2018

University of Washington School of Medicine Study Finds Two Different Next-Generation Genetic Tests Can Produce Widely Different Results in the Same Patient

New Insights into Genetic Mechanisms Common to Humans and Simpler Species May Form the Basis for New Diagnostic Tests Performed by Clinical Pathology Laboratories

Scientists participating in the modENCORE study have the goal of understanding the causes of hereditary genetic diseases in humans

New discoveries about the interaction of genes and transcription factors in creating different types of RNA will be of interest to pathologists and clinical chemists performing genetic tests and molecular diagnostic assays in their medical laboratories.

The goal of this research is to better understand hereditary genetic disease in humans. The new knowledge is based on studies of the common fruit fly, or Drosophila melanogaster (D. Melanogaster), and to a lesser extent a tiny worm Caenorhabditis elegans (C. elegans). Both have been used as research models to study the human condition.

Research Could Give Pathologists New Diagnostic Tools (more…)

PeaceHealth and University of Washington School of Medicine Form Strategic Alliance, Further Integrating Academic and Community Care Settings

There’s more consolidation in the hospital marketplace as institutions look to build scale and offer a fuller menu of healthcare services

Across the United States, multi-hospital health systems and stand-alone academic medical centers are looking for the right collaborations, alliances, and consolidation opportunities. This is happening because hospitals of all sizes and types recognize the need to be part of a comprehensive, integrated provider network in their region.

This is a trend that has ramifications for clinical laboratories and pathology groups that operate in the regions where these alliances and collaborations happen. That is because such collaborations can often change the competitive market for medical laboratory testing in the communities served by the partners in the alliance.