Category Archives: Genetic Medicine

Pharmacogenetics presents clinicians an attractive option to optimize drug therapy, minimize harmful effects, and contain costs; but, payers may not be taking full advantage of cost-saving potential by choosing only to cover the costs associated with interrogating a single gene.

Reports vary, but the cost of testing a single gene appears to range from $100 to $500, depending on the source. The cost of running an entire panel is a similar price.

Despite the virtually negative cost differential, payers are reluctant to cover the cost of running a full panel of tests. This common practice raises the question of why many payer organizations do not pay for running an entire test panel. Experts differ in their speculations as to why this is the case.

I dont think theyre familiar with the total body of knowledge, says Ruben Bonilla-Guerrero, MD, FACMG, FAACC, MB(ASCP), CGMBS, medical director of medical affairs at Admera Health, a leader in personalized medicine and non-invasive cancer testing in South Plainfield, New Jersey. Insurance companies consider running a pharmacogenetic test panel as experimental even though the labels on more than 200 drugs mention pharmacogenetics testing.

Related:Genetic Testing in Treatment Decision Making Goes Mainstream

Pharmacogenetic testing offers important advantages by facilitating the prescribers ability to select, initiate, and adjust a pharmaceutical drug product with a much higher level of precision than previously available with conventional dose titration. Pre-emptive testing also helps prevent adverse drug events that occur as a result of overdosing medications.

However, like many areas of healthcare, weighing the cost against the purported benefits is also critical.

Payers want to reimburse for tests that are done for a specific indication and that have evidence-based, actionable treatments based on the results, says Erin Lopata, PharmD, MPH, senior director of the Access Experience Team at Precision for Value, part of Precision Value & Health, which performs value and access consulting services for entities that may be involved in value-based contracting.

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The Benefits of Pharmacogenetic Testing - Managed Healthcare Executive

Jan 08, 2020 11:04 AM EST

There are 500 animals studied so far in the mouse lemur project, a collaboration that aims to parse the genetics of this diminutive, prosimian primate. It is the brainchild of Stanford biochemist Mark Krasnow.

Because all 24 species of mouse lemurs look similar, the most reliable way for scientists to tell them apart is through genetic testing. (Scientists have recently identified three new species of mouse lemurs in Madagascar.)

They are quite possibly the answer to medical researchers' dreams.

This world's smallest primate may soon replace fruit flies, worms, and even mice as the primary lab animal for scientific research.

According to Stanford University School of Medicine researchers, they have the potential to serve as an ideal model for a wide range of primate biology, behavior, and medicine, including cardiovascular disease and Alzheimer's disease.

Mice, fruit flies, and worms as genetic models have routinely failed to mimic many aspects of primate biology, including many human diseases, said Mark Krasnow, MD, Ph.D., professor of biochemistry.

Krasnow and his colleagues turned to the mouse lemur and began conducting detailed physiologic and genetic studies on them.

It was reported that they already have identified more than 20 individual lemurs with unique genetic traits, including obesity, high cholesterol, high blood sugar, cardiac arrhythmias, progressive eye disease and motor and personality disorders.

The researchers hope it will soon become a genetic model organism that will help us better understand many aspects of primate biology, behavior, and health, including lemur and human diseases.

According to the June issue of GENETICS, Ezran et al.'s genetic research on these primates began as a project for three high school laboratory interns to find an appropriate model organism for primate genetics.

Mouse lemurs are more human than mice, as genetic research on mice has led to countless important discoveries, but their physiology and behavior differ in many ways from that of humans and other primates. They potentially rival the common laboratory mouse Mus musculus, at least for certain questions.

Mice, fruit flies, and worms were the prototypical lab specimen because they were inexpensive to maintain, easy to study, and reproduced quickly enough to offer researchers a constant stream of samples. According to Krasnow, MD, Ph.D., a professor of biochemistry at Stanford University, the genetic makeup of the 3 animals hasn't been a close enough match to humans to work well for the studies today's researchers need to conduct.

Krasnow's project is studying a large population of grey and brown mouse lemurs - Microcebus murinus and Microcebus rufus, respectively - in the wild to work out how their genes link to differences in biology, health, and behavior.

Other than being closely related to humans, they still have many of the advantages of mice in terms of small size, rapid reproduction, and relatively large litters.

These researchers hope that continued study of these abundant primates could lead to a better understanding, and possibly better treatments, of these and other conditions in lemurs and humans.

RELATED ARTICLE: DNA Analysis Helps Researchers Identify New Mouse Lemur Species

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Mouse Lemurs Just Might Be the Next Big Thing in Genetics - Nature World News

Borna disease virus 1 (BoDV-1) causes a bizarre and deadly neurological infection in horses, sheep and other domesticated mammals in parts of Germany, Switzerland, Liechtenstein and Austria. Borna disease was named after a city in eastern Germany where it once killed numerous horses in the late 19th century. Infected animals have been known to engage in strange behaviors, such as smashing their heads into things, as well aspipe smokingan informal term for when animals are eating hay and suddenly stop chewing mid-mouthful, with the uneaten portion protruding like a pipe. But the disease does not appear to spread between horses; they are thought to acquire it from shrews, which can live in hay and secrete or excrete fluids containing the virus.

About 14 years ago, researchers identified the bicolored white-toothed shrew as a reservoir hostan organism in which a virus replicates but does not usually cause illnessfor BoDV-1. Horses and sheep are considered dead-end hosts that cannot spread the pathogen. For decades, scientists had debated whether the virus is zoonotic, or capable of jumping from animals to humans. Several studies even suggested that it might be present in people with psychiatric disorders such as depression, schizophrenia and bipolar disorder. It was later shown, however, that the viral RNA sequences detected in these studies were likely the result of laboratory contamination, and research on human infections subsided.

But in 2015 a related type of bornavirus found in exotic squirrels was implicated in at least four human deaths. Then, between 2018 and 2019, scientists detected the classical bornavirus, BoDV-1, in five people in Germany who suffered serious or fatal encephalitis (brain inflammation caused by infection)three of whom were recipients of organ transplants and were taking drugs to suppress their immune system. Now, in a study published Tuesday in Lancet Infectious Diseases, researchers have reported eight additional cases of BoDV-1 infection in humans who died of encephalitis. The pathogen appears to have flown under the radar for decades, but the researchers say doctors should be considering it a potential cause in such deaths.

We now have eight more cases, and these provide additional material for a better understanding of the disease, says Martin Beer, head of the Institute of Diagnostic Virology at the Friedrich Loeffler Institute in Germany, who was co-senior author of the new study and was also part of the team that reported the squirrel bornavirus infections. The findings confirm that the virus can infect humans and cause deadly encephalitis. But the risk is, to our opinion, pretty low, Beer says.

Beer and his colleagues analyzed postmortem brain tissue from 56 patients in southeastern Germanys state of Bavaria between 1999 and 2019. The samples were tested for genetic material from BoDV-1, which the researchers verified by additional testing for antibodies to it. Seven out of nine patients who died of encephalitis of unknown cause at one diagnostic center later tested positive for the virus (one of these cases had been reported previously). An additional two cases that tested positive were also included in the analysis.

The results confirm the virus had caused eight new encephalitis cases; two of these were immune-compromised individuals who had received organ transplants, and six were not. Because other recipients of organs from the same donor did not test positive for the virus, researchers think the transplant recipients that died from the virus probably acquired it from being immune-compromised, not from the donor. The patients suffered symptoms including headache, fever and confusion, which later progressed to coma and ultimately death.

All of the patients lived in rural areas and worked or spent a lot of time outside. Most had also been around cats, which are known to catch shrews and sometimes present them to their owners. Beer and his team hypothesize that the patients were exposed to BoDV-1 this way or perhaps by inhaling dust containing dried shrew urine. Future research will be needed to determine the exact infection route, he says.

Once in a human or horse host, the virus is thought to cross the blood-brain barrier into the central nervous system, where it triggers the hosts immune system to attack brain tissue. Its not the virus killing the brain cell or nerve tissue, Beer explains. Its the [hosts] own immune system recognizing the infection and starting to kill parts of brain.

There is no known treatment for the disease, but researchers are exploring whether antivirals such as ribavirinwhich has been shown to kill a range of bornaviruses in cells grown in a dish and in animal studiescould be effective in treating BoDV-1 infections in humans. Beer and his colleagues have plans to test newer antivirals against the virus in animal studies.

I think its an excellent paper, says Norbert Nowotny, a professor of virology at the University of Veterinary Medicine, Vienna, who was not involved in the new study but was part of the group that discovered shrews were a reservoir host for the virus. This Borna disease is really a strange diseaseits not like a flu, he adds, noting that it does not cause epidemics. Its a single-animal disease, and it seems to be the same in humans.

The virus itself is somewhat unusual in that it has a very short genome and makes only a few proteins. It does not seem to infect many individualsbut when it does, it kills them very efficiently. Numerous other zoonotic viruses infect many people but are seldom deadly. Previous research has found that humans and most mammals actually have bornavirus sequences in their genomes, which may help organisms protect themselves against infection, some hypothesize.

Fortunately, the virus does not appear to be transmitted between humans. I think we are all happy that this is not a virus that can spread easily, Beer says. But in light of these new findings, doctors should consider BoDV-1 as a possible cause of encephalitis in areas where it has been known to infect humans and horses.

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Virus Spread by Shrews Linked to Human Deaths from Mysterious Brain Infections - Scientific American

Luke Fletcher,1,2 Sunil K Joshi,13 Elie Traer1,2

1Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR 97239, USA; 2Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA; 3School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA

Correspondence: Elie TraerOregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code: KR-HEM, Portland, OR 97239, USATel +1 503 494 3553Fax +1 503 494 3465Email traere@ohsu.edu

Abstract: Acute myeloid leukemia (AML) is a clonal hematologic neoplasm characterized by rapid, uncontrolled cell growth of immature myeloid cells (blasts). There are numerous genetic abnormalities in AML, many of which are prognostic, but an increasing number are targets for drug therapy. One of the most common genetic abnormalities in AML are activating mutations in the FMS-like tyrosine kinase 3 receptor (FLT3). As a receptor tyrosine kinase, FLT3 was the first targetable genetic abnormality in AML. The first generation of FLT3 inhibitors were broad-spectrum kinase inhibitors that inhibited FLT3 among other proteins. Although clinically active, first-generation FLT3 inhibitors had limited success as single agents. This led to the development of a second generation of more selective FLT3 inhibitors. This review focuses on quizartinib, a potent second-generation FLT3 inhibitor. We discuss the clinical trial development, mechanisms of resistance, and the recent FDA decision to deny approval for quizartinib as a single agent in relapsed/refractory AML.

Keywords: FLT3, quizartinib, AML, resistance, clinical trials, QuANTUM

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Profile of Quizartinib for the Treatment of Adult Patients with Relaps | CMAR - Dove Medical Press

IN the summer of 2019, a mother in Nashville, Tennessee in the United States, with a seemingly incurable genetic disorder finally found an end to her suffering by editing her genome.

Victoria Grays recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research gene therapy.

I have hoped for a cure since I was about 11, the 34-year-old said.

Since I received the new cells, I have been able to enjoy more time with my family without worrying about pain or an out-of-the-blue emergency.

Over several weeks, Grays blood was drawn so that doctors could get to the cause of her illness stem cells from her bone marrow that were making deformed red blood cells.

The stem cells were sent to a Scottish laboratory, where their DNA was modified using Crispr/Cas9 pronounced Crisper a new tool informally known as a molecular scissors.

The genetically-edited cells were transfused back into Grays veins and bone marrow. A month later, she was producing normal blood cells.

Medics warn that caution is necessary, but theoretically, she has been cured.

This is one patient. This is early results. We need to see how it works out in other patients, said her doctor, Haydar Frangoul, at the Sarah Cannon Research Institute in Nashville.

But these results are really exciting.

In Germany, a 19-year-old woman was treated with a similar method for a different blood disease beta thalassemia.

She had previously needed 16 blood transfusions per year. Nine months later, she is completely free of that burden.

For decades, the DNA of living organisms such as corn and salmon has been modified. But Crispr, invented in 2012, made gene editing more widely accessible.

It is much simpler than preceding technology, cheaper and easy to use in small labs.

The technique has given new impetus to the perennial debate over the wisdom of humanity manipulating life itself.

Its all developing very quickly, said French geneticist Emmanuelle Charpentier, one of Crisprs inventors and the co-founder of Crispr Therapeutics, the biotech company conducting the clinical trials involving Gray and the German patient.

Gene cures

Crispr was the latest breakthrough in a year of great strides in gene therapy, a medical adventure that started three decades ago, when the first TV telethons were raising money for children with muscular dystrophy.

Scientists practising the technique insert a normal gene into cells containing a defective gene.

It does the work the original could not, such as making normal red blood cells in Grays case or making tumour-killing super white blood cells for a cancer patient.

Crispr goes even further: instead of adding a gene, the tool edits the genome itself.

After decades of research and clinical trials on a genetic fix to genetic disorders, 2019 saw a historic milestone: approval to bring to market the first gene therapies for a neuromuscular disease in the US and a blood disease in the European Union.

They join several other gene therapies bringing the total to eight approved in recent years to treat certain cancers and an inherited blindness.

Serge Braun, the scientific director of the French Muscular Dystrophy Association, sees 2019 as a turning point that will lead to a medical revolution.

Twenty-five, 30 years, thats the time it had to take, he said. It took a generation for gene therapy to become a reality. Now, its only going to go faster.

Just outside Washington, at the US National Institutes of Health (NIH), researchers are also celebrating a breakthrough period.

We have hit an inflection point, said US NIHs associate director for science policy Carrie Wolinetz.

These therapies are exorbitantly expensive, however, costing up to US$2 million (RM8.18 million) meaning patients face grueling negotiations with their insurance companies.

They also involve a complex regimen of procedures that are only available in wealthy countries.

Gray spent months in hospital getting blood drawn, undergoing chemotherapy, having edited stem cells reintroduced via transfusion and fighting a general infection.

You cannot do this in a community hospital close to home, said her doctor.

However, the number of approved gene therapies will increase to about 40 by 2022, according to Massachusetts Institute of Technology (MIT) researchers.

They will mostly target cancers and diseases that affect muscles, the eyes and the nervous system.

In this Oct 10, 2018, photo, He speaks during an interview at his laboratory in Shenzhen, China. The scientist was recently sentenced to three years in prison for practicing medicine illegally and fined 3 million yuan (RM1.76 million). AP

Bioterrorism potential

Another problem with Crispr is that its relative simplicity has triggered the imaginations of rogue practitioners who dont necessarily share the medical ethics of Western medicine.

In 2018 in China, scientist He Jiankui triggered an international scandal and his excommunication from the scientific community when he used Crispr to create what he called the first gene-edited humans.

The biophysicist said he had altered the DNA (deoxyribonucleic acid) of human embryos that became twin girls Lulu and Nana.

His goal was to create a mutation that would prevent the girls from contracting HIV (human immunodeficiency virus), even though there was no specific reason to put them through the process.

That technology is not safe, said Kiran Musunuru, a genetics professor at the University of Pennsylvania, explaining that the Crispr scissors often cut next to the targeted gene, causing unexpected mutations.

Its very easy to do if you dont care about the consequences, he added.

Despite the ethical pitfalls, restraint seems mainly to have prevailed so far.

The community is keeping a close eye on Russia, where biologist Denis Rebrikov has said he wants to use Crispr to help deaf parents have children without the disability.

There is also the temptation to genetically edit entire animal species, e.g. malaria-causing mosquitoes in Burkina Faso or mice hosting ticks that carry Lyme disease in the US.

The researchers in charge of those projects are advancing carefully however, fully aware of the unpredictability of chain reactions on the ecosystem.

Charpentier doesnt believe in the more dystopian scenarios predicted for gene therapy, including American biohackers injecting themselves with Crispr technology bought online.

Not everyone is a biologist or scientist, she said.

And the possibility of military hijacking to create soldier-killing viruses or bacteria that would ravage enemies crops?

Charpentier thinks that technology generally tends to be used for the better.

Im a bacteriologist -- weve been talking about bioterrorism for years, she said. Nothing has ever happened. AFP Relaxnews

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Gene editing breakthroughs that cured genetic diseases in 2019 - The Star Online

When Anne Weber became pregnant with her first child at age 28, little did she suspect that, rather than bringing home a bundle of joy, she would have to contend with a cancer diagnosis that would change the course of her life.

At her first ultrasound, not only did she find out that she had miscarried but also that she had a large cyst on one of her ovaries. That cyst turned out to be cancer.

"Because I didn't have a strong family history of cancer, everyone assumed it would be benign," she recalled in an interview with Medscape Medical News. "We were all very surprised when the pathology report came back with ovarian cancer."

Although the incidental finding may have been heartbreaking, it may also have been lifesaving. Because it was caught early, her ovarian cancer was of stage I. She underwent surgery and is now telling her story, 10 years later.

Weber is now a patient advocate at FORCE (Facing Our Risk of Cancer Empowered), a national nonprofit organization dedicated to individuals affected by hereditary breast, ovarian, and related cancers, andpreviously worked for a while at genetic testing company Myriad Genetics.

How Weber developed ovarian cancer at such a young age was initially a mystery. Without a family history and without symptoms or personal risk factors for it, her physician did not suspect a hereditary cancer even though at the time, National Comprehensive Cancer Network (NCCN) guidelines recommended that physicians consider genetic testing for anyone younger than 50 who are found to have ovarian cancer. However, her physician didn't offer genetic testing, or even counsel her about it.

Weber was left with nagging questions. She wanted to know why she'd gotten ovarian cancer and how she could prevent a recurrence. So she started sleuthing around on the Internet.

"When I was diagnosed, I knew nothing about this. Literally, I didn't know what terms to type into the search engine," she said.

When she stumbled onto an online forum that linked her to the NCCN guidelines, the pieces of the puzzle began fitting together.

This was 2009, and she was living in Atlanta at the time. She asked her physician about genetic testing, and her doctor referred her to the only genetic counselor in the city, who was at Emory University. At that time, the wait time for genetic testing was 6 months.

"Six months when you're dealing with something like cancer can be pretty dire," Anne said.

Genetic testing for breast and ovarian cancer has not always been straightforward, and fast-moving research means that genetic testing is becoming more and more complex all the time.

The NCCN may have recently provided a step in the right direction. On December 4, the NCCN released updated clinical practice guidelines on genetic/familial high-risk assessment for breast and ovarian cancer.

The guidelines represent a fairly radical shift from previous recommendations, which focused on BRCA genes, according to Robert Pilarski, MS, LGC, MSW, LSW, a genetics counselor and professor of clinical internal medicine at Ohio State University's Comprehensive Cancer Center. He was also vice chair of the NCCN guidelines panel that updated the guidelines.

The NCCN recommendations remain anchored in strong, unbiased evidence and reflect a conservative approach regarding genes for which there is lack of evidence, he said. But the guidelines also acknowledge a shift toward panel testing and include a table of 17 moderate- and high-penetrance genes that should be considered in addition to BRCA genes. They also provide management recommendations for people who carry these genes.

"Most people now are doing panel testing where the panel involves multiple genes besides BRCA," Pilarski said, "This guideline update is the closest that we've got to a consensus [regarding breast, ovarian, and pancreatic cancer] because it now specifies a set of genes that are reasonable to include in at least a basic panel."

The use of multigene panels is controversial, as previously reported by Medscape Medical News. A study published in early 2019 in the Journal of Clinical Oncology suggested that roughly half of breast cancer patients who carry a pathogenic or likely pathogenic mutation are missed by current genetic testing guidelines. That study used an 80-gene panel, and the authors recommended expanded panel testing for all patients with breast cancer.

Critics shot back, arguing that universal testing is not warranted and that large, multigene panels may create undue anxiety among patients as well as confusion among physicians. Research is in its infancy for many of these genes, and physicians don't know how or even whether to act on results for some of them. That's especially true for variants of unknown significance, which have not been confirmed to increase risk for disease.

Perhaps in response to this controversy, the NCCN guidelines do not recommend universal testing for breast or ovarian cancer. Instead, they provide clinical scenarios in which genetic testing is clinically indicated, may be considered, or has low probability of clinical utility. The NCCN authors hedge their bets by not endorsing for or against multigene panel testing.

"I think we held back from becoming too definitive because there may be times when other genes are appropriate," Pilarski explained. "We didn't want to lock patients out of insurance coverage, and we didn't want to lock ourselves into a set of genes that could change next week with changing evidence."

This "wishy-washiness" over multigene panels creates a problem for Mehmet Copur, MD, FACP, an oncologist who wrote a critical response to the study published earlier this year. He is affiliated with the Morrison Cancer Center in Hastings, Nebraska, and is an adjunct professor at the University of Nebraska Medical Center in Omaha.

"I believe they have tried to please both parties, and they have been too nice," he said. "My personal opinion is that I would go for high-penetrance genes in clinically suspicious settings. I would ignore that disclaimer note and say, 'I'm going to do this 17-gene panel.' "

Going one step further, he suggested the creation of commercially available gene panels based on the NCCN recommendations for these 17 genes.

"There are a wide variety of panels available with different genes on different panels. There is a lack of consensus among experts regarding which genes should be tested in different clinical scenarios. If possible, it would be helpful to create commercially available gene panels based on the updated NCCN recommendations," he said.

In another major change, the guidelines now include pancreatic cancer for the first time. But in contrast to breast and ovarian cancer, the NCCN recommends that all patients with newly diagnosed pancreatic cancer receive genetic testing.

"Approximately 1 in 20 patients with pancreatic cancer will have an inherited susceptibility gene. Most people with pancreatic cancer who carry these mutations do not have a family history of pancreatic cancer, so you can't rely on family history to guide you about who should get genetic testing," Michael Goggins, MD, MBBCH, who was also involved in updating the NCCN guidelines, told Medscape Medical News. Goggins is director of the Pancreatic Cancer Early Detection Laboratory at Johns Hopkins University School of Medicine, Baltimore, Maryland.

Advantages of genetic testing for pancreatic cancer include guidance regarding choice of chemotherapy and the possibility of cascade testing for prevention or earlier detection of pancreatic cancer in family members.

Other additions to the guidelines include new recommendations for genetic testing for individuals with Ashkenazi Jewish ancestry, as well as new or updated recommendations for Li-Fraumeni syndrome and Cowden/PTEN hamartoma tumor syndrome.

The guidelines also offer an expanded section on genetics risk assessment and genetic counseling. Genetic testing has become increasingly complex, and the NCCN emphasizes the importance of genetic counseling throughout the testing process.

It has been 10 years since Anne Weber was diagnosed with ovarian cancer. Because she was diagnosed at a young age (28 years) and her other ovary was unaffected, she opted for surgery to remove only the ovary with the tumor.

After her own Internet research and at her own request, Weber underwent genetic testing. She found out that she is a carrier of the BRCA2 mutation, which carries high risk for breast, ovarian, and pancreatic cancer.

Current recommendations are that people with BRCA2 mutations start breast cancer screening at age 25, so Weber was screened immediately.

Her first breast MRI revealed a mass that was found to be stage I breast cancer. At that point, she chose to have her other ovary removed, as well as both fallopian tubes and both breasts, which significantly reduces her risk for recurrence.

"I'm so incredibly grateful that I found the information. All the guidelines say that I shouldn't even have had my first mammogram at my current age of 39. So there is low likelihood that I would have been diagnosed by now, and it certainly would not have been stage I," she said.

Since her diagnosis, she and her husband have adopted a child.

"Genetic testing isn't right for everyone. People aren't going to make the same decisions I did," she said. "The biggest thing is to understand that being positive doesn't mean that you're going to get cancer. It just allows you to have that circle of care to try to prevent cancer, or at least catch it earlier, when it's more treatable."

NCCN. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Version 1.2020. Full text

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Heartbreaking News, Then Tumor Find Leads to Genetic Testing - Medscape