Meeri Kim

Over Mother’s Day weekend 2011, Kimberly Schuetz took her 2-year-old son on a road trip from their hometown of Fall River, Wisconsin, to visit family in Illinois. Leading up to the journey, Austin had been his normal, energetic self.

“He was eating like a horse and being very active, very playful. No sicknesses, fevers, or anything like that,” Schuetz says.

On Saturday, Schuetz’s father-in-law noticed something alarming while tickling his grandson. One of Austin’s lymph nodes on his neck had swollen to the size of a golf ball. As an oncology nurse, Schuetz immediately had a sick feeling in her stomach. Her mind went straight to thoughts of cancer.

While her gut reaction told her to take Austin to the emergency department, Schuetz decided to wait until Monday to visit his pediatrician back home. After all, her son was acting fine.

A week later, after visits to two pediatricians, the emergency department at their local hospital and pediatric hematologists at a children’s hospital, a bone marrow biopsy confirmed that Austin had acute lymphoblastic leukemia (ALL). A cancer of the blood and bone marrow, ALL is the most common type of cancer that occurs in children.

“I literally felt like I was living somebody else’s life, like I was watching a movie. I remember sitting there and listening to the doctor, but I also felt like I was floating above myself,” Schuetz says. “I was numb and couldn’t cry. Your brain just goes into this state of shock.”

Omar Durani, a family physician in Dallas, Texas, went through similar feelings when his 9-month-old daughter Kenza received an acute myeloid leukemia (AML) diagnosis. In 2016, her swollen lymph nodes signaled to Durani and his wife that something wasn’t right.

“As a physician and dad, it’s kind of difficult to figure out what hat to wear when, and how much to worry about things like that,” he says. “When the swelling worsened, we started advocating for blood work, but all the doctors we visited only kept giving her antibiotics.”

Finally, an emergency department physician who Durani knew personally listened to their concerns and performed blood testing. The results came back with white cell counts through the roof, confirming the family’s worst fears: Kenza had cancer.

Both ALL and AML are treated initially with chemotherapy, and for the vast majority of children, it works. More than 95% of children with ALL and about 85% to 90% of those with AML enter remission after the first phase of chemotherapy. However, remission does not necessarily mean a cure.

Austin relapsed in October 2012 after two phases of chemotherapy, and despite receiving a bone marrow transplant, his ALL came back a third time in May 2013. About 10% to 20% of children with ALL have a disease that relapses or is resistant to treatment. At that point, with no treatment options left, Austin’s parents were told he had three to six months to live.

“We live 45 minutes away from the hospital, and our doctor ended up driving to our house, not to offer any solutions, because we didn’t have a plan, but just to sit and cry with us, because she was so heartbroken and, in such disbelief,” Schuetz says.

Some cancer in children does not respond to chemotherapy. After three rounds of chemotherapy, doctors told Durani that his daughter’s only hope would be a bone marrow transplant. But as a child of Asian descent and mixed ethnic background, Kenza had a less than 2% chance of finding a bone marrow donor match.

While research in adult blood cancers has led to an explosion of new targeted therapies and immunotherapies, such progress has been slower for younger patients. This can leave children such as Austin and Kenza without a path forward. Even for patients who do achieve long-term survival, the lingering toxicity of chemotherapy can lower their quality of life as adults.

“Only four cancer treatments have been approved for first use in children in the last 40 years, compared with hundreds approved for treating adults during this same time frame,” said Dr. Gwen Nichols, chief medical officer of the 

“Out of all the federal funding that goes into cancer research, only 4% goes toward pediatric cancer research,” said Dr. Deepa Bhojwani, director of the Leukemia and Lymphoma Program

at Children’s Hospital Los Angeles in California. “That being said, I would say within the last five to 10 years, there has been a lot more progress in terms of targeted treatment and immunotherapy than there was in the past.”

But the tide may be turning for this young, vulnerable population with new research initiatives dedicated to applying precision medicine to pediatric blood cancers. Much of today’s research in pediatric blood cancers aims to find tailored alternatives to chemotherapy that could prove just as or more effective with fewer harmful side effects.

Cancer is still the leading cause of death from disease among children and adolescents in the United States. From 2012 to 2016, leukemia and lymphoma accounted for 38.7% of all cancer types for patients under age 20. Approximately 40% of children with AML and 20% of those with ALL experience a relapse of their disease. Non-Hodgkin lymphoma, the most common type of lymphoma in children under age 14, that is resistant to first-line therapy has a very poor prognosis.

Before joining LLS, Nichols worked for a pharmaceutical company. She says that getting pediatric drugs tested and approved may be difficult because they typically do not bring in as much revenue as adult therapies.

As a result, upon arriving at LLS she was determined to figure out a faster, more efficient way to bring new agents and therapies to children with blood cancers.

In 2016, LLS launched the Beat AML Master Trial for adults with AML. It represented a paradigm shift in the format of clinical trials by testing several different targeted therapies in individual study arms instead of only one drug or combination of drugs at a time. Patients had a genomic screening to determine whether they had one of the genetic mutations that would make them eligible for one of the study arms to test a particular targeted therapy.

“It’s about 50% less expensive to do a master trial than it is to do one drug at a time. So, we needed to do something similar in pediatrics to make it more cost-efficient. But even more than that, if you want to get targeted therapies to kids, you have to have the right kids to test the drug,” Nichols said. “If you’re doing one drug at a time, you have to screen thousands of kids to find the five that fit your drug, which costs time and money.”

In 2019, LLS announced a collaboration with the National Cancer Institute and the Children’s Oncology Group called LLS PedAL (Pediatric Acute Leukemia), a global precision medicine master clinical trial in the same vein as the Beat AML trial. Children with relapsed acute leukemia will undergo genomic screening to match the specific abnormalities driving their cancer with one of several targeted therapies.

As part of The LLS Children’s Initiative: Cures and Care for Children, a $100 million, multiyear effort to take on pediatric blood cancers, LLS PedAL will test multiple agents simultaneously at up to 200 sites worldwide. Trials will follow the same format so that data from multiple institutions can be shared and consolidated.

Nichols and her colleagues hoped to begin the trial this year, but with the coronavirus disease 2019 pandemic, LLS PedAL’s start date has been pushed back to early 2021.

Another inspiring research project is the Pediatric Cancer Genome Project (PCGP), a joint initiative from St. Jude Children’s Research Hospital and Washington University School of Medicine. Since 2010, the two insti- tutions have pioneered efforts to define the genomic landscape of pediatric cancer by sequencing the genomes of normal and cancer cells from 800 patients.

“That work really filled in much of the landscape of mutations that drive ALL, AML and many of the other kinds of pediatric cancer,” says Dr. James R. Downing, president and CEO of St. Jude, who was instrumental in launching the PCGP. “In particular, important fundamental discoveries came out for ALL in terms of new understandings related to the identification of new genetic subtypes, amplifications, fusions and chromosomal translocations of the disease.”

For instance, the PCGP pinpointed genes linked to an ALL subtype with a poor prognosis known as Philadelphia chromosome-like ALL (Ph-like ALL). In 2009, St. Jude scientists were among the first to describe Ph-like ALL in children. Five years later, next-generation sequencing revealed the genetic alterations that give rise to Ph-like ALL, which could be targeted with drugs widely used to treat other types of leukemia more common in adults.

A 2017 study from the PCGP identified potential targets for immunotherapies in pediatric cancers, finding that 88% of leukemias have at least one that could be exploited. A 2018 pan-cancer analysis that examined commonalities and differences among various cancer types, including ALL and AML, suggest that half of the cancers studied may have a targeted treatment available or under development.

“The second phase of the genome project is moving all that technology into frontline diagnostics,” Downing says. “So now we’re getting the whole genome, whole exome and RNA sequencing of every patient, and we gain insight that can be funneled into a protocol that allows them to be treated.”

St. Jude’s frontline ALL protocol includes an unparalleled level of genomic sequencing on the patient, on both cancer and normal cells, which allows physicians to make personalized therapeutic decisions. Downing hopes that collecting such a wealth of data will help usher in new therapies and lead to a further improvement in outcomes.

“So the momentum is there, the studies are ongoing, and hopefully five years from now, we will have a huge variety of therapies to offer our kids instead of just one,” Bhojwani says.

Bhojwani participates in the Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) consortium, which has its headquarters at Children’s Hospital Los Angeles. TACL brings together children’s hospitals and universities to accelerate the progress of new therapies for pediatric leukemia and lymphoma. The consortium includes 31 institutions in the United States and Australia that collaborate on clinical trials of new drugs and novel therapy combinations in the hopes of expanding the number of treatments available.

Both Kenza and Austin were saved by an experimental treatment called chimeric antigen receptor (CAR)-T cell therapy administered in a clinical trial. It involves engineering the body’s T cells, a type of white blood cell, to produce receptors on their surface called chimeric antigen receptors (CARs). The engineered cells are infused back into the patient, where they can recognize and kill cancer cells.

The Duranis couldn’t find a bone marrow donor match for Kenza, despite having more than 60 donor drives inspired by her diagnosis that registered more than 5,000 new potential bone marrow donors around the country. At that point, they decided to move forward with CAR-T cell therapy coupled with a haploidentical, or partially matched, stem cell transplant in August 2016.

“It was a no-brainer for us since there were no other therapies available besides a standard bone marrow transplant,” Durani says. “Now Kenza’s been in remission for four years, and she’s doing fantastic. She’s a thriving, spunky 5-year-old.”

After his third relapse, Austin’s parents enrolled him in a clinical trial to receive CAR-T cell therapy as a last- ditch effort to save their son. He received the treatment at the beginning of October, and on Halloween – which also happens to be his mother’s birthday – they received the good news that his biopsy showed no traces of cancer.

“I immediately started screaming and crying. I was just elated. It was the best birthday present that I could ever, ever have. Nothing will ever top that,” Schuetz says.

Today, Austin is a typical 12-year-old boy who enjoys video games, swimming with his friends and complaining about household chores. He and Kenza are living proof that innovations such as CAR-T cell therapy give children who have run out of options another chance at life.

Articles

For years, childhood blood cancers were understudied forcing patients’ treatments into a one size-fits-all approach. But new efforts are changing that.

Coming of Age: New Research Efforts are Improving Treatment of Childhood Blood Cancers

KATHLEEN PACKARD and her daughter, AMY, took this picture on the seventh day of chemotherapy to show unity during her cancer battle. - PHOTO BY KIM SMITH

The biggest battle of Kathleen Packard’s life began in late 2016 with sudden severe pain in her abdomen. The 59-year-old resident of Amherst, New York, couldn’t remember the last time she had been sick, but this kind of stomachache warranted a trip to the hospital.

The doctors discovered that Packard had pancolitis, a severe form of ulcerative colitis that had spread throughout her large intestine, and ordered a blood test. From there, her life took an unexpected and tumultuous turn.

“My white blood cell count was 86,000, whereas normal is 4,500 to 11,000. They sent me to Roswell Park Comprehensive Cancer Center immediately, where I met the phenomenal Dr. Eunice Wang,” Packard recalls. “She made sense out of madness.”

Wang, M.D., chief of the Leukemia Service at Roswell Park in Buffalo, New York, diagnosed Packard with acute myeloid leukemia (AML) and started her on treatment the very next day. In patients with AML, the bone marrow makes abnormal malignant blood cells such as myeloblasts (a type of white blood cell), red blood cells or platelets. It is one of the four main types of leukemia.

The American Cancer Society estimates that in 2017, there were 21,380 new cases and 10,590 deaths from AML. Although AML can occur in children, adults aged 45 years and older are generally most susceptible. The disease is slightly more common in men than in women, but the average lifetime risk for both sexes is less than half of 1 percent.

A bone marrow sample at diagnosis confirmed that Packard had a subtype of AML characterized by a mutation in the FMS-like tyrosine kinase 3 (FLT3) gene, which plays an important role in blood-forming stem cell survival and proliferation. About 1 in 3 patients with AML has this mutation, which may be associated with a particularly poor prognosis. But Wang offered Packard hope through participation in a clinical trial for a new drug specifically targeting FLT3-mutated AML.

Patients with AML are typically treated with two phases of chemotherapy: induction and consolidation. Induction involves treatment with the chemotherapy drugs cytarabine and daunorubicin. Consolidation chemotherapy occurs after remission — clearance of malignant leukemia cells in the marrow followed by regeneration of normal marrow blood-forming cells &mdash; to help prevent a relapse and usually includes high doses of cytarabine, often followed by an allogeneic stem cell transplant.

At Roswell Park, Packard took the two induction drugs in combination with crenolanib, an experimental FLT3 tyrosine kinase inhibitor. “I was on heavy chemotherapy for 13 days, and I was very sick,” she says. “I had every side effect they had to offer. It was a horrific time.”

In January 2017, Packard had an allogeneic bone marrow transplant from an unrelated donor. Today, she remains in remission and recently restarted maintenance therapy with crenolanib as part of another clinical trial.

“My blood went from 99.9 percent filled with leukemia to 99.9 percent cancer-free. I got over that hump,” Packard says. “It was a horrible situation, but when you’re going through it, you learn very quickly that you’re a strong person.”

Packard represents one of countless patients who have benefited from a growing number of treatment options for AML. After 40 years of little to no improvement in higher remission or cure rates since the advent of cytarabine and daunorubicin, four new agents were approved for AML by the Food and Drug Administration (FDA) in 2017 alone: Rydapt (midostaurin), Vyxeos (CPX-351), Mylotarg (gemtuzumab ozogamacin) and Idhifa (enasidenib). Several other promising drugs, such as crenolanib, are still in the pipeline but expected to gain approval in the near future. More treatment options will translate into better outcomes for patients, because oncologists can figure out which of several agents will work best for a given individual. For instance, through a bone marrow sample, Wang found out at diagnosis about Packard’s FLT3 mutation and gave her a targeted drug.

“I think it will change the work that we do upfront to better stratify patients in order to offer the benefits of these targeted therapies,” Wang says. “We have an abundance of riches, and it’s up to physicians to understand that it will take a little time to identify the particular individuals who will benefit.”

The sudden bounty is the culmination of AML research and knowledge that built up for decades — patient genome sequencing, identifying new mutations and understanding their consequences, performing clinical trials, and so on. The discovery of mutations that characterize subtypes of AML led to more personalized treatment options that could outperform the standard regimen.

“We’re reaping the benefits of major innovations in basic science which are sometimes not immediately cancer related, like sequencing the human genome,” says Akil Merchant, M.D., assistant professor of medicine at the University of Southern California in Los Angeles. “These aren’t directly studies of cancer, but they ultimately lay the foundation for these kinds of rapid approvals.”

Typically, about a quarter of adults with AML can be expected to survive three or more years and may be cured. But a number of factors, such as advanced age, systemic infection at diagnosis, elevated white blood cell count, central nervous system involvement with leukemia and certain genetic mutations, lead to poorer outcomes.

Factors that increase a person’s risk of AML include advanced age, being male, previous cancer treatment with certain chemotherapy drugs, exposure to radiation, smoking, toxins (some solvents, for example), other blood disorders, genetic syndromes and family history. Signs and symptoms in the early stages of AML, such as fever, bone pain, fatigue, shortness of breath and pale skin, can mimic the flu or other common diseases.

Because it doesn’t usually form tumors, AML is not staged the same way other cancers are. Instead, lab tests determine subtypes and a patient’s outlook. The French- American-British classification divides AML into subtypes, M0 to M7, based on the type of cell from which the leukemia develops and how mature the cells are. An updated classification by the World Health Organization separates AML into several groups by considerations such as the presence of certain genetic abnormalities, disease related to previous chemotherapy or radiation, and disease related to blood disorders.

“AML is not one disease. What it will come down to one day is that if you have a disease like AML, it will be as unique as you are,” Merchant says. “That’s where we’re heading with precision medicine and really tailoring the therapy to that individual.”

To that end, two of the new agents target subtypes of AML characterized by specific genetic abnormalities. In April 2017, the FDA approved Rydapt for the treatment of adults with newly diagnosed FLT3-positive AML in combination with standard two-phase chemotherapy. The phase 3 RATIFY trial randomized 717 patients with AML who had the FLT3 mutation to standard induction and consolidation chemotherapy plus Rydapt (360 patients) or placebo (357 patients).

Median overall survival was 74.7 months with Rydapt versus 25.6 months with chemotherapy alone.

Four months later, Idhifa was approved for treating patients who have relapsed or refractory isocitrate dehydrogenase 2 (IDH2)-mutated AML based on the promising results of a phase 1/2 study.

The IDH2 gene encodes for metabolic enzymes found in mitochondria, the energy- producing centers within cells. The single- arm, multicenter clinical trial included 199 adults with relapsed or refractory AML who had an IDH2 mutation. They took the oral drug daily, and 19.3 percent experienced complete remission with a median duration of 8.2 months.

Both Rydapt and Idhifa were approved along with companion diagnostic tests, the LeukoStrat CDx FLT3 Mutation Assay and the RealTime IDH2 Assay, respectively. As a result, the diagnostic workup for patients will change to identify those who would benefit from the new drugs. “With these new agents in our arsenal, we’ll be able to translate the positive results in clinical trials to improving the outcome of patients with these mutations,” says Bruno Medeiros, M.D., associate professor of hematology at Stanford Cancer Center in California. “Information about the patient which used to be prognostic is now relevant and critical for treatment. It changes the potential outcome for patients, but it also changes how physicians and patients should expect the initial workup to take place.”

Common side effects of Rydapt include low levels of white blood cells with fever (febrile neutropenia), nausea, inflammation of the mucous membranes (mucositis), vomiting and headache. Idhifa’s side effects include nausea, vomiting, diarrhea, increased levels of bilirubin (a substance found in bile) and decreased appetite.

In August 2017, the FDA approved Vyxeos, a repackaged formulation of induction chemotherapy drugs cytarabine and daunorubicin, for two subtypes of AML with typically poor prognoses. Therapy-relatedAML occurs as a result of specific types of chemotherapy or radiation, and AML with myelodysplasia-related changes is characterized by a history of certain blood disorders and other mutations within cancer cells.

Vyxeos combines the two drugs into a single formulation encapsulated in liposomes. In a clinical trial, 309 patients newly diagnosed with one of the two AML subtypes received either Vyxeos or separately administered treatments of daunorubicin and cytarabine. Those who received Vyxeos had a median overall survival of 9.56 months versus 5.95 months for patients who received the two drugs separately. Side effects of Vyxeos include hemorrhage, febrile neutropenia, rash, swelling of tissues, nausea, mucositis and fatigue.

Lastly, anti-CD33 antibody drug conjugate Mylotarg received approval in September 2017 for adults with newly diagnosed AML whose tumors express the CD33 antigen. The drug combines an antibody with chemotherapy to attack tumor cells with CD33. It was originally approved in 2000 but voluntarily withdrawn from the market after several early deaths and lack of evidence of efficacy.

“Mylotarg was previously approved and now has been reapproved,” Wang says. “It was taken off the market for several years because of questions by the FDA that required additional analysis based on patients who developed liver issues. Liver problems with Mylotarg are still an issue, but the incidence has decreased.”

The agent has a new dosing regimen that has been shown to be more safe and efficient. A randomized phase 3 trial, ALFA-0701, compared daunorubicin and cytarabine with or without the addition of Mylotarg in 271 patients with CD33-positive AML. Those who received Mylotarg had a median event-free survival of 17.3 months compared with the control group’s 9.5 months. However, no significant improvement in overall survival was seen with Mylotarg.

Severe side effects of Mylotarg include low blood counts, infections, liver damage, blockage of veins in the liver, infusion-related reactions, and severe bleeding. In the clinical trial, patients who took Mylotarg were seven times more likely to experience side effects compared with those in the control group.

“These are exciting times, but with that excitement comes questions,” Medeiros says. “All of these agents were tested in isolation of one another, so it’s going to be a challenge for us to learn how to use and combine these agents.

But there are more opportunities for treatment, which will, hopefully, lead to improvements in the survival of a disease that is very hard to treat.”

Last year brought many new possibilities in the treatment of AML, and it appears 2018 does likewise. Specifically, Medeiros says ivosidenib, an IDH1 inhibitor that targets IDH1-mutated disease, has a good chance of hitting the market early this year. It was submitted to the FDA in December following phase 1 trial results that showed a complete response or complete response with partial hematologic recovery rate of 30.4 percent, which lasted for a median duration of 8.2 months.

Another potential target is B-cell lymphoma 2 (BCL-2), the protein that makes cancer cells resistant to therapy. BCL-2 inhibitors have shown promise for patients who aren’t good fits for induction chemotherapy, such as older adults. Venclexta (venetoclax), previously approved for patients with chronic lymphocytic leukemia, recently demonstrated a complete remission in up to 50 percent of patients aged 60 years or older with relapsed or refractory AML.

Although Rydapt is already on the market, Merchant expects other FLT3 inhibitors to follow suit: “Rydapt is the first but not the best FLT3 inhibitor. There is a whole crop of FLT3 inhibitors that are more targeted, more specific, and have fewer side effects and greater activity than Rydapt. I think the three or four agents on the horizon are even more exciting.”

In a recent study conducted by Wang, crenolanib combined with chemotherapy saw very high response rates of over 80 percent complete remission or complete remission with incomplete hematologic recovery. While most FLT3 inhibitors bind only to the receptor in its inactive configuration, crenolanib can bind for FLT3 in both active and inactive configurations.

Packard says she owes her survival to Wang and other members of her care team at Roswell Park who are willing to take a chance with new therapies. She takes crenolanib in pill form three times a day, every eight hours, which disrupts her sleep schedule and normal routine. But her main objective is survival, and although the treatment has been tough, she feels grateful to be alive.

“The most important thing to believe in is your doctor,” says Packard. “Have a strong bond with your doctor and realize that you matter. It’s your journey, and you have the right to have a bad day, but you need to get back up. You have to reach the top of that mountain and have a strong will to live.”

New drugs bring advancements to acute myeloid leukemia after 40 years.

Lab of Plenty: New Drugs Bring Hope for AML Treatment

BECAUSE OF UNCERTAINTIES ASSOCIATED with multigene panels, not everyone should get the tests.

Recommended for testing are people with or without breast cancer whose personal or family history of the disease suggests a genetic susceptibility. Guidelines followed by most physicians and also used by insurance companies for reimbursement come from the National Comprehensive Cancer Network..

For instance, people who have a family member with any of the following should be tested: a BRCA1 or BRCA2 mutation, breast cancer at 50 or younger, breast cancer in both breasts, triple-negative breast cancer under age 60 or ovarian cancer. Also, individuals who had breast cancer at age 50 or younger, or who are of Ashkenazi Jewish descent with breast cancer in the family, should be tested. Finally, all women diagnosed with ovarian cancer, and males with breast cancer, should be tested..

Generally, health insurance covers the cost of genetic testing recommended by a physician. However, some patients who had BRCA testing in the past have had trouble getting reimbursed for a follow-up panel test. The outof- pocket cost for a single panel test can be up to $5,000, although lower-cost tests are available.

“If you have only one bullet in your gun and can only get the test reimbursed by health insurance once, are you going to evaluate just two genes, or all genes associated with the risk of breast cancer?” asks Gregory Idos, M.D., assistant professor of clinical medicine at the University of Southern California. “In the field, you’re starting to see a lot of practitioners move toward panels so they can get as much important information for their patients, that will be appropriately covered by insurance, (as possible).”

Some companies are willing to work directly with patients using their own physicians, but Couch says that genetic testing should be ordered by a doctor who knows the patient’s history. The Food and Drug Administration, Federal Trade Commission and Centers for Disease Control and Prevention all caution against using at-home testing kits for breast cancer risk.


Generally, health insurance covers the cost of genetic testing recommended by a physician. However, some patients who had BRCA testing in the past have had trouble getting reimbursed for a follow-up panel test. The outof- pocket cost for a single panel test can be up to $5,000, although lower-cost tests are available.

The Logistics of Multigene Panel Testing in Breast Cancer

SUSAN KARNICK was surprised when a genetic test found she had three genetic mutations that might increase her risk of developing breast cancer. — PHOTO BY RENATÉ BIMBI

When a genetic counselor recommended multigene panel testing based on her family history, Susan Karnick didn’t anticipate anything significant in the results.

Relatives on her mother’s side of the family had experienced breast cancers, some at an early age, as well as a number of other cancer types, and their mammograms had often appeared abnormal. Karnick, too, had received abnormal mammogram results, but she had thankfully reached the age of 51 without a cancer diagnosis.

The counselor explained that the test would examine 32 different genes to look for mutations associated with an elevated risk of cancer. Until a few years ago, genetic testing focused on only a few cancer susceptibility genes in a given patient — for instance, BRCA1 and BRCA2 for breast cancer.

“I thought I would probably have some weird variants, but I wasn’t expecting any major results to come up,” says Karnick, a resident of Crystal Lake, Illinois, who took the panel test in March. “So imagine my surprise when I tested positive for abnormal PALB2, ATM and a variant of PTEN which is likely to be pathological.”

All three gene mutations are known to increase breast cancer risk. A healthy PALB2 gene interacts with BRCA2 to repair damaged DNA. A 2014 study of 311 women who had a PALB2 mutation found that their breast cancer risk was 9.47 times higher than average. The ATM gene also helps to repair damaged DNA and stop cell division until this repair is complete, and a metaanalysis of abnormal variants points to a relative breast cancer risk of 2.8 times higher than average. Mutations in PTEN are linked to Cowden syndrome, in which patients have a high risk of both benign and cancerous breast tumors.

The results were extremely unusual, as it’s rare for genetic counselors to find more than one cancer-associated gene mutation in any patient. Karnick, shocked by the results and their seemingly dire outlook, said she felt an immense amount of stress and anxiety. Although grateful for the knowledge, she was confused about what to do next. Similarly, Uduak Andy, M.D., had mixed feelings after receiving her panel test results earlier this year. At just 35, Andy already has had cancer twice. In 2012, she was diagnosed with breast cancer and had a bilateral mastectomy, but tested negative for BRCA1 and BRCA2 mutations.

Only a few years later, shortly after her second daughter was born, doctors found low-grade cancer in Andy’s appendix.

Andy then took a panel test for mutations to 28 genes that can cause cancer susceptibility. Although she felt relief that no major mutations were found, the positive results that did come up were unclear. Two variants of unknown significance (VUS) were identified in the APC and CHEK2 genes. These have yet to be classified by researchers as harmless or pathogenic.

However, it is known that people with APC gene mutations can develop pre-cancerous polyps in their colon and rectum, and abnormal variants of the CHEK2 gene are known to confer moderate risk of breast cancer, with an estimated relative risk of three times greater than average.

“We did all that testing, and nothing was clearly positive. It’s great that nothing major was found, but we don’t really know what these variants of unknown significance mean,” says Andy, who works as a urogynecologist in Philadelphia. “In that respect, the results have been both good and frustrating.”

Sometimes, over time and by tracking large groups of patients who carry an inherited genetic mutation, experts can figure out if a particular VUS is associated with cancer and reclassify it as either pathogenic or benign.

That’s one dynamic that has led to the replacement of smaller, more focused tests with broader panel testing of several genes at once. For individuals who have a strong family history of cancer, like Karnick, or who were diagnosed at a young age, like Andy, panel testing offers a chance to take early action and manage risk with preventive strategies such as surgery. In people who already have cancer, genetic testing can provide clues about which targeted or other drugs might be the most effective treatments.

A major barrier to gathering any of this information is simply low participation. Seventy-five percent of eligible women have never discussed genetic testing with a health care provider, according to a study recently published in the Journal of Clinical Oncology. In many cases, this may be because providers are not up to date about when a patient should be referred for genetic counseling. Another deterrent is a lack of genetic counselors in many regions.

Those who do participate are confronted with some gray areas. The jury is still out on which genes should be included on tests, because, even as some VUSs join the ranks of mutations classified as dangerous or benign, others with less certain effects are are likely to show up.

“If somebody has a BRCA1 mutation, we can tell her that she has a 65 percent lifetime risk of breast cancer.

These numbers for BRCA1 and BRCA2 are really wellknown at this point, and we can give detailed recommendations on what to do next,” said Fergus Couch, Ph.D., the Zbigniew and Anna M. Scheller Professor of Medical Research at the Mayo Clinic. “For the newer genes on these panels, we don’t necessarily have all that information.”

Those kinds of results raise questions about whether a patient is really at risk and in need of enhanced screening or even preventive surgery.

Furthermore, some gene mutations, even if they are known to promote cancer, are not specifically treatable with any targeted drugs.

Although BRCA-driven breast cancers may respond well to a class of drugs known as PARP inhibitors, there may be no specialized treatments for cancers driven by mutations that are not yet targetable.

THE ORIGINS OF GENETIC TESTING FOR CANCER RISK

Genetic testing for breast cancer risk originated with the discovery of the gene BRCA1. In 1990, geneticists at the University of California, Berkeley discovered that the long arm of chromosome 17 contains a segment of DNA that tracks with inherited susceptibility to breast cancer in families with early-onset disease. Then, the race to find a gene and an associated mutation was on. In 1994, University of Utah researchers identified the complete sequence of BRCA1 and confirmed mutations in some high-risk families, marking the discovery of the first gene associated with hereditary breast cancer. A mere two years later, scientists did the same with a second breast cancer susceptibility gene, BRCA2.

Commercial genetic testing for BRCA1 and BRCA2 soon followed. In November 1996, Myriad Genetics, a University of Utah spin-off, began offering a commercial test called BRACAnalysis. In the United States, women with a BRCA1 mutation have a 55 to 65 percent chance of developing breast cancer by age 70, compared with an average lifetime risk of about 12 percent, and those with a BRCA2 mutation have a 45 percent chance.

Myriad Genetics held patents on the genes’ DNA sequences and attempted to sue other companies offering their own BRCA tests. However, in a landmark decision, the Supreme Court ruled in June 2013 that human genes cannot be patented because they are products of nature. Commercial multigene panel tests that included BRCA1 and BRCA2 began appearing more frequently, and at lower costs.

In addition, innovations in sequencing technology and bioinformatics led to the ability to test for multiple genes at the same time. Next-generation sequencing, or NGS, allows millions of DNA fragments to be sequenced in parallel for fast turnaround times and low cost.

So, although breast cancer susceptibility genes other than BRCA1 and BRCA2 were previously identified — for instance, the association with CHEK2 has been known since 2002 &mdash; they weren’t commonly included in tests until more recently. A 2015 study in the New England Journal of Medicine reported that today’s panel tests cover mutations to more than 100 genes, with 21 of those associated with breast cancer risk.

But just because technology can sequence dozens of genes at once, does that mean it automatically should? Experts warn patients to think carefully about the pros and cons of getting several genes tested before diving in. Aside from BRCA1 and BRCA2, high-risk genes typically include PALB2, PTEN, CDH1 and TP53. Gene mutations known to confer moderate risk are those in CHEK2, NF1 and ATM. Limited information exists for more recently discovered genes, such as BARD1, BRIP1, FANCC, NBN, RAD51C, RAD51D and XRCC2. Some of these genes are associated with certain other cancer types, too. For instance, PTEN can contribute to the development of colorectal or endometrial cancers, melanoma and others, and TP53 can be associated with all of those, plus ovarian, pancreatic, gastric and prostate cancers.

Even less is known about other genes that panels can include. The NEJM study found that STK11, CDH1 and NBN variants have an established link to breast cancer, but risk estimates remain too imprecise to categorize as high, moderate or low. It also concludes that risks attributed to PTEN, STK11 and CDH1 variants may be overestimated.

“If you test for BRCA1 and BRCA2 only, you miss about 40 percent of the predisposing mutations for breast cancer — but there are caveats to that,” says Couch, who also coauthored the study. “The major issue is that there are genes on these panels that we don’t actually know with certainty drive breast cancer. It may be that, as we move forward, some of these panels will shrink.”

In other cases, gene mutations are clearly associated with a variety of cancers — for example, TP53 mutations are thought to drive more than half of all cancers &mdash; but no drugs exist yet that target them.

Testing for such genes might not give doctors information they can act on, but it can open the door to clinical trials, or to drugs that will be approved in time.

Despite the caveats, many physicians and patients believe the advantages of panel testing outweigh the possible disadvantages. The main benefit is having the knowledge to take on measures to lower or manage one’s cancer risk.

For BRCA1 or BRCA2 mutations, women can choose to get more intensive breast cancer screening, take risk-reducing medications such as tamoxifen or raloxifene, which block the body’s production of estrogen, or have preventive surgery to remove both breasts and/or ovaries. The National Comprehensive Cancer Network has established guidelines for managing risks due to other some other gene mutations: increased breast screening and possible risk-reducing mastectomy in those with mutations to the ATM or CDH1 genes, and consideration of preventively removing the ovaries and fallopian tubes at ages 45 to 50 for those with BRIP1 mutations.

For women who have breast cancer, being aware of the presence of some of these mutations may help determine which chemotherapies and/or targeted drugs are likely to be the most effective.

Another advantage of panel testing is being able to alert other family members, such as children or siblings, to their possible cancer risk. Testing might be recommended for them, as well, if the results show a mutation.

Many of these mutations also drive more than one type of cancer, which could expand screenings to other areas of the body. For instance, Karnick will now get a colonoscopy every three years and an abdominal MRI with contrast every six months, because her mutations predispose her to gastrointestinal cancers in addition to breast cancer. Also, she will be screened for breast cancer every six months, alternating between MRI and ultrasound exams. She ultimately plans to have a bilateral mastectomy.

Because physicians simply don’t have enough information regarding certain aspects of panel testing, patients often must make decisions based on their own preferences and judgment.

“If you only want information consistent with your family history, you could limit the number of genes on your panel test. Or you could be someone that can deal with uncertainty, and so you can choose to do a big panel,” says Susan Domchek, executive director of the Basser Center for BRCA and the Basser Professor in Oncology at the University of Pennsylvania.

As in Andy’s case, a large number of genes on the panel means a greater probability of detecting a VUS. For BRCA1 and BRCA2, the VUS rates are down to about 2 percent, says Domchek, but a 40-gene panel could end up with 20 to 30 percent of people getting a confusing result.

In addition, VUS rates are known to be higher among ethnic minorities due to lower testing volume and less data available about genetic variants among diverse populations.

Part of Andy’s frustration over her results came from the fact that her genetic variant, seen in individuals of African ancestry more than 50 percent of the time, remains inconclusive. As a black woman, she hopes her results add to the pool of available data on African-American women to help future generations better assess their cancer risk.

Despite the initial stress, Karnick has no regrets about taking a panel test. Finding out about her mutations not only pushed her to take preventive measures, but also motivated her to finally attend graduate school for social work. She also volunteers as a peer navigator for Facing Our Risk of Cancer Empowered, a nonprofit organization devoted to supporting those predisposed to hereditary cancers. There, she mentors people with mutations similar to her own.

“I really believe knowledge is power,” says Karnick, who also underwent genetic testing for the sake of her three children. She wants to be with them for as long as possible, and she wants them to be fully informed when they make their own health care decisions someday. In that spirit, she has donated blood to be used to study these mutations, and hopes that this will help her children and others in the future.

“Overall, I’m really happy I have this knowledge and, moving forward, I can be as proactive as possible,” she says. “I’m grateful for that.”

As mutations in more genes are linked to the development of cancer, tests that identify the glitches are growing more expansive &mdash; but some gray areas remain.

Meeri Kim

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