The good fight: Cancer ‘like a moss’ and a young Lafayette girl’s journey through it

It was Halloween 2007. Nichol Mattson and Eric Ellefson, of Lafayette, were at Presbyterian/St. Luke’s Medical Center in Denver. It had been six days since they took their 3-year-old daughter, Zaida, to the doctor for a routine wellness visit. Six days since the pediatrician noticed her protruding stomach, swollen past the bounds of ordinary toddler tummy. Six days to get the diagnosis.

It was cancer.

That would begin a nearly decade-long fight for Zaida and her family, one that would involve more than 100 rounds of chemo, five major surgeries, a few periods of relative calm, one inquiry about hospice care, one trip to Disney World, one Hail Mary medical treatment, and one gala event to celebrate her miraculous recovery.

Zaida’s journey would also involve the local bioscience community. Two Boulder companies pooled their talent and time, becoming part of the family’s personal, but ultimately futile, effort to keep her alive.

It is a story of success, or at least what passes for success in the realm of pediatric oncology. Millions of dollars have been poured into the field to fund improvements in diagnostics, research, treatment and drug development. Some battles have been won; thousands of lives saved or, at the very least, extended. Cancer is no longer a death sentence. Unless it is.

Some patients go quickly, surrendering to the inevitable. Others and their families grapple with the disease, sometimes for a decade or more. They beat back the shadow first cast on their lives at diagnosis, again and again, until there is at last no light left to shine into dark corners; no strong wind to blow away the stinking cloud that signifies certain death; no disinfectant powerful enough to scrub the stain of disease from the skin, the organs, the bone, the blood. All that is left is a body and a family fresh out of fight, succumbing to forces stronger than them.

This is Zaida’s story.

Simple symptoms

Abdominal swelling is one of seven known early warning signs of childhood cancer. Many symptoms on the list are also common ailments of active kids. Separately, they are easily mistaken as benign marks of youth: the bloated belly seen as a healthy layer of baby fat; the cough caught from a sick counterpart at school; the bruises and bleeding tokens of a playground tussle.

According to the American Childhood Cancer Organization, by the time a diagnosis of cancer is handed down, a majority of kids are already hosting a malignancy that has metastasized, spread from the site of the original tumor.

A camera was inserted into Zaida’s abdomen for the doctors’ first look at her cancer. It was “like moss over every crevice,” said Eric.

A surgeon went in to cut out the tumors. Zaida’s uterus was removed; as was her omentum, the membrane that surrounds vital organs. Later surgeries would claim her spleen and right ovary. Portions of the tumor were the consistency of cottage cheese, clumping up on every available surface and the spaces in between.

The first surgeon “came out overwhelmed,” Eric recalled, unable to get it all. So he and Nichol went looking for another. Surgeons at Mayo Clinic and the University of Minnesota told them the best that could be done was to “buy time,” Nichol remembered, but one from MD Anderson in Houston, Texas, said it could be done: All the tumor could be gotten.

The procedure Zaida would eventually undergo was an experimental one, in the first phase of study. Her abdomen was sliced open, every visible piece of the tumor taken out. Then her organs were deluged in a bath of chemotherapy medicine, heated to 106 degrees, for 90 minutes. The surgeons physically pushed, pulled and kneaded her body to wash the liquid around the cavity until it came in contact with every piece of the tumor. The process had never before been performed on a child.

It took 13 hours. Zaida would repeat this same routine three more times in her short life.

Success and failure

This year in the United States, some 15,270 children under the age of 19 will be diagnosed with cancer, according to the American Cancer Society.

Overall, 83 percent of children with cancer will be ushered into the pool of survivors, a limited definition that means they will live five years past diagnosis, or that their death during that time will be caused by something other than cancer.

Realistically, the odds depend greatly on the diagnosis. Acute lymphoblastic leukemia (ALL), the most common form of childhood cancer, accounts for nearly one in three childhood cancer diagnoses. In the 1960s, chances of survival from ALL were less than 10 percent. Today, it is closer to 89 percent, according to the National Institutes of Health.

Other childhood cancers have seen little improvement in prognosis. Many types of brain tumors, which affect about 4,000 U.S. children each year, still carry essentially “a zero percent chance” of survival from diagnosis, said Jamie Bloyd, director of government relations and external affairs for the American Childhood Cancer Organization, a patient advocacy group.

Because of the relatively small pool of pediatric oncology patients — kids represent less than 1 percent of all cancers diagnosed each year in the U.S — fewer resources are allocated toward what are essentially rare diseases.

Only four new drugs have been approved by the Food and Drug Administration specifically for use in pediatric cancer patients in the past 35 years, the most recent in August. For adults, 190 such treatments have made it to market.

Funding, too, lags behind. Only 5.6 percent of the National Cancer Institute’s $5.2 billion in 2016 was dedicated to pediatric cancer.

It’s not a figure Bloyd likes to dwell on. A mother of a child with Burkitt’s lymphoma, she is grateful for every dollar that funds research or drug development or financial aid for families. After all, she points out, it wasn’t solely new drugs that improved the outlook for her son, that kept him and other kids with lymphoma or leukemia alive, but also vast improvements in post-transplant care and coordinated efforts of advocates, patients and caregivers.

The fighters

Zaida didn’t have leukemia or lymphoma. Her cancer never fit into a neat little box. The root cause — which wouldn’t be discovered for nine years — had never been reported in scientific literature, never given a name. Some doctors thought it resembled mesothelioma, while others argued for ovarian cancer. Neither are common in children; both are extremely deadly.

Fewer than 5 percent of ovarian cancer cases occur in children; mesothelioma is so rare in kids that statistics are hard to come by. One international study of the disease in children found 80 patients worldwide.

Adults with mesothelioma have a 5 percent to 10 percent chance of living five years, depending on the disease’s progression at time of discovery. Ditto for ovarian cancer: If caught in early stages, 92 percent of patients will live five more years. But only 15 percent of cases are found that soon; survival in later stages is 45 percent.

Eric and Nichol knew those numbers going in. When they received the diagnosis, Nichol asked, “Is Zaida going to die?” She recalled the doctor, with tears in her eyes, answering, “She might.”

Before that first surgery in 2007, they were given a choice: To treat or not treat. To fight or not fight.

They chose fight.

Chemo had nuked Zaida’s taste buds and appetite, so she never wanted to eat. A feeding tube was threaded through her nose and into her stomach, through which nutrients could be delivered. It was a struggle every time to feed her, so that tube went, replaced by a tube that pumped liquid food directly into her stomach. For each meal and while she slept every night, she was hooked to a machine that filled her belly.

Every feeding became a battle royale. Her protests extended preparation from a quick three-minute process to one that lasted 30 minutes or more, Zaida’s stepmom, Savannah Sheets, recalled, with a small shake of her head, half in admiration, half in frustration.

“She fought it every single time,” Sheets said. “Four times a day.”

Her parents at first made every ounce of food by hand, blending quinoa and beets and carrots rather than buying sugar-laden pre-made mixes. Hundreds of dollars a month were spent on supplements. Eric, a senior computer analyst for Atlanta-based GeoDigital, worked from home when he could; Nichol, an administrative professional with Boulder County Housing and Human Services, spent hours researching every possible cause and treatment for Zaida’s still-unnamed cancer. They asked questions; they challenged doctors’ recommendations; they sought second, third, and fourth opinions.

The world revolved around Zaida, around her cancer, Eric said. “Even when I wasn’t with Zaida, I was still thinking about Zaida.”

That singular focus would eventually take its toll on Nichol and Eric’s marriage. They separated in June 2015 and divorced the following year.

Zaida, too, wrestled against the life cancer imposed on her. “Some people handle it with so much strength and hope and fire, uplifted and grateful and looking on the bright side,” Nichol said. “Zaida wasn’t like that.”

She wasn’t mean or rude, Nichol explained, but she wasn’t overly cheerful. “She wasn’t nice to (all) the nurses. She liked who she liked and she ignored who she didn’t.”

There were times of respite, too. The surgeries and the chemo would do their job, and Zaida’s CA-125 — a measure of the cancer growth in her body — would drop to a near-normal level. There were trips to the beach or to Disney World, a stay at Give Kids the World, a resort in Kissimmee, Fla,. for kids with life-threatening illnesses.

During these times, Zaida’s life gained a semblance of normalcy. She attended school through fifth grade before illness forced her home. Her closest friends became those she met online; she Skyped with kids from across the country. Her love of art class morphed into an intense passion for Minecraft; she posted frequent videos to YouTube of her playing the game, underscored by a soundtrack of popular music or else her own voice narrating the action, punctuated with giggles. She loved everything with an element of magic or fantasy: My Little Pony, Legend of Zelda. Harry Potter. She played and fought with her older sister, Runa. When she craved solid food, it was usually something sweet.

They were times of rest, but not of peace. Always, her parents were watching, waiting for the cancer to make a reappearance. And it always did, following a two-year cycle: First, her cancer burden would begin to climb, options would be reevaluated, the latest drugs tested and proven ineffective. Then, finally, the surgery and the hot chemo wash that would buy her another two years of life.

Oncological weaponry

Developed from mustard gas during World War II, chemotherapy is still the dominant form of cancer treatment. Chemo works by killing cells; because cancer cells replicate faster, they are more vulnerable to the drugs. The destruction of normal cells accounts for the terrible side effects: hair loss, weight changes, nausea and vomiting, mouth sores, fertility issues.

Drugs that would target only cancer cells began showing up in the late ’90s and early ’00s, brought about by an increased knowledge of genetics and rapid technological advances in data processing and storage. It is now possible to sequence the DNA of a tumor and compare it to the DNA of a healthy cell. Each of the changes is a potential target for a drug.

The DNA of a tumor is like “a sentence of 6 billion letters,” explained Dr. Michael Rothenberg, a Denver-based cancer researcher who worked on Zaida’s case. As sequencing technology advances, “we can read the order and identity of more and more of those letters, compare normal cells to cancer cells and see the differences in one fell swoop.”

Sometimes there are 10 changes in the sentence; sometimes there are 10,000. Previously reported scientific literature help researchers know which changes are potentially significant. Those that are become the targets for biopharma firms.

The FDA has approved more than 75 targeted drugs for use in 28 distinct cancers and conditions, including a handful used in children, according to the NIH. The “poster child” is imatinib, developed in 2001 by Swiss pharmaceutical giant Novartis and marketed as Gleevec.

Gleevec boosted the chances of survival from less than one in three to over 90 percent for patients with chronic myeloid leukemia (CML). Most patients treated with the drug since 2001 are still alive, according to the American Cancer Society. The NIH reports that CML patients in remission after two years of imatinib treatment have the same life expectancy as people who never had the disease.

There are limits to these promising drugs. Developed resistance is nearly universal, Rothenberg said: The tumor will mutate, finding a way to overpower the drug or a way to go around it, accomplishing growth without whatever portion of its DNA is being blocked by the drug.

The drugs buy time for patients in clinical trials who otherwise have no options. Sometimes it’s months; sometimes years. “But inevitably,” Rothenberg said, “they stop responding.”

When that happens, the entire R&D process begins again. Companies sequence mutant tumor DNA to identify what changed. If something can be found, a second drug is developed. If and when the tumor becomes resistant to that, work starts on a third-generation treatment.

In this way, the enemy has been pushed back and back, though not eradicated. It can take 10-15 years for a drug to complete all three phases of the clinical trial needed for federal approval, so advances are often a decade or more apart. The patients who benefitted from the first breakthrough rarely see the next.

An unknown enemy

For physicians to take a meaningful shot at Zaida’s killer, first they needed to find it.

A genetic profiling of her tumor had been done by Massachusetts-based Foundation Medicine in November 2015. The genomic diagnostics company analyzed 300 genes, producing a 28-page report of its findings: what irregularities were present, which ones might be meaningful, what mutations might be treated with drugs currently on the market or in testing.

Nichol obtained a copy. Via parents of Zaida’s classmates, she connected with two Boulder-based companies, Array BioPharma and Archer DX. It was Array that looped in Rothenberg, in whose hands the Foundation study ended up.

The report had found two potentially significant mutations, but no treatments existed for them. Buried in the back was “all the stuff they didn’t know what to do with,” said Rothenberg. That was where he went looking.

Foundation’s sequencing had turned up the presence of a mutation in AKT1, a known cancer gene. Archer, Array and Rothenberg all suspected a change in the gene might be the wellspring of Zaida’s cancer. A closer look with more specialized technology was needed to determine the precise location of the possible mutation, and whether or not it made sense biologically as the driver of Zaida’s cancer.

At Archer, a team was assembled and a test built to look at AKT1. Fused with that gene could be any of 3 billion bases, paired chemicals that make up the rungs on the ladder of DNA. The problem could be in any one of them, but only certain combinations of bases would lead to cancerous growths.

The first pass found nothing. A second panel, more custom, was made. This time, Archer’s scientists saw something unusual. AKT1 had fused with another gene, LAMTOR1.

Ryan Walters, senior director of assay and product development, described a gene fusion this way: “Your genome is a set of encyclopedias. Someone goes in and rips out part of one book and shoves it inside of another. You’re going to be reading through that and going like, ‘What the hell does this mean?'”

Often, it means nothing. Such gene rearrangements are common in cancer patients. Zaida might have had 30 additional genetic changes in her tumor, Rothenberg said. The particular fusion Archer uncovered had never been reported before; there was no literature, anywhere, to confirm what had been found. But what the data showed was indisputable to Rothenberg.

“It took the business end of the AKT1 gene and put it next to the activation end” of LAMTOR1, essentially turning it into a highly productive tumor machine.

Finally, Zaida’s enemy had a name.

A tumor by another name

In the future, many cancers may be described this way, not by their location in the body, but by their root cause, the gene that goes bad for whatever reason and in whatever way. Instead of breast cancer, we might refer to a mutation of the BRCA2 gene presenting in the breast, or of BRAF in the skin.

“It used to be the philosophy that a tumor in your breast was different than a tumor in your lung,” said April Giles, president and CEO of the Colorado Bioscience Association. “Now they’re discovering those tumors may be the same the mutation” and the only difference is “where they ended up.”

Giles said industry groups are pushing the FDA to view cancer in these terms, which will help increase the speed and decrease the cost of drug development. Biopharmaceutical companies are testing targeted therapies for use in multiple indications, industry-speak for diseases. Boulder’s Clovis Oncology, for example, is studying the effects of its drug rucaparib on two distinct cancers, breast and prostate.

But the process needed for approval must be replicated for each new indication. A drug trial must be run for lung cancer patients; a separate one is needed to test that same drug in patients with pancreatic cancer.

It now costs $2.6 billion to take a drug from idea to commercialization, according to a 2014 study from Tufts University. A report published in the Journal of the American Medical Association earlier this year found that the median cost to develop 10 cancer drugs currently on the market was $757 million; half were higher, half lower.

The more recent study did not account for all the drugs that failed along the way. For every treatment that receives approval, nine more failed in clinical trials, Giles said, part of the reason that trials account for 80 percent of the cost of drug development.

These extraordinary costs are part of the reason so few drugs for children have been developed — the market is too small to guarantee profits. Additional complexities exist, including the difficulty of recruiting participants for clinical trials from the relatively tiny population of pediatric patients, and the adjustments needed to accommodate children’s physiology.

Two pieces of legislation were passed in the early 2000s to increase the number of drugs being developed and tested for pediatric uses. One was a requirement that clinical trials be run for both children and adults for applicable drugs; the other granted an extra six months of exclusivity for any drug companies that conducted pediatric studies.

It was a “carrot and stick” approach, said George Dahlman, CEO of Washington, D.C.-based Children’s Cause for Cancer Advocacy. But neither were particularly effective: The incentive too small and the requirement too subject to exemptions.

Companies had to test in both kids and adults for the same disease, but children are afflicted with cancers different than those impacting adults. A drug for lung cancer, for instance, has very little real-world benefit in pediatric oncology.

A new law, passed this year, should help. The Research to Accelerate Cures and Equity (RACE) for Children Act requires companies to test their drugs in any children who would be likely to benefit, based on molecular changes rather than diagnosis.

Science comes through

As the summer of 2016 approached, there were few options left for Zaida. Dr. Rothenberg knew of 10 AKT inhibitors, none approved, in various stages of clinical trial. Drugs like these essentially prevent the tumor cells from growing by blocking key functions — keeping them from replicating — or inducing apoptosis, which is cell death.

With Zaida’s cancer burden climbing and her parents contemplating end-of-life care, Rothenberg set about contacting each of the companies that had the five possibly life-saving drugs in their possession.

San Francisco’s Genentech, a subsidiary of Swiss multinational Roche, responded. In its arsenal was a drug called ipatasertib, developed in partnership with Boulder’s Array. The drug is in clinical trials for adult patients with breast and prostate cancer, with promising results. It had never been tested in a pediatric patient.

Julia Haas, a research investigator at Array, coordinated efforts to connect Zaida’s family with Memorial Sloan Kettering, where the drug would eventually be administered. A team of doctors came together, a treatment plan put in place.

One more organization would need to agree to Zaida’s treatment. The FDA.

The government agency has had some form of its expanded access program in place since 1987. Commonly called compassionate use, it allows for patients to use drugs still in the testing process. Approximately 1,000 requests are received each year; 99 percent of them are granted. Data on outcomes is not collected, according to an FDA spokesperson.

Zaida’s first treatment with Array’s drug was Oct. 6. 2016. An oral medication typically taken by mouth, Zaida took hers through her feeding tube.

Her CA-125 dropped more than half in two weeks. In a month, it had halved again. On Halloween, nine years to the day of her diagnosis, she was at Memorial Sloan Kettering for PET and CT scans. Administrative delays, all too familiar to the family, kept her and father Eric there for hours; it was after 5 when Dr. Emily Slotkin gave them a call.

“She said the tumors, all the little ones are gone and the big ones are shrinking,” Eric recalled. “She was excited, so that got me excited. I hadn’t had that feeling before.”

Nichol wrote an update that same night on Caring Bridge, the online journal she used to chronicle Zaida’s journey: “Holy shit! Great news!!! It’s really working, you guys!!!”

Workers at Archer and Array were following along, ecstatic to see the results of their labor. “Even my mom” followed it, said Josh Haimes, Archer’s group lead of applications. “(She) would forward me the details.”

“Everybody was so emotional,” said Namitha Manoj, senior associate of NGS Applications. “We all work on this every day (but) we don’t get to hear back from cases like this. This was very special.”

“We were really pleased,” added Haas. “It seemed like science came through.”

A gala was thrown together in early December to celebrate the local bioscience companies and their role in a turnaround of mythical proportions. There was dinner and drinks and dancing, and a hot pink-haired Zaida zipping up and down the hallways of the St. Julien, a luxury hotel, with her friends. A video was produced heralding the possibilities of targeted therapies and concentrated efforts of a dedicated community.

The next morning, her CA-25 would start to climb.

A survivor in death

It was easy to believe, to hope. Even Zaida’s parents — with all their years of knowledge and experience of ups and downs — thought that maybe, just maybe, this was it. The treatment that would stick.

“Parents always want to believe it’s going to be the miracle,” Eric said. “The hope… it never went away.”

The optimism of those in the oncology field was more tempered. But they were still taken aback by her swift decline.

“Three months felt short to me,” Rothenberg said. “We would have been pleased for six months of benefit, we would have been thrilled for a year, we would have been amazingly, extremely, pleasantly surprised for anything longer.”

Archer got another sample of the tumor. It was sequenced again. Nothing new was revealed; the tumor had found a way around the drug without changing its DNA. Options, though thin, were discussed. Nichol wanted to pursue them; Eric dissented.

In the end, it didn’t matter. There was no time to try another surgery, or one more drug.

Zaida died at 7:19 p.m. on Friday, March 10, three months and one day after the party for her recovery. She was 12.

In the statistics of childhood cancer, Zaida was a survivor, a tick in the ‘win’ column. She lived nine years, four months and 10 days past diagnosis. She was an example of what can happen when everything goes right. She had every drug, every surgery, every technology within reach. She had educated parents who asked the right questions and advocated for her at every turn. She had a community of experts in the field behind her, researching, networking, sharing knowledge.

In 2017, 1,790 children will die from cancer in the U.S., more than from any other illness, second in cause of death only to accidents. Ten times that many will die in the rest of the world, despite the fact that 80 percent of childhood cancers are considered curable.

These numbers are what drove many employees at Archer and Array to the industry, what keeps them working past 5 p.m. on Fridays. Zaida made those impulses more urgent; her life the amalgamation of everything that can be accomplished and everything still left to do.

“Had we had our technology in place and had we just been a few years earlier, could we have helped her more?” asked Paula Roberts, senior associate of custom assay development at Archer. “We just weren’t there yet.”

“We gave her one more Thanksgiving, one more Christmas,” said Walters. “But that’s not enough. We can make our products even better, we can turn them around faster, we can figure out ways to make them cheaper and get them adopted more widely.

“Nobody should have to wait nine years to figure out what’s killing them.”

Life everlasting

Zaida’s story is not quite over. Her cells live on, in a lab at Memorial Sloan Kettering, to be studied as long as resources exist to keep them alive. The first paper on her case will be published in coming months. It doesn’t answer the big questions — Where did her tumor come from? How did it outsmart the final treatment? What, if anything, could have been done to give her two more years, or months?

There will be more, Dr. Slotkin promised. Followup papers that will perhaps answer those questions. Because the cells can theoretically be kept alive forever, it’s impossible to know who they might help, and when.

“We’re going to help the people we’re going to help,” added Dr. Rothenberg. “I don’t care if it’s one in a million.”

That possibility — that Zaida might be one in a million — is what kept her parents defiantly striving in the face of overwhelming odds, what kept them hoping when reality was altogether hopeless. It’s what keeps cancer researchers and patient advocates and scientists in the lab working diligently, despite all the setbacks. It’s what motivates us all, in so many aspects of our lives, whether facing down a deadly disease or striving to improve the human condition: The knowledge that our best today is better than the best of 50 years ago, and 50 years from now we’ll be better still. We go on because we must, because to do anything else, though understandable, feels like a betrayal. Not only of ourselves, but to those we might have helped.

Not every family fights, of course. Nichol and Eric know that. They were given a choice, when Zaida was 3 and again every time she got sick again. There’s no wrong decision, to fight or not, Nichol said, no judgment for the families that choose a quicker end. But for her, for Zaida, there was only ever one way.

“I would have fought forever,” she said. “You learn more from fighting.”

Editor’s note: Due to a production error, a previous, unedited version of this article gave the incorrect spelling for Julia Haas’ surname and the cancer drug Gleevec, and also gave the incorrect statistic for how many children are diagnosed with ALL each year.

Shay Castle: 303-473-1626, castles@dailycamera.com or twitter.com/shayshinecastle