What treatment options are there?” This is one of the first questions to enter the minds of parents whose child receives a cancer diagnosis. Of course, the answer to this question is dependent on the type of cancer that has been diagnosed. But for children with solid tumors, the answer may also one day depend on their genetic characteristics.
The idea of treating a child with a solid tumor based on their genetic traits falls into a field known as “precision medicine,” and it is a field that has gained increasing interest for the treatment of disease in adults.
According to the National Institutes of Health (NIH), “precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.”
In simple terms, precision medicine is the opposite of the “one-size-fits-all” approach that has become the norm for the treatment of human disease. Instead, it refers to therapies that are tailored to each person.
In the case of a woman with breast cancer, for example, the patient may be treated based on the unique genetic mutations present in her breast tumor.
It is hoped that precision medicine will enable faster, more effective treatment for cancer and a wealth of other diseases.
But while the approach has gained acclaim as a feasible treatment strategy for adults with cancer, the development of personalized medicine for childhood cancers is lagging.
The barriers to precision medicine for childhood cancer
One factor that has been holding back precision medicine for childhood cancer is the inability to gather enough data on the genetic mutations that contribute to cancerous tumors in children.
Childhood cancers are far less common than adult cancers. This year, it is estimated that 10,380 children in the US under the age of 15 will receive a cancer diagnosis. For comparison, there will be more than 246,000 new cases of breast cancer alone diagnosed among women in the US this year.
It is obviously positive that childhood cancers are not more prevalent, but their rarity makes it harder for researchers to gather a sufficient amount of genetic data.
What is more, childhood cancers hold significantly fewer genetic mutations than adult cancers, primarily because children have been exposed to fewer environmental and lifestyle factors that can alter DNA.
Another barrier to precision medicine for pediatric cancer is that there are few targeted drugs – experimental and approved – available for children. Most drug companies focus on developing targeted therapies for adults, and for existing targeted drugs, current formulations or dosing guidelines are often unsuitable for children.
But it seems the idea of precision medicine for children with cancer may finally be gaining momentum.
Assessing the feasibility of genomic sequencing for pediatric cancer
In January this year, researchers of a study published in JAMA Oncology claimed their findings show genomic sequencing is viable for children with cancer and can be used to both diagnose and treat solid tumors.
The research – called the Individualized Cancer Therapy (iCat) Study – was led Dr. Katherine Janeway, clinical director of the Solid Tumor Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts.
Dr. Janeway and her team collected tumor samples from 100 cancer patients with a median age of 13.4 years.
All patients had visited one of four academic medical centers in the US between August 2012 and November 2013 for a relapsed pediatric solid tumor, and the patients were followed up for an average of 6.8 months.
The researchers used a number of sequencing techniques, including next-generation sequencing, that allowed them to assess the tumor samples for all known cancer mutations in 305 genes.
If the team identified any gene mutations in the tumor samples that were deemed “clinically actionable” – that is, a gene mutation for which experimental or approved therapies exist that can be given in doses and formulations suitable for children – then a treatment recommendation, or “iCat recommendation,” to the patient’s oncologist was made.
31% of pediatric patients had clinically actionable tumors
“We designed the study such that if we could make an iCat recommendation for 14% of participants, we could say that clinical sequencing was feasible,” says Dr. Janeway. “We exceeded this benchmark.”
The researchers were able to make a treatment recommendations for 31 of the 100 patients. Of these, three underwent the recommended treatment, although none of them responded.
For the remaining 28 patients, reasons for not receiving the recommended treatment included ineligibility, a good response to current therapy or death.
The team identified gene mutations in the tumors of a further 12 patients, which demonstrated either a predisposition to cancer and/or a change in cancer diagnosis.
Dr. Janeway and colleagues say their findings demonstrate the feasibility of using genome sequencing for pediatric solid tumors to help aid diagnosis and targeted treatment, and they note that theirs are not the first to do so.
On the next page, we further investigate how research is advancing the use of genomic sequencing in pediatric oncology, and how the pharmaceutical industry is hampering the progress of precision medicine.
A better understanding of genomic sequencing in pediatric oncology
Another study – published in the same issue of JAMA Oncology and led by researchers from the Baylor College of Medicine in Houston, TX – used whole-exome sequencing to identify “diagnostic and/or potentially actionable” gene mutations in almost 40% of 150 children with solid brain tumors.
“Pediatric oncology has lagged behind adult oncology when it comes to incorporating targeted drugs and genomic testing or tumor profiling into treatment,” says Dr. Janeway. “Together these studies indicate that we’re starting to understand how to carry out clinical sequencing in pediatric oncology and which patients might benefit from it.”
Demonstrating the increased focus on making precision medicine for childhood cancer a reality, research into genomic sequencing for children with the disease has now expanded to the UK.
Just last month, researchers from the Institute of Cancer Research (ICR) and The Royal Marsden National Health Service (NHS) Foundation Trust announced the launch of a pilot study that will use a novel genomic sequencing test to assess the tumors of hundreds of children with cancer.
According to study leader Louis Chesler, professor of pediatric cancer biology at ICR, and colleagues, the newly created test has the ability to assess solid tumors for the presence of 81 cancer-related gene mutations.
Due to start later this year, the 2-year trial will test the tumors of around 400 children with cancer who are under the age of 14.
“We still face major barriers in obtaining targeted cancer drugs for children and using them in robustly designed clinical trials,” notes Chesler.
“But my hope is that through this and other initiatives like it, we can help to drive forward the use of targeted drugs in children, and make the case very clearly that they should be more widely available, as they have been for adults.”
Is pharma holding back pediatric precision medicine?
While current research is clearly bringing us closer to the availability of clinical genomic sequencing for pediatric cancer, there are some important hurdles to overcome before precision medicine becomes standard practice.
Fortunately, the current treatment success rates for children with cancer are high, with more than 80% of those diagnosed with the disease in the US surviving at least 5 years.
However, this high success rate – combined with the rarity of childhood cancers – can deter pharmaceutical companies from developing targeted therapies for children with cancer, with many researchers noting that such treatments are not deemed profitable.
As such, Dr. Andrew Kung – professor of pediatrics and chief of the Division of Hematology, Oncology and Stem Cell Transplantation at Morgan Stanley Children’s Hospital at New York-Presbyterian and Columbia University Medical Center – notes that is important to gain a better understanding of how existing targeted therapies used for adults can be applied to children.
“As we understand more precisely what the underlying molecular defects of cancer are using sequencing technologies, we come to learn that, in most cases, the abnormalities in genes and signaling that result in the development of pediatric cancers have similar counterparts in adult cancers,” explains Dr. Kung, talking to the American Association of Cancer Research (AACR) last year.
“The ability to recognize the similarities allows us to take advantage of therapies that were developed for adult indications and redirect them toward pediatric use,” he adds.
Precision medicine ‘poised to make a huge difference to cancer patients’
However, this approach also has its challenges. Dr. Kung points out that even when an existing targeted therapy is identified based on a child’s genomic sequencing results, most insurance companies will not cover the use of the drug because it has not been formulated for pediatric use.
“In many instances, a lot of time is spent appealing decisions, seeking compassionate use and writing single-patient INDs [investigational new drug application submitted to the FDA] to be able to get the drug,” he adds.
“We have determined that on average, it takes about 40 hours’ worth of work over a period of 4-6 weeks to ultimately get a drug to a patient. So, even as we try to be more efficient in getting the test results back to clinicians, quite often, the back end becomes the real hurdle to getting drugs to patients.”
Still, Dr. Kung and many other health care professionals believe that when it comes to precision medicine for children with cancer, the future is bright.
Trials assessing the feasibility of genomic sequencing for child cancer patients are ongoing, and last year, the National Cancer Institute (NCI) announced the launch of Pediatric MATCH – a counterpart of the adult NCI-MATCH trial that plans to test targeted therapies in children with advanced cancers who have limited treatment options.
As Dr. Kung says, the “national landscape is rapidly changing” for children with cancer: