We are taught early on that every person is unique-that no two human beings are exactly alike. Yet, historically, medical professionals have often been forced to take a "one-size-fits-all" approach to treating patients due to our inability to distinguish between those who would benefit from a therapy from those who would not. With the advent of next-generation sequencing, we as physicians are becoming more adept at tailoring our treatment to the genetic features of each distinct individual patient (and case). This is especially true in the field of oncology, where precision medicine has the potential to greatly improve disease evaluation and treatment for some of our most critically ill patients.
Traditional cytotoxic chemotherapy works by destroying cancer cells at a slightly higher rate than cells in normal tissues, resulting in a host of undesirable and potentially deadly adverse effects, including immunosuppression, mucositis, and cardiotoxicity. In contrast, precision oncology involves in-depth investigation of the biology of each patient in order to select treatments that will have a maximal targeted impact on the cancer with minimal side effects. One example of such targeted therapy is the use of vemurafenib, a BRAF inhibitor, in patients with melanoma found to carry the BRAF V600E mutation.
This approach is most successful when we pair both tumor and germline analyses, as it enables us to determine definitively whether a mutation is present exclusively in the tumor or will be potentially heritable for future generations. Additionally, while tumor sequencing can provide information about driver mutations that can be targeted by specific therapies, germline sequencing can also supply important information about which medications should be avoided. For example, patients with mutations in the DPYD gene can present with dihydropyrimidine dehydrogenase (DPD) deficiency, which can make them uniquely prone to toxicity from commonly used chemotherapy such as 5-Fluorouracil (5FU) and capecitabine. Knowing such a patient's susceptibility prior to treatment could be potentially lifesaving.
The potential of precision oncology is exciting; however, many questions remain to be answered, such as how these tumors evolve over time in response to our therapies, and how to effectively study smaller numbers of patients. This is a particular challenge in pediatric oncology, as even our most common tumors are present in much smaller numbers than in adults. Additionally, drug discovery in pediatric oncology is especially difficult as historically it has been limited to agents for which some experience (including toxicity data) have already been obtained in adult cancer patients.
Pediatric MATCH
Moving forward, there is a need to rigorously test the utility of precision oncology approaches for the clinical care of childhood cancer patients. One such large-scale effort, the NCI-Children's Oncology Group (NCI-COG) Pediatric MATCH (Molecular Analysis for Therapy Choice) Trial, has recently opened (July 2017) at institutions across the U.S. In this study, the NCI and COG have partnered to conduct a pediatric precision medicine cancer treatment trial that explores whether targeted therapies can be effective for children and adolescents with solid tumors that harbor specific gene mutations.
This phase II trial is open for children and adolescents ages 1-21 who have solid tumors, including non-Hodgkin lymphomas, brain tumors, and histiocytosis, that no longer respond to standard treatment or have recurred after treatment. Pediatric MATCH plans to study a large set of molecularly targeted drugs, each targeting a defined set of gene mutations, in order to match patients with therapies aimed at the molecular abnormalities in his or her tumor. A similar, but separate trial for adults, the NCI-MATCH study, began enrolling adult patients in August 2015.
Enrollment in Pediatric MATCH will be available through about 200 COG sites in the U.S. in anticipation of screening 1,000 eligible patients. In contrast to cancers that occur in adult patients, key cancer mutations for which experimental drugs are currently available are expected to be found in only about 10 percent of tumors from children and adolescents with cancer.
Each patient will initially enroll for a screening study, in which a sample of his or her relapsed tumor will undergo DNA and RNA sequencing to detect genetic abnormalities that could be targeted by one or more of the drugs being studied. If a genetic abnormality is identified in the tumor and a drug is available in Pediatric MATCH that targets the abnormality, the patient can then enroll in the corresponding treatment arm if he or she meets the eligibility criteria.
Pediatric MATCH will use a single sequencing test to screen tumor DNA and RNA for many molecular abnormalities at once, including mutations, fusion genes, and amplifications. The test, which is also being used for the adult NCI MATCH trial, was developed by the Molecular Characterization Laboratory at the NCI Frederick National Laboratory for Cancer Research in Frederick, Md. The latest version of this test looks for alterations in more than 160 genes associated with cancer.
Although most of the DNA mutations identified in study patients will be tumor-specific (i.e., somatic mutations), some may have been inherited, which could have clinical implications for testing and cancer prevention strategies in family members. Accordingly, Pediatric MATCH includes sequencing of a blood sample from each patient in addition to their tumor sample, with plans to return these germline testing results to their treating oncologists and provide access to educational resources and genetic counseling as needed.
As it is anticipated that only a small number of patients will have a tumor with an identified genetic abnormality that can be targeted, the complete results from the tumor screening test for all patients will be shared with their oncologists. These patients may be able to enroll in other studies through consortia such as the COG Developmental Therapeutics Program, Pediatric Brain Tumor Consortium, New Approaches to Neuroblastoma Therapy, or other pharmaceutical trials identified through clinicaltrials.gov.
More information about Pediatric MATCH can be found online at http://pediatricmatch.org/.
SAMARA L. POTTER, MD, MBA, is Pediatric Oncologist at Texas Children's Cancer and Hematology Centers, Houston.