Precision Medicine in Pediatric Oncology: Advancing Tailored Care for Every Child

Precision Medicine in Pediatric Oncology: Advancing Tailored Care for Every Child

Pediatric oncology has made remarkable strides over the past several decades, dramatically raising survival rates for many childhood cancers. These improved outcomes are primarily due to new immunotherapies, targeted therapies and advanced molecular diagnostics.

The team at UCSF Benioff Children’s Hospitals is at the forefront of these developments. Leveraging clinical-grade DNA and RNA sequencing, researchers are refining diagnoses, exploring risk-adapted therapy and unlocking new treatment options. Amanda Marinoff, MD, a pediatric hematologist-oncologist and assistant professor of pediatrics at UCSF, explains how she and her team are helping to change the outlook for children with cancer.

Clinical-grade sequencing with UCSF500

At the heart of UCSF’s precision medicine program is UCSF500. This clinical-grade DNA and RNA sequencing platform evaluates approximately 500 genes via DNA assays and the entire transcriptome via RNA sequencing.

This platform is particularly valuable because it’s embedded . “We don’t need separate samples on a research-grade protocol,” Marinoff explains. “Our pathologists use these same samples to make diagnoses, and we can add the sequencing platform into the treatment plan to make more informed decisions.”

The DNA and RNA assays provide valuable information. DNA sequencing identifies mutations, copy number changes and structural variants. RNA sequencing excels at detecting gene fusions, which are particularly important in pediatric and adolescent cancers. In these cases, many tumors are driven by gene fusions that are not readily detectable on DNA assays alone. “UCSF500 informs our diagnosis, prognosis, treatment options and cancer predisposition screening,” says Marinoff.

Reaching beyond pathology for a precise diagnosis

Some pediatric tumors look remarkably similar under the microscope but have vastly different prognoses and treatment approaches. UCSF500 can clarify these diagnoses by identifying specific molecular signatures.

For example, some small round blue cell tumors appear histologically identical but require different treatment strategies. Molecular testing can distinguish Ewing sarcoma (with an EWS-FLI1 fusion) from desmoplastic small round cell tumor (EWS-WT1 fusion) or CIC-rearranged sarcoma (CIC-DUX4 fusion).

“UCSF500, particularly the RNA component, can really clarify the diagnosis for similar-looking tumors,” says Marinoff.

Harnessing risk-adapted therapy

Beyond diagnosis, molecular features help clinicians understand each patient’s risk profile at the time of diagnosis. This allows for risk-adapted therapy, which matches treatment intensity to the patient’s likelihood of responding to standard care.

Consider two infants with neuroblastoma: one with MYCN amplification and one without. The MYCN-negative patient may be managed with observation alone, while the MYCN-amplified patient requires intensive multimodal therapy.

“We want to know about the risk right away so we can intensify therapy,” Marinoff explains. “If a patient has a tumor that has a low risk of spread or recurrence, we want to de-intensify therapy to spare them short and long-term toxicities.” 

Unlocking targeted treatments

Marinoff and her team have also handled cases where UCSF500 identifies actionable alterations that open the door to targeted therapies. Examples include:

• 8-year-old with refractory B-cell acute lymphoblastic leukemia. UCSF500 results revealed the NUP214-ABL1 fusion, leading to treatment with imatinib and subsequent remission.
• 4-year-old with metastatic thyroid cancer. The team found an ETV6-NTRK3 fusion and successfully treated the child with larotrectinib.
• 11-year-old with two different cancers. This child had germ cell tumor and systemic mastocytosis, with the same KIT mutation in both tumors, and achieved disease control in both with avapritinib.

“It’s wonderful to see a patient respond to a new option,” Marinoff says. “Currently, our ability to sequence is better than our ability to match targeted therapy. But throughout the process, we’re uncovering additional opportunities. Eventually, we hope to see more pediatric tumors with high-evidence, targetable alterations.”

Identifying inherited cancer risk

Every patient who undergoes tumor sequencing at UCSF also receives germline testing, which involves sequencing the normal tissue to identify inherited cancer predispositions. This information informs surveillance protocols, family counseling and long-term care for patients and their relatives.

UCSF has a robust genetic counseling and hereditary cancer program to support these patients, though referring physicians can also coordinate genetic counseling at their home institutions. The team has developed a Pediatric Hereditary Cancer Clinic that provides surveillance and counseling for patients with germline findings. “It’s a collaborative process,” Marinoff emphasizes. “We offer resources that can help the physicians and patients, and we work with them throughout the patient’s care.”

In addition, UCSF offers Neurofibromatosis Type 1 (NF-1) and NF/Ras Pathway clinics, which provide coordinated multidisciplinary care for patients with specific germline conditions. The clinics bring together specialists from neurology, developmental pediatrics, cardiology, dermatology and oncology in one place.

Translating research into clinical action

UCSF is committed to improvement through research. The UCSF Helen Diller Family Comprehensive Cancer Center’s Molecular Oncology Initiative (MOI) is a key component of UCSF’s Precision Medicine Initiative. Its mission is to guide the development and implementation of precision medicine for cancer patients at UCSF by integrating molecular analyses into patient care.

The MOI provides several key resources, including cBioPortal and Project GENIE. These resources link de-identified clinical and molecular data, allowing researchers and clinicians to learn from every tumor. The MOI also houses a molecular tumor board, focused on providing an in-depth review of a tumor’s molecular findings to determine how they can inform treatment for patients.

UCSF’s pediatric precision oncology program is comprised of a multidisciplinary team that reviews every UCSF500 report, including those from patients treated outside of UCSF. The team then communicates with the patient’s primary oncology team to provide tailored recommendations based on the molecular findings. These resources enable researchers and clinicians to learn from every tumor. 

How to refer patients

Physicians may refer for consultations or second opinions through the Pediatric Oncology Program and the Precision Medicine Cancer Program. You may also send tumor samples to UCSF for UCSF500 sequencing, and the team will return results with interpretation and recommendations for next steps.

To refer a patient, call 877-822-4453 or complete the online referral form.