Pediatric oncologist Amanda Marinoff, MD, discusses how the multidisciplinary team at UCSF Benioff Children’s Hospitals individualizes patient care to increase treatment effectiveness while minimizing side effects in children with cancer. She describes the UCSF500 Cancer Gene Panel, a clinical-grade DNA and RNA sequencing platform that guides diagnosis and treatment and helps to identify cancer predisposition. Marinoff provides case examples of targeted treatment for children with refractory B-cell acute lymphoblastic leukemia, metastatic thyroid cancer, a germ cell tumor and systemic mastocytosis.
Hi, I'm Amanda Marinoff, a pediatric oncologist at UCSF Benioff Children's Hospitals. I'm excited to talk with you today about precision medicine at UCSF and pediatric oncology, where our goal is to deliver the right diagnosis and the right treatment to every patient every time. I have no disclosures. Here's an overview of what we'll talk about today. We'll talk about what precision medicine is and why it matters. The UCSF 500, which is the engine behind many of our precision medicine efforts here at UCSF, precision medicine in action through patient stories, how results become care, improving precision medicine through research, and finally, a summary and some information about referrals. First, what do we mean by precision medicine? Precision medicine individualizes care by considering each patient's genetic background and the molecular features of their individual tumors. The goal is to increase the effectiveness of treatment while minimizing side effects, which is especially important for children who have many decades of life ahead of them. At UCSF, the backbone of our precision medicine program is the UCSF 500, a clinical grade DNA and RNA sequencing platform used in routine patient care. On our DNA sequencing, we can identify over 500 cancer associated genes and identify mutations, copy number changes, and structural variants that drive cancer growth. We can also do concurrent testing of normal tissue or germline testing that can provide a unique profile of the patient's genetic background and in some cases identify inherited cancer risk. RNA sequencing complements this by identifying gene fusions, which are especially important in pediatric, adolescent, and young adult cancers. Many of these tumors are defined by fusions that cannot be distinguished by histology or by DNA changes alone. UCSF is one of the few centers nationally with a clinical grade RNA sequencing platform embedded directly into routine clinical care. Together, integrated DNA and RNA sequencing provide a comprehensive molecular profile that guides diagnosis, prognosis, treatment, and cancer predisposition. Next, I'll walk through examples of how these results directly shape patient care in each of these areas. For many pediatric cancers, molecular testing is essential for accurate diagnosis. As you can see here, these three tumors can look very similar under the microscope, making them difficult to distinguish based on histology alone. What differentiates them is their underlying biology. Each of these tumor types is defined by a specific gene fusion, which requires molecular testing to detect. The UCSF 500 RNA sequencing assay has been particularly helpful in identifying gene fusions that can be challenging to detect using traditional. Methods. Here are 3 tumors that appear similar on histology and are distinguished by 3 distinct fusions associated with a distinct diagnosis, prognosis, and treatment approach. Molecular findings don't just inform diagnosis, they can also help us predict outcome. They can tell us how a tumor is likely to behave and allow us to tailor our therapy to match how aggressive the disease is. For patients with high-risk tumors, this means delivering more intensive therapy to minimize the chance of relapse and maximize the chance of cure. At the same time, for patients whose tumors can be cured with less treatment, accurate risk assessment allows us to spare them unnecessary toxicity, both in the short and long term. Here's an example. These are two infants with neuroblastoma whose clinical presentation and imaging looked nearly identical. Both had a primary tumor in the adrenal gland with metastases to the liver and skin. Patient A was carefully observed, and over time, the tumor regressed on its own. Patient B, on the other hand, required approximately 18 months of intensive therapy, consisting of chemotherapy, surgery, transplant, radiation, and immunotherapy. What made the difference was molecular testing. Patient B's tumor showed a high-risk feature called MCN amplification, whereas Patient A did not have MCN amplification and had tumor biology consistent with a disease that could be safely observed without therapy. Without molecular testing, we would not be able to distinguish between these two patients, despite their very different clinical courses. In some cases, sequencing directly identifies new treatment options for patients with refractory disease. I'll walk through three cases. The first is An 8-year-old who had refractory B-cell acute lymphoblastic leukemia. The patient had received 8 prior lines of therapy. When they came to UCSF, their tumor underwent UCSF 500 testing, which identified a gene fusion that was targetable with a therapy called imatinib. They then received 1 cycle of imatinib and entered a remission, which was then consolidated with a transplant, and 5 years later, the patient is thriving. The second case is a 4-year-old with metastatic thyroid cancer. UCSF 500 here showed an ERC fusion that was targetable with a treatment called larotretinib. The patient received this therapy and had good disease control and symptom control, um, and ultimately was cured with definitive therapy. The third patient is an 11-year-old who had two distinct cancers, a germ cell tumor and systemic mastive cytosis. Here, UCSF 5. identified the same underlying kit mutation, which were both targetable with avapritinib. The patient received this therapy and had disease control with both cancers. UCSF 500 also includes germline testing, which identifies inherited cancer predispositions in approximately 17% of patients. Um, these data are from a manuscript that's currently in review, and you can see that for some cancers like osteosarcoma, more than A third of patients have an underlying cancer predisposition. These findings are critical for informing surveillance, family counseling, and long-term care for patients and their relatives. Sequencing results only matter if they're thoughtfully integrated into clinical care. At UCSF, the UCSF 500 results are reviewed in multiple complementary forums to discuss how sequencing results impact diagnosis, prognosis, treatment, and cancer predisposition. We have our pediatric precision oncology program, fondly known as PPOP, uh, which includes a multidisciplinary review of UCSF 500 results for every pediatric patient, whether they're treated at UCSF or elsewhere. Our molecular tumor board provides an opportunity for a deep review of molecular findings to identify actionable targets. And molecular results are incorporated into routine tumor board decision making in our disease specific tumor boards every week. Precision medicine at UCSF is supported by many multidisciplinary teams and specialized programs. Our pediatric hereditary cancer clinic provides tailored surveillance plans and genetic counseling for patients with cancer predispositions. For patients with germline NF1 and RAST pathway alterations, our specialized clinics bring together providers from multiple subspecialties across UCSF to deliver unified care to these patients in a single clinic visit. In our survivorship clinic, our team provides every patient treated with cancer with a tailored plan to understand and manage the long-term effects of their specific cancer diagnosis and treatment exposure. UCSF is also one of the few centers across the country that offers MIBG, a form of targeted radiation therapy for certain patients with neuroblastoma and other neuroendocrine tumors. And finally, we have a robust early phase clinical trials program that offers clinical trials that incorporate novel targeted therapies and precision approaches for patients across nearly every pediatric cancer diagnosis. Here are examples of the many, uh, precision oncology clinical trials that our team offers. Despite this progress, we still have a lot more work to do. Only 17% of pediatric tumors have high evidence targetable alterations. So at UCSF we're committed to learning from every single patient to continue to improve how we diagnose and treat pediatric cancers. Using de-identified clinical and genomic data, UCSF contributes to and leverages shared resources that allow us to look across hundreds to thousands of tumors. Platforms like CBio Portal, as shown here, provide a user-friendly format for helping us identify patterns in tumor biology that's linked to treatment response and outcomes that would not be visible from individual cases alone. UCSF is also one of about 20 institutions that contributes to a project called Genie that helps to advance precision medicine. Across all tumor types. In parallel, our tissue banking efforts ensure that patient samples are available to support ongoing discovery and translational research from the bench to the bedside and back. Together, these resources create a learning system where each patient's experience helps inform better care for the next. Across pediatric oncology, physician researchers at UCSF are advancing precision medicine across every single disease area, including leukemia, solid tumors, brain tumors, rare cancers. discovery and patient care, and working to ensure that advances in precision medicine are available to every single pediatric patient who faces cancer. UCSF pediatric oncology is embedded in a broad ecosystem of unique resources at UCSF that are helping to advance precision medicine in every domain, including the Precision Imaging for Cancer and therapy Program, Living Therapeutics Initiative, collaborations with the Gladstone Institute and Genomic Institute at UC Berkeley to advance transformative approaches to precision medicine. And in the era of big data, machine learning, and artificial intelligence, UCSF has cutting edge computational resources to help synthesize the growing amounts of data now available and translate them responsibly into insights that advance care for all patients. In summary, at UCSF clinical grade DNA and RNA sequencing guides diagnosis, risk assessment, and treatment. Multidisciplinary teams translate molecular results into real-time care. And finally, UCSF is committed to learning from every patient to continually improve outcomes. Thank you to everyone who makes precision medicine and pediatric oncology possible and is continuing to work to make it better, including my colleagues in UCSF pediatric oncology, the molecular Oncology Initiative, the Clinical Cancer Genomic Laboratory, and bioinformaticians who provide the foundation for everything we talked about today. And finally, here are links to learn more about and refer your patients to our specialized multidisciplinary care clinics, including our pediatric hereditary cancer clinic, NF1 clinic, grassopathy clinic, survivorship clinic, MIBG therapy, and our early phase clinical trials program.
