This is a promising time for osteosarcoma treatment. Though rare, osteosarcoma accounts for the most cases of childhood bone cancer,1 and the ways clinicians care for pediatric patients with the disease are evolving. Novel agents or therapeutic regimens offer new treatment options, and genetic testing helps clinicians gauge the risk of future malignancies.2
“One thing that’s really changed is our understanding that osteosarcoma may be the first presentation of a cancer predisposition syndrome,” said pediatric hematologist-oncologist Amit J. Sabnis, MD, MS, assistant professor of pediatrics at UCSF and sarcoma investigator at UCSF Benioff Children’s Hospitals. “Across all the cancers we treat, we’ve changed how we approach counseling families about the need for and benefits of genetic testing. The data are very clear, however, that osteosarcoma stands out as a disease that may signal an increased risk for developing a secondary cancer in the patient’s lifetime and a shared risk in their family.”
The presence or absence of metastatic disease, Sabnis said, plays a key role in determining both treatment and prognosis. That’s why he and his colleagues are collaborating to interpret chest CT scans that increasingly find indeterminate lung nodules in patients with osteosarcoma.2
“I’m not sure if the quality of our CT scans is improving or other factors are leading to our finding these small nodules, but we want to determine if they represent metastatic disease or not,” Sabnis said. “In those situations, an experienced team that includes thoracic surgeons, orthopedic oncologists, pediatric oncologists and radiologists is an outstanding resource.”
Growing evidence of genetic links
Several factors can increase a child’s risk of osteosarcoma, including Paget’s disease and other bone disorders and obstruction of blood supply to a bone. A history of radiation treatment, although uncommon in children, can also increase vulnerability to osteosarcoma.1
In addition, increasing evidence links the risk of osteosarcoma to certain genetic mutations.2
“There are now strong data suggesting many patients who develop osteosarcoma have an underlying genetic risk,” Sabnis said. “Li-Fraumeni syndrome, which is a mutation in the TP53 gene, is the classic genetic cancer syndrome we think of, but other, rarer cancer predisposition syndromes can present with osteosarcoma as well.”
When to refer a patient for suspected osteosarcoma
Most common in the distal femur, proximal tibia and proximal humerus,3 according to the American Cancer Society, osteosarcoma often begins with intermittent pain that becomes sustained over time.1 A palpable bone mass typically accompanies this discomfort, Sabnis said. These symptoms, along with atypical findings on imaging studies, warrant referral to a cancer specialist.2
“Well-trained, high-volume radiologists can determine a lot from an X-ray, but sometimes osteosarcoma findings can be quite subtle,” Sabnis said. “Anytime a patient’s imaging shows an abnormality that’s not well explained, or a patient has an abnormal X-ray and significant pain or difficulty functioning, they would benefit from a review by an orthopedic oncologist and a pediatric oncologist working together.”
A greater role for genetics in treatment
Once a biopsy confirms a diagnosis of osteosarcoma and staging is complete, the cancer care team orders additional testing, such as blood tests and an echocardiogram, to assess the health of the patient’s organ systems before treatment begins. The patient and family may meet with a reproductive endocrinologist to discuss fertility preservation options – certain treatments may affect fertility – as well as with a genetic counselor to discuss the possibility of germline testing.2
“Osteosarcoma has been recognized to have some clinical heterogeneity for some time, but with more advanced sequencing technologies and the ability to use them in real time, we’re now, for the first time, able to identify molecular biomarkers that can tell us how likely a patient’s tumor is to be cured on first pass-through,” Sabnis said. “The hope is that we can also start using these genetic tests to identify novel therapeutic approaches for patients whose tumors are either metastatic at diagnosis or have come back.”
That day may be approaching. UCSF Benioff Children’s Hospitals participated in a multi-institutional study investigating a particular gene’s potential to help stratify patients for risk of osteosarcoma recurrence.4
“This study of panel sequencing identified amplification of the MYC oncogene as an adverse prognostic factor in osteosarcoma,” Sabnis said. “It was the first time we were able to use a gene, as opposed to a clinical factor – such as metastases at diagnosis or poor response to chemotherapy – in a way that really stratifies patients and [lets us] think about who’s going to be at the highest risk for relapse.”
The typical course of treatment for patients with osteosarcoma, Sabnis said, is 10 weeks of chemotherapy followed by surgery to remove the primary bony lesion. Surgical options, such as implantation of expandable prostheses to prevent a leg length discrepancy and rotationplasty to preserve joint function after knee removal, help patients maximize their functional abilities and quality of life.2
Fueling the future of treatment
Experimental treatments under investigation in early-phase clinical trials are helping to reshape osteosarcoma care. One such trial, by the Children’s Oncology Group and National Cancer Institute’s Pediatric Early Phase Clinical Trials Network (in which UCSF Benioff Children’s Hospitals are active), is studying the beta-catenin inhibitor tegavivint as a treatment for recurrent and refractory solid tumors, including osteosarcomas.
In another study, researchers are investigating whether the oral agents olaparib and ceralasertib are effective at treating recurrent osteosarcoma.
“Both agents were found to inhibit DNA damage repair pathways based on work done at UCSF and elsewhere, demonstrating that these pathways seem to be essential for osteosarcoma cells to survive,” Sabnis said. “What’s nice about this study is it’s an all-oral regimen for relapsed patients, with pretty tolerable side effects. We’re not asking them to go through additional intensive chemotherapy when we know that’s not necessarily going to change the outcome.”
When relapsed disease is resected, Sabnis said, investigators scrutinize specimens in the lab at UCSF to understand how olaparib and ceralasertib affected the cancers and what this information indicates about who benefits most from the medications – providing additional valuable data points in the continuing quest to identify and develop more effective osteosarcoma treatments.
Refer a patient with suspected osteosarcoma online or by calling the Pediatric Access Center at (877) 822-4453 (877-UC-CHILD).
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1 https://orthoinfo.aaos.org/en/diseases--conditions/osteosarcoma/
2 Interview with Dr. Sabnis
3 https://www.cancer.org/cancer/types/osteosarcoma/about/what-is-osteosarcoma.html and confirmed by additional sources: https://secure.ssa.gov/poms.nsf/lnx/0423022120 and https://emedicine.medscape.com/article/988516-clinical?form=fpf and https://now.aapmr.org/pediatric-osteogenic-sarcoma/
4 https://ascopubs.org/doi/10.1200/PO.22.00334
