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Using MicroRNA Profiling to Guide Osteosarcoma Treatment

In This Article

  • A study by a Massachusetts General Hospital ortho-oncology surgeon has shown that patients with osteosarcoma have different microRNA profiles, depending on whether they had a pathological fracture
  • A particular profile was associated with a poorer prognosis, lower overall survival and more risk of metastasis
  • Those patients might benefit from surgery before chemotherapy, a change to the traditional treatment paradigm
  • Future directions include determining whether surgery before chemotherapy does indeed improve outcomes in certain patients, as well as the development of a clinical decision tool

Researchers at Massachusetts General Hospital have shown that microRNA profiling can be used to determine which patients with osteosarcoma may benefit from early surgery to prevent pathological fracture.

"We want to identify patients who are at risk for fracture so we can treat those patients surgically before a fracture happens, then provide better care in terms of progression and quality of life and administering chemotherapy without interruptions," says lead author, Santiago Lozano-Calderon, MD, PhD, surgeon in the Orthopaedic Oncology Service.

MicroRNA testing can show which patients would benefit from surgical intervention very early in the disease course—before a fracture occurs—as opposed to a more traditional treatment course involving chemotherapy, then a delay for surgery, then more chemotherapy.

Evolving Understanding of Pathological Fractures in Osteosarcoma

Though rare, osteosarcoma is the most common primary bone cancer. Malignant cells create irregular bone, which often causes a pathologic fracture even before a patient begins treatment, says Dr. Lozano-Calderon. Such fractures occur in 5% to 10% of all osteosarcoma patients, often at presentation or during presurgical chemotherapy.

Historically, oncologists have used chemotherapy and radiation therapy to try to obtain better local control, with the assumption that the bone would break and then the cancer would contaminate the local area. Trying to achieve local control was even an indication for amputation.

"We started to believe that the fracture is not really the problem," says Dr. Lozano-Calderon. "That, instead, the fracture is really just another manifestation of the biologic aggressiveness of the tumor. But there was no way to prove that—until we did this study."

Profile of Aggressive Biology and Poor Outcomes

In a retrospective study published in fall 2019 in Clinical Orthopaedics and Related Research, Dr. Lozano-Calderon and his team examined microRNAs: small, noncoding RNAs that play important roles in regulating gene expression. They applied microRNA analysis, a process that performs genetic analyses on tissue samples to elucidate the signatures of very small molecules.

The researchers found that patients with osteosarcoma had very different microRNA profiles depending on whether they had pathological fractures or not. A particular profile was associated with a poorer prognosis, lower overall survival and more risk of metastasis.

This knowledge that certain osteosarcomas have more aggressive biology will help orthopedic oncologists identify patients who are at risk for fracture so that they can have early surgery.

"Traditionally, patients get chemotherapy, and then surgery, and then chemotherapy again. The reason we like to do that is that when you give chemotherapy and then resect the tumor, the pathologist can look at the tumor and assess whether the patient is responding to the chemotherapy. Most oncologists are reluctant to resect a tumor in advance without knowing how the patient is responding to chemotherapy," Dr. Lozano-Calderon says. "But if we have a patient who we know is at risk for fracture, who already has markers of poor prognosis, then we can implement a more organized way of treating them."

Developing a Clinical Prediction Tool

This same technology has been applied to other cancers, with success, he says.

"We have microRNA signatures that can predict whether patients with leukemia or colon cancer are going to respond to treatments, and there are models like these in lung cancer. So this is not a concept that we will have to prove. Now, it's about identifying the signatures and having enough patients to include in future research because osteosarcoma is rare."

The next steps will be to prove that surgery, followed by chemotherapy, does indeed improve outcomes. "We are planning to create a calculator that will be able to predict response to chemotherapy," he says. "Using artificial intelligence technology, the calculator will be able to learn from additional patient data, so that the more widely it is used, the more efficient it becomes."

"Using microRNA to determine which patients are going to do well with chemotherapy and which ones are not going to do well is going to be a very useful tool to develop more personalized and cost-effective protocols."

Learn more about the Orthopaedic Oncology Service

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