P16, P21 Biomarkers Linked to Treatment Response in Osteosarcoma

C. Parker Gibbs, MD

The presence of the proteins p16 and p21 has shown to be predictive of treatment response in patients with osteosarcoma, a disease that previously had no identified biomarkers to indicate whether or not patients would benefit from therapy, explained C. Parker Gibbs, MD.

“We may finally have a way to predict how well a patient is going to do with osteosarcoma prior to initiating any therapy,” said Gibbs.

In a study, 104 patients with osteosarcoma were evaluated to determine if p16 and p21 expression are able to serve as predictive biomarkers for this patient population. All patients received standard neoadjuvant chemotherapy after initial diagnosis followed by surgical resection. Immunohistochemistry (IHC) for the cell cycle checkpoint regulator proteins p16 and p21 was performed on paraffin-embedded chemotherapy-naïve biopsy specimens.

The study showed that >90% expression of p16 in the initial biopsy is strongly related with good histologic response to neoadjuvant chemotherapy (P <.0001), a lower rate of metastasis (P = .0118), and a higher rate of survival (P = .0294).

Meanwhile, tumors that had p21 expression at <1% or >50% were related to poor chemotherapy—induced tumor necrosis (P = .025), a higher rate of metastatic disease (P = .002), and overall poor survival (P = .0305). Higher expression of both markers showed a stronger relationship to predicting necrotic response to chemotherapy, metastasis, and survival versus each biomarker alone.

Overall, the findings showed that p16 alone as well as p16 plus p21 combined are independent predictors of response to chemotherapy, overall survival (OS), and metastatic disease in patients with osteosarcoma.

In an interview with OncLive, Gibbs, a Eugene L. Jewett Professor of Orthopaedic Surgery, Division Chief of Orthopaedic Oncology and Chief Medical Officer of University of Florida Health Department of Orthopaedics and Rehabilitation College of Medicine, discussed the research behind p16 and p21 as predictive biomarkers for treatment response in patients with osteosarcoma.

OncLive: What are the current unmet needs of osteosarcoma?

Gibbs: Osteosarcoma is a highly malignant disease in both children and adolescents. Currently, there are very few prognostic markers to tell us how a child or an adolescent is going to do long-term after chemotherapy and surgery. The gold standard for predicting how well a patient will do with this disease is looking at the tumor after chemotherapy and after surgical resection to determine how necrotic the tumor is. We don't have a way to predict response to chemotherapy or risk of metastatic disease or death prior to the initiation of chemotherapy or surgery.

What are the findings of the study looking at p16 and p21 as predictive biomarkers?

Our study looked at 2 cell cycle checkpoint regulators—p21 and p16—that had previously shown promise for indicating biologic aggressiveness in our cell culture studies. When we looked at these 2 biologic markers in over 100 osteosarcoma cases, we found a strong correlation between their expression, metastatic disease, and OS in children and young adults with osteosarcoma. We believe this is a major advance because it gives us the opportunity to stratify patients going forward prior to therapy, as opposed to submitting them to terribly toxic chemotherapy upfront with no real indication of whether or not it will help them.

How does the testing of p16 and p21 occur?

The testing for p16 and p21 is done on the biopsy tissue. When a patient presents with osteosarcoma, we always do a surgical or a needle biopsy to obtain tissue to learn the diagnosis and how to treat it. Right now, we take a piece of that tissue and we stain it via IHC for p21 or p16, which are cell cycle checkpoint regulator proteins. We are able to determine what the relative risk of metastatic disease or death is in these patients by how much [these proteins] are expressed.

How can physicians implement this information into their practice?

The potential for including this information in individual surgeon or pediatric oncologist practice is that we may be able to change what chemotherapy drugs we offer upfront. Instead, we may offer surgery upfront rather than after chemotherapy, as well as counsel patients regarding how well they may or may not do, depending on the results of this test that we perform on the biopsy tissue. This is an early study and needs to move on to a much larger prospective analysis before I would incorporate it in daily practice.

What are the next steps of the study?

The next steps of the study are to incorporate other institutions to validate the statistical significance of our results across other groups of patients and the hands of other surgeons and oncologists.

Nasri E, Vasilopoulos T, Knapik J, et al. Cell cycle checkpoints p16 and p21 — strong predictors of clinicopathologic outcome in high-grade osteosarcoma. Presented at: 2019 Musculoskeletal Tumor Society Annual Meeting; October 2-4, 2019; Portland, OR. Abstract 37.