Dr Patel on the p53 IHC Positivity as Potential Surrogate for Multi-Hit TP53 Mutations in MDS and AML

"It is important to know this information because early identification of multi-hit TP53 might change the overall plan or the goals of care for a given patient. For example…patients [with multi-hit TP53 status] might benefit from expedited stem cell transplant or from just knowing this prognostic information early on."

Shyam A. Patel, MD, PhD, an associate professor at the University of Massachusetts Chan Medical School and a hematologist and oncologist at the UMass Memorial Medical Center, highlighted findings from a bootstrap analysis designed to determine the optimal p53 immunohistochemistry (IHC) positivity threshold that correlates with multi-hit TP53 mutational status in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).

The aim of this analysis was to assess whether IHC could serve as a surrogate marker for TP53 allelic state, thereby informing risk stratification and guiding early therapeutic decisions, Patel began.

Although the 2022 International Consensus Classification (ICC) provides a clinical framework for defining multi-hit TP53 status, it does not fully equate to biallelic TP53 disruption, he explained. Therefore, identifying a reproducible and accessible method to infer multi-hit status remains a clinical priority, Patel stated.

Findings from the study showed that, among 82 patients with concurrent IHC and next-generation sequencing (NGS) data, a p53 IHC positivity threshold of 7% was found to best correlate with multi-hit TP53 status, Patel reported. Furthermore, increasing p53 IHC positivity was associated with poorer overall survival, supporting its prognostic relevance. Notably, false-negative IHC results occurred exclusively in patients with sole TP53 nonsense or frameshift mutations, highlighting a potential limitation in the assay's sensitivity for certain mutation types.

Patel emphasized the clinical implications of early TP53 risk identification. Patients found to harbor multi-hit TP53 status may be candidates for expedited allogeneic stem cell transplant or other intensive interventions, he added. The ability to stratify patients based on a widely available and relatively low-cost assay like IHC could allow for earlier prognostic discussions and treatment planning, particularly in centers where comprehensive genomic testing may not be readily accessible, Patel noted. These findings support incorporating p53 IHC into initial diagnostic workflows for patients with suspected MDS or AML, Patel concluded.