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FEATURED , Genetics , Genomics , Genetic Testing

Alan Stolier, MD/

Mutation Predicts Survival but only in ER-positive Patients

IMPLICATIONS OF TP53 SOMATIC MUTATIONS ARE MOLECULAR SUBTYPE SPECIFIC

MIGHT SYSTEMIC THERAPY IMPAIR THE SUCCESS OF IMMUNOTHERAPY

The somatic mutation TP53—in addition to being critical in maintaining the stability of the genome-- has been known to be a strong prognostic marker in breast cancer; however, since prior studies have been small, the effects of somatic TP53 mutations have not been understood. In a research article published in Clinical Cancer Research, the authors were able to study somatic TP53 mutations in 1420 patients with breast cancer using the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) database in order to better understand the impact of prognosis based on TP53.

The researchers used the PAM50 test to determine the molecular subtypes and found that the subtypes with the highest frequency of TP53 mutations were basal-like (65%) and Her2-enriched (53.4%). The ER positive subtypes Luminal B (24.8%) and A (9.3%) had fewer TP53 mutations.  

They found that patients with somatic TP53 mutations had a significantly inferior breast cancer specific survival but what was interesting is that when stratified, the prognostic effect of TP53 was limited to ER-positive disease. Essentially TP53 status is an independent predictor of survival only in ER-positive patients. Furthermore, no survival effect was noted in either basal-like or luminal A tumors.

As seen in this and other studies, basal-like tumors such as BRCA were frequently mutated and one might have thought that the high frequency of TP53 mutations would be associated with a worse prognosis. Yet the TP53 mutations were not prognostic for this subtype, which was an unexpected result. The authors contend that the abrogation of the TP53 pathway is “an early, initiating and required event in most basal-like tumors.” It remains unknown as to whether TP53 invokes an immune response in ER negative tumors or whether the immune response is only effective against wild-type tumors.

In conclusion, this is one of the largest studies in the literature of TP53 mutations in breast cancer showing an impact on TP53 mutations on prognosis; but interestingly, it is limited only to ER-positive disease.

 

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