Mutual exclusivity of ESR1 and TP53 mutations in endocrine resistant metastatic breast cancer

Abstract

Both TP53 and ESR1 mutations occur frequently in estrogen receptor positive (ER+) metastatic breast cancers (MBC) and their distinct roles in breast cancer tumorigenesis and progression are well appreciated. Recent clinical studies discovered mutual exclusivity between TP53 and ESR1 mutations in metastatic breast cancers; however, mechanisms underlying this intriguing clinical observation remain largely understudied and unknown. Here, we explored the interplay between TP53 and ESR1 mutations using publicly available clinical and experimental data sets. We first confirmed the robust mutational exclusivity using six independent cohorts with 1,056 ER+ MBC samples and found that the exclusivity broadly applies to all ER+ breast tumors regardless of their clinical and distinct mutational features. ESR1 mutant tumors do not exhibit differential p53 pathway activity, whereas we identified attenuated ER activity and expression in TP53 mutant tumors, driven by a p53-associated E2 response gene signature. Further, 81% of these p53-associated E2 response genes are either direct targets of wild-type (WT) p53-regulated transactivation or are mutant p53-associated microRNAs, representing bimodal mechanisms of ER suppression. Lastly, we analyzed the very rare cases with co-occurrences of TP53 and ESR1 mutations and found that their simultaneous presence was also associated with reduced ER activity. In addition, tumors with dual mutations showed higher levels of total and PD-L1 positive macrophages. In summary, our study utilized multiple publicly available sources to explore the mechanism underlying the mutual exclusivity between ESR1 and TP53 mutations, providing further insights and testable hypotheses of the molecular interplay between these two pivotal genes in ER+ MBC.

Genomic profiling and pre-clinical modelling of breast cancer leptomeningeal metastasis reveals acquisition of a lobular-like phenotype

“…Of note, there was a relative lack of ESR1 mutations detected in CSF cfDNA (1/21), despite fourteen patients having previously received aromatase inhibitor therapy ( Supplementary Table 1 ). This may reflect the mutual exclusivity of TP53 and ESR1 mutations in metastatic breast cancer 53 .…”

“…5; Supplementary Table 11 ). Although loss of ER expression is found in ∼25% of PDO derived from ER+ tumour samples, likely secondary to establishing PDO culture, reduced ER expression in metastases from ER+ primary breast cancers is also reported 44-46 , and linked to more frequent TP53 mutation in endocrine therapy-resistant metastatic diease 47 . Our BCLM samples showed higher rates of TP53 mutation and copy number loss in CSF cfDNA (12/21) than the primary tumour (6/18) ( Supplementary Fig.…”

Tumor Infiltrating Lymphocytes across Breast Cancer Subtypes: Current Issues for Biomarker Assessment

“…Lastly, the most intriguing data derive from the correlations between tumoral features and the immune landscape. In fact, TILs and immune-related genes in HR+/HER2-BC have been associated with a poor response to therapy with aromatase inhibitors as well as lower ESR1 expression levels, which are shown to be mutually exclusive with TP53 mutations in metastatic endocrine-resistant HR+/HER2-BC [58][59][60][61][62]. Furthermore, TP53 mutations are known to be more prevalent in HR+/HER2-BC with the PAM50-basal intrinsic subtype and are associated with a higher infiltration of CD8+ T cells and B cells [62,63].…”

“…In fact, TILs and immune-related genes in HR+/HER2-BC have been associated with a poor response to therapy with aromatase inhibitors as well as lower ESR1 expression levels, which are shown to be mutually exclusive with TP53 mutations in metastatic endocrine-resistant HR+/HER2-BC [58][59][60][61][62]. Furthermore, TP53 mutations are known to be more prevalent in HR+/HER2-BC with the PAM50-basal intrinsic subtype and are associated with a higher infiltration of CD8+ T cells and B cells [62,63]. Considering these data, the higher prevalence of TILs in the luminal B-like subtype, and the prognostic value of TILs in luminal-like BCs, TILs may be a marker of luminal-like BCs with an intrinsic basal subtype.…”

Association ofESR1germline variants withTP53somatic variants in breast tumors in a genome-wide study

“…Mutant TP53 is correlated with lower ESR1 gene expression which is thought to be due in part to TP53 binding to the ESR1 promoter to activate expression [85]. Mutant TP53 tumors have lower estrogen response signatures compared to TP53 wildtype tumors which may be caused by both decreased transcriptional activation of ESR1 by mutant TP53 and increased levels of ESR1-targeting miRNAs [84].…”