1024 - TP53 Mutations and Brain Metastases in Primary Breast Tumors: Insights from the MSK CHORD Cohort

Purpose/Objective(s):

Routine screening for brain metastases (BM) in breast cancer (BC) remains controversial, despite the significant morbidity and mortality associated with its development. Current international guidelines generally do not recommend routine brain MRI screening for asymptomatic patients. The incidence of BM varies substantially, occurring in approximately 10-50% of all BC patients, with HER2+ and triple-negative subtypes at highest risk. Identifying additional risk factors for BM could help refine risk stratification and inform more individualized surveillance and treatment strategies. We analyzed somatic mutations in primary breast tumors to identify predictors of BM.

Materials/Methods:

We analyzed initial stage I–III breast cancer patients from the MSK-CHORD (Clinicogenomic Harmonized Oncologic Real-World Dataset) cohort, which integrates primary tumor mutational sequencing data from the MSK-IMPACT targeted assay with annotated clinical data. Multivariable logistic regression was performed to assess the association of mutations with BM, adjusting for age, gender, race, smoking status, and histology.

Results:

The cohort consisted of 1,943 BC patients, comprised of predominantly females (98.8%) with a median age of 59 years, and a median follow-up of 63.8 months. Of these, 74% were White, and 64% were classified as never-smokers. Histologically, invasive ductal carcinoma comprised 77.3%, and invasive lobular carcinoma 10.2% of the cohort. Of the entire cohort 10.2% (n=198) developed BM. Of all mutations reported in this dataset, TP53 mutations were notably present in 39.2% of the cohort, with a statistically significant association between TP53 mutation status and the risk BM development (53.0% vs. 37.6%; p<0.001). On multivariable analysis, TP53 mutational status was found to be independently associated with BM development (OR 1.86, 95% CI 1.53–2.56, p<0.001).

Conclusion:

Beyond traditional clinicopathologic factors (tumor morphology, subtype, and disease burden), tumor genetics may also predict risk. In this large BC cohort, TP53 mutation was an independent predictor of BM. These findings may inform clinical decision-making, including CNS screening in high-risk patients. Earlier detection of limited BM may allow stereotactic radiosurgery instead of whole-brain radiation, improving local control while reducing cognitive toxicity. Further studies are needed to validate these findings and integrate molecular risk stratification into practice.