Comprehensive mapping elucidates high risk genotypes in primary metastatic breast cancer.

Among women with primary metastatic breast cancer (pMBC), around 5 % of women with primary invasive breast cancer, high-risk mutations associated with disease progression and poor prognosis is shown. The heterogeneity and clinical implications of these genomic alterations remains to be fully elucidated. We performed comprehensive gene mapping on 211 tumors of women diagnosed with pMBC at Rigshospitalet 2014-2021. After DNA purification 203 tumor samples were eligible for analysis. Median age in our cohort was 69 years, 68 % were ER-positive/HER2-negative, 23 % HER2-positive and 9 % triple-negative. A high tumor mutational burden (TMB), shown in 10 %, was in univariable analysis associated with a poor prognosis and a median overall survival of 5.3 months (95 % CI, 2.5-51.3) but no significant association after adjusting for subtype and age. 65 % of tumors had an actionable biomarker, including a PIK3CA mutation in 39 %. TP53 mutations were found in 33 % of tumors and were associated with an increased risk of death (adjusted HR: 1.60, 95 % CI; 1.07-2.40). We have found that for women with pMBC, the disease is driven by several targetable genetic mutations across subtypes, however our results suggest a reduced prognostic value of TMB for this complex patient group. Taken together, our findings substantiate the value of early genomic profiling to actively identify women that may be eligible for a more individualized treatment scheme.