A whole-genome analysis of estrogen-receptor-positive breast cancer revealed significant mutations linked to treatment response to aromatase inhibitors. The study analyzed 77 tumor samples from two clinical trials, identifying 18 significantly mutated genes, including those previously associated with hematological disorders. Mutations in MAP3K1 were linked to luminal A status, low-grade histology, and low proliferation rates, while TP53 mutations were associated with the opposite pattern. GATA3 mutations were linked to reduced proliferation upon aromatase inhibitor treatment. Pathway analysis showed that mutations in MAP2K4, a MAP3K1 substrate, produced similar effects as MAP3K1 loss. The study found that distinct phenotypes in estrogen-receptor-positive breast cancer are associated with specific somatic mutations in cellular pathways related to tumor biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings would require comprehensive genome sequencing. The study also identified mutations in genes such as PIK3CA, TP53, GATA3, CDH1, and others, and found correlations between these mutations and clinical outcomes. The findings suggest that mutations in MAP3K1 may be a tumor suppressor, while TP53 mutations are associated with resistance to aromatase inhibitors. The study also identified druggable tyrosine kinase domains and provided insights into the genetic mechanisms underlying treatment response. The results highlight the importance of genomic analysis in understanding breast cancer and its response to aromatase inhibitors. The study was supported by various grants and institutions, and the findings have implications for the development of targeted therapies for breast cancer.A whole-genome analysis of estrogen-receptor-positive breast cancer revealed significant mutations linked to treatment response to aromatase inhibitors. The study analyzed 77 tumor samples from two clinical trials, identifying 18 significantly mutated genes, including those previously associated with hematological disorders. Mutations in MAP3K1 were linked to luminal A status, low-grade histology, and low proliferation rates, while TP53 mutations were associated with the opposite pattern. GATA3 mutations were linked to reduced proliferation upon aromatase inhibitor treatment. Pathway analysis showed that mutations in MAP2K4, a MAP3K1 substrate, produced similar effects as MAP3K1 loss. The study found that distinct phenotypes in estrogen-receptor-positive breast cancer are associated with specific somatic mutations in cellular pathways related to tumor biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings would require comprehensive genome sequencing. The study also identified mutations in genes such as PIK3CA, TP53, GATA3, CDH1, and others, and found correlations between these mutations and clinical outcomes. The findings suggest that mutations in MAP3K1 may be a tumor suppressor, while TP53 mutations are associated with resistance to aromatase inhibitors. The study also identified druggable tyrosine kinase domains and provided insights into the genetic mechanisms underlying treatment response. The results highlight the importance of genomic analysis in understanding breast cancer and its response to aromatase inhibitors. The study was supported by various grants and institutions, and the findings have implications for the development of targeted therapies for breast cancer.