This study investigates the correlation between clinical features of estrogen receptor-positive breast cancer and somatic alterations using massively parallel sequencing of pretreatment tumor biopsies from patients in two neoadjuvant aromatase inhibitor therapy trials. Eighteen significantly mutated genes were identified, including five previously linked to hematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology, and low proliferation rates, while mutant TP53 was associated with the opposite pattern. Mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis revealed that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. The findings suggest that distinct phenotypes in estrogen receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumor biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.This study investigates the correlation between clinical features of estrogen receptor-positive breast cancer and somatic alterations using massively parallel sequencing of pretreatment tumor biopsies from patients in two neoadjuvant aromatase inhibitor therapy trials. Eighteen significantly mutated genes were identified, including five previously linked to hematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology, and low proliferation rates, while mutant TP53 was associated with the opposite pattern. Mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis revealed that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. The findings suggest that distinct phenotypes in estrogen receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumor biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.