Background: While molecular alterations in PI3K pathway, including PIK3CA mutations, are common in HR+ breast cancer, molecular alterations in MAPK pathway, including KRAS and BRAF mutations, are considered rare in HR+ breast cancer. However, tumors can acquire new molecular alterations over time, and blood-based genotyping via circulating tumor DNA (ctDNA) could provide a more accurate molecular snapshot. Methods: This study analyzed data collected from metastatic breast cancer (MBC) patients who had genotyping (2016-2017) via a next generation sequencing-based (NGS) assay that detects ctDNA mutations (Guardant 360 panel), including alterations in MAPK pathway. Mutation profiles were also analyzed in tissue biopsies via SNaPshot-NGS, an institutional genotyping assay. Multivariate analysis was performed to evaluate the hazard ratio (HR) for the association between these mutations and time to progression (TTP), adjusting for key prognostic variables. Results: Among the HR+ MBC patients (N = 174), 25% (N = 44) were found to have molecular alterations in MAPK pathway in ctDNA, including mutations in BRAF (7.5%), KRAS (5.7%), NRAS (0.57%), MAP2K1 (1.1%) and NF-1 (14.4%); 14.5% had a concurrent PIK3CA mutation, 9.2% had a concurrent TP53 mutation, and multiple alterations were acquired. Among patients with MAPK molecular alterations versus not, there was no significant difference in baseline characteristics, including age at metastatic diagnosis (57 vs 55; p = 0.78) and visceral metastases (74% vs 81%; p = 0.87). In multivariate analysis, patients with MBC harboring MAPK molecular alterations had worse TTP (HR: 2.08; p = 0.02) compared to controls. However, there was no difference among those with PIK3CA mutant tumors versus not (HR: 1.09; p = 0.74). Conclusions: Molecular alterations in MAPK pathway, hitherto considered rare in primary HR+ breast cancer, are not uncommon in metastatic HR+ breast cancer and are associated with worse outcomes. The study highlights the value of blood-based assays for identification of novel targets and their potential clinical utility in development of genotype driven trials for patients with MBC.