PI3K/AKT signaling pathway is activated in breast cancer and associated with cell survival. We explored the prevalence of PI3K pathway alterations and co-expression with other markers in breast cancer subtypes. Samples of non-matched primary and metastatic breast cancer submitted to a CLIA-certified genomics laboratory were molecularly profiled to identify pathogenic or presumed pathogenic mutations in the pathway using next generation sequencing. Cases with loss of PTEN by IHC were also included. The frequency of co-alterations was examined, including DNA damage response pathways and markers of response to immuno-oncology agents. Of 4,895 tumors profiled, 3,558 (72.7%) had at least one alteration in the pathway: 1,472 (30.1%) harbored a mutation, 174 (3.6%) an mutation, 2,682 (54.8%) had PTEN alterations ( mutation in 7.0% and/or PTEN loss by IHC in 51.4% of cases), 81 (1.7%) harbored a mutation, and 4 (0.08%) a mutation. Most of the cohort consisted of metastatic sites ( = 2974, 60.8%), with mutation frequency increased in metastatic (32.1%) compared to primary sites (26.9%), < 0.001. Other mutations were identified in 388 (7.9%) specimens, classified as "off-label," as they were not included in the FDA-approved companion test for mutations. Notable co-alterations included increased PD-L1 expression and high tumor mutational burden in mutated cohorts. Novel concurrent mutations were identified including mutations. Findings from this cohort support further exploration of the clinical benefit of PI3K inhibitors for "off-label" mutations and combination strategies with potential clinical benefit for patients with breast cancer.