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Background:  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.   Methods:  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  PIK3CA-AKT1-PTEN  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.   Results:  Of 4,895 tumors profiled, 3,558 (72.7%) had at least one alteration in the  PIK3CA-AKT1-PTEN  pathway: 1,472 (30.1%) harbored a  PIK3CA  mutation, 174 (3.6%) an  AKT1  mutation, 2,682 (54.8%) had PTEN alterations ( PTEN  mutation in 7.0% and/or PTEN loss by IHC in 51.4% of cases), 81 (1.7%) harbored a  PIK3R1  mutation, and 4 (0.08%) a  PIK3R2  mutation. Most of the cohort consisted of metastatic sites ( n  = 2974, 60.8%), with  PIK3CA  mutation frequency increased in metastatic (32.1%) compared to primary sites (26.9%),  p  < 0.001. Other  PIK3CA  mutations were identified in 388 (7.9%) specimens, classified as “off-label,” as they were not included in the FDA-approved companion test for  PIK3CA  mutations. Notable co-alterations included increased PD-L1 expression and high tumor mutational burden in  PIK3CA-AKT1-PTEN  mutated cohorts. Novel concurrent mutations were identified including  CDH1  mutations.   Conclusions:  Findings from this cohort support further exploration of the clinical benefit of PI3K inhibitors for “off-label”  PIK3CA  mutations and combination strategies with potential clinical benefit for patients with breast cancer.

Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations and Co-alteration of Other Molecular Markers in Breast Cancer