Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations and Co-alteration of Other Molecular Markers in Breast Cancer
Katia Khoury, Antoinette R. Tan, Andrew Elliott, Joanne Xiu, Zoran Gatalica, Arielle L. Heeke, Claudine Isaacs, Paula R. Pohlmann, Lee S. Schwartzberg, Michael S. Simon, W. Michael Korn, Sandra M. Swain, Filipa Lynce
Abstract
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 4895 tumors profiled, 3558 (72.7%) had at least one alteration in the PIK3CA-AKT1-PTEN pathway: 1472 (30.1%) harbored a PIK3CA mutation, 174 (3.6%) an AKT1 mutation, 2682 (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.