AUTHOR=Khoury Katia , Tan Antoinette R. , Elliott Andrew , Xiu Joanne , Gatalica Zoran , Heeke Arielle L. , Isaacs Claudine , Pohlmann Paula R. , Schwartzberg Lee S. , Simon Michael , Korn W. Michael , Swain Sandra M. , Lynce Filipa 

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

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.01475

DOI=10.3389/fonc.2020.01475

ISSN=2234-943X

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