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 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.
Highlights
Phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway is dysregulated in various carcinomas including breast cancer, through several genomic abnormalities
We report the prevalence of PI3K pathway alterations and co-expression with other markers of clinical interest in different breast cancer subtypes, based on somatic molecular profiling
A retrospective review of molecular profiles was performed for 4,845 female and 50 male breast cancer cases submitted to Caris Life Sciences, a Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP)/ISO15189/New York State Department of Health (NYSDOH)-certified clinical laboratory (Phoenix, AZ), between January 2015 and June 2019
Summary
Phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway is dysregulated in various carcinomas including breast cancer, through several genomic abnormalities. Alpelisib (PIQRAY, Novartis Pharmaceuticals Corporation), a PI3K inhibitor, received FDA approval in combination with fulvestrant for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative PIK3CA-mutated advanced breast cancer. Approval was based on SOLAR-1, a phase 3 randomized trial that showed a benefit of 5.3 months in progression-free survival with the addition of alpelisib in the cohort of patients with PIK3CA-mutated breast cancer [12]. PIK3CA mutations that were considered for trial enrollment in SOLAR-1 included C420R, E542K, E545A, E545D (1635G > T only), E545G, E545K, Q546E, Q546R, H1047L, H1047R, and H1047Y. The FDA approved the therascreen R PIK3CA RGQ PCR Kit, (QIAGEN Manchester, Ltd.), a companion test able to select patients who have these specific mutations. We explored the prevalence of PI3K pathway alterations and co-expression with other markers in breast cancer subtypes
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