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

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.

Integrative genomic and transcriptomic analysis reveals immune subtypes and prognostic markers in ovarian clear cell carcinoma

“…We tried to get some hint from the coexistence of PIK3CA mutation and enrichment of PD-1 signalling in OCCC. In breast cancer, the PI3K pathway alterations might also be related to the high immune status [ 39 ]. In the exploratory analyses of a clinical trial of breast cancer, high CD8 infiltration was related to unfavourable survival and PI3K pathway alterations was correlated to the tumour microenvironment [ 40 ].…”

Genomic Signatures from Clinical Tumor Sequencing in Patients with Breast Cancer Having Germline BRCA1/2 Mutation

“…As two of the major cancer driver mutations, our findings provide an evidence for their mutual exclusiveness, consistent with previous studies [ 24 , 27 ]. A recent study also showed that breast cancer with altered phosphoinositide 3-kinase pathway harbors a significantly low rate of homologous recombination co-alterations [ 28 ]. In the future, we intend to explore the correlation between germline and somatic mutations using more genomic data from a larger sample size.…”

Biomineralization associated alkaline phosphatase as a potential marker of bone metastasis in the patients with invasive breast cancer

“…The physiological functions of ALPL include its effects on vascular endothelial cell growth factor, chondrocyte growth, apoptosis and MAPK signaling ( Nam et al, 2017 ). The biochemical interactions between ALPL and MAP4K1 , MAP4KAPK2 and PIK3C2b reflect the evident role of ALPL in MAPK and PI3K-Akt signaling pathways and these pathways also have well-established studies in breast cancer pathogenesis ( Han et al, 2017 , Bai et al, 2019 , Paplomata and O'Regan, 2014 , Jiang et al, 2020 , Khoury et al, 2020 ). Therefore, this study aimed to understand the role of ALP genes in relevance with breast cancer pathogenicity.…”