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Review
. 2016 Apr:45:87-96.
doi: 10.1016/j.ctrv.2016.03.004. Epub 2016 Mar 9.

New insights on PI3K/AKT pathway alterations and clinical outcomes in breast cancer

Sherry X Yang  1 , Eric Polley  2 , Stanley Lipkowitz  3
Affiliations
Review

New insights on PI3K/AKT pathway alterations and clinical outcomes in breast cancer

Sherry X Yang et al. Cancer Treat Rev. 2016 Apr.

Abstract

PI3K/AKT signaling pathway plays an important role in tumorigenesis and regulates critical cellular functions including survival, proliferation and metabolism. PIK3CA mutations and AKT activation by phosphorylation (pAKT) are often detected in many cancers and especially at high frequencies in breast cancer. Mounting data suggest that PIK3CA mutations or pAKT are mostly associated with better or insignificant outcomes in estrogen receptor-positive (ER+) early stage breast cancer and tend to be with worse prognosis in ER- disease. pAKT expression has been identified to predict paclitaxel chemotherapy benefit in node-positive breast cancer. Preclinical and neoadjuvant trial data suggest that PIK3CA alterations confer resistance to HER2-targeted therapy and are associated with lower pathological complete response (pCR) rate in HER2-positive breast cancer. However, recent results from randomized clinical trials of adjuvant and metastatic settings show that patients with mutant and wildtype PIK3CA tumors derived similar benefit from anti-HER2 therapy. This article, with our new insights, aims to decipher the mixed data and discusses the influence of the potential confounding factors in the assessments. We also share our views for validation of PI3K/AKT alterations in relation to clinical outcome in the context of specific breast cancer subtypes and treatment modalities towards further advance of the precision medicine for breast cancer treatment.

Keywords: Breast cancer; Chemotherapy; HER2; PIK3CA mutations; Paclitaxel; pAKT.

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Conflict of interest statement

Conflict of interest

Dr. Sherry Yang is one of the inventors on the United States National Institutes of Health patent – US 8,546,091 B2. Drs. Polley and Lipkowitz declare no conflicts of interest.

Figures

Fig. 1.
Fig. 1.
(A) ER and PI3K/AKT/mTOR signaling and endocrine therapy in ER+ early breast cancer. Schematic interaction of the two signaling pathways and dominant effects of adjuvant endocrine therapy on the cellular output and its overall impact within 10 years after surgery. Abbreviations: AI, aromatase inhibitors; DFS, disease-free survival; E2, estradiol; ERE, estrogen receptor element; OS, overall survival; PIP, phosphatidylinositol phosphate; RTK, receptor tyrosine kinase. (B) PI3K/AKT/mTOR signaling and chemotherapy in ER− early breast cancer. DNA damaging agents upregulate pAKT [20] that facilitates DNA repair, which may contribute to early recurrence [87]. Taxanes counteract AKT activity at certain extent [19,50,88]. Abbreviations: PIP, phosphatidylinositol phosphate; RTK, receptor tyrosine kinase.
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