J Breast Cancer.  2017 Dec;20(4):321-326. 10.4048/jbc.2017.20.4.321.

Biomarkers of Everolimus Sensitivity in Hormone Receptor-Positive Breast Cancer

Affiliations
  • 1Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. drmafei@126.com

Abstract

Activation of the mammalian target of rapamycin (mTOR) signaling pathway is an important mechanism of resistance to endocrine therapy in breast cancer. Everolimus, an mTOR inhibitor, has been shown to increase the efficacy of endocrine therapy and overcome resistance to endocrine therapies. Clinical studies have suggested that everolimus combined with endocrine therapy prolongs progression-free survival in hormone receptor-positive breast cancer patients. However, because breast cancer includes a group of highly heterogeneous tumors, patients may have different responses to everolimus. Therefore, finding biomarkers that can predict a patient's positive response or resistance to everolimus is critical. Numerous preclinical studies have shown that PIK3CA/PTEN mutations are predictive of sensitivity to everolimus; however, clinical trials have not confirmed the correlation between mutation status and clinical response. KRAS or BRAF mutations can bypass the phosphatidylinositol 3-kinase pathway; therefore, mutations in KRAS or BRAF may lead to resistance to mTOR inhibitors, and preclinical studies have shown that PIK3CA mutant cells which also contain KRAS mutations are resistant to everolimus. However, there are no clinical data in breast cancer patients to support this conclusion. Therefore, large-scale clinical studies are needed to identify biomarkers of efficacy and resistance to everolimus.

Keyword

Biomarkers; Breast neoplasms; Everolimus

MeSH Terms

Biomarkers*
Breast Neoplasms*
Breast*
Disease-Free Survival
Everolimus*
Humans
Phosphatidylinositol 3-Kinase
Sirolimus
Biomarkers
Everolimus
Phosphatidylinositol 3-Kinase
Sirolimus

Figure

  • Figure 1 The PI3K/AKT/mTOR signaling pathway, showing cascading pathway activation and regulatory feedback loops. PI3K=phosphatidylinositol 3-kinase; mTOR=mammalian target of rapamycin; ER=estrogen receptor; IRS=insulin-receptor substrate; PTEN=phosphatase and tensin homolog; Erk=extracellular signal-regulated kinase; 4E-BPI=4E-binding protein 1; S6K1=ribosomal protein S6 kinase.


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