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

• Yi Z
• Ma F

• KMID: 2398200
• DOI: http://doi.org/10.4048/jbc.2017.20.4.321

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.

Reference

1. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016; 66:115–132.

2. Torre LA, Sauer AM, Chen MS Jr, Kagawa-Singer M, Jemal A, Siegel RL. Cancer statistics for Asian Americans, Native Hawaiians, and Pacific Islanders, 2016: converging incidence in males and females. CA Cancer J Clin. 2016; 66:182–202.

3. Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ, Cao X, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013; 45:1446–1451.

4. Ma CX, Reinert T, Chmielewska I, Ellis MJ. Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer. 2015; 15:261–275.

5. Paplomata E, O'Regan R. The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers. Ther Adv Med Oncol. 2014; 6:154–166.

6. Margariti N, Fox SB, Bottini A, Generali D. “Overcoming breast cancer drug resistance with mTOR inhibitors”. Could it be a myth or a real possibility in the short-term future? Breast Cancer Res Treat. 2011; 128:599–606.

7. Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013; 30:870–884.

8. Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Lebrun F, Ito Y, et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2†. Ann Oncol. 2014; 25:2357–2362.

9. Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012; 30:2718–2724.

10. Wander SA, Hennessy BT, Slingerland JM. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J Clin Invest. 2011; 121:1231–1241.

11. Villarreal-Garza C, Cortes J, Andre F, Verma S. mTOR inhibitors in the management of hormone receptor-positive breast cancer: the latest evidence and future directions. Ann Oncol. 2012; 23:2526–2535.

12. Dhillon S. Everolimus in combination with exemestane: a review of its use in the treatment of patients with postmenopausal hormone receptor-positive, HER2-negative advanced breast cancer. Drugs. 2013; 73:475–485.

13. Ahmad F, Badwe A, Verma G, Bhatia S, Das BR. Molecular evaluation of PIK3CA gene mutation in breast cancer: determination of frequency, distribution pattern and its association with clinicopathological findings in Indian patients. Med Oncol. 2016; 33:74.

14. Kalinsky K, Jacks LM, Heguy A, Patil S, Drobnjak M, Bhanot UK, et al. PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res. 2009; 15:5049–5059.

15. Cizkova M, Susini A, Vacher S, Cizeron-Clairac G, Andrieu C, Driouch K, et al. PIK3CA mutation impact on survival in breast cancer patients and in ERalpha, PR and ERBB2-based subgroups. Breast Cancer Res. 2012; 14:R28.

16. Barbareschi M, Buttitta F, Felicioni L, Cotrupi S, Barassi F, Del Grammastro M, et al. Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res. 2007; 13:6064–6069.

17. Pérez-Tenorio G, Alkhori L, Olsson B, Waltersson MA, Nordenskjöld B, Rutqvist LE, et al. PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res. 2007; 13:3577–3584.

18. Zagouri F, Sergentanis TN, Chrysikos D, Filipits M, Bartsch R. mTOR inhibitors in breast cancer: a systematic review. Gynecol Oncol. 2012; 127:662–672.

19. Shtivelband MI. Everolimus in hormone receptor-positive advanced breast cancer: targeting receptor-based mechanisms of resistance. Breast. 2013; 22:405–410.

20. Awada A, Cardoso F, Fontaine C, Dirix L, De Grève J, Sotiriou C, et al. The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer: results of a phase I study with pharmacokinetics. Eur J Cancer. 2008; 44:84–91.

21. Massarweh S, Romond E, Black EP, Van Meter E, Shelton B, Kadamyan-Melkumian V, et al. A phase II study of combined fulvestrant and everolimus in patients with metastatic estrogen receptor (ER)-positive breast cancer after aromatase inhibitor (AI) failure. Breast Cancer Res Treat. 2014; 143:325–332.

22. Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008; 68:8022–8030.

23. Gonzalez-Angulo AM, Blumenschein GR Jr. Defining biomarkers to predict sensitivity to PI3K/Akt/mTOR pathway inhibitors in breast cancer. Cancer Treat Rev. 2013; 39:313–320.

24. Janku F, Wheler JJ, Westin SN, Moulder SL, Naing A, Tsimberidou AM, et al. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol. 2012; 30:777–782.

25. Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009; 27:2630–2637.

26. Treilleux I, Arnedos M, Cropet C, Wang Q, Ferrero JM, Abadie-Lacourtoisie S, et al. Translational studies within the TAMRAD randomized GINECO trial: evidence for mTORC1 activation marker as a predictive factor for everolimus efficacy in advanced breast cancer. Ann Oncol. 2015; 26:120–125.

27. Hortobagyi GN, Chen D, Piccart M, Rugo HS, Burris HA 3rd, Pritchard KI, et al. Correlative analysis of genetic alterations and everolimus benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from BOLERO-2. J Clin Oncol. 2016; 34:419–426.

28. Helwick C. Search for biomarkers of mTOR inhibitor benefit in breast cancer fails to pan out. ASCO Post;Accessed October 17th, 2017. http://www.ascopost.com/issues/july-10-2013/search-for-biomarkers-of-mtor-inhibitor-benefit-inbreast-cancer-fails-to-pan-out.aspx.

29. Moynahan ME, Chen D, He W, Sung P, Samoila A, You D, et al. Correlation between PIK3CA mutations in cell-free DNA and everolimus efficacy in HR(+), HER2(−) advanced breast cancer: results from BOLERO-2. Br J Cancer. 2017; 116:726–730.

30. Hong DS, Bowles DW, Falchook GS, Messersmith WA, George GC, O'Bryant CL, et al. A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2012; 18:4173–4182.

31. O'Brien C, Wallin JJ, Sampath D, GuhaThakurta D, Savage H, Punnoose EA, et al. Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models. Clin Cancer Res. 2010; 16:3670–3683.

32. Hurvitz SA, Kalous O, Conklin D, Desai AJ, Dering J, Anderson L, et al. In vitro activity of the mTOR inhibitor everolimus, in a large panel of breast cancer cell lines and analysis for predictors of response. Breast Cancer Res Treat. 2015; 149:669–680.

33. Johannessen CM, Reczek EE, James MF, Brems H, Legius E, Cichowski K. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci U S A. 2005; 102:8573–8578.

34. Lim SM, Park HS, Kim S, Kim S, Ali SM, Greenbowe JR, et al. Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus. Oncotarget. 2016; 7:10547–10556.

35. Chandarlapaty S, Sung P, Chen D, He W, Samoila A, You D, et al. cfDNA analysis from BOLERO-2 plasma samples identifies a high rate of ESR1 mutations: exploratory analysis for prognostic and predictive correlation of mutations reveals different efficacy outcomes of endocrine therapy-based regimens. In : 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium; 2015. Abstract #S2-07.

36. Breuleux M, Klopfenstein M, Stephan C, Doughty CA, Barys L, Maira SM, et al. Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition. Mol Cancer Ther. 2009; 8:742–753.

37. O'Reilly T, McSheehy PM. Biomarker development for the clinical activity of the mTOR inhibitor everolimus (RAD001): processes, limitations, and further proposals. Transl Oncol. 2010; 3:65–79.

38. Di Nicolantonio F, Arena S, Tabernero J, Grosso S, Molinari F, Macarulla T, et al. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest. 2010; 120:2858–2866.

39. Mahoney CL, Choudhury B, Davies H, Edkins S, Greenman C, van Haaften G, et al. LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition. Br J Cancer. 2009; 100:370–375.

40. Zunder ER, Knight ZA, Houseman BT, Apsel B, Shokat KM. Discovery of drug-resistant and drug-sensitizing mutations in the oncogenic PI3K isoform p110 alpha. Cancer Cell. 2008; 14:180–192.