Expression of the PI3K/AKT/mTOR pathway as a prognostic factor in patients with advanced high grade serous ovarian carcinoma treated with neoadjuvant chemotherapy

Background: The aim of this study was to search biomarkers in patients with high grade serous ovarian carcinoma (HGSOC) treated with neoadjuvant chemotherapy (NACT) among the components of PI3K/AKT/mTOR pathway. Material and Methods: The authors assessed 49 patients with HGSOC (FIGO IIIC-IV) treated with NACT. The expression of PI3KCA, PTEN, pAKT473, mTOR, and p70S6K were assessed immunohistochemically. Results: The expression of PI3KCA and p70S6K in tumour tissue after NACT was significantly decreased compared to before chemotherapy (p = 0.0005 and p = 0.0256, respectively). Multivariate analysis demonstrated that high mTOR expression, suboptimal range of interval debulking surgery (IDS), platinum resistance, and the lack of paclitaxel in the NACT were independent adverse prognostic factors (HR= 3.86, 95% CI (1.75-8.56); HR= 3.94, 95% CI (1.76-8.83); HR= 2.29, 95% CI (1.13-4.64); and HR= 4.76, 95% CI (1.80-12.59), p < 0.05). Conclusions: The mTOR expression may be an independent prognostic factor, but further investigations are needed.

High grade serous ovarian carcinoma; PI3K/AKT/mTOR pathway; Neoadjuvant chemotherapy

[1] ICancer Genome Atlas Research Network: “Integrated genomic analyses of ovarian carcinoma”. Nature, 2011, 474, 609.

[2] Mabuchi S., Kuroda H., Takahashi R., Sasano T.: “The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer”. Gynecol. Oncol., 2015, 137, 173.

[3] Dobbin Z.C, Landen C.N.: “The Importance of the PI3K/AKT/ MTOR Pathway in the Progression of Ovarian Cancer”. Int. J. Mol. Sci., 2013, 14, 8213.

[4] Sato S., Itamochi H.: “Neoadjuvant chemotherapy in advanced ovarian cancer: latest results and place in therapy”. Ther. Adv. Med. Oncol., 2014, 6, 293.

[5] Rutten M.J., Sonke G.S., Westermann A.M., van Driel W.J., Trum J.W., Kenter G.G., et al.: “Prognostic Value of Residual Disease after Interval Debulking Surgery for FIGO Stage IIIC and IV Epithelial Ovarian Cancer”. Obstet. Gynecol. Int., 2015, 2015, 464123.

[6] Wright A.A., Bohlke K., Armstrong D.K., Bookman M.A., Cliby W.A., Coleman R.L., et al.: “Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline”. Gynecol. Oncol., 2016, 143, 3.

[7] Eisenhauer E.A., Therasse P., Bogaerts J., Schwartz L.H., Sargent D., Ford R., et al.: “New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)”. Eur. J. Cancer Oxf. Engl., 1990, 2009, 45, 228.

[8] Janku F., Kaseb A.O., Tsimberidou A.M., Wolff R.A., Kurzrock R.: “Identification of novel therapeutic targets in the PI3K/AKT/mTOR pathway in hepatocellular carcinoma using targeted next generation sequencing”. Oncotarget, 2014, 5, 3012.

[9] Hirashima K., Baba Y., Watanabe M., Karashima R-I., Sato N., Imamura Y., et al.: “Aberrant activation of the mTOR pathway and antitumour effect of everolimus on oesophageal squamous cell carcinoma”. Br. J. Cancer, 2012, 106, 876.

[10] Trigka E.A., Levidou G., Saetta A.A., Chatziandreou I., Tomos P., Thalassinos N., et al.: “A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features”. Oncol. Rep., 2013, 30, 623.

[11] Bostner J., Karlsson E., Pandiyan M.J., Westman H., Skoog L., Fornander T., et al.: “Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit”. Breast Cancer Res. Treat., 2013, 137, 397.

[12] Mahdi H., Xiu J., Reddy S.K., DeBernardo R.: “Alteration in PI3K/mTOR, MAPK pathways and Her2 expression/amplification is more frequent in uterine serous carcinoma than ovarian serous carcinoma”. J. Surg. Oncol., 2015, 112, 188.

[13] Bakkar R.M., Xie S-S., Urbauer D.L., Djordjevic B., Vu K., Broaddus R.R.: “Intact PTEN Expression by Immunohistochemistry is Associated With Decreased Survival in Advanced Stage Ovarian/Primary Peritoneal High-grade Serous Carcinoma”. Int. J. Gynecol. Pathol., 2015, 34, 497.

[14] Wang L., Wang C., Jin S., Qu D., Ying H.: “Expression of NF-κB and PTEN in primary epithelial ovarian carcinoma and the correlation with chemoresistance”. Int. J. Clin. Exp. Pathol., 2015, 8, 10953.

[15] Lee Y-K., Park N-H.: “Prognostic value and clinicopathological significance of p53 and PTEN in epithelial ovarian cancers”. Gynecol. Oncol., 2009, 112, 475.

[16] No J.H., Jeon Y-T., Park I-A., Kim Y-B, .Kim J.W., Park N-H., et al.: “Activation of mTOR signaling pathway associated with adverse prognostic factors of epithelial ovarian cancer”. Gynecol. Oncol., 2011, 121, 8.

[17] Wang S., Sun Y., He A., Zheng C., Zheng X.: “Predictive value of phosphorylated mammalian target of rapamycin for disease-free survival in breast cancer patients receiving neoadjuvant chemotherapy”. Oncol. Lett., 2014, 8, 2642.

[18] Marques A.E.M., Elias S.T., Porporatti A.L., Castilho R.M., Squarize C.H., De Luca Canto G., et al.: “mTOR pathway protein immunoexpression as a prognostic factor for survival in head and neck cancer patients: a systematic review and meta-analysis”. J. Oral Pathol. Med., 2016, 45, 319.

[19] Xiao L, Wang YC, Li WS, Du Y. The role of mTOR and phosphop70S6K in pathogenesis and progression of gastric carcinomas: an immunohistochemical study on tissue microarray. J. Exp. Clin. Cancer Res. CR. 2009;28:152.