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Open Access 01-12-2019 | Ovarian Cancer | Research

TOP2A as marker of response to pegylated lyposomal doxorubicin (PLD) in epithelial ovarian cancers

Authors: Eleonora Ghisoni, Furio Maggiorotto, Fulvio Borella, Gloria Mittica, Sofia Genta, Gaia Giannone, Dionyssios Katsaros, Alberto Sciarrillo, Annamaria Ferrero, Ivana Sarotto, Jessica Erriquez, Maria Flavia Di Renzo, Massimo Aglietta, Giorgio Valabrega

Published in: Journal of Ovarian Research | Issue 1/2019

Abstract

Objective

Relapsed epithelial ovarian cancer (EOC) is frequently treated with pegylated liposomal doxorubicin (PLD). Unfortunately, most patients do not benefit from treatment. Prediction of response is crucial to optimize PLD use and avoid unnecessary toxicities. We aimed at assessing the value of topoisomerase II alpha (TOP2A) expression as predictive marker of response to PLD-based therapy in patients with relapsed EOCs.

Methods

We retrospectively analyzed Formalin Fixed Paraffin Embedded (FFPE) tissues from 101 patients with platinum resistant (PR) or partially platinum-sensitive (PPS) EOCs treated with PLD-based chemotherapy beyond second line in three referral cancer centers between January 2010 and June 2018. TOP2A expression was measured by immunohistochemistry (IHC): images of each sample were acquired by optical microscope and analyzed by using automatic counter software. Correlation between TOP2A expression and response to PLD was assessed. Since no cut-off for positivity has been validated yet, we dichotomized TOP2A expression based on a cut-off of 18% (mean value in this study).

Results

TOP2A expression beyond cut-off was not prognostic for primary platinum-free interval in our series (p = 0.77) neither for optimal cytoreduction (p = 0.9). TOP2A > 18% was associated with a longer time to progression (TTP) following PLD-treatment, although not statistically significant (p = 0.394). No difference was observed between PR and PPS patients’ groups (p = 0.445 and p = 0.185, respectively). Not unexpectedly, patients with TOP2A expression > 18% treated with PLD monotherapy achieved a longer TTP compared with PLD-doublet therapy (p = 0.05).

Conclusions

Our data suggest that TOP2A status might predict activity of PLD in patients with PR/PPS EOCs.

Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66(4):271–89.PubMedCrossRef

Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl 6):vi24–32.PubMedCrossRef

Oza AM, Cook AD, Pfisterer J, Embleton A, Ledermann JA, Pujade-Lauraine E, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol. 2015;16(8):928–36.PubMedPubMedCentralCrossRef

Colombo N, Lorusso D, Scollo P. Impact of recurrence of ovarian Cancer on quality of life and outlook for the future. Int J Gynecol Cancer. 2017;27(6):1134–40.PubMedPubMedCentralCrossRef

du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d'Investigateurs Nationaux pour les etudes des cancers de l'Ovaire (GINECO). Cancer. 2009;115(6):1234–44.PubMedCrossRef

Karam A, Ledermann JA, Kim JW, Sehouli J, Lu K, Gourley C, et al. Fifth ovarian Cancer consensus conference of the gynecologic Cancer InterGroup: first-line interventions. Ann Oncol. 2017;28(4):711–7.PubMedCrossRef

Wilson MK, Pujade-Lauraine E, Aoki D, Mirza MR, Lorusso D, Oza AM, et al. Fifth ovarian Cancer consensus conference of the gynecologic Cancer InterGroup: recurrent disease. Ann Oncol. 2017;28(4):727–32.PubMed

Edwards SJ, Barton S, Thurgar E, Trevor N. Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for advanced recurrent or refractory ovarian cancer: a systematic review and economic evaluation. Health Technol Assess. 2015;19(7):1–480.PubMedPubMedCentralCrossRef

Lawrie TA, Bryant A, Cameron A, Gray E, Morrison J. Pegylated liposomal doxorubicin for relapsed epithelial ovarian cancer. Cochrane Database Syst Rev. 2013;7:CD006910.

10.

Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, et al. Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: overall survival analysis. Eur J Cancer. 2012;48(15):2361–8.PubMedCrossRef

11.

Bozkaya Y, Doğan M, Umut Erdem G, Tulunay G, Uncu H, Arık Z, et al. Effectiveness of low-dose oral etoposide treatment in patients with recurrent and platinum-resistant epithelial ovarian cancer. J Obstet Gynaecol. 2017;37(5):649–54.PubMedCrossRef

12.

Ferrandina G, Ludovisi M, Lorusso D, Pignata S, Breda E, Savarese A, et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol. 2008;26(6):890–6.PubMedCrossRef

13.

Krasner CN, Poveda A, Herzog TJ, Vermorken JB, Kaye SB, Nieto A, et al. Patient-reported outcomes in relapsed ovarian cancer: results from a randomized phase III study of trabectedin with pegylated liposomal doxorubicin (PLD) versus PLD alone. Gynecol Oncol. 2012;127(1):161–7.PubMedCrossRef

14.

Ferrandina G, Amadio G, Paris I, Distefano M, Palluzzi E, de Vincenzo R, et al. Real-world Management of Trabectedin/Pegylated liposomal doxorubicin in platinum-sensitive recurrent ovarian Cancer patients: a National Survey. Int J Gynecol Cancer. 2017;27(6):1141–8.PubMedCrossRef

15.

Nikolaou C, Bermúdez I, Manichanh C, García-Martinez J, Guigó R, Pérez-Ortín JE, et al. Topoisomerase II regulates yeast genes with singular chromatin architectures. Nucleic Acids Res. 2013;41(20):9243–56.PubMedPubMedCentralCrossRef

16.

Roca J. Topoisomerase II: a fitted mechanism for the chromatin landscape. Nucleic Acids Res. 2009;37(3):721–30.PubMedCrossRef

17.

Li D, Yuan Z, Chen S, Zhang C, Song L, Gao C, et al. Synthesis and biological research of novel azaacridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors. Bioorg Med Chem. 2017;25(13):3437–46.PubMedCrossRef

18.

Nitiss JL. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer. 2009;9(5):338–50.PubMedPubMedCentralCrossRef

19.

Petit T, Wilt M, Velten M, Millon R, Rodier JF, Borel C, et al. Comparative value of tumour grade, hormonal receptors, Ki-67, HER-2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. Eur J Cancer. 2004;40(2):205–11.PubMedCrossRef

20.

Durbecq V, Paesmans M, Cardoso F, Desmedt C, Di Leo A, Chan S, et al. Topoisomerase-II alpha expression as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel. Mol Cancer Ther. 2004;3(10):1207–14.PubMed

21.

Di Leo A, Biganzoli L, Claudino W, Licitra S, Pestrin M, Larsimont D. Topoisomerase II alpha as a marker predicting anthracyclines’ activity in early breast cancer patients: ready for the primetime? Eur J Cancer. 2008;44(18):2791–8.PubMedCrossRef

22.

Cardoso F, Di Leo A, Larsimont D, Gancberg D, Rouas G, Dolci S, et al. Evaluation of HER2, p53, bcl-2, topoisomerase II-alpha, heat shock proteins 27 and 70 in primary breast cancer and metastatic ipsilateral axillary lymph nodes. Ann Oncol. 2001;12(5):615–20.PubMedCrossRef

23.

Di Leo A, Desmedt C, Bartlett JM, Piette F, Ejlertsen B, Pritchard KI, et al. HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data. Lancet Oncol. 2011;12(12):1134–42.PubMedCrossRef

24.

Slamon DJ. Studies of the HER-2/neu proto-oncogene in human breast cancer. Cancer Investig. 1990;8(2):253.CrossRef

25.

Koshiyama M, Fujii H, Kinezaki M, Morita Y, Nanno H, Yoshida M. Immunohistochemical expression of topoisomerase IIalpha (topo IIalpha) and multidrug resistance-associated protein (MRP), plus chemosensitivity testing, as chemotherapeutic indices of ovarian and endometrial carcinomas. Anticancer Res. 2001;21(4B):2925–32.PubMed

26.

Faggad A, Darb-Esfahani S, Wirtz R, Sinn B, Sehouli J, Könsgen D, et al. Topoisomerase IIalpha mRNA and protein expression in ovarian carcinoma: correlation with clinicopathological factors and prognosis. Mod Pathol. 2009;22(4):579–88.PubMedCrossRef

27.

Annaratone L, Marchiò C, Russo R, Ciardo L, Rondon-Lagos SM, Goia M, et al. A collection of primary tissue cultures of tumors from vacuum packed and cooled surgical specimens: a feasibility study. PLoS One. 2013;8(9):e75193.PubMedPubMedCentralCrossRef

28.

Erriquez J, Becco P, Olivero M, Ponzone R, Maggiorotto F, Ferrero A, et al. TOP2A gene copy gain predicts response of epithelial ovarian cancers to pegylated liposomal doxorubicin: TOP2A as marker of response to PLD in ovarian cancer. Gynecol Oncol. 2015;138(3):627–33.PubMedCrossRef

29.

van der Zee AG, de Vries EG, Hollema H, Kaye SB, Brown R, Keith WN. Molecular analysis of the topoisomerase II alpha gene and its expression in human ovarian cancer. Ann Oncol. 1994;5(1):75–81.PubMedCrossRef

30.

Pujade-Lauraine E, Alexandre J. Update of randomized trials in recurrent disease. Ann Oncol. 2011;22(Suppl 8):viii61–viii4.PubMedCrossRef

31.

Previs RA, Bevis KS, Huh W, Tillmanns T, Perry L, Moore K, et al. A prognostic nomogram to predict overall survival in women with recurrent ovarian cancer treated with bevacizumab and chemotherapy. Gynecol Oncol. 2014;132(3):531–6.PubMedCrossRef

32.

Ejlertsen B, Jensen MB, Nielsen KV, Balslev E, Rasmussen BB, Willemoe GL, et al. HER2, TOP2A, and TIMP-1 and responsiveness to adjuvant anthracycline-containing chemotherapy in high-risk breast cancer patients. J Clin Oncol. 2010;28(6):984–90.PubMedCrossRef

33.

Farmer P, Bonnefoi H, Anderle P, Cameron D, Wirapati P, Becette V, et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med. 2009;15(1):68–74.PubMedCrossRef

34.

Durbecq V, Desmed C, Paesmans M, Cardoso F, Di Leo A, Mano M, et al. Correlation between topoisomerase-IIalpha gene amplification and protein expression in HER-2 amplified breast cancer. Int J Oncol. 2004;25(5):1473–9.PubMed

35.

Desmedt C, Di Leo A, de Azambuja E, Larsimont D, Haibe-Kains B, Selleslags J, et al. Multifactorial approach to predicting resistance to anthracyclines. J Clin Oncol. 2011;29(12):1578–86.PubMedCrossRef

Title: TOP2A as marker of response to pegylated lyposomal doxorubicin (PLD) in epithelial ovarian cancers
Authors: Eleonora Ghisoni
Furio Maggiorotto
Fulvio Borella
Gloria Mittica
Sofia Genta
Gaia Giannone
Dionyssios Katsaros
Alberto Sciarrillo
Annamaria Ferrero
Ivana Sarotto
Jessica Erriquez
Maria Flavia Di Renzo
Massimo Aglietta
Giorgio Valabrega
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Ovarian Cancer
Ovarian Cancer
Published in: Journal of Ovarian Research / Issue 1/2019
Electronic ISSN: 1757-2215
DOI: https://doi.org/10.1186/s13048-019-0492-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

TOP2A as marker of response to pegylated lyposomal doxorubicin (PLD) in epithelial ovarian cancers

Abstract

Objective

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objective

Methods

Results

Conclusions

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