Biomarker analysis of the MITO2 phase III trial of first-line treatment in ovarian cancer: predictive value of DNA-PK and phosphorylated ACC
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Francesco Perrone1,*, Gustavo Baldassarre2,*, Stefano Indraccolo3,*, Simona Signoriello4, Gennaro Chiappetta1, Franca Esposito5, Gabriella Ferrandina6, Renato Franco1,15, Delia Mezzanzanica7, Maura Sonego2, Elisabetta Zulato3, Gian F. Zannoni6, Vincenzo Canzonieri2, Giovanni Scambia6, Roberto Sorio2, Antonella Savarese8, Enrico Breda9, Paolo Scollo10, Antonella Ferro11, Stefano Tamberi12, Antonio Febbraro13, Donato Natale14, Massimo Di Maio1,16, Daniela Califano1, Giosuè Scognamiglio1, Domenica Lorusso7, Silvana Canevari7, Simona Losito1, Ciro Gallo4,** and Sandro Pignata1,**
1 Istituto Nazionale per lo Studio e la Cura dei Tumori - Fondazione G.Pascale, IRCCS, Napoli, Italy
2 Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy
3 Istituto Oncologico Veneto, IRCCS, Padova, Italy
4 Dipartimento di Salute Mentale, Fisica e Medicina Preventiva, Statistica Medica, Seconda Università, Napoli, Italy
5 Università di Napoli Federico II, Napoli, Italy
6 Catholic University, Roma, Italy
7 Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
8 Istituto Nazionale Tumori Regina Elena, IRCCS, Roma, Italy
9 Ospedale S. Giovanni Calibita Fatebenefratelli, Roma, Italy
10 Ospedale Cannizzaro, Catania, Italy
11 Ospedale S. Chiara, Trento, Italy
12 Ospedale Civile, Faenza, Italy
13 Ospedale Fatebenefratelli, Benevento, Italy
14 Ospedale S. Massimo, Penne (PE), Italy
15 Dipartimento di Salute mentale, Fisica e Medicina Preventiva, Anatomia Patologica, Seconda Università, Napoli Italy
16 Università degli Studi, Torino, Italy
* co-first author
** co-last author
Sandro Pignata, email:
Keywords: ovarian cancer, phase 3 clinical trial, predictive factors, pACC, DNA-PK
Received: June 11, 2016 Accepted: August 03, 2016 Published: September 15, 2016
Background: No biomarker is available to predict prognosis of patients with advanced ovarian cancer (AOC) and guide the choice of chemotherapy. We performed a prospective-retrospective biomarker study within the MITO2 trial on the treatment of AOC.
Patients and methods: MITO2 is a randomised multicentre phase 3 trial conducted with 820 AOC patients assigned carboplatin/paclitaxel (carboplatin: AUC5, paclitaxel: 175 mg/m², every 3 weeks for 6 cycles) or carboplatin/PLD-pegylated liposomal doxorubicin (carboplatin: AUC5, PLD: 30 mg/m², every 3 weeks for 6 cycles) as first line treatment. Sixteen biomarkers (pathways of adhesion/invasion, apoptosis, transcription regulation, metabolism, and DNA repair) were studied in 229 patients, in a tissue microarray. Progression-free and overall survival were analysed with multivariable Cox model.
Results: After 72 months median follow-up, 594 progressions and 426 deaths were reported; there was no significant difference between the two arms in the whole trial. No biomarker had significant prognostic value. Statistically significant interactions with treatment were found for DNA-dependent protein kinase (DNA-PK) and phosphorylated acetyl-coenzymeA carboxylase (pACC), both predicting worse outcome for patients receiving carboplatin/paclitaxel.
Conclusion: These data show that in presence of DNA-PK or pACC overexpression, carboplatin/paclitaxel might be less effective than carboplatin/PLD as first line treatment of ovarian cancer patients. Further validation of these findings is warranted.
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