Biomarker analysis of the MITO2 phase III trial of first-line treatment in ovarian cancer: Predictive value of DNA-PK and phosphorylated ACC

// Francesco Perrone 1,* , Gustavo Baldassarre 2,* , Stefano Indraccolo 3,* , Simona Signoriello 4 , Gennaro Chiappetta 1 , Franca Esposito 5 , Gabriella Ferrandina 6 , Renato Franco 1,15 , Delia Mezzanzanica 7 , Maura Sonego 2 , Elisabetta Zulato 3 , Gian F. Zannoni 6 , Vincenzo Canzonieri 2 , Giovanni Scambia 6 , Roberto Sorio 2 , Antonella Savarese 8 , Enrico Breda 9 , Paolo Scollo 10 , Antonella Ferro 11 , Stefano Tamberi 12 , Antonio Febbraro 13 , Donato Natale 14 , Massimo Di Maio 1,16 , Daniela Califano 1 , Giosue Scognamiglio 1 , Domenica Lorusso 7 , Silvana Canevari 7 , Simona Losito 1 , Ciro Gallo 4,** and Sandro Pignata 1,** 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 Universita, Napoli, Italy 5 Universita 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 Universita, Napoli Italy 16 Universita degli Studi, Torino, Italy * co-first author ** co-last author Correspondence to: 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 Abstract 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.