F Guffanti1, M F Alvisi2, A Anastasia3, F Ricci1, M Chiappa1, A Llop-Guevara4, V Serra4, R Fruscio5, A Degasperi6,7, S Nik-Zainal6,7, M R Bani3, M Lupia8, R Giavazzi3, E Rulli2, G Damia9. 1. Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. 2. Laboratory of Methodology for Clinical Research, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. 3. Laboratory of Cancer Metastasis Therapeutics, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. 4. Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain. 5. Clinic of Obstetrics and Gynecology, Department of Medicine and Surgery, San Gerardo Hospital, University of Milan Bicocca, Monza, Italy. 6. MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK. 7. Academic Laboratory of Medical Genetics, Lv 6 Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Box 238, Cambridge, CB2 0QQ, UK. 8. Unit of Gynecological Oncology Research, European Institute of Oncology, Milan, Italy. 9. Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. giovanna.damia@marionegri.it.
Abstract
BACKGROUND: The search for biomarkers to evaluate ovarian cancer (OC) homologous recombination (HR) function and predict the response to therapy is an urgent clinical need to improve the selection of patients who could benefit from platinum- and olaparib (poly-ADP ribose polymerase inhibitors, PARPi)-based therapies. METHODS: We used a large collection of OC patient-derived xenografts (PDXs) (n = 47) and evaluated their HR status based on BRCA1/2 mutations, BRCA1 promoter methylation and the HRDetect score. RAD51 foci were quantified in formalin-fixed, paraffin-embedded untreated tumour specimens by immunofluorescence and the messenger RNA expression of 21 DNA repair genes by real-time PCR. RESULTS: Tumour HR deficiency predicted both platinum and olaparib responses. The basal level of RAD51 foci evaluated in geminin-positive/replicating cells strongly inversely correlated with olaparib response (p = 0.011); in particular, the lower the foci score, the greater the sensitivity to olaparib, while low RAD51 foci score seems to associate with platinum activity. CONCLUSIONS: The basal RAD51 foci score is a candidate predictive biomarker of olaparib response in OC patients as it can be easily translatable in a clinical setting. Moreover, the findings corroborate the importance of OC-PDXs as a reliable tool to identify and validate biomarkers of response to therapy.
BACKGROUND: The search for biomarkers to evaluate ovarian cancer (OC) homologous recombination (HR) function and predict the response to therapy is an urgent clinical need to improve the selection of patients who could benefit from platinum- and olaparib (poly-ADP ribose polymerase inhibitors, PARPi)-based therapies. METHODS: We used a large collection of OC patient-derived xenografts (PDXs) (n = 47) and evaluated their HR status based on BRCA1/2 mutations, BRCA1 promoter methylation and the HRDetect score. RAD51 foci were quantified in formalin-fixed, paraffin-embedded untreated tumour specimens by immunofluorescence and the messenger RNA expression of 21 DNA repair genes by real-time PCR. RESULTS: Tumour HR deficiency predicted both platinum and olaparib responses. The basal level of RAD51 foci evaluated in geminin-positive/replicating cells strongly inversely correlated with olaparib response (p = 0.011); in particular, the lower the foci score, the greater the sensitivity to olaparib, while low RAD51 foci score seems to associate with platinum activity. CONCLUSIONS: The basal RAD51 foci score is a candidate predictive biomarker of olaparib response in OC patients as it can be easily translatable in a clinical setting. Moreover, the findings corroborate the importance of OC-PDXs as a reliable tool to identify and validate biomarkers of response to therapy.
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