Sara Gagno1, Mario Rosario D'Andrea2, Mauro Mansutti3, Chiara Zanusso1, Fabio Puglisi4, Eva Dreussi1, Marcella Montico5, Paola Biason6, Erika Cecchin1, Donatella Iacono3, Stefania Russo3, Marika Cinausero3, Silvana Saracchini7, Giampietro Gasparini2, Donata Sartori8, Mario Bari8, Elena Collovà9, Rosa Meo10, Ghassan Merkabaoui11, Ilaria Spagnoletti12, Arianna Pellegrino13, Lorenzo Gianni14, Paolo Sandri15, Elisabetta Cretella16, Emanuela Vattemi16, Andrea Rocca17, Patrizia Serra17, Maria Agnese Fabbri18, Giovanni Benedetti19, Laura Foghini20, Michele Medici21, Umberto Basso22, Vito Amoroso23, Ferdinando Riccardi24, Anna Maria Baldelli25, Mario Clerico26, Salvatore Bonura27, Chiara Saggia28, Federico Innocenti29, Giuseppe Toffoli30. 1. Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano, Italy. 2. Department of Oncology, San Filippo Neri Hospital, Rome, Italy. 3. Department of Oncology, University Hospital of Udine, Udine, Italy. 4. Medical Oncology and Cancer Prevention Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano, Italy; Medical Oncology, Department of Medicine, University of Udine, Udine, Italy. 5. Scientific Directorate, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano, Italy. 6. Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano, Italy; Medical Oncology Unit 1, Istituto Oncologico Veneto IOV IRCCS, Padova, Italy. 7. Medical Oncology Unit, Santa Maria degli Angeli Hospital, Pordenone, Italy. 8. Medical Oncology Department, General Hospital, Mirano, Italy. 9. Oncology Operative Unit, ASST Ovest Milanese, Ospedale di Legnano, Legnano, Italy. 10. Medical Oncology Unit, Presidio Ospedaliero Sant'Alfonso Maria dei Liguori, Cerreto Sannita, Italy. 11. Medical Oncology Unit, Azienda Ospedaliera Universitaria Federico II di Napoli, Napoli, Italy. 12. Medical Oncology Unit, Ospedale Sacro Cuore di Gesù, Fatebenefratelli, Benevento, Italy. 13. Medical Oncology Unit, Ospedale San Pietro Fatebenefratelli, Rome, Italy. 14. Department of Oncology, Infermi Hospital, Rimini, Italy. 15. Medical Oncology Unit, San Vito al Tagliamento Hospital, Pordenone, Italy. 16. Medical Oncology, Azienda Sanitaria dell'Alto Adige, Bolzano, Italy. 17. Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy. 18. Division of Oncology, Complesso Ospedaliero Belcolle, AUSL Viterbo, Viterbo, Italy. 19. Oncology Unit, Civitanova Marche Hospital, Macerata, Italy. 20. Oncology Unit, Macerata Hospital, Macerata, Italy. 21. Department of Medical Oncology, Azienda ULSS 3 Serenissima, Mestre, Italy. 22. Medical Oncology Unit 1, Istituto Oncologico Veneto IOV IRCCS, Padova, Italy. 23. Medical Oncology Unit, Spedali Civili Hospital, Brescia, Italy. 24. Medical Oncology Unit, Ospedale Cardarelli, Napoli, Italy. 25. Medical Oncology Unit, Azienda Ospedaliera Ospedali Riuniti Marche Nord, San Salvatore Hospital, Pesaro, Italy. 26. Department of Oncology, Ospedale degli Infermi, Biella, Italy. 27. Department of Oncology, Latisana Hospital, Latisana, Italy. 28. Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy. 29. University of North Carolina, Chapel Hill, NC. 30. Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano, Italy. Electronic address: gtoffoli@cro.it.
Abstract
INTRODUCTION: Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival. PATIENTS AND METHODS: Three hundred two locally advanced or MBC patients treated with first-line exemestane were genotyped for 74 germ line polymorphisms in 39 candidate genes involved in drug activity, hormone balance, DNA replication and repair, and cell signaling pathways. Associations with progression-free survival (PFS) and overall survival (OS) were tested with multivariate Cox regression. Bootstrap resampling was used as an internal assessment of results reproducibility. RESULTS: Cytochrome P450 19A1-rs10046TC/CC, solute carrier organic anion transporter 1B1-rs4149056TT, adenosine triphosphate binding cassette subfamily G member 2-rs2046134GG, fibroblast growth factor receptor-4-rs351855TT, and X-ray repair cross complementing 3-rs861539TT were significantly associated with PFS and then combined into a risk score (0-1, 2, 3, or 4-6 risk points). Patients with the highest risk score (4-6 risk points) compared with ones with the lowest score (0-1 risk points) had a median PFS of 10 months versus 26.3 months (adjusted hazard ratio [AdjHR], 3.12 [95% confidence interval (CI), 2.18-4.48]; P < .001) and a median OS of 38.9 months versus 63.0 months (AdjHR, 2.41 [95% CI, 1.22-4.79], P = .012), respectively. CONCLUSION: In this study we defined a score including 5 polymorphisms to stratify patients for PFS and OS. This score, if validated, might be translated to personalize locally advanced or MBC patient treatment and management.
INTRODUCTION: Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival. PATIENTS AND METHODS: Three hundred two locally advanced or MBCpatients treated with first-line exemestane were genotyped for 74 germ line polymorphisms in 39 candidate genes involved in drug activity, hormone balance, DNA replication and repair, and cell signaling pathways. Associations with progression-free survival (PFS) and overall survival (OS) were tested with multivariate Cox regression. Bootstrap resampling was used as an internal assessment of results reproducibility. RESULTS:Cytochrome P450 19A1-rs10046TC/CC, solute carrier organic anion transporter 1B1-rs4149056TT, adenosine triphosphate binding cassette subfamily G member 2-rs2046134GG, fibroblast growth factor receptor-4-rs351855TT, and X-ray repair cross complementing 3-rs861539TT were significantly associated with PFS and then combined into a risk score (0-1, 2, 3, or 4-6 risk points). Patients with the highest risk score (4-6 risk points) compared with ones with the lowest score (0-1 risk points) had a median PFS of 10 months versus 26.3 months (adjusted hazard ratio [AdjHR], 3.12 [95% confidence interval (CI), 2.18-4.48]; P < .001) and a median OS of 38.9 months versus 63.0 months (AdjHR, 2.41 [95% CI, 1.22-4.79], P = .012), respectively. CONCLUSION: In this study we defined a score including 5 polymorphisms to stratify patients for PFS and OS. This score, if validated, might be translated to personalize locally advanced or MBCpatient treatment and management.
Authors: Mona Khyri Alkasaby; Abeer Ibrahim Abd El-Fattah; Iman Hassan Ibrahim; Hesham Samir Abd El-Samie Journal: Pharmgenomics Pers Med Date: 2020-08-06