Anna P Sokolenko1,2, Tatiana V Gorodnova3, Ilya V Bizin4, Ekaterina Sh Kuligina4, Khristina B Kotiv3, Alexandr A Romanko4, Tatiana I Ermachenkova4, Alexandr O Ivantsov4, Elena V Preobrazhenskaya4, Tatiana N Sokolova4, Robert V Broyde5, Evgeny N Imyanitov4,6,7. 1. Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, 197758, Russia. annasokolenko@mail.ru. 2. Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg, 194100, Russia. annasokolenko@mail.ru. 3. Department of Oncogynecology, N.N. Petrov Institute of Oncology, Saint-Petersburg, 197758, Russia. 4. Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, 197758, Russia. 5. City Cancer Center, Saint-Petersburg, 197758, Russia. 6. Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg, 194100, Russia. 7. Department of Oncology, I.I. Mechnikov North-Western Medical University, Saint-Petersburg, 191015, Russia.
Abstract
BACKGROUND: Patients with advanced high-grade serous ovarian cancer (HGSOC) are usually treated with paclitaxel and carboplatin; however, predictive markers for this drug combination are unknown. METHODS: Tumor samples from 71 consecutive HGSOC patients, who received neoadjuvant chemotherapy with paclitaxel and carboplatin, were subjected to molecular analysis. RESULTS: BRCA1/2 germline mutation carriers (n = 22) had longer treatment-free interval (TFI) than non-carriers (n = 49) (9.5 months vs. 3.8 months; P = 0.007). Fifty-one HGSOCs had sufficient quality of tumor DNA for the next-generation sequencing (NGS) analysis by the SeqCap EZ CNV/LOH Backbone Design panel. All 13 tumors obtained from BRCA1/2 germline mutation carriers and 12 sporadic HGSOCs showed a high number of evenly spread chromosomal breaks, which was defined as a BRCAness phenotype; median TFI for this combined group approached 9.5 months. The remaining 26 HGSOCs had similarly high global LOH score (above 20%); however, in contrast to BRCAness tumors, LOH involved large chromosomal segments; these patients had significantly lower TFI (3.7 months; P = 0.006). All patients with CCNE1 amplification (n = 7), TP53 R175H substitution (n = 6), and RB1 mutation (n = 4) had poor response to paclitaxel plus carboplatin. CONCLUSION: This study describes a cost-efficient method of detecting the BRCAness phenotype, which is compatible with the laboratory-scale NGS equipment. Some molecular predictors allow the identification of potential non-responders to paclitaxel plus carboplatin, who may need to be considered for other treatment options.
BACKGROUND: Patients with advanced high-grade serous ovarian cancer (HGSOC) are usually treated with paclitaxel and carboplatin; however, predictive markers for this drug combination are unknown. METHODS: Tumor samples from 71 consecutive HGSOC patients, who received neoadjuvant chemotherapy with paclitaxel and carboplatin, were subjected to molecular analysis. RESULTS: BRCA1/2 germline mutation carriers (n = 22) had longer treatment-free interval (TFI) than non-carriers (n = 49) (9.5 months vs. 3.8 months; P = 0.007). Fifty-one HGSOCs had sufficient quality of tumor DNA for the next-generation sequencing (NGS) analysis by the SeqCap EZ CNV/LOH Backbone Design panel. All 13 tumors obtained from BRCA1/2 germline mutation carriers and 12 sporadic HGSOCs showed a high number of evenly spread chromosomal breaks, which was defined as a BRCAness phenotype; median TFI for this combined group approached 9.5 months. The remaining 26 HGSOCs had similarly high global LOH score (above 20%); however, in contrast to BRCAness tumors, LOH involved large chromosomal segments; these patients had significantly lower TFI (3.7 months; P = 0.006). All patients with CCNE1 amplification (n = 7), TP53 R175H substitution (n = 6), and RB1 mutation (n = 4) had poor response to paclitaxel plus carboplatin. CONCLUSION: This study describes a cost-efficient method of detecting the BRCAness phenotype, which is compatible with the laboratory-scale NGS equipment. Some molecular predictors allow the identification of potential non-responders to paclitaxel plus carboplatin, who may need to be considered for other treatment options.
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