Abstract
Abstract Approximately 15-25% ovarian cancer (OC) patients carry germ-line mutation in BRCA1 or BRCA2 genes. BRCA deficiency underlies the pronounced sensitivity of tumor cells to platinum-containing cytotoxic therapy. However, significant variations in platinum sensitivity are observed even within BRCA1/2 mutation-driven carcinomas. It has been shown, that chemoresistant tumor tissues could be characterized by the restoration of the BRCA1 function via additional somatic genetic events. This investigation aimed to analyze the role of BRCA status within the group of patients receiving preoperative platinum-based therapy. We addressed the question, whether intratumoral LOH status of BRCA1 gene may be altered during neoadjuvant therapy. At first, we tested for Slavic founder BRCA mutations 225 ovarian cancer patients, who started their treatment with a few cycles of platinum-based therapy, and underwent debulking surgery afterwards. 34 BRCA1 and 1 BRCA2 mutation carriers were identified. Complete clinical response was documented in 12/35 (34%) mutation carriers and 8/190 (4%) non-carriers (P = 0.000002). Histopathologic response was observed in 16/35 (46%) women with the germ-line mutation versus 42/169 (25%) patients with the wild-type genotype (P = 0.02). Surprisingly, somatic loss of heterozygosity (LOH) for the remaining wild-type BRCA1 allele was detected only in 7/24 (29%) post-neoadjuvant therapy residual tumor tissues as compared to 9/11 (82%) BRCA1-associated OC, which were not exposed to systemic treatment before the surgery (P = 0.009). We hypothesize that the low frequency of LOH is related to the selection of tumor clones with somatically preserved BRCA1 gene during the therapy. We obtained for the LOH-analysis paired biological specimens from 8 patients; the pairs included cytological slides prepared at diagnosis and corresponding surgical material removed after neoadjuvant therapy. The restoration of BRCA1 heterozygosity was revealed in 4 out of 6 post-treatment tumor samples presenting with LOH at diagnosis. Another two ovarian carcinomas did not demonstrate somatic LOH before the treatment, and their status did not change during the neoadjuvant therapy. Thus, even though chemonaive OC specimens demonstrate somatic loss of the wild-type BRCA1 allele, the intratumoral BRCA1 heterozygosity could be restored in the platinum-exposed tissue, probably via expansion of LOH-negative clones. Conclusion: The obtained data confirm high sensitivity of BRCA-driven ovarian cancer to platinating agents and provide evidence for a rapid selection of tumor cell clones without LOH during the platinum-based therapy. Citation Format: Ekaterina Sh. Kuligina, Tatyana V. Gorodnova, Anna P. Sokolenko, Aleksandr O. Ivantsov, Aglaya G. Iyevleva, Evgeny N. Imyanitov. Accumulation of tumor cells with retained heterozygous BRCA1 status during platinum therapy: A probable mechanism of attenuation of tumor response in BRCA1-driven ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2928.
Published Version
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