Rapid selection of BRCA1-proficient tumor cells during neoadjuvant therapy for ovarian cancer in BRCA1 mutation carriers. (1st July 2017)

• Record Type: Journal Article
• Authors: Sokolenko, Anna P.; Savonevich, Elena L.; Ivantsov, Alexandr O.; Raskin, Grigory A.; Kuligina, Ekatherina S.; Gorodnova, Tatiana V.; Preobrazhenskaya, Elena V.; Kleshchov, Maxim A.; Tiurin, Vladislav I.; Mukhina, Marina S.; Kotiv, Khristina B.; Shulga, Andrey V.; Kuznetsov, Sergey G.; Berlev, Igor V.; Imyanitov, Evgeny N.
• Is Part Of: Cancer letters. Volume 397(2017)
• Page Start: 127
• Page End: 132
• Publication Date: 2017-07-01
• Subjects: BRCA1 -- Ovarian cancer -- Neoadjuvant therapy -- Loss-of-heterozygosity -- Treatment resistance; HRM high-resolution melting -- IDS interval debulking surgery -- IHC immunohistochemistry -- LOH loss-of-heterozygosity -- NACT neoadjuvant chemotherapy -- OC ovarian carcinoma -- PDS primary debulking surgery -- SNP single nucleotide polymorphisms; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.03.036
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Ovarian carcinomas (OC) often demonstrate rapid tumor shrinkage upon neoadjuvant chemotherapy (NACT). However, complete pathologic responses are very rare and the mechanisms underlying the emergence of residual tumor disease remain elusive. We hypothesized that the change of somatic BRCA1 status may contribute to this process. The loss-of-heterozygosity (LOH) at the BRCA1 locus was determined for 23 paired tumor samples obtained from BRCA1 germ-line mutation carriers before and after NACT. We observed a somatic loss of the wild-type BRCA1 allele in 74% (17/23) of OCs before NACT. However, a retention of the wild-type BRCA1 copy resulting in a reversion of LOH status was detected in 65% (11/17) of those patients after NACT. Furthermore, we tested 3 of these reversion samples for LOH at intragenic BRCA1 single nucleotide polymorphisms (SNPs) and confirmed a complete restoration of the SNP heterozygosity in all instances. The neoadjuvant chemotherapy for BRCA1-associated OC is accompanied by a rapid expansion of pre-existing BRCA1-proficient tumor clones suggesting that continuation of the same therapy after NACT and surgery may not be justified even in patients initially experiencing a rapid tumor regression. Highlights: BRCA1-driven cancers are usually platinum-sensitive due to somatic loss of the remaining BRCA1 allele. Surgery for ovarian cancer is often preceded by neoadjuvant chemotherapy (NACT). This study shows that NACT results in a rapid selection of pre-existing BRCA1-proficient cells. The post-NACT residual tumor mass is composed of cells with retained BRCA1 heterozygosity. This may explain high relapse rates after adjuvant platinum therapy.