1658P - Somatic loss of the wild-type BRCA1 allele is not necessarily the first event in the pathogenesis of hereditary ovarian cancer: implications for no...

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Ovarian Cancer
Familial Cancer
Gynaecologic Malignancies
Translational Research
Presenter Evgeny Imyanitov
Citation Annals of Oncology (2017) 28 (suppl_5): v573-v594. 10.1093/annonc/mdx390
Authors E. Imyanitov1, E. Savonevich2, A. Ivantsov1, G. Raskin3, E. Kuligina1, T. Gorodnova4, E. Preobrazhenskaya1, M. Kleshchov1, V. Tiurin1, A. Togo1, A. Sokolenko1
  • 1Department Of Tumor Biology, N.N. Petrov Institute of Oncology, 197758 - St.-Petersburg/RU
  • 2Department Of Obstetrics And Gynecology, Grodno State Medical University, 230023 - Grodno/BY
  • 3Department Of Pathology, Russian Research Centre for Radiology and Surgical Technologies, 197758 - St.-Petersburg/RU
  • 4Department Of Oncogynecology, N.N. Petrov Institute of Oncology, 197758 - St.-Petersburg/RU

Abstract

Background

Ovarian cancers (OC) arising in BRCA1 germ-line mutation carriers usually demonstrate high sensitivity to neoadjuvant chemotherapy (NACT), but almost inevitably relapse even after complete cytoreduction and continuation of systemic platinum treatment after surgery.

Methods

Changes in the somatic BRCA1 loss-of-heterozygosity (LOH) status were monitored in OC samples obtained before NACT, after NACT and at disease relapses.

Results

Loss of the wild-type BRCA1 allele was documented in 19 out 28 chemonaive OC samples included in the study. Surprisingly, 13 (68%) of these 19 OC demonstrated the retention of BRCA1 heterozygosity in the tumor tissue, which was surgically removed after median 3 cycles of NACT. TP53 mutations were easily detectable in some of the post-NACT samples thus confirming the good quality of microdissection. FISH assay and the analysis of adjacent SNPs revealed that the reversion of LOH status was attributed to selection of preexisting BRCA1-proficient clones but not to the second mutation in BRCA1 gene. Four tumor relapses were available for analysis; 3 out of these 4 tumors “restored” BRCA1 LOH during platinum-free interval. Next-generation sequencing analysis identified additional molecular events associated with evolution of OC clones upon platinum exposure and during treatment-free periods.

Conclusions

Isolated BRCA1 proficient cells are still present in chemonaive ovarian carcinomas with BRCA1 LOH, indicating that the somatic loss of the wild-type BRCA1 is not necessarily the first event in the pathogenesis of hereditary OC. These clones rapidly expand during even short-term systemic therapy. BRCA1-deficient cells have selective advantage in the absence of drug exposure and repopulate the tumor mass during platinum-free intervals. These fluctuations of BRCA1 LOH status explain why conventional platinum-based therapy, being capable to produce excellent tumor responses in BRCA1 germ-line mutation carriers, is not curative when considering long-term outcomes.

Clinical trial identification

Legal entity responsible for the study

Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, St.-Petersburg

Funding

Russian Scientific Fund (grant 14-25-00111)

Disclosure

All authors have declared no conflicts of interest.