Changes in Cyclin E1 expression and CCNE1 amplification in high-grade ovarian carcinomas post-PARP inhibitor exposure

Therapeutic options are limited for patients with high-grade ovarian carcinoma (HGOC) progressing after poly(adenosine diphosphate-ribose) polymerase-inhibitor (PARPi). WEE1/CDK2-inhibitors efficacy is under investigation in HGOC harbouring CCNE1 amplification/Cyclin E1 overexpression. However, Cyclin E1 expression evolution after PARPi has not been studied. We aimed to describe Cyclin E1 expression/CCNE1 copy number in post-PARPi HGOC samples and compare to paired samples from diagnosis and/or post-neoadjuvant chemotherapy (post-NACT).

Thirty-eight patients with available post-PARPi samples were included; paired samples from diagnosis (n = 26) and/or post-NACT (n = 24) were collected. Cyclin E1 expression was quantified using immunohistochemistry (IHC). CCNE1 copy number was evaluated using fluorescent in situ hybridisation (FISH).

Seventy-two percent (26/36) of HGOC were homologous recombination deficient. Intratumoral Cyclin E1 expression was homogenous in samples from synchronous but anatomically distinct tumour sites. However, Cyclin E1 expression increased significantly between diagnosis and progression post-PARPi (median H-score = 113 versus 163, respectively; p = 0.034). The proportion of Cyclin E1-high (H-score ≥ 150) tumours was 31% (8/26) at diagnosis, 42% (10/24) post-NACT, and increased significantly to 61% (23/38) post-PARPi (versus diagnosis; p = 0.024). In contrast, only 10% (2/20) of Cyclin E1-high HGOC exhibited CCNE1 amplification ( ≥ 8 CCNE1 copies).

Cyclin E1 expression in HGOC increases at post-PARPi progression, independently of CCNE1 amplification.