Abstract B035: Cyclin E1 positive staining is frequent and independent of prior platinum treatment in high grade serous ovarian cancer
Authors: Olivier Harismendy, Heekyung Chung, Astha Bhatia, Adrian M. Jubb, Carrie Brownstein, Mark R. Lackner, Funda Meric-Bernstam, Joyce F. Liu
Journal: Cancer Research (2024)

Abstract High Grade Serous Ovarian Cancer (HGSOC) is characterized by high genomic instability, a consequence of high replication stress and inactivation of the G1/S checkpoint often via TP53 and/or CCNE1 alterations. Such alterations increase dependency on cell cycle checkpoints, creating a genetic vulnerability targetable via inhibition of the WEE1 kinase. Importantly, either CCNE1 amplification or high Cyclin E1 expression in the absence of amplification can contribute to this dependency. Cyclin E1 expression has been shown to predict progression free survival after treatment combining the WEE1 inhibitor azenosertib with chemotherapy1. Cyclin E1 high expression and CCNE1 amplification are also indicative of poor prognosis in HGSOC populations. However, the relationships between Cyclin E1 expression, CCNE1 copy number and clinical features, such as platinum (Plt) sensitivity, have not been extensively described in real world specimens. Tumor samples from 167 patients were obtained from an ongoing azenosertib clinical trial (ZN-c3-002, N=111) and procured samples (N=56). Cyclin E1 protein expression levels (H score) were measured using a validated immunohistochemistry assay and compared to CCNE1 copy number (N=141) or transcript abundance (N=49). Samples were classified as Cyclin E1+ (H&amp;gt;50, the previously reported predictive threshold in ZN-c3-002) or Cyclin E1-high (H&amp;gt;135, the lowest score obtained from samples with CCNE1 amplification). Cyclin E1 was evaluated in the context of patient clinical features at the time of tissue collection. Across all 167 samples, 153 (90%) were Cyclin E1+, of which 114 (60%) were Cyclin E1-high. Thirteen (9%) of the 141 samples evaluated for copy number were CCNE1-amplified. Eighty five percent (71/84) of Cyclin E1-high samples evaluable were not CCNE1-amplified. H score was highly correlated with CCNE1 transcript level (rho=0.5, p&amp;lt;1E-3). Of 108 patients with Plt treatment information available, 75 (69%) had specimens that were collected before or during initial Plt therapy (pre-Plt), while 33 (31%) had specimens collected at the time of recurrence after receiving prior Plt (post-Plt). The proportion of Cyclin E1+ samples collected from Pre-Plt and Post-Plt patients was 89% and 82%, respectively. Similarly, the proportion of Cyclin E1-high samples collected from Pre-Plt and Post-Plt patients was 61% and 45%, respectively. These proportions were not significantly different between the two groups (Fisher Exact Test, p=0.35 for Cyclin E1+, p=0.14 for Cyclin E1-high). Furthermore, HRR mutational status, tissue age or site of collection did not influence Cyclin E1 levels. The majority of CCNE1 non-amplified HGSOC samples express Cyclin E1 at a H score of 50 or at higher levels. Prior Plt treatment does not influence the proportion of HGSOC that are Cyclin E1+ or Cyclin E1-high, indicating that WEE1 inhibition with azenosertib may be broadly effective across ovarian cancer patients independent of Plt status. 1. Liu J, et al. J Clin Oncol. 2023;41 (Suppl 16; abstr 5513) Citation Format: Olivier Harismendy, Heekyung Chung, Astha Bhatia, Adrian M. Jubb, Carrie Brownstein, Mark R. Lackner, Funda Meric-Bernstam, Joyce F. Liu. Cyclin E1 positive staining is frequent and independent of prior platinum treatment in high grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B035.