Clinical characteristics and outcomes of phase I cancer patients with CCNE1 amplification: MD Anderson experiences

Abstract

Cyclin E is frequently encoded by CCNE1 gene amplification in various malignancies. We reviewed the medical records of patients with solid tumors displaying CCNE1 amplification to determine the effect of this amplification for future therapeutic development. We reviewed the medical records of patients with advanced solid tumors harboring CCNE1 amplification who were seen at the phase I clinic between September 1, 2012, and December 31, 2019. Among 79 patients with solid tumors harboring CCNE1 amplification, 56 (71%) received phase 1 clinical trial therapy, 39 (49%) had 3 or more concurrent genomic aberrances, and 52 (66%) had a concurrent TP53 mutation. The median overall survival (OS) after patients’ initial phase I visit was 8.9 months and after their initial metastasis diagnosis was 41.4 months. We identified four factors associated with poor risk: age < 45 years, body mass index ≥ 25 kg/m2, presence of the TP53 mutation, and elevated LDH > upper limit of normal. In patients treated with gene aberration-related therapy, anti-angiogenic therapy led to significantly longer OS after their initial phase I trial therapy than those who did not: 26 months versus 7.4 months, respectively (P = 0.04). This study provided preliminary evidence that CCNE1 amplification was associated with frequent TP53 mutation and aggressive clinical outcomes. Survival benefit was observed in patients who received antiangiogenic therapy and gene aberration-related treatment, supporting the future development of a personalized approach to combine gene aberration-related therapy with antiangiogenesis for the treatment of advanced malignancies harboring CCNE1 amplification.

Club cell‐specific telomere protection protein 1 (TPP1) protects against tobacco smoke‐induced lung inflammation, xenobiotic metabolic dysregulation, and injurious responses

“…Cyclin E1, CCNE1, was significantly increased in TPP1 CreCC10 mice. CCNE1, the regulator of CDK, is amplified in malignant growths in 7.5% of tumor types 48 . These data suggest that CCNE amplification may be associated with malignancies we observed in TPP1 CreCC10 mice.…”

Investigation of evolutionary dynamics for drug resistance in 3D spheroid model system using cellular barcoding technology

“…Copy-number alteration (CNA) analysis using WES data in dabrafenib-resistant 3D-HT-29 spheroids, detected at least in two replicates, showed focal amplification of CCNE1 , NSD3 , RNF6 genes in comparison to DMSO-treated 3D-HT-29 spheroids ( Fig 4A–4C ) ( S6 Table ). As previously reported, CCNE1 amplification was detected in colorectal cancer patients and both increased and decreased expression of CCNE1 were found to be associated with drug resistance in colon cancer, depending on the therapeutics used [ 49 , 50 ]. Furthermore, the overexpression of NSD3 was observed in cancer types including colorectal cancer and it enhances the phosphorylation levels of ERK1/2 in CRC cell lines [ 51 , 52 ].…”

Multicenter Phase II Trial of the WEE1 Inhibitor Adavosertib in Refractory Solid Tumors Harboring CCNE1 Amplification

“…The traditional strategy of including unselected patients with cancer may not meet the challenges of the current landscape of early drug development. Further evaluation of adavosertib or other WEE1-directed therapy, alone or in combination with other therapeutic agents targeting concurrent gene aberrations, 44 is warranted in patients with advanced malignancies harboring CCNE1 amplification and TP53 aberration. Change From Baseline (%)…”