Abstract P2-01-09: Clinical impact of ESR1 mutation ctDNA on survival outcome is dependent on PI3KCA/TP53 ctDNA mutation status
Authors: Chen Tom Wei-Wu , Hsiao Wen , Dai Ming-Shen , Lin Ching-Hung , Chang Dwang-Ying , Chen I-Chun , Wang Ming-Yang , Huang Ling-Yi , Chang Shu-Han , Huang Shu-Min , Cheng Ann-Lii , Tan Kien Thiam , Lu Yen-Shen 
Published: March 2022

Abstract
Background: With more endocrine therapies- (ET) based treatment (tx) available, genomic markers that could assist in the prediction of tx outcome is critical. The role of ctDNA mutations in ER+/HER2- metastatic breast cancer (MBC) after prior ET is based on retrospective study results. Methods: ER+/HER2- MBC patients (pts) starting ET-based salvage tx were eligible (NCT04212702). Cell-free DNA (cfDNA) was extracted from plasma before tx, and prepared for next-generation sequencing (NGS) analysis. The targeted NGS for ctDNA included regions of the ESR1 ligand-binding domain, PIK3CA hotspot mutations, and TP53 DNA-bonding domain mutations. 96% of the samples were sequenced at an average depths &gt;10000x using the Ion Torrent platform. Progression-free survival (PFS) was defined from the start of the salvage tx to the date of progression. Results: From 2015/08 to 2020/05, a total of 163 pts treated with ET-based tx were prospectively enrolled. The median age was 60 (32-92). 13%, 15%, 48%, and 17% of pts received ET only, ET + CDK4/6 inhibitor, ET + everolimus, and ET + metronomic chemotherapy, respectively. Only 14 patients received fulvestrant as ET. The median level of recovered cfDNA was 38.5 ng (range 4.4-1935) and the level of cfDNA was significantly and inversely correlated with PFS (p = 0.0032). With mutation ctDNA ≥ 0.5% as a threshold for positive calling, 100 (61.3%), 41 (25.1%), and 25 (15.3) pts have at least one ESR1, PIK3CA, and TP53 mutation, respectively and 61 (37.4%) pts had &gt;1 ESR1 mutation genotypes. The median PFS of the cohort (n=163) was 8.3 mos (95% CI 5.7 – 11.1 mos). PIK3CA mutation (MT) in ctDNA was associated with a worse outcome in all patients (HR 1.91, 95% CI 1.20 to 3.04, p = 0.0064) and the subgroups of ET + everolimus (HR 2.20, 95% CI 1.10 – 4.39, p = 0.025) and ET + metronomic chemotherapy (HR 5.34, 95% CI 1.63- 17.54, p = 0.006). The presence of TP53 MT ctDNA was also associated with worse PFS (HR 1.81, p = 0.043, n = 163) but also exerted a poor prognostic impact in pts with wild type (WT) PIK3CA (HR 3.28, 95% CI 1.44 – 7.48, p = 0.0048). However, the variant allelic frequency (VAF) of PIK3CA MT (p = 0.0421), but not TP53 MT (p = 0.7723), had a inverse linear correlation with PFS. Surprisingly, pts with ESR1 MT had a better PFS as compared to ESR1 WT pts (HR 0.68 95% CI 0.46 – 0.99, p = 0.049). However, if the threshold for. variant calling was raised to 2%, then ESR1 MT (n= 52, 31.9%) vs WT pts had similar PFS (median PFS 8.6 vs 7.8 mos, HR 0.92, 95% CI 0.62-1.37, p = 0.69), suggesting that defining different VAF threshold of MT ESR1 may have divergent PFS impact. How ERS1 MT ctDNA affected PFS was dependent on PIK3CA/TP53 status. When either PIK3CA or TP53 MT ctDNA was present, the ESR1 MT ctDNA did not have any impact on PFS, regardless of VAF. In pts with WT PIK3CA/TP53, pts with ESR1 MT ctDNA VAF 0.5 – 2.0% had a significant better PFS as compared with triple WT pts (HR 1.9, p = 0.0035). Conclusion: Using a 3-gene panel for ctDNA testing with MT ctDNA ≥ 0.5% as a threshold for positive calling in ER+/HER2- MBC pts treated with ET-based tx, the presence of PIK3CA and TP53 mut in ctDNA conferred a worse prognosis. The positive prognostic impact of ESR1 was only noticeable in pts with PIK3CA and TP53 WT ctDNA, and the presence of a low VAF ESR1 MT ctDNA, which may suggest an ER denpendency, was significantly correlated with a better outcome.
Table 1.Median PFS of pts with and without PIK3CA, TP53 and ESR in ctDNAPopulation (n)Genotype(s)Median PFS (mos)Hazard Ratiop-valueAll (163)PIK3CA MT (41) vs. WT (122)(VAF ≥ 0.5%)5.4 vs. 10.31.910.0064TP53 MT (25) vs. WT (143)(VAF ≥ 0.5%)4.1 vs. 8.91.810.0439ESR1 MT vs. WT(VAF ≥ 0.5%)9.8 vs. 5.80.680.0493ET + everolimus (82)PIK3CA MT vs. WT(VAF ≥ 0.5%)2.8 vs. 5.92.200.0254PIK3CA and TP53 WT (106)WT vs ESR1 MT (VAF ≥ 0.5% - &lt; 2%)6 vs 15.61.910.0035WT vs ESR1 MT (VAF ≥ 2%)6 vs 121.360.355
Citation Format: Tom Wei-Wu Chen, Wen Hsiao, Ming-Shen Dai, Ching-Hung Lin, Dwang-Ying Chang, I-Chun Chen, Ming-Yang Wang, Ling-Yi Huang, Shu-Han Chang, Shu-Min Huang, Ann-Lii Cheng, Kien Thiam Tan, Yen-Shen Lu. Clinical impact of ESR1 mutation ctDNA on survival outcome is dependent on PI3KCA/TP53 ctDNA mutation status [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-01-09.