Abstract P5-01-21: PIK3CA and ESR1 mutations detected in circulating tumor DNA (ctDNA) are predictive factors for late-line hormone-based therapies in ER+/HER2- metastatic breast cancer (MBC)
Authors: Tom Wei-Wu Chen, Ming-Shen Dai, Dwang-Ying Chang, Ching-Hung Lin, I-Chun Chen, Ming-Yang Wang, Ling-Yi Huang, An Hsu, De-Wei Zhuo, Kien Thiam Tan, Yen-Jung Lu, Shu-Han Chang, Ann-Lii Cheng, Yen-Shen Lu
Journal: Cancer Research (2020)

Abstract Background: With more hormonal therapies (HT) based treatment (tx) available, predictive markers that could lead to a selection of the optimal tx is necessary. The predictive role of ctDNA mutations in ER+/HER2- MBC after prior HT is less well characterized in Asian patients (pts). Methods: ER+/HER2- MBC pts starting HT based salvage tx after refractory to at least one-line of HT were eligible. ctDNA was extracted from pre- and post-tx plasma and prepared for next-generation sequencing (NGS) analysis. The targeted NGS mutations included regions of ESR1 ligand-binding domain, PIK3CA mutation hotspots, and TP53 mutation hotspots. 96% of the samples were sequenced at an average depths &amp;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 2019/04, a total of 129 and 70 pts treated with HT based tx had pre- and post-tx ctDNA tested, respectively. The median age is 60 (32-92). 14%, 7%, 55%, and 19% of pts received HT only, HT + CDK4/6 inhibitor, HT + everolimus, and HT + metronomic chemotherapy, respectively. With mutation ctDNA &amp;gt; 0.5% as a threshold for positive calling, 79 (61.2%), 33 (25.6%), and 23 (17.8%) pts have at least one ESR1, PIK3CA, and TP53 mutation, respectively and 48 (37.3%) pts have &amp;gt;1 ESR1 mutation genotypes. When compared to other clinical trial data, Asian ER+ MBC pts had significantly higher ESR1 mutation rate as compared to the Western population (p &amp;lt; 0.001) (Table 1). Detectable PIK3CA and TP53 mutation pre-tx was significantly (median PFS 9.8 vs 4.8 months (mos), p= 0.002) and marginally (median PFS 7.9 vs 5.2 mos, p = 0.08) associated with shorter PFS, respectively; but neither the presence of at least one single or multiple clones of ESR1 mutation(s) was associated with PFS (p = 0.52). Conversely, pts without any detectable ctDNA mutation had marginally better PFS (median 12.0 vs 6.5 mos, p = 0.051). With respect to the impact of each ESR1 mutation genotype, the presence of E380Q is associated with significantly shorter PFS (median PFS 7.9 vs 3.4 mos, p = 0.033) while Y537S, D538G, and Y537C were not. When the threshold for the positive calling of ctDNA was raised to 2.5%, ESR1 Y537S mutation became a significant factor for shorter PFS (median PFS 9.1 vs 4.4 mos, p = 0.041); PIK3CA remained as a significant factor for shorter PFS (median 9.3 vs 4.4 mos, p &amp;lt;0.001). In the HT + everolimus cohort (n = 71), PIK3CA mutation ctDNA remained as a poor PFS factor (median PFS 5.9 vs 2.6 mos, p = 0.01) but neither TP53 or ESR1 mutations were significantly associated with PFS. When pre- and post-treatment ctDNA were included in the analysis, the emergence of ESR1 mutations was associated with a better PFS (p = 0.05) while the loss of ESR1 mutations or gain/loss of PIK3CA mutations are not associated with PFS in the HT-treated cohort. Conclusion: PIK3CA and ESR1 Y537S and E380Q mutations detected by ctDNA had predictive impact for late-line HT based tx but PIK3CA mutation is a better predictor marker than ESR1 mutation in pts treated with HT + everolimus. Table 1 A comparison of the proportion and distribution of ESR1 mutation genotypes among the Taiwan cohort and other clinical trial studiesStudiesESR1 mutation (%)% of ESR1-positive patients withY537SD538GY537CPALOMA3 (n = 360) Fribbens et al. 201691(25.3)25565SoFEA (n = 161) Fribbens et al. 201663(39.1)25465FERGI (n = 156) Spoerke et al. 201657(37.3)33545Taiwan cohort (n = 129)79(61.2)538153 Citation Format: Tom Wei-Wu Chen, Ming-Shen Dai, Dwang-Ying Chang, Ching-Hung Lin, I-Chun Chen, Ming-Yang Wang, Ling-Yi Huang, An Hsu, De-Wei Zhuo, Kien Thiam Tan, Yen-Jung Lu, Shu-Han Chang, Ann-Lii Cheng, Yen-Shen Lu. PIK3CA and ESR1 mutations detected in circulating tumor DNA (ctDNA) are predictive factors for late-line hormone-based therapies in ER+/HER2- metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-01-21.