Abstract 4458: Clinical significance of PIK3CA and ESR1 mutations in ctDNA and FFPE samples from the MONARCH 2 study of abemaciclib plus fulvestrant
Authors: Tolaney Sara M. , Toi Masakazu , Neven Patrick , Sohn Joohyuk , Grischke Eva-Maria , Llombart-Cussac Antonio , Soliman Hatem , Litchfield Lacey M. , Wijayawardana Sameera , Forrester Tammy , Jansen Valerie M. , Sledge George W. 
Published: August 2019

Abstract
BACKGROUND: Mutations in PIK3CA and ESR1 have been implicated in resistance to endocrine therapy in HR+ metastatic breast cancer. Herein, we assessed the clinical significance of PIK3CA and ESR1 mutations from ctDNA and FFPE samples from patients treated with abemaciclib plus fulvestrant and placebo plus fulvestrant.
METHODS: Baseline plasma samples (n = 334) and FFPE tumor samples (n = 434) from 669 patients enrolled in MONARCH 2 were analyzed. Extracted DNA was analyzed by droplet digital PCR for four hotspot mutations of PIK3CA (E542K; E545K; H1047L; H1047R) and ESR1 (D538G; Y537C; Y537N; Y537S). Samples that failed DNA QC or where mutation status could not be determined were excluded from analysis.
RESULTS: PIK3CA mutations were detected in 96 (40.3%) of 238 plasma samples and 133 (39.9%) of 333 FFPE samples. H1047R was the most frequent mutation followed by E545K, E542K, and H1047L. The concordance of PIK3CA mutations in ctDNA and FFPE samples was 62.8%. ESR1 mutations were detected in 190 (64.4%) of 295 plasma samples and 15 (4.4%) of 344 FFPE samples. D538G was the most frequent mutation followed by Y537C, Y537N, and Y537S. The concordance of ESR1 mutations in ctDNA and FFPE samples was 37.1%; this rate of detection of ESR1 mutations in ctDNA and FFPE samples is explained in part by the site of the biopsy (primary vs metastatic). Co-mutations in PIK3CA and ESR1 were observed in 86 (36.1%) plasma and 5 (1.5%) FFPE samples. Finally, we examined the relationship of PIK3CA and ESR1 mutation status and benefit from abemaciclib therapy as shown in Table 1.
CONCLUSIONS: PIK3CA and ESR1 mutations in ctDNA but not in archived FFPE samples correlated with response to abemaciclib, confirming the potential use of ctDNA analysis. The addition of abemaciclib to fulvestrant in MONARCH 2 demonstrated improvement in PFS regardless of PIK3CA or ESR1 status; however, the magnitude of benefit was numerically greater for patients with tumors harboring PIK3CA/ESR1 mutations.
Table 1.Abemaciclib + FulvestrantPlacebo + FulvestrantMutation Status (Plasma)nMedian PFS (95% CI)nMedian PFS (95% CI)Hazard Ratio (95% CI)PIK3CA wild-type9120 (14, NA)5112.7 (7.9, NA)0.68 (0.42, 1.09)PIK3CA mutant5815 (9.4, NA)385.7 (3.8, 15)0.46 (0.27, 0.78)ESR1 wild-type7216.3 (12.4, 22.8)3311.6 (7.4, 23.1)0.69 (0.41, 1.18)ESR1 mutant11821.9 (15, NA)7210.3 (5.7, 15.6)0.49 (0.33, 0.73)
Citation Format: Sara M. Tolaney, Masakazu Toi, Patrick Neven, Joohyuk Sohn, Eva-Maria Grischke, Antonio Llombart-Cussac, Hatem Soliman, Lacey M. Litchfield, Sameera Wijayawardana, Tammy Forrester, Valerie M. Jansen, George W. Sledge. Clinical significance of PIK3CA and ESR1 mutations in ctDNA and FFPE samples from the MONARCH 2 study of abemaciclib plus fulvestrant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4458.