In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P2-01-04-P2-01-04
Abstract:
Introduction: Metastatic breast cancer (MBC) is a challenging clinical condition because most tumors will develop resistance to endocrine treatment as the cancer progresses. We previously reported the correlation of ESR1 mutations in circulating tumor DNA (ctDNA) and CTCs resulted in worse prognosis in MBC (ASCO-2020). In this study, we report a new finding that specific hotspots of ESR1 ctDNA mutations are associated with endocrine therapy resistance status in MBC and their allele frequency (AF) can be used to monitor response. . Methods: Plasma cfDNA were collected from a total of 299 MBC patients (2016-2019) after informed consent under an IRB-approved trial at the Lurie Cancer Center at Northwestern University. ER+ patients are 180 out of 297 (61%). Patients with HR+ MBC were evaluated before endocrine therapy (Anastrozole, Exemestane and Letrozole ) +/- CDK4/6 inhibitors (Palbociclib, Ribociclib, Abemaciclib), and every six months after initiation of therapy. Response to therapy was recorded according to the different time points. Endocrine resistance is defined as relapse during the first 2 years of adjuvant endocrine therapy or progressive disease within the first 6 months of first-line endocrine therapy for metastatic breast cancer. Plasma ctDNA was isolated using a Qiagen circulating nucleic acid kit, and then was analyzed using the Guardant360 Health next-generation sequencing (NGS)-based assay (Guardant Health). In this study, only patients with ESR1 mutations were included for statistical analyses of correlation between the hotspots mutation with the endocrine therapy resistance by using Causal Inference approach. All statistical analyses were conducted Mann-Whitney U test by IBM SPSS version 23.0. Results: There were total of 239 ESR1 ctDNA mutations detected in 18 hotspots from 42 patients at different time points, among which there were 131 endocrine therapy resistance status in all time points. The numbers of ESR1 hotspots mutations and the corresponding endocrine therapy resistance cases were found in the following hotspots respectively as Q314 (3 cases with mutation, 0 cases with resistance), T347T (4, 0), N359I (4, 0), K362N (4, 0), E380Q(32, 16), V392I (1, 1), G442R(3, 0), F461I(3, 0), S463P (3, 2), S464 (1, 0), I487M(14, 0), K520K (2, 0), M528V (5, 0), L536H (31, 19), Y537N/C/S (46, 34), D538G (77, 59), D545D(2, 0) and Q565 (4, 0). There were 50%, 61.2%, 73.9% and 76.6% patients developed endocrine therapy resistance when they had E380Q, L536H, Y537N/C/S and D538G mutations respectively at any time points. Furthermore, among these 4 hotspot mutations, the MBC patients with lack of response to endocrine therapy have significantly higher percentage of mutated DNA than the patients with sensitive response. For the patients with E380Q mutation, the mean percentage of mutation DNA was 8.44% for those with lack of response and lower than 0.01% for those with sensitive response (P & lt;0.001). For the patients with L536H mutation, the mean percentage of mutation DNA was 3.48% for those with lack of response and lower than 0.01% for those with sensitive response (P & lt;0.001). For the patients with Y537N/C/S mutation, the mean percentage of mutation DNA was 5.23% for those with lack of response and 0.02% for those with sensitive response (P & lt;0.001). For the patients with D538G mutation, the median percentage of mutation DNA was 5.13% for those with lack of response and 0.01% for those with sensitive response (P & lt;0.001). Conclusions: The outcome of this study demonstrated that patients with mutations on known ESR1 hotspots (E380Q, L536H, Y537N/C/S and D538G) develop clinical resistance to endocrine therapy. Evaluation of these ESR1 hotspots mutations by ctDNA could be reliably used to monitor the response to endocrine therapy and predict the prognosis for MBC patients. Citation Format: Qiang Zhang, Paolo D'Amico, Weijun Qin, Jianhua Jiao, Andrew A. Davis, Lorenzo Gerratana, Saya L. Jacob, Youbin Zhang, Jeannine Donahue, Wenan Qiang, Ami N. Shah, Amir Behdad, Lisa Flaum, William Gradishar, Leonidas C Platanias, Massimo Cristofanilli. Esr1 hotspot mutations in circulating tumor DNA mutation are associated with endocrine therapy resistance in metastatic breast cancer [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 P2-01-04.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.SABCS21-P2-01-04
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2022
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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