Serial analysis of ESR1 and PIK3CA mutations in cell-free DNA from metastatic breast cancer during 1st line endocrine therapy.

Authors

null

Soo Yeon Baek

Department of Surgery, Ajou University School of Medicine, Suwon, South Korea

Soo Yeon Baek , Meehyang Hong , Seungah Lee , Seulgi Joo , JungPil Jang , Chinkoo Jung , Sae Byul Lee , Tae-Kyung Yoo , Il Yong Chung , Hee Jeong Kim , Beom Seok Ko , Jong Won Lee , Byung Ho Son , Hyehyun Jeong , Jae Ho Jeong , Jin-Hee Ahn , Kyung Hae Jung , Sung-Bae Kim , Hee Jin Lee , Jisun KIM

Organizations

Department of Surgery, Ajou University School of Medicine, Suwon, South Korea, Genopeaks Co., Ltd., Seoul, South Korea, Division of Breast Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea, Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

Research Funding

Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea
Genopeaks Co.,Ltd.

Background: Activating mutations ofESR1 and PIK3CA genes are known mechanisms of endocrine resistance. Recent analysis supported benefit of early intervention at presence of ESR1 mutation in blood (bESR1) before clinical progression. We aimed to investigate ESR1 and PIK3CA mutations detected in cell-free DNA (cfDNA) from patients with hormone receptor-positive, HER2-negative metastatic breast cancer (MBC) and its impact on progression-free survival (PFS). Methods: Thirty patients undergoing 1st line endocrine therapy (ETx) were identified from a prospective cohort. Seven ESR1 hotspot mutations in the ligand binding domain were tested in cfDNA with droplet digital polymerase chain reaction (ddPCR) assay (Genopeaks Co., Ltd). Eleven PIK3CA hotspot mutations were tested using amplicon-targeted sequencing method (Genopeaks Co., Ltd) in both tumor and cfDNA. PFS analyses were performed using Kaplan-Meier methods and compared with the log-rank test. Results: We examined serial cfDNA samples from 26 patients collected every 3-6 months. ESR1 mutations were found in 61.5% (16/26) patients at any timepoint during 1st line endocrine therapy, with D538G being the most common followed by Y537C and 68.8% (11/16) being polyclonal. Among the 50.0% (8/16) bESR1 positive patients with clinical progression, 4 had bESR1 detected before clinical progression while 4 were diagnosed clinical progression concurrently, suggesting the necessity of closer intervals of cfDNA analyses. While presence of bESR1 did not affect PFS overall, 18.8% of patients with bESR1 detected within 6 months after 1st line ETx, displayed worse outcome (median PFS 5 vs 52 months). Also, patients with clearance of bESR1 mutation in subsequent cfDNA (81.3%, 13/16) were shown to have a better outcome (median PFS 52 vs 41 months). Among 14 patients with clinical progression, 8 had bESR1 mutation. Median PFS between patients with bESR1 positive vs negative was 14 vs 9 months. PIK3CA mutations were detected in 69.5% (16/23) of cfDNA at diagnosis of distant metastasis, among them 53.3% (8/15) had co-occurrence with bESR1 mutations. While presence of PIK3CA mutation in primary tumor tissue did not affect disease-free survival nor PFS, patients with blood PIK3CA mutation at diagnosis of metastasis displayed significantly worse outcome (p = 0.041). Conclusions: Substantial number of hormone receptor-positive, HER2-negative MBC patients were detected with ESR1 and PIK3CA mutation in plasma. Though it was a small-sized analysis to accurately assess statistical significance, we observed worse outcome in patients with 1) early detection (<6 months) of bESR1 and with 2) sustained bESR1 during palliative ETx. Patients with clinical progression without bESR1 mutation displayed shorter PFS than patients with bESR1. PIK3CA mutations in cfDNA were prognostic supporting the benefit of combined targeted therapy.

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Abstract Details

Meeting

2024 ASCO Annual Meeting

Session Type

Publication Only

Session Title

Publication Only: Breast Cancer—Metastatic

Track

Breast Cancer

Sub Track

Hormone Receptor-Positive

Citation

J Clin Oncol 42, 2024 (suppl 16; abstr e13060)

DOI

10.1200/JCO.2024.42.16_suppl.e13060

Abstract #

e13060

Abstract Disclosures