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. 2024 Oct 27:18:11782234241288671.
doi: 10.1177/11782234241288671. eCollection 2024.

Multicenter Prospective Study in HER2-Positive Early Breast Cancer for Detecting Minimal Residual Disease by Circulating Tumor DNA Analysis With Neoadjuvant Chemotherapy: HARMONY Study

Momoko Tokura  1   2   3 , Mark Malalay Ando  4 , Yuki Kojima  1   2 , Rui Kitadai  1 , Shu Yazaki  1   2 , Cyrielle Marie N Atutubo  5 , Rubi K Li  5 , Minda Z Perez  6 , Agnes E Gorospe  5 , Manuelito A Madrid  7 , Mel Valerie C Ordinario  5 , Marcelo Severino B Imasa  5 , Kazuki Sudo  1   2   8 , Tatsunori Shimoi  1   2 , Akihiko Suto  9 , Shinji Kohsaka  10 , Ryunosuke Machida  11 , Ryo Sadachi  11 , Masayuki Yoshida  12 , Yasushi Yatabe  12 , Tomomi Hata  13 , Kenichi Nakamura  2 , Kan Yonemori  1   2   8 , Sho Shiino  9
Affiliations

Multicenter Prospective Study in HER2-Positive Early Breast Cancer for Detecting Minimal Residual Disease by Circulating Tumor DNA Analysis With Neoadjuvant Chemotherapy: HARMONY Study

Momoko Tokura et al. Breast Cancer (Auckl). .

Abstract

Background: Biomarkers to predict the recurrence risk are required to optimize perioperative treatment. Adjuvant chemotherapy for patients with human epidermal growth factor 2-positive (HER2-positive) early breast cancer is decided by pathological responses of neoadjuvant chemotherapy (NAC). However, whether pathological responses are appropriate biomarkers is unclear. Currently, there are several studies using minimal residual disease (MRD) as a predictor of prognosis in solid tumors. However, there is no standard method for detecting MRD.

Objectives: This study aimed at prospectively evaluating the relationship between MRD detection and recurrence in Asian patients with HER2-positive early breast cancer.

Design: Prospective, observational, single-group, and exploratory. This study will include 60 patients from 2 institutions in Japan and the Philippines. The invasive disease-free survival (IDFS) rates of the MRD-positive and MRD-negative groups are compared in patients with HER2-positive early breast cancer who undergo surgery after receiving NAC.

Methods and analysis: Circulating tumor DNA (ctDNA) levels of patients will be evaluated 6 times: before NAC, after NAC, after surgery, and annually after surgery for 3 years. We will analyze the genetic profile of blood and tissue samples using the Todai OncoPanel (TOP) and the methylation level of DNA. The primary endpoint is IDFS. Secondary endpoints include overall survival (OS) and disease-free survival (DFS). Patient enrollment began in June 2022, and new participants are still being recruited.

Ethics: This study has been approved by the National Cancer Center Hospital Certified Review Board in March 2022 and has been approved by the Research Ethics Board of the participating center.

Discussion: Our findings will contribute to determining whether MRD detection using TOP is useful for predicting the recurrence of HER2-positive early breast cancer. If this is proven, MRD detected by TOP could be used in the future as a biomarker to assist in the de-/escalation of treatment strategies in the next interventional trial, thereby avoiding overtreatment in patients at low risk, and in the addition of intensive treatment modalities for those in patients at high risk.

Keywords: Asia; HER2-positive breast cancer; Todai OncoPanel; ctDNA; ctRNA; minimal residual disease.

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Conflict of interest statement

A conflict of interest (COI) is a situation in which a person or organization is involved in multiple interests, financial or otherwise, one of which could possibly corrupt the motivation or decision-making of that individual or organization. National Cancer Center Hospital is sponsoring the study and will be financing (study doctor/institution) to conduct the study. We have no conflicts of interest directly relevant to the content of this study. We will inform you on the website of NCCH when there are any changes. If you have any questions about potential conflicts of interest, please ask your study doctor.The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Part of this research will be conducted under a joint research agreement between the National Cancer Center and the H.U. Group Research Institute G.K., a limited liability company that will bear the costs associated with specimen processing.

Figures

Figure 1.
Figure 1.
Flow diagram of the HARMONY protocol. The eligibility criteria are HER2-positive invasive breast carcinoma, scheduled for neoadjuvant chemotherapy followed by surgery, and clinical stages IIA-IIIC. A total of 60 patients will be enrolled. Blood samples are collected 6 times: before neoadjuvant chemotherapy, after neoadjuvant chemotherapy, after surgery, and annually after surgery for 3 years. When recurrence occurs, blood is collected only at that time, and no further blood samples are collected. Biopsy samples before treatment and surgical specimens will be collected. Genetic analysis of blood and tissue samples will be performed for MRD detection. The primary endpoint is the invasive disease-free survival (IDFS), whereas the secondary endpoints are overall survival (OS) and disease-free survival (DFS). Subgroup analysis will be performed.
Figure 2.
Figure 2.
Schedule of the study. Eligibility screening, pathological findings of biopsy sample, and informed consent are required before enrollment. Tissue samples and blood samples are collected during treatment period. Blood samples and information about recurrence/survival status are collected during follow-up period.
See this image and copyright information in PMC

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