Molecular Subtype-Guided Postoperative Radiotherapy for Phyllodes Tumor of the Breast: A Randomized Controlled Trial

Official title

Efficacy and Safety of Molecular Subtype-Guided Postoperative Radiotherapy for Phyllodes Tumor of the Breast: A Prospective, Open-Label, Randomized Controlled Trial

Overview

Phyllodes tumor (PT) of the breast is a rare fibroepithelial neoplasm, and the role of postoperative radiotherapy (PORT) remains controversial. Our team has previously established a molecular subtyping system for PT, classifying patients into four subtypes. Among them, the malignant novel 1/2 (MN1/MN2) subtypes exhibit extremely high risk of local recurrence, and retrospective data suggest that PORT may significantly improve local control in these subtypes. This study aims to evaluate the efficacy and safety of molecular subtype-guided postoperative radiotherapy (PORT) in patients with MN-subtype phyllodes tumor of the breast. This prospective, multicenter, open-label, randomized controlled trial plans to enroll 160 patients with molecularly confirmed MN1 or MN2 subtype who have undergone R0 resection. Patients will be randomized in a 1:1 ratio to either the PORT group or the observation-only group, with stratification by negative margin width (\<1 cm vs. ≥1 cm) and molecular subtype (MN1 vs. MN2). The primary endpoint is 2-year local recurrence-free survival (LRFS). Secondary endpoints include distant metastasis-free survival (DMFS), disease-free survival (DFS), overall survival (OS), and the incidence of acute and late radiotherapy-related toxicities. By using an innovative molecular subtyping system to precisely select the target population, this study seeks to assess the benefit and safety of PORT in MN-subtype phyllodes tumors. The results are expected to provide the highest level of evidence for this specific subgroup, advance treatment strategies toward "molecular subtype-guided precision radiotherapy," improve patient outcomes, and inform future clinical guidelines.

Interventions

• Radiation Postoperative Radiotherapy (PORT)
  Radiotherapy delivered after R0 resection. For breast-conserving surgery: whole-breast irradiation (50 Gy in 25 fractions, 2 Gy/fraction, 5 fractions/week) followed by sequential tumor bed boost (10-16 Gy in 5-8 fractions, 2 Gy/fraction). For mastectomy: chest wall irradiation (50 Gy in 25 fractions). Techniques allowed: IMRT, VMAT, or TOMO. No routine regional nodal irradiation unless pathologically confirmed nodal involvement. Target volume and organ-at-risk constraints as per protocol (e.g.,

Primary outcome measures

• 2-year Local Recurrence-Free Survival (LRFS) [Time frame: From randomization up to 2 years post-randomization (primary analysis at 2 years)]

Secondary outcome measures (4)

• Distant Metastasis-Free Survival (DMFS) [Time frame: From randomization up to 5 years (primary analysis for secondary endpoints will be performed at 2 years, with extended follow-up up to 5 years)]
• Disease-Free Survival (DFS) [Time frame: From randomization up to 5 years (primary analysis of secondary endpoints at 2 years, with extended follow-up to 5 years)]
• Overall Survival (OS) [Time frame: From randomization up to 5 years]
• Incidence of Acute and Late Radiotherapy-Related Toxicities [Time frame: From start of radiotherapy up to 5 years post-randomization (acute: within 90 days; late: from 90 days to 5 years)]

Eligibility criteria

Inclusion criteria

• Female patients aged ≥18 years and ≤75 years.
• Histologically confirmed breast phyllodes tumor (PT) by the central laboratory, with molecular classification as MN1 or MN2 subtype via transcriptome sequencing or IHC;
• Primary or ipsilateral local recurrence following R0 resection (negative margins) before enrollment;
• Pathologically confirmed borderline or malignant PT;
• No evidence of distant metastasis (M0);
• ECOG performance status 0-1;
• Signed informed consent before treatment;
• Expected randomization and study entry within 8-12 weeks (no later than 16 weeks) after surgery.

Exclusion criteria

• Previous radiation to the same-side breast or chest;
• women, or those of childbearing potential refusing effective contraception; Pregnancy, lactation, or refusal of contraception by fertile subjects;
• Grade III-IV bone marrow suppression: WBC≤1.9\*109/L，ANC≤0.9\*109/L，PLT≤49\*109/L，AST, ALT≥2\*ULN;
• Significant diarrhea, severe active infection, uncontrolled systemic disease, interstitial lung disease, active connective tissue disease, or LVEF < 50%;
• Significant diarrhea, severe active infection, uncontrolled systemic disease, interstitial lung disease, active connective tissue disease, or LVEF < 50%;
• Prior or planned systemic anti-tumor therapy (chemotherapy, targeted therapy, immunotherapy, or investigational agents) during the study;
• Participation in other clinical trials that precludes study inclusion;
• Any other condition that, in the opinion of the investigator, renders the patient unsuitable for the trial.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 4 centers

• Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University — Guangzhou
• Peking University Shenzhen Hospital — Shenzhen
• The Second Hospital of Shandong University — Jinan
• The Affiliated Hospital of Qingdao University — Qingdao

Publications

• Zheng WH, Long ZQ, Kou J, Sun JY, Li FY, Zhang LL, He ZY. Postoperative radiation therapy in localized breast malignant phyllodes tumors: RPA-derived risk model identifies high-benefit subgroups with local control improvement. Breast. 2025 Dec;84:104617. doi: 10.1016/j.breast.2025.104617. Epub 2025 Oct 22. PMID 41135329
• Kim YJ, Kim K. Radiation therapy for malignant phyllodes tumor of the breast: An analysis of SEER data. Breast. 2017 Apr;32:26-32. doi: 10.1016/j.breast.2016.12.006. Epub 2016 Dec 22. PMID 28013032
• Ma B, Li X, Zhuang Z, Han M, Zhang Y, Ye F, Bi Z, Deng W, Zhang J, Yang Y, Nie Y. Effects of radiotherapy in borderline and malignant phyllodes tumors after R0 resection: a propensity score analysis. Ther Adv Med Oncol. 2025 Oct 27;17:17588359251387556. doi: 10.1177/17588359251387556. eCollection 2025. PMID 41179117
• Varghese SS, Sasidharan B, Manipadam MT, Paul MJ, Backianathan S. Radiotherapy in Phyllodes Tumour. J Clin Diagn Res. 2017 Jan;11(1):XC01-XC03. doi: 10.7860/JCDR/2017/24591.9167. Epub 2017 Jan 1. PMID 28274029
• Zhao W, Tian Q, Zhao A, Wang B, Yang J, Wang L, Zhang L, Dong D, Chen L, Yang J. The role of adjuvant radiotherapy in patients with malignant phyllodes tumor of the breast: a propensity-score matching analysis. Breast Cancer. 2021 Jan;28(1):110-118. doi: 10.1007/s12282-020-01135-7. Epub 2020 Aug 3. PMID 32748225
• Barth RJ Jr, Wells WA, Mitchell SE, Cole BF. A prospective, multi-institutional study of adjuvant radiotherapy after resection of malignant phyllodes tumors. Ann Surg Oncol. 2009 Aug;16(8):2288-94. doi: 10.1245/s10434-009-0489-2. Epub 2009 May 8. PMID 19424757
• Donato AR, Goncalves R, Maesaka JY, Aguiar FN, Soares JM Jr, Ruiz CA, Filassi JR, Baracat EC. Phyllodes tumors of the breast: A comprehensive review of diagnosis, treatment, and follow-up. Clinics (Sao Paulo). 2025 Mar 14;80:100617. doi: 10.1016/j.clinsp.2025.100617. eCollection 2025. PMID 40088524
• Zhang H, Tang S, Biskup E, Zhang Y, Yong L, Chen L, Cai F. Long-term Survival After Diverse Therapeutic Modalities in Malignant Phyllodes Tumors of the Breast. Technol Cancer Res Treat. 2022 Jan-Dec;21:15330338221121086. doi: 10.1177/15330338221121086. PMID 36000314

Identifiers

NCT: NCT07657169 · SYSKY-2026-390-02

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗