Precise Therapy for Refractory HER2 Positive Advanced Breast Cancer

Phase 3

• Conditions: HER2+ Breast Cancer
• Interventions: Drug: Trastuzumab; Drug: Pyrotinib; Drug: Anti-PD-1 monoclonal antibody; Drug: CDK4/6 inhibitor; Drug: Pertuzumab; Drug: Capecitabine; Drug: Nab paclitaxel; Drug: AI; Drug: T-DM1; Drug: Everolimus

• Registration Number: NCT05429684
• Lead Sponsor: First Affiliated Hospital Xi'an Jiaotong University

Brief Summary

This is an open, prospective and interventional clinical study. Patients with advanced Human Epidermal Growth Factor Receptor 2 (HER2) positive breast cancer resistant to trastuzumab will be enrolled in the study. Histological specimens obtained from different metastatic foci of patients, are used to conduct genome-wide sequencing together with Circulating tumor DNA (ctDNA) of blood samples. Meanwhile, investigator will construct PDO model based on biopsy tissue. Patients as well as their paired Patient-derived organoids (PDO) models are divided into six groups according to genomic signatures. Each group of patients will receive the best targeted treatment scheme from the current clinical perspective, while the matched PDO model will accept a variety of potential effective schemes intervention. The future treatment plan of patients will be timely adjusted based on the tumor inhibition rate of PDO models. This study is the first time to explore the best individualized application sequence of targeted therapy for refractory HER2 positive breast cancer by combining genome sequencing with drug sensitivity test of PDO model. The results are expected to improve the prognosis of patients with advanced HER2 positive breast cancer.

Detailed Description

In previous studies, investigator found that dynamic genomics detection of metastatic foci can fully reveal the mechanism of trastuzumab resistance. Different anti-HER2 treatment strategies for different mechanisms can improve the efficacy of HER2 positive advanced breast cancer, and the PDO drug sensitivity test model of breast cancer can be prior to patients' response to the exact efficacy of specific regimens.This study aimed to explore the optimal individualized drug combination and order for patients with advanced HER2 positive breast cancer resistant to trastuzumab based on a variety of existing diagnosis and treatment methods. This is an open, prospective and interventional clinical study. Patients with advanced HER2 positive breast cancer resistant to trastuzumab will be enrolled in the study. Histological specimens obtained from different metastatic foci of patients, are used to conduct genome-wide sequencing together with ctDNA of blood samples. Meanwhile, investigator will construct PDO model based on biopsy tissue. Patients as well as their paired PDO models are divided into six groups according to genomic signatures. Each group of patients will receive the best targeted treatment scheme from the current clinical perspective, while the matched PDO model will accept a variety of potential effective schemes intervention. The future treatment plan of patients will be timely adjusted based on the tumor inhibition rate of PDO models. This study is the first time to explore the best individualized application sequence of targeted therapy for refractory HER2 positive breast cancer by combining genome sequencing with drug sensitivity test of PDO model. The results are expected to improve the prognosis of patients with advanced HER2 positive breast cancer.

Study Timeline

• Study Start: 2021-01-01
• Study First Submitted: 2021-12-12
• Status Verified: 2022-05
• Study First Submitted QC: 2022-06-20
• Last Update Submitted: 2022-06-20
• Study First Posted: 2022-06-23
• Last Update Posted: 2022-06-23
• Primary Completion: 2024-02-28
• Study Completion: 2024-02-28

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: Female
• Target Recruitment: 120

Inclusion Criteria

1. 18-70 years old;
2. Women;
3. ECOG score 0-2;
4. Locally advanced or metastatic breast cancer confirmed by histopathology;
5. Positive HER2 expression in cancer tissues (IHC 3 +, or IHC 2 + but FISH amplification);
6. Resistant to trastuzumab (including disease progression during or after withdrawal of trastuzumab);
7. There were enough specimens for immunohistochemistry, gene detection and establishment of PDO model;
8. Hematology and liver and kidney function were normal within 2 weeks before treatment;
9. Imaging examination showed measurable lesions (according to RECIST v1.1);
10. Women of childbearing age agree to contraception or take contraceptive measures;
11. Be able to understand the research program and participate voluntarily.

Exclusion Criteria

1. Symptomatic, untreated or progressive central nervous system metastases;
2. Severe heart disease (poor cardiac function);
3. Within 5 years, there was a history of other malignant tumors other than breast cancer;
4. In this study, chemotherapy, radiotherapy, immunotherapy or surgery were performed within 3 weeks before the first treatment;
5. Patients who are pregnant or lactating, or plan to become pregnant during enrollment.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
A. HER2 low expression	Trastuzumab	Phenotype was signatured by HER2 low expression.
A. HER2 low expression	Nab paclitaxel	Phenotype was signatured by HER2 low expression.
E. Hormone receptor pathway activation	AI	Signatured by both ER and PR strongly expressed,or CCND1 amplified.
F. Immune activation	Anti-PD-1 monoclonal antibody	Signatured by high TMB or PD-L1 positively expressed.
E. Hormone receptor pathway activation	CDK4/6 inhibitor	Signatured by both ER and PR strongly expressed,or CCND1 amplified.
F. Immune activation	Trastuzumab	Signatured by high TMB or PD-L1 positively expressed.
B. HER2 amplified	Nab paclitaxel	Signatured by wild type HER2 amplified.
D. HER2 downstream mutation	Nab paclitaxel	Signatured by HER2 downstream mutation of PI3KCA, TP53 or PTEN.
C. HER2 mutation	Pyrotinib	Signatured by HER2 mutation.
D. HER2 downstream mutation	Trastuzumab	Signatured by HER2 downstream mutation of PI3KCA, TP53 or PTEN.
D. HER2 downstream mutation	T-DM1	Signatured by HER2 downstream mutation of PI3KCA, TP53 or PTEN.
D. HER2 downstream mutation	Everolimus	Signatured by HER2 downstream mutation of PI3KCA, TP53 or PTEN.
A. HER2 low expression	Pertuzumab	Phenotype was signatured by HER2 low expression.
B. HER2 amplified	Trastuzumab	Signatured by wild type HER2 amplified.
B. HER2 amplified	Pertuzumab	Signatured by wild type HER2 amplified.
E. Hormone receptor pathway activation	Trastuzumab	Signatured by both ER and PR strongly expressed,or CCND1 amplified.
C. HER2 mutation	Capecitabine	Signatured by HER2 mutation.

Primary Outcome Measures

Name	Time	Method
ORR	Up to six weeks, first evaluation	objective response rate (ORR) according to RECIST (version 1.1) of each group
PDO model inhibition rate	during the procedure	Tumor regression rate based on the calculation of the long diameter in each group

Secondary Outcome Measures

Name	Time	Method
PFS1	during the procedure	Progress free survival (PFS) according to RECIST (version 1.1) of each group

Trial Locations

Locations (2)

The First Affiliated Hospital of Xi'an Jiaotong University; 🇨🇳 Xi'an, Shaanxi, China

Jin Yang; 🇨🇳 Xi'an, Shaanxi, China