Precise Therapy for Refractory HER2 Positive Advanced Breast Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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Precise Targeted Therapy for Refractory HER2 Positive Advanced Breast Cancer Based on Genome Signature and Drug Sensitivity of PDO Model

Conditions
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HER2+ Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab
* Drug: Pertuzumab
* Drug: Nab paclitaxel
* Drug: Pyrotinib
* Drug: Capecitabine
* Drug: T-DM1
* Drug: Everolimus
* Drug: CDK4/6 inhibitor
* Drug: AI
* Drug: Anti-PD-1 monoclonal antibody


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-70 years old; Women; ECOG score 0-2; Locally advanced or metastatic breast cancer confirmed by histopathology; Positive HER2 expression in cancer tissues (IHC 3 +, or IHC 2 + but FISH amplification); Resistant to trastuzumab (including disease progression during or after withdrawal of trastuzumab); There were enough specimens for immunohistochemistry, gene detection and establishment of PDO model; Hematology and liver and kidney function were normal within 2 weeks before treatment; Imaging examination showed measurable lesions (according to RECIST v1.1); Women of childbearing age agree to contraception or take contraceptive measures; Be able to understand the research program and participate voluntarily. Exclusion Criteria: Symptomatic, untreated or progressive central nervous system metastases; Severe heart disease (poor cardiac function); Within 5 years, there was a history of other malignant tumors other than breast cancer; In this study, chemotherapy, radiotherapy, immunotherapy or surgery were performed within 3 weeks before the first treatment; Patients who are pregnant or lactating, or plan to become pregnant during enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A. HER2 low expression<br>Phenotype was signatured by HER2 low expression. | Drug: Trastuzumab<br>* Trastuzumab (6mg/Kg, iv.drip, d1, q3w)<br>* Other names: herceptin；Inetetamab;Drug: Pertuzumab<br>* Patuzumab (420mg iv.drip, d1,q3w)<br>* Other names: Perjeta;Drug: Nab paclitaxel<br>* nab-paclitaxel (200mg iv.drip, d1,d8, q3w)<br>* Other names: Abraxane;|
| Experimental: B. HER2 amplified<br>Signatured by wild type HER2 amplified. | Drug: Trastuzumab<br>* Trastuzumab (6mg/Kg, iv.drip, d1, q3w)<br>* Other names: herceptin；Inetetamab;Drug: Pertuzumab<br>* Patuzumab (420mg iv.drip, d1,q3w)<br>* Other names: Perjeta;Drug: Nab paclitaxel<br>* nab-paclitaxel (200mg iv.drip, d1,d8, q3w)<br>* Other names: Abraxane;|
| Experimental: C. HER2 mutation<br>Signatured by HER2 mutation. | Drug: Pyrotinib<br>* Pyroltinib (400mg po qd)<br>* Other names: SHR-1258;Drug: Capecitabine<br>* Capecitabine (1250mg/m2, po, bid, d1-d14, q3w).<br>|
| Experimental: D. HER2 downstream mutation<br>Signatured by HER2 downstream mutation of PI3KCA, TP53 or PTEN. | Drug: Trastuzumab<br>* Trastuzumab (6mg/Kg, iv.drip, d1, q3w)<br>* Other names: herceptin；Inetetamab;Drug: Nab paclitaxel<br>* nab-paclitaxel (200mg iv.drip, d1,d8, q3w)<br>* Other names: Abraxane;Drug: T-DM1<br>* T-DM1(3.6mg/Kg, iv.drip, d1, q3w)<br>* Other names: Trastuzumab Emtansine;Drug: Everolimus<br>* Everolimus (4mg, po, qd)<br>* Other names: RAD001;|
| Experimental: E. Hormone receptor pathway activation<br>Signatured by both ER and PR strongly expressed,or CCND1 amplified. | Drug: Trastuzumab<br>* Trastuzumab (6mg/Kg, iv.drip, d1, q3w)<br>* Other names: herceptin；Inetetamab;Drug: CDK4/6 inhibitor<br>* Palbociclib (125mg, po, qd)<br>* Other names: Palbociclib；;Drug: AI<br>* Letrozole (2.5mg, qd).<br>* Other names: Letrozole;|
| Experimental: F. Immune activation<br>Signatured by high TMB or PD-L1 positively expressed. | Drug: Trastuzumab<br>* Trastuzumab (6mg/Kg, iv.drip, d1, q3w)<br>* Other names: herceptin；Inetetamab;Drug: Anti-PD-1 monoclonal antibody<br>* Cindilimab (200mg, iv.drip, d1, q3w)<br>* Other names: Sintilimab;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS1 | Progress free survival (PFS) according to RECIST (version 1.1) of each group | during the procedure |