Markers to Evaluate the Efficacy of PH-based Regimen as a Neoadjuvant Therapy for Operable HER2 Positive Breast Cancer

Study Overview
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Brief Summary
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This study is to explore the markers in early prediction of the efficacy of pre-operative pertuzumab plus trastuzumab (PH) combined with chemotherapy for early stage or locally advanced human epidermal growth factor receptor-2 (HER-2) positive primary breast cancer.

Detailed Description
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This study is to evaluate the correlation between early changes in multiple markers and pathological complete response in breast and lyphm nodes (tpCR) in patients with HER2-positive breast cancer receiving carboplatin, docetaxel and trastuzumab plus pertuzumab (TCHP) pre-operatively. The markers would be examined by gene expression assays, fluorodeoxyglucose positron emission tomography (18F-FDG-PET), 68 Ga-Affibody HER-2 Imaging PET, and organoid drug sensitivity test. Approximately 94 patients were treated with PH-based neoadjuvant therapy followed by surgery, and would complete 1 year of PH-based regimen in the adjuvant setting. The primary endpoint is the percent change of SUVmax from baseline to Day 15 (after the first cycle of anti HER-2 targeting drug treatment) on FDG PET and HER-2 imagining PET in correlation with pathological complete response (pCR) in patients treated with preoperative pertuzumab and trastuzumab. pCR was defined as no viable invasive cancer in breast and axilla by local pathology review.

Official Title
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Gene Expression Assays and 68 Ga-Affibody HER-2 Imaging PET in Predicting Response to Treatment With Trastuzumab and Pertuzumab Before Surgery in Chinese Patients With HER2 Positive Breast Cancer

Conditions
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HER2-positive Breast Cancer

Intervention / Treatment
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* Diagnostic Test: TCHP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or male, presenting for the first time with operable breast cancer, who had not received any previous treatment for an invasive malignancy. Primary tumor greater than (>) 2 cm in diameter. Age ≥ 18 years and < 70 years. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (</=) 1. Baseline left ventricular ejection fraction (LVEF) greater than or equal to (>/=) 55% Availability of tumor tissue specimen after surgery. Participants agree to undergo a core needle biopsy for genomic testing and organoid drug sensitivity assay. Histologically proven diagnosis of breast cancer. Patients have HER2-positive disease. HER2-positive disease was defined as follows: disease which overexpresses HER-2 by immunohistochemistry (IHC) 3+ and/or has HER2 amplification according to fluorescence in situ hybridization (FISH). Had hormonal receptors (ER and PgR) assessed. Signed informed consent. Able to comply with the protocol. Exclusion Criteria: Metastatic disease (Stage IV) or bilateral breast cancer. Any previous systemic therapy (including chemotherapy, immunotherapy, HER2 targeted agents, and antitumor vaccines) for cancer, or radiation therapy for cancer. Prior breast or non-breast malignancy within 5 years prior to study entry. Inadequate bone marrow, renal, or liver function History or evidence of cardiovascular condition Severe, uncontrolled systemic disease Participants with poorly controlled diabetes or with evidence of clinically significant diabetic vascular complications. Pregnancy or breast-feeding women. Participants who received any investigational treatment within 4 weeks of study start. Participants with known infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus. Current chronic daily treatment with corticosteroids (dose >10 mg methylprednisolone or equivalent [excluding inhaled steroids]). Known hypersensitivity to any of the study drugs or excipients

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

Sexes Eligible for Study
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All

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: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TCHP<br>Neoadjuvant Therapy (Cycles 1-7): Cycle 1: Pertuzumab (840mg loading dose, 420mg maintenance dose) + Trastuzumab (8mg/kg loading dose, 6-mg/kg maintenance dose) Cycle 2-7: Pertuzumab (840mg loading dose, 420mg maintenance dose) + Trastuzumab (8mg/kg loading dose, 6-mg/kg maintenance dose) + followed by carboplatin at target area under the plasma concentration-time curve (AUC) 6 and docetaxel at a starting dose of 75 mg/m2 then to 60mg/m2 (q3w). Adjuvant Therapy:patients would complete 1 year of PH-based regimen in the adjuvant setting. Patients are assessed by [18F]Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) and 68Ga-Affibody HER-2 Imaging PET. Besides, the changes of biomarkers would be examined by gene sequencing and organoid drug sensitivity test. | Diagnostic Test: TCHP<br>* Drug: Trastuzumab 8 mg/kg loading dose, then 6 mg/kg every 3 weeks, IV Other Name: Herceptin Drug: Pertuzumab 840 mg as a loading dose, then 420 mg every 3 weeks, IV Other Name: Perjeta Drug: carboplatin at target area under the plasma concentration-time curve (AUC) 6 Drug: docetaxel at a starting dose of 75 mg/m2 then to 60mg/m2 (q3w). All study drugs were administered intravenously. Procedure: 18-FDG-PET and 68 Ga-Affibody HER-2 Imaging PET will be performed at baseline, on day 15 and before surgery Genomic alterations (mutations/somatic rearrangements) are detected at baseline, on day 15 and before surgery.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Standardized Uptake Value (SUV) on Positron Emission Tomography and Change in Gene Expression With Response | Change in SUVmax from baseline to Day 15 on 18-FDG PET and 68Ga-Affibody HER-2 Imaging PET in correlation with pathological complete response (pCR) in patients treated with preoperative pertuzumab/trastuzumab. | From baseline to day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic complete response in the breast and lymph nodes (ypT0/Tis ypN0) | To determine whether the composite markers can predict pathologic complete response in the breast and lymph nodes in HER-2 positive breast cancer with PH combination with chemotherapy adjuvant therapy. Defined as the absence of any invasive component in the resected breast specimen and all resected lymph nodes following completion of neoadjuvant therapy (ypT0/Tis ypN0). | Immediately after the surgery | 
| Invasive disease-free survival (iDFS) (excluding Second Primary Non-Breast Cancer [SPNBC]) | To determine the correlation between the composite markers and invasive disease free survival in HER-2 positive breast cancer patients receiving docetaxel, carboplatin, and trastuzumab plus pertuzumab pre-operatively. iDFS event was defined as the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence; ipsilateral local-regional invasive breast cancer recurrence; distant recurrence; death attributable to any cause; contralateral invasive breast cancer. All SPNBCs and in situ carcinomas (including ductal carcinoma in situ [DCIS] and lobular carcinoma in situ [LCIS]) and non-melanoma skin cancer were excluded as an event. | Following surgery until Year 5 | 
| iDFS (including SPNBC) | The iDFS event was defined as the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence; ipsilateral local-regional invasive breast cancer recurrence; distant recurrence; death attributable to any cause; contralateral invasive breast cancer; SPNBC (with the exception of non-melanoma skin cancers and in situ carcinoma of any site). | Following surgery until Year 5 | 
| Overall survival (OS) | To determine the correlation between the composite markers and overall survival in HER-2 positive breast cancer patients receiving docetaxel, carboplatin, and trastuzumab plus pertuzumab pre-operatively. Percentage of participants who died due to any cause is reported. | Following surgery until Year 5 |