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Breast Diseases

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Trastuzumab

Antineoplastic Agents, Immunological

A single dose of Trastuzumab (Herceptin, Hoffman La Roche) at 8 mg/Kg as a 90 minute infusion in 250 ml of normal saline, in the window period of 14 days (both days inclusive) prior to the planned date of surgery.

A 90 minute intravenous infusion of saline as placebo

Placebo

Rajendra A Badwe, MS

Background Information and Rationale:

Trastuzumab is a humanized monoclonal antibody that acts extracellularly on the erbB-2 receptor.Trastuzumab is a recombinant humanized IgG1 monoclonal antibody against the human epidermal growth factor receptor 2 (HER2/erbB-2),which has shown in both in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress erbB-2. Additionally, trastuzumab is a potent mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, trastuzumab-mediated ADCC has been shown to be preferentially exerted on erbB-2 overexpressing cancer cells compared with cancer cells that do not overexpress erbB-2. Trastuzumab has emerged as a widely accepted standard of care for erbB-2-positive disease. (Metastatic/ adjuvant/neoadjuvant.

Our current hypothesis suggests that the cells which are disseminated at the time of surgery will encounter an inhospitable environment which will be anti-HER in nature. Therefore combining the above mentioned streams of thought, we would like to assess the effect of a short pre-operative course of Trastuzumab on breast cancer relapse. The study is proposed in HER2 positive patients with operable breast cancer.

Objectives :

Primary:

The primary objective of the study is to see the effect of short duration of peri-operative Trastuzumab on disease-free survival in comparison in all patients

Secondary:

The safety of the pre-operative therapies including the early post operative morbidity

1. Overall survival (OS) in all patients and in pathologically node positive patients.
2. The level of circulating tumor cells (CTCs) in the peripheral blood assessed before starting pre-operative therapy and at the same time point in the control arm, level of CTCs 10 minutes prior to start of surgery, during surgery and 10 days after surgery on 40 consecutive consenting patients (20 in each arm). The levels of circulating chromatin will also be estimated at the same time points as CTC for these 40 patients.
3. Evaluation of the paraffin blocks for pTEN loss6-8 and p95ErbB2 truncated form of HER2 on 100 consecutive consenting patients (50 in each arm).9-11

Study Design :

This is phase 3, randomized Double blinded parallel group study of Trastuzumab in pre operative setting in operable breast cancer patients.

Approximately 1000 patients with Women with HER2neu positive, T1/T2/T3 and N0/N1. clinical T4 and/or N2 disease who are considered operable by the treating surgeon with histopathological diagnosis on core biopsies, will be included in the study. Patients with T4 or N2 (locally advanced and large operable for neo-adjuvant chemotherapy) will not be included. All node positive patients will receive single injection of Depot Inj. Progesterone 500 mg deep IM 4 -14 days prior to surgery

Patients will be stratified, before randomization for Tumor size, menopausal status, and affordability for Trastuzumab and centre of the study. These patients will then be randomized 1:1 to receive the following

Intervention arm: .A single dose of Trastuzumab (Herceptin, Hoffman La Roche) at 8 mg/Kg as a 90 minute intravenous infusion in 250 ml of normal saline, in the window period of 10-15 4 to 14 days (both days inclusive) prior to the planned date of surgery.

Control arm: A 90 minute intravenous infusion of saline as placebo

All patients will thereafter receive standard post-operative adjuvant therapy as per local institutional practice including hormonal therapy, chemotherapy and radiation therapy.

Pre Operative Trastuzumab in Operable Breast Cancer

A Phase III Double Blind Randomized Placebo Controlled Study of Trastuzumab as Short Duration Preoperative Therapy in Patients With HER2-neu Positive Operable Breast Cancer

Survival follow-up visits (or information Collected via telephone call) will be conducted approximately every 6 months (ie, 24 weeks) starting from the last day of primary (adjuvant) treatment.

The subject will be called at clinic and will be carefully examined by a member of study team. A mammogram will be done every 18 months. If patient is symptomatic,additional investigations will be performed. Subject status as alive, alive with disease will be documented in the source file.

4.1.1. Overall survival (OS) in all patients and in pathologically node positive patients.

Tata Memorial Hospital

Dr Rajendra A. Badwe

Director and Professor , Surgical Oncology, Tata Memorial Hospital

Carcinoma, Ductal, Breast

Carcinoma, Ductal

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Intraoperative electron radiotherapy (IOERT) is delivered after completion of the lumpectomy and sentinel node procedure. IOERT is performed on a mobile self-shielded magnetron-driven X-band linear accelerator specifically developed for use in the operating room. This machine produces megavoltage electron beams of energy ranging between 4 and 12 MeV. The radiation is delivered from the device to the tumor bed through an attached applicator. A single dose of 21 Gy calculated to the 90% depth posterior to the tumor bed will be administered and will last approximately 2.5 minutes.

Intraoperative Electron Radiotherapy (IOERT) is delivered after completion of the lumpectomy and sentinel node procedure.

Intraoperative Electron Radiotherapy

Barbara Krueger, MD FACS

The overall objective of this study is to determine the feasibility and tolerability of single dose Intraoperative Electron Radiation Treatment ("IOERT") as definitive therapy when administered at the time of breast conserving surgery for patients with early stage breast cancer.

Evaluate local and distant recurrence rates and cosmetic outcomes. Both clinical evaluation of cosmetic outcome by the Surgeon, and subjective impression of cosmetic outcome by the patient, are evaluated using questionnaire.

Local recurrence is evaluated under the same imaging protocol used for Whole breast radiation.

Lumpectomy Followed By Intraoperative Electron Radiation Therapy (IOERT)

Lumpectomy Followed By Intraoperative Electron Radiation Therapy (IOERT) As A Single, Full Dose Partial Breast Irradiation For Early Stage, Node Negative, Invasive Breast Cancer

Subjects will be followed for recurrence rates at one month, three months, six months, twelve months, and then annually for up to 10 years. This will include: history and physical exam, as well as radiographic images at physician discretion and per study protocol.

Assessment of the overall patient satisfaction related to the therapy and cosmetic outcome. Cosmesis will be scored by both the physician and patient using the RTOG cosmesis rating system at one month, three months, six months, twelve months, and 24 months. The secondary outcome measure will only take place in the first two years of the 10 year time frame for patient follow up. After 24 month evaluations, patients will only be followed for incidence of local and distance recurrence rates.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pre Operative Trastuzumab in Operable Breast Cancer	NCT01785420	Carcinoma Breas... HER2 Positive B...	Trastuzumab Placebo	18 Years - 80 Years	Tata Memorial Hospital
Lumpectomy Followed By Intraoperative Electron Radiation Therapy (IOERT)	NCT01960803	Invasive Ductal... Carcinoma Breas...	Intraoperative ...	50 Years - 95 Years	Advocate Health Care
Pre Operative Trastuzumab in Operable Breast Cancer	NCT01785420	Carcinoma Breas... HER2 Positive B...	Trastuzumab Placebo	18 Years - 80 Years	Tata Memorial Hospital

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