6. Other Local Therapy 6.1 Phase II Pilot Study of MRI-Guided Focused Ultrasound Ablation in Women with Stage I-IIIA Breast Cancer

Objectives

I. Determine the incidence and severity of adverse events during and after MRI-guided focused ultrasound ablation in women with stage I-IIIA breast cancer.

II. Determine the ability to accurately and thoroughly coagulate a target volume of breast carcinoma, in terms of real-time target volume temperature profile, follow-up MRI, and histology, using this procedure.

III. Compare the appearance of gross and microscopic histopathologic tissue post coagulation with the pre- and post-coagulation magnetic resonance appearance of the targeted volume and measure any residual cancer cells in patients following this procedure.

IV. Determine patient acceptance of this procedure in terms of positioning, pain, safety, and follow- up cosmesis.

Participation Criteria

• Histologically confirmed invasive breast cancer (T1, N0-2, M0).
  
  
• Single focal lesion no greater than 2 cm in diameter by MRI.
  
  
• No lesions difficult to target, defined as less than 1 cm from skin, nipple, or rib cage.
  
  
• No microcalcifications as sole sign of disease.
  
  
• No extensive intraductal components on core biopsy, defined as intraductal carcinoma comprising 25% or more of the invasive breast cancer AND intraductal carcinoma in surrounding normal tissue.
  
  
• No breast implants. n At least 3 months since prior chemotherapy.
  
  
• Concurrent hormone replacement therapy allowed.
  
  
• Concurrent tamoxifen allowed.
  
  
• No concurrent steroids.
  
  
• No prior external radiotherapy or laser therapy to ipsilateral breast.

Protocol

Patients undergo MRI-guided focused ultrasound (MRgFUS) ablation of the breast lesion using a series of pulses. Within 72 hours after MRgFUS procedure, patients undergo gadolinium-enhanced MRI to evaluate ablation borders. Within 7-10 days after MRgFUS procedure, patients undergo an ultrasound exam, and metallic beads may be placed to assist in pre-surgical lesion localization. Within 10-21 days after MRgFUS procedure, patients undergo segmental resection or mastectomy. Patients are followed at 5-10 days post-surgery.

Robert W. Newman, Chair
Ph: 214-630-2000 TxSonics, Inc. Principal Investigator Darrell Smith Ph: 617-732-5228 Dana-Farber Cancer Institute Boston, Massachusetts

6.2 Phase I Study of Intralesional Gene Therapy Plus Chemotherapy in Patients with Breast Cancer

Objectives

I. Determine the effect of adenovirus p53 (Ad-p53) on chemotherapy-induced apoptosis in lesions in patients with breast cancer.

II. Determine p53 protein expression following intralesional injections of Ad-p53 by immunohistochemistry and reverse transcriptase polymerase chain reaction in this patient population.

III. Determine the time course and magnitude of the development of a humoral antibody response to the adenoviral vector in this patient population.

IV. Determine the ability of transfected p53 to upregulate downstream signals important in G1 arrest by assaying for WAF1 mRNA and apoptosis in this patient population.

V. Determine the toxicities and side effects of intralesional injections of Ad-p53 given in combination with standard chemotherapy in patients with cutaneous and subcutaneous metastatic breast cancer amenable to injections and biopsies.

VI. Determine if there is an increase in apoptosis induced by Ad-53 compared to baseline in this patient population.

Participation Criteria

• Histologically confirmed epithelial breast cancer.
  
  
• At least 3 cutaneous or subcutaneous lesions required.
  
  
• Measurable disease that includes, but is not limited to, cutaneous or subcutaneous metastases.
  
  
• Hormone receptor status: Not specified.
  
  
• Concurrent cytotoxic chemotherapy allowed, if stable and responding.
  
  
• At least 4 weeks since prior chemotherapy, if starting a new regimen.
  
  
• At least 4 weeks since radiotherapy.
  
  
• Prior adjuvant radiotherapy to the chest wall allowed.
  
  
• At least 6 months since radiotherapy to lesions that are to be injected.

Protocol

Patients undergo biopsy of one of their skin nodules prior to any treatment. Patients receive the Ad-p53 gene therapy in one nodule and injection of a second nodule with Dulbecco's phosphate-buffered saline. The next day, patients begin chemotherapy, which may be given weekly and continues every 21-28 days for up to 6 courses. On day 3, patients return for biopsy of injected nodules. Biopsies are only performed during the first course. Patients may receive further injections of the Ad-p53 gene with subsequent courses of chemotherapy, for up to six courses.

Margaret von Mehren, Chair
Principal Investigator
Ph: 215-728-2626 Fox Chase Cancer Center Philadelphia, Pennsylvania