Fibroblast growth factor 4 transfection of MCF-7 cells produces cell lines that are tumorigenic and metastatic in ovariectomized or tamoxifen-treated athymic nude mice.

Successful antiestrogen treatment in patients with tamoxifen-responsive breast tumors is often followed by an outgrowth of tumors cells that are antiestrogen resistant, implying that estrogen-dependent tumors can become estrogen-independent. In an effect to mimic this progression, we have transfected fibroblast growth factor 4 into MCF-7 cells, a human breast carcinoma cell line that is estrogen-dependent for growth in nude mice. This transfection results in cell lines that form progressively growing, metastatic tumors when injected s.c. into untreated or tamoxifen-treated ovariectomized nude mice. In contrast to the parental cell line, growth of transfected cells in ovariectomized nude mice is stimulated by tamoxifen treatment and inhibited by estrogen treatment of the mice. Parental MCF-7 cells were transfected with an expression vector for beta-galactosidase, conferring the ability to convert the chromogenic substrate, 5-bromo-4-chloro-3-indoyl-beta-galactoside, to a blue color and allowing the detection of their presence within tumors developing after coinoculation with fibroblast growth factor 4-transfected cells. The fibroblast growth factor 4-transfected cells could support growth and metastasis of the beta-galactosidase-expressing parental cell line when both lines were coinjected into the same site in untreated or tamoxifen-treated, ovariectomized mice. These data suggest a possible role for fibroblast growth factors in the progression of breast tumors to an estrogen-independent, antiestrogen-resistant, metastatic phenotype. They also support a role for paracrine factors in mixed populations of tumor cells of differing states of malignant progression.

Intensive outpatient adjuvant therapy for breast cancer: results of dose escalation and quality of life.

PURPOSE: A dose-escalation study was conducted to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cyclophosphamide (CY) in combination with granulocyte colony-stimulating factor (G-CSF0 and doxorubicin (DOX) given every 2 weeks for eight cycles as outpatient adjuvant therapy for node-positive breast cancer. A pilot study to assess quality of life (QOL) was performed. PATIENTS AND METHODS: From March 1991 to April 1993, 19 patients were entered. Patients received escalating doses of CY intravenously (i.v.) (1,000 mg/m2, 1,500 mg/m2, 2,000 mg/m2, or 2,500 mg/m2) with DOX 40 mg/m2, G-CSF 10 micrograms/kg/d on days 2 to 12, and mesna, every 2 weeks for eight cycles. QOL was measured by the Profile of Mood States (POMS), the Psychosocial Adjustment to Illness Scale-Self Report (PAIS-SR), and a 27-item QOL scale. RESULTS: The CY dose of 2,500 mg/m2 every 2 weeks elicited toxicities that required dose reductions secondary to a combination of thrombocytopenia, hematuria, and anemia that required transfusion. The dose of 2,000 mg/m2 resulted in an acceptable toxicity profile. Ninety-two percent of cycles at the 2,000-mg/m2 dose were delivered on schedule and 77% without hospitalization. QOL assessments indicated high levels of distress measured by POMS in 47%, poor overall quality of life in 40%, and significant problems with physical symptoms in less than 27% of all patients for any given cycle. CONCLUSION: A dose of CY at 2,000 mg/m2 can be administered every 2 weeks with DOX and G-CSF for eight cycles in the outpatient setting with manageable toxicity. The majority of women described levels of physical symptoms and emotional distress as tolerable during treatment.

Tamoxifen for the reduction in the incidence of breast cancer in women at high risk for breast cancer.

Recent legislation, including the Prescription Drug User Fee Act (1992) and the FDA Modernization Act (FDAMA) (1997), has provided an environment in which new drug applications (NDA) can be efficiently reviewed, resulting in rapid access to new drugs or to new uses for approved drugs by the public. The recent submission of a supplemental NDA for tamoxifen for the reduction in the incidence of breast cancer in women at high risk for breast cancer is an excellent example of the application of this legislation. First, the application received expedited but thorough multidisciplinary and interdivisional review by the FDA. Second, it required collaboration between the manufacturer (AstraZeneca Pharmaceuticals), the National Surgical Adjuvant Breast and Bowel Project (NSABP), the National Cancer Institute (NCI), and the FDA. This process worked well and demonstrated that cooperative group data can be used effectively to support an application. Third, a single large adequate and well-controlled trial was sufficient to support the effectiveness of tamoxifen for this indication. The quantity of evidence required to support approval has been discussed in FDA guidances ("Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products") and is part of FDAMA.

Mitoxantrone, 5-FU, and leucovorin in breast cancer.

Eighteen patients (17 evaluable for response) with metastatic breast cancer were treated with mitoxantrone 10 mg/m2 day 1, followed by 5-fluorouracil 375 mg/m2 day 1-5, and high-dose leucovorin 500 mg/m2 day 1-5 given every 28 days. There was one complete and four partial responses for an objective response rate of 30% and 41% stable disease. The major toxicities were hematologic and gastrointestinal. This regimen has activity in metastatic breast cancer comparable to conventional and/or standard chemotherapy regimens for advanced disease.

Clinical breast cancer research core.

The primary purpose of the clinical breast cancer research core is to support the research of the five SPORE projects, and the high priority projects and other studies of SPORE Investigators. The specific aims of the CORE are as follows: The first aim is to provide the project investigators of the SPORE grant with access to a clinical research facility. A second aim is to provide the investigators with a clinical database linked to the tumor bank for the facilitation of studies to improve the diagnosis and prognosis of breast cancer. A third aim is to develop and maintain a serum and DNA lymphocyte bank which will enable investigators to take prognostic or therapy response factors developed in the laboratory and evaluate their clinical significance.

A phase II trial of paclitaxel (Taxol) as first line treatment in advanced breast cancer.

Paclitaxel (Taxol) is a natural product with a broad spectrum of activity against various solid tumors. This report includes nineteen patients with advanced breast cancer who have not previously received chemotherapy for metastatic disease. Fifteen patients had received adjuvant chemotherapy, eight of which were doxorubicin based. Patients were treated with 135 mg/m2 over 24 hours by continuous infusion given every 21 days. There were 2 complete and 4 partial responses for an objective response rate of 32% (95% C.I.: 14%, 57%) and eight patients or 42% with stable disease. Three of eight patients (38%) who had received adjuvant doxorubicin did respond to paclitaxel. Responses occurred in lung, liver, and soft tissue. The primary toxicity was hematologic with 13 hospitalizations for febrile neutropenia in 180 cycles (7%). Paclitaxel has moderate activity in a small number of patients with metastatic breast cancer at the dose of 135 mg/m2 over 24 hours in this study.