A Pilot Trial of Tamoxifen and 4-HPR (4-N-Hydroxyphenyl Retinamide) in Persons at High Risk for Developing Breast Cancer
A Pilot Trial of Tamoxifen and 4-HPR (4-N-Hydroxyphenyl Retinamide) in Persons at High Risk for Developing Breast Cancer
This is a pilot, chemoprevention study. Patients receive fenretinide daily for 25 of every 28
 days for 4 months and tamoxifen daily for 23 months, beginning the second month of
 fenretinide.

 Patients are removed from study for unacceptable toxicity, the development of invasive breast
 cancer, or for dysfunctional uterine bleeding.
This is a pilot chemo-prevention study of the combination tamoxifen and 4-HPR in persons at
 increased risk of developing invasive breast cancer. The objectives of the study are to
 determine the acute and cumulative toxicity of tamoxifen and 4-HPR in high risk persons; to
 assess the feasibility of obtaining adequate tissue to study potential intermediate
 biomarkers of proliferative disease and malignancy using nipple aspiration, four quadrant
 fine needle aspirates, and breast core needle biopsies; and to study the effects of tamoxifen
 and 4-HPR on TGF-beta isoforms and the proliferative markers ki67 and PCNA pre- and
 post-therapy.
POPULATION CHARACTERISTICS:

 Women and men at increased risk for the development of breast cancer by at least one of the
 following criteria:

 Histologically documented ductal carcinoma in situ (DCIS), including DCIS with minimal
 invasion or microinvasion.

 Histologically documented lobular neoplasia, including lobular hyperplasia and lobular
 carcinoma in situ (LCIS).

 Histologically documented atypical ductal hyperplasia in postmenopausal women.

 Histologically documented atypical ductal hyperplasia in premenopausal women with 1
 first-degree relative (mother or sister) diagnosed with breast cancer.

 Histologically documented atypical ductal hyperplasia in premenopausal women with 3 or more
 relatives diagnosed with breast cancer provided at least 1 is a second-degree relative.

 3 or more first- or second-degree relatives diagnosed with breast or ovarian cancer with at
 least 1 diagnosed with breast cancer.

 2 or more premenopausal (under age 50) first-degree relatives diagnosed with breast cancer.

 1 or more first-degree relatives diagnosed with breast cancer if at least 1 relative in the
 extended pedigree had ovarian cancer.

 3 or more relatives with breast cancer with at least 1 first-degree relative diagnosed with
 premenopausal breast cancer.

 Previously diagnosed Stage I breast cancer with surgery and/or radiotherapy only (without
 prior adjuvant chemo- or hormonal therapy).

 Positive for the BRCA1/BRCA2 gene.

 No history of other invasive breast cancer.

 No evidence of malignancy on breast and gynecologic exams.

 Participants with a family history of breast cancer will be seen in consultation by the
 Family Studies Branch, NCI.

 PRIOR/CONCURRENT THERAPY:

 Mastectomy or lumpectomy plus radiotherapy required prior to entry for patients with DCIS.
 Patients with DCIS who have participated in protocol NCI-MB-348 eligible.

 No participation in any other breast cancer prevention study involving pharmacologic
 intervention.

 No prior chemotherapy or hormonal therapy for invasive breast cancer.

 At least 3 months since estrogen or progesterone replacement therapy or hormonal
 contraceptives.

 PATIENT CHARACTERISTICS:

 Age: 35 and over.

 Performance status: Ambulatory.

 Life expectancy: At least 10 years.

 Hematopoietic: Complete blood count normal.

 Hepatic:

 Bilirubin normal.

 Alkaline phosphate normal.

 AST normal.

 PT, PTT normal.

 No history of bleeding disorder.

 No history of chronic hepatitis or cirrhosis.

 Renal:Creatinine less than 1.5 mg/dL.

 Cardiovascular:

 No history of deep venous thrombosis.

 No history of pulmonary embolus.

 Other:

 No allergy to any study medication.

 Capable of tolerating multiple diagnostic procedures.

 No history of abnormal vaginal bleeding. Hysterectomy for vaginal bleeding of benign
 etiology allowed.

 No history of retinal disease, macular degeneration, or night blindness.

 No medical or psychiatric risk due to nonmalignant systemic disease that would preclude
 study participation.

 No history of malignancy except: Curatively treated nonmelanomatous skin cancer. Curatively
 treated in situ cervical carcinoma. Hodgkin's disease treated more than 5 years ago.

 No pregnant women.

 Adequate contraception required of fertile patients during and for 12 months after
 fenretinide and for 2 months after tamoxifen.