Young age at first pregnancy does protect against early onset breast cancer in BRCA1 and BRCA2 mutation carriers.

PURPOSE: Previous research assessing the impact of pregnancy and age at first pregnancy on breast cancer risk in BRCA1 and BRCA2 mutation carriers has produced conflicting results, with some studies showing an increased risk following early first pregnancy in contrast to the reduced risk in the general population of women. The present study addresses these inconsistencies. METHODS: Female BRCA1 and BRCA2 carriers from North West England were assessed for breast cancer incidence prior to 50 years of age comparing those with an early first full-term pregnancy (< 21 years) to those without a full-term pregnancy. Breast cancer incidence per decade from 20 years and Kaplan-Meier analyses were performed. RESULTS: 2424 female mutation carriers (1278 BRCA1; 1146 BRCA2) developed 990 breast cancers under the age of 50 years. Women who had their first term pregnancy prior to age 21 (n = 441) had a lower cancer incidence especially between age 30-39 years. Kaplan-Meier analysis showed an odds ratio of 0.78 for BRCA1 (p = 0.005) and 0.73 for BRCA2 (p = 0.002). CONCLUSIONS: The present study demonstrates a clear protective effect of early first pregnancy on breast cancer risk in both BRCA1 and BRCA2 mutation carriers.

In vitro growth and drug sensitivity of tumor colony-forming units from human tumor xenografts.

To investigate the feasibility of using tissue obtained from human tumor xenografts for in vitro screening of antineoplastic agents, we grew human tumor colony-forming units (CFU) in semisold agar from xenografts serially passaged in nude mice. Growth of human tumor CFU was accomplished from nine xenografts representing five different histological tumor types (ovarian carcinoma, adenocarcinoma of the colon, malignant melanoma, epidermoid carcinoma of the lung, and malignant astrocytoma). Cloning efficiency ranged from 0.04 to 0.1% and showed significant variability both between tumor types and between individual animals bearing the same type of xenograft. A high percentage of tumor CFU was in S phase [47 +/- 20% (S.D.)] as determined by the thymidine "suicide" technique. The number of tumor CFU observed increased linearly with increasing numbers of cells plated. In vitro drug sensitivity of the tumor CFU was assessed to Adriamycin, cis-platinum, and melphalan. The patterns of drug sensitivity were found to be reproducible and stable over a period of 9 months. Drug sensitivity curves to Adriamycin for five xenografts representing four tumor types showed complex patterns with plateau portions similar to those described for tumor CFU from primary tumors. The rank order of sensitivity of the tumors was compared to that of normal granulocyte-macrophage progenitors and, with the exception of the melanomas, was found to correlate well with clinical experience (order of sensitivity = colon less than ovary less than bone marrow). Growth of human tumor CFU from xenografts represents a reproducible and stable means for the study of the biology of tumor CFU and has potential applications as a means for screening new anticancer agents.

Nephrotoxicity of cis-platinum (II) dichlorodiammine.

The renal function of 15 patients receiving cis-platinum (II) dichlorodiammine (CPDD) was examined prospectively in detail to elucidate early evidence of nephrotoxicity. Patients were given a total of 49 couses of CPDD at 20 mg/m2/day for 5 days with 1,000 ml of saline prehydration. Renal function was monitored by serial determinations of serum creatinine and glomerular filtration rate (measured as 125I-iothalamate clearance) and by measurement of parameters of tubular function, including tubular reabsorption of phosphorus, urine-to-serum glucose ratio, total protein, and total free immunoglobulin light chain excretion, serum electrolytes, and urine pH and specific gravity. There was no significant change in mean serum creatinine within a course of treatment, nor was there a cumulative increase in the serum creatinine. In 9 of 19 evaluable courses there was a small transient fall in glomerular filtration rate with prompt recovery. There was no cumulative decrease in glomerular filtration rate through 3 courses of treatment. Four of the patients with preexisting renal insufficiency suffered no significant additional nephrotoxicity. There was no tubular dysfunction demonstrable in any of the patients. This study represents the first prospective detailed examination of multiple parameters of renal function in patients treated with CPDD and reveals that the only parameter to show any change with this schedule of drug administration was the glomerular filtration rate.