Serum estrogen and androgen levels following treatment for cervical cancer.

Endogenous sex hormones seem to influence the risk of several common and debilitating diseases. With a view toward better understanding the effects of surgical removal of the ovaries and high-dose pelvic radiotherapy on plasma sex hormone levels, we measured estrogen and androgen concentrations cross-sectionally among 147 women who had been treated for cervical cancer 0.3-18.5 years previously. Pelvic radiotherapy (mean dose to ovaries, 50 Gy) and bilateral ovariectomy were associated with similarly reduced hormone concentrations relative to levels among nonirradiated women with intact ovaries, most of whom had had early-stage disease and were treated by hysterectomy. There was little evidence that radiotherapy in addition to ovariectomy further lowered concentrations below levels associated with ovariectomy alone, such as might be expected if radiation was suppressing adrenal endocrine function. Among women age 50 years or older at the time of blood drawing, the removal or irradiation of the ovaries was associated with approximately 45% lower concentrations of estradiol (mean ratio [MR], 0.55; 95% confidence interval [CI], 0.32-0.95) and testosterone (MR, 0.57; 95% CI, 0.32-0.99), and 25-30% lower concentrations of estrone (MR, 0.69; 95% CI, 0.44-1.09) and androstenedione (MR, 0.76; 95% CI, 0.47-1.23), relative to the hysterectomy-only group. Among women younger than 50, ovariectomy and radiotherapy, alone or in combination, were associated with 83% lower estradiol concentrations (MR, 0.17; 95% CI, 0.09-0.31), 46% lower estrone concentrations (MR, 0.54; 95% CI, 0.37-0.81), 23% lower androstenedione concentrations (MR, 0.77; 95% CI, 0.57-1.04), and 14% lower testosterone levels (MR, 0.86; 95% CI, 0.64-1.15).(ABSTRACT TRUNCATED AT 250 WORDS)

Modifying effect of reproductive risk factors on the age at onset of breast cancer for German BRCA1 mutation carriers.

Female carriers of mutations in the BRCA1 gene on chromosome 17q have a very high risk of developing breast and/or ovarian cancer during their lifetime. There is, however, little knowledge of to what extent non-genetic risk factors, such as age at menarche, age at first birth, and body mass index, alter the age at onset of disease. We identified individuals showing a high probability of linkage to BRCA1 and examined the effect of other known risk factors on disease risk. A total of 43 families with at least three breast or ovarian cancer cases, including two affected before 60 years of age, were studied for linkage to the susceptibility locus BRCA1. Blood samples from relevant family members were used to genotype for at least three chromosome 17q polymorphic markers. Information on reproductive history, hormone use and lifestyle factors was collected from female members using a self-administered questionnaire. Diagnoses of breast and ovarian cancer were verified through pathology reports and paraffin blocks were obtained when available. Multipoint LOD (logarithm of the odds) scores were calculated and individuals from 10 families with a posteriori probability for linkage greater than 0.90 were used for further analysis. Forty-six BRCA1 carriers were identified by the disease haplotype; 30 were affected with breast cancer and 5 with ovarian cancer. Proportional- hazards analysis of age at onset of breast cancer yielded increased relative risks of 1.74 for early age at menarche (< 14 years), 1.58 for late age at first birth (> or = 25 years) or nulliparity, and 2.78 for recent year of birth (> or = 1940); however, none of the risk estimates was statistically significant. When both breast and ovarian cancer were considered as disease endpoints, the birth cohort effect was stronger and age at first birth showed no effect. Our data provide some evidence that reproductive risk factors for breast cancer have an effect on age at onset for BRCA1 carriers. However, considering that our analyses were based on limited numbers, these results warrant further clarification.

Antibody reactivity with HBLV (HHV-6) in U.S. populations.

500 sera representing healthy blood donors and a random representation of the U.S. population collected 10 years ago were screened by ELISA for antibody reactivity with purified, disrupted HBLV virions. In each group, the ELISA results were normally distributed with no evidence of bimodality. All sera were subsequently retested after preincubation of each with well-characterized preparations of disrupted HSB-2 cells or HBLV-infected HSB-2 cells. Sera showing significant levels of HBLV-specific neutralization (50% or more) were found in Minneapolis, Kansas City, and in a random population survey (81, 88 and 97% of donors, respectively). Mean ELISA test values were the same for all groups and for males and females within the same group. Sera from these normal donors reacted preferentially with viral antigens of 120 and 58 kDa by Western blot. In a hospital-based prevalence study, frequent IgM and IgG seroconversions were apparent among infants less than 1 year old, and mean ELISA test values reached the adult level before school age. Antigen preparations used in blocking experiments showed no competitive cross-reactivity with antisera against EBV, CMV, HSV, VZV, HIV, or adenovirus type 2 at levels which reduced antibody binding to HBLV by more than 90%. Antibody cross-reactivities towards HBLV and other human herpesviruses were assessed by cross-correlation of viral antibody titers against all of the viruses and by cross-absorptions of antisera against the other viruses with HBLV. In these experiments no antibody cross-reactivity between HBLV and other human herpesviruses were detected. The significance of these findings with respect to health/disease status is presently unknown. Further seroepidemiologic studies of quantitative levels of HBLV antibody reactivity to measure the age of primary infection and progressive changes in healthy and selected disease populations are needed to determine the risk of disease associated with HBLV infection.

[The importance of genetic factors for development of breast cancer]. / Die Bedeutung genetischer Faktoren für die Entstehung von Brustkrebs.

It is well documented that breast cancer aggregates in certain families suggesting a genetic etiology for this cancer. Numerous epidemiologic studies have shown that women with a first degree relative (mother, sister) with breast cancer have double the risk of developing this cancer when compared to women in the general population. More recent studies have shown that the magnitude of the risk of developing breast cancer is dependent on the age at diagnosis and the number of relatives affected. Aggregation of breast cancer in families in itself does not clarify the true nature of the underlying factors which could be genetic or due to familial resemblance in other risk factors. Complex segregation analyses of breast cancer families suggest that breast cancer susceptibility is inherited in some families as an autosomal dominant trait. Recently, a breast cancer susceptibility gene, BRCA1, has been mapped to chromosome 17q12-q21 through linkage analyses. BRCA1 appears to play a role in families with a large number of breast cancer cases who have developed breast cancer before the age 45, and/or who have breast and ovarian cancer cases. The risk of cancer for female carriers of the BRCA1 mutation has been estimated to be 87% for breast cancer and 44% for ovarian cancer by the age of 70. BRCA1 seems to play a role in only a proportion of affected families and it is likely that other genes are also involved. In the majority of breast cancer families with two or three cases, BRCA1 appears to play a small role.

Familial risk and genetic susceptibility for breast cancer.

Clinical observations suggest that breast cancer is occasionally inherited as an autosomal dominant disease in families. Epidemiologic studies consistently have shown that a history of breast cancer in a first-degree relative increases a woman's risk of breast cancer when compared with the general population. The risk is similar if a mother or sister is affected and is increased further if both are affected. The difficulty with such an observation is that in itself it does not clarify the nature of the true underlying risk factors which could be genetic or due to the aggregation of environmental risk factors in families. Complex segregation analysis of breast cancer aggregation in families suggests that breast cancer susceptibility is due to an autosomal dominant inheritance of one or more rare genes in a few families in which carriers have a high probability of developing the disease perhaps as great as 100 percent. Close linkage of a breast-cancer-susceptibility gene (BRCA1), between markers of the chromosomal region 17q12-q21 on the long arm of chromosome 17, with breast cancer recently has been reported. Families linked to BRCA1 were more likely to have early onset of breast cancer or have breast and ovarian cancer in the family. It is likely that other genes play a role in the unlinked breast-cancer families. Both the epidemiologic and genetic data suggest that breast cancer is a heterogeneous disease.

Impact on second malignancy risk of the combined use of radiation and chemotherapy for lymphomas.

The risk of a second malignancy was determined for 999 patients given primary treatment using chemotherapy only, radiation therapy only, or both for Hodgkin's Disease or a non-Hodgkin's lymphoma at Duke University Medical Center between 1970 and 1981. The incidence, 10-year actuarial risk, and relative risk of developing an acute leukemia, solid tumor, or second lymphoma were determined by treatment modality and initial lymphoma type. Among the 313 Hodgkin's disease patients, the acute leukemia actuarial risk was 2.0% after chemotherapy, 1.4% after radiation therapy, and 0.9% after combined treatment with chemotherapy and radiation therapy. Their relative risk for acute leukemia was 51.3 overall (95% confidence interval [CI] 13.8 to 131.8) and was elevated in each treatment group. Among the 686 non-Hodgkin's lymphoma patients, the acute leukemia actuarial risk was zero after radiation therapy, 4.6% after chemotherapy, and 4.5% after the combined treatment, again not significantly different between treatment groups. The leukemia relative risk was 10.6 (95% CI 3.4 to 24.8) in the chemotherapy and 11.9 (95% CI 3.2 to 30.6) in the combined treatment group. Among both the Hodgkin's disease and non-Hodgkin's lymphoma populations, the combined treatment group had a lower actuarial risk for solid tumors than either the chemotherapy or radiation therapy group (P less than 0.02). Solid tumor actuarial risk did not differ significantly between the chemotherapy and radiation therapy groups. Hodgkin's disease patients had a solid tumor relative risk that was elevated significantly after radiation therapy (6.5; 95% CI 2.4 to 14.0) and to a lesser extent after chemotherapy (2.6; 95% CI 0.8 to 6.1) or combined treatment (1.7; 95% CI 0.2 to 6.0). Solid tumor relative risk among non-Hodgkin's lymphoma patients was 0.3 for the combined treatment, 0.8 for the chemotherapy, and 1.0 for the radiation therapy group. None of the Hodgkin's disease patients developed a non-Hodgkin's lymphoma. This study found no significant difference in leukemia risk among lymphoma patients treated with chemotherapy and the combined treatment. It also found that the overall risk of a second malignancy is no higher after treatment with the combined therapy than with chemotherapy or radiation therapy alone.

Impact of radiation therapy and/or chemotherapy on the risk for a second malignancy after breast cancer.

The risk of any second malignancy was determined for all patients treated for a primary cancer of the breast without evidence of distant metastasis at Duke University Medical Center between 1970 and 1981. The incidence, 10-year actuarial risk (AR), and relative risk (RR) of a second malignancy developing were calculated for the 407 patients who were treated with surgery alone, 226 who were treated with surgery followed by adjuvant chemotherapy (CT), 140 who were treated with surgery plus adjuvant radiation therapy (RT), and 308 who received all three modalities (CRT). The AR of a subsequent cancer (8.4% for CRT, 8.7% for CT, 8.7% for RT, and 11.7% for surgery only patients) did not differ significantly between treatment groups. The overall second cancer RR was 1.0% after CRT (95% confidence interval [CI], 0.4 to 2.0), 1.3% after RT (95% CI, 0.6 to 2.5), 1.6% after CT (95% CI, 0.9 to 2.6), and 1.7% after surgery alone (95% CI, 1.2 to 2.4). Contralateral breast cancers (RR of 4.2%; 95% CI, 2.7 to 6.3) account for the statistically significant excess of second malignancies among the surgery alone patients. The AR for contralateral breast cancer in the surgery group was higher than in either group receiving CT (P less than 0.01), but was not significantly different from the RT group. The RR for solid tumors other than breast cancer was not significantly different from unity in any of the treatment groups. The RR for acute leukemia was 16.7% in the CRT group (95% CI, 0.2 to 92.7), 11.1% in the CT group (95% CI, 0.1 to 61.8), 10.0% in the surgery alone group (95% CI, 1.1 to 36.1), and 0.0% in the RT group (95% CI, 0.0 to 61.1). This study indicated that inclusion of RT and/or CT in the initial treatment of breast cancer did not impact negatively on patients' overall risk for a subsequent malignancy during the first decade after therapy, and that adjuvant CT with or without RT may decrease their risk of a contralateral breast cancer.

Breastfeeding and breast cancer risk by age 50 among women in Germany.

BACKGROUND: Epidemiological evidence which suggests that prolonged breastfeeding protects against breast cancer has accumulated in recent years. Issues with regard to the timing of breastfeeding and effect modification by correlates of breastfeeding and other risk factors of breast cancer remain unresolved. METHODS: A population-based case control family study of breast cancer among women diagnosed by the age of 50, conducted in two geographic areas in Germany, was used to evaluate the effect of breastfeeding on risk of breast cancer. RESULTS: Among parous women in this study (553 cases, 1094 age-matched population controls), having ever breastfed a child for at least 1 month did not confer protection (odds ratio of 0.9 and 95% confidence interval (CI) 0.8-1.2). However, risk of breast cancer significantly decreased with increasing duration of breastfeeding (p for trend = 0.01) and the estimated relative risk was 0.6 (95% CI 0.4-0.9) for 13-24 months of cumulative breastfeeding and 0.5 (95% CI 0.3-1.1) for 25 months or more. Risk was less related to number of children breastfed than to increasing average length of breastfeeding per child (p for trend = 0.03). CONCLUSIONS: The reduction in risk associated with duration of breastfeeding was not primarily due to breastfeeding the firstborn and more evident in women who were older (> 25 years) when they first breastfed and among women who experienced a recent full-term pregnancy. Risks were modified somewhat by a first-degree family history of breast cancer whereby a greater reduction in risk per additional month of breastfeeding was observed among women with a family history than those without (0.9 vs. 1.0). The study results support a protective role of prolonged breastfeeding against the development of breast cancer in predominantly premenopausal women in Germany.

Increasing incidence of primary brain lymphoma in the US.

There have been a number of clinical reports suggesting an increasing incidence of primary brain lymphoma unrelated to acquired immune deficiency syndrome (AIDS) and organ transplantation. To investigate this issue, the US incidence of this rare lymphoma was assessed using data from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program (1973 through 1984). Never-married men, a relatively high risk group for AIDS, were excluded from the analyses. Brain lymphoma incidence increased from 2.7 in 1973 through 1975 to 7.5 cases per ten million population in 1982 through 1984 (chi-square trend, 15.25; P less than 0.001), and it increased among both men (chi-square trend, 6.74; P = 0.009) and women (chi-square trend, 10.48; P = 0.001). Increases in incidence also were observed among persons younger than 60 years of age (chi-square trend, 4.10; P = 0.04) and persons 60 years of age and older (chi-square trend, 9.16; P = 0.002). This increased incidence of brain lymphoma appears to be real: It antedates the AIDS epidemic and does not appear to be related to organ transplantation, another cause of increased risk of brain lymphoma. Although part of the increase may be an artifact of improvements in diagnostic technology and practice, most of the observed increase antedates the widespread use of such technologies. Finally, the increase in incidence of brain lymphoma does not appear to be related to overall trends in the incidence of brain tumors and non-Hodgkin's lymphoma, and it is not related to time trends in nosology.

Estrogen and androgen levels in women treated with radiation for cervical cancer--possible influence on breast cancer risk.

In 1984-1985, estrogen and androgen levels in blood sera were measured in 320 women who had been treated for cervical cancer in the early 1960s. Study subjects were from US clinics in Baltimore, Maryland; Boston and Norfolk, Massachusetts; Buffalo, New York; Houston, Texas; and San Juan, Puerto Rico. These clinics had participated in a larger international follow-up study of cervical cancer in which a 20-30% reduction in breast cancer risk was linked to prior pelvic irradiation, even when treatment occurred after menopause. Overall, the 203 irradiated and 117 nonirradiated women had similar mean levels of estradiol, estrone, androstenedione, and testosterone. However, there appeared to be negative, albeit inconsistent, trends for androstenedione, testosterone, and estrone, suggesting that the irradiated women had lower levels of these hormones when compared with the nonirradiated women. These differences did not reach the level of statistical significance. While chance could partially explain these findings, it is plausible that the frequently observed protective association of breast cancer with pelvic irradiation could be due in part to a decrease in steroid hormones that is secondary, perhaps, to adrenal irradiation.