Timing of HPV16-E6 antibody seroconversion before OPSCC: findings from the HPVC3 consortium.

BACKGROUND: Human papillomavirus type 16 (HPV16)-E6 antibodies are detectable in peripheral blood before diagnosis in the majority of HPV16-driven oropharyngeal squamous cell carcinoma (OPSCC), but the timing of seroconversion is unknown. PATIENTS AND METHODS: We formed the HPV Cancer Cohort Consortium which comprises nine population cohorts from Europe, North America and Australia. In total, 743 incident OPSCC cases and 5814 controls provided at least one pre-diagnostic blood sample, including 111 cases with multiple samples. Median time between first blood collection and OPSCC diagnosis was 11.4 years (IQR = 6-11 years, range = 0-40 years). Antibodies against HPV16-E6 were measured by multiplex serology (GST fusion protein based Luminex assay). RESULTS: HPV16-E6 seropositivity was present in 0.4% of controls (22/5814; 95% CI 0.2% to 0.6%) and 26.2% (195/743; 95% CI 23.1% to 29.6%) of OPSCC cases. HPV16-E6 seropositivity increased the odds of OPSCC 98.2-fold (95% CI 62.1-155.4) in whites and 17.2-fold (95% CI 1.7-170.5) in blacks. Seropositivity in cases was more frequent in recent calendar periods, ranging from 21.9% pre-1996 to 68.4% in 2005 onwards, in those with blood collection near diagnosis (lead time <5 years). HPV16-E6 seropositivity increased with lead time: 0.0%, 13.5%, 23.7%, and 38.9% with lead times of >30 years (N = 24), 20-30 years (N = 148), 10-20 years (N = 228), and <10 years (N = 301 cases) (p-trend < 0.001). Of the 47 HPV16-E6 seropositive cases with serially-collected blood samples, 17 cases seroconverted during follow-up, with timing ranging from 6 to 28 years before diagnosis. For the remaining 30 cases, robust seropositivity was observed up to 25 years before diagnosis. CONCLUSIONS: The immune response to HPV16-driven tumorigenesis is most often detectable several decades before OPSCC diagnosis. HPV16-E6 seropositive individuals face increased risk of OPSCC over several decades.

Polymorphisms in the estrogen receptor alpha gene (ESR1), daily cycling estrogen and mammographic density phenotypes.

BACKGROUND: Single nucleotide polymorphisms (SNPs) involved in the estrogen pathway and SNPs in the estrogen receptor alpha gene (ESR1 6q25) have been linked to breast cancer development, and mammographic density is an established breast cancer risk factor. Whether there is an association between daily estradiol levels, SNPs in ESR1 and premenopausal mammographic density phenotypes is unknown. METHODS: We assessed estradiol in daily saliva samples throughout an entire menstrual cycle in 202 healthy premenopausal women in the Norwegian Energy Balance and Breast Cancer Aspects I study. DNA was genotyped using the Illumina Golden Gate platform. Mammograms were taken between days 7 and 12 of the menstrual cycle, and digitized mammographic density was assessed using a computer-assisted method (Madena). Multivariable regression models were used to study the association between SNPs in ESR1, premenopausal mammographic density phenotypes and daily cycling estradiol. RESULTS: We observed inverse linear associations between the minor alleles of eight measured SNPs (rs3020364, rs2474148, rs12154178, rs2347867, rs6927072, rs2982712, rs3020407, rs9322335) and percent mammographic density (p-values: 0.002-0.026), these associations were strongest in lean women (BMI, ≤23.6 kg/m2.). The odds of above-median percent mammographic density (>28.5 %) among women with major homozygous genotypes were 3-6 times higher than those of women with minor homozygous genotypes in seven SNPs. Women with rs3020364 major homozygous genotype had an OR of 6.46 for above-median percent mammographic density (OR: 6.46; 95 % Confidence Interval 1.61, 25.94) when compared to women with the minor homozygous genotype. These associations were not observed in relation to absolute mammographic density. No associations between SNPs and daily cycling estradiol were observed. However, we suggest, based on results of borderline significance (p values: 0.025-0.079) that the level of 17ß-estradiol for women with the minor genotype for rs3020364, rs24744148 and rs2982712 were lower throughout the cycle in women with low (<28.5 %) percent mammographic density and higher in women with high (>28.5 %) percent mammographic density, when compared to women with the major genotype. CONCLUSION: Our results support an association between eight selected SNPs in the ESR1 gene and percent mammographic density. The results need to be confirmed in larger studies.

Estimating risks for variants of unknown significance according to their predicted pathogenicity classes with application to BRCA1.

Sequence-based testing of disease-susceptibility genes has identified many variants of unknown significance (VUSs) whose pathogenicity is unknown at the time of their measurement. Female breast cancer cases aged 20-49 years at diagnosis and who have VUSs in BRCA1 and no mutations in BRCA2 have previously been identified through the population-based Los Angeles County Cancer Surveillance Program. These nominal BRCA1 VUSs have been classified as "low," "medium," and "high" risk by four classification methods: Align-GVGD, Polyphen, Grantham matrix scores, and sequence conservation in mammalian species. Average hazard ratios (HRs) for classes of variants, i.e., the age-specific incidences of cancer for carriers of such variants divided by the population incidences, were estimated from the cancer family histories of first- and second-degree relatives of the index cases using modified segregation analysis. The study sample comprised 270 index cases and 4,543 of their relatives. There was weak evidence that the risk of breast cancer increases with the degree of sequence conservation (P = 0.03) and that missense variants at highly conserved sites are associated with a 5.6-fold (95 % confidence interval 1.4-22.2; P = 0.05) increased incidence of breast cancer. An upper bound of 2.3 is given for the average breast cancer HRs corresponding to variants classified as "low risk" by any of the four VUS classification methods. In summary, we have given a method to estimate cancer risks for groups of VUSs by combining existing classification methods with traditional penetrance analyses. This analysis suggests that classification methods for BRCA1 variants based on sequence conservation might be useful in a clinical setting. We have shown in principle that our method can be used to classify VUSs into clinically useful risk categories, but our specific findings should not be put into clinical practice unless confirmed by larger studies.

Meat consumption and the risk of type 2 diabetes: a systematic review and meta-analysis of cohort studies.

AIMS/HYPOTHESIS: Diet is thought to play an important role in the aetiology of type 2 diabetes. Previous studies have found positive associations between meat consumption and the risk of type 2 diabetes, but the results have been inconsistent. We conducted a systematic review and meta-analysis of cohort studies of meat consumption and type 2 diabetes risk. METHODS: We searched several databases for cohort studies on meat consumption and type 2 diabetes risk, up to December 2008. Summary relative risks were estimated by use of a random-effects model. RESULTS: We identified 12 cohort studies. The estimated summary RR and 95% confidence interval of type 2 diabetes comparing high vs low intake was 1.17 (95% CI 0.92-1.48) for total meat, 1.21 (95% CI 1.07-1.38) for red meat and 1.41 (95% CI 1.25-1.60) for processed meat. There was heterogeneity amongst the studies of total, red and processed meat which, to some degree, was explained by the study characteristics. CONCLUSIONS/INTERPRETATION: These results suggest that meat consumption increases the risk of type 2 diabetes. However, the possibility that residual confounding could explain this association cannot be excluded.

Postmenopausal hormone therapy with estradiol and norethisterone acetate and mammographic density: findings from a cross-sectional study among Norwegian women.

BACKGROUND: Although a number of studies have evaluated the associations between use of postmenopausal hormone therapy (HT) and mammographic density, few have assessed the effects of the medications containing estradiol (E2) plus norethisterone acetate (NETA). In particular, there are few data on the effects of the low-dose E2/NETA regimen. METHODS: We included data from 724 women, aged 50-70 years, residing in south-east Norway, who participated in a cross-sectional study conducted within the Norwegian Breast Cancer Screening Program. We assessed mammographic density using a previously validated computer-assisted method. RESULTS: After adjusting for age at screening, number of children and body mass index, women who currently used HT had 6.0% higher percent mammographic density than never-users, p < 0.0001. Women who used either low- or high-dose continuous combined E2/NETA regimens had 7.7% (p < 0.0001) and 8.8% (p < 0.0001) higher percent mammographic density than never-users, respectively. CONCLUSION: Our study suggests that the effect of E2/NETA regimens on mammographic density could be at least as detrimental to the breast tissue as several other estrogen + progestin regimens. Our results suggest that both low- and high-dose E2/NETA influence mammographic density, but there were some indications in our analyses that the effect of low-dose E2/NETA could be slightly lower than that of the older high-dose regimen.

Family history of haematopoietic malignancies and non-Hodgkin's lymphoma risk in the California Teachers Study.

Family history of haematopoietic malignancies appears to be a risk factor for non-Hodgkin's lymphoma (NHL), but whether risk varies by family member's gender is unclear. Among 121 216 women participating in the prospective California Teachers Study, NHL risk varied by type of haematopoietic malignancy and gender of the relative.

Reproductive factors and subtypes of breast cancer defined by hormone receptor and histology.

Reproductive factors are associated with reduced risk of breast cancer, but less is known about whether there is differential protection against subtypes of breast cancer. Assuming reproductive factors act through hormonal mechanisms they should protect predominantly against cancers expressing oestrogen (ER) and progesterone (PR) receptors. We examined the effect of reproductive factors on subgroups of tumours defined by hormone receptor status as well as histology using data from the NIHCD Women's Contraceptive and Reproductive Experiences (CARE) Study, a multicenter case-control study of breast cancer. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) as measures of relative risk using multivariate unconditional logistic regression methods. Multiparity and early age at first birth were associated with reduced relative risk of ER + PR + tumours (P for trend=0.0001 and 0.01, respectively), but not of ER - PR - tumours (P for trend=0.27 and 0.85), whereas duration of breastfeeding was associated with lower relative risk of both receptor-positive (P for trend=0.0002) and receptor-negative tumours (P=0.0004). Our results were consistent across subgroups of women based on age and ethnicity. We found few significant differences by histologic subtype, although the strongest protective effect of multiparity was seen for mixed ductolobular tumours. Our results indicate that parity and age at first birth are associated with reduced risk of receptor-positive tumours only, while lactation is associated with reduced risk of both receptor-positive and -negative tumours. This suggests that parity and lactation act through different mechanisms. This study also suggests that reproductive factors have similar protective effects on breast tumours of lobular and ductal origin.

Oral contraceptive use and mammographic patterns.

High-risk mammographic patterns represent an increased risk of contracting breast cancer and may be used as a surrogate endpoint for the disease. We examined the relationship between oral contraceptive (OC) use and mammographic patterns among 3218 Norwegian women, aged 40-56 years. Information on ever OC use, duration, and age of first OC use and other epidemiological data were obtained through questionnaires. The mammograms were categorized into five groups. Patterns I-III were combined into a low-risk group and patterns IV and V into a high-risk group. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression and adjusted for age, menopausal status, parity, age at first birth, and body mass index. Women who reported ever having used OCs were 20% more likely (OR 1.27, 95% CI 1.0-1.6) to have high-risk mammographic patterns compared with those reporting never having used OCs. There was no dose response between different measures of OC use and high-risk patterns. Among nulliparous women, ever OC users were four times more likely (OR 4.65, 95% CI 2.1-10.3) to have high-risk patterns compared with never users. Our findings suggest that, especially among nulliparous women, ever OC use may exert its effect on breast cancer risk through changes in breast tissue, which can be observed on a mammogram.

Ethnic differences in mammographic densities.

BACKGROUND: Breast cancer incidence is considerably lower among Japanese and Chinese women than among Caucasian and Native Hawaiian even in second and third generation migrants. Mammographic densities, which refer to the radiological appearance of the healthy female breast, are related to breast cancer risk. The purpose of this project was to explore the hypothesis that women from ethnic groups at high breast cancer risk are more likely to have high levels of densities than women from low breast cancer risk groups. METHODS: In a cross-sectional design, 514 pre- and post-menopausal women recruited at mammography screening clinics completed a self-administered questionnaire. We used a computer-assisted method to measure the dense and the total areas of the breast and to compute per cent breast density. Student's t-tests and multiple linear regression were applied to examine ethnic differences and to explore determinants of mammographic densities, respectively. RESULTS: The unadjusted mean dense area was 15% smaller in Chinese and Japanese women than in the Caucasian/Hawaiian group. However, because of their smaller breast size, the per cent of the breast occupied by dense tissue in Chinese and Japanese women was 20% higher than in Caucasian women. Body mass index, age, menopausal status, parity, and oestrogen therapy were associated with mammographic densities, but they did not account for all ethnic differences. CONCLUSIONS: Whereas this study detected some ethnic differences in mammographic densities, the importance of dense areas and per cent densities as indicators of breast cancer risk in ethnically diverse populations remains to be clarified.

Reversal of gonadotropin-releasing hormone agonist induced reductions in mammographic densities on stopping treatment.

Previously, we described the reduction in mammographic densities that occurred in premenopausal women after 12 months on a hormonal regimen designed to be chemopreventive for breast (and ovarian) cancer consisting of a gonadotropin-releasing hormone agonist (GnRHA) plus low-dose add-back estrogen-progestin. We sought to determine whether the density reduction persisted with continuation of the regimen for 24 months, and, if so, whether the densities would return to baseline after the regimen was discontinued. Twenty-one women, 27-40 years of age, with a 5-fold greater than normal risk of breast cancer, were randomly assigned in a 2:1 ratio to the treatment group (14 women) and to a control group (7 women). The percentage of mammographic densities, calculated as the proportion of the breast area on the mammogram containing densities, were assessed blindly using a computer-based threshold method at baseline, after 12 and 24 months of treatment, and at between 6 and 12 months after treatment was stopped. The previously described percentage of mammographic density reductions of 9.7% (P = 0.012) after 12 months of treatment were increased slightly to 11.4% (P = 0.010) after 24 months of treatment, but the additional change was not statistically significant. Ten of 11 treated women assessed at 24 months had reduced percentages of mammographic densities compared with baseline. Six to 12 months after completion of treatment, the mean percentage of mammographic density in the treated group was no different from that at baseline (mean decline of 2.0%; P = 0.73). The women in the control group had no statistically significant changes in densities over the period of the study. Reductions in mammographic densities engendered by the GnRHA plus a low-dose add-back estrogen-progestin regimen persist as long as the women receive treatment. The densities return to baseline when the women resume normal menstrual cycles. These results confirm that mammographic densities are influenced by ovarian function. Improved efficacy of mammographic screening is to be expected as long as a woman continues on such a regimen. Whether such a regimen is chemopreventive for breast cancer remains to be established, but the recent report on a randomized trial of use of GnRHA alone in premenopausal breast cancer cases showing a marked reduction in incidence of contralateral disease provides strong support for the hypothesis.

Determinants of mammographic densities among women of Asian, Native Hawaiian, and Caucasian ancestry.

This cross-sectional study explored the relation between mammographic densities (a predictor of breast cancer risk), ethnicity, and dietary factors among women in Hawaii. Thirty-nine postmenopausal women with Japanese, Chinese, Caucasian, and Native Hawaiian ancestry who had received a screening mammogram completed a medical, reproductive, and dietary history. Using a computerized method, we determined the total and the dense area of the breast and calculated the ratio between the two. Blood lipids were measured using standard methods. For statistical analysis, we applied analysis of variance and multiple linear regression. Whereas the mean dense area of the breast was one third smaller in Asian than in Caucasian and Native Hawaiian women, the percent of the breast occupied by dense tissue in the Asian women was slightly higher than in the Caucasian/Hawaiian group, possibly a result of the Asian women's smaller breast size. The exploratory analysis indicated inverse relations of body mass index, high-density lipoprotein cholesterol (HDLC), age at menarche, and soy intake with mammographic densities, as well as direct relations of estrogen use and family history with mammographic densities. The results of this study suggest that variations in these factors may be responsible for ethnic differences in mammographic densities and in breast cancer risk.

Do urinary estrogen metabolites reflect the differences in breast cancer risk between Singapore Chinese and United States African-American and white women?

Breast cancer risk is substantially lower in Singapore than in women from the United STATES: Part of the risk discrepancy is probably explained by differences in the production of endogenous estrogens, but differences in the pathway by which estrogen is metabolized may also play a role. We undertook a study to determine whether the ratio of urinary 2-hydroxyestrone (2OHE(1)):16alpha-hydroxyestrone (16alpha-OHE(1)) was higher in Singapore Chinese than in a group of United States (predominantly African-American) women living in Los ANGELES: We also wanted to determine whether any difference in estrogen metabolite ratio between these two groups of women was greater than that in estrone (E(1)), estradiol (E(2)) and estriol (E(3)). The participants in this study were randomly selected healthy, non-estrogen using women participating in the Singapore Chinese Health Study (n = 67) or the Hawaii/Los Angeles Multiethnic Cohort Study (n = 58). After adjusting for age and age at menopause, mean urinary 2-OHE(1) was only 23% (P = 0.03) higher in Singapore Chinese than in United States women, and there were no statistically significant differences in 16alpha-OHE(1) levels or in the ratio of 2-OHE(1):16alpha-OHE(1) between the two groups. The adjusted mean 2-OHE(1):16alpha-OHE(1) ratio was 1.63 in Singapore Chinese and 1.48 in United States women (P = 0.41). In contrast, the adjusted mean values of E1, E2, and E3 were 162% (P < 0.0001), 152% (P < 0.0001), and 92% (P = 0.0009) higher, respectively, in United States women than in Singapore Chinese women. Our study suggests that urinary E1, E2, and E3 reflect the differences in breast cancer risk between Singapore Chinese and United States women to a stronger degree than the estrogen metabolites 2OHE(1) and 16alpha-OHE(1) or the ratio of 2OHE(1):16alpha-OHE(1.)

Mammographic density changes during the menstrual cycle.

The ability to detect small tumors is impaired in dense mammograms. It has been suggested that the sensitivity of mammograms could be lower in mammograms obtained during the luteal phase of the menstrual cycle. We examined the change in mammographic density from the follicular to the luteal phase of the menstrual cycle in 11 women. Although the average increase in densities was quite small (1.2%; P = 0.08), six women had clinically significant increases (1.4-7.8%), suggesting that premenopausal women should undergo mammographic examinations in the follicular part of the menstrual cycle.

Breast cancer and oral contraceptive use in Asian-American women.

Breast cancer incidence has historically been 4-7 times higher in the United States than in Asia. A previous study by the authors in Asian-American women demonstrated a substantial increase in breast cancer risk in women who migrated from Asia to the United States, with the risk almost doubling during the first decade after migration. Increased use of oral contraceptives soon after migration to the United States could possibly explain this rapid rise in risk. In a population-based case-control study of Chinese, Filipino, and Japanese-American women, aged 20-55 years, who lived in San Francisco-Oakland, California; Los Angeles, California; and Oahu, Hawaii during 1983-1987, 597 cases (70% of those eligible) and 966 controls (75%) were interviewed. Controls were matched to cases on age, ethnicity, and area of residence. Oral contraceptive (OC) use increased with time since migration; 15.0% of Asian-born women who had been in the West <8 years, 33.4% of Asian-born women who had been in the West > or =8 years, and 49.6% of Asian women born in the West had ever used OCs. However, duration of OC use (adjusted for age, ethnicity, study area, years since migration, education, family history of breast cancer and age at first full-term birth) was not associated with increased risk of breast cancer. Moreover, neither OC use before age 25 years nor before first full-term birth was associated with increased risk. Results were unchanged when restricted to women under age 45 years or under age 40 years. After adjustment for duration of OC use, women who had been in the United States > or =8 years were still at almost twice the risk of breast cancer compared with women who had been in the United States 2-7 years. This study suggests that OC use cannot explain the elevated risk observed in Asian women who migrated to the United States > or =7 years ago.

PIP: The relationship between oral contraceptive (OC) use and breast cancer was investigated among Asian-American women. A population-based case-control study of Chinese, Japanese, and Filipino women, ages 20-25 years were interviewed. Results showed that women who had been in the West for 2-7 years had the lowest prevalence of use. About 15.0% were OC users, and 1.4% had been OC users for more than 5 years. Asian-Americans born in the West had the highest prevalence of OC use. However, there were only slight differences of OC use among women living in rural or urban areas while in the East. An inverse association is shown between the duration of OC use and breast cancer among migrants more than 8 years ago. There were no increased risks associated with the use of OC and the duration of OC use. Women who started using OC at an early age were not associated with an increased risk of breast cancer and with a decreased risk at the very onset of use (age 21 years). Recent OC use (last OC use during last 5 years) was not associated with an increased risk of breast cancer. Consequently, women who had been in the US more than 8 years were at almost twice the risk of breast cancer [odds ratio (OR) = 0.67] as women who had been in the country 2-7 years (OR = 0.34). This study suggests that OC use cannot explain the elevated risk observed in Asian-American women who migrated more than 7 years ago.

Urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio and risk of breast cancer in postmenopausal women.

BACKGROUND: It has been suggested that women who metabolize a larger proportion of their endogenous estrogen via the 16alpha-hydroxylation pathway may be at elevated risk of breast cancer compared with women who metabolize proportionally more estrogen via the 2-hydroxylation pathway. However, the supporting epidemiologic data are scant. Consequently, we compared the ratio of urinary 2-hydroxyestrone (2-OHE1) to 16alphahydroxyestrone (16alpha-OHE1) in postmenopausal women with breast cancer and in healthy control subjects. METHODS: Estrogen metabolites were measured in urine samples obtained from white women who had participated in a previous population-based, breast cancer case-control study at our institution. All P values are from two-sided tests. RESULTS: All of the urinary estrogens measured, with the exception of estriol, were higher in the 66 case patients than in the 76 control subjects. The mean value of urinary 2-OHE1 in case patients was 13.8% (P = .20) higher than that in control subjects, 16alpha-OHE1 was 12.1% (P = .23) higher, estrone was 20.9% higher (P = .14), and 17beta-estradiol was 12.0% higher (P = .36). The ratio of 2-OHE1 to 16alpha-OHE1 was 1.1% higher in the patients (P = .84), contrary to the hypothesis. Compared with women in the lowest third of the values for the ratio of urinary 2-OHE1 to 16alpha-OHE1, women in the highest third were at a nonstatistically significantly increased risk of breast cancer (odds ratio = 1.13; 95% confidence interval = 0.46-2.78), again contrary to the hypothesis. CONCLUSION: This study does not support the hypothesis that the ratio of the two hydroxylated metabolites (2-OHE1/16alpha-OHE1) is an important risk factor for breast cancer.

Use of oral contraceptives and risk of breast cancer in young women.

Many studies have shown that oral contraceptive (OC) use increases a young woman's risk of breast cancer, although some studies suggest that the risk may be limited to recent use. The objective of this study was to determine what particular aspects of OC use could be important for breast cancer development at an early age in the cohort of women who had the opportunity to use OCs all of their reproductive life. The cases were first diagnosed with breast cancer at age 40 or younger between 1983 and 1988, and identified by the Los Angeles County Cancer Surveillance Program. Control subjects were individually matched to participating cases on birth date (within 36 months), race (white), parity (nulliparous versus parous), and neighborhood of residence. Detailed OC histories were obtained during in-person interviews with subjects. In general the risk estimates were small, and not statistically significant. Compared to no use, having used OCs for 12 years or more was associated with a modest non-significant elevated breast cancer risk with an odds ratio (OR) of 1.4 (95% confidence interval (CI) = 0.8-2.4). Long-term (12 years or more) users of high-dose estrogen pills had a non-significant 60% higher breast cancer risk than never users (CI = 0.9-3.2). Early use was associated with slightly higher ORs among young women (age < or =35), and among parous women. Recent use was associated with somewhat higher ORs among parous women and women above age 36. Analyses by stage, body weight, and family history yielded similar results. This study is consistent with a modest effect of early OC use on breast cancer risk in young women.

PIP: The relationship of breast cancer risk in young women to particular patterns of oral contraceptive (OC) use was investigated in a case-control study conducted in Los Angeles County, California (US), in 1983-89. Enrolled as cases were 744 White women 40 years or younger at the time of breast cancer diagnosis who were located through a population-based cancer registry. One community control was matched to each of these cases on birth date, race, parity, and neighborhood of residence. OCs had been used by 83.3% of breast cancer cases and 84.4% of controls; 68.6% of cases and 69.3% of controls had used OCs for 12 months or more. In general, the results revealed only a modest effect of early OC use on breast cancer risk in young women. Compared to never use, OC use for 12 or more years was associated with a small, nonsignificant elevated breast cancer risk (odds ratio (OR), 1.40; 95% confidence interval (CI), 0.81-2.40). Women who used high-dose estrogen formulations for 12 years or more had a nonsignificant increased risk compared with nonusers (OR, 1.64; 95% CI, 0.85-3.18). Among women below age 35 years at diagnosis, compared with never users, women who had used OCs for 1 year or more before the age of 18 years were at almost twice the risk of developing breast cancer (OR, 1.97; 95% CI, 0.90-4.32). Among women over age 35 years at diagnosis, compared with never users, those who had used OCs for 3 or more years during the past 5 years were at a 2.54-fold increased risk (95% CI, 0.94-6.88). Analyses by cancer stage, body weight, and family history failed to detect any significant effects.

The detection of changes in mammographic densities.

We previously reported reductions in mammographic densities in women participating in a trial of a gonadotropin-releasing hormone agonist (GnRHA)-based regimen for breast cancer prevention. In our previous report, we compared (by simultaneous evaluation) three basic elements of mammographic densities. The purpose of the present study was to evaluate whether a standard (expert) method of measuring mammographic densities would detect such changes in densities and whether a novel nonexpert computer-based threshold method could do so. Mammograms were obtained from 19 women at baseline and 12 months after randomization to the GnRHA-based regimen. The extent of mammographic densities was determined by: (a) a standard expert outlining method developed by Wolfe and his colleagues (Am. J. Roentgenol., 148: 1087-1092, 1987); and (b) a new computer-based threshold method of determining densities. The results from both the expert outlining method and the computer-based threshold method were highly consistent with the results of our original (simultaneous evaluation) method. All three methods yielded statistically significant reductions in densities from baseline to the 12-month follow-up mammogram in women on the contraceptive regimen. The difference between the treated and the control group was statistically significant with the expert outlining method and was of borderline statistical significance with the computer-based threshold method. The computer-based results correlated highly (r > 0.85) with the results from the expert outlining method. Both the standard expert outlining method and the computer-based threshold method detected the reductions we had previously noted in mammographic densities induced by the GnRHA-based regimen.

Androgens in serum and the risk of prostate cancer: a nested case-control study from the Janus serum bank in Norway.

We tested the hypothesis that serum levels of testosterone (T), dihydrotestosterone (DHT), and the DHT metabolite 3 alpha,17 beta-androstanediol glucuronide are positively associated with the risk of prostate cancer. This nested case-control study was based on the cohort of men who donated blood to the Janus serum bank at Oslo University Hospital (Oslo, Norway) between 1973 and 1994. Cancer incidence was ascertained through linkage with the Norwegian Cancer Registry. The study included sera from 59 men who developed prostate cancer (cases) subsequent to blood donation and 180 men who were free of any diagnosed cancer (controls) in 1994 and were of similar age (+/- 1 year) and had similar blood storage time (+/- 6 months) to the cases. Neither T, DHT, nor the ratio T:DHT was associated with risk of developing prostate cancer. Compared to the bottom quartile, the odds ratio (OR) associated with the top quartile of T was 0.83 [95% confidence interval (CI), 0.36-1.93]; the OR for the top (compared to the bottom) quartile of DHT was 0.83 (95% CI, 0.36-1.94), and the equivalent OR for T:DHT was 1.31 (95% CI, 0.58-2.97). Similarly, 3 alpha,17 beta-androstanediol glucuronide showed no association with prostate cancer risk; the OR for the top (compared to the bottom) quartile was 1.10 (95% CI, 0.41-2.90). These results showed no association, positive or negative, between androgens measured in serum and the subsequent risk of developing prostate cancer.