Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients.

Mutations in certain genes that regulate the cell cycle, such as p16 and p53, are frequently found in human cancers. However, tumor-specific mutations are uncommon in genes encoding cyclin E and the CDK inhibitor p27Kip1, two cell-cycle regulators that are also thought to contribute to tumor progression. It is now known that levels of both cyclin E and p27 can be controlled by posttranscriptional mechanisms, indicating that expression of these proteins can be altered by means other than simply mutation of their respective genes. Thus, changes in p27 and cyclin E protein levels in tumors might be more common than previously anticipated and may be indicators of tumor behavior.

Genetic variation in CXCL12 and risk of cervical carcinoma: a population-based case-control study.

CXCL12 provides a chemotactic signal-directing leucocyte migration and regulates metastatic behaviour of tumour cells. We conducted a population-based case-control study to test the hypothesis that common genetic variation in CXCL12 individual single nucleotide polymorphism (SNP) alleles and haplotypes] is associated with the risk of cervical carcinoma. Cases (n = 917) were residents of western Washington State diagnosed with invasive squamous cell cervical carcinoma (SCC), invasive adenocarcinoma or adenosquamous carcinoma, or adenocarcinoma in situ of the cervix. Control participants (n = 849) were identified from the source population by random digit telephone dialling and frequency matched to cases on county and age. Nine CXCL12 tagSNPs chosen from the SeattleSNPs database were genotyped. The minor allele of intronic SNP rs266085 was inversely associated with cervical cancer under a recessive genetic effects model (OR = 0.74, 95% CI: 0.56-0.98). Among the ten common haplotypes inferred from the nine tagSNPs, one haplotype defined by minor alleles at 5'-flanking SNP rs17885289 and rs266085, and common alleles at the other seven SNPs occurred among 7.8% of cases and 10.6% of controls (dominant model OR = 0.72, 95% CI: 0.56-0.93; recessive model OR = 0.35, 95% CI: 0.12-0.97; and log-additive model OR = 0.72, 95% CI: 0.57-0.90). A stepwise procedure identified rs17885289, rs266085 and 3'-untranslated region (UTR) SNP rs266093 as the most parsimonious subset of SNPs necessary to define the haplotype inversely associated with cervical cancer risk in our study. A 3'-UTR SNP, rs1801157, previously found to be related to HIV pathogenesis, was not associated with cervical cancer risk. Further population-based studies are warranted to confirm these associations between genetic variation in CXCL12 and cervical cancer risk.

Differential patterns of allelic loss in estrogen receptor-positive infiltrating lobular and ductal breast cancer.

The two main histological types of infiltrating breast cancer, lobular (ILC) and the more common ductal (IDC) carcinoma are morphologically and clinically distinct. To assess the molecular alterations associated with these breast cancer subtypes, we conducted a whole-genome study of 166 archival estrogen receptor (ER)-positive tumors (89 IDC and 77 ILC) using the Affymetrix GeneChip(R) Mapping 10K Array to identify sites of loss of heterozygosity (LOH) that either distinguished, or were shared by, the two phenotypes. We found single nucleotide polymorphisms (SNPs) of high-frequency LOH (>50%) common to both ILC and IDC tumors predominately in 11q, 16q, and 17p. Overall, IDC had a slightly higher frequency of LOH events across the genome than ILC (fractional allelic loss = 0.186 and 0.156). By comparing the average frequency of LOH by chromosomal arm, we found IDC tumors with significantly (P < 0.05) higher frequency of LOH on 3p, 5q, 8p, 9p, 20p, and 20q than ILC tumors. We identified additional chromosomal arms differentiating the subtypes when tumors were stratified by tumor size, mitotic rate, or DNA content. Of 5,754 informative SNPs (>25% informativity), we identified 78 and 466 individual SNPs with a higher frequency of LOH (P < 0.05) in ILC and IDC tumors, respectively. Hierarchical clustering of these 544 SNPs grouped tumors into four major groups based on their patterns of LOH and retention of heterozygosity. LOH in chromosomal arms 8p and 5q was common in higher grade IDC tumors, whereas ILC and low-grade IDC grouped together by virtue of LOH in 16q.

Incidence of vulvar carcinoma in relation to menstrual, reproductive, and medical factors.

Fifty-seven female residents of King and Pierce Counties (Washington State) with a new diagnosis of in situ or invasive vulvar carcinoma during 1976-79 were interviewed concerning their menstrual, reproductive, and medical histories. A random sample of women residing in the same area was interviewed for comparison. A greater proportion of women with in situ vulvar tumors than control subjects were of low educational level, reported a history of oral contraceptive use, experienced early age at first birth, late age at menopause, and were current or former cigarette smokers. Menstrual and reproductive factors were similar between women with invasive vulvar cancer and controls, but a greater proportion of cases reported a history of diabetes and of cigarette smoking. The factors found in this study to be associated with in situ vulvar carcinoma are similar to those observed among women with cervical cancer. In addition, since the vulva and cervix both are derived from cloacal tissue, and neoplasms of the two sites occur together more often than would be expected by chance, in situ vulvar and cervical tumors may share some common etiologies.

Incidence of thyroid cancer in women in relation to previous exposure to radiation therapy and history of thyroid disease.

Female residents of 13 counties of Western Washington, in whom papillary, follicular, or mixed papillary-follicular thyroid carcinomas had been diagnosed between 1974 and 1979 were interviewed regarding their medical and reproductive histories and past exposure to radiation treatments. For comparison, a random sample of women from the same population was interviewed. Women who had received radiation treatments to the head or neck prior to 5 years before interview were 16.5 times (95% confidence interval = 8.1-33.5) more likely than unexposed women to develop cancer. The relative risk (RR) was highest for papillary cancer (19.4) but also was elevated substantially for follicular and mixed papillary-follicular tumors. Women first irradiated at age 19 years or younger had a much higher RR than did women irradiated at age 20 or older. Regardless of prior radiation exposure, women who ever had had a goiter were at increased risk of developing thyroid cancer. Women who had ever developed a goiter had 17 times the risk of developing follicular cancer and almost 7 times the risk of developing papillary cancer as compared with women who never had had a goiter. Risk of thyroid cancer was elevated even among women who had had a history of goiter many years prior to diagnosis. A history of thyroid nodules was also a risk factor for papillary and mixed thyroid cancer. Neither a history of hypothyroidism nor hyperthyroidism was found to increase the risk of thyroid cancer.

Incidence of cancer of the large bowel in women in relation to reproductive and hormonal factors.

Female resident of King and Pierce Counties (Washington) in whom carcinoma of the colon or rectum was diagnosed during a 15-month period in 1976-77 were interviewed regarding their menstrual and reproductive histories. A random sample of women from the same population was interviewed for comparison. On the average, women with colon cancer had given birth to fewer children than had controls; compared to the incidence of colon cancer in nulliparous women, the incidence in women with 1 or 2 children was reduced by 30%, whereas the incidence in women with 3 or more children was reduced by 50% (P=0.004). No association was present between parity and rectal cancer. Neither contraceptive nor noncontraceptive estrogen use was related to the incidence of colon cancer. Use of oral contraceptives was more common among women with rectal cancer than among controls, but this result could well have arisen by chance (P=0.09). The data were not adequate to determine whether it was the inability to conceive and deliver a child that was related to colon cancer or the failure to undergo the physiologic changes that accompany pregnancy. Nonetheless, the association of low parity with the incidence of colon cancer has now observed several times, in each instance to a moderately strong degree. This observation suggests that events of reproductive life have a bearing on a woman's subsequent risk of developing colon cancer.

Birth weight and the incidence of childhood cancer.

The relationship of weight at birth to the occurrence of childhood cancer was studied with emphasis on the influence of age at diagnosis. Birth certificates for 681 children with cancer born in Washington State were linked with cancer registry data. Among children diagnosed with cancer during the first several years of life, there was an increased proportion with a high birth weight (greater than 4,000 g). The relationship was strongest for children under 2 years of age; about twice as many of them had high birth weights. However, the relationship was not present at all in those whose cancer was diagnosed at age 4 or older. This excess risk in young children associated with high birth weight was distributed among several types of cancer, including the two most common ones (leukemia and neuroblastoma).

Breast cancer among young U.S. women in relation to oral contraceptive use.

BACKGROUND: While most studies have found no association between oral contraceptive use and breast cancer, several studies of younger women have reported an association with long-term oral contraceptive use. PURPOSE. We studied the relationship of patterns of oral contraceptive use to breast cancer risk among younger women. These women have had oral contraceptives available their entire reproductive lives and are now entering the breast cancer-prone years. METHODS: A population-based, case-control study of breast cancer was conducted in three counties in western Washington State among women born in 1945 or later, ages 21-45. Case patients were 747 women with breast cancer diagnosed in 1983-1990 and identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry. Control subjects were 961 women identified by random-digit telephone dialing. Subjects were interviewed in person, using pictures of brands of oral contraceptives and calendars of life events as recall aids. RESULTS: There was no increased incidence of breast cancer associated with ever having used oral contraceptives. Because only 8% of this cohort had never used oral contraceptives, short-term users (< 1 year) were combined with never users as the reference group for further analyses. A small increased risk of breast cancer was associated with long duration of oral contraceptive use (odds ratio for > or = 10 years = 1.3; 95% confidence interval [CI] = 0.9-1.9; P for trend = .03), particularly among women aged 35 years or younger (odds ratio for > or = 10 years = 1.7; 95% CI = 0.9-3.1). Breast cancer was also modestly related to oral contraceptive use early in reproductive life (odds ratio for use within 5 years of menarche = 1.3; 95% CI = 1.0-1.8; P for trend = .04) and to use of high-progestin-potency oral contraceptives for at least 1 year (odds ratio = 1.5; 95% CI = 1.1-2.1). These associations were adjusted for age, age at menarche, term pregnancy, induced abortion, and family history of breast cancer. The associations were not further confounded by case-control differences in education, religion, breast feeding of offspring, or infertility; in oral contraceptive contraindications, indications, or complications; or in measures of breast cancer detection such as mammography or breast biopsy. CONCLUSIONS: Long-term oral contraceptive use among young women or use beginning near menarche may be associated with a small excess breast cancer risk, possibly due to susceptibility to genetic damage in breast epithelial cells at ages of high breast cell proliferative activity. IMPLICATIONS: Future studies should investigate whether the patterns of risk we reported are present as this cohort ages.

PIP: A case control study was conducted in Washington among 21-45 year old white women from King, Pierce, and Snohomish counties (i.e., Seattle metropolitan area) to examine the relationship between oral contraceptive (OC) use and breast cancer. The 747 cases were diagnosed with invasive breast cancer between January 1983 and April 1990. The researchers combined short term OC users with never users since just 8% of all subjects had never used OCs. They controlled for age, age at menarche, term pregnancy, induced abortion, and family history of breast cancer. Longterm use (i.e., =or 10 years) of OCs was associated with a small increased risk of breast cancer (odds ratio [OR] = 1.3; p for trend = 0.03), especially among women not older than 35 years (OR = 1.7). This finding was consistent with results of other studies. OC use early in reproductive life (i.e., within 5 years of menarche) was also associated with a moderate increase in breast cancer (OR = 1.3; p for trend = 0.04). Breast cancer risk was also elevated among women who used high progestin potency OCs (as defined by the Dickey method for classifying OC potency) for at least 1 year (OR = 1.5). Case control differences in education, religion, breast feeding of children, or infertility; in OC contraindications, indications, complications; or in measures of breast cancer detection (e.g., mammography or breast biopsy) did not confound the associations. An association between breast cancer and long term OC use among young women and OC use beginning close to menarche suggest that puberty, a time when breast epithelial cells are undergoing considerable proliferative activity, are susceptible to genetic damage. Further research is needed to determine whether the aforementioned patterns of breast cancer risk continues as the cohort becomes older.

Tamoxifen therapy for primary breast cancer and risk of contralateral breast cancer.

BACKGROUND: Women diagnosed with breast cancer have a twofold to sixfold greater risk of developing contralateral breast cancer than women in the general population have of developing a first breast cancer. Tamoxifen therapy reduces this risk, but it is unclear if this benefit exists for both estrogen receptor (ER)-positive and ER-negative contralateral tumors. METHODS: Using data from a population-based tumor registry that collects information on the ER status of breast tumors, we followed 8981 women residing in western Washington State who were diagnosed with a primary unilateral invasive breast cancer during the period from 1990 through 1998 to identify cases of contralateral breast cancer. We restricted our analyses to women who were at least 50 years old and whose first breast cancer had a localized or regional stage; women who received adjuvant hormonal therapy but not chemotherapy (n = 4654) were classified as tamoxifen users, while those who received neither adjuvant hormonal therapy nor chemotherapy (n = 4327) were classified as nonusers of tamoxifen. By reviewing selected patient abstracts, we estimated that 94% of the subjects were classified correctly with respect to tamoxifen use. The risk of contralateral breast cancer associated with tamoxifen use was estimated with the use of Cox regression. All statistical tests were two-sided. RESULTS: Of the 89 tamoxifen users and 100 nonusers of tamoxifen diagnosed with contralateral breast cancer, 112 had ER-positive tumors, 20 had ER-negative tumors, and 57 had tumors with an ER status that was unknown or had not been determined by an immunohistochemical assay. The risk of developing an ER-positive and an ER-negative contralateral tumor among tamoxifen users was 0.8 (95% confidence interval [CI] = 0.5 to 1.1) and 4.9 (95% CI = 1.4 to 17.4), respectively, times that of nonusers of tamoxifen. This difference in risk by ER status was statistically significant (P<.0001). CONCLUSIONS: Tamoxifen use appears to decrease the risk of ER-positive contralateral breast tumors, but it appears to increase the risk of ER-negative contralateral tumors.

Rising incidence of breast cancer among young women in Washington State.

The prevalence of several known or suspected risk factors for breast cancer is changing among young women. The time trend in incidence of breast cancer among young women in western Washington was analyzed as a possible predictor of trends in future incidence rates. Data were from the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry. For women age 25-44 years (n = 1,869 cases), the incidence of breast cancer increased by 22% (P less than .001) between the time periods 1974-77 and 1982-84. The estimated annual increase was 2.5% (P less than .001). The increase in incidence over time appeared to be greater among those residing in low-income census tracts of urban counties and among black women. Possible relationships between the observed increase in rates and trends of risk factors for breast cancer are discussed.

Childhood brain tumors and paternal occupation in the aerospace industry.

Data from a case-control study of childhood brain tumors were analyzed to examine the possibility that paternal occupation in the aerospace industry is related to the development of a brain tumor in offspring. Parents of 51 children with brain tumors diagnosed in western Washington State during 1978-81 were interviewed, and their responses were compared to those of parents of 142 children selected at random from this population. Among all children, proportions of case and control fathers who had ever been employed in the aerospace industry were nearly identical [relative risk (RR) = 0.94; 95% confidence interval (CI) = 0.40-2.19]. Employment in the aerospace industry during the period from 1 year prior to birth to the time of diagnosis and any employment in the manufacturing part of the industry were not associated with increased risk. However, stratification by age at diagnosis revealed an increased risk associated with father's ever-employment in the industry (RR = 2.10; 95% CI = 0.79-5.60) for children under 10 years old. A corresponding decreased risk (RR = 0.12; 95% CI = 0.01-1.08) was found for children over 10 years old. Because of the relatively small number of cases with a positive paternal occupational history, interpretations of the difference in the direction of the association according to age at diagnosis must remain tentative ones.

Risk of breast cancer among young women: relationship to induced abortion.

BACKGROUND: Certain events of reproductive life, especially completed pregnancies, have been found to influence a woman's risk of breast cancer. Prior studies of the relationship between breast cancer and a history of incomplete pregnancies have provided inconsistent results. Most of these studies included women beyond the early part of their reproductive years at the time induced abortion became legal in the United States. PURPOSE: We conducted a case-control study of breast cancer in young women born recently enough so that some or most of their reproductive years were after the legalization of induced abortion to determine if certain aspects of a woman's experience with abortion might be associated with risk of breast cancer. METHODS: Female residents of three counties in western Washington State, who were diagnosed with breast cancer (n = 845) from January 1983 through April 1990, and who were born after 1944, were interviewed in detail about their reproductive histories, including the occurrence of induced abortion. Case patients were obtained through our population-based tumor registry (part of the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute). Similar information was obtained from 961 control women identified through random digit dialing within these same counties. Logistic regression analysis was used to estimate odds ratios and confidence intervals (CIs). RESULTS: Among women who had been pregnant at least once, the risk of breast cancer in those who had experienced an induced abortion was 50% higher than among other women (95% CI = 1.2-1.9). While this increased risk did not vary by the number of induced abortions or by the history of a completed pregnancy, it did vary according to the age at which the abortion occurred and the duration of that pregnancy. Highest risks were observed when the abortion was done at ages younger than 18 years--particularly if it took place after 8 weeks' gestation--or at 30 years of age or older. No increased risk of breast cancer was associated with a spontaneous abortion (RR = 0.9; 95% CI = 0.7-1.2). CONCLUSION: Our data support the hypothesis that an induced abortion can adversely influence a woman's subsequent risk of breast cancer. However, the results across all epidemiologic studies of this premise are inconsistent--both overall and within specific subgroups. The risk of breast cancer should be reexamined in future studies of women who have had legal abortion available to them throughout the majority of their reproductive years, with particular attention to the potential influence of induced abortion early in life.

PIP: Epidemiologists compared data on 845 white women who were diagnosed with breast cancer between January 1983 and April 1990, were born after 1944, and lived in King, Pierce, or Snohomish counties in Washington State with data on 961 white women with no breast cancer from the same counties. They wanted to determine whether induced abortion increases the risk of breast cancer. Restricting cases to women born after 1944 allowed the researchers to focus only on legal induced abortions. When the researchers limited the analysis only to women who had been pregnant at least once, the risk of developing breast cancer in women who had had at least 1 induced abortion was 50% greater than those who had not had an induced abortion. This risk differed depending on the age at which the women underwent the induced abortion and the duration of that pregnancy. A gestational age (at the time of the first aborted pregnancy) of 9-12 weeks carried the highest risk of breast cancer (RR = 1.9 vs. 1.4 for =or 8 weeks and =or 13 weeks). Further, the breast cancer risk was greatest among women who underwent the induced abortion when they were less than 18 years old (relative risk [RR] = 2.5). It was especially high for women who were less than 18 years old and who had the abortion between 9 and 24 weeks of gestation (RR = 9). It was also high for those who were at least 30 years old at the time of the abortion (RR = 2.1). Spontaneous abortion was not associated with an increased risk (RR = 0.9). Neither the number of induced abortions nor the history of a completed pregnancy were associated with an increased risk of breast cancer. These findings suggest that an induced abortion during the last month of the first trimester increases the risk of breast cancer and that women who were at a very young age at the time of the first induced abortion face an increased risk of breast cancer.

Noncontraceptive estrogen use and the occurrence of ovarian cancer.

Female residents of six counties in Washington and Utah in whom ovarian cancer was diagnosed during 1975-79 were interviewed concerning prior use of noncontraceptive estrogens. Interviews with a random sample of women drawn from these counties were obtained for comparison. Taken as a whole, women with epithelial ovarian tumors reported estrogen use for 1 year or more somewhat more often than did controls [relative risk (RR) = 1.3, 95% confidence interval (CL) = 0.9-1.8]. The proportion of women who had used estrogens varied according to the histology of their tumor; notably, of 17 women with endometrioid tumors, 12 had used estrogens (RR = 3.1, 95% CL = 1.0-9.8). The excess risk of endometrioid carcinoma related to estrogen use was not further increased when these hormones were taken for long durations, in high doses, or proximate to the time of diagnosis. Neither was there any evidence of increased risk from estrogen use in the small group of women with clear cell tumors, a histologic tumor type believed to be closely related to endometrioid carcinoma. Thus the observed association between menopausal estrogen use and the occurrence of ovarian endometrioid tumors should be interpreted cautiously until the results of additional studies are available.

Toxic substance exposure and multiple myeloma: a case-control study.

By means of a population-based, multicenter case-control investigation, certain toxic substances were evaluated as risk factors for multiple myeloma. Interviews were completed on 698 subjects with newly diagnosed multiple myeloma, and 1,683 controls were selected from the same geographic areas as those of the cases. Respondents were asked if they had ever been "highly" exposed" to one or more of a list of toxic substances or to other substances not on the list. With the aid of a toxicologist, responses were then categorized into 20 exposure groups. Those who reported past exposure to pesticides had an estimated relative risk of 2.6 for multiple myeloma [95% confidence interval (CI) = 1.5-4.6]. Subjects exposed to a variety of compounds commonly used by painters had an estimated relative risk of 1.6 (95% CI = 1.1-2.4). An increased risk also was found for those who were exposed to sources of carbon monoxide (relative risk = 1.8, 95% CI = 1.0-3.2). Associations of borderline statistical significance were found for metals and organically high polymers (plastics and elastomers). No statistically significant associations were seen for exposure to fertilizers; dyes and inks; alkalies; acids; other caustic substances; chemical asphyxiants; aliphatic, chlorinated, or aromatic hydrocarbons; aldehydes and ketones; ethers; esters; oils; dusts; or asbestos.

Population-based study of tamoxifen therapy and subsequent ovarian, endometrial, and breast cancers.

BACKGROUND: The success of tamoxifen in reducing the occurrence of contralateral breast cancer among breast cancer patients in clinical trials has prompted the study of its use in the primary prevention of breast cancer. Long-term risks associated with tamoxifen therapy, however, are still being evaluated, particularly with respect to subsequent cancer occurrence at sites other than the breast. PURPOSE: This population-based, nested case-control study investigated the risks of second primary cancers of the ovary, endometrium, and contralateral breast among women receiving tamoxifen for breast cancer in conventional medical practice. METHODS: A cohort of women diagnosed with breast cancer during 1978 through 1990 was identified from a population-based cancer registry. Case subjects included all women in the cohort who subsequently developed second primary ovarian (n = 39), endometrial (n = 42), or contralateral breast (n = 234) cancer prior to 1992. Control subjects were a random sample of the cohort who did not develop a second primary malignancy; they were matched to the case subjects on age, disease stage, and year of initial breast cancer diagnosis (approximately two control subjects per case subject). Information on tamoxifen use as well as on potential risk factors for the second primary cancers was obtained through medical record abstractions and physician questionnaires. RESULTS: The percentage of women who had received tamoxifen was 18% and 20%, respectively, among ovarian cancer case subjects and control subjects; 26% and 31%, respectively, among endometrial cancer case subjects and control subjects; and 10% and 18%, respectively, among contralateral breast cancer case subjects and control subjects. The mean duration of tamoxifen use was less than 2 years for all groups. The relative risks for ovarian and endometrial cancers in women who took tamoxifen were relatively low but were consistent with no association (for ovarian cancer, matched odds ratio [mOR] = 0.6 and 95% confidence interval [CI] = 0.2-1.8; for endometrial cancer, mOR = 0.6 and 95% CI = 0.2-1.9). Tamoxifen therapy was associated with a decreased risk of contralateral breast cancer (mOR = 0.5; 95% CI = 0.3-0.9), especially if the drug had been taken for more than 1 year (mOR = 0.4; 95% CI = 0.2-0.9) or if the women were postmenopausal at initial breast cancer diagnosis (mOR = 0.4; 95% CI = 0.2-0.8). CONCLUSIONS AND IMPLICATIONS: These data suggest that short durations of tamoxifen therapy are not associated with an increased risk of endometrial or ovarian cancer but are associated with a reduction in contralateral breast cancer risk. It would not be appropriate, however, to generalize these results to women who receive tamoxifen for longer periods.

History of circumcision, medical conditions, and sexual activity and risk of penile cancer.

BACKGROUND: Epidemiological evidence suggests lack of neonatal circumcision as the strongest risk factor for penile cancer, but the role of sexually transmitted diseases in the etiology of penile cancer has remained unclear. PURPOSE: To further clarify risk factors for penile cancer, we examined the role of circumcision, personal characteristics and habits (such as smoking), sexually transmitted diseases, past sexual activity, and medical conditions of the penis. METHODS: A population-based, case-control study was conducted in western Washington state and in the province of British Columbia. We interviewed 110 men with penile cancer diagnosed from January 1979 to July 1990 and 355 control subjects from the general population, frequency matched to case subjects on age and date of diagnosis. Tumor tissue from 67 case subjects was tested for human papillomavirus (HPV) DNA by polymerase chain reaction. Results of blood tests from 69 case subjects and 208 control subjects were available for study. STATISTICALLY SIGNIFICANT RESULTS: Relative to men circumcised at birth, the risk for penile cancer was 3.2 times greater among men who were never circumcised and 3.0 times greater among men who were circumcised after the neonatal period. For current smokers, the risk was 2.8 times that of men who never smoked. The risk among men reporting a history of genital warts was 5.9 times that of men reporting no such history. Of 67 tumors tested for HPV DNA, 49% were positive; the majority of these positive tumors (70%) were type 16, which has been associated with anogenital carcinoma. Relative risks (RRs) associated with a reported history of penile rash or penile tear were 9.4 and 3.9, respectively. Among men not circumcised at birth, RRs associated with presence of smegma and difficulty in retracting the foreskin were 2.1 and 3.5, respectively. Twenty-eight percent of case subjects, compared with only 10% of control subjects, reported 30 or more sexual partners, and men with HPV-positive tumors were more likely to report a greater number of sexual partners. CONCLUSIONS: These results suggest that the absence of neonatal circumcision and potential resulting complications are associated with penile cancer. Additionally, medical conditions of the penis, sexual activity, infection with HPV, and smoking may increase the risk for penile cancer. IMPLICATIONS: A larger study would allow examination of interrelationships of circumcision, infection with HPV, and smoking as risk factors.

Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality.

BACKGROUND: Hormone replacement therapy (HRT) is typically avoided for women with a history of breast cancer because of concerns that estrogen will stimulate recurrence. In this study, we sought to evaluate the impact of HRT on recurrence and mortality after a diagnosis of breast cancer. METHODS: Data were assembled from 2755 women aged 35-74 years who were diagnosed with incident invasive breast cancer while they were enrolled in a large health maintenance organization from 1977 through 1994. Pharmacy data identified 174 users of HRT after diagnosis. Each HRT user was matched to four randomly selected nonusers of HRT with similar age, disease stage, and year of diagnosis. Women in the analysis were recurrence free at HRT initiation or the equivalent time since diagnosis. Rates of recurrence and death through 1996 were calculated. Adjusted relative risks were estimated by use of the Cox regression model. All statistical tests were two-sided. RESULTS: The rate of breast cancer recurrence was 17 per 1000 person-years in women who used HRT after diagnosis and 30 per 1000 person-years in nonusers (adjusted relative risk for users compared with nonusers = 0.50; 95% confidence interval [CI] = 0.30 to 0.85). Breast cancer mortality rates were five per 1000 person-years in HRT users and 15 per 1000 person-years in nonusers (adjusted relative risk = 0.34; 95% CI = 0.13 to 0.91). Total mortality rates were 16 per 1000 person-years in HRT users and 30 per 1000 person-years in nonusers (adjusted relative risk = 0.48; 95% CI = 0.29 to 0.78). The relatively low rates of recurrence and death were observed in women who used any type of HRT (oral only = 41% of HRT users; vaginal only = 43%; both oral and vaginal = 16%). No trend toward lower relative risks was observed with increased dose. CONCLUSION: We observed lower risks of recurrence and mortality in women who used HRT after breast cancer diagnosis than in women who did not. Although residual confounding may exist, the results suggest that HRT after breast cancer has no adverse impact on recurrence and mortality.

Oral contraceptives and breast cancer risk among younger women.

BACKGROUND: Several studies have suggested a link between oral contraceptive use and breast cancer in younger women, but it is possible that chance or bias, including selective screening of contraceptive users, contributed to the putative association. PURPOSE: Given that oral contraceptives were first marketed in the United States in the early 1960s, we conducted a population-based case-control study to examine the relationship between use of oral contraceptives and breast cancer among women in a recently assembled cohort, focusing on women younger than 45 years of age who had the opportunity for exposure throughout their entire reproductive years. METHODS: Breast cancer patients and healthy control subjects were identified, the latter group by random-digit dialing, in Atlanta, Ga., Seattle/Puget Sound, Wash., and central New Jersey. In Seattle and New Jersey, the study was confined to women 20 through 44 years of age; in Atlanta the age range was extended through 54 years. Patients included women with in situ or invasive breast cancer newly diagnosed during the period of May 1, 1990, through December 31, 1992. In-person interviews were completed by 2203 (86.4%) of 2551 eligible patients and 2009 (78.1%) of 2571 eligible control subjects. Analyses focused on women younger than 45 years of age (1648 patients and 1505 control subjects) to maximize opportunities for extended exposure. Logistic regression analyses were used to obtain maximum likelihood estimates of relative risks (RRs) and their 95% confidence intervals (CIs). RESULTS: Among women younger than 45 years, oral contraceptive use for 6 months or longer was associated with an RR for breast cancer of 1.3 (95% CI = 1.1-1.5). Risks were enhanced for breast cancers occurring prior to age 35 years (RR = 1.7; 95% CI = 1.2-2.6), with the RR rising to 2.2 (95% CI = 1.2-4.1) for users of 10 or more years. The RR for breast cancer for those whose oral contraceptive use began early (before age 18 years) and continued long-term (> 10 years) was even higher (RR = 3.1; 95% CI = 1.4-6.7). The RRs observed for those who used oral contraceptives within 5 years of cancer diagnosis were higher than for those who had not, with the effect most marked for women younger than age 35 years (RR = 2.0; 95% CI = 1.3-3.1). Oral contraceptive associations were also strongest for cancers diagnosed at advanced stages. Evaluation of screening histories and methods of diagnosis failed to support the speculation that associations could be due to selective screening. Among women 45 years of age and older, no associations of risk with use of oral contraceptives were noted. CONCLUSIONS: The relationship between oral contraceptives and breast cancer in young women appears to have a biologic basis rather than to be an artifact or the result of bias.

PIP: A population-based case control study examined the relationship between use of oral contraceptives and breast cancer among women in a cohort, focusing on women younger than 45 years old who had the opportunity for exposure throughout their entire reproductive years. Breast cancer patients and healthy control subjects were identified, the latter group by random-digit dialing, in Atlanta, Georgia, Seattle/Puget Sound, Washington, and central New Jersey. In Seattle and New Jersey, the study was confined to women 20-44 years old; in Atlanta the age range was extended through 54 years. Patients included women with in situ or invasive breast cancer newly diagnosed during the period of May 1, 1990, through December 31, 1992. In-person interviews were completed by 2203 (86.4%) of 2551 eligible patients and 2009 (78.1%) of 2571 eligible control subjects. Analyses focused on women younger than 45 years old (1648 patients and 1505 control subjects) to maximize opportunities for extended exposure. Logistic regression analyses were used to obtain maximum likelihood estimates of relative risks (RRs). Among women under 45, oral contraceptive use for 6 months or longer was associated with an RR for breast cancer of 1.3. Risks were enhanced for breast cancers occurring prior to age 35 years (RR = 1.7) with the RR rising to 2.2 for users of 10 or more years. The RR for breast cancer for those whose oral contraceptive use began before age 18 years and continued long-term ( 10 years) was even higher (RR = 3.1). The RRs observed for those who used oral contraceptives within 5 years of cancer diagnosis were higher than for those who had not, with the effect most marked for women younger than 35 years (RR = 2.0). Oral contraceptive associations were also strongest for cancers diagnosed at advanced stages. The relationship between oral contraceptives and breast cancer in young women appears to have a biologic basis rather than to be an artifact or the result of bias.

Cofactors with human papillomavirus in a population-based study of vulvar cancer.

BACKGROUND: Human papillomavirus (HPV) has been previously associated with vulvar cancer. In a population-based study, we examined whether exposure to HPV, cigarette smoking, or herpes simplex virus 2 (HSV2) increases the risk of this cancer. METHODS: Incident cases of in situ (n = 400) and invasive (n = 110) squamous cell vulvar cancer diagnosed among women living in the Seattle area from 1980 through 1994 were identified. Serum samples were analyzed for antibodies against specific HPV types and HSV2. HPV DNA in tumor tissue was detected by means of the polymerase chain reaction. In most analyses, case subjects were compared with population-based control subjects (n = 1403). Relative risks of developing vulvar cancer were estimated by use of adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Increased risks of in situ or invasive vulvar cancer were associated with HPV16 seropositivity (ORs = 3.6 [95% CI = 2.6-4.8] and 2.8 [95% CI = 1.7-4.7], respectively), current cigarette smoking (ORs = 6.4 [95% CI = 4.4-9.3] and 3.0 [95% CI = 1.7-5.3], respectively), and HSV2 seropositivity (ORs = 1.9 [95% CI = 1.4-2.6] and 1.5 [95% CI = 0.9-2.6], respectively). When the analysis was restricted to HPV16 DNA-positive tumors (in situ or invasive), the OR associated with HPV16 seropositivity was 4.5 (95% CI = 3.0-6.8). The OR for vulvar cancer was 18.8 (95% CI = 11.9-29.8) among current smokers who were HPV16 seropositive in comparison with never smokers who were HPV16 seronegative. CONCLUSIONS: Current smoking, infection with HPV16, and infection with HSV2 are risk factors for vulvar cancer. Risk appears particularly strong among women who are both current smokers and HPV16 seropositive.

Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection.

BACKGROUND: Experimental models and analyses of human tumors suggest that oncogenic, sexually transmittable human papillomaviruses (HPVs) are etiologic factors in the development of oral squamous cell carcinoma (SCC). We conducted a population-based, case-control study to determine whether the risk of this cancer is related to HPV infection and sexual history factors. METHODS: Case subjects (n = 284) were 18-65-year-old residents of three counties in western Washington State who were newly diagnosed with oral SCC from 1990 through 1995. Control subjects (n = 477) similar in age and sex were selected from the general population. Serum samples were tested for HPV type 16 capsid antibodies. Exfoliated oral tissue collected from case and control subjects and tumor tissue from case subjects were tested for HPV DNA. Odds ratios (ORs) were calculated after adjusting for age, sex, cigarette smoking, and alcohol consumption. RESULTS: Among males only, oral SCC risk increased with self-reported decreasing age at first intercourse, increasing number of sex partners, and a history of genital warts. Approximately 26% of the tumors in case subjects contained HPV DNA; 16.5% of the tumors contained HPV type 16 DNA. The prevalence of oncogenic HPV types in exfoliated oral tissue was similar in case and control subjects. The ORs for HPV type 16 capsid seropositivity were 2.3 (95% confidence interval [CI] = 1.6-3.3) for all oral SCCs and 6.8 (95% CI = 3.0-15.2) for oral SCCs containing HPV type 16 DNA. The joint association of cigarette smoking and HPV type 16 capsid seropositivity with oral SCC (OR = 8.5; 95% CI = 5.1-14.4) was stronger than predicted from the sum of individual associations with current smoking (OR = 3.2; 95% CI = 2.0-5.2) and seropositivity (OR = 1.7; 95% CI = 1.1-2.6). CONCLUSIONS: HPV type 16 infection may contribute to the development of a small proportion of oral SCCs in this population, most likely in combination with cigarette smoking.