Estrogen replacement therapy and breast cancer survival in a large screening study.

BACKGROUND: Hormone replacement therapy has been associated in some studies with reductions in breast cancer mortality among women who develop this disease. It is unclear whether this association reflects the biologic activity of the hormones or the earlier detection of tumors among hormone users. We examined breast cancer mortality among women who were diagnosed with axillary lymph node-negative and node-positive breast cancer according to the currency of estrogen use at diagnosis. METHODS: Vital status through June 1995 was determined for 2614 patients with postmenopausal breast cancer diagnosed during the period from 1973 to January 1981. We estimated adjusted hazard-rate ratios (adjusting for tumor size, age, race, Quetelet [body mass] index, and number of positive lymph nodes in women with node-positive disease) and unadjusted cumulative probabilities of breast cancer death over time since diagnosis. RESULTS: Among patients with node-negative disease, rate ratios for breast cancer mortality associated with current use compared with nonuse at diagnosis were 0.5 (95% confidence interval [CI] = 0.3-0.8) until 144 months after diagnosis and 2.2 (95% CI = 0.9-5.2) thereafter. Mortality was not statistically significantly lower in past users. The cumulative probabilities of breast cancer mortality at the end of follow-up were 0.14, 0.14, and 0.09 in nonusers, past users, and current users, respectively. Among women with node-positive disease, the rate ratios associated with current and past use were both 0.5 until 48 months after diagnosis (95% CI = 0.3-0.8 for current users; 95% CI = 0.3-0.9 for past users) and were 1.1 (95% CI = 0.7-1.7) and 1.8 (95% CI = 1.2-2.7), respectively, thereafter. The cumulative probabilities of breast cancer mortality were 0.32, 0.39, and 0.27 in nonusers, past users, and current users, respectively. CONCLUSIONS: Patients with breast cancer who were using replacement estrogens at the time of diagnosis experienced reductions in breast cancer mortality, which waned with the time since diagnosis.

Serum concentrations of organochlorine compounds and endometrial cancer risk (United States).

OBJECTIVES: Endogenous and exogenous estrogens are important in the development of endometrial cancer. Several organochlorine compounds, such as o,p'-DDT, have estrogenic properties. The objective of this case-control analysis was to examine serum concentrations of organochlorine compounds and risk of endometrial cancer. METHODS: Analyses were based on a sample of 90 endometrial cancer cases and 90 individually matched community controls from a multicenter case-control study in five geographic regions of the United States. Information on potential confounders, including menstrual and reproductive factors, cigarette smoking, diet, and weight, was obtained by interview. RESULTS: The adjusted relative risk of endometrial cancer in the highest quartile of exposure compared with women in the lowest quartile was 0.7 (95 percent confidence interval [CI] = 0.2-2.0) for p,p'-DDE, and 0.9 for total polychlorinated biphenyls (PCBs) (CI = 0.4-2.5). CONCLUSIONS: These findings do not support the hypothesis that organochlorine compounds are linked to the development of endometrial cancer.

Evidence for a common etiology for endometrial carcinomas and malignant mixed mullerian tumors.

OBJECTIVE: To elucidate factors linked to the development of malignant mixed mullerian tumors (MMMT) and determine whether the risk factor profile for these tumors corresponds with that for the more common endometrial carcinomas. METHODS: A multicenter case-control study of 424 women diagnosed with endometrial carcinoma, 29 women diagnosed with MMMT, and 320 community controls was conducted. Review of pathological reports and slides was performed to classify cases by histological type. All participants were asked to respond to a questionnaire which ascertained information on exposure to factors postulated to be linked to the development of uterine tumors. RESULTS: Women with endometrial carcinomas and MMMTs were similar with respect to age and educational attainment. Women diagnosed with MMMTs were more likely than those diagnosed with carcinomas to be of African-American descent (28% vs 4%; P = 0.001). Weight, exogenous estrogen use, and nulliparity were related to risk of both tumor types. Marked obesity was associated with a 4.8-fold (95% CI = 3.0,7.6) increase in risk of carcinoma and a 3.2-fold (95% CI = 1.1,9.1) increase in risk of MMMT development. Use of exogenous estrogens increased the odds of developing carcinomas by 2-fold (95% CI = 1.3,3.2) and that of developing MMMTs by 1.8-fold (95% CI = 0.57,5.5). Nulliparity was associated with a 2.9-fold (95% CI = 1.9,4.8) increase in risk of carcinomas and a 1.7-fold (95% CI = 0.53,5.6) increase in risk of MMMTs. Oral contraceptive use protected against the development of both carcinomas (OR = 0.39; 95% CI = 0.26,0.58) and MMMTs (OR = 0.76; 95% CI = 0.25,2.3). Current smokers were at a reduced risk of developing endometrial carcinomas (OR = 0.34; 95% CI = 0.21,0.55) and MMMTs (OR = 0.57; 95% CI = 0.15,2.3), while former smokers were at an increased risk of MMMT (OR = 2.7; 95% CI = 1.1,6.8) but not carcinoma development (OR = 0.81; 95% CI = 0.56,1.2). CONCLUSION: Results from this study suggest that MMMTs and carcinomas have a similar risk factor profile. This observation is compatible with the hypothesis that the pathogenesis of these two histological types of uterine tumors is similar.

Analysis of histopathological features of endometrioid uterine carcinomas and epidemiologic risk factors.

A large case-control study was performed to determine whether risk factors for endometrioid carcinoma, the most common type of endometrial cancer, vary according to the histological features of the tumor. Study subjects consisted of 328 women with newly diagnosed endometrioid adenocarcinoma and 320 population-based control subjects. Variables studied included age at menarche, menopausal estrogen use, weight, parity, cigarette smoking, and oral contraceptive use. The risk factor profile for endometrioid carcinomas with and without squamous differentiation was very similar. No striking differences in risk factors were observed between endometrioid cancers with and without adjacent endometrial hyperplasia. Finally, none of the risk factors varied substantially between early-stage and late-stage tumors or low-grade and high-grade tumors. In summary, this study indicates that risk factors for endometrioid carcinomas are not related to the morphological features of the tumor.

Intrauterine device use and endometrial cancer risk.

BACKGROUND: Because intrauterine devices (IUD) invoke acute and chronic inflammatory responses in the endometrium, it is possible that prolonged insertion of an IUD could induce endometrial cancer. METHODS: We examined the relation between use of an IUD and endometrial cancer risk using data from a multicentre case-control study involving 405 endometrial cancer cases and 297 population controls. RESULTS: A total of 20 (4.9%) cases and 34 (11.4%) controls reported any use of an IUD. After adjustment for potential confounders, IUD use was not associated with an increased risk of endometrial cancer (RR = 0.56 for ever use; 95% CI: 0.3-1.0). Little reduction in risk was observed among women who last used an IUD within 10 years of the index date (RR = 0.84; 95% CI: 0.3-2.4) but risk was decreased among women who used an IUD in the more distant past (RR = 0.45; 95% CI: 0.2-1.0). Risk did not vary consistently with number of years of IUD use or with years since first use. Risk was not increased among women who used inert devices (RR = 0.46; 95% CI: 0.3-3.6) or those who used devices containing copper (RR = 1.08; 95% CI: 0.1-3.6). CONCLUSION: These data are reassuring in that they do not provide any evidence of an increased risk of endometrial cancer among women who have used IUD.

PIP: IUDs invoke acute and chronic inflammatory responses in the endometrium. The authors therefore explored whether the prolonged insertion of an IUD increases one's risk of developing endometrial cancer. The relation between the use of an IUD and endometrial cancer risk was examined using data from a multicenter case-control study involving 405 endometrial cancer cases and 297 population controls. 20 cases and 34 controls reported using an IUD. After adjusting for potential confounders, IUD use was not associated with an increased risk of endometrial cancer. A small reduction in risk was observed among women who last used an IUD within 10 years of the index date, with the risk further reduced among women who last used an IUD more than 10 years ago. Risk did not vary consistently with the number of years of IUD use or with years since first use. Furthermore, the level of risk was not increased among women who used inert devices or those who used copper-containing devices.

Second primary cancers after vulvar and vaginal cancers.

OBJECTIVE: Our objective was to examine the occurrence of second primary cancers after vaginal and vulvar cancers. STUDY DESIGN: Women in whom cancers of the vagina (in situ, n=461; invasive, n=888) and vulva (in situ, n=2898; invasive, n=2685) were diagnosed between 1973 and 1988 were identified from nine population-based cancer registries. Subjects were followed through 1989 for the development of a subsequent primary cancer. RESULTS: We found increased risks of all second cancers combined among women with cancer of the vulva (observed/expected in situ = 1.5; observed/expected invasive = 1.3) and vagina observed/expected invasive = 1.2). Most of the excess second cancers were smoking related (e.g., cancers of the lung, buccal cavity and pharynx, esophagus, nasal cavity and larynx) or related to infection with human papillomavirus (e.g., cervix, vulva, vagina, and anus). CONCLUSION: These associations indicate that the follow-up care of women with cancers of the vulva and vagina should involve efforts to promote smoking cessation. The data are also consistent with a common sexually related cause for cancers of the cervix, vulva, vagina, and anus.

Geographic variation in mortality from breast cancer among white women in the United States.

BACKGROUND: For several decades, mortality from breast cancer has been higher in the northeastern part of the United States than in other regions, particularly the South. Rates have also been somewhat higher in the Midwest and West than in the South, especially among older women. The reasons for these geographic variations are not well understood. PURPOSE: The objective of this study was to evaluate geographic differences in U.S. breast cancer mortality rates in 1987, after taking into account regional differences in the distribution of recognized breast cancer risk factors (e.g., late age at first live birth) and certain prognostic factors (e.g., mammography use). METHODS: The 1987 breast cancer mortality rates for four regions of the country were obtained from the National Center for Health Statistics. Regional data on the distribution of breast cancer risk factors were obtained from 1987 National Health Interview Cancer Epidemiology Supplement interviews with 9778 white women aged 20-79 years. Regional data on the distribution of mammography use were obtained from 1987 National Health Interview Cancer Control Supplement interviews with 3795 white women aged 50-79 years. RESULTS: Age-adjusted mortality ratios (MRs) among women 50 years and older were 1.15, 1.18, and 1.30 in the West, Midwest, and Northeast, respectively, compared with the South. Corresponding MRs among women 20-49 years old were 1.01, 1.08, and 1.07 in the West, Midwest, and Northeast, respectively, compared with the South. After adjustment for recognized risk factors and certain prognostic factors, MRs among older women were 1.13 (95% confidence interval [CI] = 1.04-1.23), 1.08 (95% CI = 1.01-1.16), and 1.13 (95% CI = 1.04-1.23) in the West, Midwest, and Northeast, respectively, compared with the South. Corresponding MRs among younger women were 0.94 (95% CI = 0.76-1.16), 1.05 (95% CI = 0.92-1.18), and 0.99 (95% CI = 0.86-1.14), respectively. CONCLUSION: Before adjustment for regional differences in recognized risk factors and prognostic factors, mortality excesses among younger women in the Northeast, Midwest, and West were less than 10% compared with the South. After adjustment, MRs were near unity for all regions. Among older women, the excess mortality was more substantial before adjustment for relevant factors, ranging from 15% in the West to 30% in the Northeast. Approximately 50% of the excesses in the Northeast and Midwest and 10% of the excess in the West could be explained on the basis of regional differences in the prevalence of recognized breast cancer risk factors and prognostic factors. After adjustment for these factors, the magnitude of excess in breast cancer mortality in the Northeast (13%) was comparable to that in the West (13%) but still slightly higher than that in the Midwest (8%).

Evidence of a healthy estrogen user survivor effect.

We examined the relation between menopausal estrogen use and all-cause and cause-specific mortality in a cohort of over 49,000 women followed between 1979 and 1989 in the Breast Cancer Detection Demonstration Project (BCDDP) Follow-Up Study. We found a lower all-cause mortality rate among women who took estrogens [rate ratio (RR) = 0.7; 95% confidence interval (CI) = 0.7-0.8], particularly current users (RR = 0.3; 95% CI = 0.2-0.4), than among women who never took them. Additional analyses, however, revealed that women who had recently stopped taking estrogens had a higher all-cause mortality rate than women who had never taken them (RR = 1.4; 95% CI = 1.2-1.7). Women who had recently stopped taking estrogens also had higher mortality rates from circulatory disease (RR = 1.3; 95% CI = 1.0-1.8) and cancer (RR = 1.6; 95% CI = 1.2-2.2) than women who never took them. The most likely explanation for these results is that women stop taking estrogens when they develop symptoms of serious illness. As a consequence of this "healthy estrogen user survivor effect," nonexperimental studies are susceptible to overestimating the benefits of menopausal estrogen use, particularly current use, on mortality.

Menopausal estrogen and estrogen-progestin replacement therapy and risk of breast cancer (United States).

This study examines the relationship between menopausal estrogen and estrogen-progestin replacement therapy and risk of breast cancer, focusing on whether associations differ according to whether the tumors are in situ or invasive. Data are from a prospective study conducted 1980-89 on 49,017 selected participants in the Breast Cancer Detection Demonstration Project, a five-year screening program conducted between 1973 and 1980 in the United States. Overall, the rate ratio for estrogen-only use compared with no-hormone use was 1.0, and that for the estrogen-progestin combination was 1.2 (95 percent confidence interval [CI] = 1.0-1.6). However, the associations differed according to whether the tumors were in situ or invasive. The rate ratios of in situ breast cancer associated with use of estrogens alone and the combination regimen were 1.4 (CI = 1.0-2.0) and 2.3 (CI = 1.3-3.9), respectively. Duration of estrogen-only use also was associated with risk of in situ tumors, with users for 10 or more years at twice the risk of nonusers (P-value for trend test = 0.02). Duration of use was not associated with risk of invasive cancer. Our results are consistent with the hypothesis that hormone replacement therapy is related to earlier-stage breast cancer; however, the possibility that the results reflect increased breast cancer surveillance among those taking hormones cannot be ruled out.

Associations between bladder cancer risk factors and tumor stage and grade at diagnosis.

Using data on 1,860 bladder cancer cases and 3,934 population-based controls from the National Bladder Cancer Study, we examined associations between suspected bladder cancer risk factors and tumor stage and grade. Employment in a high-risk occupation was associated with the entire clinical spectrum of bladder cancer rather than a particular tumor stage or grade. For example, relative risks (RR) were similar for noninvasive and invasive disease (1.5 and 1.6, respectively). Cigarette smoking also increased risk of the entire clinical spectrum of bladder cancer, but the more advanced the stage, the stronger the effect. For example, relative risks of noninvasive and invasive bladder cancer for current heavy smokers were 3.0 and 5.2, respectively. Cigarette smoking was associated with higher risk of low-grade than high-grade tumors, once stage of disease was taken into account. Compared with whites, nonwhites were at a lower risk of noninvasive bladder cancer (RR = 0.4) but at similar risk of invasive bladder cancer (RR = 1.1), a pattern indicating racial differences in health practices related to bladder cancer detection. History of urinary tract infections and bladder stones was associated with increasing relative risks for advanced tumor stage. Heavy artificial sweetener use was associated with higher-grade, poorly differentiated tumors. Coffee consumption and family history of bladder cancer were not consistently associated with tumor stage or grade. Overall, different clinical presentations of bladder cancer share most suspected bladder cancer risk factors, including employment in a high-risk occupation and cigarette smoking.

Past and present physical activity and endometrial cancer risk.

We examined the relation between physical activity and endometrial cancer using data from a multicentre case-control study involving 405 endometrial cancer cases and 297 population controls. Estimates of recreational (i.e. active sport, walks and hikes) and nonrecreational activity (i.e. house cleaning, climbing stairs and walking or standing on the job) were obtained using interview information. After adjustment for age, study area, education, parity, years of use of oral contraceptives, years of use of menopausal oestrogens and cigarette smoking, recent recreational inactivity was associated with increased risk (RR = 1.9 for lowest vs highest tertile). Similarly, recent nonrecreational inactivity was associated with increased risk (RR = 2.2 for lowest vs highest tertile). Further adjustment for body mass and nonrecreational activity attenuated the association between risk and recent recreational inactivity (RR = 1.2; 95% CL = 0.7-2.0) but adjustment for body mass and recreational activity did not alter the association between risk and recent nonrecreational inactivity (RR = 2.0; 95% CL = 1.2-3.1). To evaluate the relation between risk and sustained inactivity, we simultaneously examined activity levels at three periods (RR i.e. age 20-29, age 30-39 and recently) in women age 50 and older. After adjustment for potential confounders and body mass, risk was elevated among women who were always recreationally inactive (RR = 1.5 for always active vs always inactive) and among women who were always nonrecreationally inactive (RR = 1.6 for always active vs always inactive). This study suggests that physically inactive women may be at increased risk of endometrial cancer because they are more likely to be overweight or obese. Our data also suggest that inactivity per se may be associated with an increased risk of endometrial cancer. However, we cannot rule out the possibility that our results, particularly those for nonrecreational activity, reflect unmeasured confounding factors. Future studies should attempt to obtain more detailed assessments of physical activity, including the intensity with which an individual engaged in an activity and the actual time involved in exertion.

Racial differences in ill defined cancer mortality in the United States and in the District of Columbia.

STUDY OBJECTIVE: The aim was to examine the epidemiology of unknown primary cancer mortality in the USA during 1979 to 1988 by age, sex, race, year, and geographical area. DESIGN: National (US) and state data were abstracted for deaths due to ill defined cancer (ICD-9 195.0 to 199.1) and all cancers combined (ICD-9 140.0-209.9). Age adjusted mortality rates were calculated using the 1980 USA population as the standard, and standardised rate ratios were derived. National total cancer incidence data were obtained from the surveillance, epidemiology and end results (SEER) program, and age and sex specific relative (black/white) cancer incidence rates were derived and compared to relative (black/white) mortality rates for ill defined cancer. State and regional median family income levels were obtained from the 1980 census and compared to corresponding mortality rates. SETTING: This study used data for the US population, the 50 states, and the District of Columbia. MEASUREMENTS AND MAIN RESULTS: During 1984-1988, ill defined cancers accounted for an average of 34,921 deaths each year in the USA (13.7 per 100,000 population). The mortality rate due to ill defined cancers is greater among blacks (19.3 per 100,000) than whites (13.2 per 100,000) (RR = 1.5) and has not declined since 1979. There is considerable geographical variation in the ill defined cancer mortality rate. Thus among blacks the highest rates were clustered in the central states (23 per 100,000) and the lowest rates were seen in the mountain and western states (17 per 100,000). The District of Columbia had the highest overall rate (21.7 per 100,000) when compared to all other states. The black/white relative mortality rate due to ill defined cancer was consistently greater than the black/white relative incidence of all cancers. CONCLUSIONS: Ill defined cancer mortality is the fourth leading site of cancer mortality in the USA, and accounts for 7.4% of cancer deaths annually. The large proportion of ill defined cancer deaths may have biased the accuracy of national and local cancer incidence and mortality statistics. The higher mortality of ill defined cancer among blacks is not explained by the higher overall cancer incidence among blacks and suggests the influence of socioeconomic or cultural barriers that may result in underutilisation of health services or substandard health care. Ill defined cancer mortality may be a sentinel indicator of deficiencies in the health care delivery system as well as a measure of progress against cancer.

In situ and invasive vulvar cancer incidence trends (1973 to 1987).

OBJECTIVE: The objective of this study was to examine recent trends in the incidence of vulvar cancer. STUDY DESIGN: Cases of in situ and invasive squamous cell vulvar cancer were identified from nine Surveillance, Epidemiology, and End Results cancer registries. RESULTS: The incidence rate of in situ vulvar cancer nearly doubled between 1973 to 1976 and 1985 to 1987, whereas the rate of invasive squamous cell carcinoma remained relatively stable. CONCLUSIONS: Possible reasons for this discordance include the following: (1) Women affected by the "sexual revolution" are not yet old enough to have invasive vulvar carcinoma; (2) early diagnosis and treatment of in situ carcinoma have mitigated anticipated increases in invasive vulvar carcinoma incidence; (3) in situ and invasive carcinomas of the vulva have different etiologies, with the sexually transmitted human papillomavirus involved in the etiology of in situ carcinoma and other factors involved with most invasive squamous cell carcinoma.

Diet and the risk of vulvar cancer.

In this case-control study, 201 case patients with vulvar cancer and 342 community control subjects responded to a 61-item food frequency questionnaire. Risk was unrelated to intake of dark green vegetables, citrus fruits, legumes, and vitamins A and C and folate. Risk increased modestly with decreased intake of dark yellow-orange vegetables; the relative risk for the lowest versus the highest quartile was 1.6. Analyses using preliminary determinations of the major carotenoids in common fruits and vegetables suggested that alpha carotene might be the protective constituent in dark yellow-orange vegetables. Intake of beta carotene and provitamin A carotenoids was unrelated to risk. Multivitamin users were at lower risk, compared to nonusers, but no trend was observed with increasing years of use, suggesting that this association was due to unmeasured differences in life-style factors. Risk increased irregularly with the number of cups of coffee consumed per week whereas consumption of alcohol was unrelated to risk.

A comparison of primary breast cancer management in small, intermediate and large community hospitals and a comprehensive cancer center.

The results presented above indicate clearly that the size of a hospital is associated not only with the type of patient population treated there in terms of demographic and disease related characteristics but also with the type of treatment given. Smaller hospitals were more likely to have older and later stage disease patients for whom they used fewer diagnostic tests and less conservative surgical procedures than larger hospitals. The patients in smaller hospitals also tended to stay for longer periods of time. Interestingly, in terms of the comparison between the community hospital groups and the comprehensive cancer center, no consistent pattern was found. Large hospitals were more like MSKCC in their patient population and length of stay, but the small hospitals were more like MSKCC in the number of tests and type of surgical procedures performed.