The relation of reproductive factors to mortality from breast cancer.

Young women with breast cancer have been reported to have an increased risk of dying from their disease if they have given birth in <2 years before diagnosis. The prognostic factors associated with the tumors of these women have not been thoroughly studied. We examined the tumors of the women who had a recent birth and compared the tumor characteristics with those of women who were nulliparous or had given birth > or =5 years before diagnosis. A follow-up study was conducted of 1174 women <45 years old whose invasive ductal breast cancer was diagnosed from January 1983 to December 1992 in three counties of western Washington. These women had participated previously in a population-based, case-control study. Mean follow-up time was 105.4 months. Histological slides were collected for 79.1% of the tumors and reviewed by the study pathologist. Using immunoperoxidase assays, tumor tissue was tested for prognostic markers for 70.4% of the tumors from the women. Cox proportional hazards models were used to estimate the relative risk of dying from breast cancer associated with reproductive events. Logistic regression was used to obtain estimates of the association between various reproductive factors and tumor characteristics. At the end of follow-up, 48.2% of the women (n = 83) whose last birth occurred in < 2 years of diagnosis had died, compared with 23.3% of nulliparous women (n = 189) and 24.4% of the women (n = 661) whose last birth was > or =5 years before diagnosis. The tumors of the women with a recent birth (<2 years before diagnosis) were more likely to be progesterone receptor negative, odds ratio (OR) = 2.2, 95% confidence interval (CI) = 1.2-3.9, to be p53 positive, OR = 2.6, 95% CI = 1.5-4.7, to be of high histological grade, OR = 5.9, 95% CI = 1.7-20.1, to have high mitotic count, OR = 2.2, 95% CI = 1.4-4.4, to be node positive, OR = 2.1, 95% CI = 1.3-3.5, to have a high S phase fraction, OR = 2.3, 95% CI = 1.1-4.8, and to have a high American Joint Committee on Cancer stage (III+), OR = 2.8, 95% CI 1.3-5.8, compared with the tumors of nulliparous women. After adjusting for tumor characteristics and treatment, the risk of mortality associated with a birth in < 2 years of diagnosis of breast cancer remained an independent predictor of mortality, hazard radio (HR) = 2.7, 95% CI = 1.6-4.3. Our study provides evidence that reproductive factors influence the biological behavior of breast cancer in young women and prognosis. Clinicians need to be aware that women who have delivered a child in < 2 years before diagnosis are at increased risk of having tumors with especially adverse prognostic profiles and have a poorer survival rate than women who are nulliparous or whose last birth was some years in the past.     

Incidence of female breast cancer in relation to prevalence of risk factors in Denmark

The extent to which changes in prevalence of risk determinants for female breast cancer could explain the temporal variation in incidence was examined using incidence figures from Denmark for the years 1943–1989. Significant increases in incidence were observed for more recent time periods and birth cohorts. Using deviance statistics from Poisson regression measures of variability explained, only a small proportion of the increase in incidence could be accounted for by fertility rates, average age at menarche and exposure to exogenous hormones. Dietary factors, on the other hand, accounted for the greater proportion of the variation observed by time period or birth cohort. In particular, there was a strong positive association of incidence with alcohol consumption and a negative association with carbohydrate intake.     

Menstrual and reproductive factors in relation to ovarian cancer risk

We assessed menstrual and reproductive factors in relation to ovarian cancer risk in a large, population-based, case-control study. 563 cases in Massachusetts and New Hampshire were ascertained from hospitals and statewide tumour registries; control women (n = 523) were selected through random digit dialing and matched to case women by age and telephone sampling unit. We used multivariate logistic regression to evaluate factors in relation to risk of ovarian cancer and the major tumour histologic subtypes. Ovarian cancer risk was reduced among parous women, relative to nulliparous women (OR = 0.4; 95% CI = 0.3-0.6). Among parous women, higher parity (P = 0.0006), increased age at first (P = 0.03) or last (P = 0.05) birth, and time since last birth (P = 0.04) were associated with reduced risk. Early pregnancy losses, abortions, and stillbirths were unrelated to risk, but preterm, term, and twin births were protective. Risk was lower among women who had breast-fed, relative to those who had not (OR = 0.7; 95% CI = 0.5-1.0), but the average duration of breast-feeding per child was unrelated to risk (P for trend = 0.21). Age at menarche and age at menopause were unrelated to risk overall, although increasing menarcheal age was protective among premenopausal women (P = 0.02). Menstrual cycle characteristics and symptoms were generally unrelated to risk, although cycle-related insomnia was associated with decreased risk (OR = 0.5; 95% CI = 0.3-0.8). We found no association between the type of sanitary product used during menstruation and ovarian cancer risk. In analyses by histologic subtype, reproductive and menstrual factors had most effect on risk of endometrioid/clear cell tumours, and least influential with regard to risk of mucinous tumours. Overall, our findings offer some support to current hypotheses of ovarian pathogenesis, and show aetiologic differences among the tumour subtypes.     

Traditional breast cancer risk factors in relation to molecular subtypes of breast cancer

At least four major categories of invasive breast cancer have been reproducibly identified by gene expression profiling: luminal A, luminal B, HER2-type, and basal-like. These subtypes have been shown to differ in their outcome and response to treatment. Whether this heterogeneity reflects the evolution of these subtypes through distinct etiologic pathways has not been clearly defined. We evaluated the association between traditional breast cancer risk factors and risk of previously defined molecular subtypes of breast cancer in the Nurses’ Health Study. This analysis included 2,022 invasive breast cancer cases for whom we were able to obtain archived breast cancer tissue specimens. Tissue microarrays (TMAs) were constructed, and slides were immunostained for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin 5/6 (CK5/6), and epidermal growth factor receptor (EGFR). Using immunostain results in combination with histologic grade, cases were grouped into molecularly defined subtypes. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). We observed differences in the association between risk factors and subtypes of breast cancer. In general, many reproductive factors were most strongly associated with the luminal A subtype, although these differences were not statistically significant. Weight gain since age 18 showed significant differences in its association with molecular subtypes (P-heterogeneity = 0.05) and was most strongly associated with the luminal B subtype (P-trend 0.001). Although there was not significant heterogeneity for lactation across subtypes, an inverse association was strongest for basal-like tumors (HR = 0.6, 95% CI 0.4–0.8; P-heterogeneity = 0.88). These results support the hypothesis that different subtypes of breast cancer have different etiologies and should not be considered as a single group. Identifying risk factors for less common subtypes such as luminal B, HER2-type and basal-like tumors has important implications for prevention of these more aggressive subtypes.     

Risk of contralateral breast cancer in Denmark 1943-80

The incidence of a second primary breast cancer in the contralateral breast among 56,237 women with a first primary breast cancer diagnosed between the years 1943-80 in Denmark was established. The relative risk (RR) for a breast cancer patient to get yet another breast cancer was studied, taking account of age, stage and treatment of the first primary breast cancer. Based on 345,573 women years at risk and 1,840 non simultaneous contralateral breast cancer cases the overall relative risk (RR) of invasive cancer in the contralateral breast following a first primary breast cancer, was found to be 2.8 (95% Confidence Interval (CI); 2.7-3.0). Among women who survived 10 or more years the risk was higher among those irradiated for the primary breast cancer (RR = 2.6) than among non-irradiated (RR = 2.0). In the large group of patients with localized disease the association with radiation was obvious for all ages combined (irradiated RR = 3.0, not irradiated RR = 1.6), but not obvious among premenopausal (age less than 45 years) and perimenopausal (age 45-54 years) women at primary breast cancer until followed for 20 years. The RR was higher among irradiated than non-irradiated post-menopausal (age greater than 55 years) women from the time of diagnosis of the first cancer, but was not significant after 14 years of follow-up. The probability for a woman diagnosed with breast cancer at 45 years of age or younger, of developing a contralateral breast cancer if surviving to the age of 75 years, is 25%. Close surveillance of the remaining breast of breast cancer patients is advised, especially if young or following an irradiated localized primary breast cancer.     

Risk factors for breast cancer in Japan, with special attention to anthropometric measurements and reproductive history

BACKGROUND: Breast cancer incidence has increased rapidly in Japan recently, but there have been only a few studies on the risk factors for breast cancer in Japan. A case-control study was conducted to evaluate the roles of anthropometric and reproductive factors in the etiology of breast cancer in Osaka. METHODS: Based on information from a self-administered questionnaire at Osaka Medical Center for Cancer and Cardiovascular Diseases, body mass index, body weight and height were compared between 376 cases and 430 controls, together with other factors such as age at menarche, age at first delivery and family history of breast cancer by menopausal status. Logistic regression analysis was employed for adjusting confounding factors and estimating odds ratios with their 95% confidence interval for breast cancer. RESULTS: A body mass index of >25 was significantly associated with the risk among post-menopausal women (age-adjusted odds ratio: 1.90, 95% confidence interval: 1.10-3.24) as compared with the risk for a body mass index of < or = 20. A weight of > or =58 kg showed significantly increased risk compared with a weight of < or = 47 kg among post-menopausal women (1.83, 1.10-3.01), while height of > or = 159 cm showed a significantly elevated risk than height of < or = 149 cm among pre-menopausal women (2.51, 1.17-5.39). Age at menarche of < or = 13 years resulted in a higher risk of breast cancer among post-menopausal women, while age at first delivery of > or = 28 years was associated with the risk among pre-menopausal women. Family history of breast cancer was associated with the risk for breast cancer. CONCLUSIONS: These results were all very consistent with findings observed in western countries.     

Testicular cancer and cryptorchidism in relation to prenatal factors: case-control studies in Denmark

To explore prenatal risk factors that are common to testicular cancer and cryptorchidism, two parallel case-control studies were conducted in Denmark. Information about characteristics of the mother, the pregnancy, and the birth were obtained from the mothers of cases and controls, using a mailed self-administered questionnaire. A maternal age above 30 years was associated with odds ratios (OR) of 1.9 (95 percent confidence interval [CI]= 1.2-3.0) for cryptorchidism and 2.0 (CI = 1.2-3.6) for testicular seminoma; the latter effect was particularly high when the boy was the first child of the mother (OR = 4.1, CI = 1.1-14.6). Birth weights below 3,000 g or above4,000 g were associated with increased risks of testicular cancer, with OR sup to 2.6 (CI = 1.1-5.9) for birth weight below 2,500 g. For cryptorchidism, there was a monotonous trend in the OR from 0.4 in birth weights above 4,500 g to 2.3 in birth weights below 2,500 g. The association between cryptorchidism and testicular cancer was not attenuated by adjustment for maternal age and birthweight, indicating that all three variables are independent risk factors for testicular cancer. With the exception of high maternal age, which consistently is associated more strongly with seminoma than withnon-seminoma, it remains most likely that seminoma and non-seminoma have similar causes. This revised version was published online in July 2006 with corrections to the Cover Date.     

Risk factors of breast cancer in burma

A hospital-based case-control study of breast cancer was undertaken in Rangoon. The age-standardized incidence rate, 25.1 per 100,000 woman-years and the shape of the age-incidence curve show that Rangoon women have an intermediate level of breast cancer risk compared to women of other countries in the world. The analysis is based on 193 cases and 400 controls. Breast cancer risk was found to be directly related to educational attainment. There was an increased risk associated with early menarche and late menopause. The most striking finding was the strong inverse relationship between risk and parity; women who had six or more children have only one-third the breast cancer risk of married women who had less than four children. This association is not confounded by case-control differences in age at birth of first child. The association of breast cancer risk with age at first birth was not striking; only women with a first birth after age 30 were at increased risk. Breast cancer risk was unrelated to lactation. Overall, the epidemiology of breast cancer in Burma is similar to that in most other countries. However, the possibility of an unusual relationship of risk to parity and age at first parturition warrants further exploration.     

Risk of breast cancer among Greek women in relation to nutrient intake

A case-control study of the role of diet in the cause of breast cancer was conducted in Athens, Greece. The case series consisted of 120 consecutive patients with histologically confirmed breast cancer admitted to either of two teaching hospitals over a 12-month period. The controls were 120 patients admitted to a teaching hospital for trauma and orthopedic conditions during the same period. Dietary histories concerning the frequency of consumption of 120 foods and drinks were obtained by interview. Nutrient intakes for individuals were estimated by multiplying the nutrient content of a selected typical portion size for each specified food item by the frequency that the food was used per month and summing these estimates for all food items. Cases reported significantly less frequent consumption of vitamin A after controlling for total caloric intake, potential external confounding variables and other nutrients associated with breast cancer risk. The odds ratio estimated for consumption of vitamin A equal to the value of the 90th centile versus consumption equal to the value of the 10th centile was 0.46 with 90% confidence limits 0.26-0.82. There was no evidence that high intake of dietary fat increases the risk of breast cancer.     

Risk factors for male breast cancer

To investigate risk factors in male breast cancer, a case-control study of 52 histologically diagnosed cases and 52 controls--matched for age, race, marital status, and hospital--was conducted in 5 U.S. metropolitan areas. Cases were significantly more likely to be Jewish than were the controls, supporting earlier suggestions of an increased risk in Jewish males. A significant association of male breast cancer with mumps infections at age 20 years or older, along with the possible association with antecedent testicular injury and the excess frequency of mumps orchitis among cases, suggests that testicular factors may be important in the development of breast cancer among males. An increased frequency of breast cancer among persons who have worked in blast furnaces, steel works, and rolling mills is of interest because of the possible testicular effect of high environmental temperatures. The observed association between breast cancer and a prior history of swollen breast is difficult to interpret because of potential recall bias, and a possible relationship with military service needs further confirmation.     

Menstrual and reproductive factors in relation to risk of endometrial cancer in Chinese women

Menstrual, reproductive and contraceptive factors have been associated with risk of endometrial cancer in populations where the incidence of this tumor is high. To investigate associations between these factors in a low-risk population with a low prevalence of hormone replacement therapy, we conducted a cohort study among 267,400 women employed in the textile industry in Shanghai, China. Menstrual, reproductive and other factors were ascertained at baseline in 1989–1991, and women were followed for incident endometrial cancer through 31 December 1998 (n = 206). Cox proportional hazards modeling was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Risk of endometrial cancer decreased with increasing age at menarche (p-trend = 0.004). Among menopausal women, risk increased with age at menopause and increasing years of menstruation. Compared to women with one live birth, risk was increased in relation to nulliparity (Hazard ratio = 3.95, 95% CI 1.43–10.86). Risk was decreased with increasing age at first live birth (p-trend = 0.03). There was a decreased risk associated with ever use of an intrauterine device (HR = 0.56, 95% CI 0.35–0.88) and use of oral contraceptives for ≥2 years (HR = 0.50, 95% CI 0.23–1.07). This prospective study confirms findings from previous case–control studies relating menstrual, reproductive, and contraceptive factors and endometrial carcinoma.     

Survival of breast cancer patients in relation to factors which affect the risk of developing breast cancer

In order to evaluate the prognostic significance of risk factors for developing breast cancer, a population-based study was conducted of 2,445 breast cancer patients diagnosed in Denmark, 1983-1984. Data on clinical and pathological characteristics of breast cancer were derived from the Danish Breast Cancer Cooperative Group and data on risk factors from a self-administered questionnaire. Among 1,744 patients (71%) with complete information, survival was determined primarily by size of the tumour, skin invasion, number of positive lymph nodes and grade. No significant association was found between survival and reproductive or hormonal risk factors, dietary variables, alcohol consumption and smoking. Low current body weight and weight loss indicated a poor prognosis, independent of the clinical characteristics of the tumour.     

Risk factors for colorectal cancer following breast cancer

Objective. To investigate risk factors for colorectal cancer following breast cancer. Methods. In this nested case-control study, all women (n=14,900) with a first primary breast cancer (1978–1992) were identified from the western Washington population-based Surveillance, Epidemiology, and End Results Cancer Registry. Cases (n=160) developed a second primary colorectal cancer before 1995, at least 6 months after the first cancer diagnosis. Controls (n=310, matched to the cases on calendar year, age and breast cancer stage) were randomly selected from those who did not develop a second primary cancer and who survived to the case's colorectal cancer diagnosis date. Characteristics of the cases and controls at initial diagnosis were compared using conditional logistic regression. Results. The incidence of colorectal cancer was associated with a family history of breast cancer (v.s. no family history, matched odds ratio (mOR)=2.1, 95% confidence interval (CI): 1.1–4.1), high body mass index (30 kg/m² v.s. <30 kg/m², mOR=2.2, CI: 1.2–3.9), and lobular breast cancer histology (v.s. ductal, mOR=2.0, CI: 0.9–4.4). Risk was unrelated to menopausal status, prior hormone replacement therapy and estrogen/progesterone receptor status of the breast tumors. Conclusions. The risk of developing a second primary colorectal cancer may be elevated among certain subsets of breast cancer patients.     

Risk and aggressiveness of breast cancer in relation to plasma organochlorine concentrations.

Several organochlorines identified as "hormone mimics" were proposed as possible risk factors for breast cancer. We conducted a case-control study to assess breast cancer risk and disease aggressiveness in relation to plasma concentrations of several organochlorine compounds. Plasma lipid concentrations of 11 chlorinated pesticides and 14 polychlorinated biphenyl congeners were measured in 315 women newly diagnosed with breast cancer, 219 hospital-based controls, and 307 population controls from the Quebec City area (Canada). Concentrations of hormonally active organochlorines or their surrogates were compared between cases and controls as well as between groups of cases defined according to tumor size and axillary-lymph-node involvement. We found similar levels of organochlorines in cases and controls and no relationship between the relative risk of breast cancer and organochlorine exposure. However, the probability of lymph-node invasion among cases increased with exposure to 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene [p,p'-DDE; odds ratio, 2.54; 95% confidence interval (CI), 1.20-5.35; between the highest and the lowest tertiles]. Furthermore, p,p'-DDE exposure was associated with a dose-related increased relative risk of exhibiting both lymph-node involvement and a large tumor. Indeed odds ratio raised to 2.33 (95% CI, 0.94-5.77) for the second tertile relative to the first tertile and reached 3.51 (95% CI, 1.41-8.73) for the third tertile relative to the first tertile. Similar associations were noted with beta-hexachlorocyclohexane, oxychlordane, and transnonachlor. We conclude that exposure to persistent, hormonally active organochlorines during adulthood is not associated with breast cancer risk. The possibility that some organochlorines and especially p,p'-DDE may increase breast cancer aggressiveness deserves further attention.     

Risk factors for breast cancer in nulliparous women

The relation between hormonal and lifestyle factors and breast cancer risk in nulliparae was investigated using data from two case-control studies conducted in Italy between 1983 and 1994. The study included 1041 nulliparae with histologically confirmed incident breast cancer and 1002 nulliparous controls admitted to hospital for a wide range of acute, non-neoplastic, nonhormone-related diseases. In premenopausal nulliparae, there was an inverse relation with age at menarche [odds ratios (OR) 0.45; 95% confidence intervals (CI) 0.24-0.86 for > or = 15 years vs < 12], while no association emerged in postmenopausal. Breast cancer risk increased with age at menopause, the OR being 1.91 (95% CI 1.26-2.90) for nulliparae reporting age at menopause > or = 53 years compared with < 45. Abortion was not related to breast cancer risk, the OR being 0.92 for any spontaneous, 0.97 for any induced and 0.77 for > or = 2 total abortions compared to none. The OR was 1.75 (95% CI 1.03-2.97) for women reporting their first abortion at age > or = 30 years compared with < 30. Oral contraceptives and hormone replacement therapy in menopause were moderately related to risk. The OR was 2.71 (95% CI 1.85-3.95) in nulliparae with a family history of breast cancer and 1.60 (95% CI 1.20-2.14) in those with a history of benign breast disease. Compared with nulliparae reporting a low physical activity, the OR was 0.79 (95% CI 0.54-1.16) for those reporting intermediate/high activity. Breast cancer risk increased with total energy intake, the OR being 1.65 (95% CI 0.99-2.75) in the highest tertile; beta-carotene was inversely related to risk (OR 0.60, 95% CI 0.38-0.95) for the highest tertile. Thus, most risk factors for breast cancer in nulliparae were similar to those in women generally.     

Risk factors for breast cancer in black women

Risk factors for breast cancer were examined in black women in a hospital-based case-control study of 529 black women with breast cancer and 589 controls. Late age at menarche was associated with a reduced risk of breast cancer. Women having 5 or more children had a reduced risk relative to that of women with fewer or no children. Late age at first birth was associated with an elevated risk of breast cancer. Among postmenopausal black women, obesity [as measured by body mass index (BMI)] was associated with an increased risk; among premenopausal women, there was no association of breast cancer with BMI. Women whose menopause occurred at or after age 50 were at increased risk relative to those whose menopause occurred earlier. There was no association between number of years of education and breast cancer in black women. History of benign breast disease and history of breast cancer in mother or sisters both were risk factors. The risk factor profile for breast cancer in black women was similar to that observed in whites.     

Hormonal and other factors in relation to survival among breast cancer patients

We have examined the relationship between all-cause mortality and various hormonal and other factors in over 1,200 women with breast cancer recruited into 2 consecutive case-control studies between 1969 and 1984. The age at diagnosis ranged from 24 to 59 years, and the majority (74%) were pre-menopausal at diagnosis. Analyses were based on follow-up to 1 January 1994, by which time 608 (50%) of the women had died. Of the factors examined, weight was most strongly associated with survival, with a significant increase in the risk of death with increasing weight. Two hormonal factors, time since last birth and time since last oral contraceptive use, were also independently associated with survival. All of these associations remained after adjustment for stage and histological nodal status. Our findings provide new evidence to suggest that reproductive factors and exogenous hormones in the form of oral contraceptives may influence survival in women with breast cancer, even after differences in stage and nodal status have been taken into account.     

Breast cancer risk following Hodgkin lymphoma radiotherapy in relation to menstrual and reproductive factors

Background:

Women treated with supradiaphragmatic radiotherapy (sRT) for Hodgkin lymphoma (HL) at young ages have a substantially increased breast cancer risk. Little is known about how menarcheal and reproductive factors modify this risk.

Methods:

We examined the effects of menarcheal age, pregnancy, and menopausal age on breast cancer risk following sRT in case–control data from questionnaires completed by 2497 women from a cohort of 5002 treated with sRT for HL at ages <36 during 1956–2003.

Results:

Two-hundred and sixty women had been diagnosed with breast cancer. Breast cancer risk was significantly increased in patients treated within 6 months of menarche (odds ratio (OR) 5.52, 95% confidence interval (CI) (1.97–15.46)), and increased significantly with proximity of sRT to menarche (P_trend<0.001). It was greatest when sRT was close to a late menarche, but based on small numbers and needing reexamination elsewhere. Risk was not significantly affected by full-term pregnancies before or after treatment. Risk was significantly reduced by early menopause (OR 0.55, 95% CI (0.35–0.85)), and increased with number of premenopausal years after treatment (P_trend=0.003).

Conclusion:

In summary, this paper shows for the first time that sRT close to menarche substantially increases breast cancer risk. Careful consideration should be given to follow-up of these women, and to measures that might reduce their future breast cancer risk.     

Risk factors for renal-cell carcinoma in Denmark. III. Role of weight,physical activity and reproductive factors

A population-based case-control study of risk factors for renal-cell carcinoma was conducted in Denmark from 1989 to 1992. A total of 368 histologically verified cases and 396 controls were included. Information on weight, height, physical activity and reproductive factors were collected in a structured interview, along with information on other suspected risk factors. A significant increase in risk was seen for obese women but not obese men. Although there was no clear gradient, the risk was highest among women with a relative weight in the upper 5% (OR 6.1; 95% CI, 2.3 to 16.1). The increased risk was most evident for high relative weight in ages 30 to 50. No association was observed for height or physical activity. Use of amphetamines was associated with increased risk but, because of the close link with obesity, we were unable to provide evidence that amphetamines are an independent risk factor. We found some evidence for an association with reproductive variables, including decreased risk for women with late menarche and first pregnancy and birth. We observed no association with number of pregnancies or age at menopause, or use of estrogen-containing medication. © 1994 Wiley-Liss, Inc.