Leif Bergkvist

The Risk of Breast Cancer after Estrogen and Estrogen–Progestin Replacement

To examine the risk of breast cancer after noncontraceptive treatment with estrogen, we conducted a prospective study of 23,244 women 35 years of age or older who had had estrogen prescriptions filled in the Uppsala region of Sweden. During the follow-up period (mean, 5.7 years) breast cancer developed in 253 women. Compared with other women in the same region, the women in the estrogen cohort had an overall relative risk of breast cancer of 1.1 (95 percent confidence interval, 1.0 to 1.3). The relative risk increased with the duration of estrogen treatment (P = 0.002), reaching 1.7 after nine years (95 percent confidence interval, 1.1 to 2.7). Estradiol (used in 56 percent of the treatment periods in the cohort) was associated with a 1.8-fold increase in risk after more than six years of treatment (95 percent confidence interval, 0.7 to 4.6). No increase in risk was found after the use of conjugated estrogens (used in 22 percent of the treatment periods) or other types, mainly estriols (used in 22 percent of the treatment periods). Although the numbers of women were smaller, the risk of breast cancer was highest among the women who took estrogen and progestin in combination for extended periods. The relative risk was 4.4 (95 percent confidence interval, 0.9 to 22.4) in women who used only this combination for more than six years. Among women who had previously used estrogens alone, the relative risk after three years or more of use of the combination regimen was 2.3 (95 percent confidence interval, 0.7 to 7.8). We conclude that in this cohort, long-term perimenopausal treatment with estrogens (or at least estradiol compounds) seems to be associated with a slightly increased risk of breast cancer, which is not prevented and may even be increased by the addition of progestins.

Cancer incidence and mortality in women receiving estrogen and estrogen‐progestin replacement therapy—long‐term follow‐up of a Swedish cohort

We analyzed cancer incidence and mortality in a cohort of 22,597 Swedish women who were prescribed replacement hormones. After 13 years of follow‐up in national registries, 2,330 incident cancer cases and 848 cancer deaths were observed. Overall, our results were reassuring since incidence rate ratios (SIRs) for 16 cancer sites and mortality ratios (SMRs) for all 10 examined sites were at, or lower than, unity. However, we found that exposure to an estrogen‐progestin combined brand was associated with an increasing relative risk of breast cancer with follow‐up time, the SIR reaching 1.4 (95% CI 1.1–1.8) after 10 years of follow‐up. The relative risk of endometrial cancer was substantially increased, with the highest SIR of 5.0 (95% CI 1.6–5.9) in women prescribed estrogens alone, whereas those given an estrogen‐progestin combination showed no elevation in risk. The risk estimates for liver and biliary tract cancers and for colon cancer were reduced by about 40%, notably in women prescribed the estradiol‐progestin compound. Further detailed analyses revealed no evidence of adverse or protective effects on the risk of ovarian, uterine cervical, vulvar/vaginal, rectal, pancreatic, renal, lung, thyroid and other endocrine cancers, brain tumors, malignant melanoma or other skin cancers. Hormone replacement therapy was not associated with an increase in mortality for any cancer site, at this time of follow‐up. For breast and endometrial cancers, SMRs were below baseline but tended to increase with follow‐up time. We conclude that hormone replacement increases the endometrial‐cancer risk after unopposed estrogens and the breast‐cancer risk—notably after estrogen‐progestin combined therapy—and tentatively suggest that it exerts a protective effect against colon and liver cancer risks.

Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement

Objective: We studied the risk of breast and endometrial cancer in a cohort of 11,231 Swedish women prescribed different replacement hormone regimens.Methods: All 10,472 women at risk of developing breast cancer and 8,438 women at risk of endometrial cancer were followed up from the time of the questionnaire in 1987–88 through 1993, by record-linkages to the National Swedish Cancer Registry. Using data from a questionnaire we analyzed the relationships between hormone exposures and cancer risk, with non-compliers and users of less than 1 year as a reference group.Results: For breast cancer, women reporting use of estrogens combined with progestins had evidence of an increased risk relative to women denying intake or taking hormones for less than 1 year; relative risk (RR) = 1.4 (95% confidence interval 0.9–2.3) after 1–6 years of intake, and RR=1.7 (95% CI 1.1–2.6) after more than 6 years. This excess risk seemed confined to recent exposure. We found no association with intake of estrogens alone using non-compliers and short-term takers as the reference group. The risk of invasive endometrial cancer was increased four-fold in women using medium-potency estrogens alone for 6 years or longer, RR = 4.2 (95% CI 2.5–8.4). Women on such long-term progestin-combined treatment had a lower, non-significant, excess risk (RR = 1.4; 95% CI 0.6–3.3).Conclusions: We conclude that long-term recent use of estrogen–progestin combined replacement therapy may increase the risk of breast cancer. Exposure to estrogen alone substantially elevates the risk of endometrial cancer, an increase that can be reduced or perhaps avoided by adding progestins.

Red meat consumption and risk of cancers of the proximal colon, distal colon and rectum : the Swedish Mammography Cohort

Although there is considerable evidence that high consumption of red meat may increase the risk of colorectal cancer, data by subsite within the colon are sparse. The objective of our study was to prospectively examine whether the association of red meat consumption with cancer risk varies by subsite within the large bowel. We analyzed data from the Swedish Mammography Cohort of 61,433 women aged 40–75 years and free from diagnosed cancer at baseline in 1987–1990. Diet was assessed at baseline using a self‐administered food‐frequency questionnaire. Over a mean follow‐up of 13.9 years, we identified 234 proximal colon cancers, 155 distal colon cancers and 230 rectal cancers. We observed a significant positive association between red meat consumption and risk of distal colon cancer (p for trend = 0.001) but not of cancers of the proximal colon (p for trend = 0.95) or rectum (p for trend = 0.32). The multivariate rate ratio for women who consumed 94 or more g/day of red meat compared to those who consumed less than 50 g/day was 2.22 (95% confidence interval [CI] 1.34–3.68) for distal colon, 1.03 (95% CI 0.67–1.60) for proximal colon and 1.28 (95% CI 0.83–1.98) for rectum. Although there was no association between consumption of fish and risk of cancer at any subsite, poultry consumption was weakly inversely related to risk of total colorectal cancer (p for trend = 0.04). These findings suggest that high consumption of red meat may substantially increase the risk of distal colon cancer. Future investigations on red meat and colorectal cancer risk should consider cancer subsites separately.

Hormone Replacement Therapy and the Risk for First Hip Fracture: A Prospective, Population-based Cohort Study

OBJECTIVE To determine the relative risk for sustaining a first hip fracture after hormone replacement therapy. DESIGN Prospective population-based cohort study with an average observation period of 5.7 years. SETTING A prescription-based cohort in the Uppsala health care region in Sweden. PARTICIPANTS The cohort (23 246 women) comprised virtually all women of 35 years of age and older who received noncontraceptive estrogens from April 1977 through March 1980. Comparisons were made with women in the background population. MEASUREMENTS Follow-up through 1983 was done with regard to hospital admissions for a first cervical or trochanteric hip fracture. The observed number of cases was compared with that expected on the basis of person-years of observation in the cohort and incidence rates in the background population. Analyses were made in exposure categories, based solely on prescription data. MAIN RESULTS During 133 022 person-years of observation, 163 cases of first hip fracture occurred, compared with the 205.5 expected, yielding an overall relative risk of 0.79 (95% CI, 0.68 to 0.93). The greatest protective effect (relative risk, 0.37; CI, 0.13 to 0.79) was found against trochanteric fracture among women receiving potent estrogens who were under 60 years of age at cohort entry. This group also had the highest proportion of treatments with combinations of estrogens and progestogen (41%). Treatment with less potent estrogens, mainly estriols, had no protective effect. Data indicated that the baseline risk for hip fracture was not lower in the cohort women than in the background population. CONCLUSIONS Treatment with potent estrogens, both alone and possibly when combined with progestogens, reduces the risk for both cervical and trochanteric hip fractures within the first decade after menopause.

Whole grain consumption and risk of colorectal cancer: a population-based cohort of 60 000 women

We examined prospectively the association between whole grain consumption and colorectal cancer risk in the population-based Swedish Mammography Cohort. A total of 61 433 women completed a food-frequency questionnaire at baseline (1987–1990) and, through linkage with the Swedish Cancer Registry, 805 incident cases of colorectal cancer were identified during a mean follow-up of 14.8 years. High consumption of whole grains was associated with a lower risk of colon cancer, but not of rectal cancer. The multivariate rate ratio (RR) of colon cancer for the top category of whole grain consumption (⩾4.5 servings day−1) compared with the bottom category (<1.5 servings day−1) was 0.67 (95% confidence interval (CI), 0.47–0.96; P-value for trend=0.06). The corresponding RR after excluding cases occurring within the first 2 years of follow-up was 0.65 (95% CI, 0.45–0.94; P-value for trend=0.04). Our findings suggest that high consumption of whole grains may decrease the risk of colon cancer in women.

Overall obesity, abdominal adiposity, diabetes and cigarette smoking in relation to the risk of pancreatic cancer in two Swedish population-based cohorts

We examined the associations of body mass index (BMI), waist circumference, a history of diabetes, and cigarette smoking with risk of pancreatic cancer among 37 147 women and 45 906 men followed up during 560 666 person-years in the Swedish Mammography Cohort and the Cohort of Swedish Men; 136 incident cases of pancreatic cancer were diagnosed. The multivariate rate ratio (RR) of pancreatic cancer for obese women and men (BMI ⩾30 kg/m2) was 1.81 (95% CI: 1.04–3.15) compared to those with a BMI of 20–25 kg/m2. For a difference of 20 cm (about two standard deviations) in waist circumference, the multivariate RRs were 1.32 (95% CI: 0.73–2.37) among women and 1.74 (95% CI: 1.00–3.01) among men. Pancreatic cancer risk was associated with history of diabetes (multivariate RR: 1.88; 95% CI: 1.09–3.26) and cigarette smoking (multivariate RR for current compared with never smokers: 3.06; 95% CI: 1.99–4.72). Current smokers of ⩾40 pack-years had a five-fold elevated risk compared with never smokers. Risk among past smokers approached the RR for never smokers within 5–10 years following smoking cessation. Findings from this prospective study support positive relationships of overall obesity, abdominal adiposity, diabetes and smoking with risk of pancreatic cancer.

Chronic pain 5 years after randomized comparison of laparoscopic and Lichtenstein inguinal hernia repair.

Chronic postoperative pain is a major drawback of inguinal hernia repair. This study compared the frequency of chronic pain after laparoscopic (totally extraperitoneal patch, TEP) and open (Lichtenstein) repairs.

Tumour markers in breast carcinoma correlate with grade rather than with invasiveness

Ductal breast carcinoma in situ (DCIS) is regarded as a precursor to invasive breast cancer. The progression from in situ to invasive cancer is however little understood. We compared some tumour markers in invasive and in situ breast carcinomas trying to find steps in this progression. We designed a semi-experimental setting and compared histopathological grading and tumour marker expression in pure DCIS (n = 194), small invasive lesions (n = 127) and lesions with both an invasive and in situ component (n = 305). Grading was done according to the Elston–Ellis and EORTC classification systems, respectively. Immunohistochemical staining was conducted for p53, c-erbB-2, Ki-67, ER, PR, bcl-2 and angiogenesis. All markers correlated with grade rather than with invasiveness. No marker was clearly associated with the progression from in situ to invasiveness. The expression of tumour markers was almost identical in the 2 components of mixed lesions. DCIS as a group showed a more ‘malignant picture’ than invasive cancer according to the markers, probably, due to a higher proportion of poorly differentiated lesions. The step between in situ and invasive cancer seems to occur independently of tumour grade. The results suggest that well-differentiated DCIS progress to well-differentiated invasive cancer and poorly differentiated DCIS progress to poorly differentiated invasive cancer.

ALCOHOL INTAKE AND PANCREATIC CANCER RISK: A POOLED ANALYSIS OF FOURTEEN COHORT STUDIES

Background: Few risk factors have been implicated in pancreatic cancer etiology. Alcohol has been theorized to promote carcinogenesis. However, epidemiologic studies have reported inconsistent results relating alcohol intake to pancreatic cancer risk. Methods: We conducted a pooled analysis of the primary data from 14 prospective cohort studies. The study sample consisted of 862,664 individuals among whom 2,187 incident pancreatic cancer cases were identified. Study-specific relative risks and 95% confidence intervals were calculated using Cox proportional hazards models and then pooled using a random effects model. Results: A slight positive association with pancreatic cancer risk was observed for alcohol intake (pooled multivariate relative risk, 1.22; 95% confidence interval, 1.03-1.45 comparing ≥30 to 0 grams/day of alcohol; P value, test for between-studies heterogeneity = 0.80). For this comparison, the positive association was only statistically significant among women although the difference in the results by gender was not statistically significant (P value, test for interaction = 0.19). Slightly stronger results for alcohol intake were observed when we limited the analysis to cases with adenocarcinomas of the pancreas. No statistically significant associations were observed for alcohol from wine, beer, and spirits comparing intakes of ≥5 to 0 grams/day. A stronger positive association between alcohol consumption and pancreatic cancer risk was observed among normal weight individuals compared with overweight and obese individuals (P value, test for interaction = 0.01). Discussion: Our findings are consistent with a modest increase in risk of pancreatic cancer with consumption of 30 or more grams of alcohol per day. (Cancer Epidemiol Biomarkers Prev 2009;18(3):765–76)