Per Lenner

Chlamydia trachomatis infection as a risk factor for invasive cervical cancer

Cervical carcinoma is a sexually transmitted disease most strongly linked with human‐papillomavirus (HPV) infection. We conducted a prospective sero‐epidemiologic study to evaluate the role of Chlamydia trachomatis infection in the development of cervical carcinoma, with invasive cancer as an end point. A nested case‐control study within a cohort of 530000 Nordic women was performed. Linking data files of 3 Nordic serum banks and the cancer registries of Finland, Norway and Sweden identified 182 women with invasive cervical carcinoma diagnosed during a mean follow‐up of 5 years after serum sampling. The serum samples of the cases and matched cancer‐free controls were analyzed for IgG antibodies to C. trachomatis, C. pneumoniae (a control microbe) and HPV types 16, 18 and 33, as well as for serum cotinine (an indicator of tobacco smoking). Serum antibodies to C. trachomatis were associated with an increased risk for cervical squamous‐cell carcinoma (HPV‐ and smoking‐adjusted OR, 2.2; 95% CI, 1.3–3.5). The association remained also after adjustment for smoking both in HPV16‐seronegative and ‐seropositive cases (OR, 3.0; 95% CI, 1.8–5.1; OR, 2.3, 95% CI, 0.8–7.0 respectively). No such association was found for C. pneumoniae. Our prospective study provides sero‐epidemiologic evidence that infection with C. trachomatis confers an increased risk for subsequent development of invasive squamous‐cell carcinoma of the uterine cervix. Int. J. Cancer 85:35–39, 2000.

Vascular endothelial growth factor polymorphisms in relation to breast cancer development and prognosis.

Purpose: Angiogenesis is a necessary step in tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is a major mediator of breast cancer angiogenesis. Therefore, we investigated the association of polymorphisms in the VEGF gene with breast cancer risk and prognostic characteristics of the tumors in a large case-control study. Experimental Design: We examined three polymorphisms in the VEGF gene (−2578C/A, −1154G/A, and +936C/T) in 571 familial breast cancer cases from Poland and Germany and −2578C/A, −634G/C, and +936C/T polymorphisms in 974 unselected breast cancer cases from Sweden together with ethnically and geographically selected controls. Results: None of the polymorphisms or any haplotype was significantly associated with either familial or unselected breast cancers. Our study suggests that the +936C/T polymorphism is unlikely to be associated with breast cancer. We also analyzed the unselected cases for genotypes or haplotypes that associated with tumor characteristics. The −634CC genotype and the −2578/−634 CC haplotype were significantly associated with high tumor aggressiveness (large tumor size and high histologic grade, P < 0.01) and the −2578AA genotype and the −2578/−634 AG haplotype with low histologic grade tumors (P = 0.04). The genotypes and haplotypes were not related with other tumor characteristics such as regional or distant metastasis, stage at diagnosis, or estrogen or progesterone receptor status. Conclusions: Although none of the polymorphisms studied in the VEGF gene was found to influence susceptibility to breast cancer significantly, some of the VEGF genotypes and haplotypes may influence tumor growth through an altered expression of VEGF and tumor angiogenesis.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

Background:Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood.Methods:Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies.Results:Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer.Conclusion:Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Prospective study of IGF-I, IGF-binding proteins, and breast cancer risk, in northern and southern Sweden.

Objective: To examine the possible relationships of breast cancer risk to prediagnostic plasma levels of insulin; insulin-like growth factor-I (IGF-I); and IGF-binding proteins -1, -2, and -3. Methods: Within two prospective cohorts in Umeå and Malmö we measured plasma concentrations of insulin, IGF-I, and IGFBPs for a total of 513 incident breast cancer cases and 987 matched controls. Results: Globally, risk was unassociated with levels of IGF-I, IGFBP-3, or IGF-I adjusted for IGFBP-3. When breaking down the analysis by subgroups of age at blood donation, an increase in risk was observed for increasing levels of IGF-I in women aged 55 or older, in the Umeå cohort only (odds ratios of 1.00, 1.73, 1.76, 1.90; ptrend = 0.05). This effect weakened, however, when the analysis was restricted to subjects who did not use exogenous hormones for the treatment of menopausal symptoms. Levels of IGF-I and IGFBP-3 were not related to risk in younger women, recruited before age 50, contrary to observations from previous studies. In a subcohort where blood samples had been collected after at least four hours of fasting, breast cancer risk showed no clear associations with levels of insulin, IGFBP-1, or IGFBP-2. Conclusions: Our results do not confirm earlier findings of an association of plasma IGF-I levels with breast cancer risk especially in young women, but suggest a possible association with postmenopausal breast cancer risk, possibly among ERT/HRT users only. Our results do not support the hypothesis that elevated plasma insulin levels, and reduced levels of IGFBP-1 and IGFBP-2, are associated with increased breast cancer risk.

Reduction in breast cancer mortality from organized service screening with mammography : 1. Further confirmation with extended data.

Background: In an earlier publication, our evaluation of data from breast cancer screening programs in seven Swedish counties suggested a 40% reduction in incidence-based breast cancer mortality among women actually screened. In the current study, we expand the previous analysis from seven counties to 13 large areas within nine counties, including six of the original counties and seven additional areas, examine a longer period of follow-up (20-44 years), apply new analytic methods for the evaluation of incidence-based breast cancer mortality, and estimate the number needed to screen to save one life. Methods: Data from six of the original counties (one being excluded as it does not yet have 10 years of follow-up after the initiation of screening), with increased follow-up, and seven additional large areas, within three counties, representing ∼45% of Swedish women, provide information about age at diagnosis, age at death, and screening history for 542,187 women in the prescreening and 566,423 women in the screening epochs. Regardless of year of diagnosis, there were a total of 6,231 deaths due to breast cancer in the period of study as a whole. Of these, 4,778 were incidence-based deaths in the two epochs, i.e., death among cases diagnosed within either the prescreening or screening period. Data were analyzed using Poisson regression and adjusted, when necessary, for self-selection bias, contemporaneous changes in incidence, and changes in mortality independent of screening. Results: Attendance was uniformly high, averaging 75% in the screening epochs. Recall rates for assessment varied from 4% to 5% at the first round of screening and ∼3% at later rounds. Detection rates averaged five breast cancers per 1,000 women screened in the first round, and four breast cancers per 1,000 women screened in subsequent rounds. There was a significant 45% reduction in incidence-based breast cancer mortality among screened women in the screening epoch relative to incidence-based breast cancer mortality in the prescreening epoch (relative risk, 0.55; 95% confidence intervals, 0.51-0.59). After adjusting for self-selection bias, there still was a significant 43% reduction in incidence-based breast cancer mortality associated with screening (relative risk, 0.57; 95% confidence intervals, 0.53-0.62). Conclusions: These results indicate a reduction in breast cancer mortality of between 40% and 45% in association with screening, after adjustment for self-selection bias. These results were obtained with modest human costs: the number needed to screen to save one life was estimated as 472. (Cancer Epidemiol Biomarkers Prev 2006;15(1):45–51)

Circulating levels of sex steroid hormones and risk of endometrial cancer in postmenopausal women

Experimental and epidemiological data support a role for sex steroid hormones in the pathogenesis of endometrial cancer. The associations of pre‐diagnostic blood concentrations of estradiol, estrone, testosterone, androstenedione, DHEAS and SHBG with endometrial cancer risk were investigated. A case‐control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). Cases were 124 postmenopausal women with invasive endometrial cancer. For each case, 2 controls were selected, matching the case on cohort, age and date of recruitment. Only postmenopausal women who did not use exogenous hormones at the time of blood donation were included. Odds ratios (OR) and their 95% confidence intervals (CI) were estimated by conditional logistic regression. ORs (95% CI) for endometrial cancer for quartiles with the highest hormone levels, relative to the lowest were as follows: 4.13 (1.76–9.72), ptrend = 0.0008 for estradiol, 3.67 (1.71–7.88), ptrend = 0.0007 for estrone, 2.15 (1.05–4.40), ptrend = 0.04 for androstenedione, 1.74 (0.88–3.46), ptrend = 0.06 for testosterone, 2.90 (1.42–5.90), ptrend = 0.002 for DHEAS and 0.46 (0.20–1.05), ptrend = 0.01 for SHBG after adjustment for body mass index, use of oral contraceptives and hormone replacement therapy. The results of our multicenter prospective study showed a strong direct association of circulating estrogens, androgens and an inverse association of SHBG levels with endometrial cancer in postmenopausal women. The effect of elevated androstenedione and testosterone levels on disease risk seems to be mediated mainly through their conversion to estrogens, although an independent effect of androgens on tumor growth cannot be ruled out, in particular in the years close to diagnosis.

Breast Cancer Survival Is Associated with Telomere Length in Peripheral Blood Cells

Telomeres are essential for maintaining chromosomal stability. Previous studies have indicated that individuals with shorter blood telomeres may be at higher risk of developing various types of cancer, such as in lung, bladder, and kidney. We have analyzed relative telomere length (RTL) of peripheral blood cells in relation to breast cancer incidence and prognosis. The study included 265 newly diagnosed breast cancer patients and 446 female controls. RTL was measured by real-time PCR, and our results show that the patient group displayed significantly longer telomeres compared with controls (P < 0.001). Age-adjusted odds ratios (OR) for breast cancer risk increased with increasing telomere length, with a maximal OR of 5.17 [95% confidence interval (95% CI), 3.09-8.64] for the quartile with the longest telomeres. Furthermore, RTL carried prognostic information for patients with advanced disease. Node positive (N+) patients with short telomeres (</=median) showed an increased survival compared with N+ patients with long telomeres (P = 0.001). For patients with ages <50 years with tumors >16 mm (median tumor diameter), short telomeres were associated with a significantly better outcome than longer telomeres (P = 0.006). Cox regression analysis showed that long RTL was a significant independent negative prognostic factor (hazards ratio, 2.92; 95% CI, 1.33-6.39; P = 0.007). Our results indicate that blood RTL may serve as a prognostic indicator in breast cancer patients with advanced disease.

Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer†

Conditions related to chronic hyperinsulinemia, such as obesity, noninsulin dependent diabetes mellitus and polycystic ovary syndrome, are associated with an increased risk of endometrial cancer. Elevated plasma IGF‐I and decreased levels of IGF‐binding proteins have been shown to be associated with increased risk of several cancer types that are frequent in affluent societies. We investigated for the first time in a prospective study the association of pre‐diagnostic blood concentrations of C‐peptide (a marker of pancreatic insulin production), IGF‐I, IGFBP‐1, ‐2 and ‐3 with endometrial cancer risk. A case‐control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). It included 166 women with primary invasive endometrial cancer and 315 matched controls, of which 44 case and 78 control subjects were premenopausal at recruitment. Endometrial cancer risk increased with increasing levels of C‐peptide (ptrend = 0.0002), up to an odds ratio (OR) of 4.76 [95% confidence interval (CI) = 1.91–11.8] for the highest quintile. This association remained after adjustment for BMI and other confounders [OR for the top quintile = 4.40 (1.65–11.7)]. IGFBP‐1 levels were inversely related to endometrial cancer [ptrend = 0.002; OR in the upper quintile = 0.30 (0.15–0.62)], but the association was weakened and lost statistical significance after adjustment for confounders [ptrend = 0.06; OR in the upper quintile = 0.49 (0.22–1.07)]. Risk was unrelated to levels of IGF‐I, IGFBP‐2 and IGFBP‐3. Chronic hyperinsulinemia, as reflected by increased circulating C‐peptide, is associated with increased endometrial cancer risk. Decrease in the prevalence of chronic hyperinsulinemia, through changes in lifestyle or medication, is expected to prevent endometrial cancer.

Body mass index and cancer : Results from the Northern Sweden Health and Disease Cohort

Excess weight has been associated with increased risk of cancer. The effect of body mass index (BMI, kg/m2) on overall cancer risk and on risk of developing several common cancer types was examined in a population‐based cohort study. Height and weight measurements were available for 35,362 women and 33,424 men recruited in the Northern Sweden Health and Disease Cohort between 1985 and 2003. Among cohort members, 2,691 incident cancer cases were identified. The association of BMI with cancer risk was examined using Poisson regression. Women with BMI > 27.1 (top quartile) had a 29% higher risk of developing any malignancy compared to women with BMI of 18.5–22.2 (lowest quartile), which increased to 47% in analysis limited to nonsmokers. Analyses according to WHO cut‐off points showed that obese women (BMI ≥ 30) had a 36% higher risk of cancer than women with BMI in the normal range (18.5–25). Individual cancer sites most strongly related to obesity were endometrium (risk for top quartile = 3.53, 95% confidence interval 1.86–7.43), ovary (2.09, 1.13–4.13) and colon (2.05, 1.04–4.41). BMI was inversely related to breast cancer occurring before age 49 (0.58, 0.29–1.11, ptrend < 0.04). In men, there was no association of BMI with overall cancer risk. Obese men (BMI ≥ 30), however, were at increased risk of developing kidney cancer (3.63, 1.23–10.7) and, after exclusion of cases diagnosed within 1 year of recruitment, colon cancer (1.77, 1.04–2.95). Our study provides further evidence that BMI is positively associated with cancer risk. In women from northern Sweden, up to 7% of all cancers were attributable to overweight and obesity and could be avoided by keeping BMI within the recommended range.

The individual blood cell telomere attrition rate is telomere length dependent.

Age-associated telomere shortening is a well documented feature of peripheral blood cells in human population studies, but it is not known to what extent these data can be transferred to the individual level. Telomere length (TL) in two blood samples taken at ∼10 years interval from 959 individuals was investigated using real-time PCR. TL was also measured in 13 families from a multigenerational cohort. As expected, we found an age-related decline in TL over time (r = –0.164, P<0.001, n = 959). However, approximately one-third of the individuals exhibited a stable or increased TL over a decade. The individual telomere attrition rate was inversely correlated with initial TL at a highly significant level (r = –0.752, P<0.001), indicating that the attrition rate was most pronounced in individuals with long telomeres at baseline. In accordance, the age-associated telomere attrition rate was more prominent in families with members displaying longer telomeres at a young age (r = –0.691, P<0.001). Abnormal blood TL has been reported at diagnosis of various malignancies, but in the present study there was no association between individual telomere attrition rate or prediagnostic TL and later tumor development. The collected data strongly suggest a TL maintenance mechanism acting in vivo, providing protection of short telomeres as previously demonstrated in vitro. Our findings might challenge the hypothesis that individual TL can predict possible life span or later tumor development.