Risk of basal cell carcinoma in a randomized clinical trial of aspirin and folic acid for the prevention of colorectal adenomas.

BACKGROUND: Aspirin may reduce the risk of several types of cancer. OBJECTIVES: To evaluate if folic acid is associated with risk of basal cell carcinoma (BCC). METHODS: BCC incidence was evaluated in a randomized, double-blind, placebo-controlled clinical trial of aspirin (81 mg daily or 325 mg daily for ~3 years) and/or folic acid (1 mg daily for ~6 years) for the prevention of colorectal adenomas among 1121 participants with a previous adenoma. BCC was confirmed by blinded review of pathology reports. RESULTS: One hundred and four of 958 non-Hispanic white participants were diagnosed with BCC over a median follow-up of 13·5 years. Cumulative incidence of BCC was 12% [95% confidence interval (CI) 7-17] for placebo, 16% (95% CI 11-21) for 81 mg aspirin daily and 15% (95% CI 10-20) for 325 mg aspirin daily [hazard ratio (HR) for any aspirin 1·45 (95% CI 0·93-2·26); HR for 81 mg daily 1·57 (95% CI 0·96-2·56); HR for 325 mg daily 1·33 (95% CI 0·80-2·20)]. BCC risk was higher with aspirin use in those without previous skin cancer but lower with aspirin use in those with previous skin cancer (Pinteraction = 0·02 for 81 mg aspirin daily; Pinteraction = 0·03 for 325 mg aspirin daily). Folic acid supplementation was unrelated to BCC incidence (HR 0·85; 95% CI 0·57-1·27). CONCLUSIONS: Neither aspirin nor folic acid treatment had a statistically significant effect on risk of BCC. Subgroup analysis suggested that chemopreventive effects of nonsteroidal anti-inflammatory drugs may be specific to those at high risk for BCC.

Characterisation of familial colorectal cancer Type X, Lynch syndrome, and non-familial colorectal cancer.

BACKGROUND: Familial Colorectal Cancer Type X (FCCTX) is defined as individuals with colorectal cancer (CRC) who families meet Amsterdam Criteria-1 (AC1), but whose tumours are DNA-mismatch-repair-proficient, unlike Lynch syndrome (LS). FCCTX does not have an increased risk of extra-colonic cancers. This analysis compares epidemiologic and clinicopathologic features among FCCTX, LS, and 'non-familial' (non-AC1) CRC cases. METHODS: From the Colon Cancer Family Registry, FCCTX (n=173), LS (n=303), and non-AC1 (n=9603) CRC cases were identified. Questionnaire-based epidemiologic information and CRC pathologic features were compared across case groups using polytomous logistic regression. RESULTS: Compared with LS, FCCTX cases were less likely to be current (vs never) smokers; have a proximal subsite (vs rectal) tumour; or have mucinous histology, poor differentiation, or tumour-infiltrating lymphocytes. There were no observed differences in co-morbidities or medication usage. CONCLUSIONS: FCCTX were less likely to be current tobacco users; other exposures were similar between these groups. Histopathologic differences highly suggestive of LS CRCs do not appear to be shared by FCCTX.

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.

BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation.

KRAS-mutation status in relation to colorectal cancer survival: the joint impact of correlated tumour markers.

BACKGROUND: Mutations in the Kirsten Ras (KRAS) oncogene are common in colorectal cancer (CRC). The role of KRAS-mutation status as a prognostic factor, however, is unclear. We evaluated the relationship between KRAS-mutation status and CRC survival, considering heterogeneity in this association by tumour and patient characteristics. METHODS: The population-based study included individuals diagnosed with CRC between 1998-2007 in Western Washington State. Tumour specimens were tested for KRAS exon 2 mutations, the BRAF p.V600E mutation, and microsatellite instability (MSI). We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between KRAS-mutation status and disease-specific and overall survival. Stratified analyses were conducted by age, sex, tumour site, stage, and MSI. We conducted additional analyses combining KRAS-mutation, BRAF-mutation, and MSI status. RESULTS: Among 1989 cases, 31% had KRAS-mutated CRC. Kirsten Ras (KRAS)-mutated CRC was associated with poorer disease-specific survival (HR=1.37, 95% CI: 1.13-1.66). This association was not evident in cases who presented with distant-stage CRC. Cases with KRAS-wild-type/BRAF-wild-type/MSI-high CRC had the most favourable prognosis; those with CRC exhibiting a KRAS- or BRAF-mutation and no MSI had the poorest prognosis. Patterns were similar for overall survival. CONCLUSION: Kirsten Ras (KRAS)-mutated CRC was associated with statistically significantly poorer survival after diagnosis than KRAS-wild-type CRC.

Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes.

BACKGROUND: Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers. METHODS: A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry. RESULTS: During 122,304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kg m(-2) increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08-1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02-2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05-1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96-1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56). CONCLUSION: Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers.

Oral bisphosphonates and risk of ischemic stroke: a case-control study.

UNLABELLED: Bisphosphonates have been associated with an increased risk of atrial fibrillation and may thus be associated with an increased risk of ischemic stroke. This would have substantial clinical and public health implications. We found no evidence of an association between bisphosphonate use and risk of ischemic stroke. INTRODUCTION: Bisphosphonates have been associated with an increased risk of atrial fibrillation in some studies and may be associated with an increased risk of ischemic stroke. However, data regarding these possibilities are limited. METHODS: We conducted a population-based case-control study of 6,257 female cases of ischemic stroke and 31,285 age- and gender-matched population controls. Data on bisphosphonate use, other medication use, comorbidity, and ischemic stroke were obtained from medical databases. Current bisphosphonate use was defined as at least one redeemed prescription within 90 days before diagnosis/index date. We estimated the odds ratio (OR) of ischemic stroke among users and nonusers of bisphosphonates using conditional logistic regression, controlling for potential confounding factors. RESULTS: One hundred eighty-two (2.9%) cases and 901 (2.9%) controls were current users of bisphosphonates. Etidronate and alendronate were prescribed with similar frequency among cases and controls. The adjusted OR of ischemic stroke for bisphosphonate users compared with nonusers was 0.97 (95% confidence interval [CI], 0.82-1.15). New and continuing bisphosphonate users had adjusted ORs for ischemic stroke of 1.16 (95% CI, 0.69-1.96) and 0.97 (95% CI, 0.81-1.16), respectively. Excluding patients with known atrial fibrillation/flutter yielded an OR of 1.00 (95% CI, 0.85-1.19). The OR for ischemic stroke was 0.59 (95% CI, 0.32-1.09) among patients with a history of previous hospitalization for cardiovascular disease and 1.07 (95% CI, 0.88-1.18) among those without (P < 0.001). The OR for former users was 1.23 (95% CI, 1.01-1.49). CONCLUSION: We found no evidence of an association of oral bisphosphonate use with the risk of ischemic stroke.

Hospitalisation for venous thromboembolism in cancer patients and the general population: a population-based cohort study in Denmark, 1997-2006.

BACKGROUND: Venous thromboembolism (VTE) frequently complicates cancer. Data on tumour-specific VTE predictors are limited, but may inform strategies to prevent thrombosis. METHODS: We computed incidence rates (IRs) with 95% confidence intervals (CIs) for VTE hospitalisation in a cohort of cancer patients (n=57,591) and in a comparison general-population cohort (n=287,476) in Denmark. The subjects entered the study in 1997-2005, and the follow-up continued through 2006. Using Cox proportional-hazards regression, we estimated relative risks (RRs) for VTE predictors, while adjusting for comorbidity. RESULTS: Throughout the follow-up, VTE IR was higher among the cancer patients (IR=8.0, 95% CI=7.6-8.5) than the general population (IR=4.7, 95% CI=4.3-5.1), particularly in the first year after cancer diagnosis (IR=15.0, 95% CI=13.8-16.2, vs IR=8.6, 95% CI=7.6-9.9). Incidence rates of VTE were highest in patients with pancreas (IR=40.9, 95% CI=29.5-56.7), brain (IR=17.7, 95% CI=11.3-27.8) or liver (IR=20.4, 95% CI=9.2-45.3) tumours, multiple myeloma (IR=22.6, 95% CI=15.4-33.2) and among patients with advanced-stage cancers (IR=27.7, 95% CI=24.0-32.0) or those who received chemotherapy or no/symptomatic treatment. The adjusted RR (aRR) for VTE was highest among patients with pancreas (aRR=16.3, 95% CI=8.1-32.6) or brain cancer (aRR=19.8 95% CI=7.1-55.2), multiple myeloma (aRR=46.1, 95% CI=13.1-162.0) and among patients receiving chemotherapy, either alone (aRR=18.5, 95% CI=11.9-28.7) or in combination treatments (aRR=16.2, 95% CI=12.0-21.7). CONCLUSIONS: Risk of VTE is higher among cancer patients than in the general population. Predictors of VTE include recency of cancer diagnosis, cancer site, stage and the type of cancer-directed treatment.

Newer cyclo-oxygenase-2 selective inhibitors, other non-steroidal anti-inflammatory drugs and the risk of acute pancreatitis.

BACKGROUND: Case reports have suggested that the use of newer cyclo-oxygenase-2 selective inhibitors may cause acute pancreatitis, but there has been no formal study of the association. AIM: To assess the relationship between the use of cyclo-oxygenase-2 inhibitors and other non-steroidal anti-inflammatory drugs, and risk of acute pancreatitis. METHODS: A population-based case-control study was conducted using hospital discharge and prescription data from Denmark. Using conditional logistic regression with adjustment for multiple covariates, we estimated the relative risk of acute pancreatitis for use of the cyclo-oxygenase-2 inhibitors celecoxib and rofecoxib and for other non-steroidal anti-inflammatory drugs. RESULTS: A total of 3083 cases of acute pancreatitis and 30 830 population controls were identified. For current use the relative risk estimate for celecoxib was 1.4 (95% CI: 0.8-2.3) and for rofecoxib was 1.3 (95% CI: 0.7-2.3). The overall relative risk for other non-steroidal anti-inflammatory drugs was 2.7 (95% CI: 2.4-3.0) with a substantial variation in risk between the individual drugs. The highest relative risk was for diclofenac (odds ratio 5.0, 95% CI: 4.2-5.9) and the lowest for naproxen (odds ratio 1.1, 95% CI: 0.7-1.7). CONCLUSION: Cyclo-oxygenase-2 selective inhibitors are associated with a lower risk of acute pancreatitis than most other non-steroidal anti-inflammatory drugs.

Maternal age and breast cancer risk.

Maternal age at time of birth was investigated as a risk factor for breast cancer in a study of 1,176 matched case-control pairs. There was no pattern of increasing adjusted relative risk of breast cancer with increasing maternal age, nor was the mean maternal age of cases older than that of controls. Similar negative results were found among the subset of subjects up to 35 years old, a group previously found to show marked maternal age effects. Thus previous reports of an association between breast cancer and advanced maternal age may have been due to chance, extraneous factors, or a misleading reliance on unadjusted mean maternal ages, rather than on relative risks.

Reduced risk of large-bowel adenomas among aspirin users. The Polyp Prevention Study Group.

BACKGROUND: Epidemiological studies have indicated that aspirin consumption can lower the risk of large-bowel cancer. These studies are not entirely consistent, however, and their interpretation has been complicated by the possibility that cancer symptoms may have led patients to avoid aspirin or that aspirin may have influenced cancer diagnosis and treatment. PURPOSE: Our purpose was to determine the effect of aspirin on risk of large-bowel neoplasms in a study in which aspirin use would not be expected to affect tumor detection and tumor-related symptoms would not likely influence aspirin use. A less complicated assessment of the relationship between aspirin and large-bowel tumors should thus be possible. METHODS: We studied 793 patients enrolled in a clinical trial of nutrient supplements to prevent large-bowel adenomas. Unlike invasive cancers, adenomas usually do not cause symptoms or detectable gastrointestinal bleeding; thus, adenomas are unlikely to influence aspirin use. Each patient had at least one large-bowel adenoma diagnosed and removed shortly before study entry and had been judged to be free of further tumors by colonoscopy. Use of aspirin was assessed by responses on questionnaires administered 6 and 12 months after enrollment. We performed complete colonoscopies on all patients 1 year after they entered the study and removed all polyps. RESULTS: Patients who reported taking aspirin on both questionnaires (consistent users) had a lower risk of new adenomas at their 1-year follow-up colonoscopy (odds ratio = 0.52; 95% confidence interval = 0.31-0.89) compared with patients who did not report using aspirin on either of the questionnaires. The apparent protective effect of consistent aspirin use was present among both men and women and did not appear to be influenced by the number of prior adenomas. CONCLUSIONS: These data further support the hypothesis that aspirin has an antineoplastic effect in the large bowel. Nevertheless, the question of whether aspirin should be used to prevent large-bowel tumors would be best answered by a randomized controlled clinical trial specifically designed to address this issue.

Cigarette smoking in women with cancers of the breast and reproductive organs.

This case-control study addressed the relationship between cigarette smoking and cancers of the breast (1,741 cases), endometrium (476 cases), uterine cervix (1,174 cases), and ovary (296 cases). The lifetime smoking history of cases was compared with that of 2,128 controls, and relative risks (odds ratios) for smoking were estimated using multiple logistic regression to adjust for potential confounding by age, marital status, number of pregnancies, and Quetelet's index. With increasing amount smoked there was a statistically significant decrease in endometrial cancer risk and a statistically significant increase in cervical cancer risk. In the highest smoking category (greater than or equal to 15 pack-yr), the endometrial cancer relative risk was 0.57 [95% confidence interval (CI) of 0.37, 0.86] and the cervical cancer relative risk was 1.81 (95% CI of 1.47, 2.22). There was no apparent relationship between smoking and cancers of the breast or ovary.

Incidence of lung cancer by cell type: a population-based study in New Hampshire and Vermont.

Identified were 1,906 cases of confirmed lung cancer that occurred among all residents of New Hampshire and Vermont over a 4-year period. Medical records, pathologists' reports, and, when possible, pathology slides were obtained and reviewed to assign cases to a specific histologic diagnosis. The diagnosis made by the original pathologist was generally confirmed upon review, except for the large cell undifferentiated cell type which appeared to be an unreliable classification. Among men at all ages incidence rates for squamous cell cancer far exceeded those for adenocarcinoma and small cell undifferentiated carcinoma, and the three age-incidence curves showed a similar pattern, rising until the eighth decade of life and then declining. Among women these three major cell types occurred about equally often, but the age-incidence curves differed in shape with adenocarcinoma reaching a peak incidence at an earlier age.

Calcium supplementation and rectal mucosal proliferation: a randomized controlled trial.

BACKGROUND: Data from studies using rodents suggest that dietary calcium inhibits bile acid-induced mucosal damage and experimental carcinogenesis in the large bowel. However, in humans, the effect of dietary calcium and calcium supplementation on proliferation and carcinogenesis in the large bowel has been unclear. PURPOSE: To assess the effect of calcium supplementation on rectal mucosal proliferation in humans, we conducted a multicenter, randomized, placebo-controlled, double-blinded trial. METHODS: Participants were part of a larger multicenter chemoprevention trial; all were at high risk for large-bowel neoplasia, with at least one large-bowel adenoma removed endoscopically within the 3 months before study entry but with no known polyps remaining. Subjects were randomly assigned to receive daily either 3000 mg of calcium carbonate (providing 1200 mg elemental calcium) or an identical-appearing placebo tablet. During a scheduled endoscopy 6-9 months after random assignment (approximately 1 year after the qualifying endoscopy), rectal mucosal samples were obtained from 333 patients (173 assigned to calcium and 160 assigned to placebo). Proliferating cell nuclear antigen (PCNA) labeling indices (LIs) were computed as the measure of proliferation in specimens from 146 patients receiving calcium and 129 patients receiving placebo. Bromodeoxyuridine (BrdU) labeling was used to measure proliferation in a smaller number of specimens (27 calcium-receiving and 31 placebo-receiving participants). For each scorable crypt having at least one labeled cell (or surrounded by crypts with at least one labeled cell), a crypt LI was calculated as the number of labeled cells divided by the total number of crypt cells. Crypt LIs were averaged to produce a participant's average LI. RESULTS: The overall unadjusted mean PCNA LIs (+/- SE) were similar in the calcium and placebo groups (3.85% +/- 0.08% versus 3.92% +/- 0.08%, respectively, P = .30). The overall unadjusted mean BrdU LIs (+/- SE) were 3.88% +/- 0.30% in the calcium group and 3.54% +/- 0.21% in the placebo group (P = .54). PCNA labeling indices in the most luminal 40% of the crypt were small but, if anything, were higher in the calcium group. There was no patient subgroup within which calcium had an antiproliferative effect; the overall findings persisted among patients with high and low calcium intake, high and low fat intake, and high and low fiber intake. CONCLUSIONS: Calcium supplementation does not decrease rectal mucosal proliferation, as measured by PCNA (and BrdU) immunohistochemistry, in patients with previous large-bowel adenomas. This study, therefore, does not provide evidence for an anticarcinogenic effect of calcium.

Risk of basal cell and squamous cell skin cancers after ionizing radiation therapy. For The Skin Cancer Prevention Study Group.

BACKGROUND: Human evidence that ionizing radiation is carcinogenic first came from reports of nonmelanoma skin cancers (NMSCs) on the hands of workers using early radiation devices. An increased risk of NMSC has been observed among uranium miners, radiologists, and individuals treated with x rays in childhood for tinea capitis (ringworm of the scalp) or for thymic enlargement; NMSC is one of the cancers most strongly associated with the atomic bombing of Hiroshima and Nagasaki. Although exposure to ionizing radiation is a known cause of NMSC, it is not yet clear whether therapeutic radiation causes both major histologic types of NMSC, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Additionally, the potentially modifying effects, such as latency, age when treated, and type of treatment, are not well understood. PURPOSE: We investigated the relative risks of BCC and SCC associated with previous radiation therapy and evaluated these risks in relation to age and time since initial treatment and the medical condition for which radiation therapy was given. METHODS: The study group comprised individual diagnosed with at least one BCC or SCC from January 1980 through February 1986, who were recruited to participate in a skin cancer prevention trial designed to test whether oral beta-carotene supplementation would reduce the risk of new NMSCs. Patients were identified through the dermatology and pathology records of academic medical centers in Hanover, NH; Los Angeles, CA; San Francisco, CA; and Minneapolis, MN. Each participant completed a questionnaire detailing lifetime residence, pigmentary characteristics, occupational and recreational sun exposure, and history of radiation therapy. At enrollment, a study dermatologist assessed skin type (tendency to burn or tan) and extent of actinic skin damage. Participants were followed with an annual dermatologic examination for an average of 4 years. Of the 5232 potentially eligible individuals, 1805 were enrolled in the trial. We excluded 112 patients who reported previous radiation therapy for skin cancer only and three with missing information on whether they were ever treated with radiation therapy, leaving 1690 patients for the analysis. Approximately 4% of the patients died or discontinued participation for other reasons during each study year. We examined time to occurrence of first new histopathologically confirmed BCC and SCC during the follow-up period in relation to history of radiation therapy (for reasons other than NMSC) using a proportional hazards model. A multiple end points survival model was used to compare the rate ratios (RRs) for BCC and SCC. We also used a longitudinal method of analysis to compute the RR of total new BCC and SCC tumors per person per study year associated with radiation therapy. Using this method, we additionally assessed the potential modifying effects of age at treatment, latency, and type of therapy. All P values were derived from two-sided statistical tests of significance. RESULTS: Among the participants we studied, 597 developed a new BCC (n = 1553 tumors) and 118 developed a new SCC (n = 179 tumors). The time to first new BCC, but not SCC, was associated with prior radiation therapy (RR = 1.7; 95% confidence interval [CI] = 1.4-2.0 and RR = 1.0; 95% CI = 0.6-1.7, respectively; P = .03 for the difference between the RRs). The RR of total BCC tumors was slightly higher (RR = 2.3; 95% CI = 1.7-3.1), but it was still unity for SCC (RR = 1.0; 95% CI = 0.5-1.9). BCC risk appeared to increase with younger age at exposure and time since initially treated, although these effects were only marginally statistically significant (P for trend = .06 and .07, respectively). Also, risk of BCC was more strongly related to treatment for acne (RR = 3.3; 95% CI = 2.1-5.2) than other conditions. CONCLUSIONS AND IMPLICATIONS: Our data suggest that exposure to therapeutic radiation is associated with BCC but not with SCC.

Risk of endometrial cancer following estrogen replacement with and without progestins.

BACKGROUND: Unopposed estrogen replacement therapy (i.e., estrogen without progestins) increases the risk of endometrial cancer. In this study, we examined the endometrial cancer risk associated with combined estrogen-progestin regimens currently in use, since the safety profiles of these regimens have not been clearly defined. METHODS: We conducted a nationwide population-based, case-control study in Sweden of postmenopausal women aged 50-74 years. We collected information on use of hormone replacement from 709 case patients with incident endometrial cancer and from 3368 control subjects. We used unconditional logistic regression to calculate odds ratios (ORs) as estimates of relative risks. All individual comparisons were made with women who never used the respective hormone replacement regimens. RESULTS: Treatment with estrogens alone was associated with a marked duration- and dose-dependent increase in the relative risk of endometrial cancer. Five or more years of treatment had an OR of 6.2 for estradiol (95% confidence interval [CI] = 3.1-12.6) and of 6.6 for conjugated estrogens (95% CI = 3.6-12.0). Following combined estrogen-progestin use, the association was considerably weaker than that for estrogen alone; the OR was 1.6 (95% CI = 1.1-2.4) after 5 or more years of use. This increase in risk was confined to women with cyclic use of progestins, i.e., fewer than 16 days per cycle (most commonly 10 days per cycle [OR = 2.9; 95% CI = 1.8-4.6 for 5 or more years of use]), whereas continuous progestin use along with estrogens was associated with a reduced risk (OR = 0.2; 95% CI = 0.1-0.8 for 5 or more years of use). CONCLUSION: The risk of developing endometrial cancer is increased after long-term use of estrogens without progestins and with cyclically added progestins. Continuously added progestins may be needed to minimize the endometrial cancer risk associated with estrogen replacement therapy.

Exposure to breast milk in infancy and adult breast cancer risk.

BACKGROUND: There is considerable interest in the possibility of an infectious etiology for human breast cancer. Although studies have shown that certain strains of mice transmit mammary tumor virus via breast milk, few epidemiologic studies have addressed this topic in humans. METHODS: We evaluated the relationship between having been breast-fed as an infant and breast cancer risk among 8299 women who participated in a population-based, case-control study of breast cancer in women aged 50 years or more. Case women were identified through cancer registries in three states (Massachusetts, New Hampshire, and Wisconsin); control women were identified through statewide driver's license lists (age <65 years) or Medicare lists (ages 65-79 years). Information on epidemiologic risk factors was obtained through telephone interview. We used multiple logistic regression to assess having been breast-fed and maternal history of breast cancer in relation to breast cancer occurrence both in premenopausal women (205 case women; 220 control women) and in postmenopausal women (3803 case women; 4071 control women). RESULTS: We found no evidence that having been breast-fed increased breast cancer risk in either premenopausal women (odds ratio [OR] = 0.65; 95% confidence interval [CI] = 0.41-1.04) or postmenopausal women (OR = 0.95; 95% CI = 0.85-1.07). In addition, breast cancer risk was not increased by having been breast-fed by a mother who later developed breast cancer. CONCLUSION: Our results do not support the hypothesis that a transmissible agent in breast milk increases breast cancer risk. Because premenopausal women were not well represented in our study population, our findings with regard to this group may not be generalizable and should be viewed with caution.

Folate intake, alcohol consumption, cigarette smoking, and risk of colorectal adenomas.

BACKGROUND: Recent evidence suggests that folic acid (and derivatives) could contribute to the protective effect of fruits and vegetables against the risk of large-bowel cancer. Other evidence indicates that alcohol drinking and cigarette smoking may impair the biologic actions of folate. We used data from an adenoma prevention trial to investigate the occurrence of colorectal adenomas (possible precursors of colorectal cancer) in association with folate intake, alcohol consumption, and cigarette smoking. METHODS: Patients with at least one recent large-bowel adenoma were followed with colonoscopy 1 year and 4 years after their qualifying colon examinations. Adenomas detected after the year 1 examination were used as end points. A food-frequency questionnaire was administered at study entry and at study completion; nutrient intake at study entry was used in this analysis. All statistical tests were two-sided. RESULTS: After adjustment for caloric intake, dietary folate had a significant protective association with the risk of recurrence of large-bowel adenoma (P for trend = .04). However, this inverse association was attenuated by further adjustment for intake of dietary fiber and fat. Use of folate supplements was not associated with a reduction in risk. Alcohol intake (seven or more drinks/week) was associated with increased risk (odds ratio = 2.04; 95% confidence interval = 1.28-3.26). Cigarette smoking, even smoking for long duration, was not related to adenoma recurrence. CONCLUSIONS: These data provide only modest support for previous findings suggesting beneficial effects of folate on colorectal adenoma risk. We find no evidence that cigarette smoking increases risk. These findings do suggest a substantial increase in risk with alcohol consumption.

Histamine receptor antagonists and incident colorectal adenomas.

BACKGROUND: Prior studies suggest that histamines may modulate the development of colorectal neoplasia. AIM: To assess whether histamine receptor antagonist use was associated with adenoma formation. METHODS: Patients (n = 2366) were drawn from three adenoma chemoprevention trials. All underwent baseline colonoscopy with removal of adenoma(s) and were deemed free of remaining lesions; they were followed with surveillance colonoscopy. Medication use was assessed by questionnaire. Adjusted risk ratios for adenoma formation related to histamine receptor antagonist use (histamine H1 and H2 receptor, H1RA and H2RA) were determined using log linear models. RESULTS: In pooled analyses, H1RA exposure was not associated with subsequent adenoma risk (RR = 1.10; 95% CI 0.97-1.25) or multiple adenoma formation (RR = 0.85; 95% CI 0.67-1.07). H2RA use also was not associated with adenoma (RR = 0.90; 95% CI 0.77-1.06), or multiple adenoma (RR = 0.77; 95% CI 0.57-1.04) in the pooled analyses, but H2RA users in the first trial had a decreased risk of adenoma (RR = 0.70; 95% CI 0.48-1.03) and multiple adenoma (RR = 0.31; 95% CI 0.12-0.79). CONCLUSION: H2RA use was associated with reduced risk for adenoma in one trial, but not in the pooled analyses. Further study would be warranted before undertaking randomized trials of H2RAs for adenoma chemoprevention.

Cholesterol and coronary heart disease. The importance of patient-specific attributable risk.

The value of treating hypercholesterolemia remains controversial despite extensive investigation, in part because of the research orientation of much of the relevant literature. Most published studies report relative measures of risks such as the risk ratio. However, clinicians are concerned with the magnitude of risk, or attributable risk, the difference in risk in those with highest and lowest serum cholesterol levels. Since maximum risk modification is rarely achieved, the attributable risk often overstates the potential benefit of risk factor reduction. A variant of the attributable risk, the practical attributable risk, gives a more realistic estimate of potential benefit. Since clinicians treat individuals and not populations, these measures of risk are most useful if reported for subgroups of patients (eg, men and women, as well as those of varying age). To illustrate these concepts, we review the literature on hypercholesterolemia, report the risk ratio, attributable risk, and practical attributable risk for important patient populations, and discuss the implications for clinical practice.

Cholesterol and coronary heart disease. The attributable risk reduction of diet and drugs.

The efficacy of treating hypercholesterolemia is often expressed in relative terms as the ratio of risk in treated vs untreated populations. However, the clinical impact of treatment is best measured by the difference in risk, which is called the attributable risk reduction. Attributable risk reduction is most useful clinically if it is reported for specific subgroups of patients according to age, sex, and other risk factors. To illustrate this concept, its applications and limitations, we review the literature on the primary and secondary treatment of hypercholesterolemia, present the attributable risk reduction, and describe its implications for clinical practice.