Hedy S. Rennert

Use of Bisphosphonates and Risk of Postmenopausal Breast Cancer

PURPOSE Bisphosphonates are commonly used for the treatment of osteoporosis and for prevention and treatment of skeletal lesions due to malignancy. However, the association between the use of bisphosphonates and the risk of developing breast cancer has not been reported. PATIENTS AND METHODS The Breast Cancer in Northern Israel Study is a population-based case-control study in northern Israel of patients with breast cancer and age-, clinic-, and ethnic-group matched controls. Use of bisphosphonates was assessed in 4,039 postmenopausal patients and controls, members of Clalit Health Services, using pharmacy records. RESULTS The use of bisphosphonates for longer than 1 year before diagnosis, but not for shorter than 1 year, was associated with a significantly reduced relative risk of breast cancer (odds ratio [OR], 0.61; 95% CI, 0.50 to 0.76). This association remained significant after adjustment for age, fruit, and vegetable consumption, sports activity, family history of breast cancer, ethnic group, body mass index, use of calcium supplements, hormone replacement therapy use, number of pregnancies, months of breast feeding, and age at first pregnancy (OR, 0.72; 95% CI, 0.57 to 0.90). Breast cancer risk did not change further if bisphosphonates were used for more years. Breast tumors identified in bisphosphonates users were more often estrogen receptor positive and less often poorly differentiated. CONCLUSION The use of bisphosphonates for longer than 1 year was associated with a 28% relative reduction in the risk of postmenopausal breast cancer. Tumors developing under bisphosphonates treatment tended to have a favorable prognostic factors profile.

Genetic variation in 8q24 associated with risk of colorectal cancer

Chromosome 8q24 harbors oncogenes known to be involved in pathogenesis of colorectal cancer (CRC) as well as uncharacterized genetic variants that have recently been shown to influence inherited risk of prostate cancer. In a population-based case-control study of colorectal cancer in northern Israel, we investigated the association between variation in 8q24 and risk of CRC. Among 1,861 incident cases and 1,937 population-based controls matched on age, gender, ethnicity, and clinic, rs10505477 was associated with risk of CRC in a dominant model, with an odds ratio = 1.23, 95% confidence interval = 1.05 -1.43, (p=0.008). This association was independently validated in an analysis of cancer among relatives of carriers of the risk allele, with a hazard ratio of 3.2 (95% bootstrap CI = 1.16 – 17.8). Genetic variation at rs10505477 on 8q24 potentially accounts for 14% of CRC in this population and should be replicated in other studies.

Use of Bisphosphonates and Reduced Risk of Colorectal Cancer

PURPOSE Bisphosphonates are commonly used for the treatment of osteoporosis and bone metastases caused by breast cancer and were recently reported to be associated with a reduced risk of breast cancer, possibly acting through the mevalonate pathway, but their association with risk of other cancers is unknown. PATIENTS AND METHODS The Molecular Epidemiology of Colorectal Cancer study is a population-based, case-control study in northern Israel of patients with colorectal cancer and age-, sex-, clinic-, and ethnic group-matched controls. Long-term use of bisphosphonates before diagnosis was assessed in a subset of 933 pairs of postmenopausal female patients and controls, enrolled in Clalit Health Services, using computerized pharmacy records. RESULTS The use of bisphosphonates for more than 1 year before diagnosis, but not for less than 1 year, was associated with a significantly reduced relative risk (RR) of colorectal cancer (RR, 0.50; 95% CI, 0.35 to 0.71). This association remained statistically significant after adjustment in a model for vegetable consumption, sports activity, family history of colorectal cancer, body mass index, and use of low-dose aspirin, statins, vitamin D, and postmenopausal hormones (RR, 0.41; 95% CI, 0.25 to 0.67). Concomitant use of bisphosphonates and statins did not further reduce the risk. CONCLUSION The use of oral bisphosphonates for more than 1 year was associated with a 59% relative reduction in the risk of colorectal cancer, similar to the recently reported association of this drug class with reduction in breast cancer risk.

The Relationship Between Serum 25(OH)D and Parathyroid Hormone Levels

OBJECTIVE Low 25(OH)D levels are associated with increased parathyroid hormone levels leading to progressive bone loss. The serum levels of 25(OH)D sufficient to keep the parathyroid hormone level at a range that will prevent bone loss are still unclear. The current study was aimed at evaluating the relationship between 25(OH)D levels and concomitant parathyroid hormone levels. METHODS The computerized laboratory database of Clalit Health Services, a not-for-profit health maintenance organization covering more than half of the Israeli population, was searched for all 25(OH)D and parathyroid hormone tests performed in 2009. Concomitant tests of parathyroid hormone and 25(OH)D were identified in 19,172 people. RESULTS Serum parathyroid hormone levels were inversely correlated with 25(OH)D levels (r = -0.176, P < .001); 25(OH)D levels less than 50 nmol/L were associated with a steep increase in parathyroid hormone levels and hyperparathyroidism, which decreased with increasing 25(OH)D levels and reached a plateau at 25(OH)D levels of 75 to 85 nmol/L. The quadratic fit with plateau model showed that parathyroid hormone stabilizes at 25(OH)D level of 78.9 nmol/L. However, after excluding 5449 people with hypercalcemia or renal failure, the parathyroid hormone plateau was attained at a significantly lower 25(OH)D cut point of 46.2 nmol/L. CONCLUSION Our data suggest that a 25(OH)D threshold of 50 nmol/L is sufficient for parathyroid hormone suppression and prevention of secondary hyperparathyroidism in persons with normal renal function. 25(OH)D levels greater than 75 nmol/L do not seem to be associated with additional change in parathyroid hormone levels.

Survival of first and second primary breast cancer.

Background. A second primary tumor (SPT) in the breast is the most common one seen in clinical practice. There are conflicting reports regarding the incidence and survival of patients with SPT in the breast.

Increased risk of lung cancer in individuals with a family history of the disease: A pooled analysis from the International Lung Cancer Consortium

BACKGROUND AND METHODS Familial aggregation of lung cancer exists after accounting for cigarette smoking. However, the extent to which family history affects risk by smoking status, histology, relative type and ethnicity is not well described. This pooled analysis included 24 case-control studies in the International Lung Cancer Consortium. Each study collected age of onset/interview, gender, race/ethnicity, cigarette smoking, histology and first-degree family history of lung cancer. Data from 24,380 lung cancer cases and 23,305 healthy controls were analysed. Unconditional logistic regression models and generalised estimating equations were used to estimate odds ratios and 95% confidence intervals. RESULTS Individuals with a first-degree relative with lung cancer had a 1.51-fold increase in the risk of lung cancer, after adjustment for smoking and other potential confounders (95% CI: 1.39, 1.63). The association was strongest for those with a family history in a sibling, after adjustment (odds ratios (OR) = 1.82, 95% CI: 1.62, 2.05). No modifying effect by histologic type was found. Never smokers showed a lower association with positive familial history of lung cancer (OR = 1.25, 95% CI: 1.03, 1.52), slightly stronger for those with an affected sibling (OR = 1.44, 95% CI: 1.07, 1.93), after adjustment. CONCLUSIONS The occurrence of lung cancer among never smokers and similar magnitudes of the effect of family history on lung cancer risk across histological types suggests familial aggregation of lung cancer is independent of those risks associated with cigarette smoking. While the role of genetic variation in the aetiology of lung cancer remains to be fully characterised, family history assessment is immediately available and those with a positive history represent a higher risk group.

Use of Hormone Replacement Therapy and the Risk of Colorectal Cancer

PURPOSE Estrogen/progestin replacement therapy is prescribed to women in menopause for purposes of postmenopausal symptom control or prevention of hormone deficiency-related diseases such as osteoporosis. Such treatments have formerly been shown to be associated with lower colorectal cancer risk in an as yet unknown mechanism. PATIENTS AND METHODS The Molecular Epidemiology of Colorectal Cancer study was a population-based case-control study in northern Israel of patients with colorectal cancer who were diagnosed between 1998 and 2006, and age-, sex-, clinic-, and ethnicity-matched population controls. Use of hormone replacement therapy (HRT) was assessed using a structured interview and validated by studying prescription records in a subset of patients for whom they were available. RESULTS Two thousand four hundred sixty peri/postmenopausal women were studied from among 2,648 patients with colorectal cancer and 2,566 controls. The self-reported use of HRT was associated with a significantly reduced relative risk of colorectal cancer (odds ratio [OR], 0.67; 95% CI, 0.51 to 0.89). This association remained significant after adjustment for age, sex, use of aspirin and statins, sports activity, family history of colorectal cancer, ethnic group, and level of vegetable consumption (OR, 0.37; 95% CI, 0.22 to 0.62). Statistically significant interactions were seen between use of HRT and use of aspirin and involvement in sports activity. Using pharmacy data, only users of combined oral preparations demonstrated a significant negative association with colorectal cancer. CONCLUSION The use of oral HRT was associated with a 63% relative reduction in the risk of colorectal cancer in postmenopausal women after adjustment for other known risk factors. This effect was not found in aspirin users and women with intensive sports participation.

Genetic Variation in 3-Hydroxy-3-Methylglutaryl CoA Reductase Modifies the Chemopreventive Activity of Statins for Colorectal Cancer

Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis, modifies the effect of statins on serum cholesterol levels. Long-term use of statins is associated with a reduced risk of colorectal cancer (CRC) in some, but not all, studies. We genotyped variants in 40 candidate genes important for cholesterol synthesis and metabolism in a population-based case-control study of CRC involving 2,138 incident cases and 2,049 population-based controls. We identified a single-nucleotide polymorphism in the HMGCR gene that significantly modified the protective association between statins and CRC risk. Compared with nonusers, the unadjusted odds ratio of CRC among statin users with the A/A genotype of rs12654264 in HMGCR was 0.3 (95% confidence interval, 0.18-0.51) and among statin users with the T/T genotype was 0.66 (95% confidence interval, 0.41-1.06; P-interaction = 0.0012). This genetic variant (A/A genotype of rs12654264) also was associated with lower serum levels of low-density lipoprotein among all cases and controls. In colon cancer cell lines, the reduction in cholesterol levels after statin treatment was substantially stronger in cells carrying the A/A genotype, and this difference was related to alternative splicing involving the HMGCR statin-binding domain. We anticipate that these data may advance the development of personalized statin use for reducing the risk of cancer as well as cardiovascular disease among the approximately 25 million people currently using statins worldwide. Cancer Prev Res; 3(5); 597–603. ©2010 AACR.

Epidemiology of Candidemia – A Nationwide Survey in Israel

SummaryBloodstream infections with Candida are often lethal and have been reported to be increasing in frequency. The current retrospective study describes the magnitude and epidemiological characteristics of candidemia in all western-type hospital facilities in Israel in 1994. Comprehensiveness of the data from the reporting hospitals was checked by cross-study of the data from the infectious diseases records and from the hospitalization records. Vital status of all reported cases was evaluated 1 year after the diagnosis. Data on 298 newly diagnosed cases of candidemia were received from 14 of the 18 general hospitals in Israel. The proportion of candidemia in the Israeli hospitals ranged from 0.1 to 0.01% of all admissions, with a mean of 0.05%. The incidence of candidemia differed significantly between the wards from 4–5/10,000 in general surgery and internal medicine wards to about 60/10,000 and 80/10,000 in intensive care and preterm units, respectively. Of all detected cases 53.6% were Candida albicans. Another nine specific species of Candida (mainly Candida parapsilosis, Candida tropicalis and Candida glabrata) were detected, with major differences between the various hospitals. The species of Candida differed significantly by sex and age. Of the cases of candidemia 21.5% died within 30 days of the isolation of the pathogen. The one-year mortality rate was 31.9%. Species-specific 30-day mortality rate was highest for C. glabrata. Throughout the analysis, C. glabrata emerged as a unique cause of candidemia, producing higher mortality, appearing at a younger age and predominating among females.

FGFR2 Is a Breast Cancer Susceptibility Gene in Jewish and Arab Israeli Populations

Genetic variation in FGFR2 is a newly described risk factor for breast cancer. We estimated the relative risk and contribution of FGFR2 polymorphisms to breast cancer risk in diverse ethnic groups within Jewish and other Middle Eastern populations. We genotyped four FGFR2 single nucleotide polymorphisms (SNP) and tested for association of these SNPs and haplotypes with breast cancer risk in a population-based case-control study of 1,529 women with breast cancer and 1,528 controls. We found significant associations between breast cancer risk and all four studied SNPs in FGFR2 (Ptrend for all SNPs < 0.0001). In ethnicity-specific analysis, all four SNPs were significantly associated with breast cancer risk in Ashkenazi and Sephardi Jews, with a similar but not significant trend in Arabs. Haplotype analysis identified five common haplotypes (>1%). The previously described AAGT risk haplotype was significantly associated with breast cancer risk in Ashkenazi [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.07-1.45; P = 0.0059] and Sephardi Jews (OR, 1.46; 95% CI, 1.17-1.80; P = 0.0006) compared with the reference GGAC haplotype. The AAAC haplotype was significantly associated with breast cancer risk in Sephardi Jews (OR, 1.97; 95% CI, 1.16-3.35; P = 0.0125) but not in Ashkenazi Jews (OR, 0.83; 95% CI, 0.41-1.62; P = 0.5613) or in Arabs (OR, 1.31; 95% CI, 0.80-2.14; P = 0.2881). Genetic variation in FGFR2, identified by rs1219648, may account for a substantial fraction of breast cancer in Arab (12%), Ashkenazi (15%), and Sephardi Jewish (22%) populations. The identification of population-specific risk haplotypes in FGFR2 is likely to help identify causal variants for breast cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1060–5)