Blood Lead Level as Marker of Increased Risk of Ovarian Cancer in BRCA1 Carriers.

BRCA1 mutations substantially elevate the risks of breast and ovarian cancer. Various modifiers, including environmental factors, can influence cancer risk. Lead, a known carcinogen, has been associated with various cancers, but its impact on BRCA1 carriers remains unexplored. A cohort of 989 BRCA1 mutation carriers underwent genetic testing at the Pomeranian Medical University, Poland. Blood lead levels were measured using inductively coupled plasma mass spectrometry. Each subject was assigned to a category based on their tertile of blood lead. Cox regression analysis was used to assess cancer risk associations. Elevated blood lead levels (>13.6 µg/L) were associated with an increased risk of ovarian cancer (univariable: HR = 3.33; 95% CI: 1.23-9.00; p = 0.02; multivariable: HR = 2.10; 95% CI: 0.73-6.01; p = 0.17). No significant correlation was found with breast cancer risk. High blood lead levels are associated with increased risk of ovarian cancer in BRCA1 carriers, suggesting priority for preventive salpingo-oophorectomy. Potential risk reduction strategies include detoxification. Validation in diverse populations and exploration of detoxification methods for lowering lead levels are required.

Zinc and Its Antioxidant Properties: The Potential Use of Blood Zinc Levels as a Marker of Cancer Risk in BRCA1 Mutation Carriers.

BRCA1 mutations predispose women to breast and ovarian cancer. The anticancer effect of zinc is typically linked to its antioxidant abilities and protecting cells against oxidative stress. Zinc regulates key processes in cancer development, including DNA repair, gene expression, and apoptosis. We took a blood sample from 989 female BRCA1 mutation carriers who were initially unaffected by cancer and followed them for a mean of 7.5 years thereafter. There were 172 incident cases of cancer, including 121 cases of breast cancer, 29 cases of ovarian cancers, and 22 cancers at other sites. A zinc level in the lowest tertile was associated with a modestly higher risk of ovarian cancer compared to women with zinc levels in the upper two tertiles (HR = 1.65; 95% CI 0.80 to 3.44; p = 0.18), but this was not significant. Among those women with zinc levels in the lowest tertile, the 10-year cumulative risk of ovarian cancer was 6.1%. Among those in the top two tertiles of zinc level, the ten-year cumulative risk of ovarian cancer was 4.7%. There was no significant association between zinc level and breast cancer risk. Our preliminary study does not support an association between serum zinc level and cancer risk in BRCA1 mutation carriers.

Association of the bitter taste genes TAS2R38 and CA6 and breast cancer risk; a case-control study of Polish women in Poland and Polish immigrants in USA.

It is known that the perception of bitterness is mediated by type 2 bitter taste receptors (TAS2Rs). However, recent reports have suggested that the carbonic anhydrase 6 (CA6) gene may also influence bitterness sensing. Genetic variants in these genes could influence dietary intake of brassica vegetables, whose increased consumption has been observed in the literature, though inconsistently, to decrease breast cancer (BC) risk. We hypothesized that the estimated odds ratios (ORs) for the association between BC and taster diplotype (PAV/PAV) and/or genotype A/A, will be in the direction of increased BC risk, potentially due to reduced consumption of brassica vegetables. Using a case-control study of BC in Polish women in Poland (210 cases and 262 controls) and Polish immigrant women to USA (78 cases and 170 controls) we evaluated the association of the taster diplotypes in TAS2R38 gene and genotypes in the CA6 gene and BC risk in these two populations individually and jointly. No significant increase in risk was observed for the TAS2R38 PAV/PAV diplotype (tasters) in each population individually or in the joint population. For the CA6 gene, in the joint population, we observed an increased BC risk for the combined G/A and G/G genotypes (non-tasters) vs A/A (tasters), OR = 1.41 (95% CI 1.04-1.90, p = 0.026) which after adjustment for False Discovery Rate (FDR), was not significant at p≤0.05 level. However, for the joint population and for the combined genotype of the two genes AVI/AVI+G* (non-tasters) vs. PAV/*+A/A (tasters), we observed a significant increase in BC risk, OR = 1.77 (95%CI 1.47-2.74, p = 0.01), for the non-tasters, which remained significant after FDR adjustment. In conclusion for the joint population and the joint effect for the two bitter sensing genes, we observed an increase in BC risk for the bitterness non-tasters, association which is in the opposite direction to our original hypothesis.

Are contrast enhanced mammography and digital breast tomosynthesis equally effective in diagnosing patients recalled from breast cancer screening?

Purpose: Full-field digital mammography (FFDM) is widely used in breast cancer screening. However, to improve cancer detection rates, new diagnostic tools have been introduced. Contrast enhanced mammography (CEM) and digital breast tomosynthesis (DBT) are used in the diagnostic setting, however their accuracies need to be compared.The aim of the study was to evaluate the diagnostic performance of CEM and DBT in women recalled from breast cancer screening program. Methods: The study included 402 consecutive patients recalled from breast cancer screening program, who were randomized into two groups, to undergo either CEM (202 patients) or DBT (200 patients). All visible lesions were evaluated and each suspicious lesion was histopathologically verified. Results: CEM detected 230 lesions; 119 were classified as benign and 111 as suspicious or malignant, whereas DBT identified 209 lesions; 105 were classified as benign and 104 as suspicious or malignant. In comparison to histopathology, CEM correctly detected cancer in 43 out of 44 cases, and DBT in all 33 cases, while FFDM identified 15 and 18 neoplastic lesions in two groups, respectively. CEM presented with 97% sensitivity, 63% specificity, 70% accuracy, 38% PPV and 99% NPV, while DBT showed 100% sensitivity, 60% specificity, 32%, PPV, 100% NPV and 66% accuracy. The CEM's AUC was 0.97 and DBT's 0.99. The ROC curve analysis proved a significant (p<0.000001) advantage of both CEM and DBT over FFDM, however, there was no significant difference between CEM and DBT diagnostic accuracies (p=0.23). Conclusions: In this randomized, prospective study CEM and DBT show similar diagnostic accuracy.

The impact of oophorectomy on survival from breast cancer in patients with CHEK2 mutations.

BACKGROUND: To estimate the impact of oophorectomy and other treatments on the survival of breast cancer patients with a CHEK2 mutation. METHODS: Women with Stage I-III breast cancer who were treated at 17 hospitals in Poland were tested for four founder mutations in the CHEK2 gene. 974 women (10%) were positive for a CHEK2 mutation. Control patients without a CHEK2 mutation were selected from a database of patients treated over the same time period. Information on treatments received and distant recurrences were retrieved from medical records. Treatments included chemotherapy, hormonal therapy (tamoxifen) and radiation therapy. Oophorectomies were performed for the treatment of breast cancer or for benign conditions. Dates of death were obtained from the Polish Vital Statistics Registry. Causes of death were determined by medical record review. Predictors of survival were determined using the Cox proportional hazards model. RESULTS: In all, 839 patients with a CHEK2 mutation were matched to 839 patients without a mutation. The mean follow-up was 12.0 years. The 15-year survival for CHEK2 carriers was 76.6% and the 15-year survival for non-carrier control patients was 78.8% (adjusted HR = 1.06; 95% CI: 0.84-1.34; P = 0.61). Among CHEK2 carriers, the 15-year survival for women who had an oophorectomy was 86.3% and for women who did not have an oophorectomy was 72.1% (adjusted HR = 0.59; 95% CI: 0.38-0.90; P = 0.02). Among controls, the 15-year survival for patients who had an oophorectomy was 84.5% and for women who did not have an oophorectomy was 77.6% (adjusted HR = 1.03; 95% CI: 0.66-1.61; P = 0.90). CONCLUSION: Among women with breast cancer and a CHEK2 mutation, oophorectomy is associated with a reduced risk of death from breast cancer.

Consumption of Dairy Products and the Risk of Developing Breast Cancer in Polish Women.

Lack of consistency in the relationship between dairy products consumption and breast cancer (BC) risk motivated us to evaluate this association in a case-control study of BC among Polish women. The study includes 1699 women 26-79 years of age, 823 BC cases identified in Cancer Registries and 876 randomly selected controls from the national population registry. Using a validated, semiquantitative food frequency questionnaire (FFQ), the consumption of dairy products was collected for a time period of 10-15 years prior to BC diagnosis. We used logistic regression, adjusting for potential confounders, to assess the relationship between total dairy consumption as well as individual dairy groups of milk, cottage cheese and hard cheese and BC risk for premenopausal and postmenopausal women. For total consumption, a significant decrease in BC risk was observed with increased consumption of one serving/week, OR trend = 0.98, 2% decrease in risk, for premenopausal women only. For milk, a significant decrease in BC risk was observed for an increase in consumption of one glass/week, OR trend = 0.95, 5% decrease, in both strata of menopause. In contrast, for hard cheese, a significant increase in the risk of 10% was observed only in premenopausal women, OR trend = 1.10. Cottage cheese consumption significantly reduced BC risk by 20%, OR trend = 0.80, for an increase in one serving/week for postmenopausal women only. Our results show that individual dairy products have a statistically significant but bi-directional relationship with BC risk, which differs for premenopausal and postmenopausal women.

Screening with magnetic resonance imaging, mammography and ultrasound in women at average and intermediate risk of breast cancer.

BACKGROUND: The addition of MRI to mammography and ultrasound for breast cancer screening has been shown to improve screening sensitivity for high risk women, but there is little data to date for women at average or intermediate risk. METHODS: Two thousand nine hundred and ninety-five women, aged 40 to 65 years with no previous history of breast cancer were enrolled in a screening program, which consisted of two rounds of MRI, ultrasound and mammography, one year apart. Three hundred and fifty-six women had a CHEK2 mutation, 370 women had a first-degree relative with breast cancer (and no CHEK2 mutation) and 2269 women had neither risk factor. Subjects were followed for breast cancer for three years from the second screening examination. RESULTS: Twenty-seven invasive epithelial cancers, one angiosarcoma and six cases of DCIS were identified over the four-year period. Of the 27 invasive cancers, 20 were screen-detected, 2 were interval cancers, and five cancers were identified in the second or third follow-up year (i.e., after the end of the screening period). For invasive cancer, the sensitivity of MRI was 86%, the sensitivity of ultrasound was 59% and the sensitivity of mammography was 50%. The number of biopsies incurred by MRI (n = 156) was greater than the number incurred by mammography (n = 35) or ultrasound (n = 57). Of the 19 invasive cancers detected by MRI, 17 (89%) were also detected by ultrasound or mammography. CONCLUSIONS: In terms of sensitivity, MRI is slightly better than the combination of mammography and ultrasound for screening of women at average or intermediate risk of breast cancer. However, because of additional costs incurred by MRI screening, and the small gain in sensitivity, MRI screening is probably not warranted outside of high-risk populations.

Rapid Detection Method for the Four Most Common CHEK2 Mutations Based on Melting Profile Analysis.

INTRODUCTION: CHEK2 is a tumor suppressor gene, and the mutations affecting the functionality of the protein product increase cancer risk in various organs. The elevated risk, in a significant percentage of cases, is determined by the occurrence of one of the four most common mutations in the CHEK2 gene, including c.470T>C (p.I157T), c.444+1G>A (IVS2+1G>A), c.1100delC, and c.1037+1538_1224+328del5395 (del5395). METHODS: We have developed and validated a rapid and effective method for their detection based on high-resolution melting analysis and comparative-high-resolution melting, a novel approach enabling simultaneous detection of copy number variations. The analysis is performed in two polymerase chain reactions followed by melting analysis, without any additional reagents or handling other than that used in standard high-resolution melting. RESULTS: Validation of the method was conducted in a group of 103 patients with diagnosed breast cancer, a group of 240 unrelated patients with familial history of cancer associated with the CHEK2 gene mutations, and a 100-person control group. The results of the analyses for all three groups were fully consistent with the results from other methods. CONCLUSION: The method we have developed improves the identification of the CHEK2 mutation carriers, reduces the cost of such analyses, as well as facilitates their implementation. Along with the increased efficiency, the method maintains accuracy and reliability comparable to other more labor-consuming techniques.

Plasma micronutrients, trace elements, and breast cancer in BRCA1 mutation carriers: an exploratory study.

PURPOSE: Few studies have evaluated the role of micronutrients or trace elements in breast cancer development among BRCA1 mutation carriers. To investigate a possible role of dietary and environmental exposures on cancer risk, we undertook an exploratory study, using a matched case-control design (n = 48 cases and 96 controls), to evaluate the relationships between plasma levels of 14 micronutrients and breast cancer risk among BRCA1 mutation carriers in Poland. METHODS: We estimated the univariate odds ratios (OR) and 95 % confidence intervals (CI) for breast cancer associated with plasma levels for each of 14 micronutrients. RESULTS: Of the 14 analytes quantified, significant differences between cases and controls were seen for two (iron and retinol; p = 0.009 and p = 0.03, respectively). Women in the highest tertile of plasma iron had a 57 % lower risk, compared with those in the lowest quartile (OR = 0.43; 95 % CI 0.18-1.04; p for trend = 0.06). Increasing antimony levels were associated with an increased risk of breast cancer (p for trend = 0.05). Women in the highest tertile had a 2.43-fold increase in breast cancer risk compared with women in the lowest tertile (OR = 2.43; 95 % CI 1.00-5.91). CONCLUSIONS: This study provides some preliminary evidence regarding a role of diet, specifically iron and antimony, in the etiology of BRCA1-associated breast cancer. Prospective studies are necessary to confirm these findings.

Predictions of cancer incidence in Wielkopolska in 2018.

AIM OF THE STUDY: The cancer incidence in Wielkopolska in 2008 was one of the highest in the country and was higher than in Poland by 21% in men and by 14% in women. We can quantify the future burden of cancer from two different perspectives: the number of new cancer cases due to population change and new cases due to risk change. Making predictions of number of new cancer cases in Wielkopolska in 2018. MATERIAL AND METHODS: These projections of number of cancer cases, age specific rates and age-standardized rates for 2018 (all cancers and the most frequent cancers for men and women) has been based on the historical trends of cancer incidence in Wielkopolska in 1999-2008 and demographical prognosis of Central Statistical Office using the method of Hakulinen and Dyba. RESULTS: There will be over 8000 new cancer cases in men in Wielkopolska in 2018 and over 7000 in women. Compare to the period 2004-2008 the number of cancer cases will increase by 45% for men and by nearly 30% for women. About 2/3 of the increase in Wielkopolska is predicted to be connected with demography change, 1/3 with risk change. CONCLUSIONS: The predicted increase of number of cancer cases in Wielkopolska in 2018 will be the result of: changes in the population (bigger impact of the older age groups), an influence of the risk factors (mainly smoking) and a participation in the screening programs.

Analysis of the efficacy of screening tests in colorectal cancer by faecal occult blood test--own experience.

UNLABELLED: Screening of the colon cancer seems to be important to improve the results of the surgical treatment. There are different screening programs, the most common use the fecal occult blood (FOB) tests or colonoscopy. THE AIM OF THE STUDY: was to evaluate the results of the colon cancer screening based on the FOB test and perform the algorhytm improving the effectiveness of the screening. MATERIAL AND METHODS: 941 patients with the positive results of the FOB (immunochromatographic method) test were investigated. In all cases the rectosigmoidoscopy for the detection of the lower GI tract pathology was done. 312 patients were qualified to colonoscopy. RESULTS: Adenomatous polyps and adenocarcinomas were detected in 116 patients. There was no correlation between clinical symptoms and the colorectal cancer. The colorectal cancer was recognized statistically more common at the patients with previous detected neoplasia, in the colon and other organs, with hereditary nonpolyposis colorectal cancer and with inflammatory bowel diseases. CONCLUSIONS: The colorectal cancer screening based on the FOB can be effective in the early recognition of the bowel malignancy. The previous questionnaire can eliminate from the FOB screening the patients without indications (previously done colonoscopy or barium enema) or with directly indications for colonoscopy.

Expression of estrogen receptor beta in the breast carcinoma of BRCA1 mutation carriers.

BACKGROUND: Breast cancers (BC) in women carrying mutations in BRCA1 gene are more frequently estrogen receptor negative than the nonhereditary BC. Nevertheless, tamoxifen has been found to have a protective effect in preventing contralateral tumors in BRCA1 mutation carriers. The identification of the second human estrogen receptor, ERbeta, raised a question of its role in hereditary breast cancer. The aim of this study was to assess the frequency of ERalpha, ERbeta, PgR (progesterone receptor) and HER-2 expression in breast cancer patients with mutated BRCA1 gene and in the control group. METHODS: The study group consisted of 48 women with BRCA1 gene mutations confirmed by multiplex PCR assay. The patients were tested for three most common mutations of BRCA1 affecting the Polish population (5382insC, C61G, 4153delA). Immunostaining for ERalpha, ERbeta and PgR (progesterone receptor) was performed using monoclonal antibodies against ERalpha, PgR (DakoCytomation), and polyclonal antibody against ERbeta (Chemicon). The EnVision detection system was applied. The study population comprised a control group of 120 BC operated successively during the years 1998-99. RESULTS: The results of our investigation showed that BRCA1 mutation carriers were more likely to have ERalpha-negative breast cancer than those in the control group. Only 14.5% of BRCA1-related cancers were ERalpha-positive compared with 57.5% in the control group (P < 0.0001). On the contrary, the expression of ERbeta protein was observed in 42% of BRCA1-related tumors and in 55% of the control group. An interesting finding was that most hereditary cancers (75% of the whole group) were triple-negative: ERalpha(-)/PgR(-)/HER-2(-) but almost half of this group (44.4%) showed the expression of ERbeta. CONCLUSION: In the case of BRCA1-associated tumors the expression of ERbeta was significantly higher than the expression of ERalpha. This may explain the effectiveness of tamoxifen in preventing contralateral breast cancer development in BRCA1 mutation carriers.

BRCA1 mutations and prostate cancer in Poland.

Evidence to date that BRCA1 mutation carriers are at an increased risk of prostate cancer is mixed - both positive and negative studies have been published. To establish whether or not inherited variation in BRCA1 influences prostate cancer risk we genotyped 1793 men with prostate cancer in Poland and 4570 controls for three founder mutations (C61G, 4153delA and 5382insC). A BRCA1 mutation was present in 0.45% of the cases and 0.48% of the controls (odds ratio=0.9; P=1.0). The odds ratios varied substantially by mutation. The 5382insC mutation is the most common of the three founder mutations. It was detected only in one case (0.06%), whereas it was seen in 0.37% of controls (P=0.06). In contrast, the 4153delA was more common in prostate cancer cases (0.22%) than in controls (0.04%) (odds ratio=5.1; 95% confidence interval: 0.9-27.9; P=0.1). The C61G mutation was also found in excess in cases (0.17%) compared with controls (0.07%) (odds ratio=2.6; 95% confidence interval: 0.5-12.7; P=0.5). Eight men with prostate cancer carried a mutation. Only one of these carried the 5382insC mutation, compared with 17 of 22 individuals with mutations in the control population (P=0.003). These data suggest that the 5382insC mutation is unlikely to be pathogenic for prostate cancer in the Polish population. The presence of one of the other alleles was associated with an increased risk for prostate cancer (odds ratio=3.6; 95% confidence interval: 1.1-11.3; P=0.045); in particular for familial prostate cancer (odds ratio=12; 95% confidence interval: 2.9-51; P=0.0004). We consider that the risk of prostate cancer in BRCA1 carriers varies with the position of the mutation.

Hereditary ovarian cancer in Poland.

There is increasing evidence that hereditary factors play a greater role in ovarian cancer than in any of the other common cancers of adulthood. This is attributable, to a large extent, to a high frequency of mutations in the BRCA1 or BRCA2 genes. In Poland, 3 common founder mutations in BRCA1 account for the majority of families with identified BRCA mutations. Our study was conducted in order to estimate the prevalence of any of 3 founder BRCA1 mutations (5382insC, C61G and 4153delA) in 364 unselected women with ovarian cancer, and among 177 women with ovarian cancer and a family history of breast or ovarian cancer. A mutation was identified in 49 out of 364 unselected women with ovarian cancer (13.5%) and in 58 of 177 women with familial ovarian cancer (32.8%). The majority of women with ovarian cancer and a BRCA1 mutation have no family history of breast or ovarian cancer. The high frequency of BRCA1 mutations in Polish women with ovarian cancer supports the recommendation that all Polish women with ovarian cancer should be offered testing for genetic susceptibility, and that counseling services be made available to them and to their relatives. It is important that mutation surveys be conducted in other countries prior to the introduction of national genetic screening programs.