Rosalba Amodio

Oral Contraceptive Use and BRCA Penetrance: A Case-Only Study

Background: Women with deleterious mutations in BRCA genes are at increased risk of breast cancer. However, the penetrance of the genetic trait may be regulated through environmental factors. This multinational case-only study tested the interaction between oral contraceptive use and genetic susceptibility in the occurrence of breast cancer. Methods: We recruited 3,123 patients diagnosed with breast cancer before the age of 45 years. Participants were classified according to their probability of carrying a BRCA mutation on the basis of their family history of breast and ovarian cancer. According to a case-only approach, the frequency of relevant exposures among breast cancer cases with high probability of BRCA mutation (“genetic cases”) was compared with the frequency of the same exposures among breast cancer cases with a low probability of BRCA mutation (“sporadic cases”). The interaction odds ratios (OR) and 95% confidence intervals (CI) for oral contraceptive use were estimated by unconditional logistic regression, after controlling for potentially confounding variables. Results: The analysis was carried out comparing 382 “genetic” and 1,333 “sporadic” cases. We found a borderline significant interaction between genetic breast cancer and oral contraceptive use for ever users compared with never users (OR, 1.3; 95% CI, 1.0-1.7). The greatest interaction OR was found for women who started using pill at 18 to 20 years (OR, 1.6; 95% CI, 1.1-2.3). Conclusion: These results suggest that BRCA mutation carriers, as well as women with a significant family history of breast and ovarian cancer are more vulnerable to exogenous hormones in oral contraceptives. (Cancer Epidemiol Biomarkers Prev 2009;18(7):2107–13)

Application of a New Classification to a Breast Tumor Series from a Population-Based Cancer Registry : Demographic, Clinical, and Prognostic Features of Incident Cases, Palermo Province, 2002-2004

A new classification based on gene expression profiling or immunohistochemical (IHC) characteristics may replace current histopathological classifications and predict better clinical outcomes. We used IHC markers to classify incident cases ascertained by the Palermo Breast Cancer Registry (2002–2004) into four subtypes: luminal‐A (ER+ or PgR+ and HER2/neu−); luminal‐B (ER+ or PgR+, HER2/neu+); basal‐like (ER−, PgR−, HER2/neu−); and HER2+/ER− (HER2/neu+, ER−, PgR−). We evaluated HER2/neu, ER and PgR in 1300/1985 (65%) cases. The most common IHC‐subtype was luminal‐A (68%), whereas luminal‐B, basal‐like, and HER2+/ER− accounted for 14%, 13%, and 5%, respectively. IHC‐subtypes were not associated with tumor size, geographic location within the province, or menopause, but differed by NPI (P < 0.0001), grading (P < 0.0001), lymph‐node involvement (P= 0.04), metastases (P= 0.04), and TNM stage (P= 0.04). Endocrine therapy was administered to 81% of 519 postmenopausal, luminal‐A, and luminal‐B cases and to 32% of 114 postmenopausal, basal‐like, and HER2+/ER− cases.

Dietary enterolactone affects androgen and estrogen levels in healthy postmenopausal women.

In this randomized dietary intervention study (DI) we analyzed levels of androgens, phytoestrogens, and estrogens in 12‐h urine samples of 69 healthy postmenopausal women, 37 of whom followed a traditional Mediterranean diet for 6 months (intervention group) as compared to 32 women who followed their regular diet (control group). Circulating levels of both insulin and testosterone (T) were also assayed. Overall, enterolactone (ENL) was the most prominent phytoestrogen in urines of both control and intervention women, and its levels increased by a 20% after DI. At the baseline the ENL levels were seen to be significantly associated with both the total androgens (TOT‐A) (r= 0.371, P= 0.002) and the TOT‐A/total estrogen (TOT‐E) ratio (r= 0.351, P= 0.005) in all 69 postmenopausal women. Furthermore, the DI resulted in a more pronounced negative association of both ENL with insulin (r=−0.321, P= 0.05) and insulin with TOT‐A (r=−0.421, P= 0.01). Regarding urinary androgens, ENL associated with both 3α‐androsterone (5α‐androgen, r= 0.363, P= 0.002) and 3α‐etiocolanolone (5β‐androgen, r= 0.295, P= 0.01) at baseline, while after DI, circulating insulin and T exhibited a significant negative association with the 5β‐androgen metabolite etiocolanolone (r=−0.487, P= 0.002; and r=−0.336, P= 0.042, respectively). We conclude that lignan components of the Mediterranean diet, notably ENL, are associated with urinary levels of products of androgen metabolism, including both 5α‐ and 5β‐reductase enzymes, in healthy postmenopausal women. Further studies are necessary to better understand the interplay of sex hormones with dietary phytoestrogens.

Red Wine Extract Prevents Neuronal Apoptosis in Vitro and Reduces Mortality of Transgenic Mice

Abstract:  In this work, we have investigated the effects of nutritional antioxidants as antidegenerative agents on glutamate‐induced apoptosis in primary cultures of cerebellar granule neurons (CGNs). Glutamate‐induced apoptosis is also associated with intracellular [Ca2+]i overload, generation of reactive oxygen species (ROS), depression of cell energy metabolism, cytochrome c release, and increase in caspase‐3 activity. Pretreatment (3 h) with red wine extract (5 μg/mL) and ascorbic acid (30 μM) blocks glutamate‐induced apoptosis in CGNs. In vivo experiments carried out on transgenic mice expressing the human mutated Cu, Zn superoxide dismutase (SOD1) G93A (mSOD1G93A) show that mice fed with lyophilized red wine have significantly increased survival as compared to control, untreated animals.

17β-Hydroxysteroid dehydrogenase activity in endometrial cancer cells: Different metabolic pathways of estradiol in hormone-responsive and non-responsive intact cells

In this paper we report that two human long-term endometrial cancer cell lines, Ishikawa and HEC-1A, exhibit quite different abilities in metabolizing estrogens. As a matter of fact, incubation of Ishikawa cells with close-to-physiological concentrations of estradiol (E2) as precursor resulted in: (1) elevated formation (up to 90%) of E2-sulphate (E2-S), using lower precursor concentrations; (2) very limited conversion to estrone (E1) (< 10% at 24 h incubation), as either free or sulphate; and (3) low but consistent production of other estrogen derivatives, such as 2-hydroxy-estrogens and estriol. Conversely, scant amounts (if any) of E2-S were found in HEC-1A cells, while no detectable formation of other estrogen metabolites could be observed after 24 h. On the other hand, E1 production was significantly greater (nearly 60% at 24 h) than in Ishikawa cells, a large proportion of E1 (over 50% of the total) being formed after only 6 h incubation using time-course experiments. The hypothesis that E2 metabolism could be minor in Ishikawa cells as a consequence of the high rate of E2-S formation encountered is contradicted by the evidence that conversion to E1 also remains limited in the presence of much lower E2-S amounts, seen using higher molar concentrations of precursor. Overall, we observe that 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity diverges significantly in intact Ishikawa and HEC-1A endometrial cancer cells. This difference could not merely be accounted for by the diverse amounts of substrate (E2) available to the cells, nor may it be imputed to different levels of endogenous estrogens. It should rather be sought in different mechanisms controlling 17 beta-HSD activity or, alternatively, in the presence of distinct isoenzymes in the two different cell types.

Target therapy in HER2-overexpressing breast cancer patients.

The development of new therapeutic strategies, such as monoclonal antibodies directed against human epidermal growth factor receptor-2 (HER2), has offered new hopes for women with early breast cancer whose tumors overexpress HER2. We retrospectively analyzed the population-based data of Breast Cancer Registry of Palermo in 2004-2006, and selected 1401 invasive breast cancer cases, nonmetastatic at diagnosis, having HER2/neu oncogene expression determined. We have correlated this information to age, tumor stage at diagnosis (TNM), nodal involvement, and receptor status (ER and PgR). Survival analysis was conducted dividing the patients in two different groups according to date of diagnosis: one group diagnosed in 2004 and a second group in 2005-2006. In the 460 cases of 2004, nodal involvement, receptor status, age at diagnosis and TNM maintained a strong predictive value (p < 0.0001). In this group of patients, overall survival was significantly different according to the HER2 expression levels (p = 0.001). In the second group of patients (941 incident cases in 2005-2006) there was a statistically significant survival difference comparing patients with high levels of HER2 expression treated with trastuzumab versus those untreated (p = 0.006). Our data show that elevated levels of HER2 are a negative prognostic factor. In addition, patients overexpressing HER2 show a significant increase of overall survival when treated with trastuzumab.

Comparison of Female Breast Cancer Registration in the City and Province of Palermo With Other Italian Cancer Registries

Abstract: The aim of this study was to assess the incidence of breast cancer in women from the city and province of Palermo (Sicily) in 5 yr, 1999–2003, using a population based cancer registry approach. In the last years, a sharp increase of breast cancer incidence has been observed worldwide. Overall, direct age-standardized incidence rates were 89.3 per 100,000 person-yr, being markedly higher in Palermo City (101.0) than in Palermo Province (75.0). Results show a highly significant difference in breast cancer incidence in different areas of Sicily, particularly in the older (>50 yr) age groups and a profound difference between the metropolitan area of Palermo and the surrounding areas. The evidence of the different rates of breast cancer incidence in Palermo City and in the other small municipalities of the Palermo Province suggests a different pattern of breast cancer risk as a consequence of different lifestyle and diet modifications in the urban population of Palermo City.

Epidemiology of malignant melanoma in the province of Palermo (2003-2005)

Background : The incidence of melanoma has steadily increased worldwide and shows geographical variability according to latitude. The aim of this study was to describe the incidence of cutaneous malignant melanoma (CMM) cases in the Province of Palermo during the period 2003-2005. Methods : 231 incident cases of CMM, registered by the Cancer Registry of Palermo, were analysed. Anatomic localization, histological type, thickness, ulceration, margins, any lymph node involvement and metastases were evaluated. A statistical analysis of survival rates was performed. Results : Distribution by sex and stage of diagnosis showed a slight, but not significant, difference between females and males diagnosed both in early and late stage CMM. Age incidence rates were higher in women before the age of 40 and in men over the age of 50. No statistically significant difference in stage was observed between residents in Palermo and of its Province. 148 cases (64%) were found in people living in Palermo, with an incidence rate (EU) of 7.2 over 100,000 in males and 6.1 in females, while in the province the incidence rate was lower (4.7 vs 3.9 ). Univariate analysis by gender showed better survival in females than in males and a better survival for age <49 and for stage I-II at diagnosis (p<0.05). Multivariate analysis including gender, age and cancer stage showed that survival is significantly positively related to earlier stage (p<0.05) and younger age (p=0.01) but not to sex (p=0.19). Conclusions : Diagnosis of CMM is mainly performed in the early stages, in both sexes and regardless of residence, suggesting no difference in early diagnosis and access to care between city and province. The incidence of CMM appears to be higher in the city compared to the province. Survival following diagnosis was strongly, and independently, related to age and stage of CMM, while gender did not significantly predict survival.

Endocrine therapy in metastatic breast cancer: data from Breast Cancer Registry of Palermo, 1999-2005 .

This study compares the survival of breast cancer patients who are metastatic at diagnosis (DMBC) and of recurrent metastatic breast cancer (RMBC) patients. We analyzed retrospectively the population‐based data of Breast Cancer Registry of Palermo and collected a total of 4459 breast cancer cases in the years 1999–2005. Survival analysis did not show statistically significant differences between DMBC and RMBC patients (P= 0.882). Endocrine manipulation is the treatment of choice in the case of hormone receptor‐positive breast tumors. In 91 receptor‐positive DMBC patients the endocrine treatment was associated with a prolonged overall survival (OS) (median survival 33.5 months compared to 29 months for receptor‐positive patients who did not receive hormone treatment). Receptor‐negative patients who underwent endocrine therapy (76% of cases) survived longer than receptor‐negative patients who did not receive hormone treatment (median survival 28.5 months vs. 15 months, respectively). This evidence supports the concept that endocrine therapies impinging upon molecular targets other than hormone receptors may increase survival rates of breast cancer patients.