Genetic risk transmission in a family affected by familial breast cancer.

Breast Cancer is the most common malignancy among women. Family history is the strongest single predictor of breast cancer risk, and thus great attention has been focused on BRCA1 and BRCA2 genes whose mutations lead to a high risk of developing this disease. Today, only 25% of high- and moderate-risk genes are known, suggesting the importance of the discovery of new risk modifiers. Therefore, the investigation of new polygenic alterations is of great importance, especially if considered high- and moderate-risk variants. In this study, the transmission of BRCA1-2 polymorphisms in association with the transmission of polymorphisms in the genes NUMA1, CCND1, COX11, FGFR2, TNRC9 and SLC4A7 were examined in all members of a family with the BRCA2 c.6447_6448dup mutation. This is the first study about the transmission of high-risk polygenic variants in all members of a family with a strong history of breast cancer. The results about the possible polygenic variant associations that could increase and modify the risk suggested the importance to search new variants to better manage patients and their family members.

Adipokines in hereditary breast cancer patients and healthy relatives.

Background: The role of adipocytokines and ghrelin in hereditary breast cancer syndrome (HBCS) has never been tested. Results: No significant differences in leptin, adiponectin and ghrelin plasma levels between cancer patients and healthy subjects was observed. Conversely, an higher level of adiponectin was shown in healthy subjects with BRCA 1/2 gene mutation vs those without (p < 0.03). Logistic regression analysis demonstrated that Adiponectin plasma level (OR 0.26; 95% CI:0.007-0.81; p < 0.02) and age (OR 5.51; 95% CI:1.78-19.71; p < 0.004) were the only factors independently associated with BMI; furthermore, Leptin plasma level (OR 0.23; 95% CI:0.06-0.76; p < 0.01) and age (OR 0.05; 95% CI:0.05-0.61; p < 0.007) resulted the only factors significantly associated with breast cancer. Materials and Methods: We analyzed blood plasma expression of leptin, adiponectin and ghrelin using Bio-Plex platform in 25 breast cancer patients with HBCS and in 38 healthy relatives. BRCA 1/2 gene status (presence of pathogenic mutations by direct molecular sequencing), clinical-pathological characteristics and Body Mass Index (BMI) of each subject were recorded. Conclusions: Adiponectin confirms to be associated with BMI also in subjects with HBCS. Leptin plasma level seems a direct and independent biomarker of a breast cancer risk. A validation of Leptin as a circulating biomarker of breast cancer development in larger series of HBCS subjects is needed.

Six low-penetrance SNPs for the estimation of breast cancer heritability: A family-based study in Caucasian Italian patients.

Breast cancer is a malignancy with a strong heritable component. Genetic counseling has been principally focused on families carrying high-penetrance breast cancer 1/2, early onset genes. Current modeling suggests that the majority of the unexplained fraction of familial risk is likely to be explained by a polygenic model. The aim of the present study was to estimate the heritability (h2) of breast cancer susceptibility through the analysis of 6 single nucleotide polymorphisms (SNPs), nuclear mitotic apparatus protein 1, cyclin D1, cytochrome C oxidase copper chaperone, fibroblast growth factor receptor 2, TOX high mobility group box family member 3 and solute carrier family 4 member 7. These 6 SNPs, previously identified by genome-wide association studies, were considered to evaluate the additive and common environmental components that contribute to the development of breast cancer in nuclear (pedigrees including only first degree relationships) and in extended families (with at most third degree relationships). A total of 22 extended pedigrees, subsequently split into 52 nuclear pedigrees were analyzed. An example of splitting process from extended to nuclear pedigree is shown in Fig. 1. Firstly, an underline latent continuous trait (Y*) using breast cancer status and information of 6 breast cancer-associated SNPs was calculated. This novel trait summarized the susceptibility of breast cancer in each individual. Secondly, the h2 of Y* was estimated using an additive polygenic-common environment-unique error model. h2 was evaluated in extended and immediate pedigrees, obtaining comparable results. h2 accounts for ~40% of the total phenotypic variance, indicating a fairly strong additive genetic effect of breast cancer susceptibility. The present study indicated the importance of the evaluation and consideration of these six SNPs, which can be used as instrumental variables in order to obtain improved genetic models that are useful for h2 analysis.

Epirubicin and gemcitabine as first-line treatment in malignant pleural mesothelioma.

Malignant pleural mesothelioma represents a rare disease, for which chemotherapy actually remains unsatisfactory. From August 1998 to November 2001, 28 chemo-radio-immunonaive patients were consecutively enrolled in the trial: 22/6 males/females; median age 63 years (range, 45-79); median ECOG PS 1 (range, 0-2). They were treated with epirubicin (100 mg/m2 iv on day 1) plus gemcitabine (1000 mg/m2 iv on days 1 and 8) every 4 weeks for 6 cycles. Patients who responded to chemotherapy (n = 6) were subsequently treated with interleukin-2 (4,500,000 IU) subcutaneously every other day, until progression. A total of 124 epirubicin-gemcitabine cycles were administered (median, 6/patient; range, 2-6). Twenty-six patients were evaluated for toxicity. According to WHO criteria, we observed grade III-IV hematological and gastrointestinal toxicity respectively in 3 patients (11%) and 1 patient (3%). No red cell transfusions were required and no toxic deaths occurred. Two patients (8%) could not be evaluated for response (no therapy performed). According to WHO criteria, the final responses were: partial in 4 patients (14%), stable disease in 19 patients (69%), and progression in 3 patients (10%). In 26 patients, the median survival was 55 weeks (range, 7-222) and median time to progression 30 weeks (range, 4-156). At the time of this writing, no patient is alive. The 1-year survival was 32%, 2-year survival 11%, and 4% at 3 and 4 years. All patients were at stage III, and time to progression was 58 weeks and survival 63.5 weeks, without any toxicity. This multi-center phase II clinical trial showed that epirubicin plus gemcitabine, as a first-line treatment in malignant pleural mesothelioma, has promising activity with a good tolerability profile and symptom palliation. The role of interleukin-2 in maintenance therapy for malignant pleural mesothelioma is encouraging and requires further study.

Immunoprofile from tissue microarrays to stratify familial breast cancer patients.

Familial breast cancer (BC) is a heterogeneous disease with variable prognosis. The identification of an immunoprofile is important to predict tumor behavior for the routine clinical management of familial BC patients. Using immunohistochemistry on tissue microarrays, we studied 95 familial BCs in order to analyze the expression of some biomarkers involved in different pathways. We used unsupervised hierarchical clustering analyses (HCA), performed using the immunohistochemical score data, to define an immunoprofile able to characterize these tumors. The analyses on 95 and then on a subset of 45 tumors with all biomarkers contemporarily evaluable, revealed the same biomarker and patient clusters. Focusing on the 45 tumors we identified a group of patients characterized by the low expression of estrogen receptor (P = 0.009), progesterone receptor (P < 0.001), BRCA1 (P = 0.005), nuclear Na+/H+ exchanger regulatory factor 1 (NHERF1) (P = 0.026) and hypoxia inducible factor-1 alpha (P < 0.001), and also by the higher expression of MIB1 (P = 0.043), cytoplasmic NHERF1 (P = 0.004), cytoplasmic BRCT-repeat inhibitor of hTERT expression (P = 0.001), vascular endothelial growth factor (VEGF) (P = 0.024) and VEGF receptor-1 (P = 0.029). This immunoprofile identified a more aggressive tumor phenotype associated also with a larger tumor size (P = 0.012) and G3 grade (P = 0.006), confirmed by univariate and multivariate analyses. In conclusion, the clinical application of HCA of immunohistochemical data could allow the assessment of prognostic biomarkers to be used simultaneously. The 10 protein expression panel might be used to identify the more aggressive tumor phenotype in familial BC and to direct patients towards a different clinical therapy.

Amifostine as chemoprotectant in metastatic breast cancer patients treated with doxorubicin.

Amifostine has shown to selectively protect normal tissues against cytotoxic and mutagenic effects of several anti-neoplastic drugs, such as alkylating agents, organoplatinum compounds, anthracyclines, taxanes, and ionising radiation. This cytoprotection is broad-spectrum and selective, without loss of therapeutic efficacy. In this study we have treated 31 patients affected with inoperable or metastatic breast cancer, not previously submitted to chemotherapy for advanced disease, with amifostine 910 mg/m(2) followed by doxorubicin 75 mg/m(2). The overall response rate was 52% with a median response duration of 13 months (range 6-53+) and a median overall survival of 21 months (range 3-59+). With regard to toxicity, 14 patients (45%) experienced transient g4 neutropenia which was febrile only in one case (3%). Grade 3-4 thrombocytopenia was not recorded. Nausea and vomiting occurred in 14% of cycles. Grade 3 mucositis was observed in only 1 patient, whereas 2 patients (6%) developed an asymptomatic drop of left ventricular ejection fraction (LVEF) >10% below basal value. In conclusion, this study suggests that amifostine can reduce doxorubicin related toxicity, thus improving the patients' quality of life and the efficacy/toxicity ratio of this drug.

BRCA1/2 and clinical outcome in a monoinstitutional cohort of women with hereditary breast cancer.

The clinical outcome of BRCA mutation carriers and non-carriers still remains a topic of discussion. In order to interpret controversial data, in the present study, we analyzed a large consecutive monoinstitutional series of breast cancer patients and relatives with familial features carrying or not carrying BRCA mutations. The intense research in recent years regarding the clinical genetics of patients with breast or ovarian cancer and their relatives has allowed the organization of a unique database comprising anamnestic, clinical, pathological and molecular data. Families with two or more cases of breast cancer under the age of 50 years, or with three cases at any age, were identified. From June, 2003 to June, 2010, a total of 202 patients (136 probands + 66 relatives) from 45 families were included in the analysis. A total of 136 (49 carrier and 87 non-carrier) cases had a cancer diagnosis at the time of their genetic testing. Twenty and 24 events were observed in the carrier and control group, respectively. The 10-year disease-free suvival rate was 57% for patients in the control group compared with 50% for patients carrying a BRCA mutation (P=0.15 by log-rank test). Finally, 66 (32 genetic and 34 control) cases were unaffected at the time of molecular analysis, and 6 new cases of cancer were observed in the carriers, while no new cases were detected in the control cohort. Thus, at age 50, 40% of carriers had a high risk of disease (P=0.0069 by log-rank test). Our data support the hypothesis that the presence of BRCA mutations does not alter the clinical outcome for hereditary breast cancer patients. Conversely, BRCA mutations are proven to be crucial for prediction of risk in healthy relatives from carrier families.