Distinct breast cancer phenotypes in BRCA 1/2 carriers based on ER status.

PURPOSE: BRCA1/2 genes are the two main genes associated with hereditary breast cancers (BC). In the present study, we explore clinical and molecular characteristics of BRCA-associated BC in relation to estrogen receptor (ER) status. METHODS: Three BC databases (DB) were evaluated: (i) Hadassah oncogenetics (n = 4826); (ii) METABRIC (n = 1980), and (iii) Nick-Zainal (n = 560). We evaluated age at diagnosis in BRCA positive (BP) and BRCA negative (BN) patients, and tested for mutational signature differences in cohort iii. mRNA differential expression analysis (DEA) and pathway analysis were performed in cohort ii. RESULTS: Age at diagnosis was lower in BP vs. BN tumors in all cohorts in the ER- group, and only in cohort i for the ER + group. Signature 3 was universal in BP BC, whereas several signatures were associated with ER status. Pathway analysis was performed between BP&BN, and was significant only in ER- tumors: the major activated pathways involved cancer-related processes and were highly significant. The most significant pathway was estrogen-mediated S-phase entry and the most activated upstream regulator was ERBB2. CONCLUSION: Signature 3 was universal for all BP BC, while other signatures were associated with ER status. ER + BP& BN show similar genomic characteristics, ER- BP differed markedly from BN. This suggests that the initial carcinogenic process is universal for all BRCA carriers, but further insults lead to the development of two genomically distinct subtypes ER- and ER + . This may shed light on possible mechanisms involved in BP and carry preventive and therapeutic implications.

Utilizing fluorescent life time imaging microscopy technology for identify carriers of BRCA2 mutation.

Worldwide, more than one million women are diagnosed with breast cancer every year, making it the most common female malignancy in the developed world. Germline mutations in BRCA1 and BRCA2 genes are estimated to increase the risk for developing breast cancer by up to 87%. From a clinical point of view, identification of BRCA1 and BRCA2 mutation carriers offers an opportunity to early identify or prevent the development of malignancy; therefore the ability to determine which women are more likely to carry BRCA1 or BRCA2 mutations is of great importance. The available diagnostic tests for mutation analysis of BRCA1 and BRCA2 are time- and labor-intensive, expensive, and do not allow the identification of all the functional mutations. We utilized the Fluorescent lifetime (FLT) imaging microscopy method which allows recognizing different cell populations, in order to distinguish between lymphocytes from BRCA1 and BRCA2 mutation carriers and non-carrier women by using easily obtainable lymphocyte cells from peripheral blood. Our results demonstrate that cells originated from BRCA2-mutation carriers have significantly lower FLT values compared with BRCA1 mutation carriers and control cells. This simple, inexpensive and sensitive method may be utilized in the future to detect BRCA2 mutation carriers, particularly those bearing unknown functional mutations.

Lynch Syndrome in high risk Ashkenazi Jews in Israel.

Lynch Syndrome is caused by mutations in DNA mismatch repair genes. Diagnosis is not always trivial and may be costly. Information regarding incidence, genotype-phenotype correlation, spectrum of mutations and genes involved in specific populations facilitate the diagnostic process and contribute to clinical work-up. To report gene distribution, mutations detected and co-occurrence of related syndromes in a cohort of Ashkenazi Jews in Israel. Patients were identified in dedicated high risk clinics in 3 medical centers in Israel. Diagnostic process followed a multi-step scheme. It included testing for founder mutations, tumor testing, gene sequencing and MLPA. Lynch Syndrome was defined either by positive mutation testing, or by clinical criteria and positive tumor analysis. We report a cohort of 75 Ashkenazi families suspected of Lynch Syndrome. Mutations were identified in 51/75 (68%) families: 38 in MSH2, 9 in MSH6, and 4 in MLH1. 37/51 (73%) of these families carried one of the 3 'Ashkenazi' founder mutations in MSH2 or MSH6. Each of the other 14 families carried a private mutation. 3 (6%) were large deletions. Only 20/51 (39%) families were Amsterdam Criteria positive; 42 (82%) were positive for the Bethesda guidelines and 9 (18%) did not fulfill any Lynch Syndrome criteria. We report C-MMRD and co-occurrence of BRCA and Lynch Syndrome in our cohort. Mutation spectra and gene distribution among Ashkenazi Jews are unique. Three founder Lynch Syndrome mutations are found in 73% families with known mutations. Among the three, MSH2 and MSH6 are the most common. These features affect the phenotype, the diagnostic process, risk estimation, and genetic counseling.

Serum thymidine kinase 1 activity in breast cancer.

AIMS: Thymidine kinase 1 (TK1) is an enzyme involved in DNA synthesis and an important proliferation marker. We explored the association of preoperative serum TK1 activity with clinicopathological parameters and prognosis in terms of recurrence-free survival (RFS) in breast cancer (BC) patients. PATIENTS AND METHODS: TK1 activity in serum of 120 healthy women and 161 BC patients was measured by quantitative ELISA. RESULTS: Serum TK1 activity in BC patients was significantly higher than in healthy women (P < 0.0001). In BC patients elevated TK1 activity was significantly associated with advanced T stage (P = 0.015), higher grade (P = 0.013), presence of tumor necrosis (P = 0.006), vascular invasion (P = 0.002), and lack of estrogen receptor (ER) and progesterone receptor (PR) expression (P = 0.0004 and P = 0.003). Higher TK1 activity was found in patients with BRCA1/2 mutations compared to those without the mutation (P = 0.004). Multivariate Cox proportional hazards analyses demonstrated that TK1, adjusted for stage, grade, necrosis, ER and PR negativity was retained as an independent predictor of disease recurrence (Hazard Ratio = 3.9, 95%CI 1.3-11.6, P = 0.013). CONCLUSION: Elevated serum TK1 is an important risk factor indicating a high proliferation potential of tumors at the time of excision. In multivariate analysis TK1 activity was found to be an independent prognostic factor for RFS.

Relationship between severity of symptoms and quality of life in patients with breast cancer receiving adjuvant hormonal therapy.

PURPOSE/OBJECTIVES: To describe symptoms and quality of life (QOL) of patients with breast cancer receiving adjuvant hormonal therapy and to examine possible relationships between the two measurements. DESIGN: Descriptive, correlational study. SETTING: An oncology clinic within a tertiary medical center in Israel. SAMPLE: Convenience sample of 132 patients diagnosed with primary breast cancer receiving hormonal therapy. METHODS: Data collection was conducted through the self-administered Functional Assessment of Cancer Therapy endocrine subscale and a sociodemographic and medical information questionnaire. MAIN RESEARCH VARIABLES: QOL and symptoms of hormonal therapy. FINDINGS: Ten symptoms were categorized by more than 20% of the participants as "very much" or "quite a bit." The mean QOL score for the participants was higher than that for a healthy population, although a correlation was found between fewer symptoms and higher QOL. Mood swings and irritability were the symptoms most strongly associated with a decrease in QOL. Patients who exercised had higher QOL scores. CONCLUSIONS: Adjuvant hormonal therapy did not affect the QOL of a majority of patients with primary breast cancer. A reduced number of symptoms indicated a higher QOL. Mood swings and irritability have a negative impact on QOL. IMPLICATIONS FOR NURSING: A need exists to design a program to follow up on hormonal symptoms and the QOL of patients receiving hormonal therapy and to encourage patients to engage in regular exercise.

Ethnic ancestry and increased paternal age are risk factors for breast cancer before the age of 40 years.

To study the risk factors associated with breast cancer in women younger than 40 years, a cohort study (The Jerusalem Perinatal Study) of 42 822 female offspring born in hospitals in West Jerusalem during 1964-1976 was carried out. Hazard ratios of potential parental and perinatal risk factors for early breast cancer were measured. The overall incidence of breast cancer was 5.2/100 000 person-years. The highest incidence was found among Jewish women of West Asian ancestry (8.6/100 000 person-years), specifically those whose maternal grandfathers were born in Iraq, Iran or Afghanistan (9.5/100 000 person-years). Using Cox models we found independent risk factors for early breast cancer to be paternal age (relative risk/year=1.06, 95% confidence interval=1.02-1.10, P=0.005), and ancestry from Iraq/Iran/Afghanistan (relative risk=3.1, 95% confidence interval=1.50-6.52, P=0.002). The study confirms a previously observed effect of advanced paternal age on the occurrence of early breast cancer and identifies a novel population group at increased risk for the disease. The excess risk of early breast cancer associated with ancestry from Iraq, Iran and Afghanistan suggests involvement of genetic determinants, environmental exposures and/or lifestyle factors and mandates further investigation.

Prognostic factors for survival in metastatic breast cancer during first-line paclitaxel chemotherapy.

The prognostic value of various demographic, clinical and laboratory characteristics was investigated in 54 patients with metastatic breast cancer during first-line paclitaxel chemotherapy. As a single-agent treatment, paclitaxel (175 mg/m2) was given by 3-hour infusion every three weeks. The overall response rate was 30%. The follow-up ranged from 3 to 65 months (median 17 months). The most important pretreatment prognostic factors for survival were found to be hemoglobin (Relative Risk-2.26; p = 0.02) and serum lactic dehydrogenase (RR-1.81; p = 0.04) levels. The survival showed a strong association to the type of response. The median survival for responders was 5-fold greater than for patients with progressive disease (30.2 months and 5.7 months, respectively). Following the first-line paclitaxel treatment the estimates of tumor response became the major predictor of survival (RR-12.3; p < 0.0001).