Efficacy and safety of the therapeutic cancer vaccine tecemotide (L-BLP25) in early breast cancer: Results from a prospective, randomised, neoadjuvant phase II study (ABCSG 34).

BACKGROUND: Immune-based strategies represent a promising approach in breast cancer (BC) treatment. The glycoprotein mucin-1 (MUC-1) is overexpressed in more than 90% of BC patients, and is targeted by the cancer vaccine tecemotide. We have investigated the efficacy and safety of tecemotide when added to neoadjuvant standard-of-care (SoC) treatment in early BC patients. PATIENTS AND METHODS: A total of 400 patients with HER2-early BC were recruited into this prospective, multicentre, randomised 2-arm academic phase II trial. Patients received preoperative SoC treatment (chemotherapy or endocrine therapy) with or without tecemotide. Postmenopausal women with oestrogen receptor (ER)+++, or ER++ and Ki67 < 14%, and G1,2 tumours ('luminal A' tumours) received 6 months of letrozole. Postmenopausal patients with triple-negative, ER-/+/++ and Ki67 ≥ 14%, and with G3 tumours, as well as premenopausal patients, received four cycles of epirubicin/cyclophosphamide plus four cycles of docetaxel. Primary end-point was residual cancer burden (RCB; 0/I versus II/III) at surgery. Secondary end-points included pathological complete response (pCR), safety, and quality of life. FINDINGS: We observed no significant difference in RCB 0/I rates between patients with (36.4%) and without (31.9%) tecemotide in the overall study population (p = 0.40) nor in endocrine and chemotherapy-treated subgroups (25.0% versus 13.3%, p = 0.17; 39.6% versus 37.8%, p = 0.75, respectively). The addition of tecemotide did not affect overall pCR rates (22.5% versus 17.4%, p = 0.23), MUC-1 expression, or tumour-infiltrating lymphocytes content. Tecemotide did not increase toxicity when compared to SoC therapy alone. INTERPRETATION: Neoadjuvant tecemotide is safe, but does not improve RCB or pCR rates in patients receiving standard neoadjuvant therapy.

Association between family history, mutation locations, and prevalence of BRCA1 or 2 mutations in ovarian cancer patients.

We investigated the prevalence of germline BRCA mutations in a population-based cohort of Austrian women diagnosed with ovarian cancer and its association with family history of cancer. We prospectively collected family pedigrees of 443 Austrian ovarian cancer patients who had been tested for the presence of a germline BRCA or 2 mutations and correlated the familial breast and ovarian cancer burden with the prevalence of BRCA mutations and disease onset. The probability of carrying a gBRCA mutation in patients without family history of cancer is 14% (95% CI 9%-22%), as opposed to 45% (95% CI 31%-59%) of patients with at least one family member with ovarian cancer, and 47% (95% CI 40%-54%) if other relatives have developed breast cancer. If both breast and ovarian cancer are diagnosed in the family, the probability of carrying a germline BRCA1 or 2 mutations is 60% (95% CI 50%-68%). germline BRCA1 or mutations in families with ovarian cancer only are commonly located in the Ovarian Cancer Cluster Regions when compared to families with both breast and ovarian cancer (P = 0.001, and P = 0.020, respectively). While gBRCA mutation carriers with ovarian cancer do not have a significantly different age at onset than patients with a family history of cancer, gBRCA1 carriers in general have an earlier onset than gBRCA2 carriers (P = 0.002) and patients without a mutation (P = 0.006). The rate of germline BRCA1 or 2 mutations in ovarian cancer patients without a family history or breast or ovarian cancer is low. However, in women with additional family members affected, the prevalence is considerably higher than previously reported.

Improving comprehension of genetic counseling for hereditary breast and ovarian cancer clients with a visual tool.

OBJECTIVE: Genetic counseling and testing can be offered to individuals who are at high risk of carrying a breast cancer (BRCA) gene mutation. However, the content of genetic counseling could be difficult to understand due to complex medical information. The aim of this study was to investigate if comprehension can be improved with a new genetic counseling tool (NGCT hereafter; a tool that combines complex medical information with pictures, diagrams and tables) as compared to conventional oral-only genetic counseling (CGC). METHODS: 207 clients attended genetic counseling for hereditary breast and ovarian cancer at the Medical University of Vienna between February 2015 and February 2016. Seventy clients participated in this study and were allocated into two groups: the first 36 participants received conventional (oral only) genetic counseling (CGC) and the following 34 participants received genetic counseling using a new genetic counseling tool (NGCT), which combines complex information with pictures, diagrams and tables. After genetic counseling, all consenting participants were invited to complete a questionnaire with seven questions evaluating their comprehension of the medical information provided. RESULTS: Socio-demographic backgrounds were comparable in both groups. Correct responses were significantly higher in the NGCT group compared to the CGC group (p = 0.012). NGCT also statistically improves correct response of Q1 (p = 0.03) and Q7 (p = 0.004). CONCLUSION: The NGCT leads to an overall better understanding of the content of a genetic counseling session than CGC alone.

Changes of Socio-demographic data of clients seeking genetic counseling for hereditary breast and ovarian cancer due to the "Angelina Jolie Effect".

BACKGROUND: The purpose of this study was to evaluate socio-demographic characteristics of clients claiming genetic counseling for hereditary breast and ovarian cancer (HBOC) in Austria. Furthermore, changes of these parameters before and after Angelina Jolie's (AJ) disclosure of carrying a BRCA mutation were evaluated. METHODS: In this prospective, nonrandomized study 268 consecutive clients seeking genetic counseling for HBOC at the Medical University of Vienna, Department of Obstetrics and Gynecology, Vienna, Austria between June 2012 and June 2014 were included. Socio-demographic data and source of information about HBOC and genetic counseling were evaluated. First, socio-demographic parameters were compared to the general Austrian population. Second, changes in these parameters after AJ's public disclosure of carrying a BRCA mutation were analyzed. RESULTS: Subjects were more frequent female, younger and higher educated in comparison to Austria's general population (p < 0.001). Furthermore, level of education in participants was higher before than after AJ's disclosure (p = 0.046). Most clients were informed about genetic counseling by physicians. As expected, after AJ's public announcement patients were more frequent advised to genetic counseling by social media (p = 0.043) and family or friends (p = 0.010) than before. CONCLUSIONS: In this present study we could demonstrate that particularly younger and female participants with high educational level attended significantly more often genetic counseling for HBOC. Increased presence of HBOC in media since AJ's disclosure of carrying a BRCA mutation had lead that information and awareness about HBOC was obtained by a wider audience from different social background.

Profiling of Cross-Functional Peptidases Regulated Circulating Peptides in BRCA1 Mutant Breast Cancer.

Women with inherited BRCA1 mutations are more likely to develop breast cancer (BC); however, not every carrier will progress to BC. The aim of this study was to identify and characterize circulating peptides that correlate with BC patients carrying BRCA1 mutations. Circulating peptides were enriched using our well-designed nanoporous silica thin films (NanoTraps) and profiled by mass spectrometry to identify among four clinical groups. To determine the corresponding proteolytic processes and their sites of activity, purified candidate peptidases and synthesized substrates were assayed to verify the processes predicted by the MERPOS database. Proteolytic processes were validated using patient serum samples. The peptides, KNG1K438-R457 and C 3fS1304-R1320, were identified as putative peptide candidates to differentiate BRCA1 mutant BC from sporadic BC and cancer-free BRCA1 mutant carriers. Kallikrein-2 (KLK2) is the major peptidase that cleaves KNG1K438-R457 from kininogen-1, and its expressions and activities were also found to be dependent on BRCA1 status. We further determined that KNG1K438-R457 is cleaved at its C-terminal arginine by carboxypeptidase N1 (CPN1). Increased KLK2 activity, with decreased CPN1 activity, results in the accumulation of KNG1K438-R457 in BRCA1-associated BC. Our work outlined a useful strategy for determining the peptide-petidase relationship and thus establishing a biological mechanism for changes in the peptidome in BRCA1-associated BC.

Effect of lifestyle and reproductive factors on the onset of breast cancer in female BRCA 1 and 2 mutation carriers.

BACKGROUND: The birth year-dependent onset of breast cancer (BC) in BRCA1/2 mutation carriers suggests a risk-modifying role for reproductive and life style factors. We therefore examined possible associations between these factors and age at diagnosis. METHODS: Cox regression analysis and log-Rank testing were used to estimate the effect of potential life style factors on the onset of BC in 197 BRCA mutation carriers. RESULTS: Nulliparous BRCA mutation carriers developed BC earlier than those who had delivered (36.4 vs. 40.9; P = 0.001). Similarly, smokers and women who had used oral contraceptives experienced an earlier cancer onset (39.0 vs. 41.4; P = 0.05 and 39.3 vs. 44.9; P = 0.0001, respectively). In multivariate analysis, oral contraceptive use (HR: 1.7; P = 0.006) and birth cohort (< vs. ≥1965 HR: 4.5; P = 0.001) were associated with an earlier BC onset, while previous pregnancies led to a delay (HR: 0.2; P = 0.04). Mutation carriers born ≥1965 were less likely to have experienced pregnancies and more likely to have used oral contraceptives, and consequently developed BC at an earlier age (median age: 42 vs. 58; P < 0.0001 log-Rank test). CONCLUSION: We here demonstrate that in BRCA1/2 mutation carriers the birth cohort-associated differences in the onset of BC are profound and influenced by reproductive factors.

Triple-modality screening trial for familial breast cancer underlines the importance of magnetic resonance imaging and questions the role of mammography and ultrasound regardless of patient mutation status, age, and breast density.

PURPOSE: To evaluate the breast cancer screening efficacy of mammography, ultrasound, and magnetic resonance imaging (MRI) in a high-risk population and in various population subgroups. PATIENTS AND METHODS: In a single-center, prospective, nonrandomized comparison study, BRCA mutation carriers and women with a high familial risk (> 20% lifetime risk) for breast cancer were offered screening with mammography, ultrasound, and MRI every 12 months. Diagnostic performance was compared between individual modalities and their combinations. Further comparisons were based on subpopulations dichotomized by screening rounds, mutation status, age, and breast density. RESULTS: There were 559 women with 1,365 complete imaging rounds included in this study. The sensitivity of MRI (90.0%) was significantly higher (P < .001) than that of mammography (37.5%) and ultrasound (37.5%). Of 40 cancers, 18 (45.0%) were detected by MRI alone. Two cancers were found by mammography alone (a ductal carcinoma in situ [DCIS] with microinvasion and a DCIS with < 10-mm invasive areas). This did not lead to a significant increase of sensitivity compared with using MRI alone (P = .15). No cancers were detected by ultrasound alone. Similarly, of 14 DCISs, all were detected by MRI, whereas mammography and ultrasound each detected five DCISs (35.7%). Age, mutation status, and breast density had no influence on the sensitivity of MRI and did not affect the superiority of MRI over mammography and ultrasound. CONCLUSION: MRI allows early detection of familial breast cancer regardless of patient age, breast density, or risk status. The added value of mammography is limited, and there is no added value of ultrasound in women undergoing MRI for screening.

Histopathological characterization of ulcerated breast cancer and comparison to their non-ulcerated counterparts.

Approximately 6-15 % of breast cancer patients are diagnosed with primary ulcerated breast cancer (ULBC). ULBC is known to be associated with short recurrence free and poor overall survival. Therefore, the purpose of this study was to characterize ULBC and compare the histopathological findings with those of non-ulcerative breast cancer (NULBC). A total of 152 ULBCs were evaluated and compared to 304 consecutive non-ulcerated, age-matched breast malignancies. Patients mean age was 65 years (SD = 13.0 ULBC, SD = 14.0 NULBC). ULBC was associated with a higher rate of poorly differentiated tumors (p = < 0.001), as well as larger tumor sizes (p = < 0.001). As expected, the rate of axillary lymph node involvement was higher in ULBC patients (p = <0.001). In addition to that, ULBC was associated with a higher rate of triple negative breast cancer (p = 0.002), and higher Ki67 expression (p = < 0.001). ULBC showed more aggressive histopathological features in comparison to NULBC which may contribute to the generally known poorer prognosis of women with ULBC.

Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer.

BACKGROUND: Mutations in brca1 and 2 genes lead to a significant increase in the lifetime risk of developing breast (BC) and ovarian cancer (OC). There are indications that birth cohort can influence the cancer risk in brca1 mutation carriers. Therefore, we investigated the risks for BC and OC associated with brca2 mutations in a cohort of female mutation carriers of a genetically heterogeneous Central European population. PATIENTS AND METHODS: This study included 246 women in whom a functional mutation in the brca2 gene had been identified at our institution. At the time of analysis, 153 women had developed cancer (142 BC, 9 OC, 2 BC and OC). Risks were estimated using the product limit method. The log rank test was used to compare different strata. RESULTS: After correction for risk-reducing surgeries, the cumulative risk of developing cancer to age 70 was found to be 88% for BC (95% CI 81-95%) and 31% for OC (95% CI 17-45%). Female brca2 mutation carriers born in 1958 or later were at a significantly higher risk of developing BC at a younger age (p<0.001), while no such age cohort-dependent correlation was found for OC. CONCLUSION: The age cohort-dependent early onset in BC in women born after 1958 strongly suggests the importance of exogenous factors such as lifestyle modification while this does not seem to be the case for OC. Female brca2 mutation carriers should be counseled about their age cohort-dependent breast cancer risk.

Is breast cancer in young Asian women more aggressive than in Caucasians? A cross-sectional analysis.

Ethnic differences in breast cancer are well described in studies comparing Hispanic and African-American populations to Caucasian populations. The aim of this study was to analyze the biological characteristics of breast cancer (BC) in the young Asian/Han Chinese population compared to Caucasians/Central Europeans. Histopathologies of 642 invasive BC in women at the age of 40 years and younger were analyzed in China and Austria. Pearson's chi-squared test was used to assess differences in the analyzed populations. Significantly larger BC >2 cm (p < 0.0001) and poorly differentiated BC (p = 0.02) as well as more triple-negative BC (p = 0.002) were identified among the Han Chinese group compared to the Central European group. This analysis will provide ethnic-specific insight into the biological characteristics of BC in young patients worldwide.

Association of BRCA1/2 mutations with FMR1 genotypes: effects on menarcheal and menopausal age.

OBJECTIVE: Female BRCA (breast cancer gene)-1 and BRCA-2 mutations are significantly associated with risk of developing breast and ovarian cancers, in turn, associated with female infertility. BRCA-1 mutations have also been associated with occult primary ovarian insufficiency (OPOI), as have different mutations of the FMR1 gene. We, therefore, hypothesized that FMR1 genotypes may be associated with menarcheal and menopausal ages of BRCA mutation carriers. PATIENTS: We compared the FMR1 genotype and sub-genotype distribution in 99 BRCA1/2 positive women and in 182 healthy women without a known history of familial breast and ovarian cancer and searched for associations with age at menarche and menopause. T-test was used to assess differences in menarcheal and menopause ages, with times of menarche and menopause as continuous variables. RESULTS: Women with BRCA1/2 mutations showed significantly different FMR1 genotype and sub-genotype distributions when compared with the control group (p<0.001). This result remained stable in a sub-group analysis of Caucasian BRCA1/2 carriers and healthy controls (p<0.001). In addition, BRCA1/2 carriers indicated a trend toward shorter reproductive lifespan (p=0.18). CONCLUSIONS: Our data confirm the previously reported highly skewed distribution of FMR1 genotypes and sub-genotypes toward a high preponderance of low FMR1 alleles in BRCA1/2 carriers. We could demonstrate that BRCA-1 mutations are associated with an earlier onset of menopause compared to BRCA-2 carriers, although the distribution of the het-norm/low genotype is similar in both groups. Our findings suggest that there may be other factors beside the genotype that has an influence on menarche and especially menopause age in BRCA mutation carriers.

A cross-sectional study of elderly Asian and European women with primary operable breast cancer aged 70 and older. Are there differences?

BACKGROUND: Breast cancer (BC) is becoming a disease of the elderly. Additionally, BC-incidence is rising in Asia. The aim of this study was to explore clinico-pathological characteristics and differences of breast cancer in elderly Asian/Han-Chinese compared to Caucasian/Austrian women. METHODS: A total number of 630 consecutive primary operable, unilateral breast cancer cases, 70 years and older, were analyzed. Histo-pathological findings and biological characteristics of 198 Caucasian/Austrian were compared with 432 Asian/Han-Chinese. Pearson's chi-square test was used to assess differences in the analyzed populations. RESULTS: A significantly higher rate of triple-negative BC (p=0.027) was diagnosed among the Chinese geriatric population. More estrogen-receptor positive BC was detected in the Caucasian study group (p<0.001). No statistically significant differences were detected based on tumor size, axillary lymph-node status, nor HER2-receptor expression. CONCLUSION: This study will help us gain additional ethnic-specific insight into the biological characteristics of breast cancer in the elderly Caucasian/Austrian and Asian/Han-Chinese populations.

Robust multi-parameter single-platform quantification of myeloid and B-lymphoid CD34 progenitor cells in all clinical CD34 cell sources and in thawed PBSC.

As B-lymphoid progenitor cells do not give rise to in vitro colony formation and are unlikely to support myeloid engraftment, we validated a five-color extension of the single platform Stem Cell Enumeration (SCE) kit, to routinely quantify myeloid and B-lymphoid progenitor cells. Fresh samples (n > 20 each) of granulocyte colony stimulating factor mobilized blood (peripheral blood (PB)), cord blood (CB), bone marrow (BM), and apheresis products (APs) were stained in TruCOUNT™ tubes and the results were compared with those from the two-color CD45/CD34 reagent combination and the three-color SCE kit. To address repeatability, 10 samples from one AP were prepared by four technicians. Aliquots (n = 15) of four frozen AP were analyzed after thawing. Excellent correlations were observed between the three kits (R(2) > 0.99), for the quantification of white blood cells and total CD34. The extended kit showed considerable amounts of B-lymphoid progenitors in all CD34 sources (0-20% of all CD34 in PB, AP, and CB; 3-90% in BM). Very similar results were obtained when the same sample was prepared by different technicians. After thawing of frozen AP, the recovery of viable cells varied depending on the freezing medium employed, but the results from the different quantification methods were identical. Most non-viable cells were clearly identified with 7 Aminoactinomycin D (7AAD) but an additional gate in the forward scatter/side scatter was necessary to address dead cells negative for 7AAD. The extended SCE kit allows rapid and exact quantification of viable B-lymphoid and myeloid CD34(+) cells in all cell sources and in thawed stem cell harvests, and may thus improve the correlation between CD34 number and engraftment kinetics.

BRCA1/2 mutations appear embryo-lethal unless rescued by low (CGG n<26) FMR1 sub-genotypes: explanation for the "BRCA paradox"?

BRCA1/2 mutations and recently described constitutional FMR1 genotypes have, independently, been associated with prematurely diminished ovarian reserve. Whether they interrelate in distribution, and whether observed effects of BRCA1/2 and FMR1 on ovaries are independent of each other, is unknown. In a prospective comparative cohort study, we, therefore, investigated the distribution of constitutional FMR1 genotypes, normal (norm), heterozygous (het) and homozygous (hom), and of their respective sub-genotypes (high/low), in 99 BRCA1/2 mutation-positive women and 410 female controls to determine whether distribution patterns differed between study and control patients. In contrast to controls, BRCA1/2 carriers demonstrated almost complete absence of all constitutional FMR1 genotypes except for sub-genotypes with low (CGG (n<26)) alleles. Cross tabulation between BRCA1/2-positive patients and controls confirmed significant group membership, related to FMR1 distribution (P<0.0001). These results offer as most likely explanation the conclusion that BRCA1/2 mutations are embryo-lethal, unless rescued by low (CGG (n<26)) FMR1 sub-genotypes, present in approximately one quarter of all women. Women with low FMR1 sub-genotypes, therefore, should reflect increased BRCA1/2-associated cancer risks, while the remaining approximately 75 percent should face almost no such risks. If confirmed, this observation offers opportunities for more efficient and less costly BRCA1/2 cancer screening. The study also suggests that previously reported risk towards prematurely diminished ovarian reserve in association with BRCA mutations is FMR1-mediated, and offers a possible explanation for the so-called "BRCA paradox" by raising the possibility that the widely perceived BRCA1/2-associated tumor risk is actually FMR1-mediated.

[Guideline for the prevention and early detection of breast and ovarian cancer in high risk patients, particularly in women from HBOC (hereditary breast and ovarian cancer) families]. / Leitlinie zur Prävention und Früherkennung von Brust- und Eierstockkrebs bei Hochrisikopatientinnen, insbesondere bei Frauen aus HBOC (Hereditary Breast and Ovarian Cancer) Familien.

The Austrian guideline for prevention and early detection of breast and ovarian cancer in high risk patients--particularly in women from hereditary breast and ovarian cancer families--were established with particular consideration of the most recent position paper of the European Society of Breast Cancer Specialists (EUSOMA) by the authors mentioned above. The guideline is aimed at facilitating and standardizing the care and early detection strategies in women with an elevated life time risk for breast and ovarian cancer.

Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1-Interacting Genes.

Inherited BRCA1 mutations confer elevated cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (P(FDR)) with breast cancer were identified at ATM (P(FDR) = 0.029), BRCC45 (P(FDR) = 0.019), BRIP1 (P(FDR) = 0.008), CTIP (P(FDR) = 0.017), MERIT40 (P(FDR) = 0.019), NBS1 (P(FDR) = 0.003), RAD50 (P(FDR) = 0.014), and TOPBP1 (P(FDR) = 0.011). Haplotypes at ABRA1 (P(FDR) = 0.007), BRCC45 (P(FDR) = 0.016 and P(FDR) = 0.005 in two haplotype blocks), and RAP80 (P(FDR) < 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.

The predictive value of suspicious sonographic characteristics in atypical cyst-like breast lesions.

BACKGROUND AND PURPOSE: Simple breast cysts are a common sonographic finding and do not require further diagnostic evaluation. In contrast, atypical breast cysts do harbour a risk of malignancy. The purpose of this study was to evaluate the predictive value of sonographic findings that are considered characteristic of malignant atypical cyst-like lesions. PATIENTS AND METHODS: Six descriptive sonographic criteria of 202 atypical cysts in 176 women were compared with histopathological findings after surgical excision and their statistical association was evaluated. RESULTS: Of these six criteria thick cyst wall (p < 0.0001), lobulation (p = 0.0001) and hyperechogenicity (p = 0.003) were found to be highly predictive of breast cancer. The presence of two or more sonographic criteria was associated with a 10.3 times greater risk of malignancy (p < 0.0001). CONCLUSION: The association between suspicious sonographic criteria and histology after surgery was evaluated. We propose surgical excision when two or more sonographic criteria are diagnosed in a single atypical breast cyst.

Assessment of a six gene panel for the molecular detection of circulating tumor cells in the blood of female cancer patients.

BACKGROUND: The presence of circulating tumor cells (CTC) in the peripheral blood of cancer patients has been described for various solid tumors and their clinical relevance has been shown. CTC detection based on the analysis of epithelial antigens might be hampered by the genetic heterogeneity of the primary tumor and loss of epithelial antigens. Therefore, we aimed to identify new gene markers for the PCR-based detection of CTC in female cancer patients. METHODS: Gene expression of 38 cancer cell lines (breast, ovarian, cervical and endometrial) and of 10 peripheral blood mononuclear cell (PBMC) samples from healthy female donors was measured using microarray technology (Applied Biosystems). Differentially expressed genes were identified using the maxT test and the 50% one-sided trimmed maxT-test. Confirmatory RT-qPCR was performed for 380 gene targets using the AB TaqMan® Low Density Arrays. Then, 93 gene targets were analyzed using the same RT-qPCR platform in tumor tissues of 126 patients with primary breast, ovarian or endometrial cancer. Finally, blood samples from 26 healthy women and from 125 patients (primary breast, ovarian, cervical, or endometrial cancer, and advanced breast cancer) were analyzed following OncoQuick enrichment and RNA pre-amplification. Likewise, hMAM and EpCAM gene expression was analyzed in the blood of breast and ovarian cancer patients. For each gene, a cut-off threshold value was set at three standard deviations from the mean expression level of the healthy controls to identify potential markers for CTC detection. RESULTS: Six genes were over-expressed in blood samples from 81% of patients with advanced and 29% of patients with primary breast cancer. EpCAM gene expression was detected in 19% and 5% of patients, respectively, whereas hMAM gene expression was observed in the advanced group (39%) only. Multimarker analysis using the new six gene panel positively identified 44% of the cervical, 64% of the endometrial and 19% of the ovarian cancer patients. CONCLUSIONS: The panel of six genes was found superior to EpCAM and hMAM for the detection of circulating tumor cells in the blood of breast cancer, and they may serve as potential markers for CTC derived from endometrial, cervical, and ovarian cancers.

Surgical breast lesions in adolescent females.

PURPOSE: Breast diseases in teenage girls are fortunately uncommon, with most presenting masses being benign. The aim of this study was to evaluate the histopathological results of breast lesions excised from adolescent females less than 19 years of age. METHODS: The authors reviewed the medical and pathology records at the University Hospital of Vienna, Department of Obstetrics and Gynaecology, between 1993 and 2006, retrospectively. All data included the patient age, age of menarche, pregnancy, hormonal contraception, family history of breast cancer, size of the breast lesion and its histopathology following surgery. RESULTS: Thirty-seven female patients with an average age of 16 years (ranging 12-18 years) were operated on for breast tumor and/or discharge. All tumors were palpable. Six patients had bilateral breast masses; thus, 43 breast lesions were evaluated following surgical excision. Surprisingly, breast cancer was found in two cases. Both patients were diagnosed with a noninvasive ductal carcinoma in situ (DCIS) within a fibroadenoma at the age of 16. These are the first reported cases of DCIS found in this young age group. As breast neoplasm was found in two cases, a malignancy rate of 4.7% was observed. The most common histologies were fibroadenoma (n=27) and fibrocystic disease (n=4). CONCLUSION: The incidence of primary breast cancer in adolescent women is low. However, our experience shows the need for compulsory excision of all breast masses and highlighting the importance of histopathological evaluation of all breast tumors including adolescents.

The validity of complex breast cysts after surgery.

BACKGROUND: Breast cysts are the most common cause of benign breast masses. Simple breast cysts do not need further evaluation, but complex breast cysts require additional assessment due to the potential presence of malignancy. However, these complex cysts have rarely been examined and quantified according to the associated cancer detection rate. Our study is the first investigation to evaluate the malignancy rate of complex breast cysts identified by histopathological results. METHODS: Imaging findings of complex cysts were correlated retrospectively with clinical and pathologic outcomes. We detected a malignancy rate of 14%. Sonographic criteria of a complex cyst such as thick cyst wall (P = .0006), lobulation (P = .01), and hyperechogenicity (P = .04) were predictive of neoplasm. Two or more criteria combined were associated with a 13.6-fold higher risk of malignancy (P <.0001). CONCLUSION: Based on our results we reinforce the importance of adequate assessment of complex breast cysts to prevent a missed or delayed diagnosis of malignancy.