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Background: Several prognostic clinical and pathological characteristics have been reported to be independently associated with survival in metastatic breast cancer (MBC). Circulating tumor cells (CTCs) isolated by CellSearch® from peripheral blood of MBC patients was shown to be an additional strong independent prognostic factor for survival and progression of disease. The aim of this study was to combine CTC and other predictors in a nomogram that would allow clinicians to assess, on an individual basis, the prognosis of patients starting first-line chemotherapy for MBC. Patients and Methods: CTCs were counted before the start of treatment using the US Food and Drug Administration-cleared CellSearch® technology. We used a training set of 237 MBC patients starting a first line chemotherapy from the MD Anderson Cancer Center (MDACC, Houston, TX, USA), and nomograms were established to calculate the predicted probability of overall survivals (OS) at 1, 2 and 3 years. These nomograms were externally validated using an independent data set of 260 patients starting a first line chemotherapy from the prospective Institut Curie 2006-04 study (Paris, France). Discriminatory ability of the models was assessed using Harrell's c-statistic examining the model in the training sample (U.S. data) and the validation sample (French data). Accuracy of the nomograms was assessed both within the training sample and the validation sample via calibration plots at 1, 2 and 3 years. Covariates computed in the model were: age, subtype of disease, presence of visceral metastasis, bone metastasis, performance status, and CTCs. Results: Tablei describes patient characteristics. Median follow-up was of 24.5 and 29 months, respectively in the MDACC and Institut Curie. The C-statistics for OS was 0.7338 in the training set and 0.7229 in the validation set. For the calibration plots, we averaged Cox predictions at two years within the quintiles of the ordered predictions. Within each quintile, we also estimated the unadjusted probability of death using Kaplan-Meier survival estimators. We then plotted unadjusted versus model average predictions at 1, 2 and 3 years. The nomograms discriminated OS prediction at 1, 2 and 3 years very well. Conclusions: Patients with first-line MBC present a wide range of survival duration, and our ability to assess prognosis and predict risks of progression and death on the basis of clinic-pathologic findings is limited. The validated nomograms represent an important tool for estimating prognosis, support treatment-decisions and clinical trial stratification in MBC. [ABSTRACT FROM AUTHOR]

BACKGROUND: Preliminary evidence suggests that many girls from breast cancer (BC) families are aware of their increased risk for BC. How this awareness impacts their psychosocial adjustment and health behaviors remains unknown. METHODS: 11-19 YO girls at high-risk (HR) or population-risk (PR) for BC completed self- administered quantitative surveys informed by the Self-Regulation Theory of Health Behavior. Girls with a first or second-degree relative with BC were classified as HR. For hypothesis testing, we used simple linear and logistic regressions. To account for correlation of responses within families, we used robust (cluster-corrected) standard errors or Generalized Estimating Equations. RESULTS: 47 PR and 89 HR girls have completed surveys. Age did not differ between groups (Mage = 15.6; SD=2.4). 30% of HR girls have a mother with BC. 67% of HR girls vs. 30% of PR girls reported self-perceived risk for adult BC to be "higher than other girls my age," (p = <0.01, Table 1). Perceived risk was associated with an increasing number of first and second-degree relatives with BC (p = 0.002) and older age (p = 0.01). There was no evidence that the relationship between perceived risk and age was moderated by risk status (p = 0.740 for interaction terms). The majority of both HR and PR girls reported that there are things women and girls their age can do to prevent BC. (table 1) Perceived controllability of BC did not differ significantly by age or risk status. HR girls reported higher general anxiety (p = 0.07), but not depression than PR girls. HR girls more frequently reported tobacco use than PR girls (p = 0.05). HR girls also reported greater alcohol use, more frequent performance of self-breast exams and less frequent physical activity than PR girls, although these differences were not significant. CONCLUSION: Girls from BC families are more likely to perceive themselves to be at increased risk for BC, to experience more general anxiety, and to have engaged more frequently in risk behaviors, particularly tobacco use. The majority of girls perceive BC to be preventable both for women in general and for themselves, suggesting a potential "teachable moment" among adolescents that might be sustainable across the lifespan. Further research evaluating knowledge and perceptions of breast cancer risk throughout adolescent development and differences among subgroups could inform strategies to optimize adolescent psychosocial responses to hereditary cancer risk and promote preventive health behaviors among both HR and PR girls. [ABSTRACT FROM AUTHOR]

The Neural precursor cell-Expressed Developmentally Downregulated gene 9 (NEDD9; also HEF1, CAS-L) scaffolding protein regulates many signaling pathways associated with mitosis, survival, migration, and ciliary integrity. Within the last few years, elevated NEDD9 expression has been implicated in progression and metastasis of several types of cancer, including those of the lung, skin, and brain. We have investigated the consequences of introducing a Nedd9 genotype into the MMTV-neu mouse mammary tumor model, which in many respects recapitulates features of human HER2+ breast cancer. 80% of wild-type MMTV-Neu; Nedd9+/+ animals developed tumors with an average latency of 339 days, but only 18% of MMTV-Neu;Nedd9-/- animals developed tumors with an average latency of 416 days. This highly significant difference indicates that the Nedd9-/- genotype significantly prevents neu- dependent mammary tumor formation. HER2-positive human breast tumors and MMTV-neu-induced tumors originate from mammary luminal epithelial progenitor cells. We evaluated mammary progenitor cell populations from non-tumor bearing MMTV-neu;Nedd9-/- versus MMTV-neu;Nedd9+/+ 4-month old mice (2 months prior to appearance of tumors). Flow cytometry analysis indicated a significantly reduced CD24high;CD49flow luminal progenitor subpopulation in MMTV-neu;Nedd9-/- and Nedd9-/- mammary glands, that could be contributed to the tumorigenesis resistance in the MMTV-neu;Nedd9-/- model. The MMTV-neu;Nedd9-/-genotype negatively affected the Matrigel mammosphere colony-forming potential of luminal progenitor cells compared to MMTV-neu; Nedd9+/+cells, causing formation of fewer colonies with aberrant size and morphology. Quantification of mitotic division planes of MMTV-neu;Nedd9-/- mammospheres revealed no contribution to the observed defects. However, MMTV-neu;Nedd9-/- mammospheres had defective expression of signaling proteins governing cell attachment, with reduced levels of FAK and more cytoplasmic localization of SRC. The results reported above, together with other data, support three main conclusions. First, they revealed a very substantial requirement for Nedd9 during early stages of HER2/neu- dependent tumor formation. Second, these results are the first to demonstrate a role for Nedd9 in supporting the abundance and colony-forming potential of mammary luminal progenitor cells. Third, they indicate that the defects in mammosphere growth likely involve perturbation of crucial cellular attachment signaling pathways involving FAK and SRC. In sum, these data provide a strong justification for future analysis of NEDD9 in the defective signaling of transformed mammary epithelial progenitor cell populations that initiate human breast cancer. [ABSTRACT FROM AUTHOR]

Background: Sentinel lymphadenectomy is the standard of care for evaluation of the axilla in breast cancer. Not infrequently, despite a clinically negative axilla, axillary nodes are found and removed that are only palpable intraoperatively at the time of sentinel lymph node biopsy. There is limited data suggesting that their resection is beneficial, and there is some controversy over whether these non-hot, non-blue nodes should also be called "sentinel nodes" (SNs). Methods: A retrospective chart review was conducted of breast cancer patients who underwent sentinel lymph node biopsy from 2007 to 2011 at a single institution. Patients were only included if they had SNs removed (defined as blue and/or radioactive nodes), as well as additional non-sentinel nodes that were only palpable intraoperatively (pNSNs) and not part of an axillary dissection (ALND). Pathology of both SNs and pNSNs were reviewed. Histologic nodal evaluation was performed by H&E alone. Results: From 2007 to 2011, a total of 59 patients had both SNs and pNSNs removed. Fifty-five patients (93.2%) were female and the average age was 55 years old. Fifty-two patients (88.1 %) had invasive ductal carcinoma while 7 had lobular carcinoma (11.9%). Average tumor size was 2.0 cm. Among the 59 patients, a total of 109 SNs (mean 1.8, median 1, range 1-6) and 202 pNSNs (mean 3.4, median 2, range 1-30) were removed at the same surgery. Twenty patients (33.9%) had metastases in either the SNs and/or pNSNs with 16 (80.0%) of these having metastases in the SNs alone. Sixteen patients proceeded to an ALND. There were 4 patients (6.8%, 95% CI 1.9-16.5%) who had SNs negative for tumor but pNSNs positive for tumor, and 4 (6.8%, 95% CI 1.9-16.5%) separate patients who had extracapsular extension (ECE) in their pNSNs but no ECE in the SNs. The pNSNs thus provided information altering operative treatment by American College of Surgeons Oncology Group (ACOSOG) Z0011 trial criteria in 8 patients (13.6%). Two patients (3.4%, 95% CI 0.4-11.7%) had ECE present in ALND nodes, but not present in either their SNs or pNSNs. Conclusion: pNSNs provide information that changes the surgical plan by ACOSOG Z0011 criteria in 14% of cases. Whether their removal changes patient outcomes remains unclear, especially as SNs and pNSNs may, together, be falsely-negative for ECE present within the axilla. While we recommend their removal at this time based upon the added information they provide, further study is required to determine whether the changes resulting from pNSN dissection (i.e. need for ALND) provide any outcome benefit in this era of effective systemic therapy. [ABSTRACT FROM AUTHOR]

"Race-specific" prostate-specific antigen (PSA) needs evaluation in men at high risk for prostate cancer for optimizing early detection. Baseline PSA and longitudinal prediction for prostate cancer were examined by self-reported race and genetic West African (WA) ancestry in the Prostate Cancer Risk Assessment Program, a prospective high-risk cohort. Eligibility criteria were age 35 to 69 years, family history of prostate cancer, African American race, or BRCA1/2 mutations. Biopsies were done at low PSA values (<4.0 ng/mL). WA ancestry was discerned by genotyping 100 ancestry informative markers. Cox proportional hazards models evaluated baseline PSA, self-reported race, and genetic WA ancestry. Cox models were used for 3-year predictions for prostate cancer. Six hundred forty-six men (63% African American) were analyzed. Individual WA ancestry estimates varied widely among self-reported African American men. Race-specific differences in baseline PSA were not found by self-reported race or genetic WA ancestry. Among men with > or =1 follow-up visit (405 total, 54% African American), 3-year prediction for prostate cancer with a PSA of 1.5 to 4.0 ng/mL was higher in African American men with age in the model (P = 0.025) compared with European American men. Hazard ratios of PSA for prostate cancer were also higher by self-reported race (1.59 for African American versus 1.32 for European American, P = 0.04). There was a trend for increasing prediction for prostate cancer with increasing genetic WA ancestry. "Race-specific" PSA may need to be redefined as higher prediction for prostate cancer at any given PSA in African American men. Large-scale studies are needed to confirm if genetic WA ancestry explains these findings to make progress in personalizing prostate cancer early detection.

Background: We have previously reported nuclear localization of epidermal growth factor receptor (EGFR) protein in oropharyngeal cancer tissue. Nuclear EGFR levels were inversely correlated with survival and response to radiotherapy. Here, we sought to identify the determinants and correlates of nuclear EGFR content., Methods: We analyzed an oropharyngeal cancer tissue microarray for the expression of the key molecules of the EGFR signaling cascade using an automated image analysis technique (AQUA) scored on a scale of 0 to 255, which permits protein quantitation and subcellular localization. Patients with oropharyngeal squamous cell cancer treated with radiotherapy or surgery and radiotherapy were eligible. Data were analyzed using Spearman correlations and multiple linear regression with robust SEs., Results: Of the 95 tumors included in this study, 72 (75%) had sufficient tissue for analysis of nuclear EGFR. Nuclear EGFR levels were associated with membranous/cytoplasmic EGFR levels (rho = 0.82, P < 0.001), nuclear extracellular signal-regulated kinase-2 (rho = 0.30, P = 0.01), and nuclear proliferating cell nuclear antigen (PCNA; rho = 0.36, P = 0.003). Nuclear phosphorylated-Akt, cyclin D1, phosphatase and tensin homolog (mutated in multiple cancers 1) (PTEN), p53, and proliferation marker Ki-67 levels did not correlate with nuclear EGFR level. In multivariable analysis, only PCNA retained its significant association (P = 0.01)., Conclusions: These results are consistent with preclinical data showing that EGFR may function as a tyrosine kinase in the nucleus, phosphorylating and stabilizing PCNA. The nuclear activity of EGFR may constitute a novel therapeutic target.