Search

Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

While the role of G-protein–coupled receptors (GPCR) in cancer is acknowledged, their underlying signaling pathways are understudied. Protease-activated receptors (PAR), a subgroup of GPCRs, form a family of four members (PAR1–4) centrally involved in epithelial malignancies. PAR4 emerges as a potent oncogene, capable of inducing tumor generation. Here, we demonstrate identification of a pleckstrin-homology (PH)-binding motif within PAR4, critical for colon cancer growth. In addition to PH–Akt/PKB association, other PH-containing signal proteins such as Gab1 and Sos1 also associate with PAR4. Point mutations are in the C-tail of PAR4 PH-binding domain; F347 L and D349A, but not E346A, abrogate these associations. Pc(4–4), a lead backbone cyclic peptide, was selected out of a mini-library, directed toward PAR2&4 PH-binding motifs. It effectively attenuates PAR2&4–Akt/PKB associations; PAR4 instigated Matrigel invasion and migration in vitro and tumor development in vivo. EGFR/erbB is among the most prominent cancer targets. AYPGKF peptide ligand activation of PAR4 induces EGF receptor (EGFR) Tyr-phosphorylation, effectively inhibited by Pc(4–4). The presence of PAR2 and PAR4 in biopsies of aggressive breast and colon cancer tissue specimens is demonstrated. We propose that Pc(4–4) may serve as a powerful drug not only toward PAR-expressing tumors but also for treating EGFR/erbB-expressing tumors in cases of resistance to traditional therapies. Overall, our studies are expected to allocate new targets for cancer therapy. Pc(4–4) may become a promising candidate for future therapeutic cancer treatment.

Supplementary Figure from PH-Binding Motif in PAR4 Oncogene: From Molecular Mechanism to Drug Design

Supplementary Table from PH-Binding Motif in PAR4 Oncogene: From Molecular Mechanism to Drug Design

Over the past two decades there have been significant developments in the fields of laboratory technology, genetics and bioinformatics. These developments have raised the attractiveness of liquid biopsy - a test aimed to detect tumor markers in body fluids. One of the liquid biopsy methods is based on identification of circulating tumor DNA - fragments of DNA originating from the tumor which are evident in the bloodstream - revealing the various tumor characteristics via simple blood tests. This novel approach has several advantages over the traditional biopsy: it is noninvasive and thus more convenient and safer for the patient; it reflects the characteristics of the entire tumor tissue present in the patient's body in a single test; it is performed quickly and safely by a phlebotomist and does not rely on the subjective interpretation of the pathologist. The liquid biopsy is a highly valuable tool for the diagnosis and monitoring of cancer, which can be recruited for the clinical management of breast cancer - the most common malignancy in females which is estimated to affect one in every eight women. In this review we will present the existing and the potential applications of the liquid biopsy in breast cancer patients, regarding the various settings of patient care - diagnosis, treatment and follow-up.

Background: Cell-free DNA (cfDNA) molecules circulating in blood are emerging as important non-invasive biomarkers for monitoring physiological and pathological processes. Tumor-derived circulating cell-free DNA (cfDNA) is present in the plasma of individuals with cancer. Assays aimed at detecting common cancer mutations in cfDNA are being developed for the detection of multiple cancer types. In breast cancer, however, such assays have failed to detect the disease at a sensitivity relevant for clinical use, in part due to the absence of multiple common mutations that can be co-detected in plasma. Unlike individual mutations that exist in only a subset of tumors, unique DNA methylation patterns are universally present in cells of a common type and therefore may be ideal biomarkers. Here we describe the detection and quantification of breast derived cfDNA, using a breast-specific DNA methylation signature. Methods: In order to identify regions of the genome with unique methylation patterns in breast epithelium, we compared genome-wide methylation profiles of normal breast tissue and breast cancer to genome-wide methylation profiles of other normal and cancerous tissues and aimed to identify CpG sites that are uniquely hypermethylated or hypomethylated in the breast. By quantifying the proportion of molecules in a sample that harbored 3 chosen breast-specific methylation sites, we could obtain an estimate of the proportion of the sample derived from breast epithelial cells. We have collected plasma prospectively from healthy women, metastatic breast cancer patients and patients with localized (stage II-III) breast cancer who were assigned to preoperative chemotherapy at our cancer institute. In the latter cohort, samples were collected before and throughout treatment until surgery. The trial was approved by the Institutional Ethics Committee and all patients gave written informed consent. Results: All three markers clearly distinguished between the plasma of healthy donors (n=64) and patients with metastatic disease (n=14, p-value Conclusion: A breast-unique epigenetic signature in circulating cell-free DNA can be used as a universal biomarker for breast cancer, to allow sensitive detection and monitoring of localized breast cancer treatment outcomes. Further research will aid to evaluate this promising and affordable method in additional clinical scenarios. Citation Format: Albert Grinshpun, Aviad Zick, Joshua Moss, Einat Carmon, Myriam Maoz, Bracha Ohana, Ofri Abraham, Lili Germansky, Benjamin Glaser, Ruth Shemer, Yuval Dor, Beatrice Uziely. Non-personalized detection of circulating breast-derived DNA for monitoring of preoperative breast cancer treatment [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-10.

The likelihood of recurrence in breast cancer patients with hormone receptor-positive (HR-positive) tumors is influenced by clinical, histopathological, and molecular features. Recent studies suggested that activated STAT3 (pSTAT3) might serve as a biomarker of outcome in breast cancer patients. In the present work, we have analyzed the added value of pSTAT3 to OncotypeDx Recurrence Score (RS) in patient prognostication. We have found that patients with low RS (

ERBB2 amplification is a prognostic marker for aggressive tumors and a predictive marker for prolonged survival following treatment with HER2 inhibitors. We attempt to sub-group HER2+ tumors based on amplicon structures and co-amplified genes. We examined five HER2+ cell lines, three HER2+ xenographs and 57 HER2+ tumor tissues. ERBB2 amplification was analyzed using digital droplet PCR and low coverage whole genome sequencing. In some HER2+ tumors PPM1D, that encodes WIP1, is co-amplified. Cell lines were treated with HER2 and WIP1 inhibitors. We find that inverted duplication is the amplicon structure in the majority of HER2+ tumors. In patients suffering from an early stage disease the ERBB2 amplicon is composed of a single segment while in patients suffering from advanced cancer the amplicon is composed of several different segments. We find robust WIP1 inhibition in some HER2+ PPM1D amplified cell lines. Sub-grouping HER2+ tumors using low coverage whole genome sequencing identifies inverted duplications as the main amplicon structure and based on the number of segments, differentiates between local and advanced tumors. In addition, we found that we could determine if a tumor is a recurrent tumor or second primary tumor and identify co-amplified oncogenes that may serve as targets for therapy.

ERBB2 amplification is a prognostic marker for aggressive tumors and a predictive marker for prolonged survival following treatment with HER2 inhibitors. We attempt to sub-group HER2+ tumors based on amplicon structures and co-amplified genes. We examined five HER2+ cell lines, three HER2+ xenographs and 57 HER2+ tumor tissues. ERBB2 amplification was analyzed using digital droplet PCR and low coverage whole genome sequencing. In some HER2+ tumors PPM1D, that encodes WIP1, is co-amplified. Cell lines were treated with HER2 and WIP1 inhibitors. We find that inverted duplication is the amplicon structure in the majority of HER2+ tumors. In patients suffering from an early stage disease the ERBB2 amplicon is composed of a single segment while in patients suffering from advanced cancer the amplicon is composed of several different segments. We find robust WIP1 inhibition in some HER2+ PPM1D amplified cell lines. Sub-grouping HER2+ tumors using low coverage whole genome sequencing identifies inverted duplications as the main amplicon structure and based on the number of segments, differentiates between local and advanced tumors. In addition, we found that we could determine if a tumor is a recurrent tumor or second primary tumor and identify co-amplified oncogenes that may serve as targets for therapy.

G protein-coupled receptors (GPCRs) comprise the main signal-transmitting components in the cell membrane. Over the past several years, biochemical and structural analyses have immensely enhanced our knowledge of GPCR involvement in health and disease states. The present review focuses on GPCRs that are cancer drivers, involved in tumor growth and development. Our aim is to highlight the involvement of stabilized β-catenin molecular machinery with a specific array of GPCRs. We discuss recent advances in understanding the molecular path leading to β-catenin nuclear localization and transcriptional activity and their implications for future cancer therapy research.

// Jeetendra Kumar Nag 1 , Arun Kancharla 1 , Myriam Maoz 1 , Hagit Turm 1 , Daniel Agranovich 1 , Chhedi Lal Gupta 2 , Beatrice Uziely 1 and Rachel Bar-Shavit 1 1 Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel 2 Department of Biosciences, Integral University, Lucknow, Uttar Pradesh 226026, India Correspondence to: Rachel Bar-Shavit, email: Rachelbar@ekmd.huji.ac.il Keywords: protease-activated receptors (PARs), protease, G-protein coupled receptors (GPCRs), cancer, β-catenin stabilization Received: April 14, 2016 Accepted: February 17, 2017 Published: March 16, 2017 ABSTRACT Protease-activated receptor-2 (PAR 2 ) plays a central role in cancer; however, the molecular machinery of PAR 2 -instigated tumors remains to be elucidated. We show that PAR 2 is a potent inducer of β-catenin stabilization, a core process in cancer biology, leading to its transcriptional activity. Novel association of low-density lipoprotein-related protein 6 (LRP6), a known coreceptor of Frizzleds ( Fz ), with PAR 2 takes place following PAR 2 activation. The association between PAR 2 and LRP6 was demonstrated employing co-immunoprecipitation, bioluminescence resonance energy transfer (BRET), and confocal microscopy analysis. The association was further supported by ZDOCK protein-protein server. PAR 2 -LRP6 interaction promotes rapid phosphorylation of LRP6, which results in the recruitment of Axin. Confocal microscopy of PAR 2 -driven mammary gland tumors in vivo , as well as in vitro confirms the association between PAR 2 and LRP6. Indeed, sh RNA silencing of LRP6 potently inhibits PAR 2 -induced β-catenin stabilization, demonstrating its critical role in the induced path. We have previously shown a novel link between protease-activated receptor-1 (PAR 1 ) and β-catenin stabilization, both in a transgenic ( tg ) mouse model with overexpression of human PAR 1 ( hPar1 ) in the mammary glands, and in cancer epithelial cell lines. Unlike in PAR 1 -G α13 axis, both G α12 and G α13 are equally involved in PAR 2 -induced β-catenin stabilization. Disheveled (DVL) is translocated to the cell nucleus through the DVL-PDZ domain. Collectively, our data demonstrate a novel PAR 2 -LRP6-Axin interaction as a key axis of PAR 2 -induced β-catenin stabilization in cancer. This newly described axis enhances our understanding of cancer biology, and opens new avenues for future development of anti-cancer therapies.

Gene expression assays are widely used to predict risk of recurrence in early breast cancer (BC). We report the 21-gene expression assay (Oncotype Dx) recurrence score (RS) distribution of 27 BRCA carriers with estrogen receptor (ER) positive BCs, identified at Hadassah Medical Center, combined with 2 previous studies. Treatment decision and outcomes of the 27 BRCA carriers were compared with an Israeli cohort of 1594 patients published recently. We found Oncotype Dx RS low ( 30) among 12 (21.4%), 23 (41.1%) and 21 (37.5%) of 56 BRCA1 carriers compared with 15 (17.2%), 49 (56.3%) and 23 (26.4%) of 87 BRCA2 carriers (p=0.2). The corresponding distribution in a population of 82,434 women published by Genomic Health was 53.4%, 36.3% and 10.3% for low, intermediate and high RS (p< 0.001 for BRCA1 and BRCA2). Treatment decision regarding chemotherapy according to RS was similar in BRCA1, BRCA2 and the control group. Two of 27 carriers had distant recurrence: a BRCA1 carrier with RS of 18 and a BRCA2 carrier with RS of 22; both have an excellent response to chemotherapy. We found an approximately 3 fold increased rate of high RS among BRCA1 and 2 carriers with ER positive BC compared with the general BC population. These data might indicate that hormone positive BC in BRCA carriers are molecularly unique. The surprisingly good response to chemotherapy in the metastatic setting in 2 patients may suggest that the predictive value of low-intermediate RS in carriers merits further studies. This article is protected by copyright. All rights reserved.

The 21-gene Recurrence Score (RS) assay is a validated prognosticator/predictor of chemotherapy (CT) benefit in early-stage estrogen receptor (ER)-positive breast cancer (BC). Long-term data from real-life clinical practice where treatment was guided by the RS result are lacking. We performed exploratory analysis of the Clalit Health Services (CHS) registry, which included all CHS patients with node-negative ER+ HER2-negative BC who underwent RS testing between 1/2006 and 12/2009 to determine 10-year Kaplan–Meier estimates for distant recurrence/BC-specific mortality (BCSM) in this cohort. The analysis included 1365 patients. Distribution of RS results: RS 0–10, 17.8%; RS 11–25, 62.5%; RS 26–100, 19.7%. Corresponding CT use: 0, 9.4, and 69.9%. Ten-year distant recurrence rates in patients with RS 0–10, 11–25, and 26–100: 2.6% (95% confidence interval [CI], 1.1–6.2%), 6.1% (95% CI, 4.4–8.6%), and 13.1% (95% CI, 9.4–18.3%), respectively (P P

Background Tumor-derived circulating cell-free DNA (cfDNA) is present in the plasma of individuals with cancer. Assays aimed at detecting common cancer mutations in cfDNA are being developed for the detection of several cancer types. In breast cancer, however, such assays have failed to detect the disease at a sensitivity relevant for clinical use, in part due to the absence of multiple common mutations that can be co-detected in plasma. Unlike individual mutations that exist only in a subset of tumors, unique DNA methylation patterns are universally present in cells of a common type and therefore may be ideal biomarkers. Here we describe the detection and quantification of breast-derived cfDNA using a breast-specific DNA methylation signature. Patients and methods We collected plasma from patients with localized breast cancer before and throughout treatment with neoadjuvant chemotherapy and surgery (N = 235 samples). Results Pretreatment breast cfDNA was detected in patients with localized disease with a sensitivity of 80% at 97% specificity. High breast cfDNA levels were associated with aggressive molecular tumor profiles and metabolic activity of the disease. During neoadjuvant chemotherapy, breast cfDNA levels decreased dramatically. Importantly, the presence of breast cfDNA towards the end of the chemotherapy regimen reflected the existence of residual disease. Conclusion We propose that breast-specific cfDNA is a universal and powerful marker for the detection and monitoring of breast cancer.

Background/aim This study sought to determine whether an autoimmune background could identify patients with HER2-positive early breast cancer (EBC) who derive differential benefit from primary adjuvant trastuzumab-based therapy. Patients and methods HERA is an international randomized trial of 5,102 women with HER2-positive EBC, who were enrolled to either receive adjuvant trastuzumab or not. In this exploratory analysis, the interaction between autoimmune history and the magnitude of trastuzumab benefit was evaluated. Results A total of 5,099 patients were included in the current analysis. Among them, 325 patients (6.4%) had autoimmune disease history, 295 of whom had active disease. Patients were randomly assigned to trastuzumab or no-trastuzumab groups. Similar reductions in the risk of events in patients with and without autoimmune history were observed (interaction p=0.95 for disease-free survival, and p=0.62 for overall survival). Conclusion No evidence of a differential benefit from trastuzumab in patients with a medical history of autoimmune disease was found.

Background: The 21-Gene Recurrence Score® Assay (Oncotype DX®) has been validated as a prognostic and predictive tool in estrogen receptor (ER)+ breast cancer in multiple studies using archival specimens of clinical trials with long term follow up. Prospective outcome data from patients where treatment decisions incorporated the Recurrence Score results have not been reported. We evaluated treatments and clinical outcomes in patients undergoing Recurrence Score testing in 9 medical centers within Clalit Health Services (CHS), the largest HMO in Israel. Methods: Medical records of patients with N0/Nmic ER+ HER2-negative disease undergoing testing from 12/2004 to 12/2010 in 9 medical centers (Rabin, Lin, Soroka, Meir, Kaplan, Hadassah, Ha'emek, Rambam, and Shaare Zedek) within CHS were individually reviewed to verify treatments given, recurrence, and survival status. 5-year Kaplan-Meier (KM) and standard error estimates for distant recurrence and breast cancer specific survival were determined. Results: 1594 patients were evaluated with 5.9 years median follow-up. Median age, 61 (25-85) years; N0/Nmic (90%/10%); Grade I (16%), II (48%), III (16%), N/A (19%); histology, IDC (80%), lobular (13%), other (7%). Distribution of Recurrence Score risk groups (Recurrence Score results of Conclusions: These are the first prospective long term clinical outcome data from approximately 1600 patients for whom the 21-gene Recurrence Score assay has been incorporated in real-life clinical decision making. The documented use of CT was appropriately based on the Recurrence Score result, and the outcomes for recurrence and survival are consistent with previously reported prospective-retrospective studies of the 21-gene assay. The 5 year KM estimates for distant recurrence rate in patients with low and intermediate Recurrence Score results who were treated based upon their Recurrence Score results were very low (0.5% and 1.2%, respectively). Citation Format: Stemmer SM, Steiner M, Rizel S, Soussan-Gutman L, Geffen DB, Nisenbaum B, Ben-Baruch N, Isaacs K, Fried G, Rosengarten O, Uziely B, Svedman C, Rothney M, Klang SH, Ryvo L, Kaufman B, Evron E, Zidan J, Shak S, Liebermann N. Real-life analysis evaluating 1594 N0/Nmic breast cancer patients for whom treatment decisions incorporated the 21-gene recurrence score result: 5-year KM estimate for breast cancer specific survival with recurrence score results ≤30 is >98%. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-02.

Background: Progastrin-releasing peptide (ProGRP) is a potential marker for small-cell lung cancer (SCLC) in serum; however, it may be more stable in plasma. We investigated a new plasma assay (ProGRPp) and its usefulness in diagnosing and monitoring SCLC. Methods: The marker concentrations were determined on the ARCHITECT i system. Results: The assay could distinguish SCLC from non-small-cell lung cancer (NSCLC: area under the curve 0.931, 95% CI 0.893–0.969; cross-validated accuracy 0.813; sensitivity 84.0%, specificity 96.3% at 140 pg ml−1 cutoff). The probability of SCLC when ProGRPp was >140 pg ml−1 was 91.8%, after adjusting for age, gender, and renal dysfunction. The NSCLC patients with ProGRPp >140 pg ml−1 were at high risk (odds ratio=37.0, P

Background About half of colorectal patients are diagnosed less than 65 years of age and they have a relatively high cure rate. However, little is known about their employment and related risk factors. The aim of the current study was to clarify the association between colorectal cancer (CRC) and subsequent risk of being unemployed. Methods A historical prospective cohort study included baseline socio-demographic measurements of age, sex, ethnicity, residential socio-economic position and education from the 1995 Israeli National Census, cancer incidence between 2000 and 2007 and employment data between 1998 and 2011. Binary logistic regression analyses were used to assess odds ratios for unemployment, while controlling for socio-economic measurements and employment status at 2 years prior to diagnosis. Results The final study population included 885 colorectal patients and 2646 healthy controls. After controlling for confounders, positive associations were found between stages II (odds ratio [OR] = 1.91, 95% confidence interval [CI]: 1.31–2.76 or III (OR = 1.70, 95% CI: 1.13–2.54) and increased risk for unemployment at 2 years. At 4 years follow-up, stages I (OR = 1.56, 95% CI: 1.11–2.19), II (OR = 1.57, 95% CI: 1.09–2.26) and III (OR = 2.28, 95% CI: 1.55–3.37) were associated with increased risk for unemployment. Higher risk was seen among rectal cancer patients and among patients aged ≤50 years old at the time of cancer diagnosis. Conclusions CRC patients are at increased long-term risk for unemployment, especially among rectal cancer and younger patients. The clinical ramifications of our findings emphasise the importance of an accurate evaluation and attention to unemployment status during the care of these patients.

Purpose of study To describe the association between increasing age and survival among women aged over 65 years, diagnosed with breast cancer. Materials and methods A historical prospective cohort study, comparing 3270 breast cancer patients to 13,163 non cancer age matched controls. Baseline characteristics and cancer data gathered from the Israeli Central Bureau of Statistics (1995), the Israel Cancer Registry (2000–2010). Baseline measurements included age, socioeconomic status. Cancer stage at diagnosis was clustered as stage I, stage II–III and metastatic. Cox Proportional Hazards regression models were used to determine Hazards Ratios (HR) for mortality. Results Between ages 65–69 and ≥85, metastatic disease rose from 3.9% to 23.4% and stage I disease declined from 58.6% to 30.1%. At age 80–84, 50% life expectancy among controls, stage I, and stage II–III disease was 95,92 and 90 months respectively, compared to 2 months for metastatic disease. Compared to controls, between the age 65–69 to ≥85, adjusted HR’s progressively decreased among subjects with stage I from HR 0.96 (95% CI 0.69–1.33) to 0.60 (95%CI 0.36–1.01), stage II–III from HR 3.26 (95%CI2.58–4.12) to HR 1.60 (95%CI 1.22–2.09), and metastatic disease from HR 57.40 (95%CI 39.56–83.29) to HR 20.76 (95%CI 14.73–29.24). Conclusions This study describes the increasingly poor prognosis and short life expectancy observed among women aged ≥80 diagnosed with metastatic breast. In contrast, our findings confirm the positive prognosis associated with rising age, among older women presenting with stage I breast cancer, among whom survival was similar, if not slightly better, than non-cancer age matched controls.

The needs of gastric cancer survivors have received limited attention. Returning to work after gastric cancer has not yet been described in a population-based study. We aimed to examine the unemployment risk at 2 and 4 years after gastric cancer. The present historical prospective cohort study included baseline measurements from the Israeli Central Bureau of Statistics 1995 National Census, with follow-up until 2011. A group with gastric cancer and an age-, sex-, and ethnicity-matched control group were sampled from the census population. Binary logistic regression analyses were used to assess odds ratios (ORs) for the study outcomes, controlling for socioeconomic factors, and employment status at 2 years before diagnosis. Data for 152 gastric cancer cases and 464 matched controls were analyzed. Those who died during the study period were excluded. Two years after diagnosis, 53.3 % of gastric cancer survivors and 43.8 % of controls were unemployed (p = 0.04); 4 years after diagnosis, 53.9 % of survivors, and 47.2 % of controls were unemployed (p = 0.15). In the adjusted models, gastric cancer was only associated with unemployment 2 years after diagnosis (OR = 1.47, 95 % confidence interval [CI] = 1.02–2.12). This association weakened and lost significance 4 years after diagnosis (OR = 1.42, 95 % CI = 0.89–2.28). Gastric cancer was not associated with decreased income at 2 (OR = 1.48, 95 % CI = 0.91–1.48) or 4 years (OR = 1.65, 95 % CI = 0.99–2.74) after diagnosis. Gastric cancer survivorship was associated with unemployment 2 years after diagnosis. Longer-term survivors may have the prospect of returning to work. For patients with cancer, returning to work may be an indicator for returning to a normal lifestyle after serious illness. This study highlights the need for early social support in gastric cancer survivors to promote faster recovery.

Mammalian protease-activated-receptor-1 and -2 (PAR1 and PAR2) are activated by proteases found in the flexible microenvironment of a tumor and play a central role in breast cancer. We propose in the present study that PAR1 and PAR2 act together as a functional unit during malignant and physiological invasion processes. This notion is supported by assessing pro-tumor functions in the presence of short hairpin; shRNA knocked-down hPar2 or by the use of a truncated PAR2 devoid of the entire cytoplasmic tail. Silencing of hPar2 by shRNA-attenuated thrombin induced PAR1 signaling as recapitulated by inhibiting the assembly of Etk/Bmx or Akt onto PAR1-C-tail, by thrombin-instigated colony formation and invasion. Strikingly, shRNA-hPar2 also inhibited the TFLLRN selective PAR1 pro-tumor functions. In addition, while evaluating the physiological invasion process of placenta extravillous trophoblast (EVT) organ culture, we observed inhibition of both thrombin or the selective PAR1 ligand; TFLLRNPNDK induced EVT invasion by shRNA-hPar2 but not by scrambled shRNA-hPar2. In parallel, when a truncated PAR2 was utilized in a xenograft mouse model, it inhibited PAR1-PAR2-driven tumor growth in vivo. Similarly, it also attenuated the interaction of Etk/Bmx with the PAR1-C-tail in vitro and decreased markedly selective PAR1-induced Matrigel invasion. Confocal images demonstrated co-localization of PAR1 and PAR2 in HEK293T cells over-expressing YFP-hPar2 and HA-hPar1. Co-immuno-precipitation analyses revealed PAR1-PAR2 complex formation but no PAR1-CXCR4 complex was formed. Taken together, our observations show that PAR1 and PAR2 act as a functional unit in tumor development and placenta-uterus interactions. This conclusion may have significant consequences on future breast cancer therapeutic modalities and improved late pregnancy outcome.

American College of Radiology and Society of Breast Imaging guidelines call for routine breast MRI screening only for women with the highest risk profiles for development of breast cancer, suggesting that screening of women at lower risk might result in an increased frequency of false-positive biopsy results. The purpose of this study was to test this assumption by comparing MRI-guided biopsy outcomes of lesions detected at MRI screening of women with a personal history of breast cancer with outcomes among women with genetic or familial high risk.Outcomes of 130 MRI-guided biopsies were analyzed. One group consisted of women with hereditary (genetic or familial) risk, and the other group consisted of women with a personal history of breast cancer. Biopsies were performed with a 9-gauge vacuum-assisted device or surgically after MRI localization.Of 130 MRI-guided biopsies, 20 (15%) yielded malignant histologic findings, 14 (11%) yielded high-risk lesions, and 96 (74%) had benign findings. There was a slightly higher malignancy rate for the personal-risk group (19%) compared with the hereditary-risk group (13.5%). There also was a slightly higher combined rate of malignancy and high-risk lesions (34% vs 22%) with no statistically significant difference (p0.25, p0.12). Patients in the hereditary-risk group were younger (44 ± 1.2 vs 54 ± 1.7 years; p0.001) than those in the personal-risk group.Our preliminary data show no difference between the two risk groups with respect to probability of an MRI-guided biopsy result of malignancy, calling into question the proposed assumption. Further prospective studies of the role of MRI screening combined with MRI-guided biopsy when required for patients with previously treated localized breast cancer may be indicated.

Gene expression assays are widely used to predict risk of recurrence in early breast cancer (BC). We report the 21-gene expression assay (Oncotype Dx) recurrence score (RS) distribution of 27 BRCA carriers with estrogen receptor (ER) positive BCs, identified at Hadassah Medical Center, combined with 2 previous studies. Treatment decision and outcomes of the 27 BRCA carriers were compared with an Israeli cohort of 1594 patients published recently. We found Oncotype Dx RS low (18), intermediate (18-30) and high (30) among 12 (21.4%), 23 (41.1%) and 21 (37.5%) of 56 BRCA1 carriers compared with 15 (17.2%), 49 (56.3%) and 23 (26.4%) of 87 BRCA2 carriers (p = 0.2). The corresponding distribution in a population of 82,434 women published by Genomic Health was 53.4%, 36.3% and 10.3% for low, intermediate and high RS (p 0.001 for BRCA1 and BRCA2). Treatment decision regarding chemotherapy according to RS was similar in BRCA1, BRCA2 and the control group. Two of 27 carriers had distant recurrence: a BRCA1 carrier with RS of 18 and a BRCA2 carrier with RS of 22; both have an excellent response to chemotherapy. We found an approximately ∼3 fold increased rate of high RS among BRCA1 and 2 carriers with ER positive BC compared with the general BC population. These data might indicate that hormone positive BC in BRCA carriers are molecularly unique. The surprisingly good response to chemotherapy in the metastatic setting in 2 patients may suggest that the predictive value of low-intermediate RS in carriers merits further studies.

Despite the fact that G protein-coupled receptors (GPCRs) are the largest signal-conveying receptor family and mediate many physiological processes, their role in tumor biology is underappreciated. Numerous lines of evidence now associate GPCRs and their downstream signaling targets in cancer growth and development. Indeed, GPCRs control many features of tumorigenesis, including immune cell-mediated functions, proliferation, invasion and survival at the secondary site. Technological advances have further substantiated GPCR modifications in human tumors. Among these are point mutations, gene overexpression, GPCR silencing by promoter methylation and the number of gene copies. At this point, it is imperative to elucidate specific signaling pathways of "cancer driver" GPCRs. Emerging data on GPCR biology point to functional selectivity and "biased agonism"; hence, there is a diminishing enthusiasm for the concept of "one drug per GPCR target" and increasing interest in the identification of several drug options. Therefore, determining the appropriate context-dependent conformation of a functional GPCR as well as the contribution of GPCR alterations to cancer development remain significant challenges for the discovery of dominant cancer genes and the development of targeted therapeutics.

Thymidine kinase 1 (TK1) is involved in DNA synthesis and is considered a reliable and sensitive marker of cell proliferation. The aim of this study was to investigate the prognostic value of measurements of serum TK1 activity following tumor ablation.This study was performed on 32 patients with renal cell carcinoma (RCC) who had undergone nephrectomy and 35 patients with cancer of different histology with metastases to the liver (n=28) and lung (n=7) treated with radiofrequency ablation (RFA). The TK1 activity was measured with DiviTum (Biovica) immunoassay.In patients with RCC with no evidence of disease during their observation, a significant decrease of the TK1 activity was observed on the day following nephrectomy (p0.0001). The mean calculated half-life ±SEM was 10.8±1.2 h. Taking into account the short half-life, measurements of TK1 were performed 24 h after nephrectomy or RFA of metastases. It was found that elevated TK1 activity (60 Du/l) on the day after nephrectomy independently predicted poor recurrence-free survival (hazard ratio=5.0, p=0.040), after adjustment for T-stage, age and pretreatment TK1. Patients scheduled for RFA averaged 1.4 lesions and an average lesion diameter of 2.2 cm. Multivariate Cox's regression model demonstrated the significant association of any increase of TK1 activity or decrease not reaching ≤60 Du/l on the day after ablation with poor progression-free survival (hazard ratio=4.6, p=0.001), after adjustment for the type of primary tumor, the number and size of metastases.The half-life for serum TK1 activity is 10.8±1.2 h. The measurements of TK1 activity following nephrectomy or RFA of metastases could be an important tool in prognostic evaluation.

Thyroid cancer (TC) often occurs in relatively young patients and has a high cure rate. However, decreased psychological and physical well-being may reduce the work capability of patients with TC. This study aimed to compare the risk for unemployment and decreased income in TC survivors with a matched non-cancer group at two and four years after diagnosis. The study also aimed to predict unemployment and income changes at two and four years after diagnosis. A historical prospective study design was used, with cohort inception and baseline measurements drawn from the Israeli Central Bureau of Statistics 1995 National Census, with follow-up until 2011. Cancer incidence was obtained from the Israel Cancer Registry, and employment status from the Tax Authority. A matched group was sampled from the census population. Binary logistic regression analyses were used to assess odds ratios (OR) for the study outcomes, controlled for age, sex, ethnicity, education years, socioeconomic position, and employment status at two years before diagnosis. In total, 417 cases of TC and 1277 non-cancer matched subjects were included in the study. People who died during the study period were excluded. The mean age at the time of cancer diagnosis was 43.5 years in the TC group and 43.8 years in the control group (p = 0.6). After adjusting for potential confounders, a positive association was found between TC and risk of unemployment two years after diagnosis (OR = 1.46 [confidence interval (CI) 1.09-1.95]), and decreased income two years after diagnosis (OR = 1.61 [CI 1.23-2.01]) and four years after diagnosis (OR = 1.63 [CI 1.25-2.13]). The association between TC and unemployment at four years after diagnosis weakened and lost significance (OR = 1.30 [CI 0.98-1.72]). TC survivorship was associated with unemployment at two years and decreased income at two and four years after diagnosis. Decreased income may be a marker for a shift to part-time work rather than a return to full-time work. The findings suggest that interventions to enhance the return to full-time work are needed in this population

Despite the fact that G protein-coupled receptors (GPCRs) mediate numerous physiological processes and represent targets for therapeutics for a vast array of diseases, their role in tumor biology is under appreciated. Protease-activated receptors (PARs) form a family which belongs to GPCR class A. PAR1&2 emerge with a central role in epithelial malignancies. Although the part of PAR1&2 in cancer is on the rise, their underlying signaling events are poorly understood. We review hereby past, present, and future cancer-associated PAR biology. Mainly, their role in physiological (placenta-cytotophobalst) and patho-physiological invasion processes. The identification and characterization of signal pleckstrin homology (PH)-domain-binding motifs established critical sites for breast cancer growth in PAR1&2. Among the proteins found to harbor important PH-domains and are involved in PAR biology are Akt/PKB as also Etk/Bmx and Vav3. A point mutation in PAR2, H349A, but not R352A, abrogated PH-protein association and is sufficient to markedly reduce PAR2-instigated breast tumor growth in vivo as also placental extravillous trophoblast (EVT) invasion in vitro is markedly reduced. Similarly, the PAR1 mutant hPar1-7A, which is unable to bind PH-domain, inhibits mammary tumors and EVT invasion, endowing these motifs with physiological significance and underscoring the importance of these previously unknown PAR1 and PAR2 PH-domain-binding motifs in both pathological and physiological invasion processes.

Taking the issue of tumor categorization a step forward and establish molecular imprints to accompany histopathological assessment is a challenging task. This is important since often patients with similar clinical and pathological tumors may respond differently to a given treatment. Protease-activated receptor-1(PAR1), a G protein-coupled receptor (GPCR), is the first member of the mammalian PAR family consisting of four genes. PAR1and PAR2play a central role in breast cancer. The release of N-terminal peptides during activation and the exposure of a cryptic internal ligand in PARs, endow these receptors with the opportunity to serve as a “mirror-image” index reflecting the level of cell surface PAR1&2-in body fluids. It is possible to use the levels of PAR-released peptide in patients and accordingly determine the choice of treatment. We have both identified PAR1C-tail as a scaffold site for the immobilization of signaling partners, and the critical minimal binding site. This binding region may be used for future therapeutic modalities in breast cancer, since abrogation of the binding inhibits PAR1induced breast cancer. Altogether, both PAR1and PAR2may serve as molecular probes for breast cancer diagnosis and valuable targets for therapy.

PURPOSE/OBJECTIVES To develop a tool to identify patients with cancer who suffer from cachexia throughout all stages of the disease. DESIGN Tool development study. SETTING Oncology day care, follow-up clinics, radiotherapy, and hospice home care. SAMPLE 90 patients with cancer (25 men and 65 women). METHODS The Cachexia Assessment Scale (CAS) was created based on a thorough review of the literature and was tested for its psychometric properties. MAIN RESEARCH VARIABLES Presence of cachexia. FINDINGS Measures of reliability were determined by inter-rater, test-retest, and internal consistency reliability. Measures of validity were content validity, criterion validity, sensitivity, and specificity. CONCLUSIONS The CAS possesses adequate levels of reliability and validity and can be used to evaluate cachexia at all stages of cancer. IMPLICATIONS FOR NURSING The CAS can be used as an assessment tool for cachexia in various treatment settings.

Importance The recommended extent of surgery for well-differentiated thyroid carcinoma has been modified considerably in the updated 2015 American Thyroid Association guidelines published in January 2016. To date, the changes in clinical practice after publication of these new guidelines have not been demonstrated. Objective The aim of this study was to evaluate clinical practice changes associated with implementation of the updated guidelines on the surgical procedure rates of total thyroidectomy, thyroid lobectomy, and completion thyroidectomy at a single tertiary medical center. Design, Setting, and Participants This is a retrospective cohort study of 169 patients at the Hadassah–Hebrew University Medical Center, Jerusalem, Israel. Patients with pathologically proved, well-differentiated thyroid carcinoma who underwent surgery between January 1, 2013, and December 31, 2014, were compared with patients who underwent surgery from January 1 to December 31, 2016. A total of 434 thyroidectomy procedures were performed during the study period, and 251 had pathologically proved, well-differentiated thyroid carcinoma. Patients with tumors larger than 4 cm, involved lymph nodes, or bilateral nodules were excluded. Main Outcomes and Measures Primary outcomes were the rate of up-front total thyroidectomy vs lobectomy and the rates of completion thyroidectomy before and after the implementation of the new guidelines. Results Of the 169 patients in the final analysis, 118 (69.8%) were included from 2013 to 2014 and 51 (30.2%) in 2016. The mean (SD) age for the entire cohort was 44 (13.8) years, and 129 (76.3%) were women. Up-front total thyroidectomy was performed in 72 of 118 patients (61.0%) prior to the 2015 American Thyroid Association guidelines and 16 of 51 (31.4%) following their implementation (odds ratio, 0.29; 95% CI, 0.14-0.59). The rate of completion thyroidectomy also significantly decreased between these periods (73.9% vs 20.0%; odds ratio, 0.09; 95% CI, 0.04-0.19). Conclusions and Relevance The updated 2015 American Thyroid Association guidelines implementation was associated with a significant decrease in the rates of both up-front total thyroidectomy and completion thyroidectomy. According to these findings, only 1 of 5 patients who undergoes thyroid lobectomy will require a completion procedure.

The original version of this article unfortunately contained a mistake. The family name of Beatrice Uziely was mistakenly spelled as Uzieky. The correct name is now presented above.

PURPOSE/OBJECTIVES To examine relationships between oncology nurses' attitudes toward death and caring for dying patients. DESIGN Cross-sectional, descriptive, and correlational. SETTING Israeli Oncology Nurses Society annual conference in June 2006. SAMPLE A convenience sample of 147 Israeli nurses who were exposed to death in their daily work. Most worked in oncology departments and were of Jewish faith. METHODS Completion of the Frommelt Attitude Toward Care of the Dying Scale, Death Attitude Profile-Revised Scale, and a demographic questionnaire. MAIN RESEARCH VARIABLES Attitudes toward caring for dying patients, attitudes toward death (fear of death, death avoidance, and types of death acceptance), and demographic variables (e.g., religiosity). FINDINGS Nurses demonstrated positive attitudes toward care of dying patients. The attitudes were significantly negatively correlated with death avoidance, fear of death, and approach acceptance of death. A mediating role of death avoidance was found between fear of death and attitudes toward caring for dying patients. CONCLUSIONS Nurses' personal attitudes toward death were associated with their attitudes toward the care of dying patients. The mediating model suggests that some nurses may use avoidance to cope with their own personal fears of death. Inconsistency between the current results and previous studies of associations between acceptance of death and attitudes toward care for dying patients imply that culture and religion might play important roles in the development of these attitudes. IMPLICATIONS FOR NURSING Training and support programs for oncology nurses should take into consideration nurses' personal attitudes toward death as well as their religious and cultural backgrounds.

Pathological features and consequently, tumor response differ between BRCA1/2 carriers and sporadic breast cancer (BC) cases. It is expected that BRCA1/2 associated tumors will be more vulnerable to DNA damaging agents and irradiation due to their function in DNA repair. In addition, very high pathological complete response (pCR) rate of approximately 40-50% to neo-adjuvant chemotherapy were reported by two studies. We describe the clinical outcome, i.e.; complete response (cCR), major pathological response (more than 80% reduction in tumor mass), pathologiacl CR (pCR) and local control rates in 15 BRCA1 and 7 BRCA2 carriers, all diagnosed at stage III and treated with anthracyclin based chemotherapy, mastectomy, and irradiation. cCR were found in 6/15 carriers and in 1/7 BRCA2 carriers (P = 0.3). Rate of major pathological response were 4/15 (26.6%) in BRCA1 compared with none of BRCA2 carriers (P = 0.3). Of them, pCR was recorded in 2/15 of BRCA1 carriers. Clinical and pathological nodal involvements were lower in BRCA1 carriers. While all BRCA2 carriers remained node positive as compared to 50% of BRCA1 carriers (P = 0.047), overall survival was similar in both groups. However, approximately 1/3 of BRCA1 carriers did not respond to chemotherapy and 4/15 died within 5 years of diagnosis. We found a non-significant higher clinical and pathological response rate among BRCA1 carriers in response to neo-adjuvant chemotherapy compared with BRCA2 carriers. Our results suggest chemoresistance of approximately a 1/3 of BRCA1 associated tumors. Tumors of BRCA2 carriers are resistant to chemotherapy, while the estrogen receptor positive nature of tumors results in better post recurrence survival.

Although emerging roles of protease-activated receptor1&2 (PAR1&2) in cancer are recognized, their underlying signalling events are poorly understood. Here we show signal-binding motifs in PAR1&2 that are critical for breast cancer growth. This occurs via the association of the pleckstrin homology (PH) domain with Akt/PKB as a key signalling event of PARs. Other PH-domain signal-proteins such as Etk/Bmx and Vav3 also associate with PAR1 and PAR2 through their PH domains. PAR1 and PAR2 bind with priority to Etk/Bmx. A point mutation in PAR2, H349A, but not in R352A, abrogates PH-protein association and is sufficient to markedly reduce PAR2-instigated breast tumour growth in vivo and placental extravillous trophoblast (EVT) invasion in vitro. Similarly, the PAR1 mutant hPar1-7A, which is unable to bind the PH domain, reduces mammary tumours and EVT invasion, endowing these motifs with physiological significance and underscoring the importance of these previously unknown PAR1 and PAR2 PH-domain-binding motifs in both pathological and physiological invasion processes., Protease-activated-receptor 1 and 2 (PAR1 and PAR2) are key players in tumor growth. In this study, the authors identify PAR1 and PAR2 domains that bind oncogenic signalling proteins driving breast cancer progression in vivo and placental extravillous trophoblast invasion in vitro.

Protease-activated receptor 1 (PAR1) is emerging with distinct assignments in tumor biology. We show that tissue targeted overexpression of hPar1 in mice mammary glands results in precocious hyperplasia, characterized by a dense network of ductal side branching and accelerated proliferation. These glands exhibit increased levels of wnt-4 and wnt-7b and a striking β-catenin stabilization. Nuclear localization of β-catenin is observed in hPar1 transgenic mouse tissue sections but not in the wild-type, age-matched counterparts. PAR1 induces β-catenin nuclear localization also in established epithelial tumor cell lines of intact β-catenin system (transformed on the background of mismatch repair system; RKO cells). We propose hereby that PAR1-mediated β-catenin stabilization is taking place primarily via the increase of Wnt expression. Enforced expression of a specific Wnt antagonist family member, secreted frizzled receptor protein 5 (SFRP5), efficiently inhibited PAR1-induced β-catenin stabilization. Likewise, application of either SFRP2 or SFRP5 on epithelial tumor cells completely abrogated PAR1-induced β-catenin nuclear accumulation. This takes place most likely via inhibition of Wnt signaling at the level of cell surface (forming a neutralizing complex of “Receptors-SFRP-Wnt”). Furthermore, depletion of hPar1 by small interfering RNA (siRNA) vectors markedly inhibited PAR1-induced Wnt-4. The striking stabilization of β-catenin, inhibited by SFRPs on one hand and Wnt-4 silencing by hPar1 siRNA on the other hand, points to a novel role of hPar1 in Wnt-mediated β-catenin stabilization. This link between PAR1 and β-catenin may bear substantial implications both in developmental and tumor progression processes. (Cancer Res 2006; 66(10): 5224-32)

Background: Breast cancer at a young age threatens the natural developmental tasks that characterize this phase in life including parenthood. The dilemma of whether to give birth arises due to the potential medical, psychological and social implications of pregnancy, birth and child rearing after breast cancer. The purpose of this study was to investigate the positive and negative motivations toward childbirth of breast cancer survivors and their husbands. Method: Thirty breast cancer survivors and 13 husbands were compared to 29 healthy women and 15 husbands. The study included qualitative questions and quantitative measures including: a demographic and medical questionnaire, the Parenthood Motivation Questionnaire—Revised, the ENRICH Marital Satisfaction Scale, the Brief Symptom Inventory, the Impact of Events Scale, and the Mental Adjustment to Cancer Questionnaire. Results: The experience of having breast cancer did not hinder overall positive motivations toward childbirth, nor did it increase overall negative motivations toward childbirth, among women and their husbands. However, there were several differences between the groups, which may reflect the illness experience. For example, breast cancer survivors and their husbands reported more negative motivations toward childbirth due to health concerns than did healthy women and their husbands. Copyright © 2004 John Wiley & Sons, Ltd.

Psychological distress and coping styles in women diagnosed with stages I and II breast cancer have attracted substantial clinical and research attention over the last several decades. The contradictory and, at times, controversial findings stimulated the present randomized research whose purpose was to explore the possibility and probability of predicting which variables affect the psychological distress level of women with breast cancer 1 to 5 years after diagnosis (time period 1) and 6 to 8 months after period 1 (time period 2). The study was conducted in two large oncology centers in Graz, Austria, and Jerusalem, Israel, with a sample population comprising 424 patients. The only variables that significantly predicted change in the psychological distress levels (Grand Severity Index, GSI; except for the GSI level during period 1) were Fighting Spirit (Mental Adjustment to Cancer, MAC) in the Graz sample and Perceived Family Support (PFS) in the Jerusalem sample. These results are discussed in relation to other findings. In light of these findings, it is highly important to preliminarily identify women with less adaptive psychological coping mechanisms and to provide them with efficacy tools for behavioral and cognitive changes within their own network of social and health resources.

Breast cancer is the most common malignant disease among women in developed countries. In Austria and Israel, it accounts for 15% and 18%, respectively, of all cancers and 30% of all cancers in women. The purpose of this study, conducted in Graz, Austria, and Jerusalem, Israel, was to determine whether different geographical and cultural settings differentially affect the psychological distress of women who have survived breast cancer and why. The dependence of psychological distress on psychosocial variables such as quality of life, body image, impact of cancer and coping styles was examined at time 1 in a randomized sample of 424 breast cancer women who were disease-free at the time of the study and were surveyed 1-5 years after diagnosis. The most contributing variables to the level of psychological distress in both populations were: the number of stressful life events during last year, financial problems and feeling uncomfortable with the body. Regarding coping styles, mental adjustment to cancer was the principal contributor to psychological distress level [determined by the Grand Severity Index (GSI) scores] in the Graz group, while intrusion was the principal contributor to the GSI level in the Jerusalem group.

While protease-activated receptors (PARs) play a traditional role in vascular biology, they emerge with surprisingly new assignments in tumor biology. PAR1 expression correlates with the invasion properties of breast carcinoma, whereas human PAR1 antisense reduces their ability to migrate through Matrigel. Part of the molecular mechanism of PAR1 invasion involves the formation of focal contact complexes on PAR1 activation. PAR1 induces angiogenesis in animal models in vivo and exhibits an oncogenic phenotype of enhanced ductal complexity when overexpressed in mouse mammary glands.