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Wei W.,University of Texas M. D. Anderson Cancer Center | Hawley S.T.,Canary Foundation | Fazli L.,Vancouver Prostate Center | Hurtado-Coll A.,Vancouver Prostate Center | And 12 more authors.
European Urology Focus | Year: 2016

Background: PTEN is the most commonly deleted tumor suppressor gene in primary prostate cancer (PCa) and its loss is associated with poor clinical outcomes and ERG gene rearrangement. Objective: We tested whether PTEN loss is associated with shorter recurrence-free survival (RFS) in surgically treated PCa patients with known ERG status. Design, setting, and participants: A genetically validated, automated PTEN immunohistochemistry (IHC) protocol was used for 1275 primary prostate tumors from the Canary Foundation retrospective PCa tissue microarray cohort to assess homogeneous (in all tumor tissue sampled) or heterogeneous (in a subset of tumor tissue sampled) PTEN loss. ERG status as determined by a genetically validated IHC assay was available for a subset of 938 tumors. Outcome measurements and statistical analysis: Associations between PTEN and ERG status were assessed using Fisher's exact test. Kaplan-Meier and multivariate weighted Cox proportional models for RFS were constructed. Results and limitations: When compared to intact PTEN, homogeneous (hazard ratio [HR] 1.66, p = 0.001) but not heterogeneous (HR 1.24, p = 0.14) PTEN loss was significantly associated with shorter RFS in multivariate models. Among ERG-positive tumors, homogeneous (HR 3.07, p < 0.0001) but not heterogeneous (HR 1.46, p = 0.10) PTEN loss was significantly associated with shorter RFS. Among ERG-negative tumors, PTEN did not reach significance for inclusion in the final multivariate models. The interaction term for PTEN and ERG status with respect to RFS did not reach statistical significance (p = 0.11) for the current sample size. Conclusions: These data suggest that PTEN is a useful prognostic biomarker and that there is no statistically significant interaction between PTEN and ERG status for RFS. Patient summary: We found that loss of the PTEN tumor suppressor gene in prostate tumors as assessed by tissue staining is correlated with shorter time to prostate cancer recurrence after radical prostatectomy. We used highly validated, clinical-grade assays to assess the association of PTEN and ERG protein status with recurrence-free survival (RFS) in a large multi-institutional cohort of surgically treated prostate cancer patients. We show that PTEN protein loss is most strongly associated with shorter RFS if the loss is homogeneous in all tumor tissue sampled. In addition, we demonstrate that there is not a statistically significant interaction between PTEN and ERG with respect to RFS. © 2015 European Association of Urology.


McKenney J.K.,Stanford University | Simko J.,University of California at San Francisco | Bonham M.,University of California at San Francisco | True L.D.,University of Washington | And 10 more authors.
Journal of Urology | Year: 2011

Purpose: We evaluated the reproducibility of Gleason grading as relevant to the clinical treatment of men on active surveillance. Materials and Methods: Three sets of digital images of prostatic adenocarcinoma in biopsies were reviewed and assigned Gleason scores by a total of 11 pathologists from 7 institutions. Interobserver and intra-observer reproducibility were assessed for assignment of the highest Gleason pattern (3 vs 4 or higher). We also identified 97 consecutive patients on active surveillance. Prostate biopsy glass slides from 82 of the patients were available for re-review and the frequency of carcinoma requiring the distinction of tangentially sectioned Gleason pattern 3 from 4 was determined. Results: Interobserver reproducibility for classic Gleason patterns was substantial (Light's κ 0.76). Interobserver reproducibility for the histological distinction of tangentially sectioned Gleason pattern 3 from Gleason pattern 4 was only fair (Light's κ 0.27). Intra-observer reproducibility ranged from 65% to 100% (mean 81.5%). Of the 82 patients on active surveillance 61 had carcinoma and 15 (24.5%) had a set of biopsies with at least 1 focus in which the distinction between tangentially sectioned Gleason pattern 3 and poorly formed pattern 4 glands had to be considered. Conclusions: The reproducibility of grading classic Gleason patterns is high. However, variability in grading occurred when distinguishing between tangentially sectioned pattern 3 glands and the poorly formed gland subset of pattern 4. Developing universally accepted histological and/or molecular criteria to distinguish these patterns and subsequently characterizing their natural history would be useful when treating patients on active surveillance. © 2011 American Urological Association Education and Research, Inc.


PubMed | Canary Foundation, University of Washington, Urology, Vancouver Prostate Center and 7 more.
Type: Journal Article | Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | Year: 2016

PTEN loss is a promising prognostic and predictive biomarker in prostate cancer. Because it occurs most commonly via PTEN gene deletion, we developed a clinical-grade, automated, and inexpensive immunohistochemical assay to detect PTEN loss. We studied the sensitivity and specificity of PTEN immunohistochemistry relative to four-color fluorescence in situ hybridization (FISH) for detection of PTEN gene deletion in a multi-institutional cohort of 731 primary prostate tumors. Intact PTEN immunostaining was 91% specific for the absence of PTEN gene deletion (549/602 tumors with two copies of the PTEN gene by FISH showed intact expression of PTEN by immunohistochemistry) and 97% sensitive for the presence of homozygous PTEN gene deletion (absent PTEN protein expression by immunohistochemistry in 65/67 tumors with homozygous deletion). PTEN immunohistochemistry was 65% sensitive for the presence of hemizygous PTEN gene deletion, with protein loss in 40/62 hemizygous tumors. We reviewed the 53 cases where immunohistochemistry showed PTEN protein loss and FISH showed two intact copies of the PTEN gene. On re-review, there was ambiguous immunohistochemistry loss in 6% (3/53) and failure to analyze the same tumor area by both methods in 34% (18/53). Of the remaining discordant cases, 41% (13/32) revealed hemizygous (n=8) or homozygous (n=5) PTEN gene deletion that was focal in most cases (11/13). The remaining 19 cases had two copies of the PTEN gene detected by FISH, representing truly discordant cases. Our automated PTEN immunohistochemistry assay is a sensitive method for detection of homozygous PTEN gene deletions. Immunohistochemistry screening is particularly useful to identify cases with heterogeneous PTEN gene deletion in a subset of tumor glands. Mutations, small insertions, or deletions and/or epigenetic or microRNA-mediated mechanisms may lead to PTEN protein loss in tumors with normal or hemizygous PTEN gene copy number.


PubMed | University of Texas Health Science Center at San Antonio, Canary Foundation, University of Washington, Fred Hutchinson Cancer Research Center and 6 more.
Type: Journal Article | Journal: Prostate cancer and prostatic diseases | Year: 2016

Expanding interest in and use of active surveillance for early state prostate cancer (PC) has increased need for prognostic biomarkers. Using a multi-institutional tissue microarray resource including over 1000 radical prostatectomy samples, we sought to correlate Ki67 expression captured by an automated image analysis system with clinicopathological features and validate its utility as a clinical grade test in predicting cancer-specific outcomes.After immunostaining, the Ki67 proliferation index (PI) of tumor areas of each core (three cancer cores/case) was analyzed using a nuclear quantification algorithm (Aperio). We assessed whether Ki67 PI was associated with clinicopathological factors and recurrence-free survival (RFS) including biochemical recurrence, metastasis or PC death (7-year median follow-up).In 1004 PCs (4000 tissue cores) Ki67 PI showed significantly higher inter-tumor (0.68) than intra-tumor variation (0.39). Ki67 PI was associated with stage (P<0.0001), seminal vesicle invasion (SVI, P=0.02), extracapsular extension (ECE, P<0.0001) and Gleason score (GS, P<0.0001). Ki67 PI as a continuous variable significantly correlated with recurrence-free, overall and disease-specific survival by multivariable Cox proportional hazard model (hazards ratio (HR)=1.04-1.1, P=0.02-0.0008). High Ki67 score (defined as 5%) was significantly associated with worse RFS (HR=1.47, P=0.0007) and worse overall survival (HR=2.03, P=0.03).In localized PC treated by radical prostatectomy, higher Ki67 PI assessed using a clinical grade automated algorithm is strongly associated with a higher GS, stage, SVI and ECE and greater probability of recurrence.


News Article | December 12, 2016
Site: www.eurekalert.org

Profiling the genes of lung-tumor cells from patient blood samples may be a cheap, noninvasive way to help doctors choose the right treatments, according to a study led by researchers at the Stanford University School of Medicine. The new findings strengthen the hope that evaluating the genetic profiles of tumor cells circulating in the bloodstream could transform cancer care: first, by indicating the next chemotherapy or targeted therapy to use when tumors evolve resistance to previous drugs; and, second, by providing a way to study how tumors change over time. The new blood test is safer, cheaper, faster and more effective than alternative diagnostic approaches, according to the study. The researchers created a system for isolating circulating tumor cells from the blood of cancer patients and reading a handful of genes from inside each tumor cell. Thus, they were able to obtain genetic information about the original cancer tumor that resides deep in the lungs without doing a biopsy, which can be dangerous for the patient. "We are trying to make minimally invasive technology that allows us to continuously monitor one person's health over time," said radiology instructor Seung-min Park, PhD, a lead author of the new study, which will be published online Dec. 12 in the Proceedings of the National Academy of Sciences. Park shares lead authorship of the study with former Stanford graduate students Dawson Wong, PhD, and Chin Chun Ooi. It's common for cancer therapies to fail after a few months, often because the cancer evolves resistance to the treatment. At that point, it's important to understand how the patient's tumor is changing. "Without a biopsy and genetic profiling, we are flying blind, trying to select a second or third option for therapy and hoping it works," Park said. But repeated lung biopsies are too hard on patients. Even CT scans, performed to see whether a tumor is shrinking or growing, increase the body's exposure to damaging X-rays. "Blood-based monitoring would allow us to select the right second and third therapies instead of flying blind," he said. Finding a way to look at circulating tumor cells, or CTCs, in the blood has been a goal of oncologists for years. When people die of cancer, it's usually from metastasis, the spread of tumors throughout the body. Part of metastasis is the entry of tumor cells into the bloodstream, where they circulate along with normal blood cells, eventually landing in other organs and initiating tumors there. In general, the presence of CTCs in the blood of cancer patients predicts patients will live for a shorter time. "This work fits well into our bigger vision of using blood-based diagnostics to detect and manage disease, including cancer," said Sanjiv "Sam" Gambhir, MD, PhD professor and chair of radiology and the Virginia and D.K. Ludwig Professor in Cancer Research. "By being able to characterize single CTCs, we believe cancer management, including predicting response to therapy, will be much better optimized." Gambhir shares senior authorship of the study with Shan Wang, PhD, professor of materials science and engineering and of electrical engineering, and Viswam Nair, MD, clinical assistant professor of medicine and of radiology. How it's done The blood typically contains very few CTCs, so one of the challenges for oncologists has been to separate them from ordinary blood cells. The new technique involves taking blood from lung cancer patients and then attaching antibodies to circulating tumor cells. Once the cancer cells are labeled, the team introduces magnetic nanoparticles designed to attach to the antibodies labeling the cancer cells. With each individual cancer cell labeled with a magnetic nanoparticle, the researchers can then use a device called a magnetic sifter, or MagSifter, previously developed by Wang. The MagSifter is an electromagnetic sieve that can be turned on and off. When the MagSifter is on, it pulls the nanoparticle-labeled CTCs from the blood sample and allows the rest of the blood to flow through the sifter. The CTCs pulled from the blood are then deposited into a flat array of tiny wells, each large enough for only one cell. Now the tumor cells are ready for genetic analysis. Each flat of 25,600 wells looks like a miniature muffin tin, with room for a lot of tiny muffins. The new technique serves as a proof of concept for collecting and analyzing lung cancer cells from blood samples. If the technique receives approval from the Food and Drug Administration, it could be used to tell how cancer cells have evolved in response to chemotherapy and which drug is the best to use next in individual patients. In principle, the technique should work just as well with other kinds of cancers, Wong said. "We validated our device on lung cancer because of the difficulties of doing lung biopsies," he said. "But the technology is not limited to profiling lung cancer. We could swap out markers and adapt the technique to other types of cancers." Cost of less than $30 The approach that the team developed could be used to look at mutations in three or four genes, and it requires no more than 2 milliliters of blood -- about half a teaspoon. The test can be completed in about five hours, the researcher said, and costs less than $30. For comparison, a single state-of-the art biopsy of lung tissue with DNA sequencing costs about $18,000 and takes as long as three weeks to furnish results. Johnson & Johnson's CellSearch -- another blood test, already approved by the FDA -- costs about $900 and takes a week to deliver results. "We feel that we have solved a lot of the technical hurdles," said Wong. "The blood draw is cheap enough and noninvasive enough that it could be done on a weekly basis throughout treatment." The team's work is an example of Stanford Medicine's focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill. Other Stanford co-authors are graduate students David Kurtz, MD, Amin Aalipour and Jacob Chabon; postdoctoral scholar Ophir Vermesh, MD, PhD; research assistants Kelsey Pian and Justin Carter; former research assistant Susie Suh; instructor of radiology Mehran Jamali, MD; clinical research associate Carmen Say; professor of medicine Ware Kuschner, MD; professor of medicine Erich Schwartz, MD; professor of cardiothoracic surgery Joseph Shrager, MD; assistant professor of medicine Joel Neal, MD, PhD; associate professor of medicine Heather Wakelee, MD; and assistant professor of radiation oncology Maximilian Diehn, MD, PhD. This research was supported by the National Institutes of Health (grants U54CA151459 and R21CA185804), the Canary Foundation, and the LUNGevity Foundation. Stanford's Department of Medicine also supported the work. Stanford University has filed for patents on the technology used in connection with this work. The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med. . The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children's Health. For information about all three, please visit http://med. .


Houshdaran S.,University of Southern California | Hawley S.,Canary Foundation | Palmer C.,Canary Foundation | Campan M.,University of Southern California | And 7 more authors.
PLoS ONE | Year: 2010

Background: Epithelial ovarian carcinoma is a significant cause of cancer mortality in women worldwide and in the United States. Epithelial ovarian cancer comprises several histological subtypes, each with distinct clinical and molecular characteristics. The natural history of this heterogeneous disease, including the cell types of origin, is poorly understood. This study applied recently developed methods for high-throughput DNA methylation profiling to characterize ovarian cancer cell lines and tumors, including representatives of three major histologies. Methodology/Principal Findings: We obtained DNA methylation profiles of 1,505 CpG sites (808 genes) in 27 primary epithelial ovarian tumors and 15 ovarian cancer cell lines. We found that the DNA methylation profiles of ovarian cancer cell lines were markedly different from those of primary ovarian tumors. Aggregate DNA methylation levels of the assayed CpG sites tended to be higher in ovarian cancer cell lines relative to ovarian tumors. Within the primary tumors, those of the same histological type were more alike in their methylation profiles than those of different subtypes. Supervised analyses identified 90 CpG sites (68 genes) that exhibited 'subtype-specific' DNA methylation patterns (FDR<1%) among the tumors. In ovarian cancer cell lines, we estimated that for at least 27% of analyzed autosomal CpG sites, increases in methylation were accompanied by decreases in transcription of the associated gene. Significance: The significant difference in DNA methylation profiles between ovarian cancer cell lines and tumors underscores the need to be cautious in using cell lines as tumor models for molecular studies of ovarian cancer and other cancers. Similarly, the distinct methylation profiles of the different histological types of ovarian tumors reinforces the need to treat the different histologies of ovarian cancer as different diseases, both clinically and in biomarker studies. These data provide a useful resource for future studies, including those of potential tumor progenitor cells, which may help illuminate the etiology and natural history of these cancers. © 2010 Houshdaran et al.


Drescher C.W.,Fred Hutchinson Cancer Research Center | Hawley S.,Canary Foundation | Thorpe J.D.,Fred Hutchinson Cancer Research Center | Marticke S.,Canary Foundation | And 3 more authors.
Cancer Prevention Research | Year: 2012

Ongoing ovarian cancer screening trials are investigating the efficacy of a two-step screening strategy using currently available blood and imaging tests [CA125 and transvaginal sonography (TVS)]. Concurrently, efforts to develop new biomarkers and imaging tests seek to improve screening performance beyond its current limits. This study estimates the mortality reduction, years of life saved, and cost-effectiveness achievable by annual multimodal screening using increasing CA125 to select women for TVS, and predicts improvements achievable by replacing currently available screening tests with hypothetical counterparts with better performance characteristics. An existing stochastic microsimulation model is refined and used to screen a virtual cohort of 1 million women from ages 45 to 85 years. Each woman is assigned a detailed disease course and screening results timeline. The preclinical behavior of CA125 and TVS is simulated using empirical data derived from clinical trials. Simulations in which the disease incidence and performance characteristics of the screening tests are independently varied are conducted to evaluate the impact of these factors on overall screening performance and costs. Our results show that when applied to womenat average risk, annual screening using increasing CA125 to select women for TVS achieves modest mortality reduction (∼13%) and meets currently accepted cost-effectiveness guidelines. Screening outcomes are relatively insensitive to second-line test performance and costs. Identification of a first-line test that does substantially better than CA125 and has similar costs is required for screening to reduce ovarian mortality by at least 25% and be reasonably cost-effective. ©2012 AACR.


Pan S.,University of Washington | Chen R.,University of Washington | Brand R.E.,University of Pittsburgh | Hawley S.,Canary Foundation | And 6 more authors.
Journal of Proteome Research | Year: 2012

Biomarkers are most frequently proteins that are measured in the blood. Their development largely relies on antibody creation to test the protein candidate performance in blood samples of diseased versus nondiseased patients. The creation of such antibody assays has been a bottleneck in biomarker progress due to the cost, extensive time, and effort required to complete the task. Targeted proteomics is an emerging technology that is playing an increasingly important role to facilitate disease biomarker development. In this study, we applied a SRM-based targeted proteomics platform to directly detect candidate biomarker proteins in plasma to evaluate their clinical utility for pancreatic cancer detection. The characterization of these protein candidates used a clinically well-characterized cohort that included plasma samples from patients with pancreatic cancer, chronic pancreatitis, and healthy age-matched controls. Three of the five candidate proteins, including gelsolin, lumican, and tissue inhibitor of metalloproteinase 1, demonstrated an AUC value greater than 0.75 in distinguishing pancreatic cancer from the controls. In addition, we provide an analysis of the reproducibility, accuracy, and robustness of the SRM-based proteomics platform. This information addresses important technical issues that could aid in the adoption of the targeted proteomics platform for practical clinical utility. © 2012 American Chemical Society.


Chen R.,GI Division | Crispin D.A.,GI Division | Pan S.,University of Washington | Hawley S.,Canary Foundation | And 6 more authors.
Pancreas | Year: 2010

Objectives: Biomarkers that detect pancreatic cancer at earlier stages could improve the outcome of this deadly disease. Methods: We investigated a dozen biomarker candidates for their potential as pancreatic cancer blood biomarkers using enzyme-linked immunosorbent assays. Results: Among them, the macrophage migration inhibitory factor and osteopontin blood tests were nearly perfect in distinguishing pancreatic cancer cases from healthy controls (100% and 95% sensitivity, respectively, at 100% specificity). Five biomarker candidates were then tested on an expanded set of diseased controls, which included sera from patients with pancreatitis. The sensitivity dropped significantly for all 5 candidate markers. Conclusions: Our results suggest that biomarker candidates could fail in various steps of biomarker development. Earlier knowledge of candidate biomarker flaws could lead to strategies to overcome the flaw or alternatively lead to earlier termination of biomarkers that are prone to failure in the later phases of validation testing. Copyright © 2010 by Lippincott Williams & Wilkins.


Sin D.,Columbia University | Tammemagi C.M.,Brock University | Lam S.,Columbia University | Lam S.,British Columbia Cancer Agency | And 9 more authors.
Journal of Clinical Oncology | Year: 2013

Purpose Preliminary studies have identified pro-surfactant protein B (pro-SFTPB) to be a promising blood biomarker for non-small-cell lung cancer. We conducted a study to determine the independent predictive potential of pro-SFTPB in identifying individuals who are subsequently diagnosed with lung cancer. Patients and Methods Pro-SFTPB levels were measured in 2,485 individuals, who enrolled onto the Pan-Canadian Early Detection of Lung Cancer Study by using plasma sample collected at the baseline visit. Multivariable logistic regression models were used to evaluate the predictive ability of pro-SFTPB in addition to known lung cancer risk factors. Calibration and discrimination were evaluated, the latter by an area under the receiver operating characteristic curve (AUC). External validation was performed with samples collected in the Carotene and Retinol Efficacy Trial (CARET) participants using a case-control study design. Results Adjusted for age, sex, body mass index, personal history of cancer, family history of lung cancer, forced expiratory volume in one second percent predicted, average number of cigarettes smoked per day, and smoking duration, pro-SFTPB (log transformed) had an odds ratio of 2.220 (95% CI, 1.727 to 2.853; P < .001). The AUCs of the full model with and without pro-SFTPB were 0.741 (95% CI, 0.696 to 0.783) and 0.669 (95% CI, 0.620 to 0.717; difference in AUC P < .001). In the CARET Study, the use of pro-SFPTB yielded an AUC of 0.683 (95% CI, 0.604 to 0.761). Conclusion Pro-SFTPB in plasma is an independent predictor of lung cancer and may be a valuable addition to existing lung cancer risk prediction models. © 2013 by American Society of Clinical Oncology.

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