tbuckley/cabot-search huggingface dataset:
Use of a gene profile to identify molecular subtypes of breast cancer.
Authors: W. Zwart, F. De Snoo, O. Krijgsman, P. Roepman, S. Tian, A. Glas, R. A. Bender, J. Carroll, R. Bernards
Journal: Journal of Clinical Oncology (2011)

537 Background: Classification of breast cancer into molecular subtypes may be important for the proper selection of therapy, as tumors with seemingly similar biology can have strikingly different clinical outcomes. We have previously developed an 80-gene molecular subtyping profile (BluePrint) for the classification of breast cancer into three molecular subtypes: triple-negative (“Basal-type”); hormone receptor-positive (“Luminal-type”) and ERBB2-positive (“ERBB2-type”). In this study, we sought to determine if Luminal-type tumors are characterized by active ER signaling. Methods: ERα ChIP-seq data from proliferating MCF-7 breast cancer cells was used from a publically available dataset [Ross-Innes, 2010]. The transcription start sites of the 58 genes in the gene set that identifies the Luminal-type subgroup were determined after which the presence of Estrogen Receptor binding sites was analyzed within a window of −/+ 20 kb from the transcription start site. The sequence track was visualized using the UCSC genome browser (http://genome.ucsc.edu/). Peak intensity was determined from the tag count. Results: We found that 32 of the 58 Luminal profile genes have ERα binding sites adjacent to their promoters (55%), whereas only 28% of all RefSeq genes (24,000) have ERα binding sites in their promoters. This result indicates that the genes associated with Luminal-type breast cancer are significantly enriched for those that have ERα binding sites adjacent to their promoters (p= 1.2e-5). Conclusions: The group of genes identifying Luminal-type breast cancer is highly enriched for genes having an Estrogen Receptor binding site in their promoter-proximal region suggesting that these genes are direct targets of the Estrogen Receptor. As such, the classification of breast tumors as “Luminal” by BluePrint most likely describes breast cancers that depend on Estrogen Receptor signaling. These data suggest that Luminal-type breast tumors are likely to respond to endocrine therapy.
Use of peripheral blood mRNA signature to distinguish patients with breast cancer from benign breast disease and nonconclusive mammography.
Authors: B. Yang, Q. Xu, F. Wu, F. Liu, X. Ye, X. Meng, B. Mougin, G. Liu, S. Zhimin, J. Wu
Journal: Journal of Clinical Oncology (2010)

10581 Background: Due to small volume and high-density breast, Asian women, especially the young group, are classified as BI-RADS 0 in their mammographic diagnosis when imaging cannot identify. Within the framework of Breast Cancer Screening Program of Fudan University Cancer Hospital (FUCH), this proportion is at least 10%. Follow-up is usually recommended, which requires a long, expensive and anxiety producing process, based on ultrasonography or MRI or even biopsy. No alternative based on blood biomarkers has yet succeeded to discriminate within the BI-RADS 0 patients, between breast cancer (BC) and benign breast disease (BBD). DNA-microarrays and PAXgene are used in the present study to explore gene expression repertoire in peripheral blood samples, with attractive perspectives for new biomarker discovery. Methods: 84 BC and 94 BBD patients with mammographic results and confirmed pathologic information were enrolled in our study, categorized in two groups, 79 BC + 73 BBD with BI-RADS 1-5, and 5 BC + 21 BBD with BI-RADS 0. RNA extracted from peripheral blood samples collected in PAXgene tube, were analysed after NuGEN WT-Ovation RNA amplification, using Affymetrix GeneChip HG-U133 Plus 2.0 arrays. A 28-gene panel was developed, to discriminate BC and BBD patients with BI-RADS 1-5. This model has then been tested in the BI-RADS 0 group. Results: Using this 28-gene panel, we correctly classified 88% samples in the training set of BI-RADS 1-5, and correctly predicted 73% samples in the test set of BI-RADS 0. The majority of these genes had a decreased expression level in BC patients, and predominantly encoded proteins implicated in ribosome production and translation control. In contrast, the expression of some defense-related genes was increased in those patients. Conclusions: Our work has led to identify a peripheral blood mRNA signature which can help discriminate breast cancer from benign breast disease, with a particular interest in patients with non-conclusive mammography. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration bioMerieux
A myeloid tumor suppressor role for <i>NOL3</i>
Authors: Robert F. Stanley, Richard T. Piszczatowski, Boris Bartholdy, Kelly Mitchell, Wendy M. McKimpson, Swathi Narayanagari, Dagmar Walter, Tihomira I. Todorova, Cassandra Hirsch, Hideki Makishima, Britta Will, Christine McMahon, Kira Gritsman, Jaroslaw P. Maciejewski, Richard N. Kitsis, Ulrich Steidl
Journal: The Journal of Experimental Medicine (2017)

Despite the identification of several oncogenic driver mutations leading to constitutive JAK–STAT activation, the cellular and molecular biology of myeloproliferative neoplasms (MPN) remains incompletely understood. Recent discoveries have identified underlying disease-modifying molecular aberrations contributing to disease initiation and progression. Here, we report that deletion of Nol3 (Nucleolar protein 3) in mice leads to an MPN resembling primary myelofibrosis (PMF). Nol3−/− MPN mice harbor an expanded Thy1+LSK stem cell population exhibiting increased cell cycling and a myelomonocytic differentiation bias. Molecularly, this phenotype is mediated by Nol3−/−-induced JAK–STAT activation and downstream activation of cyclin-dependent kinase 6 (Cdk6) and Myc. Nol3−/− MPN Thy1+LSK cells share significant molecular similarities with primary CD34+ cells from PMF patients. NOL3 levels are decreased in CD34+ cells from PMF patients, and the NOL3 locus is deleted in a subset of patients with myeloid malignancies. Our results reveal a novel genetic PMF-like mouse model and identify a tumor suppressor role for NOL3 in the pathogenesis of myeloid malignancies.
Comparative circulating tumor DNA levels for <i>KRAS</i> mutations in patients with nonresectable pancreatic cancer.
Authors: Julia S. Johansen, Cecile Rose T. Vibat, Dan Calatayud, Benny Vittrup Jensen, Jane Preuss Hasselby, Eric Andrew Collisson, Timothy Lu, Jason C. Poole, Mark Erlander
Journal: Journal of Clinical Oncology (2015)

288 Background: Non-resectable pancreatic cancer patients have a wide range of median time for overall survival (OS). Currently there is a lack of diagnostic tools to predict patient outcome at diagnosis. KRAS mutations are present in the vast majority of pancreatic tumors. The study objective was to determine if quantitative baseline and longitudinal monitoring of KRAS mutations from plasma circulating tumor DNA (ctDNA) could be used to stratify patients for predicting outcome. Methods: Plasma was prospectively collected from the Danish BIOPAC study for non-resectable pancreatic cancer patients undergoing treatment with gemcitabine or FOLFIRINOX. Feasibility of monitoring ctDNA KRAS mutations was assessed in 10 patients with long OS (median 493 days; range 360-1031) and 10 patients with short OS (median 66 days; range 21-136). KRAS G12A/C/D/R/S/V, and G13D mutations were PCR enriched, sequenced by massively parallel deep sequencing, quantitated and standardized by reporting number of copies detected per 10 5 genome equivalents (GE). Results: In a pilot study of 20 patients, all 18 patients with evaluable DNA had detectable KRAS mutations. Of 18 patients, 12 had baseline plus longitudinal time points (7 short, 5 long OS). Mutant KRAS copies were higher for short OS (median=994; range 0-34305 copies/10 5 GE) vs. with long OS (median 196; range, 34-278 copies/10 5 GE). Longitudinally, KRAS mutation levels remained mostly low with long OS (last time point median 204; range 8-873 copies/10 5 GE) vs. short OS where levels increased or remained high (median 2363; range 71-47919 copies/10 5 GE). Identical KRAS mutations were consistently detected for a given patient with short OS. However, long OS patients had variable KRAS mutations in longitudinal analysis. Conclusions: High levels of ctDNA KRAS mutations at diagnosis and post-treatment elevation of KRAS mutations were more associated with short OS. Different levels of KRAS mutation at diagnosis may predict patient outcome and could reflect distinct underlying tumor biology. Expansion of this prospective-retrospective biomarker cohort will be reported.
Age disparity in Oncotype DX testing in a community oncology setting.
Authors: Suheir Khajuria, Ashley Adams, Andrew Michael Schreiber
Journal: Journal of Clinical Oncology (2013)

119 Background: Oncotype Dx is a twenty-one gene prognostic assay traditionally used to predict response to systemic chemotherapy in early stage, hormone positive, node negative, HER2neu negative breast cancer. We evaluated the prevalence of Oncotype Dx testing in a local community oncology setting, co-relation with patient age and co-relation of recurrence score with receiving chemotherapy. Methods: A retrospective chart review was performed on all 406 breast cancer patients who presented to our local cancer center between January 2011 and March 2012. Pathology (ER/PR/HER2neu), eligibility for Oncotype Dx testing, patient characteristics and use of chemotherapy were analyzed. Results: Based on National Comprehensive Cancer Network guidelines, 147/406 met standard criteria for Oncotype Dx testing. Of these, 64 patients (43.8%) received testing, and 6 (4.1%) received Mammaprint testing. Oncotype Dx testing was ordered on 53.5% (54/101) of patients younger than 70 years of age and 22.2% (10/45) of patients 70 years of age or older. Increasing age was significantly related to decreased Oncotype Dx testing (p = 0.0021). Mean age of patients who did and did not undergo testing was 59.8 ± 9.9 and 66.2 ± 12, respectively. Patient age was not significantly related to the decision to undergo chemotherapy (p = 0.1085). Oncotype Dx recurrence score was a significant predictor of choosing chemotherapy when appropriate at the cancer center (p=0.0091). Conclusions: The likelihood of receiving Oncotype Dx testing decreased with the patient’s age. However, the decision to undergo chemotherapy was not related to age. Factors such as patient's aversion to chemotherapy or decision to consider chemotherapy regardless of recurrence score may have influenced the ordering of Oncotype Dx testing. Further studies are warranted to evaluate physician, patient and other barriers to Oncotype Dx testing.
Statin use and mortality in patients with colorectal cancer: A systematic review and meta-analysis of observational studies.
Authors: Arjun Gupta, Siddharth Singh, Preet Paul Singh
Journal: Journal of Clinical Oncology (2015)

686 Background: Preclinical evidence suggests that statins have anti-neoplastic properties by inhibiting cell proliferation, and inducing apoptosis. Statins may be associated with reduced risk of colorectal cancer (CRC), but their effect on CRC related mortality is unclear. We performed a meta-analysis of published observational studies evaluating statin use in patients with CRC and its association with overall and CRC-specific mortality. Methods: Through a systematic search upto August 2014, we identified 7 observational studies (64,773 patients with CRC;19.5% statin users) reporting the association between statin use and mortality in patients with CRC. Summary hazard ratio (HR) with 95% confidence intervals (CI) was estimated using the random effects model, and heterogeneity was measured using the inconsistency index (I 2 ). Results: On meta-analysis, statin use was associated with a 26% reduction in all-cause mortality in CRC patients as compared to non-use (6 studies; adjusted HR, 0.74; 95% CI, 0.67-0.83) with minimal heterogeneity (I 2 =18%), after adjusting for age, sex and CRC stage. Only one study adjusted for concomitant metformin use. Five studies evaluated CRC-specific mortality; on meta-analysis, use of statins (vs non-use) was also associated with decreased CRC-specific mortality (adjusted HR, 0.74; 95% CI, 0.70-0.83; minimal heterogeneity, I 2 =17%). On limiting analysis to statin use after diagnosis of CRC, use of statins remained significantly associated with reduced CRC-specific mortality (3 studies; adjusted HR, 0.70; 95% CI, 0.60-0.81), but not overall mortality (4 studies; adjusted HR, 0.82; 95% CI, 0.64-1.05). On restricting analysis to studies, which adjusted for concomitant use of aspirin/NSAID, the inverse association between statin use and overall- (5 studies; adjusted HR, 0.74; 95% CI, 0.66-0.84) and CRC-specific mortality (4 studies; adjusted HR, 0.76; 95% CI, 0.69-0.84) remained significant. Conclusions: Based on this meta-analysis, statin use in patients with CRC may be associated with reduced all-cause and CRC-specific mortality. This observation merits prospective investigation of statins’ effect on outcome in CRC patients.
Benchmarks of quality breast care over 10 years.
Authors: Cary Steven Kaufman, F. Lee Tucker, Barbara Rabinowitz, Teresa Heckel, Jennifer S. Gass
Journal: Journal of Clinical Oncology (2016)

272 Background: In 2005, the National Quality Measures for Breast Centers (NQMBC) was initiated as a web-based program to capture breast center performance using process of care measurements. The program participant enters data verified by the breast center director or administrator which was randomly audited. As a center submits data, their results are immediately compared with other similar centers as well as with all submitting centers. Methods: Of the 31 measures, we focus on six pertinent measures of quality breast care; time from diagnostic mammogram to needle biopsy, time from needle biopsy to initial breast cancer surgery, breast conservation rate, use of radiation therapy for breast conserving patients, use of endocrine therapy, and use of chemotherapy. Data was submitted in aggregate form, with each center submitting their average performance for any measure every 6-12 months from 2005 to 2014. Each submission included the number of patients used to calculate their submission. For this report, we have defined the “benchmark” as the average performance of all centers submitting data for a particular time period. Results: At the end of 10 years, the time from diagnostic mammogram to needle biopsy decreased by 2 days (207,425 patients reviewed), while the time from needle biopsy to initial cancer surgery increased by 5 days (86,084 patients). Breast conserving surgery markedly decreased 2.4% per year from 2005 to 2010, yet increased 2% per year from 2010 to 2014 (29,455 patients). For use of adjuvant therapies, we saw gradual increase in use. At 10 years, use of radiation therapy was at 92.5%, had increased at 0.7% per year, 6.5% overall increase (13,202 patients); use of endocrine therapy was 89%, had increased at 1.2% per year, 12% overall increase (12,684 patients); and use of chemotherapy was 97%, had increased at 0.5% per year, 10% overall increase (2,467 patients). Conclusions: Benchmarks of quality breast care are necessary as guideposts for providers. While the use of adjuvant therapies have increased over 10 years as expected, the fluctuations of use of breast conserving surgery as well as changes in time spent prior to surgery were unexpected. Benchmarks may change over time in unpredictable ways which supports ongoing monitoring the level of breast quality care.
Prognostic Factors and Long-Term Outcome for Patients with Hodgkin’s Lymphoma Who Relapse after an Autologous Stem Cell Transplantation.
Authors: Mireia Constans, Anna Sureda, Reyes Arranz, Maria Dolores Caballero, Juan Jose Lahuerta, Juan Carlos Hernandez-Boluda, Maria Jesus Vidal, Jose Garcia-Laraña, Jose Rifon, Josep Maria Ribera, Pascual Fernandez-Abellan, Jose Maria Moraleda, Maria Teresa Bernal, Maria Victoria Mateos, Maria Martin-Mateos, Rafael Cordoba, Javier Garcia-Conde, Jorge Sierra, Eulogio Conde
Journal: Blood (2004)
Eradication of metastatic HRBC resistant to trastuzumab and cetuximab after treatment with stealth nanoparticle formulation composed of clamp PNA against mRNA of sGCa1/b1,anti-MUC1 chimeric MAb,and vinorelbine tartrate
Authors: I. Athanasiadis, J. Giannios
Journal: Journal of Clinical Oncology (2008)

14640 Background: For HRBC,the unmet medical need is high due to the lack of treatment options.Overexpression of sGC,MUC1and bcl-2 causes immuno-and chemoresistance. Methods: We obtain surgically stage-IV HRBC cells from patients,characterised by upregulation of MUC1,sGCa1b1,and bcl-2.We synthesized antigene clamp PNA oligomers (DNA analogs),in which an N-C2- aminoethyl-glycine polyamide replaced PO4 ribose ring backbone,and methylene carbonyl linker connected nucleobases to central amine of N- C2-aminoethyl glycine.The 6 mer homopyrimidine triplex [(PNA)2/RNA)] hybridized to the 5’ end (Leader),and the 10 mer purine/pyrimidine duplex (PNA/RNA) hybridized to the 3’-end (Trailer) of the AUG start codon region on the mRNA of sGCa1/b1.The clampPNA anti-sGCa1/b1 was entrapped in the polar phase,and vinorelbine in the lipid phase, surrounded by a stealth polymer layer,and layer with linked chimeric MAbs against MUC1 of the nanoparticle formulation,termed as SEVINA-IV which was administered to xenograft animal models. Results: Post-treatment,downregulation of MUC1 released TKIs by blocking steric hindrance onto HER2/neu,and EGFR.Blocked phosphorylation of MUC1 inhibited Ras/Raf/Erk1/2/MAPK,PI3K/AKT,VEGF,and MMP-2.ADCC was induced.The clamp PNA formed Watson-crick double helices,and steric hindrance of the translation machinery downregulating sGCa1/b1 after assembly inhibition of the 80S ribosome initiation complex.Inhibited translation of NO blocked S-nitrosylation of cystein 118 leading to cGMP-dept downregulation of COX- 2,and NF-kB inducing p53 indpt apoptosis or type I PCD.PTEN was upregulated,and phosphorylation of pRb was blocked,inactivating mTOR,p70 S6K,and eIF-4E of the translational machinery,inhibiting cyclin D1 and ODC.Vinorelbine phosphorylated bcl-2 releasing beclin-1,and inducing type II PCD or autophagy.Also,TEM exhibited type III PCD/necrosis. Conclusion: SEVINA-IV immunochemogene Tx eradicated HRBC after phosphorylation of bcl-2,inhibition of MUC1,translation of sGCa1/b1,and downstream signaling pathways,circumventing resistance to trastuzumab,and cetuximab. No significant financial relationships to disclose.
HER2 expression in patients (pts) with surgically resected urothelial cancer at high risk of recurrence screened for the phase II randomized, open-label trial of DN24-02, an autologous cellular immunotherapy targeting HER2.
Authors: Michael F. Press, Peter H. O'Donnell, Elizabeth R. Plimack, Leonard G. Gomella, David I. Quinn, Padmanee Sharma, Todd DeVries, Robert Brownell Sims, Melissa Chen, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2013)

292 Background: HER2 overexpression has been suggested as a poor prognostic factor in pts with high-risk urothelial carcinoma (UC). Published data note a wide range of HER2 overexpression in UC, with some reports showing &lt;10% of cases and others exhibiting &gt;50% of cases with ≥2+ HER2 expression by immunohistochemistry (IHC). NeuACT (N10-1; NCT01353222) is a phase 2 trial to determine whether DN24-02, an autologous cellular immunotherapy targeting HER2 based on the same platform used for sipuleucel-T, given as adjuvant therapy following surgical resection can prolong survival (Bajorin, et al. ASCO 2012). Here we report preliminary data for HER2 expression on primary tumor and positive lymph node samples from this study. Methods: Trial eligibility criteria include surgical resection of a primary UC, with either ≥pT2 or pN+ staging, and HER2 expression ≥1+ IHC. Surgical specimens are screened for HER2 expression by central pathology laboratory review and HER2 positivity is scored using the Dako HercepTest scoring system. Results: As of August 2012, tumor specimens from 61 pts have been screened for HER2 expression. Of these pts, 49 (80%; 95% CI: 68–89%) had a HER2 expression score of ≥1+ in the primary tumor, with 27 (44%) having ≥2+ score and 3 (5%) having a 3+ score. Twenty-three pts (38%) also had HER2 expression levels evaluated in tumor from involved lymph nodes. A total of 20 (87%; 95% CI: 66–97%) of these pts had a HER2 expression score of ≥1+ in the lymph nodes, with 12 (52%) having a ≥2+ score and 3 (15%) having a 3+ score. Two pts had primary tumor samples that expressed HER2 but were negative for HER2 expression in the lymph nodes submitted for analysis. Conclusions: Although preliminary, a high frequency (≥80%) of HER2 expression score of ≥1+ in primary tumor and lymph node samples was observed. These data highlight the prevalence of HER2 protein expression in high-risk UC. Furthermore, the HER2 expression data are consistent with previously published data in pts with invasive UC. Clinical trial information: NCT01353222.
Results of a phase II trial of novel carbonic anhydrase IX radiotracer 18F-VM4-037 in renal cell carcinoma.
Authors: Adam R. Metwalli, Baris Turkbey, Yolanda McKinney, Juanita Weaver, Nana Yaqub-Ogun, Maria Merino, Maria Liza Lindenberg, W. Marston Linehan, Peter L. Choyke
Journal: Journal of Clinical Oncology (2014)

LBA400 Background: Carbonic Anydrase IX (CAIX) has been identified as a potential marker for clear cell renal cell carcinoma (ccRCC). We report the results of a phase II clinical trial of a novel small molecule radiotracer that binds to CAIX in clinically localized kidney tumors or biopsy proven metastases. Methods: Between October 2012 and May 2013, patients with kidney tumors underwent imaging with the 18F-VM4-037 radiotracer within 4 weeks of biopsy or surgery for kidney tumors. Imaging characteristics with the radiotracer were collected. All H&amp;E pathology was centrally reviewed by a single pathologist. Immunohistochemistry of the surgical specimens for CAIX and Carbonic Anhydrase XII (CAXII) was reviewed by two experienced pathologists. Primary objectives were to evaluate the biodistribution of the radiotracer within tumor and non-tumor tissues as well to assess the safety of the radiotracer in patients. Results: 12 patients were enrolled and 11 received radiotracer and images were obtained. All patients tolerated the radiotracer well with no significant adverse events. 10 of the 11 patients had histologically confirmed malignancy. 1 patient had a complex cyst with no tumor found at surgery. Two patients had extrarenal disease and 9 had tumors in the kidney only. 100% had ccRCC and 4/11 had germline VHL mutations. Mean SUV for the entire group as 5.44 in the index lesions; in patients with histologically confirmed ccRCC the mean SUV was 5.91. 12 samples were stained for CAIX and CAXII including a biopsy obtained from a lung metastasis in one patient. The concordance between pathologists for CAIX IHC was 75%, for CAXII was 67%. Of the CAIX IHC slides, 67% had 3+ staining, 25% had 2+ and one specimen did not demonstrate CAIX staining. Only one specimen demonstrated 3+ staining for CAXII; 2 specimens had no detectable staining for CAXII and the remainder stained 1-2+ for CAXII. Conclusions: The 18F-VM4-037 was well tolerated and demonstrated modest signal uptake in tumors within the kidney. Immunohistochemistry staining for CAIX and CAXII was robust in nearly all tumors making correlation with radiotracer signal difficult. Larger studies are needed to evaluate the diagnostic performance of this radiotracer. Clinical trial information: NCT01712685.