tbuckley/cabot-search huggingface dataset:
Frequent LOH of CYP2D6 in ER+ breast cancer determined by next-generation sequencing (NGS).
Authors: Mark J. Ratain, James Sun, Yusuke Nakamura, Nancy J Cox, Tarek Sahmoud, Phil Stephens, David Chen, Vincent A. Miller, Jeffrey S. Ross, Roman Yelensky
Journal: Journal of Clinical Oncology (2013)

534 Background: The role of CYP2D6 genetic variation in predicting response to tamoxifen in ER+ breast cancer is a subject of ongoing debate. There has been great variability in approaches to both genotyping and phenotyping, and in particular many investigators have extracted DNA from breast cancer samples rather than peripheral blood. We hypothesized that CYP2D6 gene copy number alterations are common in ER+ breast cancer, affecting genotype results, and used NGS to characterize CYP2D6 in patients with ER+ disease. Methods: CYP2D6 sequencing was performed as part of a comprehensive NGS profile of cancer-related genes for 261 predominantly relapsed and metastatic ER+ breast cancer FFPE specimens. Sequence data were resolved into genotypes according to the * allele nomenclature. Tumor LOH was determined at CYP2D6, and its error impact on genotyping methods was estimated. To assess biological significance, the prevalence of CYP2D6 alleles and LOH in ER+ disease was compared against a control set of 99 ER- tumors. Results: CYP2D6 allele frequencies in our full cohort (ER+, 261; ER-, 99) were consistent with prior studies; 64.4%, 16.8%, 9.0% vs. 63.1%, 17.2%, 7.0% for *1/*2, *4, and *41 respectively, and 1%-2% for the rarer alleles *9, *10, and *5. The rate of CYP2D6 LOH was higher in ER+ disease (41% vs. 26%, p&lt;0.01), with all excess arising from copy-loss (as opposed to copy-neutral) changes (22% vs. 7%, p&lt;0.002). The estimated impact of LOH on germline genotype assessment from tumor was considerable; an assay sensitive at &gt;20% minor allele frequency (e.g., Sanger sequencing) can misclassify &gt;10% of heterozygotes, leading to significant Hardy-Weinberg disequilibrium (e.g., p=8.3x10 -8 for *4). Interestingly, an enrichment of reduced or non-functional CYP2D6 alleles in ER+ samples was observed (61% vs. 47%, p&lt;0.03). Conclusions: Our results demonstrate the distorting effect of extensive LOH on genotype assessment of CYP2D6 in breast cancer. Therefore, tumor DNA should not be routinely used for determination of germline 2D6 genotype, although it appears possible to use NGS. The apparent association between reduced function CYP2D6 alleles and ER+ breast cancer in our dataset requires further investigation.
Epidermal growth factor +61 a/g polymorphisms as predictors for survival in advanced lung adenocarcinoma and squamous cell carcinoma.
Authors: Ramon Andrade De Mello, Monica Ferreira, Filipa Soares-Pires, Sandra Costa, Pedro Oliveira, Venceslau Hespanhol, Rui M Reis
Journal: Journal of Clinical Oncology (2013)

e19069 Background: Our purpose was to evaluate epidermal growth factor (EGF) +61 A/G polymorphisms as prognostic marker for progression free survival (PFS) and overall survival (OS) in advanced non-small cell lung cancer (NSCLC). Methods: 148 Portuguese Caucasian, medically treated for NSCLC between February 2010 and April 2011, were included in this study. DNA was extracted from peripheral blood leucocytes. Genotyping was performed by PCR-RFLP. Chi-square test, Kaplan-Meier estimator and cox regression hazard model were used to assess the prognostic value of selected polymorphisms. Results: Genotype frequency was A/A (25.3%), A/G (55.6%), G/G (19.2%). We found no differences in PFS among EGF+61 A/G polymorphisms and NSCLC (p = 0.339). However in G/G+A/G genotype patients group showed a trend to higher OS than A/A genotype (p = 0.055). Moreover, adenocarcinoma and squamous cell (SC) lung cancers patients harboring in A/G+G/G genotype group showed a trend to higher OS than those harboring A/A genotype (p = 0.074). Furthermore, patients in advanced stages carrying G/G genotype presented higher OS than those carrying A/A genotype: 13 months versus 3 months (adenocarcinoma); and 6 months versus 1 month (SC lung cancer), respectively, p = 0.043. Conclusions: We were able to observe the G/G genotype of EGF+61 A/G polymorphisms as a positive predictor for survival in medically treated advanced adenocarcinoma and squamous cell lung carcinoma patients. In future, our findings could be used as a biological marker in order to identify eligible NSCLC subgroups with potential improved response to EGFR tyrosine-kinase-inhibitors.
Phase I and pharmacokinetic (PK) study of pazopanib (P) in combination with two schedules of ifosfamide (I) in patients (pts) with advanced solid tumors (STs).
Authors: Paul Hamberg, Marye Boers-Sonderen, Walter J. Loos, Maja J. De Jonge, Winette T.A. Van Der Graaf, Ben B Suttle, Ferry Eskens, Jaap Verweij, Carla Van Herpen, Stefan Sleijfer
Journal: Journal of Clinical Oncology (2012)

2593 Background: P is a tyrosine kinase inhibitor of PDGFR, VEGFR and KIT. This study aimed to determine the recommended phase II dose (RP2D) of P combined with I. To assess the impact of scheduling on tolerability, two I schedules were explored. Methods: Pts with progressive ST, no standard therapy available, PS 0-1 and good organ function were eligible. Pts received daily P with 3-weekly I, 9 g/m 2 /cycle, either continuously (Iciv) or as 3 hrs boluses (Ibolus) for 3 days. P was escalated in serial cohorts of 3-9 pts per I-schedule. If in 3-6 pts dose-limiting toxicity (DLT) of 33.3% within 1 st cycle was seen 3 more pts at that dose level (DL) were enrolled. RP2D was exceeded if in &gt; 1/3 pts, &gt; 2/6 pts or ≥ 3/9 pts DLT occurred. P was maximized at 1000 mg/day. At RP2D, an expansion cohort of 6-9 pts was studied to confirm safety. PK samples of P and I were collected in all pts. Sampling allowed intra-individual comparison of I-PK with or without P and vice versa. Results: 47 pts were studied. For Iciv (25 pts), RP2D was the maximum dose of P (1000 mg), higher than the single agent RP2D. At RP2D 2 DLTs in 15 pts occurred: 1 febrile neutropenia (FN); 1 encephalopathy. With Ibolus (22 pts), P 400 mg with or without GCSF was not tolerated (5 DLTs in 10 pts: 3*FN, 1 encephalopathy; 1 proteinuria). At RP2D (P 200 mg + Ibolus + GCSF) 3 DLTs in 12 pts (FN; encephalopathy, renal insufficiency) were observed. Toxicity occurring in &gt;30% of pts in Iciv (all grades/grade 3-4,%) were neutropenia (92/92) anemia (92/8); thrombocytopenia (35/12), elevated ASAT, ALAT, alkaline phosphatase (73/4; 73/0; 62/2), nausea (58/0), vomiting (73/0), diarrhea (54/0) and hypertension (31/12). 4/25 pts in Iciv evaluable for response had PR (2 sarcoma, 2 ovary) and 10 prolonged (≥3 mths) SD. In Ibolus, 6/20 pts had PR (2 urothelial, 1 sarcoma, 1 ovary, 1 CUP, 1 mesothelioma) and 3/20 prolonged SD. Preliminary PK analysis showed no effect of P on I-exposure, neither of Ibolus or Iciv on P. Conclusions: P is tolerated at a higher dose combined with Iciv compared to Ibolus (1000 vs 200 mg). PK cannot explain this difference. This study underlines the impact of scheduling on the tolerability of VEGFR-TKI and cytotoxic drug combinations.
The influence of Tai Chi (TC) and support therapy (ST) on fatigue and quality of life (QOL) in women with breast cancer (BC)
Authors: K. M. Mustian, J. A. Katula, J. Roscoe, G. Morrow
Journal: Journal of Clinical Oncology (2004)

8143 Background: Cancer-related fatigue (CRF) is reported in up to 99% of BC patients, with 60% rating their CRF as moderate to severe, and 30% experiencing persistent fatigue 2 or more years after acute treatments. CRF has a detrimental effect on QOL and results in greater reductions in functional capacity among BC patients compared to healthy controls. Although there is no standard treatment for CRF, physical exercise has demonstrated a consistent positive influence on CRF and QOL. However, it is not clear how TC, a form of physical exercise, influences CRF, specifically persistent CRF. Thus, the purpose of this pilot study was to compare the efficacy of TC and ST for reducing CRF and enhancing QOL in women with BC. Methods: Women with BC (N=21; mean age=52; 1wk-2.5yrs post-chemotherapy/radiation) were randomized to a 12wk (3x/wk; 60min) TC or ST intervention. Participants completed self-report assessments of CRF and QOL (FACIT-F) at baseline, 6wks and 12wks. Results: Repeated-measures ANOVAs revealed a significant time main effect for QOL (\(\underline{\mathrm{F}}\)1,19=7.7, \(\underline{\mathrm{p}}\)<.05), and approached significance for fatigue (\(\underline{\mathrm{F}}\)1,19=2.8, \(\underline{\mathrm{p}}\)=.07). Although there were no significant condition or interaction effects, simple change scores revealed improvements in the TC condition on fatigue from baseline to 6wks (mean=10.8, SD=9.5) and baseline to 12wks (mean=7.0, SD=9.2), as well as QOL from baseline to 6wks (mean=3.4, SD=16.8) and baseline to 12wks (mean=14.2, SD=20.2). Among the ST condition, fatigue improved from baseline to 6wks (mean=4.2, SD=7.5), however, fatigue increased from baseline to 12wks (mean=−.20, SD=7.4), and QOL decreased from baseline to 6wks (mean=−5.7, SD=11.6) and baseline to 12wks (mean=−.48, SD=14.1). Conclusions: TC resulted in positive changes in CRF and QOL from baseline to 6wks and 12wks, while ST only improved CRF from baseline to 6wks and did not improve QOL. Funded by Susan Stout and Sally Schindel Cone Grants. No significant financial relationships to disclose.
Erratum: Selective induction of apoptosis in Hep 3B cells by topoisomerase I inhibitors: Evidence for a protease-dependent pathway that does not activate cysteine protease 32 (Journal of Clinical Investigation (December 1996) 98:11 (2588-2596))
Authors: P. N. Adjei, S. H. Kaufman, W. Y. Leung, F. Mao, G. J. Gores
Journal: Journal of Clinical Investigation (1997)
Neoadjuvant androgen pathway suppression prior to prostatectomy.
Authors: Elahe A. Mostaghel, Peter Nelson, Paul H. Lange, Daniel W. Lin, Mary-Ellen Taplin, Steven P. Balk, William J Ellis, Trevor Penning, Brett Marck, Lawrence D. True, Robert Vessella, Robert B. Montgomery
Journal: Journal of Clinical Oncology (2012)

4520 Background: Optimizing tissue androgen suppression may provide better local and systemic control of prostate cancer (PCa). Standard androgen deprivation therapy (ADT) has limited effect on tissue androgens which remain in a range which supports tumor survival. We determined whether targeting androgen metabolism using CYP17 and 5a-reductase (SRD5A) inhibitors would more effectively suppress tissue androgens and tumor volume. Methods: Open label, multicenter neoadjuvant study in men with localized PCa treated for 3 months prior to prostatectomy with zoladex and 1) avodart 3.5 mg QD; 2) avodart and casodex 50 mg QD; or 3) casodex, avodart and ketoconazole 200 mg TID. Serum and tissue androgens were measured by LC/MS/MS. Data were compared to men treated with standard ADT (LHRH agonist plus Casodex), and untreated prostatectomy tissue. The primary outcome measure was suppression of tissue dihydrotestosterone (DHT). Results: 35 men with intermediate/high risk PCa were enrolled. Tissue DHT was suppressed 30 fold (&gt; 95%) in all groups vs. LHRH agonist/Casodex (0.92 ± 0.20 pg/mg vs. 0.03± 0.03 for all groups combined, p&lt;0.0001). Tissue testosterone was 3-4 fold higher (consistent with SRD5A inhibition) in all treatment groups vs. LHRH agonist/Casodex (0.33 vs. 0.07 pg/mg, p &lt; 0.05). Differences in DHT/T between groups 1 through 3 were not statistically significant. There was no correlation between tissue and serum androgens, or tissue androgen and tumor volume (p&gt; 0.05). In subset analysis, total serum DHEA declined significantly in group 3, with free DHEA unchanged, suggesting differential effect on free and total DHEA. Pathologic complete response (CR) was seen in 2 men, and an additional 8 men had &lt;0.2 cc of tumor, with the largest number of CR or near CR in the cohort treated with ADT, CYP17 and SRD5A inhibitor, 4 of 12 men (33%). Due to small cohort size, differences were not statistically significant. Conclusions: Addition of high dose SRD5A inhibition (with and without CYP17 inhibition) achieves prostate DHT levels 30 fold below standard ADT. In this relatively high risk population, CR or near CR was seen in 10 of 35 men receiving protocol therapy. Further suppressing the androgen receptor signaling axis may provide better local and systemic control of PCa.
Effectiveness and safety of sorafenib for unresectable and advanced intrahepatic cholangiocarcinoma: A pilot study.
Authors: Xiangji Luo, Weidong Jia, Zhiyong Huang, Xiangcheng Li, Baocai Xing, Xiaoqing Jiang, Jun Li, Tian Yang, Chunfang Gao, Wan Yee Lau, Feng Shen
Journal: Journal of Clinical Oncology (2017)

405 Background: Patients with unresectable and advanced intrahepatic cholangiocarcinoma (ICC) usually have short survival due to a lack of effective treatment. This multicenter, single arm, open labeled, prospective study was conducted to evaluate the effectiveness and safety of the multikinase inhibitor, sorafenib, combined with best supportive care (BSC) in these patients. Methods: Forty-four patients with unresectable and advanced ICC were treated with sorafenib (400 mg, twice daily) and BSC. The primary endpoint was disease control rate (DCR) at week 12; secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), duration of therapy (DOT), and adverse events (AEs). Results: The DCR at week 12 was 15.9%. The median TTP was 5.6 months, and the median PFS and OS were 3.2 and 5.7 months (95% confidence interval [CI]: 2.4-4.1 months; 3.7-8.5 months), respectively. The median DOT was 1.8 months (95% CI: 1.9-3.9 months). Grades 1 and 2 AEs occurred in 75% of patients, and one grade 4 AE (hand and foot skin reaction) was observed in one patient. Conclusions: This is the first and only prospective pilot study to examine the use of sorafenib specifically for ICC. Sorafenib with BSC had an acceptable DCR and safety profile in patients with unresectable and advanced ICC. [Table: see text]
Endoglin: a novel target for therapeutic intervention in acute leukemias revealed in xenograft mouse models
Authors: Keina M. C. Dourado, June Baik, Vanessa K. P. Oliveira, Miriam Beltrame, Ami Yamamoto, Charles P. Theuer, Camila A. V. Figueiredo, Michael R. Verneris, Rita C. R. Perlingeiro
Journal: Blood (2017)
EPCR Guides Hematopoietic Stem Cells Homing to the Bone Marrow Independently of Niche Clearance
Authors: Shiri Gur-Cohen, Francesca Avemaria, Orit Kollet, Seymen Avci, Tomer Itkin, Saravana K. Ramasamy, Anjali P. Kusumbe, Karin Golan, Eman Khatib-Massalha, Anju Kumari, Mayela M. Carolina, Wei-Ling Lin, Qing-Cissy Yu, Hua-Lin Wu, Yi Arial Zeng, Ralf H. Adams, Conway M. Edward, Elizabeth J. Shpall, Ayelet Erez, Irit Sagi, Charles T. Esmon, Wolfram Ruf, Tsvee Lapidot
Journal: Blood (2016)
Association of circulating tumor cells with venous thromboembolism in advanced non-small cell lung cancer.
Authors: Robert Lewin Metcalf, Emma Halkyard, Lynsey Priest, Vikki Codlin, Karen Morris, Andrew M. Hughes, Caroline Dive, Fiona Helen Blackhall
Journal: Journal of Clinical Oncology (2014)

e22029 Background: Despite prophylactic anticoagulation during high risk periods (hospital admission and peri-operative periods), venous thromboembolism (VTE) remains a common event in cancer patients. The risk of VTE can be predicted in patients with cancer based upon clinical parameters, and in addition, the presence of ≥1 CellSearch detected circulating tumor cells (CTCs) is associated with VTE in metastatic breast cancer (Mego et al., BJC 2009). The utility of CTC evaluation for prediction of VTE in patients with lung cancer is not known. Methods: Electronic records of 156 non-small cell lung cancer (NSCLC) patients were reviewed to identify patients with VTE occurring during first line chemotherapy. CTCs were enumerated with CellSearch prior to first line therapy, according to an ethically approved protocol. CTCs were evaluated for association with VTE as a continuous variable and dichotomised using a cut off of ≥1. Clinical data was collected to perform VTE risk score according to criteria of Khorana et al., Blood 2008 (1 point each for lung primary site, Hb <10g/dL and/or use of erythropoiesis-stimulating agents, plt >350x109/L, WBC <11x109/L and BMI >35kg/m2; 1-2 intermediate risk, ≥3 high risk). Results: 23/156 (14.7%) NSCLC patients (Stage III/IV 40.7/59.3%) experienced VTE (16 pulmonary emboli, 5 deep vein thromboses, 2 other) ranging from 0-93 weeks following initiation of chemotherapy. 6 patients whose VTE occurred >4 weeks following completion of first line chemotherapy were excluded from the analysis. CTC counts in all patients ranged from 0-155/7.5 ml (median 0, mean 7). Patients with VTE had higher CTC counts than those without VTE (mean CTC count 12 v 6/7.5 ml, p=0.024). CTC count of ≥1 was seen in 10/17 (58.8%) patients with VTE and 38/133 (28.6%) without (p=0.012). However, there was no difference in risk scores between patients with and without VTE (score of 1-2 v ≥3 of 70 v 30% and 67.6 v 33.4% respectively, p=0.571). Conclusions: In this retrospective series of 156 NSCLC patients in whom CTCs were assessed prior to treatment, the presence of CTCs was associated with development of VTE during chemotherapy. CTC number may therefore help to refine VTE risk assessment for prophylaxis in patients with NSCLC.
Antagonistic Coevolution of MER Tyrosine Kinase Expression and Function
Authors: Amanda L. Evans, Jack W.D. Blackburn, Kyle Taruc, Angela Kipp, Brennan S. Dirk, Nina R. Hunt, Stephen D. Barr, Jimmy D. Dikeakos, Bryan Heit
Journal: Molecular Biology and Evolution (2017)

TYRO3, AXL, and MERTK (TAM) receptors are a family of receptor tyrosine kinases that maintain homeostasis through the clearance of apoptotic cells, and when defective, contribute to chronic inflammatory and autoimmune diseases such as atherosclerosis, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and Crohn's disease. In addition, certain enveloped viruses utilize TAM receptors for immune evasion and entry into host cells, with several viruses preferentially hijacking MERTK for these purposes. Despite the biological importance of TAM receptors, little is understood of their recent evolution and its impact on their function. Using evolutionary analysis of primate TAM receptor sequences, we identified strong, recent positive selection in MERTK's signal peptide and transmembrane domain that was absent from TYRO3 and AXL. Reconstruction of hominid and primate ancestral MERTK sequences revealed three nonsynonymous single nucleotide polymorphisms in the human MERTK signal peptide, with a G14C mutation resulting in a predicted non-B DNA cruciform motif, producing a significant decrease in MERTK expression with no significant effect on MERTK trafficking or half-life. Reconstruction of MERTK's transmembrane domain identified three amino acid substitutions and four amino acid insertions in humans, which led to significantly higher levels of self-clustering through the creation of a new interaction motif. This clustering counteracted the effect of the signal peptide mutations through enhancing MERTK avidity, whereas the lower MERTK expression led to reduced binding of Ebola virus-like particles. The decreased MERTK expression counterbalanced by increased avidity is consistent with antagonistic coevolution to evade viral hijacking of MERTK.
The role of post-SRS systemic therapy in synchronous lung cancer brain metastases.
Authors: Shyamal Patel, Waleed Fouad Mourad, Rebekah L. Young, Rafi Kabarriti, Ravindra Yaparpalvi, Linda Hong, Patrick LaSala, Shalom Kalnicki, Madhur Garg
Journal: Journal of Clinical Oncology (2015)

e13052 Background: We present our experience with SRS for patients with synchronous brain metastases from lung cancer and evaluate the prognostic significance of post-SRS systemic therapy (PSST). Additionally, we examine the impact of earlier PSST as well as definitive thoracic radiation (DTR). Methods: In this single-institution retrospective study, we reviewed 96 patients with lung cancer and ECOG PS ≤ 3 who underwent LINAC-based SRS between 2007 and 2013. Of these, 47 patients with 77 synchronous brain metastases (intracranial disease diagnosed within 2 months of primary diagnosis) were included. For analysis, clinical factors were recorded including histology, the systemic status of disease (SDS) at time of SRS, the use of PSST, and whether patients received DTR ( > 45 Gy) after SRS. The SDS was designated as either pulmonary disease (one or both lungs with adjacent nodal involvement) or distant extrapulmonary disease. For analysis, the SRS-PSST interval (SPI) was divided into ≤ 30 days and > 30 days. Univariate and multivariate analyses were performed. Results: The median age of the cohort was 66 (41-81), and 70% was male. 53% received PSST for a median duration of 2 months (1-19). 51% of patients had only pulmonary disease while 47% had extrapulmonary disease. The median SPI was 27 days and 6 patients (13%) received DTR. At a median follow-up of 5 months (1-27), the median survival was 5.8 months and the actuarial overall survival at 3, 6, 12, and 24 months was 68%, 49%, 28%, and 7%, respectively. Univariate analysis revealed the receipt of PSST (p = 0.001) and an SPI > 30 days (p = 0.007) to positively predict for survival. While SDS at time of SRS was not significant, the receipt of DTR positively trended towards significance (p = 0.069). In patients receiving PSST, an SPI > 30 days positively predicted for survival (HR 0.27, 95% CI 0.10-0.72, p = 0.009) regardless of SDS. Conclusions: Our results indicate a prognostic significance for PSST and suggest delaying the initiation of PSST to > 30 days regardless of SDS. This latter finding was potentially influenced by neurotoxicity after SRS. A benefit with DTR was also suggested by our experience. Further investigation is warranted to define the optimal SPI and further characterize the impact of DTR.