tbuckley/cabot-search huggingface dataset:
Polygenic risk score for breast cancer in high-risk women.
Authors: Mary Helen Black, Shuwei Li, Holly LaDuca, Jefferey Chen, Robert Hoiness, Stephanie Gutierrez, Hsiao-Mei Lu, Jill S. Dolinsky, Jianfeng Xu, Celine Vachon, Fergus Couch, Brigette Tippin Davis
Journal: Journal of Clinical Oncology (2018)

1508 Background: While assessment of genetic contribution to breast cancer (BC) risk was once limited to high-penetrance genes such as BRCA1/2, additional genes conferring two- to five-fold increased risks of BC, as well common SNPs with relative risks ranging 1.03-1.57, have recently been identified. Although several reports suggest that a score based on combined genotypes across a large number of SNPs may have substantial predictive value for risk stratification in the general population, few studies have examined the performance of such a score in high-risk women. Methods: We genotyped 102 BC-associated SNPs using next-generation sequencing in order to examine whether a risk score based on these SNPs was predictive of BC in 2,910 women (1,758 cases with no other cancer primaries and 1,152 controls unaffected with any cancer) referred for genetic testing at a single diagnostic laboratory. All women were self-reported Caucasian, 18-85 years of age and provided family history information at the time of testing, and tested negative for pathogenic variants in BC-related genes (mean±SD age at testing 52±13 years). We constructed a polygenic risk score (PRS), with each SNP weighted by per-allele relative risks in Caucasians from large genome-wide association studies and population-specific allele frequencies, and tested PRS association with BC using logistic regression. Results: The PRS was significantly higher in cases than controls (mean±SD 1.41±0.86 vs. 1.06±0.66, p < 0.0001). Compared to women in the 1st quartile of PRS, those in the 2nd, 3rd and 4th quartile were 1.65 (95% CI: 1.34-2.05), 2.12 (95% CI: 1.71-2.64) and 2.75 (95% CI: 2.20-3.44) times as likely to have BC (all p < 0.0001). PRS predictive performance was consistent with prior literature (AUROC = 0.61). Conclusions: These data suggest that a 102-SNP PRS assessed in high-risk patients performs similarly to risk scores reported in the broader population, and has direct implications for their clinical management. Our ongoing analysis of the ability of the PRS to discriminate among specific pathologic subtypes, as well as validity and utility of a PRS combined with clinical models to estimate residual lifetime risk, has the potential to further inform screening guidelines and improve patient care.
Restaging de novo metastatic breast cancer to refine prognostic estimates.
Authors: Jennifer Kay Plichta, Samantha M. Thomas, Amanda R Sergesketter, Oluwadamilola Motunrayo Fayanju, Rachel Adams Greenup, Laura Horst Rosenberger, Gretchen Genevieve Kimmick, Terry Hyslop, Eun-Sil Shelley Hwang
Journal: Journal of Clinical Oncology (2018)

e13083 Background: Although current staging guidelines for early stage breast cancer now include anatomic and biologic factors, there are no standard prognostic models for estimating outcomes in metastatic disease. We aim to evaluate the association of these factors with overall survival (OS) in de novo metastatic breast cancer patients and to propose a model for prognostic stratification. Methods: Adults with de novo metastatic breast cancer were identified from the National Cancer Data Base (2010-2013). Recursive partitioning analysis (RPA) was used to group patients with similar OS based on clinical T/N stage, tumor grade, ER, PR, HER2, number of metastatic sites, and presence of bone-only metastases. The splitting criteria was set to a p-value of 0.10. Categories were created by amalgamating homogeneous patient groups based on 3-year OS rates (group A: > 50%, group B: 30-50%, group C: < 30%). Results: 16,187 patients were identified with a median followup of 32 months. The most common sites of distant metastasis included: bone (73.6%), lung (35.1%), and liver (28.6%). 65.2% had 1 site of distant metastasis, 25.3% had 2 sites, and 42.9% had bone-only metastases. The RPA identified the number of metastatic sites (1 vs > 1) as the first stratification point, and ER status as the second stratification point for both of the resulting groups. Additional divisions were made based on HER2 status, PR status, cT stage, tumor grade, and presence of bone-only metastases. The RPA identified 24 groups with homogeneous OS that were then amalgamated into 3 distinct groups (Table). After adjustment, this trend remained significant; group B vs A: HR 1.58 (95% CI 1.49-1.67), group C vs A: HR 3.44 (95% CI 3.23-3.66). Conclusions: Anatomic staging factors, tumor biology, and extent of metastatic disease are associated with OS and may be used to stratify de novo metastatic patients to provide meaningful prognostic estimates. Group Total Deaths, N (%) Median OS, months (95% CI) 3-year OS Rate (95% CI) 5-year OS Rate (95% CI) Log-rank P-value A 7945 3164 (39.8%) 46.3 (44.8-47.6) 0.615 (0.603-0.627) 0.391 (0.372-0.409) B 4174 2360 (56.5%) 29.8 (28.5-31.1) 0.429 (0.412-0.446) 0.227 (0.205-0.250) < 0.001 C 4068 3086 (75.9%) 13.4 (12.8-14.1) 0.200 (0.186-0.215) 0.098 (0.083-0.114)
Assessment of tumor-infiltrating lymphocytes and immune-checkpoints expression in metastatic colorectal cancer patients.
Authors: Aurelien Gobert, Rana Mitri, Cristian Mateescu, Roger Mouawad, Gilles Le Naour, Jean Baptiste Bachet, Olivier Dubreuilh, Justine Varinot, David Khayat, Gabriel G. Malouf, Frederique Capron, Jean-Philippe Spano
Journal: Journal of Clinical Oncology (2016)

3608 Background: The immune system is known to be involved in oncogenesis and has become a target as confirmed with the immune-checkpoints (ICP) inhibitors in several cancer types. Here we evaluated the expression of ICP and lymphocyte infiltration in a metastatic colorectal cancers with MicroSatellite-Stability phenotype population, to better understand the potential mechanisms underlying a lack of response with ICP inhibitors in this population. Methods: We analyzed the correlation between the quantity and location of lymphocytic infiltrate (primary and metastasis) and ICP expression (PD-1, PD-L1, PD-L2, TIM-1) on lymphocytes, tumoral and endothelial cells with known prognostic factors in a large cohort of colorectal cancers treated in our institution between January 2009 and January 2015. For this purpose, a tissue-microarray composed of 130 samples related to 93 patients has been constructed. The results of TIL and ICP were scored as negative/low or high. Results: This immune assessment was usable for 76 patients, with 61 primary tumors and 35 metastastic sites including liver (n = 18), peritoneum (n = 11) and others (n = 5). There was no difference of TIL expression between primary tumors and metastatic sites (p = 0.79). Surprisingly, higher TIL and CD4/CD8 ratio were observed in liver metastases as compared to other sites (p = 0.0097). PD-L1 expression on lymphocytes was found to be correlated with a T4 tumor infiltration in comparison with less infiltrated tumor (p < 10^3), but there was no difference according lymph nodes involvement. The TIM-1 expression was found on tumor cells and was associated with a younger age than 60y.o. (p = 0,0278) and with a primitive located in the right colon (p = 0,045). Of note, 4 out of 17 cases with available matched primary-liver metastasis gained PD-1 expression associated with an increase of lymphocytic infiltration in metastastic sites. Conclusions: To our knowledge, this is the first study reporting the expression of these immune checkpoints and TIL in a metastatic colorectal cancer population. The TIM-1 and PD-L1 expressions were respectively associated with a younger age at diagnosis, a right colon involvement and also a locally more infiltrating tumor.
Epigenetic modulation of metabolism in glioblastoma
Authors: Zhen Dong, Hongjuan Cui
Journal: Seminars in Cancer Biology (2018)

Epigenetic and metabolic alterations incancer cells are highly associated. Glioblastoma multiforme (GBM) is a complicated pathological process with dysregulated methylation and histone modifications. Metabolic modulation of epigenetics in gliomas was previously summarized. However, epigenetic modulation is also important in metabolic decision. Recently, there has been a tremendous increase in understanding of DNA methylation, chromatin modulation, and non-coding RNAs in the regulation of cell metabolism, especially glycolytic metabolism in GBM. In this review, we summarize DNA methylation, histone alteration, and non-coding RNA mediated epigenetic modulation of metabolism in GBM and discuss the future research directions in this area and its applications in GBM treatment.
Meaningful application of precision oncology.
Authors: Jasmine Kamboj, Elie Chalhoub, Susan Hudson, Teresa Knapp, Peter Friedell
Journal: Journal of Clinical Oncology (2018)

e18806 Background: Next Generation Sequencing [NGS] has become more prevalent in recent times. We analyze use of NGS testing, at a rural Oncology center in Minnesota. Methods: We performed a retrospective analysis at Sanford Health, Bemidji, MN and collected data for patients who underwent NGS testing in 2016/17. We compared registries from 2016/17 to study trends in request for NGS testing, treatment recommendations, trial enrollments [ASCO-TAPUR (T); NCI-MATCH(M);Other (O)(MyPathway, Merck Keynote199, S1507)] and treatments received. Eligible patients had solid tumors, had progressed on palliative systemic standard treatment, had PS 0-2 and had adequate tissue for genomic studies. Results were discussed at genomic tumor board. FDA on label/off label therapy, potential enrollment on clinical trials was recommended based on actionable alterations[AAs]. AAs were defined as any alteration that was inclusion criteria for NGS based treatment arm on a trial or had potential FDA On/Off label treatment. Results: Patient lay out as follows Conclusions: The rising trends seen in request for NGS testing and recommendations based on AAs, did not correlate well with application of FDA on label treatments in practice or accrual on treatment arms in trials. We hypothesize the following reasons for this finding: Lack of guidelines for utility of these tests earlier in patient care, Lack of FDA approved treatments available for biomarkers, Scarcity of clinical trials in remote centers. 2016 2017 NGS requested 4 22 NGS concluded* 4 19 AAs 2/4 18/19 Trials Recommended T 3/4 T 12/19 M 1/4 M 8/19 O 0/4 O 4/19 Patients Enrolled T 0/4 T 1/19 M 2/4 M 3/19 O 0/4 O 5/19 FDA On Label therapy recommendation 1/4 6/19 FDA Off Label therapy recommendation 2/4 14/19 Patients Treated on trials T 0/4 T 1/19 M 0/4 M 0/19 O 0/4 O 0/19 Total Patients Treated 0 1 *2:insufficient tissue; 1:opted hospice; Trends 2016 VS 2017, for AAs[50 VS 94%]; trial recommendations[75% VS 94%]; FDA On Label therapy[25% VS 31%]; FDA Off Label therapy[50% VS 73%]; trial enrollment[50% VS 47%]; treatment received [0% VS 5.26%].
Detailed anatomic site and melanoma prognosis: A population-based study of 6288 patients.
Authors: Daniela Gordon, Johan Hansson, Max Gordon, Sandra Eloranta, Peter Gillgren, Karin E Smedby
Journal: Journal of Clinical Oncology (2016)

9563 Background: Detailed anatomic site (i.e. subsite) has been demonstrated but not fully investigated as an independent prognostic factor in localized cutaneous melanoma. Methods: We reviewed medical records for detailed anatomic site in a population-based Swedish patient cohort diagnosed with primary invasive melanoma 1976 − 2003 (n = 6288). We followed the patients from date of diagnosis until death, emigration or December 31st 2013. We evaluated melanoma-specific and overall survival defined by anatomic subareas in a multivariable regression model adjusting for prognostic factors. Results: Melanoma on the head or neck (adjusted HR 0.5, 95% CI 0.5−0.8), arms (excluding shoulders; HR 0.5, CI 0.4−0.6), legs (HR 0.6, CI 0.5−0.7) and acral sites (HR 0,7, CI 0.5−1.0) showed a more favorable prognosis compared to the trunk (including shoulders). Prognostic heterogeneity was observed within the head and neck area, with a better prognosis for the face and ears (HR 0.6, CI 0.3−1.0) compared to the neck, and within acral sites, with a better prognosis for subungual areas (HR 0.4, CI 0.2−0.8) compared to the palms and soles. Further, melanoma on intermittent peripheral ultraviolet radiation (UVR) exposure sites (lateral arms, lower legs, dorsum of feet; HR 0.7; CI 0.6−0.8) and chronic sites (face, dorsum of hands; HR 0.6; CI 0.4−0.7) showed a better prognosis than those on intermittent core sites (chest, back, neck, shoulders, thighs). Conclusions: This study confirms site as an independent prognostic factor. Detailed anatomic classification is superior to ICD-10 with respect to prognosis and shows a correlation to UVR exposure patterns.
Abstract 14154: Intra-Stent Thrombus Early After Stent Implantation is Associated With Cytochrome P450 2C19 Genotypes in Clopidogrel-Treated Patients
Authors: Masahiro Toyama, Yasuhisa Kuroda, Eiji Ojima, Yuta Oishi, Shunsuke Maruta, Shigeyuki Watanabe
Journal: Circulation (2016)

Background: Cytochrome P450 (CYP) 2C19 polymorphism is associated with poor responsiveness to clopidogrel. This study aimed to clarify the relationship between CYP2C19 polymorphism and the incidenc...
Re: Henk G. van der Poel, Roderick C.N. van den Bergh, Erik Briers, et al. Focal Therapy in Primary Localised Prostate Cancer: The European Association of Urology Position in 2018. Eur Urol 2018;74:84–91
Authors: Massimo Valerio, Mark Emberton, Hashim U. Ahmed
Journal: European Urology (2018)
Concordance in <i>RAS</i> mutation status between liquid and solid biopsies in subjects with <i>RAS</i> wild-type (wt) metastatic colorectal cancer (mCRC) in first-line treatment in Spain: PERSEIDA study (NCT02792478).
Authors: Manuel Valladares-Ayerbes, Pilar Garcia Alfonso, Jorge Muñoz Luengo, Paola Pimentel Cáceres, Jose María Vieitez, Juan J. Cruz-Hernández, Marta Llanos, Carlos García Girón, LLuís Cirera, Ariadna Lloansí Vila
Journal: Journal of Clinical Oncology (2018)

e15602 Background: Tumor biopsies are widely used in clinical practice to assess RAS mutation status in mCRC patients. However, new techniques of genotyping based on circulating tumor (ct) DNA present higher sensitivity and convenience. We studied the concordance between tissue- and blood-based RAS assessment biopsies in naïve mCRC patients, and the additional RAS mutations detected by the liquid biopsy. Methods: PERSEIDA is an ongoing, prospective, observational, multi-centre study which included 119 mCRC patients with RASwt according to solid biopsy as per clinical practice at baseline in 20 Spanish sites. Blood samples were collected prior to first-line onset and sent to Sysmex Inostics GmbH (Hamburg, GER) for BEAMing analysis. Additional liquid biopsies will be performed at 20±2 weeks and at mCRC progression. The lower limit for mutant consideration was a mutant allele fraction (MAF) ≥ 0.02%. Results: Table 1 shows the percentage of subjects with mutations on different KRAS and NRAS exons at baseline and the overall RASmt detection rate according to BEAMing (12.6%). The negative percent agreement between solid and liquid biopsies was 87.4% (95%CI: 80.1%-92.8%) Conclusions: Despite a high concordance between biopsies, newly detected RAS mutations in ctDNA were observed, but mostly at low MAF limit. However, the optimal cutoff of BEAMing is yet to be defined. Follow-up and serial ctDNA RAS analyses could help us to understand their clinical and biological significances. Study supported by Amgen Clinical trial information: NCT02792478.Table 1. Liquid biopsy results Exon Mutant allele fraction (cutoff) ≥1% ≥0.1% ≥0.02% KRAS mt, n (%) 2 3 (2.5) 5 (4.2) 11 (9.2) 3 0 (0) 0 (0) 0 (0) 4 0 (0) 0 (0) 1 (0.8) Total 3 (2.5) 5 (4.2) 12 (10.1) NRAS mt, n (%) 2 0 (0) 1 (0.8) 2 (1.7) 3 0 (0) 1 (0.8) 2 (1.7) 4 0 (0) 0 (0) 0 (0) Total 0 (0) 2 (1.7) 4 (3.4) RAS mt detection rate, % (95% CI) 2.5 (0.5 – 7.2) 5.01 (1.9 – 10.7) 12.61 (7.2 – 19.9) Negative percent agreement2, %(95% CI) 97.5 (92.8 – 99.5) 95.0 (89.4 – 98.1) 87.4 (80.1 – 92.8) 1One (n = 1) patient had both KRAS and NRAS mutations 2Percentage of concordant patients in subjects RAS wild-type according to solid biopsy CI, confidence interval; mt: mutant type
Long-term clinical outcomes of ALK inhibitors in patients with <i>ALK</i>-positive advanced non-small cell lung cancer.
Authors: Haruyasu Murakami, Akira Ono, Kazuhisa Nakashima, Shota Omori, Kazushige Wakuda, Hirotsugu Kenmotsu, Tateaki Naito, Toshiaki Takahashi
Journal: Journal of Clinical Oncology (2017)

e20542 Background: Anaplastic lymphoma kinase (ALK) inhibitors show high clinical efficacy in patients with ALK-positive advanced non-small cell lung cancer (NSCLC). However, the long-term clinical outcomes remain unknown. Methods: We retrospectively reviewed medical records of patients with ALK inhibitor-naïve ALK-positive advanced NSCLC who initiated alectinib or crizotinib therapy at the Shizuoka Cancer Center between June 2010 and December 2011. Results: This retrospective study included 14 patients (male/female, 5/9; PS 0/1, 6/8; adenocarcinoma/adenosquamous carcinoma, 13/1; smoker/never smoker, 8/6; brain metastasis presence/absence, 5/9; number of prior chemotherapy regimens 0/1/≥2, 1/7/6; alectinib/crizotinib, 4/10) with a median age of 55 years (range, 28-71). At the data cut-off (January 16, 2017), three patients were still receiving first ALK inhibitors (alectinib in two patients and crizotinib in one). One patient requested the discontinuation of alectinib therapy after five years. One patient discontinued crizotinib therapy due to unacceptable toxicity. Nine patients discontinued first ALK inhibitors due to disease progression. The overall response rate was 78.6% with complete response in two patients (14.3%), partial response in nine (64.3%), stable disease in one (7.1%), and progressive disease in two (14.3%). The median progression-free survival (PFS) for all 14 patients was 15.3 months, and the five-year PFS rate was 35.7%. The five-year PFS rates in patients treated with alectinib and crizotinib were 75.0% and 20.0%, respectively. The median overall survival (OS) for all 14 patients was 36.8 months, and the five-year OS rate was 42.9%. The five-year OS rates in patients treated with alectinib and crizotinib were 75.0% and 30.0%, respectively. Conclusions: ALK inhibitors showed favorable long-term clinical outcomes in patients with ALK inhibitor-naïve ALK-positive advanced NSCLC, especially in patients treated with alectinib.
Abstract 290: Cardiopulmonary Resuscitation Duty Cycle in Out-of-Hospital Cardiac Arrest
Authors: Thomas Rea, Bryce Johnson, Jason Coult, Carol Fahrenbruch, Jennifer Blackwood, Lawrence Sherman, Peter Kudenchuk, Michael Sayre
Journal: Circulation (2014)

Background: CPR duty cycle is the portion of time spent in compression relative to the total time of the compression-decompression cycle. Guidelines recommend a 50% duty cycle based largely on animal investigation. Little is known about duty cycle in human resuscitation and whether duty cycle correlates with other CPR measures. Methods: We calculated the duty cycle, compression depth, and compression rate during EMS resuscitation of 164 patients with out-of-hospital ventricular fibrillation cardiac arrest. We captured force recordings from a chest accelerometer to measure ten-second CPR epochs that immediately preceded each scheduled rhythm analysis. Duty cycle was calculated using two methods. The effective compression time (ECT) is the time from beginning to end of compression divided by total period for that compression-decompression cycle. The area duty cycle (ADC) is the ratio of area under the force curve divided by total area of one compression-decompression cycle. We evaluated the compression depth and compression rate according to duty cycle quartiles. Results: There were 369 ten-second epochs among 164 patients. The median duty cycle was 38.8% (SD=5.5%) using ECT and 32.2% (SD=4.3%) using ADC. A relatively shorter compression phase (lower duty cycle) was associated with greater compression depth (test for trend &lt; 0.05 for ECT and ADC) and slower compression rate (test for trend &lt; 0.05 for ADC) (Table). Sixty-one patients (37%) survived to hospital discharge. Conclusions: In this system with high survival, duty cycle was well below the 50% recommended guideline, and was associated with compression depth and rate. These findings provide rationale to incorporate duty cycle into future research to evaluate how CPR influences resuscitation.
Meta-analysis of KRAS mutation as prognostic factor in patients (pts.) with resection of colorectal (CRC) liver metastases: Tumor burden and sideness analysis.
Authors: Martin Angel, Federico Losco, Federico Esteso, Javier Mariani, Fernando Sanchez Loria, Eduardo Huertas, Matias Chacon, Juan Manuel O´Connor
Journal: Journal of Clinical Oncology (2018)

e15533 Background: In pts. with advanced CRC, KRAS mutations predicts response to treatment with EGFR inhibitor. The Liver metastases selection criteria include anatomic and biological variables. Recent evidence support the prognostic value of KRAS (molecular criteria) in pts with resectable hepatic metastases irrespective of systemic treatment. Purpose: To investigate the prognostic value of KRAS in patients undergoing liver resection for colorectal liver metastases (CRLM). Tumor sidedness and tumor burden was also evaluated. Methods: Pubmed, Emabase and Cochrane Library databases were searched systematically. Data from published full-text articles reporting KRAS-stratified survival outcomes, recurrence free survival (RFS) and/or overall survival (OS) after resection of CRLM cancer. METHEPAR results, a local multi-institutional CRLM database, was also included. Hazard ratios (HR) and 95%CI from analyses were pooled in meta-analysis, and a random-effects model was used to calculate overall results. Results: The search returned 69 articles, of which 20, including METHEPAR, met the inclusion criteria. A total of 3819 patients were included. The mutation rate was 33.5% (IQR: 26.3-38.5). Pooled analysis showed that KRAS mutations predicted a significantly worse both RFS (HR: 1.55; 95% CI: 1.38-1.75) and OS (HR: 1.85; 95% CI: 1.57-2.19) in patients who underwent surgical resection of CRLM. In a subgroup analysis regarding sideness, studies involving more proportion of ptes with right sided tumors, had similar OS compare to those with higher proportion. (HR:1.74; 95% CI1.40;2.16) p= 0.19. Liver-only mets had a similar OS compare to those with more disseminated disease burden. (HR: 1.76; 95% CI 1.46; 2.12) p= 0.19. Conclusions: This meta-analysis confirm, as in previous one that KRAS mutations is a poor prognostic biomarker, associated with worse survival outcomes, in patients undergoing hepatic resection of CRLM, regardless of tumor sidedness and disease burden. KRAS mutation should be considered in the evaluation of pts. having liver metastasis for surgical resection.