tbuckley/cabot-search huggingface dataset:
Correct decision processes in curative treatment of gallbladder cancer: Data of The German Registry.
Authors: Thorsten Oliver Goetze, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2016)

e15607 Background: In most cases an immediate radical re-resection (IRR) after simple cholecystectomy in incidental gallbladder carcinoma (IGBC) is needed. The S3 guidelines valid till 2015 have recommended IRR in T2 and more advanced stages. The new S3- guidelines recommend more aggressive surgery even in T1b. According to the data of the German- registry (GR) the indication for IRR depends more on the experience of the hospitals in liver surgery than on complying with the guidelines, so most of IGBC- patients are staged incorrectly and not treated oncological sufficient. In practice, the following questions are of interest. Is the biologic behavior of GC underestimated? Depends treatment of IGBC in Germany on the surgical or oncological expertise of the clinics? Which technique of liver resection (LR) is meaningful in which stage? What is important regarding lymph node ratio (LNR).Methods: For data analysis we used the GR. The GR includes nearly n = 1000 cases of IGBC and is the largest gbc registry in Europe. Results: More than 950 IGBC's in the GR have been analyzed. In 42 of 113 T1b there was an IRR, with a significant survival benefit for T1b after IRR. There was also a significant survival benefit for the 228 T2 and 80 T3 with IRR of the 461 T2 and 215 T3 tumors. Comparison of LR showed good results for the wedge resection technique (WRT) in T1b / T2. For T3 more radical techniques showed better results. Less than 50% of T2–3 in the registry have been re-resected. LR was performed significantly more often in High- volume (HV) clinics. In n = 212 the LNR could be calculated. Statistic showed that LNR is a significant prognostic factor. Conclusions: IGBC's up to T1b needs a radical surgery. The WRT is an attractive procedure for T1b/T2 IGBC due to lower invasiveness in spite of oncological adequacy and implantation of WRT should also be possible in LV's with few experience in liver surgery. Also the count of retrieved lymph nodes is of essential interest. By following the correct decision processes more patients have the possibility for cure. For further increasing the cure rate in T2-3 GBC a multimodal therapy trial has already been planned by the investigator of the GR under the support of the corresponding network of more than 300 clinics.
Impact on OS of 2<sup>nd</sup> and 3<sup>rd</sup> generation TKI in EGFR mt+ and ALK+ patients: Results of the NOWEL network.
Authors: Julia Roeper, Maria Netchaeva, Anne Christina Lueers, Ursula Stropiep, Cora Hallas, Markus Tiemann, Nicole Neemann, Lukas C. Heukamp, Markus Falk, Gunther Wiest, Claas Wesseler, Dieter Ukena, Sandra Sackmann, Frank Griesinger
Journal: Journal of Clinical Oncology (2017)

e20560 Background: Available clinical research data shows that early mutation testing for patients with NSCLC stage IV could lead to an effective choice of therapy for patients with proven mutations. Targeted therapies achieve a higher ORR, PFS, OS and a better quality of life than chemotherapy in mt+ patients. With the advent of 2 nd and 3 rd generation TKI´s effective in 1 st generation TKI resistant tumors, we wanted to study the impact of these drugs on the outcome of patients in a real life setting in 3 lung cancer centers. Methods: 1383 patients from the three cancer centers diagnosed with NSCLC stage IV (UICC 7) were examined. Methods for the detection of mutations included Sanger Sequencing, hybridization based COBAS testing as well as hybrid cage next generation sequencing. Results: 880/1383 (64%) consecutive patients with non-squamous cell NSCLC from the cancer centers were studied for the presence of tumor mutations, especially for EGFR and ALK mutations. The EGFR mutation rate was 16.6% (141/880), and the ALK-translocation rate 3.8% (24/635). Median OS in EGFR mt+ patients was 31 (n = 78) vs. 32 (n = 38) vs. 16 (n = 14) months respectively (center 1 vs. center 2 vs. center 3). Median OS in ALK mt+ patients was 25 (n = 17) months in center 1 and 11 (n = 5) months in center 2 (p &lt; 0.05). Use of 3 rd generation TKI Osimertinib (n = 17) lead to a significantly higher OS (n = 17, median OS 67 mo) than the use of only 1 st and 2 nd generation TKI (n = 113, median OS 24 mo, p &lt; 0.000). Similarly, use of 2 nd and 3 rd generation ALKi impacted significantly on median OS: Crizotinib alone n = 7, 17 months, Crizotinib followed by Ceritinib and/or Brigatinib (n = 9) median OS not reached, p &lt; 0.001. Conclusions: Smalldifferences in OS were observed, depending on the treatment centers, but the use of multiple EGFR and ALK-I impacted highly significantly on the outcome of patients with EGFR and ALK-alterations in a real life setting.
Non-BRCA hereditary gene mutations and breast cancer phenotype: An ISC-RAM Consortia study.
Authors: Banu Arun, Freya Ruth Schnabel, Jennifer Chun, Arielle Lutterman Heeke, Julia Anne Smith, Daniel F. Roses, Emma Kurz, Kara Landry, Angelica Gutierrez Barrera, Marie Wood, Claudine Isaacs
Journal: Journal of Clinical Oncology (2018)

1540 Background: The use of multi-gene panel testing (MGP) for hereditary breast cancer has been increasing. Currently, the indications for MGP depend on personal and/or family history of cancer, as tumor phenotype and patient characteristics for non-BRCA related cancers are not well described. The present study analyzed tumor characteristics of breast cancers associated with non-BRCA hereditary mutations. Methods: Institutional IRB-approved prospective databases from the International Society of Cancer Risk Assessment and Management (ISC-RAM) members were queried for patients with invasive breast cancer who underwent MGP between 2013-2017. Clinical and tumor characteristics for mutation carriers were analyzed using descriptive statistics and Pearson’s and Fisher’s Chi-Square analyses. Results: Of a total of 1,854 patients with invasive breast cancer who underwent MGP, 374 (20%) had a positive pathogenic gene mutation. Median age at diagnosis was 46 years (range: 22-85). Positive testing results were as follows: BRCA1: 77 (21%); BRCA2: 76 (20%); ATM: 45 (12%); CHEK2: 47 (12.5%); PALB2: 32 (8.5%); TP53: 16 (4.3%); MUTYH: 13 (3.5%); 68 (18.2%) patients tested positive for other genes (APC, BRIP1, BARD1, PTEN, STK11, CHD1, MLH, MSH, PMS, CDKN2A, NBN, NF1, RAD50, RAD51, SDHD, AXIN2, MITF, GALNT12, XRCC2). As expected, BRCA1 mutation was associated with triple negative breast cancer (p < 0.0001). The tumor characteristics of all other carriers were similar to those seen in BRCA2 carriers with two exceptions: MUTYH carriers were more likely to have invasive lobular cancers (p < 0.0001) and TP53 carriers were younger at diagnosis (p < 0.001) and more likely to have HER-2/neu positive cancers (p = 0.006). Conclusions: Our collected series of patients with non-BRCA hereditary breast cancers demonstrates specific tumor characteristics associated with TP53 and MUTYH mutations. Further exploration is warranted to expand this data set and further characterize cancers that are associated with low frequency genetic mutations. The frequency of ER positive tumors in these patients suggests that chemoprevention may be an important strategy in this population.
Association of single nucleotide polymorphisms (SNPs) in <i>ESR1</i> and <i>PRMT8</i> and response to treatment with abiraterone acetate (AA) in men with metastatic castration refractory prostate cancer (mCRPC).
Authors: Neeraj Agarwal, Anitha Alex, James M. Farnham, Shiven B. Patel, Srinivas Kiran Tantravahi, Craig Teerlink, Frederick S. Albright, Robert A Stephenson, Lisa A Cannon-Albright
Journal: Journal of Clinical Oncology (2015)

5048 Background: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict response to AA in men with mCRPC, serve as prognostic and predictive biomarkers, and guide towards more individualized therapy. Methods: 785 single nucleotide polymorphisms (SNPs) from the Illumina OmniExpress genotyping platform within the boundaries of 60 genes reported to be involved in the androgen metabolic pathway were investigated for association with time to treatment failure (TTF) in 49 Caucasian men with mCRPC undergoing treatment with AA. Cox proportional hazard analysis was employed using Gleason score as a covariate and assessing each SNP under an additive genetic model in which the number of minor alleles contributes increasing risk (or protection). Results: Five SNPs in ESR1 (estradiol-binding domain of the estrogen receptor gene), and 5 SNPs in PRMT8 (protein arginine methyl transferase 8 gene) were associated with TTF on AA therapy (p < .005) while controlling for Gleason Score (Table). Conclusions: SNPs in ESR1 and PRMT8significantly associated with TTF on AA therapy, and may serve as predictive markers to treatment with AA. Further validation is being performed in a larger cohort of men with mCRPC. Gene Chromosome SNP bp position p_value # cases (median TTF in months ) 0 rare 1 rare 2 rare ESR1 6 rs2485209 152089768 0.0008 45(4.7) 4(1.33 NA ESR1 6 rs12199102 152392561 0.0032 25(6.7) 20(3.9) 2(3.4) ESR1 6 rs9341052 152416625 0.0028 27(6.7) 17(3.5) 5(3.1) ESR1 6 rs2228480 152420095 0.0045 29(6.7) 19(3.5) 1(3.8) ESR1 6 rs3798758 152421854 0.0014 22(7.2) 22(3.9) 5(3.1) PRMT8 12 rs12371422 3360946 0.0000 38(5.9) 10(1.8) 1(1.1) PRMT8 12 rs7956298 3361251 0.0001 18(9.7) 26(4.0) 5(1.6) PRMT8 12 rs4766082 3373084 0.0004 15(9.4) 27(4.3) 7(2.8) PRMT8 12 rs7296720 3374920 0.0003 15(9.4) 27(4.3) 6(2.5) PRMT8 12 rs10848840 3399429 0.0001 42(4.8) 5(3.1) 2(.78)
Immune cell activation among lung adenocarcinoma and squamous cell carcinoma intrinsic subtypes and <i>CD274</i> (PD-L1) expression.
Authors: Hawazin Faruki, Greg Mayhew, David N. Hayes, Jonathan Stuart Serody, Charles M. Perou, Myla Lai-Goldman
Journal: Journal of Clinical Oncology (2016)

3077 Background: Gene expression based subtyping in lung Adenocarcinoma (AD) and lung Squamous Cell Carcinoma (SQ) classifies AD and SQ tumors into distinct subtypes with variable biologic and clinical features. Methods: Using previously published Bindea et al. immune cell gene signatures (24 in total) and the TCGA lung cancer gene expression datasets (AD n = 515, and SQ n = 501), we examined immune cell features in relation to AD and SQ subtypes. Signatures of both Innate Immune Cells (IIC) and Adaptive Immune Cells (AIC), as well as single immune-biomarkers (CTLA4, PDCD1, and CD274(PD-L1)) were examined in the 3 AD subtypes (Terminal Respiratory Unit (TRU), Proximal Proliferative (PP), and Proximal Inflammatory (PI)) and the 4 SQ subtypes (Primitive, Classical, Secretory, Basal). AIC signature associations with tumor subtype and with CD274 expression were evaluated using linear regression. Hierarchical clustering of immune signatures and individual gene correlations were also analyzed. Survival-signature associations were evaluated with cox proportional hazard models. Results: Hierarchical clustering of immune cell gene signatures provided separation of AD and SQ intrinsic subtypes. Immune activation was most prominent in the SQ Secretory subtype and in the AD PI subtype suggesting activation of both innate and adaptive immune cells. In contrast, the Classical subtype of SQ and the PP subtype of AD demonstrated lower immune activation. AD subtype and CD274 expression were similarly predictive of AIC features, however, among the SQ tumors, subtype associations were stronger (median F-test p-value and adjusted R-squared were 2.16e-24 and 0.20 for subtype versus 1.86e-09 and 0.07 for CD274). Survival analysis suggested Th17 and Tfh cells predicted improved survival in AD (p < 0.001). In SQ, only the Primitive subtype demonstrated significant immune cell expression associations with improved survival (p < 0.01). Conclusions: Intrinsic biologic subtypes of lung AD and SQ reveal key differences in immune cell activation, which were not always correlated with CD274 expression. Evaluation of subtypes as potential biomarkers for immunotherapy response should be investigated.
Baseline CTC subtype to predict outcomes on mCRPC patients (pts) receiving enzalutamide (E) compared to abiraterone (A).
Authors: Howard I. Scher, Adam Jendrisak, Nicole A. Schreiber, Brigit McLaughlin, Ryon P Graf, Angel Rodriguez, Martin Fleisher, Jerry Lee, James Kelvin, Yipeng Wang, Mark Andrew Landers, Ryan Vance Dittamore
Journal: Journal of Clinical Oncology (2017)

5070 Background: Prior response to A or E does not predict sensitivity to E following A or A following E. The detection of AR-V7 predicts insensitivity to either drug, but identifies only a portion of non-responders. We previously identified 15 CTC subtypes based on unique phenotypic features in mCRPC pts, each with unique biology and different degree of likelihood of predicting resistance to either drug. Here we explored the relationship between individual subtypes and sensitivity to A vs. E, but not both. Methods: 107 pre-treatment blood samples from mCRPC pts starting A (n = 47) or E (n = 60) as a 1 st or 2 nd line of Tx were analyzed for CTCs utilizing the Epic Sciences platform. Samples were assayed for CTC subtypes based upon 15 pre-defined phenotypic CTC classifiers (Type A-O). Treatment outcomes were assessed by serial PSA changes and landmarked percent time of therapy progression on radiographs, and overall survival following either A or E. Cell type prevalence was also analyzed in relation to clinical outcomes, and subsets of the CTC subtypes subject to single cell NGS to ascertain genomic drivers common to each subtype. Results: CTCs were identified in 94% (101/107) of pt samples. One, cell Type K, found in 25% (27/107) of pts, was associated with a statistically significant inferior outcomes on E for all measures. Whereas similar outcomes were seen between K+ &amp; K- pts treated with A. The distinct features of Cell Type K include a large nucleus, high nuclear entropy and high Nuclear/cytoplasmic AR terminal ratio; and a unique genomic profile enriched for cell cycle and DNA repair alterations relative to other CTC subtypes. Conclusions: The presence of specific CTC subtypes in pre-Rx phlebotomy samples associated with outcomes on A or E. A CTC subtype (Cell Type K) helped to identify pts with poor outcomes on E but not A vs. those without the cell type. Further biologic interrogation of K cells and ongoing clincial validation of the CTC subtype is planned. [Table: see text]
Progression patterns after EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated (EGFR-mut+) non small cell lung cancers (NSCLCs): Correlations with clinical oucomes.
Authors: Alessandro Russo, Valeria Smiroldo, Fabio Raiti, Tindara Franchina, Giuseppa Ferraro, Maria Picciotto, Giuseppina Ricciardi, Antonino Scimone, Vincenzo Adamo
Journal: Journal of Clinical Oncology (2016)

e20600 Background: EGFR-mut+ NSCLCs represent a distinct molecular subtype with improved outcome when treated with EGFR TKIs. However, virtually all EGFR-mut+ pts ultimately progress. We sought to analyze the different progression patterns after acquired resistance during EGFR TKIs treatment. Methods: Medical records of a total of 39 consecutive patients (pts) with stage IV NSCLCs and EGFR mutations, treated at our Institution, were included. The metastatic sites were evaluated at baseline and after EGFR TKIs treatment. Differences on progression free survival (PFS) between groups were analyzed using T-Students. Results: Thirty-nine EGFR-mut+ NSCLC pts (23 M/16 F) treated with EGFR TKIs, either as 1st (64%) or 2nd-line (36%) therapy, were included. Baseline characteristics: median age was 70 years (range 32-85); brain metastases (BMs) were found in 17% of pts, lung metastases in 54%, bone metastases in 40%, liver and adrenal metastases both in 10%, respectively. Exon 19 deletions were found in 27 pts, exon 21 in 6 and other mutations in 6 pts. 62% of pts received Gefitinib, 35% Erlotinib and 13% Afatinib; 7% re-challenged with another TKI. Overall Response Rate was: 65.5%. After a median follow-up of 17.5 months (mos), the median PFS was 11.1 mos. Major sites of progression disease (PD) were: primary tumor (50%), BMs (25%), multiple sites (25%). 50% of pts experienced a systemic PD, while 39% and 11% experienced a slow and oligo-PD, respectively. Slow and oligo-PD pts had statistically longer PFS than those with systemic PD (8.5 vs. 9.0 vs. 3.0 mos) (P-value = 0,02) and had more chances to receive subsequent treatments. Conclusions: EGFR-mutated NSCLCs progressing during EGFR TKIs are a heterogeneous group of pts with different clinical outcome. Patients stratification may be essential for the optimal treatment selection in subsequent lines of therapy.
Abstract 14728: Atrial Fibrillation After Orthotopic Heart Transplantation: Results From a Meta-analysis
Authors: Tamara Metz, Sanghamitra Mohanty, Prasant Mohanty, Chintan Trivedi, Carola Gianni, Luigi Di Biase, Andrea Natale
Journal: Circulation (2015)

Background: Atrial fibrillation (AF) is a known complication of orthotopic heart transplantation (OHT). However, post-OHT AF is yet to be well characterized as studies report diverse data on the incidence rate and clinical characteristics of this arrhythmia. This study provides a review and meta-analysis of the existing evidences on the incidence rate, time of onset and association with allograft rejection of post-OHT AF. Methods: An extensive literature search was performed on PubMed, MEDLINE and EMBASE databases (from 1990 to August 2014) and reference lists of selected articles for studies on the incidence of atrial fibrillation in OHT patients. Post OHT arrhythmia incidence data along with population characteristics were collected and pooled prevalence rate and associated 95% confidence intervals (CIs) were calculated. Results: Ten prospective studies with 3,852 patients undergoing OHT were included in the primary meta-analysis. The pooled prevalence of AF across studies was 5.4% (95% CI 7.0-10.1). AF was the most common early arrhythmia; 74% (95% CI 65-83) of the reported AF episodes were observed in &lt;30 days of OHT. The pooled prevalence of AF was much higher with allograft rejection (41.5%, 95% CI 32-52, p&lt;0.001). Additionally, two studies reported lower incidence of AF following OHT compared to the AF-incidence after other cardiac surgeries such as MAZE and double- lung transplantation, despite pulmonary vein isolation in both groups (relative OR 0.25, 95% CI 0.07-0.56), which they attributed to the antiarrhythmic benefit of cardiac denervation in the transplanted heart. Conclusion: In heart transplant recipients atrial fibrillation is uncommon; mostly seen in the early post-operative period and often in the presence of graft rejection. Of note, cardiac autonomic denervation may have a protective antiarrhythmic effect in the post-operative setting of orthotopic heart transplantation.
Precision medicine in the real-world: The impact of the genetic testing evolution in metastatic colorectal cancer.
Authors: Adrianne Waldman Casebeer, Charron Long, Dana Drzayich Antol, Patrick Racsa, Teresa Rogstad, Charles Stemple, Bryan A. Loy, Jonas A. De Souza
Journal: Journal of Clinical Oncology (2018)

e15612 Background: The emergence of anti-epidermal growth factor receptor (EGFR)-targeted antibodies has made metastatic CRC (mCRC) a model for the evolution and success of precision medicine. This study assesses the adoption of the limited (Exon 2 KRAS mutations) or extended genetic testing (KRAS exons 3/4, NRAS exons 2/3/4 and BRAF) as paradigms of this success. In addition, we describe the implications of precision medicine on the rate of targeted therapy initiation in a national sample of patients with incident mCRC. Methods: Adults enrolled in a Humana Medicare Advantage or commercial health plan with diagnosis codes indicating colon/rectal cancer on at least one inpatient or two outpatient claims (2/2012-12/2016) and new metastatic disease were identified. Genetic testing was established using paid/unpaid claims and classified as limited or extended. The Deyo-Charlson index assessed comorbidities. A risk-adjusted logistic regression model assessed patient, lab, and provider characteristics associated with use of limited versus extended testing. Results: Of the 8,656 patients with mCRC, 15.2% had evidence of genetic testing; 6.5% had limited and 8.7% had extended testing. Age, race, sex and baseline level of comorbidity did not differ by testing type. Use of genetic testing increased from 3% (2012) to 26% (2016). Fewer patients with extended testing, versus limited, initiated anti-EGFR therapy (5.7% vs 11.2%, P < 0.01). For patients with genetic testing who received any anticancer therapy, only the year of mCRC diagnosis was independently associated with the likelihood of receiving extended versus limited testing. Conclusions: This real-world data analysis revealed relatively low rates of genetic testing but increasing use of extended testing over time. Our data also suggested reduced use of anti-EGFR therapy with extended testing. As precision medicine evolves, understanding delays in its adoption and generating real-world evidence regarding its use and effectiveness is crucial.
Clinical outcome of Hodgkin lymphoma: A single center study.
Authors: Sharareh Seifi, Adnan Khosravi, Zahra Esfahani-Monfared, Babak Salimi, Hanifeh Mirtavoos-Mahyari
Journal: Journal of Clinical Oncology (2018)

e19515 Background: Even though Hodgkin lymphoma(HL) has become one of the most curable forms of neoplasm, some patients experience disease progression. The aim of this study is to describe the patient demographics and outcome in HL patients at a tertiary care hospital. Methods: This retrospective study with 172 patients from 2003 to 2017 were conducted in National Research Institute of Tuberculosis and Lung Disease, Tehran, Iran.All patients have been treated with standard ABVD regimen. We evaluated the correlation of relapse with tumor and demographic characteristic.Chi-square or Fisher's exact tests were used to compare nominal variables. Binary logistic analysis was used to assess parameters regarding progression. Results: The mean age at diagnosis was 29.4 years (range 13-71). Among patients, 50.5% were male. Mean follow up time was 3.1 years. Bone marrow involvement was reported in 4.1% patients. Nodular sclerosis sub type had most frequency (51.9%). Ninety -one patients had achieved a complete remission , refractory disease was 21.1%, disease relapse was documented in 7.2% and 10.8% died. Interestingly, among the patients, there were two sisters who both showed progressive disease. For one of them, BMT was done and unfortunately, another one expired. Concurrent tuberculosis was observed in one patient.Demographic characteristics in respect to progression were summarized in Conclusions: Comparing the clinical characteristics at diagnosis, we noticed that advanced stages and bulky disease were associated with a worse prognosis. So, refractory patients should be detected earlier . Familial HL provided a probable scenario in favor of shared predisposing risk factors. Table 1. Progression Univariate analysis(P value) Logistic regression analysis(Pvalue) Yes (%) No (%) Age < 30 64.5 35.5 0.741 0.435 ≥31 57.2 42.8 Sex Male 29.8 70.2 0.089 0.064 Female 42.3 47.7 Stage I,II 23.07 76.03 0.0001* 0.001* III,IV 51.2 49.8 B symptoms presence Yes 77.4 22.6 0.982 0.659 No 77.2 22.8 Bulky Disease Yes 28(45.1) 34(54.9) 0.062 0.035* No 34(30.9) 76(69.1) Bulky Disease Yes 28(45.1) 34(54.9) 0.062 0.035* No 1.8 98.2 LDH level Normal 56.4 43.6 0.098 0.287 High 69.4 30.6 ESR Normal 58.1 41.9 0.631 0.141 High 61.8 39.2 Sub type NS 50 50 0.753 0.793 Others 52.7 47.3