tbuckley/cabot-search huggingface dataset:
Characterization of 1,233 NSCLCs with non-del19/L858R <i>EGFR</i> mutations (<i>EGFR</i>m) using comprehensive genomic profiling (CGP).
Authors: Sai-Hong Ignatius Ou, Siraj Mahamed Ali, Jeffrey Bogart, Stephen L. Graziano, Michael D Mix, Jeffrey S. Ross, Vincent A. Miller, Alexa Betzig Schrock
Journal: Journal of Clinical Oncology (2018)

9040 Background: Exon 19 deletions (del19) and L858R are classic activating EGFRm with sensitivity to approved tyrosine kinase inhibitors (TKIs). Recently, FDA-approval of afatinib was broadened to include some more rare EGFRm (S768I, L861Q, G719X) in addition to del19/L858R. Methods: CGP was performed on 34,328 NSCLCs, of which 5,240 samples (15%; 4,592 tissue and 648 blood-based ctDNA) from 4,872 patients (pts) were positive for short variant EGFRm. Pts profiled both pre- and post-EGFR TKI were included. Variants of unknown significance were excluded from our analysis. Tumor mutational burden (TMB) was determined up to 1.2 Mbp of sequenced DNA. Results: Del19/L858R were identified in 76% of EGFRm NSCLC cases. However, less common EGFRm included exon 18 or 20 indels (11%), G719X (5.2%), L861Q (2.8%), extracellular domain (ECD, 2.6%), S768I (2.4%), E709X (1.7%), transmembrane domain (TMD, 0.1%), and other kinase domain (KD, 7.5%) mutations. Frequent mutations were: ECD: A289V/TD (20%), L62R (17%) and R108K (15%); TMD: V651M (75%); KD-other: V834L (9%), L833V (7%), V774M (7%), V769L (6%), and L861R (5%). No notable differences in pt age, gender or disease histology were observed between subsets, except that L861Q pts were more often female (76%, vs 66% all EGFRm, P = 0.02). ≥1 primary EGFRm was common in cases with E709X (100%), S768I (94%), TMD (75%), G719X (70%), KD-other (63%), ECD (57%), and L861Q (31%) relative to del19/L858R (7%), or other indels (2%). T790M co-occurred in 21% of del19/L858R cases, but only 4% of non-del19/L858R EGFRm cases. KRASm co-occurred in 1% of del19/L858R cases, 0-3% of cases with G719X, L861Q, S768I, E709X, or exon 18 or 20 indels, and 8% of KD-other. EGFR amplification was present in 10-17% of cases with E709X, ECD, KD-other, G719X, or S768I, and 20-25% of remaining EGFRm subsets. Median TMB was lowest (2.6 mut/Mb) in cases with del19/L858R or other indels, and highest (5.2 mut/Mb) in cases with G719X or ECDm. Clinical outcomes will be presented for a subset of cases. Conclusions: Diverse non-del19/L858R EGFRm represent almost 25% of EGFRm NSCLC. Many of these EGFRm co-occur in a single sample, and may be targetable using currently approved or investigational EGFR TKIs.
Physician Burnout—A Serious Symptom, But of What?
Authors: Thomas L. Schwenk, Katherine J. Gold
Journal: JAMA (2018)

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P01.153 The diagnostic pathway for brain tumours in adults Understanding factors causing slow diagnosis
Authors: K Zienius, R Grant, P M Brennan
Journal: Neuro-Oncology (2018)

Delays to brain tumour diagnosis impacts on patient well-being, and may affect available treatment options and patient outcomes. Promoting earlier diagnosis is one of the top 10 clinical research priorities for the UK neuro-oncology community. Understanding the pathway from symptom onset to treatment, and how this varies between patients, is crucial to improving the diagnostic process. A prospective cohort study of adult patients with imaging suspected intracranial tumour prior to neurosurgical treatment at a single neuro-oncology centre in South East Scotland, UK, between August 2016 and February 2018 was undertaken to provide contemporary and detailed information on clinical pathway to diagnosis and to explore factors leading to a prolonged diagnosis. Clinical pathway was described in accordance with Aarhus criteria. 180 consecutive consenting patients +/- carers with intracranial tumour were interviewed. 52% were female and mean age was 56.8 (SD 13.5) years. Glioblastoma multiforme (37.2%), meningioma (22.8%), cerebral metastases (15.6%) were the most common tumours. More prolonged time to diagnosis was associated with being female, single/divorced/widowed, non- seizure first symptom and presentation via general practice. 122 (65%) patients saw their GP at least once, while 38 (21%) had 3+ visits prior to diagnosis. 123 (68%) patients were finally diagnosed in an emergency department (ED), of which 83 (67.5%) self-presented to ED. “Non-focal” first symptom (adjusted OR=33.2, p=0.003) and female sex (aOR=4.7, p=0.02) were independent predictors of seeing a GP prior to ED admission. Seizure was the commonest symptom (n=47) leading to ED, however over half of these patients (n=26 (55.3%)), had previously complained of headache or non-focal symptoms such as memory or personality change prior to seizure. Only 65% of patients with brain tumours see their GP prior to diagnosis of a brain tumour, but >20% see the GP more than three times. GP presenting patients are more commonly female and have non-focal symptoms (e.g. headache/memory/personality change). More work needs to be done around the reasons why GPs do not recognise non-focal presentations or if there are system delays in hospital referral resulting in patients presenting in ED.
P04.04 Regulation of glioma cell invasion by 3q26 gene products PIK3CA, SOX2 and OPA1
Authors: S Leu, A Ramadoss, T Schaefer, L Tintignac, C Tostado, A Bink, G Moffa, P Demougin, S Moes, L Mariani, J Boulay
Journal: Neuro-Oncology (2018)

Diffuse gliomas progress by invading neighboring brain tissue to promote post-operative relapse. Transcription factor gene SOX2 is highly expressed in invasive gliomas and maps to 3q26 together with the genes for the PI3K/AKT signaling activator PIK3CA, and those encoding effectors of mitochondria fusion and cell invasion inhibitors MFN1 and OPA1. We aimed at investigating their respective roles in glioma cell invasion in vitro and by exploiting retrospective patient neuro-imaging data. Gene copy number analysis at 3q26 from 129 glioma patient biopsies revealed mutually exclusive SOX2amplifications (26%) and OPA1losses (19%). Both forced SOX2expression and OPA1inactivation increased LN319 glioma cell invasion. Conversely, pharmacological PI3K/AKT pathway inhibition decreased invasion and resulted in SOX2 nucleus-to-cytoplasm translocation in a mTORC1-independent manner, showing that PI3K/AKT signaling sustains SOX2 activity. Chromatin immuno-precipitation and luciferase reporter gene assays together demonstrated that SOX2 trans-activates PIK3CAandOPA1. Thus, SOX2 activates PI3K/AKT signaling in a positive feedback loop, while OPA1 deletion is interpreted to counter-act OPA1 trans-activation. Remarkably, neuro-imaging of human gliomas with high SOX2or low OPA1genomic imbalances revealed significantly larger necrotic tumor zone volumes, corresponding to higher invasive capacities of tumors. Whereas glioma invasion is activated by a PI3K/AKT-SOX2 loop, it is reduced by a cryptic invasion suppressor SOX2-OPA1 pathway. RTK/PI3K/AKT-SOX2 and mitochondria fission represent potential signaling networks to be targeted to control glioma invasion. In addition, our results indicate that necrosis volume is a potential surrogate marker for evaluation of invasion.
Clonal selection of TP53MUT and/or Del (p17) in CLL: Evaluation of 3,373 CLL patients, A real word data story.
Authors: Sheila Mpima, Thomas Moehler, Sean Kanter, Laura Mitrofan
Journal: Journal of Clinical Oncology (2017)

e19004 Background: Del (p17) or TP53MUT are important negative prognostic indicators for CLL patients (pts). Using a large European database we evaluated the influence of chemotherapies on the detection of Del (p17) and TP53MUT in advanced CLL pts requiring CLL-specific therapy. Methods: Anonymized CLL pts-level data collected through a large web-based survey between Oct 2015-2016 in EU5 (France, Germany, Italy, Spain &amp; UK) was used. Mutation testing was recorded at the beginning of each line of therapy. Chi-squared test was used to analyze the association between treatment and/or abnormalities (Del p(17) and TP53MUT). Results: Data of 3,737 CLL pts were analyzed. 33% received ≥2 prior regimens, 38% received 1 prior regimen and 29% are currently in 1L. A switch from negative to positive at 2 nd or later line occurred in 68% of pts for Del (17p) and 41% for TP53. 40% of pts bearing a Del (p17) are simultaneously TP53MUT when treated with at least 2 lines of therapy. We compared the treatment regimen of pts that remained negative during the course of treatments with those who switched to Del (17p) or TP53Mut. Analysis showed a strong association (p-value &lt; .0001) between treatment (alkylation agent in combination with an antiCD20 antibody or CYC/FLUD/R) and Del (p17) switch after 2L (total n = 906). Separately, same treatment groups showed lower association (p-value &lt; .0015) with TP53 status change at the end of 2L (total n = 598). Separate ratios have been calculated for each treatment group between pts remaining negative for Del (p17) and TP53, respectively and those who became positive. CYC/FLUD/R treated pts had a 2.2 and 2.7 fold higher ratio of remaining negative versus becoming positive for Del (p17) and TP53MUT, respectively in 2L, when compared to alkylating agent/antiCD20 combination. In addition, there is a high association (p-value &lt; .0001) across the two treatments groups between Del (p17) and TP53MUT for pts with 2L results (n = 868). Conclusions: Analysis shows that patient treated with the 3-drug regimen CYC/FLUD/R had a lower likelihood of undergoing a clonal selection for both Del (17p) and TP53MUT compared to 2-drug regimen including alkylating agent/rituximab combo.
Impact of pre-surgical germline multigene panel testing on choice of surgery for breast cancer.
Authors: Elena Zarcaro, Leif W. Ellisen, Kristen M Shannon, Erica Blouch, Steven J. Isakoff
Journal: Journal of Clinical Oncology (2018)

1579 Background: Knowledge of hereditary risk-associated mutations may impact primary surgical decision-making for breast cancer(BC) patients (pts). Since 2015, all new pts seen in the Massachusetts General Hospital (MGH) multidisciplinary BC clinic have been screened by genetic counselors (GCs) for rapid GC consultation and multigene panel testing. We sought to determine the impact of pre-surgical BC multigene panel testing on the timing and type of surgery. Methods: All pts screened and tested by the MGH GCs from July, 2016 through December, 2017 were identified, and only those who had surgery at MGH were included. Pts may have had genetic testing prior to initial visit at our institution. Screening criteria for rapid GC consultation included personal or family history of BC with the following features: age < 45, triple negative age < 60, male, bilateral, Ashkenazi Jewish descent, or ovarian ca. Surgical and genetic testing outcomes were collected by retrospective chart review and Fishers exact test was used for statistical analysis. Results: During our study period, 1341 eligible pts were screened in the MGH multidisciplinary BC clinic. Of 628 pts who met genetic testing criteria, 588 (93.6%) were tested and 50 (8.5%) were positive for a germline mutation including 16 BRCA1, 10 BRCA2, 8 ATM, 8 CHEK2, 5 PALB2 and 1 each of TP53, BRIP1, and RAD51C. In 24 pts with BRCA1/2 mutations who had genetic results prior to surgery, 21 (87.5%) had upfront bilateral mastectomies (BM). In 21 pts who tested positive for other germline mutations before surgery, 14 (66%) had upfront BM. In a cohort of 120 pts with negative test results before surgery, only 37 (30.8%) had up front BM (p < .05 compared to BRCA1/2 and other germline mutations). Conclusions: Screening newly diagnosed BC pts for rapid GC consultation and testing prior to surgery successfully identified pts with germline mutations in our population. Pts with BRCA1/2 mutations had a higher rate of BM than gene-negative pts and pts with other germline mutations also had a higher rate of BM. Further studies should explore factors influencing pre-operative decision-making in the context of non-BRCA1/2 germline mutations to assess concordance with guideline recommendations.
Outcome after autologous transplantation in the terms of comorbidity for patients with lymphoproliferative diseases: Single center experience.
Authors: Aleksandra Pivkova Veljanovska, Sonja Genco Genadieva-Stavrik, Zlate Stojanoski, Lazar Chadievski, Irina Panovska Stavridis, Sanja Aleksandar Trajkova, Lidija Cevreska, Borce Georgievski
Journal: Journal of Clinical Oncology (2017)

e19502 Background: Autologous stem cell transplantation (ASCT) improves survival in patients with myeloma and lymphoma but is associated with morbidity and nonrelapse mortality (NRM). Hematopoietic cell transplant comorbidity index (HCT-CI) was shown to predict risk of NRM and survival after allogeneic transplantation. We tested the utility of HCT-CI as a predictor of NRM and overall survival (OS) in patients undergoing ASCT. Methods: We analyzed outcomes of 220 patients after high-dose melphalan and high –dose anti lymphoma chemotherapy during year 2000 to 2015. Individual comorbidities were prospectively collected at the time of ASCT. The impact of HCT-CI and other potential prognostic factors, including Karnofsky performance score (KPS), on NRM and survival were studied in multivariate Cox regression models. Results: HCT-CI score was 0, 1, 2, 3, and &gt;3 in 42%, 18%, 13%, 13%, and 14% of the study cohort, respectively. Subjects were stratified into 3 risk groups: HCT-CI score of 0 (42%) versus HCT-CI score of 1 to 2 (32%) versus HCT-CI score &gt; 2 (26%). Higher HCT-CI was associated with lower KPS &lt; 90 (33% of subject’s score of 0 versus 50% in HCT-CI score &gt; 2). HCT-CI score &gt; 2 was associated with melphalan dose reduction (22% versus 10% in score 0 cohorts). One-year NRM was low at 2% (95% confidence interval, 1% to 4%). On multivariate analysis, overall survival was inferior in groups with HCT-CI score of 1 to 2 (relative risk, 1.37, [95% confidence interval, 1.01 to 1.87], P = .04) and HCT-CI score &gt; 2 (relative risk, 1.5 [95% confidence interval, 1.09 to 2.08], P = .01). Factors that affect OS in the autologous recipients among lymphoma and myeloma patients were: HCT-CI, Karnofsky score, number of CD34+ cells/kg and time from diagnosis until transplant (p&lt;0.05). Factors that affect TRM/NRM were HCT-CI, ECOG, Karnofsky score and number of hospital days and body weight.(p&lt;0.05). Conclusions: ASCT for MM and lymphoma is associated with low NRM, and death is predominantly related to disease progression. Comorbidity evaluation during autologous transplantation for lymphoproliferative diseases can be a useful tool in predicting transplant outcome.
Genome and transcriptome profiling of relapsed and metastatic osteosarcoma.
Authors: Chia Chin Wu, Hannah Beird, J Andrew Livingston, Shaolong Cao, Shailesh M Advani, Davis Ingram, Wei-Lien Wang, Alexander J. Lazar, Alexandre Reuben, Youyun Zheng, Jason Roszik, Wenyi Wang, Richard Greg Gorlick, Robert S. Benjamin, Shreyaskumar Patel, Najat C. Daw, Andrew Futreal, Valerae O. Lewis
Journal: Journal of Clinical Oncology (2018)

11522 Background: Osteosarcoma (OS) is characterized by genomic complexity and significant genetic heterogeneity. However, it is unknown whether relapse and metastatic samples incur additional insults to genomic integrity. To examine this, we conducted in-depth genomic profiling in a cohort of 48 pediatric and adult patients with high-grade OS including 42 patients with relapsed/metastatic disease. Methods: Whole-genome sequencing, RNA sequencing, and functional proteomic profiling were conducted on primary resection, local relapse, and metastatic OS tumor specimens and matched normal tissue/blood samples. Features including somatic mutations, structural rearrangements, copy number alterations, telomere length, and clonality were characterized. Proteomics analysis is underway. Results: Genome doubling (GD) occurred in 58% (22/38) of samples and significantly more rearrangements were found in the samples with GD than those without GD (p =0.01). TP53 (75% of samples) and RB1 aberrations (60%) were found in samples both with and without GD, with the majority being losses of heterozygosity. This indicates that TP53 and RB1 aberrations are early events and GD further propagates genome instability in OS. Mutational signatures 5 and 8 were most prevalent; mutation signature 8 significantly correlated with mutation burden (p < <0.001) and disease-free survival (p =0.02). There were no significant differences amongst genomic features analyzed when comparing primary tumors and lung metastases or tumors by OS histologic subtype. Conclusions: Despite inherent genomic complexity, the genomic landscape of OS at relapse and metastasis is comparable to post-treatment primary tumors. Profiling of primary tumors may be appropriate for guiding therapy at relapse. Introduction of novel therapies in the upfront setting could be considered for poor risk patients.
Pharmacokinetic (PK) and exposure-response (ER) analysis of pertuzumab (P) in patients (pts) with HER2-positive metastatic gastroesophageal junction and gastric cancer (mGEJC/GC).
Authors: Whitney Paige Kirschbrown, Bei Wang, Ihsan Nijem, Atsushi Ohtsu, Paulo M. Hoff, Manish A. Shah, Lin Shen, Yoon-Koo Kang, Josep Tabernero, Sandhya Girish, Amit Garg
Journal: Journal of Clinical Oncology (2018)

2564 Background: The phase 2a, dose-finding JOSHUA study reported increased P clearance (CL; 37% lower P steady-state Cmin [Cmin,ss]) in pts with HER2+ mGEJC/GC vs metastatic breast cancer (MBC). Based on these data, 840 mg q3w was selected for testing in the phase 3 JACOB study (NCT01774786) to achieve similar P concentrations (conc) to BC studies with the 840 mg then 420 mg q3w P dose. In JACOB, while there was evidence of treatment activity, addition of P to trastuzumab (H) and chemotherapy (CT) in 1st-line therapy did not significantly improve overall survival (OS) vs placebo (Pla)+H+CT (hazard ratio: 0.84 [95% CI 0.71–1.00], median OS 17.5 vs 14.2 months), in pts with HER2+ mGEJC/GC. Here we report the PK and ER analysis of P in JACOB. Methods: PK samples were collected at Cycles 1–4, 6, and 8 (predose); Cycles 1, 2, 4 and 8 (postdose); and at follow-up. P+H peak and trough conc were summarized by descriptive statistics and % pts with a Cmin,ss ≥20 μg/mL (target conc) tabulated. PK exposure was compared across geographic regions. The Kaplan-Meier method and a log-rank test were used to assess OS across Cmin quartiles. PK drug-drug interactions (DDIs) were assessed using serum Cmin geometric mean ratios. Results: Pts with ≥1 dose of P or H and ≥1 PK sample were included (P: n = 374 [P+H+CT]; H: n = 372 [P+H+CT] and 375 [Pla+H+CT]). Mean Cmin,ss Cycle 6 for P was 114±51.8 μg/mL, 99.3% of pts had Cmin,ss for P ≥20 μg/mL. There were no differences in OS across Cycle 1 and Cycle 6 (s-s) P Cmin quartiles (Q1: 0.075–30.6, Q2: 30.6–39.8, Q3: 39.8–51.9, Q4: 51.9–318; n = 349, P = 0.52 and Q1: 0.075–77.1, Q2: 77.1–110, Q3: 110–145, Q4: 145–450; n = 274, P = 0.78, respectively). Mean Cmin,ss was comparable across geographic regions. No apparent DDIs were observed for CT on P Cmin,ss, or P on H. Two of 349 (0.6%) evaluable pts tested positive for anti-drug antibodies to P; there was no impact on P PK. Conclusions: In JACOB, the 840 mg q3w P dose achieved target Cmin,ss in > 99% pts with HER2+ mGEJC/GC. ER analysis showed no correlation between P trough conc and OS. PK data were consistent with prior GC (P: 840 mg) and BC (P: 840 mg/420 mg) studies and higher P CL in HER2+ mGEJC/GC vs other tumor types. Clinical trial information: NCT01774786.
Evaluating empowerment in genetic counseling using patient reported outcomes.
Authors: Suat Ying Lee, Jeanette Yuen, John Lim, Eliza Courtney, Shao Tzu Li, Hazel Soh, Yanni Chen, Marion McAllister, Eva Fenwick, Joanne YY Ngeow
Journal: Journal of Clinical Oncology (2018)

1547 Background: Despite the demand for cancer genetic services, patient-derived benefits remain poorly captured due to a paucity of validated tools. The Genetic Counselling Outcome Scale (GCOS-24), a genetics-specific Patient Reported Outcome Measure (PROM), has been adapted to evaluate our local cancer genetic service (CGS). We aim to evaluate the psychometric properties of GCOS-24 using Rasch analysis. Methods: 155 patients who attended CGS at National Cancer Centre Singapore (May 2016-2017) were recruited. The questionnaire was interviewer-administered pre- and post-counselling. Responses were subjected to Rasch analysis, comparing individual Rasch item scores pre and post. Multiple regression analysis was used to assess the association of baseline characteristics with changes in scores. Results: GCOS-24 questionnaire displayed good precision (person separation index > 2.0) and targeting (difference between person and item means < 1.0). Cognitive Control [post-intervention: median 1.23 (IQR -0.3-6.2); pre-intervention: median 0.46 (IQR -1.1-3.6)] and Emotional Control [post-intervention: median 0.99 (IQR -1.1-6.4); pre-intervention: median 0.61 (IQR -1.1-3.9)] scores showed significant improvement. All components of cognitive control consistently showed improvement. Notably, aspects of Emotional Control such as alleviating feelings of being upset (p = 0.88) and hopelessness (p = 0.2) did not reflect significant improvement. Family history (p = 0.047) and genetic testing (p = 0.002) were significantly correlated with cognitive control. As for emotional control, genetic testing (p = 0.002) and the female gender (p = 0.033) were also significantly correlated. Conclusions: This study shows that GCOS-24 is well adapted and validated in our population. Significant improvements in cognitive and emotional control are concordant with previous adaptations, demonstrating the value of empowerment through genetic counselling. This study highlights the need for further emphasis to be placed on improving hope and addressing emotions, through hope-based interventions and a systems-based approach to identifying and alleviating negative emotions associated with genetic conditions and testing.