tbuckley/cabot-search huggingface dataset:
Monitoring of circulating tumor DNA in non-small cell lung cancer patients treated with EGFR-inhibitors.
Authors: Remy B Verheijen, Tirsa T van Duijl, Michel M van den Heuvel, Jos H. Beijnen, Jan H.M. Schellens, Daan van den Broek, Neeltje Steeghs, Alwin Huitema
Journal: Journal of Clinical Oncology (2017)

11535 Background: Epidermal growth factor receptor (EGFR) inhibitors such as erlotinib and gefitinib are routinely used in the treatment of non-small cell lung cancer (NSCLC). Monitoring of EGFR mutations in circulating tumor DNA (ctDNA) derived from plasma has been proposed as an alternative for repeated tumor biopsies. Our aim was to investigate the dynamics of ctDNA in a cohort of NSCLC patients and explore the roles of EGFR driver and resistance mutations in predicting disease progression and progression free survival (PFS). Methods: NSCLC patients treated with either erlotinib or gefitinib as first-line anti-EGFR therapy were included. Clinical data was collected retrospectively from medical records. Plasma samples collected as part of routine care were analyzed. First DNA was isolated from plasma using the QIAsymphony SP (Qiagen). Then EGFR driver (L858R and exon 19 deletions) and resistance (T790M) mutations were quantified using the X100 Droplet Digital PCR and analyzed using QuantaSoft software (Bio-Rad). The dynamics of ctDNA mutations over time and the relationship between copy numbers and progression free survival were explored. Results: 68 NSCLC patients and 249 plasma samples (1-13 per patient) were included in the analysis. In 33 patients, the T790M mutation was detected. The median (range) T790M concentration in these samples was of 7.3 (5.1 - 3688.7) copies/mL. In 30 patients, the L858R or exon 19 deletion driver mutations were found in median concentrations of 11.7 (5.1 – 12393.3) and 27.9 (5.9 – 2896.7) copies/mL, respectively. Using local polynomial regression, the copies/mL of EGFR driver mutations increased several weeks prior to progression on standard response evaluation. In Kaplan-Meier analysis, patients with a detectable T790M mutation during the first 8 weeks of treatment had a shorter PFS (7.6 versus 14.4 months, p &lt; 0.01, log-rank test). Conclusions: Early detection of the T790M mutation in plasma ctDNA is related to poor PFS. Furthermore, an increase in the copies/mL of the EGFR driver mutation over time may predict clinical progression.
Feasibility of early withdrawal of immunosuppression (WOI) followed by dose escalation of prophylactic donor lymphocyte infusion (pDLI) after T-cell depleted (TCD) matched donor allogeneic hematopoietic cell transplantation (HCT).
Authors: Hongtao Liu, Andrew S. Artz, Masha Kocherginsky, Richard A. Larson, Olatoyosi Odenike, Justin Paul Kline, Lucy A. Godley, James Laurance LaBelle, Wendy Stock, Michael Russell Bishop
Journal: Journal of Clinical Oncology (2016)

7050 Background: We conducted a prospective trial to test the feasibility of early WOI followed by dose-escalation pDLI after alemtuzumab-based TCD conditioning for patients (pts) with high-risk hematologic diseases (as defined by ASBMT) or by unfavorable cytogenetic or molecular features. Methods: 59 pts were enrolled prior to HCT conditioning between June 2013 and October 2015. 33 pts (56%) had AML, including 19 pts not in remission. Pts received fludarabine, melphalan (n = 38), busulfan (n = 20) or TBI/etoposide (n = 1), alemtuzumab 100mg over 5 days and tacrolimus. WOI was planned for day 60 post-transplant if no GVHD or relapse, followed by escalated doses of pDLI every 4-8 weeks at pre-defined doses (2 to 50x105 CD3+ cell/kg for MRD; 1 to 20x105 for MUD). Results: 29 pts (49%) did not undergo WOI due to GVHD (n = 14), early relapse (n = 9), death (n = 5) or graft failure (n = 1), and 7 (12%) underwent WOI but did not receive pDLI due to GVHD (n = 5), death (n = 1), or too early (n = 1). The primary endpoint of successful WOI and receipt of at least one pDLI was achieved in 23 (39%) pts, with 5, 6, 4, 4, and 4 pts received 1, 2, 3, 4 and 5 pDLI respectively. Median time from transplant to 1st pDLI was 96 days (range 87 to 164). After pDLI, 5 pts developed grade I-IV aGVHD but all responded to steroids; 3 pts developed cGVHD. 33 pts (55%) were MRD, and were more likely than MUD pts to receive at least one pDLI (58% vs 15%; p < 0.01) or to get WOI (70% vs 27%, p < 0.01). 19/33 (58%) MRD pts received at least one pDLI, while only 8/26 (31%) MUD pts were able to have early WOI and only 4 (15%) received at least one pDLI. Median PFS and OS for all pts were 9.6 and 13.1 months, with deaths mostly due to relapse (68%), GVHD (16%) or infection (10%). Pts receiving at least one pDLI had two-year PFS and OS of 59% and 51% from HCT, respectively. 7 out of the 23 pts (30%) relapsed, however, there were only two (17%) relapses among 12 pts who received > = 3 pDLI. Conclusions: Our prospective trial demonstrated that early WOI followed by dose-escalation pDLI is feasible after TCD MRD HCT for pts with high risk hematologic malignancies. Clinical trial information: NCT01839916.
A web-based tool to predict chemotherapy-associated cognitive impairment during survivorship.
Authors: Sreemanee Raaj Dorajoo, Terence NG, Jung-Woo Chae, Hui Ling Angie Yeo, Maung Shwe, Yan Xiang Gan, Koon Mian Foo, Wei-Jen Kiley Loh, Si-Lin Koo, Wen Yee Chay, Tira Jing Ying Tan, Sok Yuen Beh, Elaine H. Lim, Guek Eng Lee, Rebecca Alexandra Dent, Yoon Sim Yap, Raymond C.H. Ng, Alexandre Chan
Journal: Journal of Clinical Oncology (2017)

e21609 Background: Chemotherapy-associated cognitive impairment (CACI) experienced during survivorship can dramatically impair quality of life, particularly among patients receiving treatment with curative intent. We construct a web-based tool to predict the risk of self-perceived CACI at 15 months post-chemotherapy initiation among early stage breast cancer patients, to facilitate screening and early intervention. Methods: We recruited patients receiving chemotherapy for early-stage breast cancer between 2011 and 2014. Subjective cognitive function was assessed using FACT-Cog before, during and at 15 months after initiating chemotherapy. Based on a previously established minimal clinically important difference, an 11-point reduction in FACT-Cog score relative to that at baseline was considered as clinically significant CACI. Factors evaluated as potential predictors of CACI included clinical, laboratory and demographic factors, behavioural symptom and quality of life assessments (EORTC-QLQ-C30). Logistic regression was used to construct a model predicting CACI. Validation was performed on an external cohort recruited between 2015 and 2016. Model discrimination and calibration were evaluated using the receiver operating curve (ROC) and Hosmer-Lemeshow goodness-of-fit, respectively. The model was implemented as a web-based tool. Results: A total of 131 patients were recruited for model development. The model consisted of baseline EORTC-QLQ-C30 fatigue subscale percentage [effect size (95% confidence interval), 5.0% (2.0% to 7.0%), p &lt; 0.001] and the change in FACT-Cog score after 2 cycles of chemotherapy, relative to baseline [-4.0% (-7.0% to -1.0%), p = 0.007]. The model was validated on an external cohort of 33 patients, with an ROC of 0.60, Hosmer-Lemeshow goodness-of-fit statistic of 5.86 (p = 0.44), sensitivity of 57.1% and specificity of 76.9%. The web application is accessible at http://bit.ly/CognitiveRisk Conclusions: A web application to predict CACI risk has been developed and externally validated. The tool facilitates early screening for patients at high risk for CACI and allows timely interventions to prevent or minimize the impact of CACI during survivorship.
Abstract 14953: Age Criteria Modification of Current Risk Scores Predicting Stroke in Patients With Atrial Fibrillation: A Nationwide Cohort Study From Korea
Authors: Daehoon Kim, Pil-Sung Yang, Tae-Hoon Kim, Jae-Sun Uhm, Hui-Nam Pak, Moon-Hyoung Lee, Boyoung Joung
Journal: Circulation (2016)

Background: Recently, it was suggested that lowering the age threshold for stroke risk estimation help identify truly low stroke risk in Taiwan atrial fibrillation (AF) patients. Purpose: This study hypothesized that lowering the cutoff age in current risk stratification scores (CHA2DS2-VASc, CHADS2, and R2CHADS2) might provide better stroke prediction. Methods: We included non-valvular AF patients not using oral anticoagulants (OACs) from 506,805 adults in prospective cohort data collected by the National Health Insurance Service in Korea. The younger age groups of the current risk scores were divided into 2 subgroups by a cutoff of 55 years. We assigned -1 point to the younger subgroup (<55 years of age) and did not change the points assigned to other groups. The modified risk scores were compared with each original score by calculating the c-statistics and net reclassification improvement (NRI). Results: During 14,430 person-years of follow-up, we observed 188 ischemic strokes. Annualized stroke rate w...
Phase II safety and tolerability study of Radium-223 (R223) in combination with enzalutamide (ENZA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): CTRIAL-IE (ICORG) 13-21.
Authors: Raymond S. McDermott, John Patrick Greene, Olwyn Deignan, John McCaffrey, Imelda Parker, Alison Bowes, Ausra Teiserskiene, John Feeney, Pierre Guillame Thirion, Stephen P. Finn, Paul J. Kelly
Journal: Journal of Clinical Oncology (2018)

5050 Background: R223 and ENZA are standard of care agents in the treatment of patients (pts) with mCRPC. The combination of R223 and ENZA is of interest due to differing modes of action and non-overlapping toxicity profiles, leading to the potential for synergy. Methods: This phase II, open-label, multicentre single arm study (NCT02225704) enrolled pts with mCRPC to bone with or without visceral/lymph node involvement who had progressed on androgen deprivation therapy. Prior docetaxel chemotherapy for hormone sensitive prostate cancer was allowed. Pts received 6 cycles of R223 (55 kBq/kg IV Q4W) in combination with ENZA (160mg/day), followed by ENZA alone until disease progression (PD), unacceptable toxicity or consent withdrawal. The primary endpoint was safety for the 6 months of combination therapy which is reported here. Results: From July 2015 to July 2017, 45 pts were enrolled in Ireland. 42 pts (93.3%) received all 6 cycles of combination therapy. A total of 13 pts (28.9 %) had grade (gr) 3/4 adverse events (AEs). The most frequent gr 3/4 AEs (Table) were neutropenia (n = 3, 6.6%) and fatigue (n = 3, 6.6%) followed by nausea, lower respiratory tract infection (LRTI), lymphocytopaenia, leukopaenia, hyperkalaemia, hypokalaemia, back pain, headache, urticaria, syncope and hypertension (all n = 1, 2.2%). 2 pts (4.4%) discontinued treatment due to AEs, gr 3 LRTI (n = 1) and gr 2 nausea and pain (n = 1). One pt discontinued due to symptomatic PD. There were no therapy-related deaths. Conclusions: R223 in combination with ENZA is well tolerated with acceptable early safety and toxicity profiles consistent with those seen when they are used as single agents and allowing for concomitant administration. Evaluation of secondary endpoints including skeletal related events with longer follow up is ongoing. Clinical trial information: NCT02225704.AE R223 + ENZA (n = 45) Gr 1 Gr 2 Gr 3 Gr 4 n (%) Fatigue 14 8 3 25 (55.5) Nausea 14 6 1 21 (46.6) Back pain 6 3 1 10 (22.2) Neutropenia 1 5 2 1 9 (20) Headache 4 1 1 6 (13.3) Lymphocytopaenia 1 3 1 5 (11.1) Leukopaenia 2 2 1 5 (11.1) Hypertension 4 1 5 (11.1) LRTI 3 1 4 (8.8) Urticaria 1 1 (2.2) Syncope 1 1 (2.2) Hypokalaemia 1 1 (2.2) Hyperkalaemia 1 1 (2.2)
Association of KRAS mutations detected via liquid biopsy in metastatic non-small cell lung cancer patients with high levels of FDG-PET SUV.
Authors: Seo-Hyun Kim, Ammar Karo, Lela Buckingham, Sanjib Basu, Jeffrey Allen Borgia, Philip Bonomi, Marta Batus, Mary J. Fidler
Journal: Journal of Clinical Oncology (2017)

e20594 Background: We had previously evaluated the relationship between FDG-PET SUV with TP53 and KRAS mutations in formalin fixed paraffin embedded tissue (FFPE) in non-small cell lung cancers (NSCLC) in which genomic profiling had been performed. Considering FDG-PET SUV as a surrogate of glycolysis, we found TP53 and KRAS mutations were associated with increased glycolytic activity. The aim for this study was to evaluate KRAS and TP53 in circulating tumor DNA (ctDNA) in relation to FDG-PET SUV in a different cohort of NSCLCs in which genomic profiling was performed on peripheral blood. Methods: All stage IV NSCLC patients with genomic analysis from ctDNA and baseline FDG-PET scans between December 2014 and November 2016 were included. Associations between KRAS and TP53 mutations and maximal standard uptake value (SUVmax) were assessed using the Mann-Whitney and Kruskal-Wallis test. A subset analysis studying all KRAS positive patients from FFPE and ctDNA was performed based on the specific KRAS mutation. Results:122 patients had FDG-PET scans and genomic analyses of their circulating tumor cells. 62 (51%) patients had a TP53 mutation, 20 (17%) patients had a KRAS mutation, and 13 (11%) patients had both TP53 and KRAS mutations. Patients with a KRAS mutation had a higher SUVmax with a mean of 12.32 (p = 0.019). The presence of TP53 alone or concurrent TP53/KRAS was not significantly related to SUVmax. Analyzing 48 patients with KRAS mutation from FFPE and ctDNA assay, 16 patients had mutations of G12C and 9 patients had G12V. The presence of the G12C mutation was particularly highly correlated with higher SUVmax with a mean of 17.68 (p = 0.0006). Conclusions: In analyzing ctDNA, a larger cohort, mutations in KRAS had the strongest correlation with increased SUVmax. Targeting glycolysis and cellular metabolism could be a potential therapeutic strategy for patients with KRAS mutations. Although individual numbers are small, KRAS subtype analysis showed the presence of the G12C mutation might have the strongest relationship with SUV max and increased glycolysis.
Clinical-pathological features in HER2-positive advanced gastric cancer: Italian data of the Reggio Emilia Clinical Cancer Centre.
Authors: Francesco Iachetta, Alessandra Romagnani, Candida Bonelli, Alessandra Bisagni, Loredana De Marco, Carmine Pinto
Journal: Journal of Clinical Oncology (2018)

e16067 Background: HER2 is an important biomarker in advanced gastric cancer (GC). Adding trastuzumab to chemotherapy (CHT) improved survival in patients with metastatic GC with overexpression of HER2. In the first step of the study we intend to describe the main clinical characteristics and outcome of pts with HER2 positive GC. Methods: Consecutive cases of HER2 positive GC observed at the Reggio Emilia Clinical Cancer Centre were evaluated from 2009 to 2017. We collected their pathological and clinical data. IHC for HER2 overexpression and FISH for gene amplification were used. Results: We analysed the HER2 expression in 443 pts with GC, 135 (30%) pts resulted HER2 positive, 93 men (69%) and 42 women (31%), with a mean age of 67 years (range 37-86). There was a concordance of 87% in 94 pts evaluated with both IHC and FISH. We found IHC 3+ in 63 pts (47%), IHC 2+ and FISH+ in 51 pts (38%), IHC- and FISH+ in 10 pts (7%) and only FISH+ (IHC not evaluated) in 10 pts (7%). We excluded 10 pts who did not present a metastatic disease from analysis. The primary tumour site was gastric in 76 pts (62%), gastroesophageal junction in 45 pts (35%) and unknown in 4 pts (3%). Of 125 pts, 95 (76%) presented synchronous metastasis and 30 (24%) metacronous metastasis; 66% of pts have 1 site of metastasis and 34% have multiple site of metastasis. 99 pts (79%) were treated with a first line of CHT and 95 (96%) of them received platinum/fluopirymidines regimen and trastuzumab with an 8-cycle mean duration of treatment (range 1-50). 48 pts (38%) received a second line of CHT and 16 (12%) a third line. 21 pts were not treated: 14 pts died early due to poor clinical condition and we have no data for 7 pts. See the table for survival analysis. Conclusions: In our single centre series we observed an incidence of 30% of HER2 positive GC. Almost all pts (96%) received first line trastuzumab-based CHT regimen with a longer survival in a subgroup of subjects that completed more than 6 cycles of therapy. In these responsive pts the research of biomarkers predictive of response is ongoing. HER2 positive 125 pts Treated with Trastuzumab 95 pts Trastuzumab < 6 cycles 44 pts Trastuzumab ≥6 cycles 42 pts OS % % % % 1 yr 38.5 47.7 25 76.2 2 yrs 12 14.7 2.3 28.6 3 yrs 6.5 7.4 0 16.7
Humanistic burden of disease in earlier stage metastatic (stage IIIb/c-IVM1a) versus late stage metastatic (IVM1b/c) melanoma patients in a real-world setting in the U.S.
Authors: Jacqueline Buchanan, Swaminathan Murugappan, Rebecca Moon, Adam Roughley, Alex Rider
Journal: Journal of Clinical Oncology (2017)

9561 Background: To assess melanoma specific health-related quality of life (HRQoL) and health states in patients with earlier stage metastatic (IIIb/c-IVM1a) versus late stage metastatic (IVM1b/c) melanoma. Methods: Data were collected from the Adelphi Real World Advanced Melanoma Disease-Specific Programme, a cross-sectional survey of 112 physicians and their patients (N = 666). Data were collected between March and July 2016 in the US. A subset of 183 patients completed the Functional Assessment of Cancer Therapy Melanoma (FACT-M) and EuroQol-5D (EQ-5D) one time. Patients were classified by stage of melanoma at time of consultation. Descriptive analyses of HRQoL scores between earlier and late stage metastatic melanoma were assessed using Mann-Whitney U tests. Results: The mean age of the earlier stage and late stage metastatic patients was 62 and 64 respectively. More earlier stage metastatic patients had an ECOG status of 0 or 1 versus late stage metastatic patients (85%, 75% respectively). A total of 31% of late stage metastatic patients required caregiver support and had a median time since primary diagnosis of 5.0 months whereas earlier stage metastatic patients reported 14% and 5.2 months respectively. Patients with earlier stage metastatic melanoma had better mean EQ-5D index scores versus late stage metastatic melanoma patients (0.81 (n = 84), 0.76 (n = 93); p = 0.0103). Higher scores indicating better HRQoL were observed between earlier stage metastatic versus late stage metastatic melanoma patients for the FACT-M (120.7 (n = 81), 107.4 (n = 91); p = 0.0017) and subscales (except Social Well Being). Clinically meaningful differences between groups using published minimal important differences (MIDs) were observed in in 6/7 FACT-M subscales and EQ-5D VAS. Conclusions: Differences in HRQoL and health states were observed between earlier stage metastatic and late stage metastatic melanoma populations, highlighting the detrimental effect of developing metastatic disease. These results suggest that treatments that delay progression of the disease are important to conserve patients HRQoL
Prevalence of clonal hematopoiesis of indeterminate potential (CHIP) measured by an ultra-sensitive sequencing assay: Exploratory analysis of the Circulating Cancer Genome Atlas (CCGA) study.
Authors: Charles Swanton, Oliver Venn, Alex Aravanis, Earl Hubbell, Tara Maddala, John F. Beausang, Darya Filippova, Samuel Gross, Arash Jamshidi, Ling Shen, Anton Valouev, Nan Zhang, Kelly L Bolton, Timothy Joseph Yeatman, Michael Seiden, Geoffrey R. Oxnard, Minetta C. Liu, Richard Thomas Williams, Anne-Renee Hartman, Jose Baselga
Journal: Journal of Clinical Oncology (2018)

12003 Background: CHIP is defined by the presence of age-dependent acquired mutations in hematopoietic progenitor cells and has been reported to occur in up to 30% of individuals 60-70 years of age. CHIP is a risk factor for hematologic malignancies and cardiovascular disease; its biological mechanisms and clinical significance are just now being studied. Using an assay ~100X more sensitive than exome sequencing, we determined the prevalence and features of CHIP in the CCGA cohort, and the impact on interpretation of cell-free DNA (cfDNA) somatic variants. Methods: Blood was prospectively collected (N = 1627) from 749 controls (no cancer, C) and 878 participants (pts) with newly-diagnosed untreated cancer (20 tumor types, all stages) for WBC and cfDNA isolation. Paired white blood cell (WBC) and cfDNA targeted sequencing (507 genes, 60,000X median coverage) identified somatic single nucleotide variants/indels. Unique molecular barcodes and a machine learning-based noise model achieved a specificity of 1 false positive variant call per Mb of genome targeted at a limit of detection of ~0.1% variant allele frequency (VAF). Results: 1412 samples were eligible and evaluable (576 C, 836 pts; 18 solid tumor types, all stages). Of somatic cfDNA variants matched in WBC (CHIP), 7% of individuals had CHIP with VAF > 10%, 39% had CHIP with VAF > 1%, and nearly all pts (92%) had a somatic mutation with VAF > 0.1%. The rate was similar between C and pts (median age 62, 60), increasing in prevalence by 160% per decade, such that we observed 2.5 variants/Mb at age 60. Of CHIP variants identified, 92% were unique to individual patients, most of which were present at low VAF. Genes impacted by CHIP included DNMT3A (40%), TET2 (27%), and TP53 (10%), consistent with previous reports in patients with solid tumors. Conclusions: An ultra-sensitive sequencing assay demonstrated that CHIP signal in WBC and cfDNA is much more common than previously appreciated. The clinical significance of CHIP warrants further study and must be accounted for when interpreting cfDNA variants for both early cancer detection and tumor genotyping (liquid biopsy). Clinical trial information: NCT02889978.
P01.149 Low-grade glioma post-Radiation therapy surveillance with advanced imaging techniques
Authors: A L Vasconcelos, J Tavares, M L Albuquerque
Journal: Neuro-Oncology (2018)

Optimal sequential strategy in LGG patients is complex: beyond the role of each individual treatment surgery (S); radiation therapy (RT); chemotherapy (CT), second effects can potentiate the effect of each treatment. With late toxicities concerns as median survival range 5 to 15 years with better prognosis and treatment response for pts with 1p/19q codeletion and IDH1 mutation. Symptoms mainly decreased seizures and magnetic resonance (MRI) evaluation is part of clinical follow-up.Using advanced MRI techniques such as Perfusion can help distinguish pseudoprogression (PP) from true progression (TP), which is a major concern since PP in LLG can occur up to 20%. Review in Mosaiq® and PACS imaging database, adults with primary CNS tumors. Between January 2007 and December 2017, primary CNS tumors 947 pts with were treated in our radiation therapy department. According to 2016 WHO CNS classification 22% LGG. MRI imaging follow-up was assessed 1–3 months after RT. The protocol included T2FLAIR 3D, T13D before and after gadolinium and perfusion weighted-imaging T2* (which measures cerebral blood volume -CBV). We present 7 pts with LGG diagnosis who underwent surgery/biopsy, molecular features were 57% codeletion 1p19q and 72% IDH1 mutation. MRI alterations observed were increased T2FLAIR and 57% pts enhancement in T1 after gadolinium both in PP and TP but in one with PP the CBV was reduced whereas in the other patients with TP it was increased. MRI is very useful in the follow up of LGG and advanced techniques such spectroscopy and perfusion-weighted help distinguish PP from TP.