tbuckley/cabot-search huggingface dataset:
Next generation sequencing (NGS) of primary central nervous system tumors (CNST) as part of a personalized medicine cancer research program (PMRP) to identify alterations with sensitivity to targeted inhibitors.
Authors: Tara L. Benkers, Anna Belinda Berry, Mariko Tameishi, Mary Lessig, Thomas David Brown
Journal: Journal of Clinical Oncology (2016)

2066 Background: Primary CNST demonstrate remarkable intra-tumoral and inter-tumoral heterogeneity contributing to therapeutic resistance. We report implementation of a PMRP for patients with primary CNST. Methods: An Institutional Review Board approved prospective registration protocol was activated in September 2014 as a data repository for cancer patients undergoing genomic evaluation. NGS profiling of CNST was performed using a 68-gene alteration panel. Mutations (M) were classified as Actionable (approved clinical indication), Applicable (clinical trials or off-label indication) and Unknown significance. Results: As of December 2015, sequencing was completed on 98 primary CNST. Diagnoses included glioblastoma (51), anaplastic glioma (25), low-grade glioma (7), neuronal-glial tumors (4), DLBCL (3), medulloblastoma (3), ependymoma (1), hemangiopericytoma (1), meningioma (2), pituitary adenoma (1). Mutations were identified in 97% of cases. 308 M were identified: 0 Actionable, 128 (42%) Applicable, and 180 (58%) of Unknown significance. The most common Applicable M included: TP53 (33), IDH1 (31), PTEN (14), TYMS (10), EGFR (8), TPMT (8), PIK3CA (6), BRAF (3), APC (2), CDKN2A (2), MYD88 (2), TET2 (2), KRAS (2) ATM (1), DPYD (1), IDH2 (1), JAK3 (1), and RET (1). The number of Applicable M in each case was: 0 (20%), 1 (38%), 2 (27%), 3 (10%), 4 (1%), 5 (1%). Impact of NGS testing was assessed: new therapy started (3%), declined off-label treatment option (1%), no actionable information (26%), stable on current therapy (58%), transitioned to hospice (7%). Clinical decisions were impacted by lack of evidence to change the treatment plan (36%) and off-label access and insurance coverage (68%). Conclusions: Primary CNST demonstrate a significant number of actionable mutations associated with sensitivity to targeted inhibitors along the PI3K/AKT/mTOR, EGFR, CDK, and BRAF pathways amongst others and matching to clinical trial therapies. CNST represent a unique opportunity for investigation of targeted therapies, however access to such therapies remains a barrier.
Impact of surgery vs. other treatments in carcinosarcoma of the lung: A Surveillance, Epidemiology, and End Results (SEER) Analysis.
Authors: Alexander Howard, Yimei Han, Jennifer Lynne Ersek, James Thomas Symanowski, Edward S. Kim
Journal: Journal of Clinical Oncology (2016)

1574 Background: Carcinosarcoma of the lung (CL) is a rare malignant neoplasm, composed of both epithelial and mesenchymal components. It accounts for < 1% of lung cancers. Diagnosis prior to resection is difficult; thus surgery (SURG) is the preferred initial treatment. We examined SEER data to describe demographic/clinical characteristics of CL patients (pts) and assess survival outcomes based on treatment modality and stage. Methods: Pts with a confirmed diagnosis of CL as their initial primary tumor were included. Stage was defined as localized or non-localized. Overall survival (OS) and disease-specific survival (DSS) were analyzed using Cox proportional hazards (PH) models and Kaplan-Meier methods. Results: 411 pts were identified from SEER (1973-2012). Median age was 67 (range 24-96). Other pt characteristics included: male (59.4%), White (83.5%), and upper lobe tumor (53.3%). 25.3% of pts had unknown/missing stage data. Of the 307 pts with known stage, 23.1% had localized disease. Pts were treated with SURG (49.2%), radiation (RT) (16.3%), both SURG and RT (16.6%), or neither SURG nor RT (17.8%). OS (median: 31 vs 6 mo; p < .0001) and DSS (median: 54 vs 8 mo; p < .0001) were significantly better for pts with localized disease. Treatment modality significantly impacted outcome. SURG only pts had significantly improved OS (32 mo; p < .0001) and DSS (20 mo; p < .0001) compared to other treatment modalities, including RT (OS 4 mo and DSS 4 mo). OS was analyzed with a multivariable Cox PH model, including age, stage, and treatment modality. Pts with localized disease had a 40% reduced risk of death (HR 0.60; 95% CI 0.43-0.84). Pts treated with SURG alone had a 62% reduced risk of death compared to those who had neither SURG nor RT (HR 0.38; 95% CI: 0.27-0.54) while pts treated with both SURG and RT had a 42% reduced risk of death (HR 0.58; 95% CI: 0.39-0.87). Conclusions: We believe this is the first retrospective analysis of pts with CL utilizing SEER. Significant survival improvements were observed in pts receiving SURG vs other treatment modalities, regardless of age and stage. Although this is not a prospective study, these results should be considered in the context of individual pt treatment.
Effects of gene penetrance on adherence to breast cancer screening recommendations (BCSR) among high-risk women.
Authors: Jacqueline Talea Desjardin, Mallika Sachdev Dhawan, Amie Blanco, Pamela N. Munster
Journal: Journal of Clinical Oncology (2017)

1515 Background: Adherence to cancer screening depends on the interplay between risk perception and convenience. For instance, high perceived risk is likely what motivates high-risk mutation carriers (HRMC) to adhere well to rather inconvenient BCSR. While the NCCN offers BCSR for moderate-risk genes, adherence in moderate-risk mutation carriers (MRMC) and non-carriers with negative multigene panels (NC) is unknown. Methods: Screening behavior was examined in 120 women (15 HRMC, 20 MRMC, 85 NC) 20-65 years old (y) without cancer who received genetic testing and counseling. The groups did not differ in age or family history (fhx). Medical records were reviewed pre- and post-testing to determine adherence. Average follow up was 15 months. Data were analyzed by Chi-squared test. Results: Prior to genetic testing, 93% of women were adherent to general population BCSR, and 58% were already screening in accordance with post-test counseled BCSR. Testing altered adherence to counseled BCSR for HRMC (p&lt;0.01), but not for MRMC (p=0.21) or NC (p=0.86). HRMC had better post-test adherence than MRMC (p&lt;0.05). Conclusions: MRMC are often told to follow similar BCSR to HRMC, namely annual mammogram and MRI, but MRMC may be less motivated to adhere to these BCSR due to lower risk perception. We found adherence was high in HRMC, likely due to high risk perception; intermediate in NC, likely due to manageable BCSR; and comparably low in MRMC, possibly because their risk perception was insufficient to motivate biannual imaging studies. Understanding how genetic testing influences adherence is essential to ensuring proper surveillance in high-risk women. [Table: see text]
Standardized pathological reporting improves stratification of risk for colorectal cancer (CRC) patients
Authors: K Sheahan, A White, H Mulcahy, D Fennelly, J Hyland, DP O'Donoghue
Journal: Endoscopy (2006)

Methods: Standardized pathological reporting including TNM classification has been practised in this institution for 5 years. We sought to assess its impact, in comparison to Dukes classification, in risk stratification for cancer recurrence
Development of an integrated electronic platform for patient self-report and management of adverse events during cancer treatment
Authors: P. Holch, L. Warrington, L.C.A. Bamforth, A. Keding, L.E. Ziegler, K. Absolom, C. Hector, C. Harley, O. Johnson, G. Hall, C. Morris, G. Velikova
Journal: Annals of Oncology (2017)
Long-term disease control with capecitabine in advanced breast cancer.
Authors: Giovanna Masci, Emanuela Ferraro, Rosalba Torrisi, Laura Giordano, Monica Zuradelli, Agnese Losurdo, Rita De Sanctis, Armando Santoro
Journal: Journal of Clinical Oncology (2017)

e12566 Background: Capecitabine is an active agent in the treatment of advanced breast cancer (ABC). It is commonly administered at the approved dosage of 1250 mg/m2 twice daily for 2 weeks followed by 1 week rest period. Methods: The study population included 162 pts retrospectively analyzed with ABC treated with capecitabine between 2006 and 2015 at our Institute. Capecitabine was given 14 day on,7 day off cycle at a daily dose of 1900 mg/m2, a modified schedule used to minimize side effects. The objective were overall response rate (ORR), median duration of treatment (MDT) progression-free survival (PFS), overall survival (OS). Results: The median age was 64 years (range 33-89). Pts with hormone receptor positive ABC were 133 (82%), 6 (4%) had HER-2 positive disease and 29 (18%) a triple negative profile. One hundred and thirty eight (85%) had already received chemotherapy in adjuvant and/or metastatic setting; anthracycline and taxanes were given in 64 pts (40%), anthracycline in 60 pts (37%) and taxane in 4 pts (2%), 9 pts (6%) received other regimens of chemotherapy. Twenty-five pts (15%) were chemo-naive. One hundred and thirty-three pts (82%) received endocrine therapy. Sixty-four pts (38%) had predominantly non-visceral metastases, 26 pts (16%) exclusive visceral involvement, 72 (44%) exhibited both characteristics. ORR was 58% (CR = 2%, PR = 16% SD = 40%) and MDT was 6.9 months. The median PFS and OS were 6.9 months and 21 months, respectively. We defined as “long responders” 19 pts (12%) with disease control interval &gt; 24 months and, among them, as “very long responders”, 9 pts (6%) who exceeded 36 months. Efficacy was unrelated to biological profiles, sites of metastasis or previous therapies. No grade 3 and 4 adverse events occurred. Conclusions: Our results show that in pts with ABC a lower dose of capecitabine has a good toxicity profile and similar overall response rate and survival data in comparison to the approved dose. In addition, we identified a subset of long and very long responders but further studies are warranted to evaluate clinical/biological predictors of a long-term response.
European evidence-based recommendations for diagnosis and treatment of childhood-onset systemic lupus erythematosus: the SHARE initiative
Authors: Noortje Groot, Nienke de Graeff, Tadej Avcin, Brigitte Bader-Meunier, Paul Brogan, Pavla Dolezalova, Brian Feldman, Isabelle Kone-Paut, Pekka Lahdenne, Stephen D Marks, Liza McCann, Seza Ozen, Clarissa Pilkington, Angelo Ravelli, Annet van Royen-Kerkhof, Yosef Uziel, Bas Vastert, Nico Wulffraat, Sylvia Kamphuis, Michael W Beresford
Journal: Annals of the Rheumatic Diseases (2017)

Childhood-onset systemic lupus erythematosus (cSLE) is a rare, multisystem and potentially life-threatening autoimmune disorder with significant associated morbidity. Evidence-based guidelines are sparse and management is often based on clinical expertise. SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) was launched to optimise and disseminate management regimens for children and young adults with rheumatic diseases like cSLE. Here, we provide evidence-based recommendations for diagnosis and treatment of cSLE. In view of extent and complexity of cSLE and its various manifestations, recommendations for lupus nephritis and antiphospholipid syndrome will be published separately. Recommendations were generated using the EULAR (European League Against Rheumatism) standard operating procedure. An expert committee consisting of paediatric rheumatologists and representation of paediatric nephrology from across Europe discussed evidence-based recommendations during two consensus meetings. Recommendations were accepted if >80% agreement was reached. A total of 25 recommendations regarding key approaches to diagnosis and treatment of cSLE were made. The recommendations include 11 on diagnosis, 9 on disease monitoring and 5 on general treatment. Topics included: appropriate use of SLE classification criteria, disease activity and damage indices; adequate assessment of autoantibody profiles; secondary macrophage activation syndrome; use of hydroxychloroquine and corticosteroid-sparing regimens; and the importance of addressing poor adherence. Ten recommendations were accepted regarding general diagnostic strategies and treatment indications of neuropsychiatric cSLE. The SHARE recommendations for cSLE and neuropsychiatric manifestations of cSLE have been formulated by an evidence-based consensus process to support uniform, high-quality standards of care for children with cSLE.
Efficacy of regorafenib (REG) in patients with hepatocellular carcinoma (HCC) in the phase III RESORCE trial according to alpha-fetoprotein (AFP) and c-Met levels as predictors of poor prognosis.
Authors: Michael Teufel, Karl Köchert, Gerold Meinhardt, Jordi Bruix
Journal: Journal of Clinical Oncology (2017)

4078 Background: REG is a multikinase inhibitor which improved overall survival (OS; HR 0.63, 95% CI 0.50, 0.79; P&lt;0.0001) and time to progression (TTP; HR 0.44, 95% CI 0.36, 0.55; P&lt;0.0001) compared with placebo in patients with HCC who progressed during prior sorafenib treatment in the RESORCE trial. This exploratory analysis evaluated the impact of baseline AFP and c-Met on REG treatment benefit (OS and TTP) in the RESORCE trial. Methods: Circulating AFP and c-Met protein (shed ectodomain) levels were quantified by a Luminex assay (Myriad RBM) in plasma samples collected at baseline from patients enrolled in the RESORCE trial. Valid biomarker data were available from 497 (AFP) and 499 (c-Met) out of 573 patients. Patients were subgrouped according to the median protein concentration (high vs low), and the treatment effect HR and its 95% CI were evaluated using a Cox proportional hazards model. The predictive effect was modeledas a protein–treatment interaction effect and subjected to Akaike information criterion (AIC)-based selection to assess its association with OS and TTP. Results: Baseline characteristics of patients were balanced across protein subgroups. While increased levels of both AFP (HR 1.09, 95% CI 1.07, 1.12; P&lt;0.001) and c-Met (HR 1.32, CI 95% 1.06, 1.63; P=0.011) were associated with a worse prognosis for OS, increased AFP levels were also associated with poor prognosis for TTP (HR 1.05, 95% CI 1.03, 1.07; P&lt;0.001). REG treatment benefit for both OS and TTP was independent of AFP and c-Met protein expression (Table). The protein–treatment interaction effect was not statistically significant. Conclusions: The treatment benefit of REG in patients with HCC was independent of AFP and c-MET protein expression at baseline. So far, no single protein has been associated with REG clinical benefit. Clinical trial information: NCT01774344. [Table: see text]
[<sup>177</sup>Lu]pentixather: Comprehensive Preclinical Characterization of a First CXCR4-directed Endoradiotherapeutic Agent
Authors: Margret Schottelius, Theresa Osl, Andreas Poschenrieder, Frauke Hoffmann, Seval Beykan, Heribert Hänscheid, Andreas Schirbel, Andreas K. Buck, Saskia Kropf, Markus Schwaiger, Ulrich Keller, Michael Lassmann, Hans-Jürgen Wester
Journal: Theranostics (2017)

Purpose: Based on the clinical relevance of the chemokine receptor 4 (CXCR4) as a molecular target in cancer and on the success of [ 68 Ga]pentixafor as an imaging probe for high-contrast visualization of CXCR4-expression, the spectrum of clinical CXCR4-targeting was expanded towards peptide receptor radionuclide therapy (PRRT) by the development of [ 177 Lu]pentixather.Experimental design: CXCR4 affinity, binding specificity, hCXCR4 selectivity and internalization efficiency of [ 177 Lu]pentixather were evaluated using different human and murine cancer cell lines.Biodistribution studies (1, 6, 48, 96h and 7d p.i.) and in vivo metabolite analyses were performed using Daudi-lymphoma bearing SCID mice.Extrapolated organ doses were cross-validated with human dosimetry (pre-therapeutic and during [ 177 Lu]pentixather PRRT) in a patient with multiple myeloma (MM).Results: [ 177 Lu]pentixather binds with high affinity, specificity and selectivity to hCXCR4 and shows excellent in vivo stability.Consequently, and supported by >96% plasma protein binding and a logP=-1.76,delaying whole-body clearance of [ 177 Lu]pentixather, tumor accumulation was high and persistent, both in the Daudi model and the MM patient.Tumor/background ratios (7d p.i.) in mice were 499±202, 33±7, 4.0±0.8 and 116±22 for blood, intestine, kidney and muscle, respectively.In the patient, high tumor/kidney and tumor/liver dose ratios of 3.1 and 6.4 were observed during [ 177 Lu]pentixather PRRT (7.8 GBq), with the kidneys being the dose-limiting organs.Conclusions: [ 177 Lu]pentixather shows excellent in vivo CXCR4-targeting characteristics and a suitable pharmacokinetic profile, leading to high tumor uptake and retention and thus high radiation doses to tumor tissue during PRRT, suggesting high clinical potential of this [ 68 Ga]pentixafor/[ 177 Lu]pentixather based CXCR4-targeted theranostic concept.
Impact of Oncotype DX recurrence score in the management of pN1mic early breast cancer.
Authors: Patricia Novas, Elena Galve Calvo, Maria Angeles Sala Gonzalez, Juan Fernando Arango arteaga, Borja Lopez De San Vicente, Virginia Arrazubi, Ane Zumarraga, Maria Lopez Santillan, Purificación Martinez
Journal: Journal of Clinical Oncology (2016)

e12059 Background: The 21-gene Recurrence Score (RS) asssay has been clinically validated and recommended for use in patients (pts) with estrogen receptor positive (ER+) node negative (N0) early breast cancer (EBC) to asses the 10 years risk of distant disease recurrent and predict the likelihood of reponse to adyuvant therapy. It classifies pts into 3 risk recurrence categories: low risk (LR) < 18, intermediate risk (IR) 18-30, and high risk (HR) > 30. For pts with high RS, the benefit from adjuvant chemotherapy is significant while is minimal for pts with low RS. The RS has been shown to be an independent predictor of disease free survival, overall survival, and distant recurrence-free interval in pts with ER+, N+, EBC. (Brufsky AM; Am J Clin Oncol 2014). We evaluated the impact of RS on our adjuvant treatment decisions pre and post-testing in pN1mic (AJCC 7th Edition) EBC. Methods: from 1st November 2012 to 31st December 2015, 147 EBC cases have been analyzed by Oncotype DX (ODX) in our hospital. 35 pts pN1mic were retrospective reviewed. Physicians' treatment choice were documented before and after the RS results. Results: Mean age was 57 years (41-77), women 32 pts (91%), conservative surgery 22 pts (63%), sentinel node biopsy 27 pts (77%). Tumor size: pT1a-b: 8 pts (23%), pT1c: 24 pts (69%), and pT2: 3 pts (9%). Ductal carcinoma 31 pts (89%), 25 pts (71%) histological grade 2. Ki 67 ≥ 13% 23 pts (66%). Recommendations before testing: hormonal therapy (HT) 22 pts (63%) and 13 pts (37%) chemohormonal therapy (CHT). RS results: LR 19 pts (54 %), IR 15 pts (43%) and HR 1 pts (3%). Post-testing treatment: HT 29 pts (83%) and 6 pts (17%) CHT. Therapeutics recommendation changed in 26% (9 pts): 8 pts from CHT to HT (6 pts LR and 2 pts IR). 1 pts from HT to CHT because of IR. Conclusions: In our serie, 54 % of patients with pN1mic were LR. The difference between treatment recommendations pre and post ODX testing was 26% and the 83% of patients received hormonotherapy.
Prognostic and predictive role of tumor-infiltrating lymphocytes in luminal b subtype breast cancer treated with neoadjuvant chemotherapy: A retrospective mono-institutional case series.
Authors: Matteo Duca, Biagio Paolini, Ester Antelmi, Maria Luisa Carcangiu, Luigi Mariani, Daniele Giardiello, Giuseppe Capri, Gabriella Mariani, Paola Mariani, Filippo G. De Braud, Giulia Valeria Bianchi
Journal: Journal of Clinical Oncology (2016)

e12053 Background: Several studies on tumor samples taken from patients undergoing neoadjuvant chemotherapy (NAC) for triple negative (TN) breast cancer (BC) have demonstrated that presence and amount of tumor-infiltrating lymphocytes (TILs) are a potential biomarker of prognostic and predictive significance. Luminal B subtype breast cancer is underrepresented in NAC and TILs trials. We retrospectively investigated the potential prognostic and predictive role of TILs in Luminal B subtype BC in this therapeutic context. Methods: In a consecutive mono-institutional case series we retrospectively identified Luminal B subtype BC not having a pathological complete response after standard NAC with anthracycline and taxane containing regimens. A total of 39 cases were evaluated for inflammatory infiltrate (CD45) and TILs (CD3, CD4, CD8) both on the initial tumor biopsy and on definitive surgical samples. Correlation was investigated between TILs and standard clinicopathological features, residual cancer burden (RCB) score and event-free survival (EFS). Results: TILs moderately decreased from initial biopsy to definite surgery. CD4/CD8 ratio inverted from initial biopsy (CD4 predominance) to definitive surgery. In the univariate analysis, CD3 and CD4 were positively associated with elevated Ki67 labeling index in initial biopsy (p = 0.049 and p = 0.015) in definitive surgical specimen. CD3 positive TILs in diagnostic core biopsy specimens showed a tendency toward direct correlation with the presence of vascular invasion in definitive surgical specimens. With median follow-up of 47 months no association was discovered between TILs and RCB classes or EFS. Conclusions: To our best knowledge, our study sample represents the largest homogeneous series in the literature of early Luminal B subtype BC treated with NAC in which TILs have been determined. In our study, TILs did not show a predictive or prognostic significance in Luminal B subtype BC. Nonetheless, TILs were mainly associated with unfavourable histopathological features such as high Ki67 expression and possibly presence of vascular invasion.
Osteoprotegerin (OPG) as a prognostic marker in breast cancer.
Authors: Elizaveta Maslyukova, Sergey I. Zabroda, Luiza Koritova, Oleg Korytov, V Odincov, Vladimir Sergeev, Svetlana Odincova, Grigoriy Raskin, Ekaterina Vlasova, Evgenii Obuhov, A Bondarenko
Journal: Journal of Clinical Oncology (2016)

e12541 Background: Osteoprotegerin – OPG plays a key role in the regeneration of bone and in the development of metastases in them. Overall survival and time of occurrence of bone metastases depends on the level of its content on the surface of tumor cells.Several studies have found an association between the level of expression of OPG in primary tumors (prostate cancer, multiple myeloma), and propensity to develop bone metastasis. Methods: This research investigates in the study of expression level of OPG in the tumor cells of patients with breast cancer. 83 patients with locally advanced breast cancer (T2-4N0-3M0), who received treatment from 2003 to 2010 took part in the research. Immunohistochemical study was executed in order to study the level of OPG . Expression of more than 50% of cells was regarded as high, at least 50% - as low. Results: Average level of OPG expression was 49%, median - 50%. Minimum value - 0%, maximum- 90%. According to the level of expression of the patients they were divided into two groups: the first - with a high OPG (high) (large media), the second group - with low expression of OPG (low) (less than the median). The group OPG (high) included 47 patients, the group of OPG (low) - 36 patients. By analyzing the duration and time to progression, overall survival, it was found that there is a difference in survival and time to disease progression (of metastasis) of patients with low levels of OPG in comparison with those of patients with high OPG. Conclusions: Determining the level of OPG in the tumor cells of breast cancer provides an additional opportunity to predict the course of breast cancer (survival and time to progression). Of particular interest is a group of luminal cancer when, with a favorable clinical course, part of the patients is progressing. It is not excluded that the level of OPG may be useful in the preventive prescription of medication or for enhanced surveillance.