tbuckley/cabot-search huggingface dataset:
Genetics, Biochemistry, and “Simple” Organisms Converge to Unlock Secrets in Histone Biology
Authors: Michael Grunstein, C. David Allis
Journal: JAMA (2018)

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Impact of germline BRCA identification on subsequent breast cancer stage and therapy: Implications for routine screening.
Authors: Tal Hadar, Pnina Mor, Gefen Amit, Sari Lieberman, Esther Tahover, Ora Rosengarten, Moshe Carmon, Oded Olsha, Ribhi Abu Dalo, Rachel Michaelson-Cohen, Eliahu Golomb, Rachel Rabinovitch, Ephrat Levy-Lahad
Journal: Journal of Clinical Oncology (2018)

1584 Background: Screening healthy Ashkenazi Jews (AJ) for germline BRCA1/BRCA2 mutations (gBRCA) is not standard policy, despite high (2.5%) carrier rates. Most carriers are identified only after breast cancer diagnosis. We hypothesized that pre-symptomatic knowledge of carrier status would favorably affect breast cancer stage and management. Methods: We reviewed records of gBRCA carriers who did not undergo risk-reduction mastectomy and were diagnosed with breast cancer between 4/1996-4/2016. Patient age, parity, family history, genotype, screening compliance, method of breast cancer detection, disease characteristics and treatment (breast and axillary surgery, chemotherapy) were compared between carriers whose gBRCA was identified pre-breast cancer vs. post-breast cancer. Results: 165 females with gBRCA and breast cancer were identified, of whom carrier status was determined pre-breast cancer in 45 (27%) and post-breast cancer in 120 (73%); both groups had similar mean age at cancer diagnosis (50.6y vs. 50.5y, range 27-86) and BRCA1:BRCA2 distribution (64%:36% and 65%:35%). Pre-breast cancer carriers were significantly (p < 0.001) more likely to have a suggestive family history (90% vs. 62%), prior breast cancer screening (78% vs 60%), and breast cancer diagnosed by imaging (78% vs 25%) rather than clinical symptoms (19% vs 73%). Pre-breast cancer carriers had a higher DCIS: invasive breast cancer presentation (40%:60% vs. 2%:98% in post-breast cancer) and lower stage (p < 0.005). No differences in tumor grade, ER or Her2 status were identified. Pre-breast cancer carriers were more likely to undergo sentinel lymph node biopsy (91% vs 45%), less likely to receive chemotherapy, and more likely to elect bilateral mastectomies (62% vs 10%) than post-breast cancer carriers (p≤.001 for all comparisons). Overall, pre-breast cancer gBRCA identification and routine screening predicted for early stage (0-I) breast cancer diagnosis (p < 0.001, OR 16.8). Conclusions: Presymptomatic identification of gBRCA status is significantly associated with earlier stage breast cancer diagnosis, requiring less extensive treatment. This supports routine gBRCA testing in all healthy AJ women.
Indian experience of lenvatinib in radio-iodine refractory differentiated thyroid cancer.
Authors: Satheesh Chiradoni Thungappa, Shashidhara H P, Ravi Thippeswamy, Shekar Patil, Kumarswamy Gangadharaiah Kallur
Journal: Journal of Clinical Oncology (2018)

e18107 Background: Differentiated thyroid cancer (DTC) accounts for approximately 95% of thyroid carcinomas. Chemotherapy has very limited efficacy in metastatic Radioactive Iodine (RAI)-refractory disease. With increasing knowledge of the molecular pathogenesis of DTC, novel targeted therapies have been developed. Lenvatinib is a tyrosine kinase inhibitor (TKI) with promising clinical activity based on the randomized phase III SELECT trial. As there are very limited publications on Lenvatinib in DTC from India, we conducted this study to evaluate the safety and efficacy of Lenvatinib in patients with metastatic RAI-refractory DTC at HCG hospital, Bengaluru. Methods: Patients with RAI-refractory DTC with progressive disease having good performance status (0-2) were treated with Lenvatinib at our institution from September 2015 to January 2017 with the help of Eisai compassionate program and the data was analyzed. Results: 15 patients with a median age of 63 years (37 -80) were enrolled. Male: Female ratio was 2:1. Most patients (60%) had prior therapy with sorafenib. 80 % of patients had raised baseline thyroglobulin value. Commonest sites of metastases were Lung and Lymph nodes. 60% of patients showed partial response and 40% Stable disease at 6 months of initiation of Lenvatinib. In 75% of patients serum thyroglobulin level declined more than 50 % from baseline at 6 months. Median progression free survival was 15 months and 60% of patients had median duration of treatment of more than 16 months. Common adverse events (AE) ( Grade 1- 3) were Mucositis ( 93%), Hypertension(66.6%), Hand foot syndrome (HFS)(66.6%), diarrhea (66.6%) , fatigue (46.6%), Skin rashes (33.3%) and thrombocytopenia (13.3%), out of which severe AE (Grade 3) were in the form of HFS (13.3%), Diarrhea (13.3%) and Hypertension (6.67%). All cases had dose reduction done due to adverse effects and in 66.65% of patients it was done within initial 3 months of therapy. 60% of patients are still on treatment. Conclusions: Lenvatinib is a potential treatment option with most effective clinical benefit for patients with metastatic RAI-refractory DTC. Lenvatinib is a safe drug and its toxicity can be easily manageable.
Quality improvement program in radiation oncology: Understanding patient hospitalizations, treatment breaks, and weight loss in patients receiving radiotherapy.
Authors: Varun Chowdhry, Pamela Jangro, Saveli Goldberg, Nolan Gagne, Shelley Chabot, Gary M. Proulx, Cocav A. Rauwerdink
Journal: Journal of Clinical Oncology (2018)

e18840 Background: The reporting of adverse effects is an integral aspect of a hospital quality improvement (QI) program with the goal of improving care for current and future patients. We report the results of our experience tracking patient hospitalizations, treatment breaks, and weight loss in patients receiving radiotherapy as part of a departmental QI program. Methods: In 2014, the Center for Cancer Care at Exeter hospital developed a departmental quality initiative to track adverse outcomes in a population of patients receiving radiation therapy. Criteria for inclusion in this initiative included: treatment break ≥ 3 days, hospitalization either while on treatment of within 2 weeks of treatment, any death on treatment or within 2 weeks of treatment, or weight loss of ≥10%. Patients included on this registry were reviewed at regularly scheduled departmental QI meetings, where solutions for improvement were discussed. Results: A total of 91 patients were identified as having an event that meet the above mentioned criteria. Forty-three patients were receiving concurrent chemotherapy (47.2%) Fifty-four (54.9%) patients had toxicity directly attributable to their treatment. Sixty-five patients (71.4%) were treated with curative intent. Nineteen patients (21.1%) died either during the course of radiation, or within two weeks of completion of treatment. Fifty-four patients (59.3%) completed the radiation treatment as planned. Advanced age was significantly associated with inferior overall and disease free survival in this analysis, HR 1.030 (1.006-1.054) p = 0.0125, and HR 1.034 (1.008-1.061) p = 0.010 respectively. Conclusions: We report results of our departmental quality initiative, and we believe that this protocol is effective at creating discussion among members. Our results suggest that elderly patients who experience qualifying event are at increased risk of death, and providers should be cognizant of this finding. This QI project has directly and indirectly resulted in practice changes in our cancer care program.
Historical non-treatment of metastatic non-small cell lung cancer: Implications for evaluating novel therapies.
Authors: Kenneth L. Kehl, Mariana Chavez-MacGregor, Sharon Hermes Giordano, Deborah Schrag
Journal: Journal of Clinical Oncology (2018)

e18662 Background: Recent immunotherapy and targeted therapy approvals for metastatic non-small cell lung cancer (NSCLC) were based on superior efficacy vs. cytotoxic chemotherapy. However, not all patients with advanced NSCLC are treated. For patients who might otherwise not receive chemotherapy, effectiveness of novel agents would best be compared to supportive care or radiation therapy alone. Evaluation of new treatments therefore requires a deeper understanding of real-world treatment rates. Methods: Patients with stage IV NSCLC diagnosed 2010-2013 were identified using the SEER-Medicare database. The primary outcome was any systemic therapy. Multivariable time-to-treatment analysis with competing risks of death was conducted. Landmark analysis at 12 months after diagnosis was performed. Results: We identified 9655 patients with metastatic NSCLC. By one year after diagnosis, 51% received systemic therapy; 48% received radiation therapy, and 29% died without receiving systemic therapy or radiation. Factors associated with systemic therapy are listed in the Table. Of 4705 patients with specific claims for first-line systemic therapy, 43% had subsequent claims for second-line systemic therapy. Conclusions: Half of Medicare patients with stage IV NSCLC diagnosed 2010-2013 received any systemic therapy. Assessments of the effectiveness and value of novel agents should address their impact on patients who might otherwise not be treated. Table 1: HR for systemic therapy (95% CI) Age (per year) 0.95 (0.95-0.96) Female sex (vs male) 1.14 (1.07-1.21) Comorbidity index (per unit) 0.92 (0.90-0.94) Marital status Married/partnered Ref Unmarried 0.69 (0.65-0.73) Unknown 0.76 (0.65-0.89) Race White Ref Black 0.81 (0.73-0.90) Asian 1.19 (1.06-1.33) Other 1.00 (0.88-1.14) Any hospitalization in year before diagnosis 0.90 (0.83-0.98) Any SNF stay in year before diagnosis 0.68 (0.57-0.81) County-level any college education (per quintile) 0.97 (0.95-0.99) County-level poverty (per quintile) 0.94 (0.92-0.96) Brain metastasis (Yes vs no) 0.82 (0.76-0.88) Bone metastasis (Yes vs no) 1.01 (0.95-1.07) Liver metastasis (Yes vs no) 0.84 (0.76-0.92) Lung metastasis (Yes vs no) 0.98 (0.92-1.04)
Small cell carcinoma of the urinary bladder, a single institution experience.
Authors: Gurleen Pasricha, Angela Sanguino, Lakshmi Harinath, Jan F Silverman, Shifeng Mao
Journal: Journal of Clinical Oncology (2018)

e16512 Background: Small cell carcinoma of the urinary bladder (SCCB) is a rare but aggressive malignancy associated with poor prognosis. There is no established treatment guideline. It is typically treated like small cell lung cancer (SCCL) based on histologic similarity. We conducted a retrospective review of patients with SCCB at our institution, to evaluate the clinicopathologic features and treatment response. Methods: We performed a database search (CoPath system) at Allegheny General Hospital from 2010 to 2017 and verified the diagnosis with a pathologist. Results: We identified 20 patients with diagnosis of SCCB, 15 men and 5 women with a mean age of 71 years (range 51-91). Fifteen patients (75%) were smokers with 63.6 mean pack year smoking history. Eight patients (40%) had prior malignancies (4 prostate, 2 uterine, 1 bladder and 1 SCCL). At diagnosis, 13 patients (65%) had metastatic (Met), 7 (35%) stage II-III disease. Common sites of metastases were bone (7, 50%), liver (4, 28.6%), brain and lung (2 each, 14.3%) and peritoneum (1, 7.1%). Among 19 tumor samples examined, 6 (32%) had pure small cell histology, 13 (68%) had coexisting histology, including 11 (58%) urothelial and 2 (11%) adenocarcinoma. Twelve patients received chemotherapy (platinum plus etoposide), including 2 in neoadjuvant (Neo), 3 concurrent chemoradiation (CRT), 2 adjuvant (Adj) and 5 Met settings. Six (50%) patients (4 Met, 1 Adj and 1 CRT) developed disease progression with median time-to-progression of 4.5 (range 2.3, 9.9) months. All 6 patients received subsequent lines of therapy; 4 received immunotherapy, including Atezolizumab or Ipilimumab plus Nivolumab. One responded to the combination immunotherapy. Conclusions: Systemic therapy using platinum plus etoposide offers a modest efficacy. For localized disease, neoadjuvant chemotherapy followed by radical cystectomy provides the best outcome in our patients. Efficacy of combination immunotherapy was observed in salvage setting. Further pathologic evaluation of immunogenic features of the tumor samples is ongoing.
Lung cancer genomic alterations in cell free DNA in pleural effusion compared to plasma.
Authors: Zhenzhen Zhou, Rongrong Chen, Yuxing Chu, Xingsheng Hu, Ling Yang, Xin Yi, Hongbing Zhang, Dongmei Zhang, Xuefeng Xia, Zhongxing X. Liao
Journal: Journal of Clinical Oncology (2017)

e23206 Background: Circulating tumor DNA (ctDNA) in plasma has been shown to be informative of the genomic alterations present in lung cancer and has been used to guide tumor treatment and monitor tumor progression. However, patients with lung cancer, even in advanced stage, usually present with small numbers of cancer-related genetic aberrations and low mutation allele frequency (MAF) on average. Malignant pleural effusion is one of common complications for lung cancer patients in advanced stage. Cell free DNA (cfDNA) in pleural effusion may be extensively diluted once entering into the peripheral circulation system. Methods: We implemented targeted capture NGS with a gene panel of 180 lung cancer-relevant genes on 23 paired plasma ctDNA and matched pleural cfDNA samples extracted simultaneously from the same patient with advanced lung cancer (n = 23), including 17 adenocarcinoma. Results: Overall, actionable variations with on label, off-label, or experimental drugs available, were identified in 87% (n = 20) of pleural effusion samples, whereas plasma was 48% (n = 11). Median number of pleural somatic mutations was 4, predominantly located in TP53, EGFR, and ALK; while the median number was 2 in plasma samples. Of that, 39% and 74% of plasma ctDNA and pleural cfDNA samples were observed at an average MAF above 1%, respectively. In addition, 48% and 78% of plasma ctDNA and pleural cfDNA samples were observed with the highest MAF above 1%. The concordance rate for EGFR and ALK alterations with plasma NGS was 83% and 87%, respectively. Conclusions: Our results suggest that pleural effusion-derived cfDNA is more sensitive than plasma for advanced lung cancer patients. With higher MAF and detection rate of actionable variations, pleural effusion-derived cfDNA might guide more precise lung cancer treatment.
Phase 2, open-label, multicenter study of the efficacy and safety of INCB054828 in patients (pts) with advanced, metastatic, or surgically unresectable cholangiocarcinoma (CCA) with inadequate response to prior therapy.
Authors: Mitesh J. Borad, Sarah Lindsey Davis, Maeve Aine Lowery, Christine F. Lihou, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2017)

TPS4145 Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR translocations and activating mutations is implicated in many cancers, including CCA. FGFR2 translocation, the most common FGFRalteration, occurs in ~13% of pts with intrahepatic CCA. INCB054828 is a novel, orally available, selective inhibitor of FGFR1, FGFR2, and FGFR3 tyrosine kinase activity (AACR 2015; Abstract 771). Methods: This phase 2, open-label trial will evaluate INCB054828 monotherapy in pts with advanced/metastatic or unresectable CCA (NCT02924376). Pts will be prescreened locally or centrally for FGF/FGFR status prior to enrollment (Table): FGFR2 translocation (Cohort A); other FGF/FGFR alteration (Cohort B); no FGF/FGFR alteration (Cohort C; negative control for effects of FGF/FGFR alteration on objective response rate [ORR]). Eligibility criteria include: age ≥18 years; ECOG performance status ≤2; adequate liver and renal function; life expectancy ≥12 wks; disease progression after ≥1 prior systemic therapy; no prior use of selective FGFR inhibitors. Pts will self-administer INCB054828 orally at a starting dose of 13.5 mg QD on a 21-day cycle (2 wks on; 1 wk off); treatment will continue until disease progression or unacceptable toxicity. The primary endpoint will be ORR (complete or partial response, independent radiologic review committee, RECIST v1.1) in pts with FGFR2 translocation (Cohort A). Secondary endpoints include ORR in pts positive or negative for any FGF/FGFRalteration and duration of response, PFS, OS, and safety (all cohorts). The study has currently enrolled 2 pts (recruitment ongoing; estimated primary completion, April 2018). Clinical trial information: NCT02924376. [Table: see text]
Lessons from the routine tumor molecular profiling in Russia
Authors: V. Mileyko, E. Rozhavskaya, E. Veselovsky, A. Kovtun, M. Ivanov, E.O. Ignatova
Journal: Annals of Oncology (2018)

Background: Cost-effectiveness is one of the major limitations for tumor molecular profiling along with a small fraction of patients who can benefit from precision oncology approach. Our experience of providing an affordable molecular profiling (AMP) proves that focused biomarker panels and specific selection of patients for testing are the possible ways to overcome those obstacles. Methods: NGS assays were performed with AmpliSeq targeted panels. Data were analyzed with a proprietary pipeline. Apart from routine searching for nonsynonymous substitutions, NGS data were processed with custom-built algorithms for identifying amplifications, splice-affecting variants and evaluation of tumor mutational load. Within our concept of AMP in some cases, the following techniques were used to identify the additional biomarkers: MSI-assay, FISH (gene fusions), PD-L1 and others. Results: First 79 patients were analyzed. The most common cancer types were: breast cancer - 17, colorectal cancer – 12, lung cancer – 8 and rare tumor types. In 14 cases (15.1%), patients were denied molecular profiling due to there were conventional treatment options or extremely low chances to detect actionable alterations. The average total costs of the study were - 50704 rubles or less than 700 Euros per patient. In 22% of cases, there were found biomarkers of 2B, 3A/B, and 4 levels of evidence (according to OncoKB.org) since biomarkers 1 and 2A levels have almost always been studied in patients. Our proprietary algorithm detected actionable amplifications in NGS data from 2 patients. Pretreated patient with stage IV cervical cancer was indicated to afatinib treatment due to amplified EGFR. The treatment resulted in complete response and stable remission during next 6 months. The second case was metastatic colorectal cancer with amplification of FLT3 gene who demonstrated a partial clinical response to sorafenib. In both cases, all standard treatment options were exhausted. Conclusions: Reasonable selection of biomarker panels helps to reduce costs and ensure the better clinical utility of routine tumor molecular profiling. Legal entity responsible for the study: OncoAtlas, LLC. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Impact of Nonconcordance With NCCN Guidelines on Resource Utilization, Cost, and Mortality in De Novo Metastatic Breast Cancer
Authors: Gabrielle B. Rocque, Courtney P. Williams, Bradford E. Jackson, Stacey A. Ingram, Karian I. Halilova, Maria Pisu, Kelly M. Kenzik, Andres Azuero, Andres Forero, Smita Bhatia
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) have directed the care of patients with cancer for >20 years. Payers are implementing guideline-based pathway programs that restrict reimbursement for non–guideline-based care to control costs, yet evidence regarding impact of guidelines on outcomes, including mortality, Medicare costs, and healthcare utilization, is limited. Patients and Methods: This analysis evaluated concordance of first treatment with NCCN Guidelines for women with de novo stage IV metastatic breast cancer (MBC) included within the SEER-Medicare linked database and diagnosed between 2007 and 2013. Cox proportional hazards models were used to evaluate the association between mortality and guideline concordance. Linear mixed-effects and generalized linear models were used to evaluate total cost to Medicare and rates of healthcare utilization by concordance status. Results: We found that 19% of patients (188/988) with de novo MBC received nonconcordant treatment. Patients receiving nonconcordant treatment were more likely to be younger and have hormone receptor–negative and HER2-positive MBC. The most common category of nonconcordant treatment was use of adjuvant regimens in the metastatic setting (40%). Adjusted mortality risk was similar for patients receiving concordant and nonconcordant treatments (hazard ratio [HR], 0.85; 95% confidence limit [CL], 0.69, 1.05). When considering category of nonconcordance, patients receiving adjuvant regimens in the metastatic setting had a decreased risk of mortality (HR, 0.60; 95% CL, 0.43, 0.84). Nonconcordant treatments were associated with $1,867 higher average Medicare costs per month compared with concordant treatments (95% CL, $918, $2,817). Single-agent HER2-targeted therapy was the highest costing category of nonconcordance at $3,008 (95% CL, $1,014, $5,001). Healthcare utilization rates were similar for patients receiving concordant and nonconcordant treatments. Conclusions: Despite a lack of survival benefit, concordant care was associated with lower costs, suggesting potential benefit to increasing standardization of care. These findings may influence policy decisions regarding implementation of pathway programs as health systems transition to value-based models.
Delivering all in one: Antigen-nanocapsule loaded with dual adjuvant yields superadditive effects by DC-directed T cell stimulation
Authors: David Paßlick, Keti Piradashvili, Denise Bamberger, Mengyi Li, Shuai Jiang, Dennis Strand, Peter R. Wich, Katharina Landfester, Matthias Bros, Stephan Grabbe, Volker Mailänder
Journal: Journal of Controlled Release (2018)