tbuckley/cabot-search huggingface dataset:
Survival outcomes of patients (pts) who received filgrastim (fil) or pegfilgrastim (peg) in clinical trials.
Authors: Gary H. Lyman, Maureen Reiner, Phuong Khanh H. Morrow, Jeffrey Crawford
Journal: Journal of Clinical Oncology (2014)

e17612 Background: G-CSF treatment is associated with improved relative dose intensity of chemotherapy, which may be associated with improved outcomes (Lyman et al. Ann Oncol. 2013;24:2475-84). However, the association with overall survival (OS) is not well studied. We used patient-level data to evaluate OS in pts who received G-CSF (peg or fil) in 5 randomized, double-blind, controlled trials of G-CSF sponsored by Amgen Inc. Methods: Kaplan-Meier (KM) median OS times, 6- and 12-month survival rates, and hazard ratios (HRs) for survival were estimated for pts who received ≥1 dose of peg/fil or placebo (pbo). Results: See Table. Data on the duration and incidence of severe neutropenia will be presented. Conclusions: G-CSF vs pbo was associated with a positive trend toward improved survival. Further studies are warranted to assess effects of G-CSF and relative dose intensity on long-term outcomes, including OS. Tumor (study) Regimen Events, n/N (%) Median OS, mo (95% CI) 6-mo OS, % (95% CI) 12-mo OS, % (95% CI) HR* (95% CI) Lung (8801†)‡,§,¶ Cyclophosphamide, doxorubicin, etoposide Fil 91/173 (53) 16.2 (12.8−NE) 89 (84−94) 60 (53−67) 0.78 (0.48−1.26) P=0.307* Pbo 20/34 (59) 11.1 (9.0−NE) 77 (62−91) 44 (27−61) Breast (NCT00035594)‡,§,¶ Docetaxel Peg 9/556 (2) NE NE NE 0.59 (0.24−1.45) P=0.244* Pbo 10/372 (3) NE NE NE Breast (980226†)‡,** Doxorubicin, docetaxel Peg 18/150 (12) NE 99 (97−100) 94 (91−98) 0.61 (0.34−1.09) P=0.092* Fil 30/151 (20) 32.8 (NE) 97 (95−100) 95 (91−98) Breast (990749†)‡,** Doxorubicin, docetaxel Peg 2/79 (3) NE 97 (94−100) NE 0.63 (0.10−3.77) P=0.608* Fil 3/76 (4) NE 95 (88−100) NE Colorectal (NCT00094809)§,**,†† FOLFOX4, FOLFIRI, or FOIL Peg 47/124 (38) NE (19.0−NE) 89 (83−95) 80 (73−88) 0.81 (0.54−1.20) Pbo 50/117 (43) 24.8 (19.0−NE) 86 (79−92) 72 (63−81) P=0.292* Meta-analysis (G-CSF vs pbo) 0.77 (0.58−1.03) P=0.080 FOIL=5-fluorouracil (5-FU), leucovorin, oxaliplatin, irinotecan; FOLFIRI=5-FU, leucovorin, irinotecan; FOLFOX4=5-FU, leucovorin, oxaliplatin; NE=not estimable. *Unadjusted HR (95% CI) from Cox proportional hazards model, and log-rank test p value from KM analysis. †Amgen ID. ‡Phase 3.§Included in meta-analysis.¶Crossover pts included. **Noninferiority. ††Phase 2 (interim data for OS).
SEER study of breast cancer specific mortality (BCSM) in patients with lobular tumors treated based on recurrence score results.
Authors: Frederick L. Baehner, Steven Shak, Dave P. Miller, Valentina I. Petkov
Journal: Journal of Clinical Oncology (2017)

11568 Background: Linking the 21-gene assay RS result to the SEER Registries demonstrated very low 5-y BCSM with low RS and high 5-y BCSM with high RS across subgroups, such as nodal status, age, tumor size and grade (npj Breast Cancer 2016). Given the large sample size and interest in outcomes as a function of tumor characteristics, we characterized the relationship between RS results and BCSM in patients reported by SEER with lobular morphology. Methods: Patients with RS and lobular morphology based on the registry ICD-O-3 code 8520 were eligible if node negative (N0) or node positive up to 3 positive nodes (N+mic,1-3), HR+, HER2- negative, no prior malignancy, and diagnosed between Jan 2004 and Dec 2012. No information in SEER is available regarding lobulars, ie., trabecular, alveolar, solid and pleomorphic. 5-y BCSM was estimated using actuarial methods. Results: There were 6,075 eligible patients reported with lobular morphology (11% of cases). Median age was 59 years; 88%/12% were N0/N+; 31%/62%/7% grade 1/2/3; 61%/39% ≤2 cm/&gt;2 cm. Median follow-up was 44 months. A minority (8%) had RS &gt;25. Chemotherapy (CT) use and BCSM increased with increasing RS. In multivariable analysis in N0 disease, continuous RS result and tumor size predicted BCSM (p=0.003 and p=0.04, respectively), whereas age and tumor grade were non-significant. In multivariable analysis in N+ disease, continuous RS result alone predicted BCSM (p=0.002). Conclusions: In these analyses the prognosis of patients with lobular breast cancer treated based on RS results depends on both nodal status and the RS result. The 5-y BCSM for lobular breast cancer is excellent with RS of 25 or less, and increases for RS &gt;25. [Table: see text]
Expression of uncertainty in oncology articles with marginally significant results.
Authors: Sam Rubinstein, Elizabeth Sigworth, Qingxia Chen, Jeremy Warner
Journal: Journal of Clinical Oncology (2018)

e18907 Background: Basic and clinical science suffer from a reproducibility crisis, causing many to ask whether current standards for statistical significance (P < .05) are too generous. Anecdotally, publications describing results with P of .01-.05 often use declarative statements that do not express uncertainty. This may lead to widespread adoption of new treatments despite marginally valid evidence supporting their use. We sought to objectively determine the prevalence of expression of uncertainty (EoU) in the oncology literature. Methods: HemOnc.org, a chemotherapy regimen knowledge base, was screened for two-arm randomized trials with published manuscripts reporting P of .01-.05. Prose was evaluated for presence of EoU (eg “may”; “can”; “suggests”; emphasis that results may not be generalizable). We performed univariate analysis and multivariate logistic regression to identify whether trial phase, funding source, no. of authors, journal, author nationality, or publication year correlated with EoU. Results: We identified 170 papers published from 1979-2018 (Table). 107 (63%) did not express adequate uncertainty. No statistically significant correlations were seen between EoU and funding source, no. of authors, year, or journal. Collaborations between US and international authors had more EoU in multivariate analysis (P = .003). Phase II trials trended towards having more EoU, but this did not reach statistical significance (P = .07). Conclusions: Journals often publish oncology articles with marginally significant results that fail to adequately convey uncertainty. Papers resulting from US/international collaboration may more adequately convey uncertainty than those that do not involve such collaboration. Table: Analysis results Inadequate EoU n (%) Adequate EoU n (%) Univar. P Multivar. P Total 107 63 Phase II 14 (13) 15 (24) .07 .07 III 93 (87) 48 (76) Fund. source Pharma 60 (65) 43 (77) .14 + Grant 32 (35) 13 (23) Journal High impact 95 (89) 58 (92) .49 + Other 12 (11) 5 (8) Author nationality Non-US 61 (57) 25 (40) ref ref US 23 (21) 8 (13) .91 .78 Both 23 (21) 30 (48) .002 .003 Pub. year 2008 (2004, 2014)* 2012 (2007, 2014)* .04 .31 No. of authors 16 (11,20)* 18 (12,21)* .42 .45 + Not in final model * Median (IQR)
Unplanned delays among patients receiving FOLFOX chemotherapy for colorectal cancer.
Authors: Lawrence Kogan, Mika Jankowski, Cindy L. O'Bryant, Sarah Lindsey Davis, Gabriel A. Brooks
Journal: Journal of Clinical Oncology (2018)

e15637 Background: FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) is the most commonly used chemotherapy regimen for colorectal cancer. The scheduled administration of FOLFOX is every 14 days, however toxicities frequently contribute to unplanned delays. We report the incidence of unplanned delays among patients receiving FOLFOX and describe the reasons for delays. Methods: We conducted a retrospective analysis of patients receiving mFOLFOX6 chemotherapy for colorectal cancer. Patients were treated at one of two academic cancer centers between January 2012 and April 2016. Cycles 2 through 6 were assessed for unplanned delays, and treatments were considered delayed when the interval from prior treatment was > 18 days. Prolonged treatment intervals due to holidays or other logistical factors were not considered unplanned delays. Delays were categorized based on review of clinical notes and laboratory findings. Results: We identified 166 patients receiving FOLFOX as part of standard-of-care therapy for colorectal cancer. The median age was 59.5 years, and 115 patients (69%) were treated with curative intent. Of 731 evaluable cycles, 95 (13%) had unplanned delays, and 73 of 166 patients (44%) had at least one unplanned delay in cycles 2-6. The most common reasons for unplanned delays were neutropenia (33 of 95 delayed cycles, 35%) and thrombocytopenia (18 delayed cycles, 19%). In cycles delayed for neutropenia, day 15 ANC ranged from 0.47 to 1.36 x10(3)/µL (median 0.90, interquartile range [IQR] 0.70-1.10). In cycles delayed for thrombocytopenia, day 15 platelet counts ranged from 53 to 159 x10(3)/µL (median 79, IQR 63-99). Conclusions: Unplanned delays are common in patients receiving FOLFOX chemotherapy, with nearly half of patients having at least one delay prior to completing cycle 6. Neutropenia and thrombocytopenia were the leading causes of unplanned delays, though thresholds for treatment delays were variable. Our findings justify the development of systematic approaches for preventing unplanned delays during FOLFOX chemotherapy, such as standardized laboratory treatment criteria and/or proactive dose adjustment strategies.
Does TMB Impact the Effectiveness of TKIs in <i>EGFR</i>-Mutant NSCLC?
Authors: Michael L. Cheng, Geoffrey R. Oxnard
Journal: Clinical Cancer Research (2018)

Patients with EGFR-mutant non-small cell lung cancer achieve variable benefit from targeted therapy, and biomarkers to predict degree of benefit are not in clinical use. EGFR-mutant cancers with high tumor mutational burden demonstrate poorer outcomes on EGFR-targeted therapy. Investigation into the mechanisms underlying this intriguing association is needed.See related article by Offin et al., p. 1063.
Abstract #2538: Identification of microRNAs miR-203 and miR-335 forming a network of regulation in breast cancer development
Authors: Holger Heyn, Sabine Schreek, Maria Engelmann, Philipp Ahrens, Ulrich Lehmann, Hans Kreipe, Brigitte Schlegelberger, Carmela Beger
Journal: Cancer Research (2009)

The expression of microRNAs is altered in various cancer types, leading to a nomenclature of onco- and tumor-suppressor microRNAs. In the present study, we investigated the role of two independent microRNAs, miR-203 and miR-335, for the formation of sporadic human breast cancer and their involvement in the network of proteins regulating the cancer susceptibility gene BRCA1. We performed protein quantification of the ligand dependent receptors ER\#945;, AhR, IGF1R and the transcription factors SP1 and ID4 following overexpression of the specific microRNAs. All these proteins are involved in the regulation of BRCA1 and were previously associated with sporadic breast cancer. The significance of the microRNA regulation was determined in various functional assays including cell viability, apoptosis, cell cycle status and determination of BRCA1 expression following overexpression of the microRNAs in a cell culture system. The importance for cancer formation was further validated by expression analysis of primary breast cancer specimens compared to healthy control tissues and association to clinical features. MicroRNA miR-335 is suspected to act as a tumor-suppressor microRNA. In the present study, we found a reduced expression of miR-335 in primary sporadic breast cancer specimens. The expression level of miR-335 correlates positively to the transcript level of BRCA1. Overexpression of miR-335 led to decreased cell viability, increasing rates of apoptosis and downregulation of the hormone receptors (ER\#945;, AhR) and transcription factors (SP1). MicroRNA miR-203 also influences the regulatory pathway of BRCA1 by regulating the expression of ER\#945;, AhR and IGF1R. Increasing levels of miR-203 correlate to BRCA1 downregulation. Functionally, overexpression of miR-203 resulted in a decreased cell viability associated with an increase in apoptosis and cell cycle arrest. Expression analysis of breast cancer specimens revealed two subgroups. Tumors expressing low levels of miR-203 revealed an enhanced formation of lymph node metastasis. Taking the results together, both microRNAs affect the same targets in the signaling pathways of breast cancer cells involving the regulation of the breast cancer susceptibility gene BRCA1. Functionally, they are connected with cell proliferation, apoptosis and cell cycle regulation. A misregulation during cancer development and progression might promote the tumorigenic potential on the one hand and suppress the tumor-suppressing signals on the other. Affecting several overlapping molecules at once, the microRNAs form a superior network of regulation of the breast tissue homeostasis.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2538.
External validation of the 8th Edition Melanoma Staging System of the American Joint Committee on Cancer (AJCC): Effect of adding EORTC sentinel node (SN) tumor burden criteria on prognostic accuracy in stage III.
Authors: Max Fullah Madu, Viola Franke, Bart Van De Wiel, Willem M.C. Klop, Katarzyna Józwiak, Michel W.J.M. Wouters, Alexander Christopher Jonathan Van Akkooi
Journal: Journal of Clinical Oncology (2018)

9500 Background: Now that effective adjuvant therapy has arrived in melanoma, accurate staging and patient selection to optimize a risk/benefit ratio is crucial. The new 8th Edition AJCC staging system for melanoma aims to improve risk stratification. The goal of this study was to externally validate the prognostic and discriminatory ability for survival of the 8th Edition in comparison to the 7th. Methods: Analysis of a prospective cohort of patients treated in the Netherlands Cancer Institute for AJCC 7/8th Edition stage III melanoma between 2000 and 2016. Stage III melanoma was defined as regional lymph node metastases, with or without concurrent local recurrence, (micro)satellite or in-transit metastases. Prognostic factors for melanoma-specific survival (MSS) and distant metastasis-free survival (DMFS) were analyzed. Survival differentiation of the 7th and 8th edition was assessed with log-rank tests and Cox proportional hazards models. Discriminatory ability was compared using the area under the curve (AUC) of the receiver operating statistic (ROC) obtained with Cox models. Results: 640 patients were included with a median follow-up of 59 months (interquartile range 32-108). Median MSS was 138 months, DMFS 96 months. Age, Breslow thickness, ulceration of the primary tumor and number of positive lymph nodes (N) were significant prognostic parameters for MSS and DMFS. The 8th Edition performed similarly to the 7th in terms of survival discrimination, but failed to differentiate MSS between stage IIIA and IIIB after correction for sex and age. Both in 7th and 8th edition stage IIIA melanoma, patients with an SN metastasis size < 1 had excellent DMFS and MSS. Conclusions: The AJCC 8th edition staging system differentiates survival slightly worse than the 7th edition. Survival in both 7th and 8th edition stage IIIA melanoma is heterogeneous and can be sub-classified according to EORTC SN tumor burden, which can aid clinical decision-making concerning adjuvant therapy.
Solution must be found for £116m cost of outsourcing scans, says radiologists’ president
Authors: Declan C Murphy
Journal: BMJ (2018)

The NHS spent £116m (€126m; $150m) on outsourcing patient scans in 2017, a 32% increase on 2016 when outsourcing cost £88m, the Royal College of Radiologists has said.

Nicola Strickland, president of the college, described the situation as unsustainable and called for more funding to retain and recruit “home grown” radiologists.

“Many imaging departments want to …
Abstract IA15: Targeting oligometastatic disease in prostate cancer
Authors: Kenneth J. Pienta
Journal: Cancer Research (2018)

Abstract Clinical reports of limited and treatable cancer metastases, a disease state that exists in a transitional zone between localized and widespread systemic disease, have been noted on occasion historically and termed oligometastasis (OM). The ramification of a diagnosis of oligometastasis is a change in treatment paradigm, i.e., if the primary cancer site (if still present) is controlled or resected, and the metastatic sites are ablated (surgically or with radiation), a prolonged disease-free interval, and perhaps even cure, may be possible. Contemporary imaging diagnostics are identifying more and more OM patients. For example, in prostate cancer the use of PSMA-Pyl PET imaging is leading to the diagnosis of many OM patients who have no disease on conventional clinical imaging. It is unclear if these are truly isolated sites of disease (curable) or simply a reflection of more widespread microscopic disease (incurable or at best a bridging therapy). This is especially true in the biochemical recurrence (bcr) space after primary treatment. We will present our experience with identifying and treating prostate cancer OM disease. Citation Format: Kenneth J. Pienta. Targeting oligometastatic disease in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA15.
The efficiency of apatinib plus S-1 as second-line or laterline chemotherapy for advanced non-small-cell lung cancer.
Authors: Zhiyong Wu, Jianyu Wu, Guanghai Dai, Haiyan Si, Yanrong Wang, Haiqing Zhao, Guanqing Wang, Hongli Cao
Journal: Journal of Clinical Oncology (2017)

e20549 Background: There is no standard treatment strategy for patients with advanced non-small cell lung cancer (NSCLC) who experienced progression with three or more lines of chemotherapy. Apatinib, a new tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR-2), has been shown confirming antitumor activity and manageable toxicities in breast and gastric cancers. Clinical trials of apatinib on non-small cell lung cancer show that progression-free survival is improved, but the objective response rate is still low. However, It remains to be explored whether the combined treatment of apatinib plus S1 could be further effective on NSCLC. Methods: We retrospectively assessed the efficacy and safety of apatinib plus S1 in patients with advanced NSCLC after the failure of second or third-line chemotherapy. The study group comprised 12 patients who received oral apatinib, at a dose of 250 mg daily, and S1, at a dose of 40-60mg bid D1-14, repeat every 3 weeks, for progression after the failure of second or third-line chemotherapy for advanced NSCLC. Treatment was continued until disease progression. Results: Between Mar 30, 2016 and Feb 1, 2017, 12 patients were enrolled. In 12 patients, there were 10 patients available for efficacy and safety evaluation. 4/10 (40%) patients experienced dose reduction during treatment. Followed up to Feb 1, 2016, the median during time of treatment was 3 months. According to RECIST criteria, the disease control rate was 80%, 8/10 (partial response 50%, 5/10 and stable disease 30%, 3/10). The most frequent treatment-related adverse events were secondary hypertension (40%, 4/10), oral mucositis (40%, 4/10), hand-foot syndrome (30%, 3/10) and fatigue (30%, 3/10). Main grade 3 or 4 toxicities were hypertension (20%, 2/10), oral mucositis (10%, 1/10) and fatigue (10%, 1/10). Conclusions: Apatinib plus S1 exhibits superior activity and acceptable toxicity for the heavily pretreated patients with advanced non-small cell lung cancer.
Racial composition in trials supporting the U.S. approval of anti-cancer new molecular entities (NMEs): 2011- 2016.
Authors: Lola A. Fashoyin-Aje, Laura L. Fernandes, Steven Lemery, Patricia Keegan, Rajeshwari Sridhara, Jonca C. Bull, Richard Pazdur
Journal: Journal of Clinical Oncology (2017)

6518 Background: In New Drug- and Biologics License Applications, clinical trials provide the primary safety and efficacy data upon which approval decisions are made. Low numbers of patients from racial groups that experience higher incidence and/or mortality from some cancers compared to the overall US population, may limit the generalizability of trial results. The Census estimates that the US population is 77.1%White, 13.3% Black/ African American (AA), 5.6% Asian, 1.2% American Indian/ Alaska Native (AIAN), and 0.2% Native Hawaiian/ Other Pacific Islander (NHPI). FDA conducted an analysis to compare the racial composition in trials supporting the approval of NMEs for the treatment of solid tumor malignancies. Methods: We reviewed the marketing applications of the 33 NMEs approved between 2011- 2016 to identify trials that provided the primary evidence of safety and efficacy. Results: A total of 29941 patients were enrolled. The table below illustrates enrollment by race (excluding Non-Hispanic, Hispanic, Other, Mixed Race &amp; Missing) and approval year. Conclusions: The proportion of White patients enrolled in the US (88%) is higher than the proportion of Whites in the US population. However, the enrollment of AA and NHPI/AIAN patients is low and below the proportional representation of AA and NHPI/AIAN in the US. While enrollment targets may differ across cancer type and by race, the racial composition of patients enrolled in the trials that support the approval of cancer therapeutics should be reflective of the likely US patient population for whom these agents will be prescribed. The majority of Asian patients enrolled were from RoW while the majority of AA and NHPI/AIAN patients were enrolled from the US. Increasing the representation of racial minority patients in oncology trials will require targeted recruitment and enrollment of these patients in US sites. [Table: see text]
Synthetic lethality interaction between aurora kinases and CHEK1 inhibitors in ovarian cancer.
Authors: Ana Lucía Alcaraz-Sanabria, Cristina Nieto-Jimenez, Veronica Corrales-Sanchez, Leticia Serrano-Oviedo, Gemma Serrano-Heras, Fernando Andrés Pretel, Juan Carlos Montero, Miguel Burgos, Juan Llopis, Eva María Galan-Moya, Eitan Amir, Atanasio Pandiella, Alberto Ocana
Journal: Journal of Clinical Oncology (2017)

e17089 Background: Ovarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair (HR) genes, so they rely on DNA-damage checkpoint proteins, like the Checkpoint kinase 1 (CHEK1) to induce G2 arrest. In our study, by using an in silico approach, we identified a synthetic lethality interaction between CHEK1 inhibitors and mitotic Aurora Kinase A and B (AURKA/B) inhibitors. Methods: Gene expression analyses were used for the identification of relevant biological functions. OVCAR3, OVCAR8, IGROV1 and SKOV3 were used for proliferation studies. Alisertib was tested as AURKA/B inhibitor and LY2603618 as CHEK1 inhibitor. Analyses of cell cycle and intracellular mediators were performed by flow cytometry and western-blot. Stem cell properties were evaluated with immunofluorescence. Results: Gene expression analyses followed by functional annotation identified cell cycle as a deregulated function. Identified druggable kinases within this function included AURKA/B, TTK kinase and CHEK1. CHEK1 and AURKA/B inhibitors showed a synergistic interaction in different cellular models. Combination of Alisertib and LY2603618 triggered apoptosis, reduced the stem cell population and increased the effect of taxanes and platinum compounds. AURKA and CHEK1 were amplified in 8.7% and 3.9% of ovarian cancers, respectively. Expression of these genes was linked with detrimental clinical outcome. Conclusions: Amplification of AURKA and CHEK1 was observed in more than 12% of ovarian tumors. Our data describes a synthetic lethality interaction between CHEK1 and AURKA/B inhibitors with potential translation to the clinic.