tbuckley/cabot-search huggingface dataset:
Receipt of locoregional therapy among young women with breast cancer.
Authors: Rachel A. Freedman, Katherine S. Virgo, Julia Labadie, Ann H. Partridge, Nancy Lynn Keating
Journal: Journal of Clinical Oncology (2012)

1100 Background: Although younger women with breast cancer have the most to gain from receipt of optimal care, few data are available regarding their receipt of locoregional breast cancer treatments. Methods: We identified 318,083 women aged 18-64 who were diagnosed with invasive breast cancer at hospitals reporting to the National Cancer Data Base, a large national cancer registry, during 2004-2008. We used multivariable logistic regression to assess the association of patient age with mastectomy vs. breast-conserving surgery (BCS), radiation with BCS, and post-mastectomy radiation (PMRT) with varying indications, adjusting for patient and tumor characteristics, area-level socioeconomic status, and insurance. Results: Overall, 4% of women were aged ≤35 and 7% were aged 36-40. Women aged ≤35 were significantly more likely to have mastectomy than BCS compared with women aged 56-60 (57% vs. 35%, adjusted odds ratio [OR] 1.97; 95% Confidence Interval [CI] 1.87-2.07) but were less likely to receive radiation if BCS was performed (69% vs. 80%, OR 0.77; 95% CI 0.73-0.82). For those who underwent mastectomy, although overall rates of PMRT receipt were low, women aged ≤35 were more likely to receive postmastectomy radiation (PMRT) despite the presence or absence of clinical indications for PMRT (OR 1.11; 95% CI 1.01-1.22 for strong indications, OR 1.71; 95% CI 1.53-1.91 for borderline indications, and OR 1.49; 95% CI 1.28-1.73 for no indications [all vs. ages 56-60]). Conclusions: Young women with breast cancer may not be receiving optimal locoregional therapy. We observed lower odds of radiation after BCS but higher odds of PMRT for young women regardless of indications for PMRT. Efforts are needed to further understand and improve the receipt of appropriate adjuvant radiation therapy among young women to improve their disease-free and overall survival.
CpG island methylator phenotype (CIMP) and outcome differences for African Americans (AA) and Caucasians (C) treated with FOLFOX4 or the combination with bevacizumab (B) in patients (pts) with metastatic colorectal cancer (MCRC): Results from the Eastern Cooperative Oncology Group study E3200.
Authors: Edith P. Mitchell, Paul J. Catalano, Bruce J. Giantonio, Peter J. O'Dwyer, Neal J. Meropol, Al Bowen Benson, Stanley R. Hamilton
Journal: Journal of Clinical Oncology (2014)

3605 Background: The relationship between race and poorer clinical outcomes with systemic chemotherapy in patients with metastatic colorectal cancer is uncertain. CIMP High has been associated with a lack of survival benefit from 5-fluorouracil (5FU)-based chemotherapy while conflicting results for chemotherapy combinations have been reported. We analyzed outcomes for AA and C patients enrolled in E3200 and evaluated for CIMP in pts with adequate tissue samples. Methods: A total of 820 pts enrolled in E3200 were randomized to one of three treatments: FOLFOX4, bevacizumab, or the combination. Overall survival (OS), progression free survival (PFS) and response rates (RR) and CIMP were analyzed according to race. Demographic information was collected by data management personnel at study sites and reported at registration. CIMP was analyzed in 281 pts with adequate tissue specimens; 261 were C and 20 AA. Results: There were no differences for AA and C in regards to number of metastatic sites, performance status, gender, prior therapy and age distribution. Prediction of tumor response did not differ according to treatment arm based on CIMP. AA had worse OS (p=0.03), PFS (p=0.08) and RR (p=0.02) than C pts. CIMP showed significant interaction with differences between AA and C pts. There was improved OS and PFS for C pts with CIMP values less than the median than those above while AA showed better survival with values greater than the median. Conclusions: These results suggest outcome differences based on race in the treatment of MCRC in pts may be associated with molecular features. Additional studies are required to elucidate the cause for the observed variation. [caption[Cox proportional hazards analyses comparing CIMP high versus CIMP low[/caption] Clinical trial information: NCT00897819. All C AA OS HR 1.26 1.32 0.22 p-value 0.051 0.029 0.012 PFS HR 1.43 1.51 0.54 p-value 0.0048 0.0023 0.28 Interaction tests between CIMP and race: OS,p = 0.0004; PFS, p=0.0097.
A first-in-human phase I trial of AR-12, a PDK-1 inhibitor, in patients with advanced solid tumors.
Authors: Joaquin Mateo, Johann Sebastian De Bono, Ramesh K. Ramanathan, Maryam B. Lustberg, Andrea Zivi, Dawn Basset, Matthew Ng, Anna-Mary Young, Michelle Garrett, Shaun Decordova, Florence I. Raynaud, Timothy Anthony Yap, Alexander A. Zukiwski, Stefan Proniuk, Charles L. Shapiro
Journal: Journal of Clinical Oncology (2013)

2608 Background: AR-12 (OSU-03012) is an oral celecoxib analogue lacking COX-2 inhibitory activity that inhibits pyruvate dehydrogenase kinase isoenzyme 1 (PDK-1), AKT and impacts the endoplastic reticulum stress pathway. Preclinical studies indicate antitumor activity of AR-12 in various models and enhanced activity in combination. We completed a first in human clinical trial to determine its safety and tolerability, maximum tolerated dose (MTD) and recommended phase II dose (RD). Secondary objectives included assessment of tumor response, pharmacokinetics (PK) and pharmacodynamics (PD) including food effect. Methods: Patients (pts) with advanced solid tumors, ECOG PS 0-1, and adequate organ function were recruited in a modified 3+3 dose-escalation study. Pts received a run-in dose of AR-12 to analyze PK-PD and food effect, followed by continuous daily (QD) dosing in 28-day cycles. A twice daily (BID) cohort was initiated based on safety data. PD analysis was performed in platelet-rich plasma (PRP) and paired tumor biopsies when feasible. Results: 35 pts received at least one dose of study drug; 30 were evaluable for dose limiting toxicities (DLT) at dose ranges 100-3200mg QD and 800-1600mg BID. No DLT were observed in the QD cohort; DLT in the BID cohort are listed in table 1. Drug-related events (NCI-CTCAE v3) included rash (G2-2pts; G3-1pt), fatigue (G2-2pts; G3-4pts), nausea (G2-7pts; G3-1pt) and bloating (G2-1pt). Cmax after single dose was dose-proportional but high PK variability was observed, likely due to inadequate disintegration and dissolution of the formulation in the stomach. At RD, partial GSK3ß inhibition in PRP after 4 hours suggests AKT-pathway modulation. Best response (RECIST v1.0) was stable disease &gt;6 cycles for 2 pts. Conclusions: The RD based on safety data is 800mg BID. Signs of pathway modulation were observed in concordance with the expected mechanism of action but were short-lasting. Considering limited drug absorption and PK variability, a new formulation of the drug will be developed to overcome these limitations. Clinical trial information: NCT00978523. [Table: see text]
Luminal and basal subtyping of prostate cancer.
Authors: Felix Yi-Chung Feng, Shuang Zhao, Seiwon Laura Chang, Nicholas Erho, Jonathan Lehrer, Mohammed Alshalalfa, Matthew R. Cooperberg, Won Kim, Charles J. Ryan, Robert B. Den, Stephen J. Freedland, Edwin M. Posadas, Eric A. Klein, Elai Davicioni, Ashley Ross, Edward M. Schaeffer, Paul L. Nguyen, Peter Carroll, Jeffrey Karnes, Daniel Eidelberg Spratt
Journal: Journal of Clinical Oncology (2017)

3 Background: There is a clear need to develop a clinically relevant molecular subtyping approach for prostate cancer. We hypothesized that prostate cancer can be subtyped based on luminal versus basal lineage. Methods: We applied the PAM50 classifier, which is used clinically to identify luminal and basal cancers in breast cancer, to subtype a total of 3,782 prostate cancer samples using a high-density microarray platform run in a CLIA-certified laboratory. We examined the associations of these subtypes and clinical outcomes. Results: We demonstrate that PAM50 segregates prostate cancer into three reproducible subtypes in both retrospective cohorts and on prospective validation: luminal A (33.3%-34.3%), luminal B (28.5%-32.6%), and basal (34.1%-37.1%). Luminal B prostate cancers exhibited the worst clinical prognoses, followed by basal and luminal A subtypes (10-year biochemical recurrence-free survival: 29/39/41%; distant metastasis-free survival: 53/73/73%; prostate cancer-specific survival: 78/86/89%; overall survival: 69/80/82% respectively) on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors. Known luminal lineage markers, such as NKX3.1 and KRT18, and the basal lineage CD49f signature, were enriched in luminal- and basal-like cancers respectively, demonstrating the connection between these subtypes and established prostate cancer biology. While both luminal-like subtypes were associated with increased AR expression and signaling, only luminal B prostate cancers were significantly associated with post-operative response to androgen deprivation therapy (ADT) in a subset analysis matching patients based on clinicopathologic variables (interaction p = 0.006, luminal B 10-year metastasis: 33% (treated) vs. 55% (untreated), non-luminal B: 37% (treated) vs. 21% (untreated)). Conclusions: These findings contribute novel insight into the biology of prostate cancer, and provide translatable clinical tools for personalizing post-operative ADT for patients with prostate cancer. Similar to breast cancer, these findings suggest that luminal/basal subtyping may be useful in treatment selection in prostate cancer.
Monitoring tumor specific mutations in plasma during systemic treatment of biliary tract cancer.
Authors: Lars Henrik Jensen, Rikke Fredslund Andersen, Anders Kristian Moeller Jakobsen
Journal: Journal of Clinical Oncology (2017)

318 Background: We have previously reported a rate of 23% RAS/RAF mutations in plasma from patients with KRAS exon 2 and 3 wild-type, non-resectable biliary tract tumors. We wanted to explore the changes in circulating tumor specific DNA (ctDNA) during systemic chemotherapy in these patients. Methods: Patients with non-resectable biliary tract cancer treated within a phase II trial were included if they had KRAS exon 2 and 3 wild-type tumor tissue, had quantifiable levels of tumor specific DNA in plasma and progressive disease on imaging. They received gemcitabine, oxaliplatin and capecitabine with either bevacizumab or panitumumab. Treatment continued for up to six months until progression. Blood sampling and evaluation according to RECIST 1.1 were done every 12 weeks. Droplet Digital PCR was performed on DNA isolated from 4 ml plasma. A pre-amplification step was done and adequate positive and negative controls were included. The extended RAS and BRAF mutation analysis covered 20 mutations in KRAS exons 3/4, NRAS exon 2/3, PIK3CA and BRAF V600E. The percentage of tumor specific DNA relative to total DNA was reported. Results: The inclusion criteria were met by 13 patients, 10 women and three men. The typical pattern was seen in eight cases, where the percentage of tumor specific DNA dropped at least half during therapy and rose at least two-fold at progression. In three patients, a baseline sample was not available or there was not an initial drop, but the ctDNA rose at progression. One patient had an initial drop, but not a rise a progression based on imaging. The last patient progressed rapidly. Conclusions: This exploratory analysis pointed toward changes in percentage of tumor specific mutations in plasma as a marker of effect and progression. Dynamics of liquid biopsies is a promising tool in monitoring biliary tract cancer patients during systemic therapy. Clinical trial information: NCT01206049.
Intravenous immunoglobulin contributes to the control of antimelanoma differentiation‐associated protein 5 antibody‐associated dermatomyositis with palmar violaceous macules/papules
Authors: H. Koguchi‐Yoshioka, N. Okiyama, K. Iwamoto, Y. Matsumura, T. Ogawa, S. Inoue, R. Watanabe, M. Fujimoto
Journal: British Journal of Dermatology (2017)

Autoantibodies to melanoma differentiation-associated protein 5 (MDA5) are associated with a subset of patients with dermatomyositis (DM) who have rapidly progressive interstitial lung disease (RP-ILD) with poor prognosis. Intensive immunosuppressive therapy is initiated before irreversible lung damage can occur; however, there are few lines of evidence for the treatment of RP-ILD. Here, we report three cases of anti-MDA5 antibody-associated DM with RP-ILD in which the patients were treated with combined-modality therapy, including high-dose prednisolone, tacrolimus, intravenous cyclophosphamide and intravenous immunoglobulin (IVIG). In all three cases, serum ferritin levels, which are known to represent the disease activity of RP-ILD, were decreased after IVIG administration. IVIG might contribute to the control of the disease activity of anti-MDA5 antibody-positive DM. Moreover, palmar violaceous macules/papules around the interphalangeal joints, which was observed in all three cases in the incipient stage, might be a useful sign in suggesting a diagnosis of anti-MDA5 antibody-associated DM.
Maximal mid-expiratory flow detects early lung disease in α<sub>1</sub>-antitrypsin deficiency
Authors: James A. Stockley, Asem M. Ismail, Siân M. Hughes, Ross Edgar, Robert A. Stockley, Elizabeth Sapey
Journal: European Respiratory Journal (2017)

Pathological studies suggest that loss of small airways precedes airflow obstruction and emphysema in chronic obstructive pulmonary disease (COPD). Not all α 1 -antitrypsin deficiency (AATD) patients develop COPD, and measures of small airways function might be able to detect those at risk. Maximal mid-expiratory flow (MMEF), forced expiratory volume in 1 s (FEV 1 ), ratio of FEV 1 /forced vital capacity (FVC), health status, presence of emphysema (computed tomography (CT) densitometry) and subsequent decline in FEV 1 were assessed in 196 AATD patients. FEV 1 /FVC, FEV 1 % predicted and lung densitometry related to MMEF % pred (r 2 =0.778, p&lt;0.0001; r 2 =0.787, p&lt;0.0001; r 2 =0.594, p&lt;0.0001, respectively) in a curvilinear fashion. Patients could be divided into those with normal FEV 1 /FVC and MMEF (group 1), normal FEV 1 /FVC and reduced MMEF (group 2) and those with spirometrically defined COPD (group 3). Patients in group 2 had worse health status than group 1 (median total St George's Respiratory Questionnaire (SGRQ) 23.15 (interquartile range (IQR) 7.09–39.63) versus 9.67 (IQR 1.83–22.35); p=0.006) and had a greater subsequent decline in FEV 1 (median change in FEV 1 −1.09% pred per year (IQR −1.91–0.04% pred per year) versus −0.04% pred per year (IQR −0.67–0.03% pred per year); p=0.007). A reduction in MMEF is an early feature of lung disease in AATD and is associated with impaired health status and a faster decline in FEV 1 .
Micro-RNA signature differences in lung adenocarcinoma with specific driver alterations.
Authors: Lorenza Landi, Pierluigi Gasparini, Stefania Carasi, Carmelo Tibaldi, Luciano Cascione, Greta Ali', Armida D'Incecco, Jessica Salvini, Gabriele Minuti, Antonio Chella, Gabriella Fontanini, Federico Cappuzzo, Carlo M. Croce
Journal: Journal of Clinical Oncology (2013)

11066 Background: Oncogenic driving alterations define types of lung adenocarcinoma with different prognosis and sensitivity to targeted agents. MicroRNAs (miRNAs) are a new class of non-coding RNAs involved in gene expression regulation. How miRNAs are dysregulated in lung cancer with ALK translocation, EGFR or KRAS mutation is unknown. In this study we aimed to identify miRNA signatures according to the presence of specific driver and to correlate miRNAs deregulation with patient outcome. Methods: The study was conducted in a cohort of 70 lung cancer patients (pts) including 18 ALK+ tumors, 11 ALK-/EGFR mutation+, 15 ALK-/KRAS mutation+, 26 ALK-/EGFR and KRAS wild-type and defined as triple negative. Matched normal lung tissue from 18 cases representative of the entire cohort were also included onto the analysis. RNA was isolated from formalin-fixed paraffin-embedded tissue (FFPE), using the Recover ALL kit (Ambion). NanoString nCounter system platform was used to generate the miRNA profile. We used Limma to test for differential expression analysis of data. The miR-515 family expression between tissues was validated by RT-qPCRs, analyzed using the parametric t-test (unpaired, 2-tailed for validation). Results: miRNA expression profile clusters distinctly ALK+ pts from ALK- and normal lung tissue. Within the ALK- group we found specific miRNAs subsets able to sub-stratify KRAS versus EGFR careers clustering sharply triple negative versus EGFR mutation+ and triple negative versus KRAS mutation+. miRNAs belonging to the miR-515 family seems to be the most deregulated in the ALK+ versus ALK-. Although their expression is stably high in normal tissues and ALK+ class, they are highly downregulated in KRAS mutated versus EGFR mutated and versus triple negative (p-value &lt;0.001 for all comparisons). Conclusions: miRNAs profile significantly differs in pts with ALK translocation, EGFR mutations and KRAS mutations. Analysis of miR-515 family members is ongoing in order to correlate their expression levels with pts’ outcome. In vitro modulation of miR-515 family expression levels, together with drugs treatment are ongoing in order to find possible chemo-resistance/chemo-sensitivity miRNA dependent, in ALK+ and ALK- model.
Evaluation of early response by anatomic imaging to predict survival among patients with group III rhabdomyosarcoma: A report from the Children’s Oncology Group.
Authors: Douglas S. Hawkins, Abby R. Rosenberg, Elizabeth Lyden, James Robert Anderson, David A. Rodeberg, Suzanne L. Wolden, Simon C Kao, David Parham, Carola A. S. Arndt
Journal: Journal of Clinical Oncology (2013)

10012 Background: The prognostic significance of response to induction therapy for rhabdomyosarcoma (RMS) by anatomic imaging (computerized tomographic [CT] or magnetic resonance imaging [MRI] scan) is controversial. We previously reported no relationship between early response and failure-free survival (FFS) for patients on IRS-IV. We repeated the same analysis using an independent cohort of patients with non-metastatic, initially unresected RMS treated on a more recent clinical trial. Methods: A total of 338 patients enrolled in Children’s Oncology Group study D9803 met the following inclusion criteria for this analysis: 1) non-metastatic, initially unresected (Group III); 2) embryonal (ERMS) or alveolar (ARMS) histology; 3) documented response to induction chemotherapy (excluding progressive disease) based on anatomic imaging; and 4) documented therapy beyond week 12. Response at week 12 was determined by the treating institution as complete response (CR, complete resolution), partial response (PR, decrease of &gt;= 50% of the sum of the products of maximum perpendicular diameters), or no response (NR, between 50% reduction and 25% increase in the sum of the products of maximum perpendicular diameters). FFS was estimated using the Kaplan-Meier method, and comparisons between groups were made using the log-rank test. Results: Overall objective response rate (CR+PR) at week 12 of therapy was 85%, with similar responses for ERMS and ARMS. FFS was similar among all patients with CR, PR, or NR (p=0.49). Restricting the analysis to either ERMS or ARMS, there was no difference in FFS by histology (p=0.20 and p=0.45, respectively). Conclusions: These findings provide additional evidence that anatomic imaging assessment of early response to therapy among RMS patients does not predict outcome and should not be used to tailor subsequent therapy. Clinical trial information: NCT00003958. [Table: see text]
Safety and efficacy of everolimus in Asian patients with metastatic renal cell carcinoma (mRCC) who failed previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy: A subanalysis of REACT.
Authors: Sun Young Rha, Se-Hoon Lee, Yen-Chuan Ou, Jin-Hee Ahn, Yen-Hwa Chang, Vichien Srimuninnimit, Ho Yeong Lim, Ik-Joo Chung, See-Tong Pang, Hong-Ling Xue, Ashok Panneerselvam, Jooseop Chung, Chee-Keong Toh
Journal: Journal of Clinical Oncology (2012)

e15064 Background: Some targeted agents have shown variable safety profiles in Asian vs non-Asian patients with mRCC. A retrospective analysis of sunitinib in Korean patients with mRCC found increased incidence and severity of certain adverse events (AEs) compared with previous global trials (Hong et al. Cancer Res Treat. 2009;41:67-72). The open-label, expanded-access program REACT (RAD001 Expanded Access Clinical Trial in RCC; NCT00655252) provided everolimus, a mammalian target of rapamycin (mTOR) inhibitor, before its regulatory approval to 1367 patients with VEGFr-TKI refractory mRCC from 34 countries. Final results of REACT were recently published (Grünwald et al. Eur J Cancer. 2012;48:324-332). This analysis compared study end points in Asian patients with those in the total REACT population. Methods: The primary objective of REACT was to assess the safety of everolimus 10 mg/day, as determined by the overall occurrence of grade 3/4 AEs. Best overall tumor response was evaluated based on RECIST 1.0. Results: Baseline characteristics of Asian patients (n = 109; from South Korea, Taiwan, Thailand, and Singapore) were similar to those of the total study population. Median duration of everolimus exposure was longer in Asian patients than in the total population: 24.1 (range, 2.0-72.7) vs 14.0 (0.1-83.7) weeks. Overall incidence of grade 3/4 AEs was slightly higher in Asian patients than in the total population (70.6% vs 61.6%); common grade 3/4 AEs in Asian patients and the total population, respectively, included anemia (26.6% vs 13.4%), hyperglycemia (11.9% vs 5.5%), pneumonia (10.1% vs 4.2%), stomatitis (6.4% vs 5.4%), thrombocytopenia (3.7% vs 1.0%), and pneumonitis (3.7% vs 2.7%). More patients in the Asian population than in the total population had achieved disease control: partial response, 3.7% vs 1.7%; stable disease, 67.0% vs 51.6%. Conclusions: In this subanalysis of REACT, Asian patients treated with everolimus experienced a greater clinical benefit with a slightly higher incidence of AEs. These results are supportive of the use of everolimus in the Asian population.