tbuckley/cabot-search huggingface dataset:
Molecular profiling of refractory solid tumors: Practical impact and clinical responses—Experience of a single center.
Authors: Marwan Ghosn
Journal: Journal of Clinical Oncology (2015)

e22122 Background: This study involves an analysis of the epidemiological characteristics and tumor responses of patients whose tumors underwent multiplatform molecular profiling using Caris Molecular Intelligence MI Profile (CMI) in a single-tertiary University Hospital. Methods: Retrospective single-center, observational analysis was conducted on patients with refractory or progressing metastatic solid tumors. Biopsies were sent for MP between October 2013 and October 2014.Testing was performed per physician request and included a multiplatform technology. Patient characteristics, tumor response and duration of response were reported. Results: 71 patients’ biopsy samples were sent for MP using CMI.55 patients met inclusion criteria. At time of data collection, 52 patients were treated according to MP. Average age was 58.2 years. Women represented 57.7% of cases. 96% had a PS of 1 or less. The majority of MP samples were obtained from a metastatic site (75%).Breast cancer was the most represented (21%).MP identified a molecular alteration linked to targeted therapies in 22 patients, with hormone therapy being recommended in more than two-third of the cases.13 patients had more than 2 alterations associated with targeted therapies identified. Therapy was effective in controlling disease in 63% of the patients. 4 patients (8.8%) had a CR with PR in a further 7 (15.2%).The average duration of response was 4.1 months Conclusions: Multiplatform profiling is a valuable clinical tool that is becoming a key part of everyday practice. Its use offers significant guidance in the choice of therapeutic opportunities for patients with metastatic, refractory or progressing solid tumors with good performance status. These promising results are a first step toward understanding practical translations of MP into tumor response.
Treatment tolerance, tumor response, and clinical toxicity associated with platinum-based doublets in the first-line setting for advanced nonsquamous non-small cell lung cancer (NSCLC) in Chinese patients.
Authors: Yan Wang, Jianhua Chen, Shengqi Wu, Chengping Hu, Xiaoling Li, Yuqin Wang, Yicheng Yang, Yun Chen, Narayan Rajan, Yi Chen, Zhuanzhuan Luo, Wendong Chen
Journal: Journal of Clinical Oncology (2014)

e19138 Background: Previously reported superior tumor response associated with platinum/pemetrexed in the first-line setting for for advanced non-squamous NSCLC has not been confirmed in real-world clinical settings. Methods: Patients receiving platinum-based doublets in the first-line setting for advanced non-squamous NSCLC in four Chinese tertiary care hospitals from 2007 to 2012 were retrospectively identified. Propensity score methods created matched treatment groups for platinum/pemetrexed versus other platinum-based doublets respectively for head-to-head comparisons on treatment tolerance (treatment cycles > or = 4), tumor control (partial response or stable disease), and adverse events. Results: Matching platinum/pemetrexed with other four doublets produced 95 docetaxel, 118 paclitaxel, 199 gemcitabine, and 72 vinorelbine pairs respectively. When compared to the other studied four doublets, platinum/pemetrexed had significantly higher rates of treatment tolerance (rate ratio (RR) ranged from 1.404 to 2.000) and tumor control (RR ranged from 1.357 to 2.222). Hematological adverse events were less frequent with platinum/pemetrexed than with platinum/gemcitabine (leukopenia: RR 0.762, p=0.041; thrombocytopenia: RR 0.590, p<0.001; and anemia: 0.696, p<0.001) and platinum/vinorelbine (neutropenia: RR 0.522, p=0.034). Less alopecia was observed with platinum/pemetrexed than docetaxel (RR 0.200, p=0.005), paclitaxel (RR 0.125, p=0.020), or gemcitabine doublet (0.111, p<0.001). Fatigue was observed less frequently with platinum/pemetrexed than with platinum-based paclitaxel (RR 0.370, p=0.001), gemcitabine (RR 0.290, p<0.001), or vinorelbine doublet (RR 0.565, p=0.048). Conclusions: Compared to platinum-based docetaxel, paclitaxel, gemcitabine, and vinorelbine doublets, platinum/pemetrexed demonstrated better treatment tolerance and tumor response in the first-line setting for advanced non-squamous NSCLC in Chinese patients. Platinum/pemetrexed was also associated with less toxicity than platinum-based gemcitabine or vinorelbine doublets.
Quantitative hormone receptors, triple-negative breast cancer (TNBC), and molecular subtypes: A collaborative effort of the BIG-NCI NABCG.
Authors: Maggie Chon U. Cheang, Miguel Martin, Torsten O. Nielsen, Aleix Prat, Alvaro Rodriguez-Lescure, Amparo Ruiz, Stephen K. L. Chia, Lois E. Shepherd, David Voduc, Philip Seth Bernard, Matthew James Ellis, Charles M. Perou, Angelo Di Leo, Lisa A. Carey
Journal: Journal of Clinical Oncology (2012)

1008 Background: Most TNBC trials focusing on biology of the basal-like subtype (BLBC) allow borderline (1-10% staining) estrogen receptor (ER) and progesterone receptor (PgR) expression by immunohistochemistry (IHC); however the optimal ER and PgR cut points to enrich for non-luminal subtypes has not been studied. In this study,we compared quantitative ER/PgR status with gene expression-based intrinsic subtype in order to determine if borderline cases should be included in TNBC trials. Methods: ER, PgR, and HER2 status was determined by central review of tumors collected from three phase III randomized trials: GEICAM 9906 (n=820), NCIC CTG MA.5 (n=476) and MA.12 (n=398). PAM50 intrinsic subtyping (BLBC, HER2-enriched, Luminal A, Luminal B and Normal-like) was performed using the qRT-PCR-based assay. Quantitative ER/PgR expression by IHC and subtype was tested using ANOVA and Fisher’s exact test. Results: Of 1,694 tumors, 15% were BLBC, 21% HER2-Enriched, 33% Luminal A, 25% Luminal B and 4% Normal-like. BLBC subtypes were significantly associated with low expression of ER and PgR (median = 0.05%) compared to other subtypes (p &lt; 0.001). The vast majority of BLBC (96%) did not express any ER or PgR protein by IHC. BLBC represented 73% of TNBC (borderline cases not included) and significantly more than the additional TNBC with borderline ER/PgR (p &lt; 0.001). Within borderline ER/PgR and HER2-negative cases only, 17% were BLBC and 46% were luminal subtypes (Table). Conclusions: BLBC rarely express ER or PgR by IHC. The majority of borderline TNBC (1-10% ER/PgR) are not BLBC; half of them are categorized as luminal categories that may be endocrine sensitive. TNBC trials seeking to target BLBC tumor biology should use the ASCO/CAP guidelines of 0% as the cutoffs for ER and PgR negativity. [Table: see text]
Smoking-Dependent Distal-to-Proximal Repatterning of the Adult Human Small Airway Epithelium
Authors: Jing Yang, Wu-Lin Zuo, Tomoya Fukui, IonWa Chao, Kazunori Gomi, Busub Lee, Michelle R. Staudt, Robert J. Kaner, Yael Strulovici-Barel, Jacqueline Salit, Ronald G. Crystal, Renat Shaykhiev
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Small airways are the primary site of pathologic changes in chronic obstructive pulmonary disease (COPD), the major smoking-induced lung disorder.On the basis of the concept of proximal-distal patterning that determines regional specialization of the airway epithelium during lung development, we hypothesized that a similar program operates in the adult human lung being altered by smoking, leading to decreased regional identity of the small airway epithelium (SAE).The proximal and distal airway signatures were identified by comparing the transcriptomes of large and small airway epithelium samples obtained by bronchoscopy from healthy nonsmokers. The expression of these signatures was evaluated in the SAE of healthy smokers and smokers with COPD compared with that of healthy nonsmokers. The capacity of airway basal stem cells (BCs) to maintain region-associated phenotypes was evaluated using the air-liquid interface model.The distal and proximal airway signatures, containing 134 and 233 genes, respectively, were identified. These signatures included known developmental regulators of airway patterning, as well as novel regulators such as epidermal growth factor receptor, which was associated with the proximal airway phenotype. In the SAE of smokers with COPD, there was a dramatic smoking-dependent loss of the regional transcriptome identity with concomitant proximalization. This repatterning phenotype was reproduced by stimulating SAE BCs with epidermal growth factor, which was up-regulated in the SAE of smokers, during differentiation of SAE BCs in vitro.Smoking-induced global distal-to-proximal reprogramming of the SAE represents a novel pathologic feature of COPD and is mediated by exaggerated epidermal growth factor/epidermal growth factor receptor signaling in SAE BCs.
A meta-analysis of randomized clinical trials in acute promyelocytic leukemia (APL).
Authors: Francesco Lo-Coco, Martin S. Tallman, Gisoo Barnes, Ines Guerra, Vidya Damera, Monique Martin, Udo W. Mueller
Journal: Journal of Clinical Oncology (2015)

7040 Background: All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) have dramatically improved treatment outcomes in Acute Promyelocytic Leukemia (APL). To address the question regarding the most effective and safe regimen for 1st--line APL, a meta-analysis was performed following a systematic review of the clinical literature in APL. Methods: A systematic literature review on all published randomized controlled trials (RCT) in APL identified 17 papers. One additional publication was included following discussions with a clinical expert. Comparable RCTs were grouped into networks based on similar induction and consolidation regimens, resulting in three networks for meta-analysis. Network 1 consisted of RCTs with ATRA, anthracycline (AraC), and chemotherapy (Chemo) regimens. Three trials with arsenic + ATRA arms made up Network 2; observation maintenance arms from 3 studies commprised Network 3. Results: In Network 1, ATRA + AraC + Chemo + ATO was associated with superior event-free survival (EFS) at 4 years (yrs) vs. ATRA + Chemo and ATRA followed by Chemo + AraC. The mean odds ratios (OR) were 4.45 (CI: 2.11-9.40, p = 0.00018) and 4.73 (CI: 2.44-9.16, p = 0.00001), respectively. Relative risks (RR) were not statistically significant. Mean results showed that EFS at 7 yrs for ATRA + AraC + Chemo + ATO was likely to be higher. Other outcomes did not demonstrate a statistically significant difference in treatment arms. In Network 2, ATRA + Realgar-Indigo naturalis formula (RIF, an oral arsenic derivative) in induction was associated with a higher disease-free survival (DFS) at 2 yrs compared to ATRA or ATO monotherapy. The RRs were 49.35 (CI: 1.66-1466.53, p = 0.01) and 15.53 (CI: .46-525.2, p = 0.04), respectively. Other outcomes included 2-yr DFS for monotherapy regimens of ATRA vs. ATO, complete remission rate, and liver-related adverse events, none of which had statistically significant results. In Network 3, no in DFS at 5 yrs were observed between treatment arms. Conclusions: Results suggest that regimens containing ATO or RIF appear to be associated with improved outcomes compared to those which include ATRA plus Chemo without ATO. Furthermore, the regimens which included ATO or RIF were not associated with increased toxicities.
Retrospective review of locally advanced head and neck cancer treated with concomitant chemoradiotherapy at the Miami VA Medical Center
Authors: C. Robles, C. Vale, V. Dinh, N. Savaraj, S. Spector, L. Chua, P. Bustillo, A. Furst
Journal: Journal of Clinical Oncology (2006)

15541 Management of Stage III or IV Head and Neck (H&amp;N) cancer is debatable. Standard of care is Radical Surgery (Sx) followed by Radiotherapy (XRT). However, cosmetic and functional complications are distressing and result in decreased quality of life. Therefore, organ preservation has become important when deciding best management. The VA larynx study, the EORTC 24891 and the 91–11 US intergroup trial have shown efficacy of organ preserving chemoradiotherapy (Cx+Rx) comparable to Sx and XRT. These studies are limited to laryngeal and hypopharyngeal cancers and whether same principles can be applied to other H&amp;N sites is unknown. We conducted a retrospective study of stage III &amp; IV H&amp;N cancer treated at our Institution between 1996–2004 to evaluate survival, organ preservation and toxicities. 45 males between 47 to 83 years (median 59.6) were studied. 87% were white and 13% black. 82% had history of tobacco and alcohol abuse, 4% tobacco only, 11% alcohol only and 2% never smoked or drank. The sites of disease were: nasopharynx 1 (2%), oropharynx 19 (42%), base of tongue 10 (22%), larynx 6 (13%) and pharynx 9 (20%). 15 patients (33%) where stage III and 30 (67%) stage IV. The treatment was combined Cx+Rx. The mean dose of XRT was 6697 Cgy and mean cycles of chemotherapy (Cx) were 2.2. Of those, 42 patients (93%) received cisplatin and 5FU, 2 (4%) carboplatin and 5FU and 1 (2%) carbo only. 10 patients (22%) received additional Cx and 14 (31%) underwent additional Sx (neck dissection). 19 patients (42%) are alive, 19 (42%) are death and 7 (16%) were lost to f/u. Median survival is 30.6 months. 1 patient was refractory and 6 relapsed in less than a year. Among them, 4 were local relapses, 1 a neck recurrence (no prior dissection) and 1 a distant relapse. The most common acute toxicities were: Anemia 87%, neutropenia 64%, hyperglycemia 82%, transient elevation of BUN 60% and creatinine 36%, hypo/hypernatremia 64%, severe mucositis 71%, weight loss 76%, N/V 47% and severe dysphagia 27%. Cx+Rx appears to be a safe, feasible and comparable alternative to Sx regardless of the anatomical origin in locally advanced H&amp;N cancer, with the advantage of organ preservation. Additional XRT boost, Cx or Sx could decrease relapses. Further studies are warranted to validate these hypotheses. No significant financial relationships to disclose.
Metastatic dermatofibrosarcoma protuberans (DFSP) and fibrosarcomatous DFSP (FS-DFSP): Sensitivity to imatinib (IM) and gene expression profile.
Authors: Silvia Stacchiotti, Maria A. Pantaleo, Tiziana Negri, Annalisa Astolfi, Elena Conca, Gianpaolo Dagrada, Valentina Indio, Milena Urbini, Paola Collini, Carlo Morosi, Marco Fiore, Chiara Colombo, Elena Palassini, Angelo Paolo Dei Tos, Bruno Vincenzi, Federica Grosso, Ugo Pastorino, Alessandro Gronchi, Silvana Pilotti, Paolo Giovanni Casali
Journal: Journal of Clinical Oncology (2015)

10553 Background: We report on IM activity in patients (pts) with metastatic DFSP/FS-DFSP and on the gene expression profile (GEP) analysis of pure DFSP versus FS-DFSP, aimed at identifying prognostic markers Methods: All pts treated with IM at our institution from 2007 to 2014 for metastatic DFSP/FS-DFSP were selected. To estimate the PFS, pts progressing after IM discontinuation who responded after restarting IM were considered PD at the time of definitive PD on IM. Path and cytogenetics of the primary lesion and metastases were compared. We performed RNA Sequencing of 5 DFSP and 5 FS-DFSP (3 metastatic) on HiScanSQ platform. In 2 pts the analysis was done on samples taken before and after IM. GEP analysis was done with Python function htseq-count, differential expression with Bioconductor package edgeR, hierarchical clustering and Principal Component Analysis (PCA) with Multiple Array Viewer. SNV, Ins/del, fusion transcript analyses are ongoing Results: 10 pts were identified, all evaluable for response. All showed a FS component in the metastatic tumor, 7/10 in the primary lesion. COL1A1-PDGFb was detected in all cases. Best RECIST response was: 8 PR, 1 SD, 1 PD. 5 pts received complete surgery after IM (4 while under response, 1 after PD) with evidence of path response in 4 (with aspects depending on surgical timing, affecting tumor cells and pericytes). All pts relapsed. IM was restored in 4 pts with a new response. Median PFS was 11 mos (range 2-14+). By PCA all DFSP displayed a unique GEP, clearly different from FS-DFSP. At the supervised analysis, FS-DFSP were marked by over-expression of potential biomarkers such as MCAM and TGM2 (involved in metastatic process and chemoresistance). Many genes were upregulated in pure DFSP, reflecting the enrichment in neural markers and cell adhesion molecules Conclusions: All metastatic cases were FS-DFSP. Most pts responded to IM but PFS was shorter than reported in series including all DFSP. All pts who were operated after IM relapsed, suggesting that IM cannot eradicate metastatic DFSP/FS-DFSP and the role of surgery is limited. Restart IM after surgery, as done in GIST, is to be evaluated. DFSP and FS-DFSP presented a clearly different GEP
Phase I study of ceritinib in pediatric patients (Pts) with malignancies harboring a genetic alteration in ALK (ALK+): Safety, pharmacokinetic (PK), and efficacy results.
Authors: Birgit Geoerger, Johannes Schulte, Christian M. Zwaan, Michela Casanova, Matthias Fischer, Lucas Moreno, Toby Trahair, Irene Jimenez, Hyoung Jin Kang, Alberto S. Pappo, Eric Schafer, Brian D. Weiss, Mary Ellen Healy, Ke Li, Tiffany Lin, Anthony Boral, Andrew DJ Pearson
Journal: Journal of Clinical Oncology (2015)

10005 Background: Ceritinib is a potent ALK inhibitor with durable efficacy in adult pts with ALK-translocated non-small cell lung cancer. This report describes the results of a phase I study (NCT01742286) in pediatric pts with ALK-aberrant malignancies: anaplastic large cell lymphoma (ALCL); myofibroblastic tumor (MT)/inflammatory (IMT) rhabdomyosarcoma (RMS) and neuroblastoma (NB). In these tumors ALK aberrations differ: ALCL and IMT carry gene translocations, NB amplifications or mutations, and RMS copy number gain or no change. Methods: This trial enrolled pediatric pts ≥ 1 to <18 yrs. ALK gene aberration was required, except in ALCL and RMS, where ALK+ by immunohistochemistry was sufficient. In a fasted, dose-escalation phase, pts received ceritinib at 300–560 mg/m2/day to determine the recommended dose for expansion (RDE). Pts were assessed for safety, PK and efficacy. Results: Twenty-two pts were enrolled (22 centers in 10 countries) over 13 months including: 2 ALCL, 6 IMT, 1 MT, 7 NB, 6 RMS. Median age was 10 years (range 2-17), 14 were male and 3 were crizotinib-pretreated (1 NB, 2 IMT). Completion of the fasted escalation phase established a RDE of 510 mg/m2. Common adverse events (% Any Grade [G]; G3/4) were diarrhea (86.4; 9.1), vomiting (81.8; 0), nausea (54.4; 0), elevated ALT (45.5; 18.2), abdominal pain (40.9; 9.1), decreased appetite (40.9; 0), elevated AST (36.4; 18.2), pyrexia (36.4; 0), and fatigue (31.8; 0). Two pts had dose limiting toxicity at 560 mg/m2: G3 elevated ALT and persistent G2 abdominal pain. PK at the RDE (AUC and CL/F) was comparable to that reported for adults at this dose. Early data show responses in 2 of 2 pts with ALCL and 4 of 7 pts with MT/IMT (2 CR: 1 in a crizotinib-pretreated pt). To date, one pt with ALK F1174L mutated NB had shrinkage of a retroperitoneal mass; disease progressed in the brain, where lower ceritinib exposure is expected. Dose escalation with food is ongoing. Conclusions: The RDE in children is 510 mg/m2/day without food. The toxicity profile is similar to that in adults. Food may reduce gastrointestinal symptoms and allow further dose escalation. Ceritinib showed efficacy in pediatric pts with ALCL and MT/IMT. Clinical trial information: NCT01742286.
Identification of educational gaps among oncologists who treat patients with pancreatic cancer.
Authors: Justin A Barnes, Melissa L Ellis, Sharon Hwang, Benjamin Leon Musher, Joan Emarine, Patti A. Merwin, Gregory D Salinas
Journal: Journal of Clinical Oncology (2017)

431 Background: Pancreatic ductal adenocarcinoma (PDA) is the fourth-most common cause of cancer-related death in the United States, with only 7.7% of patients surviving beyond 5 years. Given the poor outcomes associated with PDA, it is imperative that patients with PDA receive optimal care. Continuing medical education (CME) offers an effective means to improve physician performance, and CME programs are most effective when they address areas of greatest need. This study was conducted to identify and quantify the educational gaps in PDA management that can potentially be addressed with CME. Methods: A case-vignette survey instrument was developed to assess physicians’ practices related to PDA. Case vignettes are a validated means of assessing healthcare provider practice patterns. The survey instrument included three patient cases: 1) A 50 year-old man with resectable PDA; 2) a 75 year-old man with locally advanced, unresectable PDA; and 3) a 55 year-old woman with metastatic PDA. Each case was followed by a series of questions designed to assess medical decision-making, physician/patient communication, and barriers to optimal practice. Results: Survey responses were collected from 150 US oncologists in July 2016 (19% at academic centers). Several key educational gaps were identified. For Case 1, 44% of oncologists did not select an evidence-based adjuvant chemotherapy regimen from a list of options. For Case 2, in which the patient had developed metastases and neuropathy after first-line therapy, 57% of respondents did not select an evidence-based second-line option, and 35% selected a regimen with oxaliplatin. For Case 3, only 18% of oncologists recommended an initial diagnostic evaluation that included a biopsy, chest imaging, and liver function tests. Finally, for all 3 cases, little emphasis was placed on enrolling patients in clinical trials. Conclusions: This study identified appreciable discrepancies between respondents’ recommendations and standard evidence-based guidelines for treating all stages of PDA. Well-designed CME programs may help bridge the educational gaps among practicing oncologists and ultimately improve adherence to national guidelines.