tbuckley/cabot-search huggingface dataset:
Effect of nab-paclitaxel combination chemotherapy on response and survival in pancreatic cancer.
Authors: Andrew Peter Dean, Prasad Cooray
Journal: Journal of Clinical Oncology (2012)

e14718 Background: Pancreatic cancer has traditionally had few effective chemotherapy options. Recent discovery of the over-expression of SPARC (Secreted Protein Acidic Rich in Cysteine) on the majority of pancreatic cancers suggests possible utility of nab-paclitaxel, (a novel albumin-bound form of paclitaxel) as a treatment option. A small prospective study (ASCO 2009) supported this theory. We sought to retrospectively evaluate the treatment efficacy of nab-paclitaxel with gemcitabine or carboplatin in patients with pancreatic cancer to assess concordance with the previous small prospective study. Methods: Data was collected retrospectively from the medical records of pancreatic cancer patients who presented to the private clinic of two treating oncologists (n = 63) from June 2009 to December 2011 and were treated with nab- paclitaxel in combination with either gemcitabine or carboplatin. Patients were assessed on the basis of changes in serum tumour marker (CA19-9, CEA or CA15-3) and changes in tumour size on radiological imaging. Results: 39 (70%) patients had a biochemical response with a greater than 20% drop in tumour markers. Of these, 30 (94%) showed greater than 70% drop with all responders showing reduction in markers within 6 weeks of starting. The number of patients with biochemically defined disease control was 48 (86%). 36 patients were deceased by the end of the series with median overall survival being 12.9 months. The median survival time from starting nab-paclitaxel for these patients was 7.9 months. Very long survival times (up to 28.1 months following commencement nab-paclitaxel) were also observed in 2 patients at the time of data analysis. The overall disease control rate radiologically was 76.79% (43 of 56). Of the 43 responders, 10 were complete responders, 22 showed partial radiological response and 11 had stable disease. Conclusions: This retrospective case series demonstrates a near doubling of overall median survival time and also an improved response rate in patients on nab-paclitaxel treatment as compared to historical data of other treatment options for pancreatic carcinoma. It further supports Von Hoff’s data from ASCO 2010. Further prospective data is eagerly awaited.
Whole exome sequencing (WES) in HER2+ metastatic breast cancer (MBC) patients (pts) with extraordinary responses to trastuzumab (T).
Authors: Ines Maria Vaz Duarte Luis, Coyin Oh, Zhigang Wang, Pamela Dipiro, Erin Macrae Macrae, Corrie Painter, Gregory Kryukov, Ian E. Krop, Eric P. Winer, Nancy U. Lin, Nikhil Wagle
Journal: Journal of Clinical Oncology (2015)

611 Background: While 50-70% of pts with HER2+ MBC treated with T respond to therapy, the vast majority eventually develop resistance, after a median duration of 1 year. In rare cases, pts have exceptionally long durations of response to T. Understanding mechanisms of exceptional responses to anticancer therapies may improve patient selection and rational treatment designs. Methods: We conducted a retrospective screen for pts with HER2+ MBC at the Dana Farber Cancer Institute treated with T in the metastatic setting for more than 60 months. To date, we have identified 3 pts with extraordinary responses to T who provided consent for genomic studies and had sufficient tumor tissue available for study. All pts had histologic confirmation of metastatic disease and radiologic confirmation of response. Deep WES was performed on DNA extracted from pre-trastuzumab tumor biopsies and matched normal blood samples from all 3 pts, and sequencing data was analyzed for somatic point mutations, small insertions/deletions, and copy number alterations. Results: Clinical features are summarized in the Table. Mean target coverage for tumor samples were 181X, 178X, and 191X. Total number of somatic coding mutations were 161, 67, and 156. Somatic copy number analysis demonstrated HER2 amplification in all 3 tumors. Additional somatic genomic alterations included alterations in known breast cancer genes TP53, MAP2K4, and RB1. Conclusions: WES in 3 pts with HER2+ MBC treated with T in the metastatic setting for > 60 months demonstrated HER2 amplification as well as additional somatic genomic alterations. WES on tumor and germline samples from additional pts with extraordinary responses to T are underway, which may improve the power to detect underlying mechanisms of exquisite sensitivity to T. Receptor Status Sites of disease Tumor purity Site of biopsy Treatment Response duration (months) 1 ER/PR negative, HER2 3+ (IHC) Lymph nodes (LN) 60% LN Trastuzmab-paclitaxel* 88 (Ongoing) 2 ER/PR negative, HER2 3+ (IHC) Skin/Chest wall, LN 40% LN Trastuzumab-lapatinib* 72 (Ongoing) 3 ER+( low) / PR negative, HER2 3+ (IHC) Bone, Liver 50% Breast Trastuzumab-epothilone* 100 (Ongoing) Followed by trastuzumab alone.
Tumor Cell–Free DNA Copy Number Instability Predicts Therapeutic Response to Immunotherapy
Authors: Glen J. Weiss, Julia Beck, Donald P. Braun, Kristen Bornemann-Kolatzki, Heather Barilla, Rhiannon Cubello, Walter Quan, Ashish Sangal, Vivek Khemka, Jordan Waypa, William M. Mitchell, Howard Urnovitz, Ekkehard Schütz
Journal: Clinical Cancer Research (2017)

Purpose: Chromosomal instability is a fundamental property of cancer, which can be quantified by next-generation sequencing (NGS) from plasma/serum-derived cell-free DNA (cfDNA). We hypothesized that cfDNA could be used as a real-time surrogate for imaging analysis of disease status as a function of response to immunotherapy and as a more reliable tool than tumor biomarkers.Experimental Design: Plasma cfDNA sequences from 56 patients with diverse advanced cancers were prospectively collected and analyzed in a single-blind study for copy number variations, expressed as a quantitative chromosomal number instability (CNI) score versus 126 noncancer controls in a training set of 23 and a blinded validation set of 33. Tumor biomarker concentrations and a surrogate marker for T regulatory cells (Tregs) were comparatively analyzed.Results: Elevated CNI scores were observed in 51 of 56 patients prior to therapy. The blinded validation cohort provided an overall prediction accuracy of 83% (25/30) and a positive predictive value of CNI score for progression of 92% (11/12). The combination of CNI score before cycle (Cy) 2 and 3 yielded a correct prediction for progression in all 13 patients. The CNI score also correctly identified cases of pseudo-tumor progression from hyperprogression. Before Cy2 and Cy3, there was no significant correlation for protein tumor markers, total cfDNA, or surrogate Tregs.Conclusions: Chromosomal instability quantification in plasma cfDNA can serve as an early indicator of response to immunotherapy. The method has the potential to reduce health care costs and disease burden for cancer patients following further validation. Clin Cancer Res; 23(17); 5074-81. ©2017 AACR.
A prospective, randomized, double-blind phase 3 trial of extended-release granisetron (APF530) versus palonosetron (PALO) for preventing chemotherapy-induced nausea and vomiting (CINV) associated with moderately (MEC) or highly (HEC) emetogenic chemotherapy: Does a reanalysis using newer ASCO emetogenicity criteria affect study conclusions?
Authors: Harry Raftopoulos, Ralph V. Boccia, William Cooper, Erin O'Boyle, Richard J. Gralla
Journal: Journal of Clinical Oncology (2014)

9648 Background: APF530 provides controlled sustained release of granisetron to prevent acute (0-24 h) and delayed (24-120 h) CINV. In a phase 3 trial in 1395 patients, single doses of subcutaneous (SC) APF530 250 and 500 mg were noninferior to intravenous (IV) PALO 0.25 mg in preventing acute CINV after MEC or HEC; APF530 500 mg was noninferior to PALO in preventing delayed CINV after MEC, but not superior in preventing delayed CINV after HEC (Grous et al. J Clin Oncol 2009, abs 9627). The primary efficacy endpoint was complete response (CR, no emesis or rescue medication). Chemotherapy emetogenicity was assigned by Hesketh criteria (Hesketh et al. J Clin Oncol 1997). However, ASCO reclassified some chemotherapy regimens in its 2011 antiemesis guidelines (Basch et al. J Clin Oncol 2011). Methods: Study data were reanalyzed with chemotherapy regimens reclassified as MEC or HEC using ASCO criteria. Noninferiority was shown if the CI difference in CR for APF530 – PALO had a lower confidence bound greater than −15%. Results: Using ASCO emetogenicity criteria (MEC = 609; HEC = 690), APF530 maintained noninferiority to PALO for all endpoints previously reported. The table shows CR rates by group, using ASCO criteria. Conclusions: Single-dose APF530 SC is an alternative to PALO for preventing acute and delayed CINV after MEC or HEC, with generally mild and manageable adverse events. In this post hoc analysis, reclassifying chemotherapy emetogenicity by ASCO criteria did not alter the initial study conclusions. Clinical trial information: NCT00343460. CINV APF530 250 mg APF530 500 mg PALO Between- treatment P MEC N = 193 N = 205 N = 211 Acute CR, n (%) 158 (82) 171 (83) 187 (89) .135 P* .067 .157 95% CI* −14, 0.2 −12, 1.5 Delayed CR, n (%) 127 (66) 142 (69) 147 (70) .674 P* .456 1.0 95% CI* −13, 5.3 −9.4, 8.5 HEC N = 241 N = 231 N = 218 Acute CR, n (%) 173 (72) 172 (75) 147 (67) .254 P* .360 .118 95% CI* −4.1, 12.8 −1.4, 15.5 Delayed CR, n (%) 122 (51) 129 (56) 110 (51) .420 P* 1.0 .258 95% CI* −9, 9.4 −3.9, 14.7 *P and 95% CI vs PALO.
A neuroblastoma risk classification model for developing countries: A study from the International Neuroblastoma (NB) Risk Group (INRG) database.
Authors: Wendy B. London, Veronica Moroz, Barabara Hero, Julie R. Park, Dominique Valteau-Couanet, Akira Nakagawara, Frank Berthold, Katherine K. Matthay, Gudrun Schleiermacher, Andrew DJ Pearson, Susan Lerner Cohn, David Machin
Journal: Journal of Clinical Oncology (2014)

10030 Background: Current methods for stratifying NB patients (pts) at diagnosis to INRG risk/pre-treatment groups are based on prognostic clinical, genomic, and histologic factors [Cohn et al, JCO 2009]. In developing countries, testing tumors for genomic biomarkers or histologic features is not possible; however, clinical tests serum ferritin and serum lactate dehydrogenase (LDH) are likely available. Methods: Retrospective analysis included INRG pts with sufficient data for clinical risk factors and event-free survival (EFS). Survival tree regression was performed, considering only age (<18 months; ≥18 months), INSS stage (4; not 4), ferritin (<92; ≥92ng/mL), and LDH (<587; ≥587U/L). Pts were categorized into clinical pre-treatment risk groups, categorized by 5-yr EFS: very low (>85%), low (>75-≤85%), intermediate (≥50-≤75%), or high risk (<50%). EFS time was calculated from diagnosis until first event (relapse/progression, second malignancy, death), or until last contact if no event occurred. Results: From 8,800 INRG pts, 7,679 were able to be risk classified according to INRG definitions, including genomic and histological factors. Of 7,679, 3,509 had known age, stage, LDH and ferritin and a clinical pre-treatment risk group was assigned: very low (n=1319), low (n=379), intermediate (n=550), and high (n=1261). 5-yr EFS for very low-, low-, intermediate-, and high-risk groups were 90±1%, 80±3%, 65±3%, 27±2%, respectively. The clinical risk classification was the same as (58.1%) or similar to (12.8%) the INRG in 70.9% of pts. Based on 5-year EFS: INRG overestimated risk but clinical factors correctly assigned risk in 18.9% of pts; clinical factors overestimated (3.7%) or underestimated (6.4%) risk but INRG correctly assigned risk in 10.1% of pts. Conclusions: In 89.9% of pts, clinical factors (age, stage, ferritin, LDH) do as well or better than clinical, genomic, and pathologic factors currently used in INRG risk/pre-treatment group assignment. The INRG-clinical pre-treatment risk stratification shows promise for developing countries to assign treatment intensity, whereby very low-risk pts can be spared unnecessary, expensive chemotherapy.
Perioperative outcomes in major liver resections for colorectal liver metastasis (CRLM) in the Elderly: a case-control matched study.
Authors: Arie Ariche, Rony Eshkenazy, Rene Adam, Nicolas d'Angelis, Philippe Compagnon, Chaddy Salloum, Daniel Azoulay
Journal: Journal of Clinical Oncology (2015)

e14676 Background: Liver resection remains the gold standard in the treatment of liver metastases from colorectal cancer (CRLM), but major hepatectomy in elderly patients is still a challenge. Aim: To compare the outcome of major hepatic resections between young and elderly patients, analyzing a retrospective database in a case-match study. Methods: From 1974 to 2013, 2392 patients underwent liver resections for colorectal liver metastases in Western Galilee Hospital (Israel), Hopital Henri Mondor (France) and Hopital Paul Brousse (France). Of this, 1156 patients underwent major hepatectomy ( ≥ 3 segments). Among them, 728 patients met the inclusion criteria, 495 – matching 1:2. Two groups were analyzed: old group patients (OG) aged ≥ 70 and young group patients (YG) aged < 70 years old. When matching OG with YG the following criteria were considered: type of surgical resection (p > 0.999), number of resected segments (p = 0.360), size of maximal diameter nodule (p = 0.774), localization of tumors (p = 0.674), ASA (p = 0.967) and Charlson score (p = 0.303). Results: The OG included 165 patients, of which 62 (37.5%) female, and the YG included 330, of which 112 (33.9%) female (p = 0.424). Before resection, portal vein embolisation was realized in 26 patients (15.7%) of OG vs 66 patients (20%) of YG (p = 0.253). Intraoperative blood transfusion was necessary in 51 patients (30.9%) of OG vs 123 (37.3%) in YG (p = 0.162). Global morbidity was 37% in the OG vs 39.4% in the YG (p = 0.601). According to Dindo-Clavien’s classification, severe complications grade 3-4 rate was 52.8% vs 34.4% of all the complications (p = 0.012) and mortality was 4.8% vs 1.5% (p = 0.033) in OG and YG respectively. The mean hospitalization stay was 15.9 vs 16.4 days in OG and YG respectively (p = 0.532). Conclusions: Significantly highermortality and severe morbidity after major hepatectomies in old patients needs a rigorous selection for surgery in this population
Results of a phase III randomized, controlled study evaluating the efficacy and safety of idelalisib (IDELA) in combination with ofatumumab (OFA) for previously treated chronic lymphocytic leukemia (CLL).
Authors: Jeffrey Alan Jones, Malgorzata Wach, Tadeusz Robak, Jennifer R. Brown, Alexander R. Menter, Elizabeth Vandenberghe, Loic Ysebaert, Nina D. Wagner-Johnston, Jonathan Polikoff, Huda S. Salman, Kerry McDonald Taylor, Steven Coutre, Stephen Edward Forbes Spurgeon, Stephan Disean Kendall, Ian Flinn, Lyndah Dreiling, Ronald Dubowy, Yoonjin Cho, Sissy Peterman, Carolyn Owen
Journal: Journal of Clinical Oncology (2015)

7023 Background: IDELA (Zydelig) is a selective oral PI3Kδ inhibitor approved in combination with rituximab for previously treated pts with CLL. This open-label study (NCT01659021) compared IDELA + OFA v OFA in pts with relapsed CLL. Methods: Pts with CLL progressing ≤ 24 mo from last therapy, who had received ≥ 2 cycles of a purine analogue or bendamustine, were randomized 2:1 to either Arm A (IDELA 150 mg BID continuously plus OFA, 300 mg IV wk 1, then 1 gm IV wkly x 7 and q 4 wk x 4) or Arm B (OFA, same as Arm A except 2 gm was substituted for 1 gm dosing). Stratification was performed for relapsed v refractory, del17p and/or TP53 mutation, and IGHV mutation. IRC-assessed response and PD based on imaging using modified IWCLL 2008 criteria. The 1° endpoint was PFS and 2° endpoints were confirmed ORR, lymph node response (LNR), OS, PFS in pts with del(17p) and/or TP53 mutation, and CR rate. Results are from the final analysis. Results: Pt attributes were balanced in the 2 arms: Med age 67; Rai II/III/IV 18/13/51%, med no. prior regimens 3, refractory 49%, del17p/TP53mut 40%, IGHV unmut 78%. Exposure, disposition, and efficacy are shown in Table. Results were consistent across risk groups. Gr ≥ 3 AEs in Arm A included diarrhea/colitis (20.2%), pneumonia (12.7%), and febrile neutropenia (11.6%). Conclusion: IDELA + OFA yielded superior PFS, ORR, and LNR compared to OFA in relapsed CLL, including within high-risk subgroups. Safety was manageable with a profile similar to that previously observed in CLL trials. The open label design may have led to an imbalance in dropout, with a higher rate in Arm B. Clinical trial information: NCT01659021. Arm A (IDELA/OFA) Arm B (OFA) HR / OR2 Pts randomized/dosed 174/173 87/86 Months on study (range) 13.6 (1.1-24)1 5.8 (0-20) Reason for study D/C3 (%) PD 34 (19.5) 41 (47.1) Death 22 (12.6) 6 (6.9) AE / MD decision 21 (12) 19 (21.8) Withdrew consent/other 13 (7.5) 15 (17.2) Med PFS, mo 16.3 8.0 HR = 0.27, p < 0.00014 ORR, % 75.3 18.4 OR = 15.9, p < 0.00014 LNR, % 93.3 4.9 OR = 487, p < 0.00014 Med OS, mo 20.9 19.4 HR = 0.74, p = 0.27 Med PFS: del17p/TP53mut, mo 13.7 5.8 HR = 0.33, p < 0.0001 1IDELA med exposure 12.3 mo (0.2-23.9); 2odds ratio; 3per MD; 4null hypothesis formally rejected.
COX-2 Expression Does Not Predict Outcome of Celecoxib in Addition to Standard Chemotherapy in Advanced Non-Small Cell Lung Cancer
Authors: Miklos Gulyas, Johanna S. M. Mattsson, Andrea Lindgren, Christer Sederholm, Lars Ek, Kristina Lamberg, Annelie F. Behndig, Erik Holmberg, Patrick Micke, Bengt Bergman
Journal: Journal of Thoracic Oncology (2015)
Changes in prostate-specific antigen doubling time (PSADT) prior to and after treatment with hormonal therapy (HT) in men with biochemically recurrent prostate cancer (BRPC): A preliminary analysis.
Authors: Victoria J. Sinibaldi, Peng Huang, Emmanuel S. Antonarakis, Michael Anthony Carducci, Mario A. Eisenberger
Journal: Journal of Clinical Oncology (2012)

e15188 Background: PSADT is an important prognostic parameter in all clinical states of PCA. Intra -subject changes in PSADT prior to and after HT remains undefined. Methods: Men with rising serum PSA levels after local therapy were longitudinally followed from the hormone-sensitive (HS) to the castration-resistant (CR) state. PSADT was calculated according to standard formulas ( Pound et al., JAMA 1999) and previously identified prognostic subgroups (Antonarakis et al., BJU Int 2012; Freedland et al., JCO 2007) were used to evaluate the potential clinical significance of PSADT according to the following subgroups: [1] &lt; 3 months (mo); [2] 3-8.9 mo, [3] 9-14.9 mo, and [4] ≥ 15 mo). Results: 55 men with BRPC who eventually developed CR disease on HT were retrospectively analyzed. The median age of HS men was 60 y (range (r) 43-78); CR men 66 y (r 43-87). Of all men, 28 had prior surgery (S), 5 had radiation (R), 14 had S+R, 7 had neoadjuvant /adjuvant HT + local therapy, and 1 had no local therapy. PSADT in the CR state was shorter than PSADT in the HS state (signed –rank test; p=0 .012). HS men with PSADT &lt; 4 m had shorter overall survival than those with PSADT ≥ 4 mo ( 13.9 vs. 20.1 mo; HR ; 8.46). Changes in PSADT from the HS to the CR state are summarized in the Table below. The majority of men converted from a more favorable to a less favorable PSADT subgroup as they progressed from HS to CR states. Conclusions: PSADT tends to shorten from the HS to the CR states. The prediction of clinical outcome based on PSADT needs to account for the clinical state the patient is in, as PSADT may change within the same patient from state to state. [Table: see text]
Prognostic role of immune checkpoint-related genes in resectable lung adenocarcinomas.
Authors: Marta Usó, Eloisa Jantus-Lewintre, Rafael Sirera, Silvia Calabuig, Sandra Gallach, Cristina Hernando, Ana Blasco, Ricardo Guijarro, Carlos Camps
Journal: Journal of Clinical Oncology (2014)

11085 Background: Immune checkpoints blockade has demonstrated promising clinical results in NSCLC patients. In this study we have investigated the prognostic role of immune checkpoint markers (CTLA4, PD1 and PDL1) in resectable lung adenocarcinoma (ADC). Methods: RNA was isolated from fresh-frozen lung specimens (tumor and normal lung) from resectable ADC patients (n=92). RT-PCR was performed to analyze the expression of CTLA4, PD1 and PDL1 by the use of hydrolysis probes. Relative gene expression was assessed by Pfaffl formula and normalized by CDKN1B and ACTB as endogenous genes (selected by geNorm algorithm). Statistical analyses were considered significant at p<0.05. Results: Patient’s median age was 64 [37-82], 77.2% were male, 73.9 % have a performance status of 0 and 58.7% presented stage I at the time of the diagnosis. We found a significant positive correlation between expression levels of PD1 and PDL1 (r2=0.436; p<0.0001) and between PD1 and CTLA4 (r2=0.458; p<0.0001). Survival analyses revealed that patients with higher levels of CTLA4, PD1 and PDL1 presented longer progression free survival (PFS) (Table 1), and in the case of CTLA4 also increased overall survival (OS) (median 32.30 vs 81.23 months p=0.044). Furthermore, the group of patients with high levels of both PD1 checkpoints (PD1high & PDL1high) showed longer PFS (Table 1). The multivariate Cox regression analysis revealed that CTLA4 is an independent prognostic marker for PFS (HR 0.38 [0.19-0.79] p= 0.009) and OS (HR 0.38 [0.17-0.85] p=0.019]. Conclusions: Expression of immune checkpoint genes seems to have a prognostic role in lung ADC. Among these, CTLA4 has been found to be an independent prognostic marker highlighting the importance of these immune-markers in the prognosis of resectable lung ADC. PFS for CTLA4, PD1, and PDL1 in lung ADC patients. Median (months) p-value CTLA4 (≤ median vs > median) 19.23 vs 81.23 0.008 PD1 (≤ median vs > median) 19.13 vs 49.30 0.048 PDL1 (≤ median vs > median) 19.23 vs 66.96 0.034 Combined checkpoints (Other combinations vs PD1high PDL1high) 19.23 vs NR 0.008 (0.048*) * p -value with Bonferroni correction.
A prospective phase II trial of a S-1/cisplatin-based chemoradiotherapy for locoregionally advanced esophageal cancer.
Authors: Byoung Chul Cho, Hyun Chang, Yong Chan Lee, Dae Joon Kim, Mi Jin Yun, Sung Kwan Shin, Hyun Ki Kim, Han Sang Kim, Sun Min Lim, Joo-Hang Kim
Journal: Journal of Clinical Oncology (2012)

e14559 Background: Concurrent chemoradiation has similar efficacy as surgery for esophageal cancer. Phase II trial was carried out to evaluate the efficacy and safety of chemoradiation with S-1 and cisplatin in locoregionally advanced esophageal cancer. Methods: Eligible patients had stage IIA-IVA esophageal cancer. Patients received two cycles of S-1 (days 1 to 14 and 22 to 35) and cisplatin (day 1 and 22) with concurrent radiotherapy (50.4 Gy total: 1.8 Gy/fraction). Esophagectomy was performed between week 12 and 18 as determined by the specialist multidisciplinary team meeting. Results: Sixty patients were enrolled between March 2008 and August 2011. Of the 60 patients entered, 59 patients were eligible. Clinical stage was ≥T3 in 28 patients (47%) and N1 in 43 patients (73%), with squamous cell carcinoma histology in 57 patients (97%). Fifty-four patients (90%) completed the planned treatment. After the chemoradiation, clinical tumor response rate was 62.7%. The primary grade 3/4 toxicities included neutropenia (24%) and esophagitis (8.5%). All three patients died during chemoradiation (two from pneumonia and one from gastrointestinal origin septic shock). Twenty-five patients (42%) underwent esophagectomy following chemoradiation and 15 (60%) achieved complete pathologic regression. At the median follow-up duration of 34.6 months, the estimated overall survival and progression-free survival rate at 2-year was 56.5% and 45.9%, respectively. Conclusions: Concurrent chemoradiation with S-1 and cisplatin showed an encouraging activity with high complete pathologic regression. Survival data was promising compared with historical data with 5-FU/cisplatin and should be confirmed in a randomized phase III trial. Toxicities were significant but clinically manageable.