tbuckley/cabot-search huggingface dataset:
Genomic mutation profiling (GMP) and clinical outcome of patients treated with buparlisib (PI3K inhibitor) in the “Signature” program.
Authors: Sarina Anne Piha-Paul, James A. Knost, Fadi S. Braiteh, J. Thaddeus Beck, Daniel Lewis Spitz, Steven W. Papish, Beth A. Hellerstedt, Petros Nikolinakos, Matthew Hiram Taylor, Sant P. Chawla, Lee Steven Schwartzberg, David A. Smith, Sebastian Szpakowski, Lening Zhang, Theresa White, Claudia Lebedinsky
Journal: Journal of Clinical Oncology (2015)

2516 Background: Pts included in the buparlisib (BKM120) module were analyzed by a tissue-agnostic genetic alteration–specific protocol that matches pts to treatments that target tumors harboring PI3K pathway–activated tumors. The pts are identified via standard of care physician-directed profiling. Methods: Pts with measurable advanced malignancies and no established standard therapy options were eligible. A local CLIA-certified test was sufficient for eligibility, and broad molecular profiling of pt tumors (confirmatory analysis of inclusion genetic alteration) was performed centrally post hoc. The primary objective was to assess clinical benefit (CB; CR + PR + SD at 16 weeks) by local investigator assessment. Buparlisib was given orally (100 mg once daily). Analysis correlating GMP with treatment outcomes will help determine the significance of these mutations. Results: GMP data were available for 76 pts across 19 tumor types (colorectal [14; 18%], sarcoma [11; 15%], ovarian [10; 13%], and head and neck [9; 12%]. Rare tumors included vaginal [1] and appendix [1]]. Median age: 60 years (range, 24-80), 49 women (65%), median number of prior therapies: 3 (range, 1-16). Baseline actionable alterations (local labs) included 38 PIK3CA mutations (50%), 17 PTEN mutations (22%), 16 PTEN losses (21%; IHC), 7 PIK3CA amplifications (9%), and 2 PIK3R1 mutations (3%). The concordance of baseline actionable alterations between local and central labs was 67%. Overall, 11 pts (15%) achieved CB. DNA from all pts was assayed by NGS, covering a panel of 288 cancer genes. Based on the assay, the tumors had a median of 4 mutations (range, 0-12) and tissue-specific patterns of mutation burden (lowest in cervix and sarcomas: 2; highest in colorectal and vaginal: 5+). The number of prior therapies did not correlate with the mutation load. Fewer mutations were noted in pts with CB. Most commonly altered genes (8+ pts): PIK3CA, PTEN, KRAS, TP53, APC, CDKN2A, RB1, and ERBB2. Aberrations in APC, BRCA2, CDKN2A, EP300, FBXW7, LRP1B, MLL2, PTEN, RB1, and SMAD4 were enriched in pts with no CB. Conclusions: Buparlisib showed activity in some pts, indicating that specific mutations may correlate with poor outcome. Clinical trial information: NCT01833169.
Toxicity and psychological impact of TPF induction chemotherapy followed by concurrent chemoradiotherapy or by surgery plus radiotherapy in stage III-IV oropharyngeal cancer: A longitudinal comparison study.
Authors: Mario Airoldi, Massimiliano Garzaro, Luca Raimondo, Giuseppe Riva, Fulvia Pedani, Viviana Contu, Elisa Bellini, Antonella Varetto, Riccardo Torta, Giancarlo Pecorari
Journal: Journal of Clinical Oncology (2014)

e17010 Background: HNSCC and their treatments negatively affect speech, swallowing, body image and Quality of Life (QoL). We longitudinally evaluated, in oropharyngeal cancer and up to 36 months of follow up, the impact of neo-adjuvant chemotherapy (NACT) followed by exclusive chemoradiotherapy or by surgery + adjuvant radiotherapy on late toxicity, QoL and psychological functioning. Methods: Thirty-six patients were treated with surgery followed by adjuvant chemoradiotherapy (group A); 36 patients (group B) received 3 cycles of TPF cisplatin (DDP) 75 mg/m2 d.1 + Taxotere 75 mg/m2, d. 1, Fluorouracil 750 mg/m2/d 1à5 c.i.,q 3wks, followed by DDP 100 mg/m2 d. 1,22,43 concomitant with conventional radiation therapy (70 Gy, 2 Gy/d, 5 day/week). Median follow-up was 42 months (range 36-72). Results: Patients’ and tumour characteristics were superimposeable in both groups. Comparing group A and B, the late toxicity evaluation showed, in group A patients, a statistically significant prevalence (p<.05) of the following moderate-severe side effects: subcutaneous fibrosis (72% vs 17%), dysphagia (64% vs 39%), trismus (17% vs 3%), decreased pigmentation (17% vs 6%), skin toxicity (11% vs 6%). In group B patients, there was a statistically significant prevalence (p<.05), of the following moderate-severe late side effects: taste impairment (89% vs 64%), salivary functioning (72% vs 64%), mucous atrophy (34% vs 17%), hair loss (33% vs 8%). Self reported anxiety and depression were less frequent in group B : 22.2% and 13.9% vs 33.3% and 30.6% respectively. The EORTC mean Global QoL and Global Health were 71.42 and 76.47 in group A and 81.37 and 76.05 in group B. Moderate-severe dysphagia was strictly correlated with statistically lower Global Health and QoL score (p<.05). Conclusions: Pattern of late toxicity is very different in the two groups; anxiety and depression are less frequent in group B. Dysphagia has a negative impact on QoL and on psychological status.
Day 100 peripheral blood absolute monocyte/lymphocyte count prognostic score and survival in diffuse large B-cell lymphoma post-autologous peripheral blood hematopoietic stem cell transplantation.
Authors: Ana I. Velazquez, Svetomir Markovic, David James Inwards, Ivana N. M. Micallef, Patrick B. Johnston, William J. Hogan, Stephen Maxted Ansell, Luis F. Porrata
Journal: Journal of Clinical Oncology (2013)

7041 Background: Prognostic factors for diffuse large B-cell lymphoma (DLBCL) at day 100 post-autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT) have not been evaluated. We previously reported that absolute monocyte (AMC)/lymphocyte count (ALC) prognostic score (AMLCPS) at diagnosis of DLBCL patients is a prognostic factor of survival, stratifying patients into three risk groups: low- (AMC&lt;630/μL and ALC&gt;1000/μL), intermediate- (AMC ≥ 630/μL or ALC ≤ 1000/μL) and high-risk (AMC ≥ 630/μL and ALC ≤ 1000/μL) (Leukemia 25: 1502-9, 2011). Therefore, we evaluated day 100 AMLCPS as a prognostic factor of survival by landmark analysis from day 100 post-APBHSCT in DLBCL patients. Methods: DLBCL patients that achieved complete response by day 100 post-APBHSCT qualified for the study. From 2000 to 2007, 134 consecutive DLBCL patients were evaluated. Overall survival (OS) and progression free survival (PFS) were calculated using Kaplan-Meier analysis. Results: The median follow up from day 100 for the cohort was 5.5 years (range: 0.17-12.17 years) and for living patients (N=93) was 6.9 years (range: 2.5-12.17 years). Day 100 AMLCPS was able to stratify patients into three risk groups low-, intermediate-, and high-risk for OS [low: median OS = not reached, 5-year survival rate = 94% (95%CI 83.3%-98.1%); intermediate: median OS = not reached, 5-year survival rate = 70% (95%CI 58.0%-79.8%); high: median OS = 2.2 years, 5-year survival rate = 13% (95%CI 3.4%-40.5%); p&lt;0.0001] and PFS [low: median PFS = not reached, 5-year progression free rate = 87% (95%CI 74.5%-94.3%); intermediate: median PFS = 10.9 years, 5-year progression free rate = 67% (95%CI 55.4%-77.5%); high: median PFS = 1 year, 5-year progression free rate = 13% (95%CI 3.4%-40.5%); p&lt;0.0001]. The day 100 AMLCPS was balanced in relation to the International Prognostic Index (IPI; p=0.22), infused CD34+ stem cells (p=0.92), and disease status pre-APBHSCT (complete remission versus partial response; p=0.11). Conclusions: The day 100 AMLCPS is a simple biomarker that can help identify DLBCL patients post-APBHSCT with poor clinical outcomes.
Phase II study of capecitabine as palliative treatment for patients (p) with squamous head and neck cancer (HNC) with locoregional and/or metastatic relapse after previous platinum-based treatment (PBT): Final results of Spanish Head and Neck Cancer Group (TTCC)
Authors: J. Martinez-Trufero, D. Isla, J. C. Adansa, A. Irigoyen, R. Hitt, J. Lambea, J. J. Cruz
Journal: Journal of Clinical Oncology (2009)

6047 Background: PBT is widely used as first line treatment in relapsed and/or metastatic HNC. Therefore, new non-platinum drugs need to be asses as second line treatment options. We proposed this study to evaluate activity and tolerability of capecitabine (X) when used as palliative monotherapy for relapsed HNC p previously treated with PBT. Methods: Forty patients (p) aged 18–75 years, ECOG PS 0–2, with advanced squamous HNC with locoregional and/or metastatic relapse previously treated with PBT and adequate bone marrow, renal and hepatic functions were included. X (1,250 mg/m 2 BID) during 14 days was administered every 21 days, for at least 2 cycles. RECIST objective response rate (ORR) was assessed and toxicity following NCI-CTC v2 criteria. Results: Forty patients with median age 58 years old, all of them male, ECOG 0–2 (0:25%/1:70%/2:5%) and with squamous HNC, were analyzed. 34 p had local disease, 9 p regional disease and 19 p distant metastases(12 p lung). Median time since HNC diagnosis was 17.7 months and since disease extension diagnosis, 1.1 months. All p received a total of 169 cycles of X (median 4, range 1–9) and the median relative dose intensity was 91%. 7 p were not evaluable for response, since they do not receive at least 3 cycles ( 3 died, 2p due to toxicity, 2p due to decrease in ECOG PS ). ORR was 22.5 %.The median follow-up time was 5.2 months (alive p: 8.8 months), median TTP was 4.6 months and median OS was 6.2 months. Hematological toxicity G3/4 was reported in 6 p. 2p reported as grade 4 non-hematological toxicity: dysphagia and palmar-plantar erythrodysesthesia; grade III toxicities were: asthenia (4 p), anorexia (1 p), dehydratation (1 p), diarrhea (3 p), dysphagia (3 p) mucositis (4 p), weight loss (1 p), and palmar-plantar erythrodysesthesia (3 p). The most common grade II toxicity was asthenia (8 p). Conclusions: Capecitabine seems to be an active, feasible and well tolerated palliative treatment for advanced HNC patients that have previously received platinum-based schedules. No significant financial relationships to disclose.
Long non-coding RNA HSAT II as a new biomarker for the identification of high risk intraductal papillary mucinous neoplasms (IPMNs).
Authors: Francesco Pantano, Giuseppe Perrone, Bruno Vincenzi, Michele Iuliani, Marco Fioramonti, Alice Zoccoli, Giulia Ribelli, Domenico Borzomati, Gennaro Nappo, Claudio Pellegrini, Michelina Maria Amato, Daniela Righi, Francesco Maria Di Matteo, Lucio Trodella, Daniele Santini, Roberto Coppola, Andrea Onetti-Muda, Giuseppe Tonini
Journal: Journal of Clinical Oncology (2015)

e15246 Background: Satellite repeat RNAs HSAT II belongs to an heterogeneous group of non-coding transcripts, namely long non-coding RNAs. HSAT II transcripts, recently found in pancreatic ductal adenocarcinoma (PDAC), reflect global alterations in heterochromatin silencing and could potentially useful in tracking malignant progression in IPMNs. Methods: We retrospectively evaluated 37 patients (median age 69y, range: 43y-83y) with histological diagnosis of IPMN (2010-2013) obtained from Pathology Departments of Campus Bio-Medico University, Rome. 19 were associated with PDAC, 8 with biliary tract cancer, 2 with colloid adenocarcinoma, 1 with neuroendocrine tumor, 1 with ampullary adenocarcinoma (intestinal-histotype). In 6 cases, IPMN was not associated with invasive carcinoma. Patients were divided into: low (n = 15), moderate (n = 13) and severe grade dysplasia (n = 9) IPMN. For statistical analysis (Fischer exact test), moderate and severe grade dysplasia were grouped as high grade dysplasia. A semiquantitative evaluation of HSAT II status was made using RNA in situ hybridization (QuantiGene ViewRNA Assays, Affymetrix). The sections underwent RNA-ISH were compared with consecutive section stained in H&E. HSAT II expression were classified in: score 0, no staining; score 1, faint staining; score 2, moderate staining and score 3, intense staining. Invasive neoplastic tissue was used as positive control while normal pancreatic duct epithelia as negative control. Results: Normal pancreatic ducts resulted negative for HSAT II expression. Significant positive correlation between grade of dysplasia and HSAT II expression was found. High HSAT II levels were identified in 20% (3/15) of low grade IPMN and in 86% (19/22) of high grade IPMN lesions (p < 0.001) (RR: 5.867; 95% CI: 1.989 to 17.31). The sensitivity and specificity of HSAT II expression for high grade IPMNs were 80% and 86%, respectively. Positive correlation between HSATII transcript level and association with PDAC was also found (p = 0.038). Conclusions: High HSAT II expression is strongly associated with malignant progression in IPMN acting as a totally new biomarker useful for the identification of high-risk disease.
Association of serum (SR) and tissue (TX) abiraterone (ABI) levels with intraprostatic steroids and pathologic outcomes in men with high-risk localized prostate cancer (PCa).
Authors: Elahe A. Mostaghel, Brett Marck, Alvin M. Matsumoto, Daniel Tamae, Trevor M. Penning, Steven P. Balk, Philip W. Kantoff, Peter Nelson, Mary-Ellen Taplin, Robert B. Montgomery
Journal: Journal of Clinical Oncology (2014)

5015^ Background: Factors influencing efficacy of ABI in suppressing SR and TX androgens and inhibiting tumor growth in PCa are unknown. We examined the relationship of SR and TX ABI levels with SR and TX steroid levels and pathologic responses. Methods: Steroid and ABI levels were measured by mass spectrometry in SR and TX from 58 men with localized PCa in a clinical trial of castration with 3 or 6 months (mo) of ABI prior to prostatectomy. Results: Median ABI levels in SR and TX were 31 ng/ml (range 2.8-414) and 18 pg/mg (1.3-265) respectively. SR and TX ABI levels were positively correlated with SR and TX steroids upstream of CYP17A (pregnenolone [Preg], progesterone [Prog]) and inversely correlated with downstream steroids (17OH Preg, DHEA, all p<0.05). Two men at 3 mo and six at 6 mo had undetectable ABI in SR and TX, and did not show changes in steroids up or downstream of CYP17A. In men with undetectable vs detectable TX ABI levels, there was a trend toward higher cross-sectional tumor dimension, TX cellularity, tumor PSA staining and SR PSA (all p<0.10). TX ABI levels were significantly lower at 6 vs 3 mo (7.8 vs 62 pg/mg, p<0.001) while SR ABI levels were similar. At 3 mo 0/25 men had TX dihydrotestosterone (DHT) levels >1 (range 0.08-0.57 pg/mg), while at 6 mo 22% (10/46) had TX DHT >1 (1-17 pg/ml). At 3 mo TX Preg was strongly correlated with TX DHEA, while DHT was correlated with androstenedione (AED) and testosterone (T) (r>0.5, all p<0.01). At 6 mo the intraprostatic correlations of up- and downstream steroids were markedly increased (r>0.5 for TX Preg with downstream DHEA, AED, T and DHT; and for TX DHT with upstream T, AED, DHEA and Preg, all p<0.01). Conclusions: Prostate TX ABI levels are associated with TX steroids and pathologic responses in localized PCa. At 6 mo TX ABI levels decreased nearly 10-fold vs 3 mo (despite stable SR ABI levels), DHT levels markedly increased in >20% of samples, and intraprostatic correlations of DHT with steroids upstream of CYP17A inhibition became highly significant. These findings suggest that potential mechanisms of ABI resistance are induction of drug export or metabolism, and intraprostatic conversion of upstream precursors to DHT. Clinical trial information: NCT00924469.
Circulating tumor cells expressing the insulin growth factor-1 receptor (IGF-1R): Method of detection, incidence and potential applications
Authors: J. S. de Bono, A. Adjei, G. Attard, M. Pollak, P. Fong, P. Haluska, L. Roberts, D. Chainese, L. Terstappen, A. Gualberto
Journal: Journal of Clinical Oncology (2007)

3507 Purpose: To detect IGF-1R on circulating tumor cells (CTCs) as a biomarker in the clinical development of a monoclonal human antibody, CP-751,871, targeting IGF-1R. Experimental Design: An automated sample preparation and analysis system for enumerating CTCs (Celltracks) was adapted for detecting IGF-1R positive CTCs with a diagnostic antibody targeting a different IGF-1R epitope to CP-751,871. This assay was utilized in three phase I trials of CP-751,871 as a single agent or with chemotherapy and was validated using cell lines and blood samples from healthy volunteers and patients with metastatic carcinoma. Results: There was no interference between the analytical and therapeutic antibodies. CP-751,871 was well tolerated as a single agent, and in combination with docetaxel or carboplatin and paclitaxel, at doses ranging from 0.05 mg/kg to 20 mg/kg. Eighty patients were enrolled on phase 1 studies of CP-751,871, with 47 (59%) patients having CTCs detected during the study. Prior to treatment 26 patients (33%) had CTCs, with 23 having detectable IGF-1R positive CTCs. CP-751,871 alone, and CP-751,871 with cytotoxic chemotherapy, decreased CTCs and IGF-1R positive CTCs; these increased towards the end of the 21-day cycle in some patients, falling again with retreatment. CTCs were commonest in advanced hormone refractory prostate cancer (11/20). Detectable IGF-1R expression on CTCs before treatment with CP-751,871 and docetaxel was associated with a higher frequency of PSA decline by more than 50% (6/10 vs 2/8 patients). A relationship was observed between sustained falls in CTCs counts and PSA declines by more than 50%. Conclusions: IGF-1R expression is detectable by immunofluorescence on CTCs. These data support the further evaluation of CTCs in pharmacodynamic studies and patient selection, particularly in advanced prostate cancer. No significant financial relationships to disclose.
PI3K pathway (PI3Kp) dysregulation and response to pan-PI3K/AKT/mTOR/dual PI3K-mTOR inhibitors (PI3Kpi) in metastatic breast cancer (MBC) patients (pts).
Authors: Mafalda Oliveira, Alejandro Navarro, Leticia De Mattos-Arruda, Gessamí Sánchez-Ollé, Meritxell Bellet, Judith Balmaña, Patricia Gómez-Pardo, Jose Manuel Perez-Garcia, Eva Muñoz-Couselo, Maria Vidal, Vanessa Ortega, Rodrigo Dienstmann, Claudia Aura, Ludmilla Prudkin, Ana Vivancos, Jordi Rodon Ahnert, José Baselga, Josep Tabernero, Javier Cortes, Cristina Saura
Journal: Journal of Clinical Oncology (2012)

509 Background: The role of PI3Kp dysregulation as a predictor of sensitivity to PI3Kpi is unclear. We aimed to evaluate the efficacy of PI3Kpi in two cohorts of MBC pts with assessable PI3Kp status. Methods: MBC pts treated in ≥3 rd line with PI3Kpi were reviewed. PI3Kp status: (a) No dysregulation: PIK3CA wt and PTEN normal; (b) PI3Kp dysregulation: PIK3CA mutation (PIK3CAmut) or PTEN low (HScore≤50). Cohort A: pts treated with single agent PI3Kpi. Cohort B: pts treated with PI3Kpi in combination with hormonal therapy (HT), chemotherapy (CT) and/or trastuzumab (T). Results: Out of 232 MBC pts screened for PI3Kp alterations from Sep09 to Sep11, 32 were treated with PI3Kpi. Cohort A (n=17): HR+/HER2- 88%, HER2+ 6%, triple negative 6%; median age 43, median MBC lines 4 (2-9); PIK3CAmut in 10/17 (58.8%; 6 exon9, 4 exon20), PTEN low 3/17 (17.6%), 1 pt both; PI3Kp dysregulation 12/17 pts. Cohort B (n=15): HR+/HER2- 40%, HER2+ 60%; median age 49, median MBC lines 4 (2-13); PIK3CAmut 3/13 assessable (23.1%; all exon20), PTEN low 6/15 (40%), 1 pt both; PI3Kp dysregulation 8/15 pts. Time to progression to PI3Kpi (TTP), overall survival from MBC diagnosis (OSMBC) and OS from PI3Kpi beginning (OSPI3Kpi), according to PIK3CA status and PI3Kp dysregulation, are shown. No differences were found according to PTEN status. Conclusions: These results suggest that the best outcomes with PI3Kpi in PIK3CAmut MBC pts occur when they are used in combination with HT/CT/T. Activity of non selective PI3Kpi used as single agents seems to be limited, making results from prospective trials with selective PI3Kα inhibitors and PI3Kpi in combinations eagerly awaited. [Table: see text]
Markers of angiogenesis and hypoxia to cell of origin (COO) subtypes of DLBCL: Correlative studies from S0515, a phase II trial of R-CHOP plus bevacizumab.
Authors: Ambuga R. Badari, Mohammad Abu Zaid, Joseph M. Unger, Lisa M. Rimsza, Marilyn Marron, Richard I. Fisher, Thomas P. Miller, Alison Stopeck
Journal: Journal of Clinical Oncology (2013)

8562 Background: S0515 was a nonrandomized phase 2 trial of R-CHOP + bevacizumab in 64 patients with newly diagnosed DLBCL. No significant improvement in PFS or OS was observed compared with historic controls.Patients with higher baseline levels of plasma VCAM and urine VEGF had worse PFS and OS. Tumor-associated carbonic anhydrase, CA IX, is induced by hypoxia in various tumors and part of the hypoxia inducible factor -1/ hypoxia responsive element (HIF-1/HRE) system. We present additional correlative studies from S0515 including longitudinal plasma CAIX levels, and correlate expression of VEGF and VEGF receptors (VEGFR) to COO subtype [GCB vs. non-GCB] and urine VEGF and plasma VCAM. Methods: COO subtypes were determined by immunohistochemistry (IHC) using the Hans classification. VEGF and VEGFR expression was determined by IHC and scored on a scale of 0 (none) to +3 (strong). Plasma VCAM, CAIX, urine VEGF levels were measured by ELISA and samples collected at baseline and before cycles 4 and 8 of therapy. Results: Baseline CAIX levels did not predict PFS (p = 0.95) or OS (p=.66) or change with therapy. Patients with lower baseline CAIX levels (below the median) had a statistically significant increase in CAIX over the course of therapy (median 34.1 to 52.4, p=.002), whereas in patients with higher baseline CAIX, levels decreased (median 96.7 to 78.2, p=.20). CAIX correlated with plasma VCAM (P=.006), but not COO subtype. 33 lymphoma samples were classified as GCB (n = 21) or non-GCB (n=12). COO subtype did not predict difference in PFS (p=.56) or OS (p=.67). Median urine VEGF and plasma VEGF levels trended higher in non-GCB vs GCB tumors (181 vs 144pg/mL and 1499 and 821ng/mL, respectively). Lymphoma expression of VEGF did not correlate with plasma VCAM or urine VEGF. VEGR2 expression was higher in non-GCB vs GCB tumors (33% vs 5% expression). Conclusions: Plasma CAIX levels, a marker of hypoxia and HIF1alpha activation, increased only in those patients with lower baseline levels in response to therapy. COO by IHC did not predict PFS or OS. However, non-GCB tumors had higher expression of VEGFR2, plasma VCAM, and urine VEGF compared to GCB tumors consistent with increased angiogenesis. Clinical trial information: SWOG S-0515.