tbuckley/cabot-search huggingface dataset:
Borealis-2: A randomized phase II study of OGX-427 (apatorsen) plus docetaxel versus docetaxel alone in platinum-resistant metastatic urothelial cancer (mUC) (Hoosier Cancer Research Network GU12-160).
Authors: Toni K. Choueiri, Noah M. Hahn, Lillian Werner, Meredith M. Regan, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2017)

289 Background: OGX-427 (apatorsen; A) is an antisense oligonucleotide that binds Heat shock protein 27 (Hsp27) mRNA with synergistic effect with chemotherapy. Borealis-2 is a randomized multicenter phase 2 study of A in combination with docetaxel (D) vs. D alone in advanced UC patients (pts) after at least 1 prior platinum-based therapy. Methods: The primary objective was to determine whether D+A prolonged overall survival (OS) vs D. Patients were stratified (time from prior systemic chemotherapy; Bellmunt criteria) and randomized in a 1:1 ratio. D was administered for up to 10 cycles in both arms. OGX-427 maintenance continued in pts with no disease progression. Secondary objectives included safety, objective response, and serum levels of Hsp27. The trial design provided 90% power to detect a 33% decrease in OS hazard (hazard ratio [HR] = 0.667), with one-sided α = 0.10 after 162 deaths, and one interim futility analysis; a p-value &lt; 0.1 would result in a positive study for the primary endpoint. Results: 200 pts were randomized between 8/2013 and 9/2015. 72.5% had 1-3 Bellmunt risk factors and 43.5% were &lt; 3mos from prior chemotherapy. 163 pts had died (77 A+D; 86 D) at final analysis. The A+D group had a statistically-significant reduction in hazard for death vs. D (HR = 0.80; 80% CI, 0.65 to 0.98; one-sided P = 0.08). For A+D, median OS was 6.4 mos (95%CI 4.6-9.2) and 12-mo OS was 34.4% (95% CI 25.1-43.9). For D, median OS was 5.9 mos (95%CI 4.8-7.3) and 12-mo OS was 25.0% (95%CI 17.0-33.8). All causality grade 3 or higher toxicities were similar between A+D group (82%; 95%CI 73%-89%) and the D group (75%; 95%CI 65%-83%). The treatment effect of pts with baseline serum Hsp27 &lt; 5.7ng/mL (median) vs. Hsp27 ≥ 5.7ng/mL was not different (2-sided p = 0.87 for interaction). Conclusions: In this platinum-pretreated population of advanced UC, adding OGX-427 to D provided a statistically significant improvement in OS and is worthy of further investigation in previously treated metastatic UC pts. Clinical trial information: NCT01780545.
Outcome of Lower-Risk Patients With Myelodysplastic Syndromes Without 5q Deletion After Failure of Erythropoiesis-Stimulating Agents
Authors: Sophie Park, Jean-François Hamel, Andrea Toma, Charikleia Kelaidi, Sylvain Thépot, Maria Diez Campelo, Valeria Santini, Mikkael A. Sekeres, Enrico Balleari, Jennifer Kaivers, Rosa Sapena, Katharina Götze, Catharina Müller-Thomas, Odile Beyne-Rauzy, Aspasia Stamatoullas, Ioannis Kotsianidis, Rami Komrokji, David P. Steensma, Jaime Fensterl, Gail J. Roboz, Teresa Bernal, Fernando Ramos, Marisa Calabuig, Agnès Guerci-Bresler, Dominique Bordessoule, Pascale Cony-Makhoul, Stéphane Cheze, Eric Wattel, Christian Rose, Norbert Vey, Daniela Gioia, Dario Ferrero, Gianluca Gaidano, Giovanni Cametti, Fabrizio Pane, Alessandro Sanna, Ulrich Germing, Guillermo F. Sanz, François Dreyfus, Pierre Fenaux
Journal: Journal of Clinical Oncology (2017)

Purpose Most anemic patients with non-deleted 5q lower-risk myelodysplastic syndromes (MDS) are treated with erythropoiesis-stimulating agents (ESAs), with a response rate of approximately 50%. Second-line treatments, including hypomethylating agents (HMAs), lenalidomide (LEN), and investigational drugs, may be used after ESA failure in some countries, but their effect on disease progression and overall survival (OS) is unknown. Here, we analyzed outcome after ESA failure and the effect of second-line treatments. Patients and Methods We examined an international retrospective cohort of 1,698 patients with non-del(5q) lower-risk MDS treated with ESAs. Results Erythroid response to ESAs was 61.5%, and median response duration was 17 months. Of 1,147 patients experiencing ESA failure, 653 experienced primary failure and 494 experienced relapse after a response. Primary failure of ESAs was associated with a higher risk of acute myeloid leukemia (AML) progression, which did not translate into an OS difference. Of 450 patients (39%) who received second-line treatment, 194 received HMAs, 148 received LEN, and 108 received other treatments (MISC), whereas 697 received RBC transfusions only. Five-year AML cumulative incidence was 20.3%, 20.3%, and 11.3% for those receiving HMAs, LEN, and MISC, respectively ( P = .05). Five-year OS for patients receiving HMA, LEN, and MISC was 36.5%, 41.7%, and 51%, respectively ( P = .21). In a multivariable analysis adjusted for age, sex, revised International Prognostic Scoring System score, and progression at ESA failure, there was no significant OS difference among the three groups. Conclusion In this large, multicenter, retrospective cohort of patients with non-del(5q) lower-risk MDS treated with ESAs, none of the most commonly used second-line treatments (HMA and LEN) significantly improved OS. Early failure of ESAs was associated with a higher risk of AML progression.
Physiological evidence of DNA damage by carcinogens known to be present in charred and processed meats (PhIP DNA adducts) in a small cohort of patients with prostate cancer.
Authors: Christopher J. Weight, Shun Xiao, Jingshu Guo, Byeong Hwa, Peter Villalta, Resha Tejpaul, Suprita Krishna, Paari Murugan, Robert Turesky
Journal: Journal of Clinical Oncology (2017)

e580 Background: Epidemiologic studies have reported an association between frequent consumption of well-done cooked meats and prostate cancer (PC) risk. Charred red meat and cooked processed meats are known to contain heterocyclic aromatic amine (HAA) carcinogens, such as 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) the most mass abundant HAA, and are linked to PC development in a rodent model. However, unambiguous physiochemical markers of DNA damage from these meat-derived carcinogens have not been identified in human samples to support the paradigm of HAA induced human prostate carcinogenesis. Methods: Thirty-five men with biopsy proven intermediate to high-risk PC underwent radical prostatectomy at University of Minnesota from Dec 2015-Aug 2016. After prostatectomy, both tumor bearing tissue and non-tumor bearing adjacent fresh tissue was analyzed for DNA adducts using a highly sensitive nano-LC-Orbitrap mass spectrometry method. We also analyzed formalin fixed paraffin embedded (FFPE) tissues from each patient. Results: Median age of the men with PC was 65 (range 45-78). Pathology demonstrated the following Gleason Scores (GS) and pathologic staging: GS = 6 in 1 patient (2.8%), GS = 7 in 28 patients (80%) and GS = 8-10 in 6 patients (17%) and 16 men (46%) were stage 2 and 19 men were stage 3 (54%). The PhIP DNA adduct was identified in 11 out of 35 patients, at levels ranging from 2 to 120 adducts per 10 9 nucleotides. PhIP DNA adducts also were recovered quantitatively from FFPE tissues. Conclusions: Our data provide support to the epidemiological observations implicating PhIP as a DNA damaging agent that may contribute to the etiology of PC in humans. FFPE tissues can be used as a tissue source in DNA-adduct biomarker research using our mass spectrometry method
Role of FDG-PET as predictive biomarker of pathologic complete response (pCR) in locally advanced rectal cancer (LARC) treated with capecitabine-based neoadjuvant chemoradiation (NACR).
Authors: Filippo Pietrantonio, Maria Di Bartolomeo, Chiara Bampo, Francesca Valvo, Alessandra Alessi, Flavio Crippa, Pamela Biondani, Ermanno Leo, Massimo Milione, Katia F Dotti, Simona Fantini, Barbara Avuzzi, Barbara Formisano, Luigi Battaglia, Chiara Chiruzzi, Filippo G. De Braud
Journal: Journal of Clinical Oncology (2012)

e21118 Background: A favourable outcome is associated with pCR in LARC treated with NACR; pCR prediction through functional imaging may help the prospective evaluation of management strategies alternative to standard surgery. The aim of this prospective study was to identify whether FDG-PET activity and early/late response predicted independently pCR. Methods: Patients with histologically diagnosed cT3-4 and/or N+ primary rectal cancer were treated homogeneously with NACR (simultaneous boost technique radiotherapy 54 Gy on GTV/24 fractions plus capecitabine 1650 mg/mq/day) and total mesorectal excision 7-8 weeks later. FDG-PET uptake, expressed as maximum standardized uptake value, was obtained at baseline (SUV-1), at interim (2 weeks after treatment start: SUV-2) and 6 weeks after NARC completion (SUV-3) and was calculated as percentage difference (Δ-SUV). The role of SUV-1, SUV-2, SUV-3, Δ-SUV(1-2) and Δ-SUV(1-3) for pCR prediction was assessed using logistic regression analysis; ROC analysis was performed to identify the optimal thresholds. Results: The study enrolled 30 pts (median age 59 yrs; 12M:18F) treated from January 2009 to November 2011 at Istituto Nazionale Tumori of Milan. All underwent FDG-PET at baseline and post-NACR and 80% consented to an interim assessment; one patient was excluded due to surgery refusal. pCR rate was 28%. Among all parameters, only post-NACR SUV (mean 4 +/- 1.7 for pCR vs 8.7 +/-5.8 for non-pCR; P=0.001 by Mann-Whitney test) showed significant association with pCR at univariate analysis (P=0.03). At multivariate analysis including baseline SUV, post-NACR SUV, Δ-SUV, age (≤ or &gt;65 yrs), sex (F or M) and pre-treatment stage (N- or N+/cT3 or cT4), only female sex and post-NACR SUV predicted independently pCR (both P=0.01). With ROC analysis, a post-NACR SUV threshold &lt;5.5 had 88% sensitivity and 81% specificity, with 83% overall accuracy. Conclusions: The SUV cut-off of 5.5, explained by inflammatory modifications, could limit the applicability in clinical practice assuming values ≤2.5 for negativity. However, FDG-PET SUV post-NACR may serve as useful predictive biomarker in LARC.
HER2 extracellular domain (ECD) and HER2 single nucleotide polymorphisms (SNPs) in patients treated with combination trastuzumab, lapatinib, and bevacizumab.
Authors: Mei Huang, Kristin L. Parkhurst, Yunfang Jiang, Stacy L. Moulder, Aung Naing, Jennifer J. Wheler, David S. Hong, Sarina Anne Piha-Paul, Siqing Fu, Apostolia Maria Tsimberidou, Ralph Zinner, Filip Janku, Razelle Kurzrock, Gerald Steven Falchook
Journal: Journal of Clinical Oncology (2014)

e22082 Background: Biomarkers associated with efficacy of HER2-directed treatments are lacking. We evaluated HER2 ECD levels and HER2 SNPs in patients treated on a clinical trial of combination trastuzumab, lapatinib, and bevacizumab. Methods: Plasma samples were obtained at baseline, 24-48 hrs post-dose, and end of cycle 1. Plasma circulating HER2 ECD was determined using ELISA, and 5 ng/mL was the defined upper limit of normal. HER2 SNPs were analyzed from genomic DNA from PBMCs for five annotated SNPs in the HER2 gene (-3444C>T, -1985 G>T, I655A A>G, P1170A C>G, rs1810132 STR C>T) using Sanger sequencing. Clinical response was defined as stable disease ≥6 months or partial response (SD≥6 months/PR). HER2 ECD levels and percent change at baseline, 24-48 hrs, and end of cycle 1 were compared for responders vs. non-responders. Response rate (RR) and time to treatment failure (TTF) were compared for patients with baseline HER2 ECD levels >5 ng/mL vs. ≤5 ng/mL. RR and TTF were also analyzed for each of the five HER2 SNPs. Results: HER2ECD levels were evaluated in 75 patients, and HER2 SNPs were evaluated in 56 patients. A significant difference was observed between baseline HER2 ECD levels of responders (SD≥6 months/PR) (n=20) and nonresponders (n=55) (59 ng/mL vs. 10 ng/mL, p=0.005). In addition, a significant difference was observed in percent decrease of HER2 ECD levels at 24-48hrs between responders and nonresponders (93% vs. 82%, p=0.049). In contrast, no significant difference was observed in HER2 ECD levels or percent change at end of cycle 1 between responders and nonresponders. RR was higher in patients with elevated baseline HER2 ECD (>5 ng/mL) (n=25) vs. normal baseline HER2 ECD (≤5 ng/mL) (n=50) (p=0.003). TTF was also longer in patients with elevated baseline HER2 ECD (>5 ng/mL) vs. normal baseline HER2 ECD (≤5 ng/mL) (p=0.038). No significant difference in RR or TTF was observed when compared with each of the five HER2 SNPs. Conclusions: RR and TTF correlated with elevated baseline HER2 ECD levels but did not correlate with HER2 SNPs in patients treated with combination trastuzumab, lapatinib, and bevacizumab. Clinical trial information: 00543504.
A phase III study of the impact of a physical activity program on disease-free survival in patients with high-risk stage II or stage III colon cancer: A randomized controlled trial (NCIC CTG CO.21).
Authors: Christopher M. Booth, Kerry S. Courneya, Janette L. Vardy, Derek J. Jonker, Sharlene Gill, Michael Brundage, Hidde van der Ploeg, Haryana M. Dhillon, Patti O'Brien, Emma Goddard, Michael N. Pollak, Christine Friedenreich, Dongsheng Tu, Rebecca Wong, Ralph M. Meyer
Journal: Journal of Clinical Oncology (2013)

TPS3647 Background: Observational data indicate that physical activity (PA) is strongly associated with colon-cancer specific survival. NCIC CTG CO.21 (CHALLENGE) is designed to determine the effects of a structured PA intervention on disease-control outcomes for survivors of high-risk stage II or III colon cancer who have completed adjuvant chemotherapy within the previous 2-6 months. Methods: Phase III randomized controlled trial. Target sample size of 962 patients is powered to detect a Hazard Ratio of 0.75 for disease-free survival (DFS). Trial participants will be stratified by centre, disease stage, body mass index, and performance status, and will be randomly assigned to a structured, individualized PA intervention or to general health education materials. The PA intervention will consist of a behavioural support program and supervised PA sessions delivered over a 3-year period, beginning with regular face-to-face sessions and tapering to less frequent face-to-face or telephone sessions. The goal of the PA program is to increase weekly PA by 10 MET hours/week. The PA program is delivered by physical activity consultants trained in exercise physiology and behavior change. Outcomes: The primary endpoint is DFS. Important secondary endpoints include multiple patient-reported outcomes (including those that address fatigue), objective physical functioning, biologic correlative markers (including assessment of the insulin pathway), and an economic analysis. Current Enrollment: The study is open at 19 centers in Canada and 20 centers in Australia. Accrual as of February 4, 2013 includes 212 registered and 184 randomized patients. Summary: Cancer survivors and cancer care professionals are interested in the potential role of PA to improve multiple disease-related outcomes, but a randomized controlled trial is needed to provide compelling evidence to justify changes in health care policies and practice. Clinical trial information: NCT00819208.
Genetic polymorphisms to predict progression-free survival in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone therapy: Results from the NCI 9012 trial.
Authors: Costantine Albany, Stephanie Daignault-Newton, Todd C Skaar, Joseph Ipe, Javed Siddiqui, Przemyslaw Twardowski, Mark N. Stein, Lakshmi Priya Kunju, Arul M. Chinnaiyan, Robert B. Montgomery, Emmanuel S. Antonarakis, Daniel H. Shevrin, Young E. Whang, Megan Veresh Caram, David C. Smith, Felix Yi-Chung Feng, Walter Michael Stadler, Maha Hussain
Journal: Journal of Clinical Oncology (2017)

145 Background: Abiraterone is a CYP17 inhibitor approved for treatment of men with mCRPC. The NCI 9012 trial evaluated abiraterone alone with or without the PARP inhibitor veliparib in mCRPC patients. We hypothesized that germline genetic variation in the androgen axis and other metabolic enzymes would predict response to veliparib + abiraterone vs. abiraterone alone. Methods: A randomized trial cohort of (148) men with advanced mCRPC treated with abiraterone with or without veliparib was genotyped for 120 DNA polymorphisms in genes involved in androgen metabolism using Lifetech Open array chips. Blood for pharmacogenomic SNP analysis were collected at pre-treatment from each subject into 10-mL EDTA tube. Polymorphisms were tested using Cox models without treatment for prognostic testing and with treatment arm for predictive testing. Results: Genotyping was completed in 143 of 148 men; all were treated with abiraterone; 72 without veliparib (Median PFS: 10.3m) and 71 with veliparib (Median PFS: 11.3m). Polymorphisms in separate genes (SLCO2B1, KIF3C CYP19A, ESR1) were significantly (P ≤ .025) associated with progression-free survival (PFS) during abiraterone (q-value &lt; 0.69). Polymorphisms in (CYP11A1, HSD17B4, ABHD13;LIG4, CYP19A1, HSD17B4, TRMT11) were predictive for PFS in patients treated with combination of abiraterone/veliparib compared to abiraterone alone (p-value &lt; 0.025; q-value &lt; 0.28). Conclusions: This analysis examines the influence of inherited variations on the efficacy of abiraterone, establishing the importance of pharmacogenomics on individual’s response to this therapy. Genotyping patients at these loci could be predictive of improved PFS to valiparib in combination with abiraterone. Further analysis of the association of more than one polymorphisms compared to zero or one with PFS associated with improved TTP demonstrated a better response to therapy than individuals carrying zero or one is ongoing. Clinical trial information: NCT01576172.
VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer
Authors: Jianjun Gao, John F Ward, Curtis A Pettaway, Lewis Z Shi, Sumit K Subudhi, Luis M Vence, Hao Zhao, Jianfeng Chen, Hong Chen, Eleni Efstathiou, Patricia Troncoso, James P Allison, Christopher J Logothetis, Ignacio I Wistuba, Manuel A Sepulveda, Jingjing Sun, Jennifer Wargo, Jorge Blando, Padmanee Sharma
Journal: Nature Medicine (2017)
PTEN assessment and PI3K/mTOR inhibitors: Importance of simultaneous assessment of MAPK pathway aberrations.
Authors: Filip Janku, Russell Broaddus, Rania Bakkar, David S. Hong, Vanda M.T. Stepanek, Aung Naing, Gerald Steven Falchook, Siqing Fu, Jennifer J. Wheler, Sarina Anne Piha-Paul, Stacy L. Moulder, Rajyalakshmi Luthra, Apostolia Maria Tsimberidou, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2012)

10510 Background: Loss of PTEN function increases PI3K/mTOR signaling. Preclinical data suggest that PTEN aberrations can predict sensitivity to drugs targeting the PI3K/mTOR pathway. Methods: Tumors from 461 patients with diverse cancers referred to the Clinical Center for Targeted Therapy were tested for cytoplasmic immunohistochemical expression of PTEN using the following scoring system: negative (no staining); positive (intact staining); reduced staining, with stroma serving as an internal positive control. Whenever possible, tumors were also tested for mutations in the MAPK pathway (KRAS, NRAS, and BRAF). We analyzed outcomes of patients treated with PI3K /mTOR with respect to their PTEN status. Results: Of 461 patients, 47 (10%) had negative PTEN expression, 168 (36.5%) had positive PTEN expression, and 246 (53.5%) had reduced PTEN. In tumor types with &gt;10 patients tested, negative PTEN was most frequent in uterine (10/33, 33%), renal (3/11, 27%), salivary gland (2/10, 20%), colorectal (15/82, 18%), breast (2/15, 13%), pancreatobiliary (3/24, 13%), and prostate cancers (2/19, 11%). Of 206 patients tested for MAPK (KRAS, NRAS, and BRAF) pathway mutations, patients with either negative or reduced PTEN had more MAPK mutations than patients with positive PTEN expression (72/144, 50% vs. 20/62, 32%, p=0.02). A total of 153 (33%) patients received therapies with PI3K /mTOR inhibitors and 17 (11%, 95% CI 0.07-0.17) achieved a partial response (PR). Proportions of PRs were 2/13 (15%) for PTEN negative, 3/50 (6%) for PTEN positive, and 12/90 (13%) for reduced PTEN. There was no significant difference in PR rate amongst patients with positive PTEN expression compared to patients with negative or reduced PTEN (3/50, 6% vs. 14/103, 14%; p=0.27). Conclusions: Complete loss of PTEN expression was found in 10% of patients. Positive PTEN expression was found in 36.5% of patients. PTEN status did not predict response to PI3K/mTOR inhibitors, perhaps because patients with negative and reduced PTEN expression had a higher incidence of simultaneous MAPK (KRAS, NRAS, BRAF) mutations.
Biomarker validation study: Genes involved in ubiquitin proteasome system (UPS) dependent EGFR-degradation for prediction of efficacy in metastatic colorectal cancer patients treated with cetuximab.
Authors: Sebastian Stintzing, Stefan Stremitzer, Volker Heinemann, Alfredo Falcone, Fotios Loupakis, Chiara Cremolini, Carlotta Antoniotti, Yu Sunakawa, Satoshi Matsusaka, Shinichi Yamauchi, Wu Zhang, Dongyun Yang, Yan Ning, Ana Sebio, Diana L. Hanna, Saadat Siamak, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2014)

3571 Background: Epidermal growth factor receptor (EGFR) turnover is a highly regulated process controlling the amount of receptor proteins available for antibody binding. The ubiquitin proteasome system (UPS) is responsible for EGFR degradation. The single nucleotide polymorphism (SNP) rs895374 is located in UbcH7, an E2 ligase conducting neddylation of HECT E3 ligases involved in EGFR degradation. Neddylation activates E3 ligases and switches the balance between degradation and recycling towards degradation. We have previously reported that rs895374 correlates with progression free survival (PFS) in patients (n=108) treated with cetuximab in two phase II studies of further-line treatment. The aim of this study was to validate the predictive value of rs895374 in an independent cohort of cetuximab treated patients with a cetuximab-free chemotherapy arm serving as negative control. Methods: Genomic DNA was isolated from tissue samples of 455 patients (median age 64 years, male 64.2%) treated in first-line with either FOLFIRI cetuximab (n=218) or FOLFIRI bevacizumab (n=237) enrolled in the FIRE-3 trial (NCT00433927). The cetuximab arm served as validation for our previous results whereas the bevacizumab arm served as negative control arm to confirm the predictive value of this SNP. Results: The minor allele A was associated with shorter PFS in the FOLFIRI + cetuximab validation set, (10.5 months vs. 8.2 months; logrank p=0.005; HR 0.66 (0.47-0.89)). In the FOLFIRI plus bevacizumab arm, no difference in PFS were seen (10.3 months versus 10.5 months, logrank p=0.85; HR 1.03 (0.77-138)). rs895374 was neither associated with tumor response nor with median overall survival. Conclusions: The predictive value of rs895374 for cetuximab treatment could be validated and no prognostic value could be established. This is the first report proving that germline polymorphisms in the degradation process predict efficacy of cetuximab in patients with metastatic colorectal cancer. As the process of EGFR recycling is an important mechanism of cetuximab resistance, novel anti-EGFR antibodies like Sym004 may overcome resistance mechanisms by preventing EGFR recycling.