tbuckley/cabot-search huggingface dataset:
SWOG S1216: A phase III randomized trial comparing androgen deprivation therapy (ADT) plus TAK-700 with ADT plus bicalutamide in patients (pts) with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) (NCT01809691).
Authors: Neeraj Agarwal, Catherine Tangen, Maha H. A. Hussain, Shilpa Gupta, Melissa Plets, Primo "Lucky" N. Lara, Andrea Harzstark, Przemyslaw Twardowski, Channing Judith Paller, Dylan M. Zylla, Matthew R. Zibelman, Ellis Glenn Levine, Bruce J. Roth, Amir Goldkorn, Daniel A. Vaena, Manish Kohli, Tony Crispino, Nicholas J. Vogelzang, Ian Murchie Thompson, David I. Quinn
Journal: Journal of Clinical Oncology (2021)

5001 Background: Tak is an oral selective nonsteroidal 17, 20-lyase inhibitor that blocks the synthesis of gonadal and adrenal androgens. We evaluated the clinical benefit of Tak with ADT in pts with newly diagnosed mHSPC. Methods: Pts with mHSPC with a Zubrod performance status (PS) of 0-2 and a PSA of ≥ 2 ng/ml were randomized 1:1 to ADT+Tak (300 mg twice daily) or ADT+Bic (50 mg daily). Stratification factors included PS (0-1 vs ≥2), extent of disease (minimal vs extensive), and receipt of ADT prior to registration (yes vs no). The primary endpoint was overall survival (OS). Secondary endpoints were progression free survival (PFS; based on PSA, imaging or clinical progression), PSA at 7 months (≤0.2 vs 0.2 &lt; PSA; ≤-4 vs. &gt; 4 ng/ml) and adverse event (AE) profile. With 2.75 yrs to accrue 1,186 eligible pts and 3 additional yrs of follow-up, we would have 90% power to determine a 33% improvement in OS from 54 to 72 mos (1-sided α = 0.025). A final analysis was pre-specified after 523 deaths using a 1-sided α = 0.022 to account for interim analyses. Results: Between 3/2013 and 7/2017, 1,313 pts were randomized and 1,279 were included in the intention-to-treat (ITT) analysis (32 pts were ineligible and 2 pts withdrew consent). Median age was 68 yrs and 10% of subjects were Black. Median PSA was 30 ng/mL (range 2-6710) and 49% of pts had extensive disease. After a median follow-up of 4.9 yrs, PFS and PSA response were significantly improved with Tak over Bic but no significant improvement in OS was observed (Table). More grade 3/4 AEs occurred in Tak vs. Bic arms (43% vs. 14%), and included hypertension (20% vs. 5%) and fatigue (5% vs. 2%). Five pts in Tak and 1 pt in the Bic arm had grade 5 AE. Conclusions: Despite clinically meaningful improvement in various outcome measures with Tak+ADT over Bic+ADT in this representative population of mHSPC, the improvement in OS did not meet the pre-specified criteria for statistical significance. The median OS of 70 mos in the control arm (standard ADT) was higher than that reported in contemporary phase 3 trials in this setting, and 16 mos higher than originally estimated. This trial sets a new landmark for survival estimates when pts with mHSPC have access to multiple approved subsequent life-prolonging therapies. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820; U10CA180821; and in part by Millennium Pharmaceuticals, Inc. (Takeda Pharmaceutical Company LTD) Clinical trial information: NCT01809691. [Table: see text]
Fulvestrant for advanced breast cancer: A meta-analysis.
Authors: Mustafa Mohammed Al Mubarak
Journal: Journal of Clinical Oncology (2013)

e11613 Background: Fulvestrant is an endocrine agent which degrades the estrogen receptor, thereby downregulating its signaling. While fulvestrant has been consistently tested in postmenopausal women with inoperable locally advanced or metastatic breast cancer, there has been substantial heterogeneity in study populations and drug dosing. The optimal use of fulvestrant in advanced breast cancer is therefore unclear. Methods: A systematic review of electronic databases was conducted to identify randomized trials of fulvestrant versus other endocrine therapy. The hazard ratios (HR) for time to progression (TTP) and the odds ratios (OR) for serious adverse events (SAEs), discontinuation of treatment due to toxicity and commonly reported toxicities (hot flashes, venous thrombosis, gastrointestinal disturbance, arthralgia, and asthenia) were pooled in a meta-analysis. Meta-regression explored heterogeneity in study population and fulvestrant dosing. Results: Eight studies were included in the analysis. Overall, there was no difference in TTP between fulvestrant and control groups (HR:0.94, 95% CI 0.85-1.03, p=0.18). On meta-regression, fulvestrant showed reduced hazards for TTP compared to aromatase inhibitors (AI) if used in first line (p for trend &lt;0.001), in studies where fewer patients received adjuvant endocrine therapy (p for trend &lt;0.001) and at higher doses (p for trend &lt;0.001). Rates of SAEs and treatment discontinuation were similar for fulvestrant and control groups, but fulvestrant monotherapy was associated with significantly less arthralgia (OR:0.73,95% CI 0.57-0.95, p=0.02). The addition of fulvestrant to AI compared with AI alone was not associated with improved TTP (HR:0.88, 0.72-1.09,P=0.25), but led to increased hot flashes (OR: 1.68,95% CI 1.30-2.16, P&lt;0.001) and gastrointestinal disturbances (OR:1.28, , 95% CI 1.01-1.63, p=0.04). Conclusions: In unselected patients, fulvestrant monotherapy is associated with similar efficacy, but reduced arthralgia. Use of high dose fulvestrant monotherapy in first line or in patients with limited prior exposure to adjuvant endocrine therapy may delay progression compared with AI. Fulvestrant combined with AI was not associated with improved efficacy but led to increased toxicity.
An aggressive histologic phenotype in young breast cancers in India: A correlational study.
Authors: Diganta Hazarika, Marysingh Nandini, Shilpa A. Prabhudesai, Rao M. Raghavendra, Basavalinga S Ajaikumar
Journal: Journal of Clinical Oncology (2012)

e11043 Background: Breast cancer patients younger than 40 years are known to have an aggressive disease than their older counterparts. In this correlational study involving Indian women with breast cancer; we analyzed if age is related to an aggressive histopathologic phenotype and biomarker expression. Methods: Paraffin embedded tissue blocks of hundred chemotherapy naive breast cancer patients with a diagnosis of invasive breast carcinoma were stratified for age group (less than forty and above forty years) equally from the hospital biorepository. Tissue samples were analyzed for pathological stage, histological type, ER, PR and Her2 Neu receptor status, and expression of biomarkers such as Ki67, EGFR and P53 using immunohistochemistry. Data were analyzed using Chisquare test for proportions. Results: Younger age group had significantly higher grade (p=0.03), higher incidence of solid (p=0.04) and micropapillary type DCIS (p=0.004), ER negativity (p=0.04), higher proliferation rate as indicated by over expression of Ki 67 (p=0.03) and triple negativity (p= 0.03) indicating an aggressive histological phenotype compared to older age group. Conclusions: Results suggest that younger breast cancer patients have an aggressive histological phenotype that may affect treatment response. Future studies should explore relationship of these biomarkers to survival and treatment outcomes.
Overcoming erlotinib resistance with STAT3 inhibition in pancreatic cancer.
Authors: Matthew Philip Salzberg, Nipun B. Merchant
Journal: Journal of Clinical Oncology (2017)

304 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a major therapeutic challenge. Cytotoxic chemotherapy remains the standard approach in PDAC, but results in minimal survival benefit for patients, highlighting a desperate need for novel treatment strategies. Epidermal growth factor receptor (EGFR) is overexpressed in 25-90% of PDACs and has been shown to be an adverse prognostic marker for survival, making it a rational target. To date, the combination of the EGFR tyrosine kinase inhibitor, erlotinib, with gemcitabine remains the only approved targeted therapy based on a significant, yet modest, improved overall survival when compared to gemcitabine alone in a phase III clinical trial. We have previously shown that constitutively activated signal transducer and activator of transcription 3 (STAT3) signaling is a biomarker of resistance to both gemcitabine and erlotinib. Therefore, we hypothesized that combined STAT3 and EGFR inhibition would overcome resistance to erlotinib and gemcitabine in PDAC. Methods: Human pancreatic cancer cell lines MiaPaca2 ( KRAS G12C ; TP53 mut ; EGFR wt ) or BxPC-3 ( KRAS wt ; TP53 mut ; EGFR wt ) were treated in a dose dependent manner with erlotinib in the presence or absence of gemcitabine. PDAC cells were additionally treated with EC 50 doses of a STAT3 inhibitor (AZD1480), erlotinib, and/or gemcitabine. Lysates were then collected and western blot analysis was performed to detect total and phosphorylated extracellular signal regulated kinase (ERK) or STAT3. Results: EGFR inhibition with erlotinib, with or without gemcitabine, results in decreased ERK activation, however, causes an increased activation of STAT3 signaling in both MiaPaca2 and BxPC-3 cells. Combined STAT3 and EGFR inhibition results in sustained attenuation of both phosphorylated ERK and STAT3 levels. Conclusions: Our study demonstrates that activated STAT3 signaling appears to be a mechanism of resistance to erlotinib and gemicitabine treatment in PDAC. Combining STAT3 inhibition with EGFR inhibition overcomes this resistance.
A proteomic analysis of surgical cytoreduction in patients with advanced ovarian cancer.
Authors: Jamie L Lesnock, Brian L Hood, Mai Sun, Rohit Bhargava, Thomas P Conrads, Thomas C. Krivak
Journal: Journal of Clinical Oncology (2012)

e15560 Background: Optimal surgical cytoreduction (&lt;1 cm residual tumor) has been shown to improve overall survival compared to suboptimal (&gt;1cm) debulking as primary treatment for advanced stage epithelial ovarian cancer (EOC). Molecular descriptions of optimally and suboptimally debulked ovarian tumors are lacking. We have performed a global, quantitative proteomic analysis of optimally and suboptimally debulked EOC tumor samples. Methods: A cohort of 16 optimally (8) and suboptimally (8) debulked patients with archival formalin-fixed, paraffin-embedded tumor specimens was identified. Homogenous tumor cell populations were collected and protein digests were prepared and analyzed by high resolution mass spectrometry for identification and quantification by spectral counting. Immunohistochemistry (IHC) was performed and slides were scored using a semi-quantitative method (H-score). Results: An average of 1,110 proteins were identified within each cohort, of which 21 possessed significant (p&lt;0.05) differential abundances. Specifically, three proteins (annexin A1, S100-A11, and synuclein-gamma, or SNCG) which have significant roles in cell migration and cancer biology were identified. Although no H-score was statistically significant, comparison of positively-staining cells for SNCG showed a trend toward increased expression in suboptimally debulked patients, p=0.08. Conclusions: Overexpression of SNCG has been shown to be predictive of worse prognosis in papillary serous uterine cancer cell lines, and increased expression of SNCG in breast cancer correlates with advanced stage and aggressiveness of disease. Our data suggest SNCG may have similar predictive value in EOC, as tumors with elevated levels of this protein may be less amenable to optimal cytoreduction.
Interviews with cancer fatigue patients
Authors: K. E. Lasch, K. A. Jernigan, J. A. Scott, E. Piault-Louis
Journal: Journal of Clinical Oncology (2009)

e17577 Background: Approximately 90% of patients diagnosed with cancer experience fatigue associated with the effects of treatment and/or cancer itself. Despite its high prevalence and negative impact on patients’ lives, there is no consensus on a clinical definition of cancer-related fatigue (CF). Extant qualitative research has methodological limitations, small sample sizes, and varying results regarding CF. A multi-disciplinary research consortium is developing a conceptual model of CF based on 120 qualitative interviews with cancer patients varying by cancer type and stage. Exploratory interviews were conducted to test questions and suggest sensitising concepts for an unbiased interview guide. Methods: Five cancer patients with self-reported CF were purposively sampled and interviewed between September 2007 and March 2008 by a trained interviewer to discuss their CF experiences. Verbatim transcripts were coded by two researchers using qualitative data analysis software and reviewed for consistency and reliability. Data were analyzed using a constant comparison method. Results: Patients were diagnosed with cancer on average 3.5 years ago among the following primary sites: breast (n = 2), lung, colorectal, and prostate/liver. Patients provided 14 terms to describe CF: “tired” and “lack of energy” were the most commonly reported. Patients described CF as a general lack of ability to do anything, a child-like regression, and indicated that current “tiredness” differed from pre-diagnosis tiredness. Patients also described CF in terms of frequency (i.e., duration, onset, recurrence) and intensity and identified treatment as a trigger of fatigue. Patients understood the word “fatigue,” but rarely mentioned it spontaneously. Additionally, patients mentioned that CF was not relieved by rest and impacted several areas of their lives, including activities of daily living and cognitive and emotional functioning. Conclusions: Patients’ experience with CF differs from pre-diagnosis tiredness in terms of intensity, duration, onset, and impact. These results helped to refine the interview guide and provide insight for future interventions. Further research with patients with different cancer types and stages is needed to develop a comprehensive conceptualization and measurement of CF. [Table: see text]
Effect of polymorphisms and miRNAs targeting CLOCK gene on gender-related survival in metastatic colorectal cancer (mCRC) patients (pts).
Authors: Annamaria Ruzzo, Angela Torsello, Isabella Sperduti, Elisa Melucci, Elisa Giacomini, Marcella Mottolese, Roberta Fiorino, Massimo Zeuli, Edoardo Pescarmona, Mauro Magnani, Francesco Cognetti, Carlo Garufi
Journal: Journal of Clinical Oncology (2015)

e14585 Background: Experimental and clinical evidence supports a role for the circadian timing system in cancer. Gender and delivery schedule (chronomodulated or conventional) influence overall survival (OS) in mCRC pts (Giacchetti 2014). Circadian rhythms are generated by a transcription-translation–based oscillatory loop and involve a set of clock genes including PERIOD, CLOCK, BMAL1, CRY. Here we evaluated the expression of CLOCK gene-related miRNAs and SNPs in mCRC pts and their effect according to gender Methods: We studied 83 first line mCRC pts treated with chemotherapy plus cetuximab. Specific CLOCK polymorphisms (SNPs) (rs11133373C/G, rs11133391T/C, rs1801260T/C) and miRNAs expression level (miR-192-206-132-194-219) were performed on formalin fixed paraffin embedded tissues in 77 pts. OS was the primary study endpoint. Results: Median age 59 y (30-85); male/female (M/F) 50/33; median follow-up 25 m (1-132); median PFS was 14 m (CI 95% 10-19) and median OS was 35 m (CI 95% 22-47). PFS and OS were significantly better in F: PFS M/F = 12/19 m (CI 95% 8-16/11-27) p = 0.03; OS M/F = 31/50 m (CI 95% 22-39/35-64) p = 0.03. Increased OS in F vs M was related to high expression level (H) of miR206 (p = 0.003), miR219 (p = 0.003) and miR194 (p = 0.02), and low expression (L) of miR132 (p = 0.06). OS was also better in F vs M in the presence of genotype RS11133373C/C (p = 0.01), RS1801260T/T (p = 0.07) and RS11133391T/T (p = 0.06). Subgroup analysis in females showed that OS was significantly better when ≥ 2 beneficial miRNA were simultaneously expressed vs 0/1 (58 m vs 15 m, p = 0.0002) and this effect was additionally increased by the presence of RS11133391T/T polymorphism (median OS 87 m). Although no difference in OS was observed between M and F respect to L of miR206 and H of miR132, OS was significantly decreased in F when L of miR206 and H of miR132 were simultaneously expressed vs 0/1 (11 m vs 56 m, p = 0.02). No difference in OS was observed in subgroup analysis in males Conclusions: A set of SNPs and miRNAs related to CLOCK gene, principal regulator of the molecular clock, identifies a subgroup of pts who benefits of a gender related difference in survival in mCRC. Supported by AIRC11770
Incidental Finding of Malignancy by CT Angiogram of Chest in Patients Highly Suspected for Pulmonary Embolism.
Authors: Aref Agheli, Seema Naik, Alka Arora, Yelena Yadgarova, Ashish Sangal, Maged Khalil, Zili He, Elliot Bondi, William Steier, Madhumati Kalavar
Journal: Blood (2006)
Dynamic changes of miRNA and cancer related proteins (CRPs) expression during neoadjuvant chemotherapy (NAC) for locally advanced breast cancer (LABC).
Authors: Manal Al-Khanbashi, Stefano Caramuta, Adel Al-Ajmi, Ibrahim Al-Hadabi, Shiyam Kumar, Philomena charlotte Dsouza, Khawaja Farhan Zahid, Kamran Ahmed Malik, Furrukh Muhammad, Ikram A Burney, Bassim J. Al Bahrani, Weng-onn Lui, Mansour S. Al-Moundhri
Journal: Journal of Clinical Oncology (2013)

e22099 Background: NAC is used in LABC to downsize the primary tumor and eradicate metastases. This study assessed the Dynamic changes of miRNA and CRP expression during NAC with aim to identify molecular biomarkers that may predict outcome. Methods: Tissue, blood and serum samples were collected at four time points from LABC patients undergoing NAC, including time of diagnosis (base line) after 1st and 4th cycle of Adriamycin/cyclophosphamide, and after 4th cycle of Docetaxel (end point). We used microRNA-microarray for tissue samples and Proximity Ligation Assay (PLA) for serum samples to quantify global miRNA expression and 92 CRPs in LABC patients. The miRNA and CRPS were correlated with clinico-pathological features including stage, grade and clinical response.Statistical analysis was performed using Significant Analysis of Microarray ( SAM), Student's t-test, and Pearson's correlation test. Significant p value was defined as p&lt;0.05. Results: Tissue miRNA expression profiling (n=14) revealed 58 miRNA species that were differentially expressed between NAC endpoint and the baseline (FDR &lt; 15%). Reduced miR-21 expression was associated with disease recurrence. Using PLA (n=33) we identified serumosteoprotegerin, MCP-1, Prolactin, Carbonic Anhydrase IX, CXCL10, CD30L and TGF-alpha levels were significantly associated with overall clinical response (t-test, p&lt;0.05). Moreover, Prolactin and Erythropoietin showed significant associations with the stage (t-test, p&lt;0.05), while MMP3, ErbB4, Midkine, Cathepsin D and Prostasin proteins were associated with the recurrence. Analysis is ongoing to determine the dynamic changes of these biomarkers during the NAC. Conclusions: Our study identified specific miRNAs and CRPs that were differentially expressed during NAC in LABC patients which may have clinical significance.
Anti-KRAS siRNA nanoparticles for targeted colorectal cancer therapy.
Authors: Bradley Krasnick, Matthew S. Strand, Ye Bi, Peter S. Goedegebuure, Timothy Fleming, Samuel A. Wickline, Hua Pan, Ryan C Fields
Journal: Journal of Clinical Oncology (2017)

636 Background: Standard treatment for metastatic colorectal cancer (mCRC) is systemic chemotherapy with anti-EGFR treatment, depending on KRAS mutational status. However, tumors harboring a KRAS mutation do not respond to existing targeted therapy. Moreover, targeting mutant KRAS has, to date, not been possible. Herein, we explore using a KRAS inhibitory nanoparticle (NP), to directly knock down mutant KRAS. Methods: Utilizing fluorescent-labeled small interfering RNA (siRNA) NPs, uptake was assessed via fluorescent microscopy. KRAS mutant CT26 and wild-type MC38 CRC cell lines were incubated with either scramble (Sc) sequence siRNA NP, KRAS siRNA NP, or FOLFOX (fluorouracil + oxaliplatin) chemotherapy ± KRAS siRNA NP. Cell viability was assessed via a luminescent viability assay. KRAS and cleaved caspase 3 protein expression were assessed using western blotting. Results: Fluorescent NP uptake was demonstrated in CT26 cells as early as 260 minutes post treatment, with increased uptake through 780 minutes. Decreased cellular viability was seen with KRAS siRNA NP treated CT26 cells, as compared to both Sc siRNA NP and non-treated CT26 cells (both p &lt; 0.0001). Cell viability was significantly diminished with FOLFOX combined with KRAS siRNA NP as compared to FOLFOX alone for CT26 cells ( p = 0.0003), but not MC38 cells (p = 0.2259). Western blot demonstrated decreased KRAS and increased cleaved caspase 3 expression in CT26 cells treated with KRAS siRNA NP. Conclusions: A KRAS siRNA tagged NP was internalized by the CRC cells in vitro, and induced cellular death via apoptosis in mutant type KRAS CRC. In addition, KRAS siRNA NP acted synergistically with FOLFOX chemotherapy to enhance cell death. We believe KRAS inhibition based NP treatment is a promising target for mutant type KRAS CRC. [Table: see text]
A study to identify subjective gaps in survivorship knowledge of health care professionals in London.
Authors: Susannah Jane Stanway, Claire Taylor, Jillian Louise Noble, Natalie Doyle, Teresa Young, Nicola Cunningham, Marta Capelan, Mieke Van Hemelrijck, Michelle Chen, Netty Kinsella, Simon Evans, Theresa Wiseman
Journal: Journal of Clinical Oncology (2017)

63 Background: The London Cancer Alliance (LCA), created in 2011, is an integrated cancer system consisting of 14 NHS organisations serving a population of 5.7 million. The multi-professional Survivorship Pathway Group aims to improve the outcomes of adults living with and beyond cancer. Methods: A 14-15 point questionnaire was developed to identify gaps in survivorship knowledge of oncology health care professionals (HCP) working in London. We were interested in HCP’s knowledge of the existence of the Recovery Package (Holistic Needs Assessment and care plan, Treatment Summary, access to a Health and Wellbeing Event and Cancer Care Review). The survey was uploaded onto Smart Survey and sent to 434 HCPs. Results: 167 surveys were anonymously completed. The distribution of respondents included Clinical Nurse Specialists(CNS), physiotherapists, dieticians, oncologists. The majority of respondents worked in specialist centers (44%), with 35% working in acute secondary care, 27% in acute tertiary care and 6% in the community. HCPs from all tumour groups were represented, though breast cancer and head and neck cancer were best represented. The majority of respondents were familiar with some or all of the components of the Recovery Package (80%). HCPs were most confident when asking about anxiety/depression (83%) but least confident or confident to some extent asking about changes in cognitive function (49%) and bone health (49%). When addressing needs, HCPs were confident addressing fatigue (47%) but less confident addressing cardiac complications (65%) and sexual concerns (64%). CNSs in particular were confident asking and addressing most concerns but many were not confident or were only somewhat confident addressing menopausal symptoms (34%) or lymphedema (37%). Further training was identified in psychological support, sexual consequences and management of long-term side effects. The predominant research priority identified was long-term side effects. Conclusions: Data from this survey will inform local educational fora, service mapping studies and the LCA Survivorship Research Group’s future strategy.