tbuckley/cabot-search huggingface dataset:
A randomized, phase II trial of AEZS-108 in chemotherapy refractory triple-negative (ER/PR/HER2-negative) LHRH-R positive metastatic breast cancer.
Authors: Stefan Buchholz, Joerg Engel, Andrew V. Schally, Stephan Seitz, Olaf Ortmann, Guenter Emons, Reshma L. Mahtani, Stefan Gluck, Charles L. Vogel, Alberto J. Montero
Journal: Journal of Clinical Oncology (2013)

TPS11124 Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is clinically negative for expression of estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor-2 (HER2). It is characterized by its unique molecular profile, aggressive behavior, distinct patterns of metastasis, and lack of commercially available targeted therapies. Chemotherapy has been the mainstay of treatment for women with TNBC, but this current standard-of-care is suboptimal. AEZS-108 is an LHRH-cytotoxic hybrid drug whose rational design covalently couples the carrier D-Lys 6 -LHRH (an LHRH agonist) to the cytotoxic doxorubicin radical. Because LHRH receptors are expressed in a majority of TNBC, AEZS-108 represents a novel way to selectively deliver cytotoxic chemotherapy in patients with TNBC via a new therapeutic target. Methods: In this open label randomized two-arm multicenter phase II study, patients will be randomized in a 1:1 ratio into one of the two treatment arms: AEZS-108 (267 mg/m 2 every 21 calendar days) [Arm A] or SSC (standard single agent cytotoxic chemotherapy [Arm B]) at discretion of treating oncologist cycled every 21 calendar days. Stratified randomization will be used with number of prior lines of therapies (1-2 vs. &gt;2), ECOG performance status 0-1 vs. 2, and liver metastases (absent vs. present). Analysis of the main study endpoint, TTP, will follow a group sequential design with two interim analyses, including the final analysis. O’Brien Fleming stopping boundaries will be used. The primary endpoint is to evaluate the median time to progression (TTP) of AEZS-108 in patients with chemotherapy resistant advanced TNBC treated with AEZS-108 in relation to patients receiving standard single agent cytotoxic chemotherapy. Secondary endpoints include: overall response, clinical benefit, duration of response, overall survival, toxicity profile and quality of life (QoL). Clinical trial information: NCT01698281.
The association of androgen deprivation therapy and anxiety among 78,000 patients with localized prostate cancer patients.
Authors: Kathryn T Dinh, Gally Reznor, Vinayak Muralidhar, Neil E. Martin, Peter F. Orio, Quoc-Dien Trinh, Paul L. Nguyen
Journal: Journal of Clinical Oncology (2017)

19 Background: Androgen deprivation therapy (ADT) has been associated with cognitive and psychological effects, including depression. ADT may also cause an increased incidence of anxiety; however, most studies have not considered anxiety as an individual outcome. We aimed to determine if receipt of any ADT or longer duration of ADT for prostate cancer is associated with increasing risk of being diagnosed with anxiety. Methods: We identified 78,552 men over 65 with stage I-III prostate cancer using the Surveillance, Epidemiology, and End Results-Medicare linked database from 1992-2006, excluding patients with psychiatric diagnoses within the prior year. Our primary analysis was the association of pharmacologic ADT with the diagnosis of anxiety using Cox-proportional hazard regression with propensity matching. Drug-data for treatment of anxiety was not available. Our secondary analysis was the association of ADT duration with a diagnosis of anxiety. Results: Overall, 43% (33,882) of patients who received ADT and had higher 3-year cumulative incidence of anxiety (4.1% vs. 3.5%) than patients without ADT (p &lt; 0.001). Adjusted cox-analyses with propensity matching demonstrated patients with ADT had a 17% increased risk of anxiety (adjusted hazard ratio [AHR] = 1.17, 95% CI = [1.088-1.263]) compared to patients without ADT (p &lt; 0.0001). The risk of anxiety increased with duration of ADT, from 4.5% with ≤ 6 months, 5.8% with 7-11 months, to 15.7% with ≥ 12 months (p-trend = 0.0123). Conclusions: Pharmacologic ADT is associated with an increased risk of anxiety in this large study of elderly men with localized prostate cancer. This risk increased with longer duration of ADT. Anxiety should be consider among the possible psychiatric effects of ADT and should be discussed along with depression prior to initiating ADT.
Characteristics and clinical outcome of T1 breast cancer: A national multicenter retrospective cohort study.
Authors: Anthony Gonçalves, Jean-Marc Classe, Jean-Remy Garbay, Sylvia Giard, Charytansky Helene, Monique Cohen, Monique Belichard, Christelle Faure, Serge Uzan, Delphine Hudry, Pierre Azuar, Richard Villet, Pierre Gimbergues, Christine Tunon de Lara, Benjamin Esterni, Gilles Houvenaeghel
Journal: Journal of Clinical Oncology (2013)

566 Background: T1N0M0 breast cancer (BC) are generally considered as carrying good prognosis and cancer-specific survival rates after 5 to 10 years are as high as 90 or 95% in many studies. However, they constitute a heterogeneous group and many studies identified biologically-defined at-risk patients within T1 BC. The objectives of our study were to describe the main characteristics of T1a, b, and c (11-15mm) BC and to identify prognostic factors for survival. Methods: We retrospectively collected the medical files of all patients diagnosed with BC who underwent sentinel lymph node biopsy (SLNB) between January 1999 and December 2008 in 13 French sites and examined overall survival (OS) and Relapse-free survival (RFS) in T1a, T1b and T1c 11-15 mm. Results: Among 8,100 women operated, 5,423 had T1 tumors (708 T1a, 2,208 T1b and 2,508 T1c 11-15mm). T1a differed significantly from T1b tumors with respect to several parameters : younger age, more frequent negative hormonal status and positive HER2 status, less frequent lymphovascular invasion (LVI), exhibiting a mix of favorable and poor prognosis factors. After a median follow-up of 60.5 months, OS rate was 97.6% (95CI: 97.1-98) at 60 months, 95.4%(94.5-96.4) at 84 months and 90.7% (85.2-96.4) at 120 months. No significant difference was observed between T1a, T1b and T1c tumors (p=0.335). RFS rates were 94% (95CI: 93.8-95.2), 92.1% [91.1-93.2] and 83.8% (77.6-90.5) at 60, 84 and 120 months respectively. RFS was significantly higher in T1b tumors (95.9%, 95CI: 95-96.9) as compared to T1a (93.2%, 91-95.4) or T1c tumors (93.8%, 92.8-94.9), p=0.0099. In multivariate analysis, SBR tumor grade, hormone therapy and LVI were independent prognostic factors for RFS, while hormone therapy and SBR grade were independently associated with OS. Conclusions: Relatively poor outcome of patients with T1a tumors might be explained by a high frequency of risk factors in this subgroup (frequent negative hormone receptors and HER2 overexpression) and by a less frequent administration of adjuvant systemic therapy (endocrine treatment and chemotherapy). Tumor size might not be the main determinant of prognosis in T1 breast cancer.
An investigation of trastuzumab-induced cardiac dysfunction in adults with gastric and gastroesophageal junction cancer.
Authors: Frank Augustus Evans, Jennifer Liu, Richard Steingart, Yelena Yuriy Janjigian, Anthony Francis Yu
Journal: Journal of Clinical Oncology (2014)

e15005 Background: The indication for trastuzumab therapy has broadened to target HER-2 amplification in non-breast malignancies. We assessed the incidence of trastuzumab-induced cardiac dysfunction in clinical practice among patients with gastric and gastroesophageal junction (GE) cancer. Methods: Forty-four patients with HER2 (+) gastric or GE junction cancer treated with trastuzumab from 2010 to 2013 were identified. Cardiac toxicity was assessable if at least 2 determinations of left ventricular ejection fraction (LVEF) were available during trastuzumab treatment. LVEF assessments were performed at the discretion of the treating provider. Patient demographics, cancer treatment details, cardiac risk factors, and LVEF were recorded. A significant LVEF decline was defined by an absolute decrease in LVEF of >/= 10% to below 55%. Results: Cardiac toxicity was assessed in 32 patients (82% male, mean age 63.3 +/- 13.7 years). The median duration of trastuzumab therapy was 12.0 months (range 2.4-33.8), and median follow-up was 13.7 months (range 4.0-38.5). Only 1 patient was previously treated with anthracycline chemotherapy. Cardiac risk factors were common, including hypertension (42%), diabetes (21%), smoking history (47%), and dyslipidemia (25%). Three patients developed a significant decline in LVEF: 1 patient had a myocardial infarction after 5-FU treatment that resulted in trastuzumab interruption, and 2 patients experienced an asymptomatic decline in LVEF that recovered without trastuzumab interruption. At last LVEF assessment (median 9 months from start of trastuzumab, range 1-36 months), there was no significant change in LVEF compared to baseline (59.8 +/- 6.5% vs. 61.3 +/- 6.9%, p=0.15). No patients developed symptoms of heart failure during the follow-up period. Conclusions: Trastuzumab-induced cardiac dysfunction was rarely seen in patients with HER2 (+) gastric and GE junction cancer, was not persistent, and did not influence patient care. The need for LVEF monitoring in patients treated with trastuzumab but without prior anthracycline exposure is not clear and requires further investigation.
<i>RNA-seq</i> and <i>KRAS</i> mutational status in ascitic pancreatic cancer cells: Novel results and distinct subsets.
Authors: Talia Golan, S. Gail Eckhardt, Chani Stossel, Dikla Atias, Guoliang Wang, Todd M. Pitts, Dara Aisner, Colin D. Weekes, Raanan Berger, Aik-Choon Tan
Journal: Journal of Clinical Oncology (2014)

e15214 Background: Approximately 90% of pancreatic ductal-adenocarcinoma (PDAC) tumors harbor an activating mutation in the KRAS oncogene, driving proliferative and survival signals. However, this information has largely been obtained from primary tumor tissue while the prevalence of KRAS mutations in metastatic lesions is poorly studied. Since approximately 15-20% of advanced PDAC patients develop ascites, we developed a novel model system of viable ascites-derived PDAC (ad-PDAC) cells that can then be characterized and used for therapeutic studies. Methods: The KRAS oncogene was analyzed in ad-PDAC cells obtained from 19 patients by targeted next-generation or direct sequencing methods. Results: Surprisingly, 17/19 samples were WT, while the two remaining specimens harbored the p.G12R mutation. None of the ad-PDAC cells exhibited the most common p.G12D mutation. Concordance of KRAS status was observed between the ad-PDAC cells and primary tumor in only 4/7 available pairs (3 WT and 1 p.G12R). The 3 discordant primary samples harbored p.G12D (2) and p.G12V (1) with KRAS WT in the ad-PDAC cells. Additionally we analyzed another 28 ad-PDAC samples by RNA-seq. We performed unsupervised clustering on 31 transcriptomes and observed that patients clustered into two groups identified by high or low KRAS expression. The median overall survival was 8.8 and 18.2 months for the high or low KRAS expression groups, respectively (p = 0.0013). Gene set enrichment analysis of the two groups revealed that the high KRAS expression cluster was enriched with RAS/RAF/MEK, PI3K, adherens junctions and TGF signaling pathways, whereas the low KRAS expression cluster was enriched with ribosome, oxidative phosphorylation and proteoasome pathways. Conclusions: These hypothesis-generating data demonstrate discordant KRAS mutational status from what would be expected, with 90% of ad-PDAC cells exhibiting a WT KRAS genotype. Furthermore, the variability noted between the primary/ad-PDAC pairs as well as the clustering analysis, if confirmed in larger data sets, suggests that there may be ways to exploit distinct therapeutic targets in groups of pancreatic cancer patients with ascites, based on their KRAS expression profile.
Surgery and definitive chemoradiation (CRT) for locally advanced oropharyngeal cancer and impact of transoral robotic surgery (TORS).
Authors: Charles Eric Wooten, Alex Wilson, Susanne M. Arnold, Thomas Gal, Rony Aouad, Joseph Valentino, Mahesh R. Kudrimoti
Journal: Journal of Clinical Oncology (2014)

6055 Background: TORS is an emerging modality for oropharyngeal cancer. However, many patients require adjuvant therapy based on high-risk pathologic findings. We compared control rates of TORS to CRT. Methods: A retrospective review was performed evaluating all consecutive patients treated in our department for oropharyngeal cancer from January 2010 through December 2013. All patients treated with definitive CRT or surgical resection with adjuvant RT +/- chemotherapy. Results: 103 total patients identified among whom 40 were resected (33/40 TORS). Majority of patients were stage IVA (86%). 92% (37/40) of patients in the surgery group were T1/T2 vs 36% (23/63) in CRT group. p16 associated with improved locoregional control (LRC) (91% vs 43%, p=0.035). 22/40 resected patients required adjuvant radiation with chemotherapy (trimodality) due to 16/40 with extracapsular extension, 5/40 with positive margins and 2/40 with both. TORS had decreased rate of positive margins (9.1%) vs radical resection (29%). T4a primaries (3/40) had significant risk of positive margins (p=0.038). At median follow up of 20 months (3 – 50), 4 year actuarial overall survival (OS) for entire cohort was 77%. 4 year actuarial OS for trimodality was 79% vs 74% with CRT. 4 year actuarial local control with trimodality was 94% vs 86% with CRT. Compliance was 79% in the surgical group and 100% in the CRT group. Non-compliance was associated with decreased LRC (p=0.049). Sites of first recurrence for surgical and CRT groups respectively were 2.5% vs 11% primary, 10% vs 7.9% regional and 7.5% vs 11% distant. OS was negatively associated with time from initial surgery to completion of adjuvant treatment (p=0.02). Distant failure was associated with retropharyngeal nodal involvement (p=0.0043). Conclusions: No significant difference in control between both groups despite greater percentage of advanced primary tumors with CRT. Compliance with adjuvant therapy in TORS population was lower.
Epigenetic targeting of clear cell renal cell carcinoma (ccRCC) with ascorbic acid (AA) via upregulation of Ten-Eleven Translocation (TET) methylcytosine dioxygenase activity.
Authors: Niraj Konchady Shenoy, Tushar Bhagat, Lance C. Pagliaro, Thomas E. Witzig, Amit Verma
Journal: Journal of Clinical Oncology (2017)

479 Background: We and others have previously shown that the ccRCC epigenome is characterized by widespread DNA hypermethylation (CCR 2014, Nature 2014). Various important tumor suppressor genes (TSGs), such as SMAD7 (inhibitor of oncogenic TGF-β signaling), are under-expressed due to aberrantly methylated promoters or enhancers. We hypothesized that the hypermethylation in ccRCC could be due to low activity of the TET enzymes, which convert methylcytosine (5-mc) to hydroxymethylcytosine (5-hmc). Loss of function of TET enzymes can occur with an inactivating mutation (TET-2 is mutated in about 6% of ccRCC (Science Signaling 2013) or hypoactivity of normal TET enzymes, through inhibition by metabolic intermediates. AA is an essential co-factor for TET enzymes (JACS 2015). We hypothesized that high dose AA treatment of ccRCC could potentially increase the functional activity of TET enzymes leading to demethylation of the RCC genome, and enhance expression of TSGs. Methods: In vitro TET activity was performed on ccRCC cell line 769P with increasing doses of AA (L-AA). Genome wide quantitative 5-mc and 5-hmc was evaluated using mass spectrometry. SMAD7 expression was determined using qRT-PCR. Proliferation assay (MTT) was performed with AA in combination with pazopanib. Cell cycle and apoptosis assays were performed. Results: AA, at doses achieved only by the intravenous route (1-10mM), increased TET activity in ccRCC cell line 769P. Genome wide 5-mc was significantly reduced and 5-hmc was increased, correlating with increase in TET activity. SMAD7 expression was increased with AA treatment. High dose AA led to proliferation inhibition with a cell cycle arrest in the G1 phase, and had a synergistic effect with pazopanib. Since AA leads to the generation of H2O2 in-vitro, catalase was used as control. This did not reverse the effect of AA on epigenetic changes; and proliferation inhibition was seen despite catalase control. Conclusions: High dose AA causes TET mediated DNA demethylation of the hypermethylated RCC genome, resulting in the re-expression of TSGs, and proliferation inhibition. Sequencing and xenograft studies are underway.
Is there a role for oral or intravenous ascorbate (vitamin C) treatment for patients with cancer? A systematic review.
Authors: Carmel Maree Jacobs, Brian Hutton, Terry L. Ng, Mark J. Clemons
Journal: Journal of Clinical Oncology (2014)

e20598 Background: Despite a lack of high quality clinical data supporting its use,thousands of patients choose to pay for intravenous (IV) ascorbate (vitamin C) in the belief that it synergizes the anti-cancer effects of chemotherapy and reduces its toxicity. Methods: A formal systematic review of human interventional and observational studies of both oral and IV ascorbate treatment and their anti-tumor effects in cancer patients was performed. Two reviewers independently screened all abstracts and full text articles. Data collection and quality assessment of studies was performed using the Jadad and Newcastle-Ottawa scales. Results: Of 677 records initially identified, 58 full text articles were screened and 34 studies included. We identified 5 randomised controlled trials (n= 322), 12 phase I/II trials (n= 283), 6 observational studies (n= 8558) and 11 case reports (n= 264). None of these trials demonstrated any statistically significant validated anti-tumour effect of ascorbate. Evidence presented for the anti-tumour effect of ascorbate was anecdotal, observational and from uncontrolled studies. Evidence for the safety of ascorbate was shown in small single-arm trials (n=86). Case reports of significant adverse effects were found (n=6). Quality assessment of the published studies showed them to be generally of low quality. Conclusions: There is no high quality evidence to suggest that either oral or IV ascorbate supplementation in cancer patients has either anti-tumour effects or that it reduces the side effects of chemotherapy. Limited single-arm evidence suggests that IV ascorbate may be safe. However, given the high financial and time costs to patients and their families of IV ascorbate, high quality placebo-controlled trials are needed.
BBI608-224: A phase Ib/II study of cancer stemness inhibitor napabucasin (BBI-608) administered with panitumumab in KRAS wild-type patients with metastatic colorectal cancer.
Authors: Tim Larson, Waldo Feliu Ortuzar, Tanios S. Bekaii-Saab, Carlos Becerra, Kristen Keon Ciombor, Joleen Marie Hubbard, William Jeffery Edenfield, Spencer H. Shao, Axel Grothey, Laura Borodyansky, Bo Xu, Wei Li, Youzhi Li, Chiang Li, Waheed Khan
Journal: Journal of Clinical Oncology (2017)

677 Background: Napabucasin a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting Stat3-driven gene transcription. Preclinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with other agents. In a phase 1 study, napabucasin monotherapy was well tolerated with encouraging signs of anti-tumor activity at the RP2D of 500 mg BID. Methods: The current open-label, multi-center study includes phase II expansion in pts with refractory, K- Raswt mCRC to confirm safety and anti-tumor activity of napabucasin administered orally at 480mg BID in combination with panitumumab (6mg/kg bi-weekly). Results: 72 pts were enrolled, 48 pts were evaluable by RECIST of which 7 (15%) and 41 (85%) had 2 or &gt;3 prior treatment lines, respectively. Of the 48 evaluable pts, 64.6% (31/48) were previously treated with an anti-EGFR agent. No new adverse events (AEs) were observed and most common AEs included grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. Among 48 pts enrolled who received RECIST evaluation, Disease Control Rate (DCR) was observed in 25 pts (52.1%) of which 3 pts achieved PR (6%) and 22 pts achieved SD (45%). Among 31 pts previously treated with anti-EGFR therapy, DCR was observed in 15 pts (48%) compared with DCR of 59% observed in 10 out of 17 anti-EGFR naïve pts receiving a scan. Conclusions: This phase II study confirmed that napabucasin can be safely combined with panitumumab at full dose and shows encouraging anti-tumor activity in pts with K- Ras wt mCRC, regardless of prior anti-EGFR exposure, suggesting that napabucasin may sensitize pts to repeat anti-EGFR therapy. Clinical trial information: NCT01776307. [Table: see text]
Retrospective data study evaluating resource utilization among metastatic renal cell carcinoma patients receiving oral versus intravenous mTOR inhibitors.
Authors: Menaka Bhor, Thomas E. Hutson, Rahul Dhanda, Zhimei Liu, Nicholas J. Vogelzang
Journal: Journal of Clinical Oncology (2012)

e15063 Background: The purpose of this retrospective study was to compare healthcare resource utilization among metastatic renal cell carcinoma (mRCC) patients (pts) receiving everolimus (oral mTOR inhibitor), relative to pts receiving temsirolimus (intravenous mTOR inhibitor). Methods: Using US Oncology’s iKnowMed EMR in conjunction with claims and pharmacy data, we identified mRCC pts who initiated a treatment regimen of everolimus or temsirolimus from 2009 –2010 with a minimal six month follow-up period. Healthcare encounters were estimated and presented using the per patient per month metric. Poisson regression models were used to examine the impact of treatment on resource use after controlling for covariates including stage, ECOG status, and insurance type, and were stratified by line of therapy (LOT) as LOT was the most significant different baseline characteristic between the two treatment groups. Results: A total of 461 pts were identified: 143 were treated with everolimus, and 318 with temsirolimus. The everolimus group had lower usage of all types of services than the temsirolimus group and the results were statistically significant for most of the categories as per the bivariate analysis. In the multivariate analysis stratified by LOT and adjusted for baseline characteristics, the temsirolimus group had statistically significant more acute care services (1 st line), drug usages (1 st and 2 nd line), lab visits (2 nd and 3 rd line), radiation treatment and minor services (2 nd line), non-drug and other services (1 st , 2 nd , and 3 rd line), than the everolimus group. Conclusions: Results of this retrospective study suggest that overall everolimus is associated with lower patient burden in terms of health care resource utilization relative to temsirolimus.