tbuckley/cabot-search huggingface dataset:
Aromatase inhibitor-related side effects and associated treatment discontinuation.
Authors: Lisa Gallicchio, Carla Calhoun, Kathy Helzlsouer
Journal: Journal of Clinical Oncology (2016)

10076 Background: Side effects are associated with discontinuation of and non-adherence to aromatase inhibitor (AI) treatment among breast cancer patients. Musculoskeletal pain is a well-documented side effect of AIs; however, there is a gap in knowledge regarding other side effects. The purpose of this study was to examine side effects, including those related to cognition and fatigue, associated with AIs and to determine whether the side effects were related to treatment discontinuation. Methods: Data were analyzed from a cohort of 146 breast cancer patients initiating AI therapy and followed for 1-year, and a cohort of 144 postmenopausal women without a history of cancer followed for 6-months. At baseline (prior to AI therapy for breast cancer patients), and at 3-months, 6-months, and 1-year (for breast cancer patients only), a comprehensive questionnaire was administered that ascertained data on symptoms, including forgetfulness, difficulty concentrating, fatigue, and problems with vision and hearing. Odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for age, body mass index, and race were calculated using logistic regression for new onset of symptoms among the breast cancer patients compared to the women without a history of cancer. Results: Among breast cancer patients (mean age = 63y), 34.2% were treated with chemotherapy prior to AI treatment. Over the first 6 months of AI treatment, breast cancer patients had significantly higher odds of reporting new onset of forgetfulness (OR 4.0; 95% CI 1.7, 9.6), difficulty concentrating (OR 2.7; 95% CI 1.3; 5.8), fatigue (OR 4.1; 95% CI 1.1, 14.5), and hair loss (OR 4.1; 95% CI 1.9, 9.2) compared to the women without a history of cancer. Similar increases in odds were observed for the subgroup of women not treated with chemotherapy versus the comparison group. Further, among all breast cancer patients, the prevalence of hearing problems, hair loss, and forgetfulness increased significantly over the 1-year study period. Discontinuation rates were higher, but not statistically significant, among those reporting these symptoms at 1-year. Conclusions: AI-related symptoms should be monitored and addressed so that adherence to therapy is maintained.
PSA (Prostate-Specific-Antigen) screening to improve outcome in prostate cancer (PC): Reanalysis of the Prostate-Lung-Colorectal-Ovary (PLCO) randomized controlled trial (RCT).
Authors: Lulu Zhang, Hong Chang, Gary M. Strauss
Journal: Journal of Clinical Oncology (2018)

e17064 Background: PSA screening remains highly controversial. In 1960s, about 10% of PCs were localized at diagnosis. SEER data from 1965-1975 indicated that PC 5-yr survival was 54%, providing a powerful rationale for early detection. In 1992, the American Cancer Society recommended annual PSA screening among men beginning at age 50 yrs. PLCO, the only RCT in US evaluating PSA screening, was initiated in 1993, and randomized 76,683 men to an experimental group (EG = 38,340) undergoing annual PSA for 6 yrs versus a control group (CG = 38,343). The study found no reduction in PC mortality after 13 yrs. However, there is evidence that almost 90% of CG men received at least 1 PSA test before or during the trial, which clearly skewed outcomes. Objective of this report is to explore the extent to which PSA screening outside the trial influenced PLCO results. Methods: Extent of contamination is estimated from the Health Status Questionnaire (HSQ) during the first 13 yrs of follow up, which was designed to assess the extent of PSA screening outside the trial protocol in 1-2% of subjects selected randomly every 1-2 yrs. Results: Among 6178 subjects participating in HSQ, there were 4295 CG subjects (81.7% had ≥1 PSA during the trial) and 1537 EG subjects (79.6% had ≥1 PSA during the trial). Among 1098 subjects with no PSA contamination during the trial, 5.73% were diagnosed with PC in CG (N = 785) and 3.19% in the EG (N = 313). The majority of PLCO subjects do not have contamination information. Considering all PLCO participants, PC was diagnosed in 4250 EG and 3815 CG subjects after 13 yrs (RR-1.114; 95% CI 1.069-1.161; p < 0.0001). There was no significant difference in PC mortality after 13 yrs (RR-1.090; 95% CI 0.870-1.365; p = 0.455). PC survival was extremely high in both groups. Only 303 of 8065 PC patients (3.75%) died of PC after 13 yrs. Conclusions: While PLCO revealed no differences in PC mortality or survival, the high degree of PSA contamination in CG undoubtedly led to the dramatically favorable outcomes among PLCO participants. Recommendations against PSA screening are misguided. If PSA screening is abandoned in the US, PC mortality will likely increase.
SU2C-SARC032: A phase II randomized controlled trial of neoadjuvant pembrolizumab with radiotherapy and adjuvant pembrolizumab for high-risk soft tissue sarcoma.
Authors: Yvonne Marie Mowery, Karla V. Ballman, Richard F. Riedel, Brian E. Brigman, Steven Attia, Christian Frederick Meyer, Scott Schuetze, Melissa Amber Burgess, Bartosz Chmielowski, Mark Andrew Dickson, Lee P. Hartner, Mohammed M. Milhem, Gabriel Tinoco, Brian Andrew Van Tine, Andrew J. Wagner, Denise K. Reinke, David G. Kirsch
Journal: Journal of Clinical Oncology (2018)

TPS11588 Background: Radiotherapy (RT) and surgical resection achieve local tumor control for most large, high-grade soft tissue sarcomas (STS) of the extremity. However, many patients (pts) subsequently develop metastatic disease that is associated with median survival < 2 yr. SARC028 (NCT02301039), a phase II clinical trial of pembrolizumab (pembro) for metastatic sarcoma, showed promising results with PD-1 blockade with RECIST 1.1 responses in 40% of undifferentiated pleomorphic sarcoma (UPS) pts and 20% of liposarcoma (LPS) pts. RT can augment the anti-tumor immune response and synergize with immune checkpoint blockade. We hypothesized that anti-PD-1 therapy with concurrent RT will stimulate a host immune response to eliminate micrometastatic deposits of STS, preventing progression to metastatic disease. To test this hypothesis, we opened SU2C-SARC032 (NCT03092323) in July 2017. This multi-institutional (11 of 12 US sites open; 5 international sites planned) randomized phase II trial is examining the safety and efficacy of neoadjuvant pembro with RT and adjuvant pembro for high-risk STS. Methods: Eligible patients for SU2C-SARC032 are adults with non-metastatic UPS or dedifferentiated/pleomorphic LPS of the extremity or limb girdle (FNCLCC grade 2 or 3, tumor > 5 cm; stage III). Patients are randomized to neoadjuvant RT (50 Gy/25 fractions) then surgical resection vs neoadjuvant pembro and RT followed by surgical resection and adjuvant pembro. Pts receive 200 mg pembro Q3 wk for 3 neoadjuvant cycles (before, during and after RT) and up to 14 adjuvant cycles (1 yr of pembro). The primary endpoint is 2-yr disease-free survival (DFS). Target enrollment is 110 pts to achieve 51 evaluable pts/arm. This provides 80% power with a = 0.05 to distinguish between a null hypothesis of 50% 2-yr DFS and alternative hypothesis of 75% 2-yr DFS using a logrank test. Tumor specimens (pre- and post-neoadjuvant therapy) and blood will be collected for correlative studies including immunophenotyping, whole exome sequencing, RNAseq, and circulating tumor DNA analysis. Four pts have accrued. A planned toxicity evaluation is ongoing for the first 3 pts on pembro. Clinical trial information: NCT03092323.
Abstract 19363: Migration of MicroRNAs From Cardiomyocytes to Cancer Cells Interferes With Tumor Formation in the Adult Heart
Authors: Laura Graciotti, Toru Hosoda, Fumihiro Sanada, Giulia Borghetti, Christian Arranto, Fiorenza Valeriani, Ewa Wybieralska, Barbara Ogorek, Marcello Rota, Polina Goichberg, Piero Anversa, Annarosa Leri
Journal: Circulation (2014)

The low incidence of cardiac tumors has been attributed to tissue pressure dictated by myocardial mechanics and large coronary blood flow. These variables, however, have failed to consider the possibility that the rare occurrence of heart neoplasms may be dictated by the molecular characteristics of cardiomyocytes. We have shown that miR-1, miR-133a, and miR-499 translocate from myocytes to co-cultured MCF7 breast cancer cells, inhibiting their growth. The transfer of miRs is mediated by gap junction channels and is abolished by Cx43 and Cx45 silencing. Although these in vitro results provided important information on the inhibitory function of miRs in cell proliferation, co-culture of myocytes and cancer cells does not mimic the in vivo organization of the myocardium that allows the formation of multiple sites of coupling between myocytes and tumor cells. To reproduce, at least in part, the in vivo condition, we developed first a physiological model of organ culture. Thick vibratome-cut myocardial slices were placed on a multiwell plate containing an oxygen-saturated sponge. At 24-48 hours, the cultured tissue was viable and myocytes showed a well organized sarcomere structure. Two hours after plating of the organ slices, control MCF7 cells or MCF7 cells in which Cx43 and Cx45 were silenced (MCF7-shCx43-shCx45) were seeded on the myocardium. Control MCF7 cells showed a slower growth rate than MCF7-shCx43-shCx45 cells, a finding consistent with miR translocation and its blockade, respectively. Second, 1 x 106 MCF7 or MCF7 cells overexpressing miR-1, miR-133a, and miR-499 (MCF7-miRs) were injected subcutaneously in NOD-SCID mice; ~45 days later, the tumors developed from MCF7 cells were more than 10-fold larger and 3-fold heavier than those originated from MCF7-miRs cells. Third, these studies were complemented with the intramyocardial injection of 1 x 105 control MCF7 cells. Five weeks later, no neoplastic lesions were identified. However, when an excessive number of MCF7 cells were injected, 1 x 106, tumor formation was apparent. In conclusion, our results indicate that transfer of miR-1, miR-133a, and miR-499 from cardiomyocytes to cancer cells plays a critical role in preventing the generation of tumors in the myocardium.
Diffusion of innovation in oncology: A case study of immuno-oncology (IO) adoption for advanced non-small lung cancer (aNSCLC) patients across practices in the US.
Authors: Caroline Savage Bennette, Aracelis Z. Torres, Melisa Tucker, Sean Khozin, Amy Pickar Abernethy, Nicholas R Brown, Neal J. Meropol
Journal: Journal of Clinical Oncology (2018)

6537 Background: IO agents are being adopted rapidly into clinical care; however, variation in speed and breadth of adoption across oncology practices remains unknown. Our objective was to evaluate adoption patterns in the treatment of aNSCLC and identify practice characteristics associated with adoption trajectories. Methods: 43,697 patients diagnosed with aNSCLC from Jan'11-Dec'17 were obtained from the Flatiron Health electronic health record-derived database, a national sample of academic and community practices. We estimated the proportion treated each month with IO (nivolumab, pembrolizumab or atezolizumab) versus other therapies from time of first IO approval (Mar'15) through Dec'17 in 123 practices that treated aNSCLC patients during this time. We used k-means clustering to identify patterns of IO adoption. Multivariable logistic regression models were used to adjust for differences in case-mix and evaluate association of practice size, location, and Quality Oncology Practice Initiative (QOPI) certification program with IO adoption. Results: We identified 4 distinct groups of practices based on trajectories that differed in speed and extent of IO adoption (Table). 17% of practices adopted IO rapidly and extensively; 28% were slower and more limited in their adoption; 24% initially had limited IO use, but adoption accelerated rapidly after 18 months; 32% initially adopted rapidly, but slowed markedly after 1 year. In multivariable analyses, we found no significant association between a practice's size, location, or QOPI certification and IO adoption trajectory. Conclusions: There is significant variability in adoption of IO therapy by oncology practices. Further research is needed to characterize drivers of this variation at the physician level and its impact on patient outcomes. Understanding variability in the diffusion of new innovations could guide development of targeted educational interventions to optimize use of new effective therapies. Rapid & extensive adopters, N = 21 Slower & limited adopters, N = 34 Later adopters, N = 29 Decelerating adopters, N = 39 % IO use in Dec'15 19.8 10.0 10.0 20.8 % IO use in Dec'17 50.7 30.8 48.0 36.6
ATLAS: A randomized, double-blind, placebo-controlled, phase 3 trial of apalutamide (ARN-509) in patients with high-risk localized or locally advanced prostate cancer receiving primary radiation therapy.
Authors: Howard M. Sandler, Michael R. McKenzie, Bertrand F. Tombal, Edwina Baskin-Bey, Stephen J. Freedland, Mack Roach, Anders Widmark, Alberto Bossi, Adam Dicker, Thomas Wiegel, Neal D. Shore, Matthew Raymond Smith, Margaret K. Yu, Thian Kheoh, Shibu Thomas, David P. Dearnaley
Journal: Journal of Clinical Oncology (2016)

TPS5087 Background: At present, high-risk localized and locally advanced prostate cancer (PC) patients receiving primary radiation therapy (RT) and long-term androgen deprivation therapy (ADT; gonadotropin-releasing hormone [GnRH] agonist +/- antiandrogen) have a high risk of metastases and PC-specific death. We hypothesize that the addition of apalutamide, a selective androgen receptor (AR) antagonist, to GnRH agonist will improve metastasis-free survival in high-risk patients treated with primary RT. Methods: This is a randomized, multicenter, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy and safety of apalutamide in patients with high-risk localized or locally advanced PC (Gleason score of ≥ 8 and ≥ cT2c or a Gleason score of ≥ 7 and prostate-specific antigen ≥ 20 ng/mL and ≥ cT2c) receiving primary RT. Stratification: Gleason score (7 or ≥ 8), N0 or N1, brachytherapy boost (yes or no), and region (North American, European Union, or other). All patients will receive active treatment with a GnRH agonist throughout the 30 28-day treatment cycles. Randomization: 1:1 to apalutamide or control. Neoadjuvant/concurrent (cycles 1-4) to RT (74-80 Gy): apalutamide 240 mg/d vs bicalutamide 50 mg/d; adjuvant to RT (cycles 5-30): apalutamide 240 mg/d vs placebo. Primary end point: metastasis-free survival. Secondary end points: time to local-regional recurrence, time to castration-resistant disease, time to distant metastasis, and overall survival. Imaging with CT or MRI and bone scan will be conducted at baseline and then every 6 months following biochemical failure until documented distant metastasis by blinded-to-arm independent central review or death. Approximately 1500 patients will be accrued globally to provide appropriate statistical power to detect the hypothesized risk reduction (25%) in metastasis or death. An independent data monitoring committee is commissioned to review trial data. Clinical trial information: NCT02531516.
New steps forward for obstructive sleep apnoea in the era of precision medicine
Authors: Yüksel Peker, Patrick J. Strollo
Journal: European Respiratory Journal (2018)

Obstructive sleep apnoea (OSA) is a progressive disorder characterised by repeated upper-airway collapse during sleep that leads to intermittent hypoxia and hypercapnia, fragmented sleep, fluctuations in blood pressure and increased sympathetic nervous system activity [1]. Population studies in the early 1990s found OSA (defined by an apnoea–hypopnoea index (AHI) >5 events·h−1) in 9% of middle-aged women and 24% of middle-aged men [2]. A report from a working group on obstructive sleep apnoea discusses the current challenges in the field and proposes topics for future research <http://ow.ly/vcAi30kW8V5>
MicroRNAs (miRNAs) as predictors of extreme response to tyrosine kinase inhibitors in renal cell cancer (RCC).
Authors: Carmen Garrigos, Sonia Molina-Pinelo, Marta Espinosa, Antonio Lerma, Rainiero Ávila, Rafael Medina, Ana Salinas, Ricardo Melendez, Jesus Garcia-Donas, Cristina Rodriguez-Antona, Ignacio Duran
Journal: Journal of Clinical Oncology (2017)

e16076 Background: A number of different drugs are approved for the 1 st line treatment of mRCC and provide a median PFS of ≈ 11 months. Yet, a small subset of pts will present an unusually either short or prolong response [extreme responders]. MiRNAs are small fragments of RNA that modulate gene expression controlling cell development and differentiation. Promising results about their value as predictors of drug response have been published in lung and colorectal cancer [Molina-Pinelo]. This study aims to define miRNA profiles in RCC and determine whether they can predict “extreme responses”. Methods: The expression of 754 miRNAs was analyzed with TaqMan Low Density Array Human MicroRNA Panel (TLDA) (ThermoFisher). QPCR was carried out in the System of Gene Expression and Genotyping Arrays module ViiA7. We defined long-term response pts (LR) (PFS˃11 months, n = 7) and primary refractory pts (PR) (progression as best response, n = 8). MiRNAs differentially expressed were independently analyzed by individual qPCR assays in the study cohort and in an external validation cohort of pts (n = 35). Statistical analysis was performed with SPSSv20. Results: Four miRNAs were significantly associated with patient response and differentially expressed in PR vs LR (up-regulated in PR: miR-425-5p, down-regulated in PR: miR-139-3p, let-7d and let-7e). Let-7d and let-7e were validated internally (p &lt; 0.05) and all of them showed the same tendency but without statistically significance in the external validation cohort. Fourteen miRNAs had differential expression in tumor vs healthy tissue and seven were validated in the study cohort (tumor up-regulated: miR-146b, miR-21, miR-155, miR-122; tumor down-regulated: miR-135a, miR-200c and miR-187). When externally validated four (miR-135a, miR-200c, miR-187 and miR-21) (p &lt; 0.05) were confirmed. Conclusions: MiRNAs could represent a valid predictive biomarker in the development of RCC and its treatment. These results have been validated in an independent cohort. MiRNAs regulation in PR vs LR patients need to continue being validated in a more extensive cohort of pts.
Interaction of α2-macroglobulin with kallikrein and plasmin in ascitic fluid in ovarian cancer.
Authors: Tatiana Moiseenko, Elena Mikhaylovna Frantsiyants, Larisa Kozlova, Lyudmila Dmitriyevna Tkalya, Meri Viktorovich Adamyan, Oksana E. Kravtsova, Tatiyana Georgievna Chalabova, Oleg I. Kit
Journal: Journal of Clinical Oncology (2017)

e17030 Background: The kallikrein (KLKs) family is considered to be a regulator of many systems of limited proteolysis but can also be involved into pathology. Plasmin (P) regulates functions and density of the extracellular matrix, angiogenesis, maturation of gametes, sanation of cavities, tissues and body fluids, development of inflammation and malignant tumors. α2-Macroglobulin (α 2 M) is a molecular component of the body's endogenous protection. Ascitic fluid (AF) in various diseases of the ovaries is the biological environment valuable for the study of the affected organism containing protein about 20-50 g/L. KLKs, their proenzymes (pro-KLKs), Р, plasminogen (PG) and α 2 М in AF are poorly studied. Our purpose was to analyze the proteinase-inhibitory balance in AF of patients with ovarian cystadenocarcinoma (CAC) and tuberculosis of the uterine appendages (TA) to reveal its role in the development of the diseases and targets for the therapy. Methods: KLKs, pro-KLKs, Р, PG and α 2 М in AF in CAC of one ovary (n=26, T 3-4 N 0 M 0 ) were compared with the levels in AF of TA patients before treatment (n=11). All women were menopausal, aged 56.5±2.6 years. KLKs, pro-KLKs, Р, PG and α 2 М were determined before treatment using the U-2900 UV Solutions double-beam spectrophotometer (USA), the result was calculated per 1 mg of protein (by Lowry). The protein content in AF was comparable to the blood plasma one, so we took the values in the plasma of healthy donors as the norm (N). The data were processed using the Statistica 10 program. Results: The exudate is believed to occur mainly from inflammation-damaged vessels. High protein content in AF in CAC and TA allowed us to consider AF as the exudates. The pro-KLKs/KLKs ratio reflecting the rates of KLKs formation in AF was decreased in TA and CAC by 4.6 and 6.7 times compared to N. The РG/Р ratio in AF in CAC was decreased by 3.8 times; in TA it was similar to N with increased PG and P. The KLKs/α 2 М ratio in TA and CAC exceeded N by 4.6 and 2.7 times. The Р/α 2 М ratio in TA and CAC was 6.5 and 4.5 times higher than N. Conclusions: Activity of KLKs and P in AF in CAC and TA was higher than in the blood plasma of healthy donors. Activity of α 2 М in AF in CAC and TA was not sufficient to control KLKs and P.
Preoperative olaparib in early-stage endometrial cancer (EC): A phase 0, window of opportunity trial to evaluate the PARP inhibition effect, targeting cell cycle-related proteins (POLEN study).
Authors: Ignacio Romero, M. Jesús Rubio, Manuel Medina, Raquel Serrano, Eva Mª Guerra, Alfonso Cortes Salgado, Belén Pérez, Lucas Minig, Antonio Casado, Pluvio Coronado, Juan Fernando Cueva, Ana Vilar, Aureli Torné, Jaume Ordi, Sara Cros, Gaspar Salinas, Maria Santacana, Juan Antonio Schoenenberger-Arnaiz, Antonio Llombart-Cussac, Andres Poveda
Journal: Journal of Clinical Oncology (2018)

5598 Background: Olaparib (AZD2281, KU-0059436) is a poly ADP ribose polymerase (PARP) inhibitor. Biomarkers that predict a response to olaparib in EC are not fully established. The aim of this study is to identify pharmacodynamic and pharmacogenetic biomarkers associated with a short term exposure to olaparib in type I primary EC surgical patients (pts). Methods: In this phase 0, multicenter, single arm, window of opportunity trial, women diagnosed with type I primary EC received olaparib tablets (oral 300mg/BID; 4 weeks) before surgery. Biological effects were evaluated by comparing the initial biopsy and the tumor tissue at surgery. The primary endpoints were the significant inhibition of cyclin D1, Ki67 and active caspase 3 activity. Secondary objectives included the correlation between PARP inhibition and cell proliferation, angiogenesis and tumor-tissue biomarkers. The predictive role of PTEN, PMS2 and MSH6 mutations were evaluated. We control multiple testing issues with a false discovery rate (FDR) of 10%. Results: From March 2016, 41 pts have been screened, 36 included, 23 treated and 19 could be studied in biomarker analysis. Median age was 63y (51-82); 100% were endometrioid and clinical stage was I (17, 89.5%) and stages II, III and IV (2, 10.5%). Median time of olaparib exposure was 21 days (13-32). Significant inhibition was declared for cyclin D1 (p = 0.01), but not for Ki67 and active caspase 3 immunostaining. Differences in PARP1 baseline and post-treatment immunostaining correlates (Rho > 0.45; p < 0.05) with differences in pre-post cyclin D1, Ki67, phospho-histone H3, p50, VEGF and HIF1α measures. However, only cyclin D1 (Rho = 0.771, p < 0.001) showed a significant correlation under FDR criterion. Genetic alterations did not show differences in pre-post treatment measures. The most common AEs were nauseas (31.6%), vomiting (21.1%) and fatigue (21.1%) grade 1 and 2. No surgery was delayed due to toxicity. Conclusions: The study has identified some potential biomarkers associated with olaparib exposure in cell proliferation/apoptosis pathways that might help select best candidates. Clinical trial information: NCT02506816.