tbuckley/cabot-search huggingface dataset:
Baseline analysis of circulating tumor cell (CTC) enumeration and androgen receptor (AR) localization in men with metastatic castration-resistant prostate cancer (mCRPC) in TAXYNERGY.
Authors: Scott T. Tagawa, Giuseppe Galletti, Emmanuel S. Antonarakis, Shinsuke Tasaki, Ada Gjyrezi, Daniel Worroll, Luigi Portella, Brian J. Kirby, John Stewart, Atef Zaher, Fred Saad, Marie Vanhuyse, Shalu Suri, Timothy B Lannin, Conor Gruber, Erica Pratt, Guru Sonpavde, Mario A. Eisenberger, David M. Nanus, Paraskevi Giannakakou
Journal: Journal of Clinical Oncology (2015)

5031 Background: Microtubule-targeted therapy with taxanes is the only chemo with survival benefit in advanced PC. Emerging molecular evidence suggests sensitivity/resistance to taxanes may relate to the ability of microtubules to inhibit AR nuclear trafficking. CTCs represent a real-time biomarker for molecular testing including taxane-induced microtubule stabilization and AR nuclear localization. Methods: TAXYNERGY is an international, multicenter phase 2 trial in progressive, chemo-naïve mCRPC men randomized (2:1) to docetaxel or cabazitaxel. Pre-treatment CTCs were enriched from 1 ml blood via a prostate-specific microfluidic device, enumerated, and analyzed by multiplex confocal microscopy for AR cellular localization. Nuclear AR % was calculated by integrating fluorescence intensity in the total cell and nuclear area. Bivariate correlations and multiple regressions examined associations between baseline characteristics and % nuclear AR or CTC count. Results: 63 men were randomized (median age 70 [range 53–84], median PSA 89 [2.4–1558], 24 [38%] previously received a CYP17 inhibitor and/or enzalutamide, 17 [27%] had visceral metastases). Of 59 with evaluable samples, CTCs were detected in 52 (88%), median 10 CTCs/mL of blood [0–542]. 638 CTCs were analyzed for AR localization with a mean 61.2% [30–85] nuclear AR per subject. Higher baseline LDH, pain assessments, and ECOG performance status were associated with higher CTC counts; LDH (p = 0.013) and analgesic scores (p = 0.036) remained significant on multivariate analysis. Visceral metastases were associated with a lower fraction of nuclear AR, remaining significant on multivariate analysis (p = 0.045). Conclusions: Nearly 90% of men with progressive chemo-naïve mCRPC have detectable CTCs available for molecular analysis using this platform, with higher CTC counts associated with adverse prognostic variables. Lower percent of nuclear AR was associated with visceral metastases, suggesting progressive visceral CRPC may be less AR-driven. The predictive value of these biomarkers for taxane response is being evaluated. Clinical trial information: NCT01718353.
Phase I/II study of the safety, pharmacokinetics, and efficacy of pomalidomide in the treatment of Kaposi sarcoma in individuals with or without HIV.
Authors: Mark Niccolo Polizzotto, Thomas S. Uldrick, Kathleen Wyvill, Karen Aleman, Irini Sereti, Giovanna Tosato, Denise Whitby, Margaret Bevans, Frank Maldarelli, William Douglas Figg, Seth M. Steinberg, Robert Yarchoan
Journal: Journal of Clinical Oncology (2013)

TPS10595 Background: Kaposi sarcoma (KS) is a multicentric angioproliferative tumor seen most frequently in people with HIV. It is caused by the gammaherpesvirus Kaposi-sarcoma associated herpesvirus (KSHV, or human herpesvirus 8) and is remarkable for its tendency to progress or regress based on host immune factors. Pomalidomide is an orally available third generation thalidomide derivative with immunomodulatory and antiangiogenic properties that may address unmet clinical needs in KS. Methods: The primary objective is to assess the safety, tolerability and pharmacokinetics of pomalidomide in subjects with KS, whether HIV associated or not, and to explore its antitumor effect at the tolerable dose once determined. This is the first assessment of this agent in patients with HIV and/or KS. Subjects with confirmed KS and no symptomatic pulmonary or visceral KS are eligible. Those with HIV must be compliant with HAART; have achieved an HIV viral load &lt;10,000 copies/mL; and in the phase II portion have KS increasing despite HAART and HIV suppression for ≥2months, or stable despite HAART for ≥3months. In the phase I portion, up to 6 subjects will be treated with pomalidomide 5mg orally daily for 21 days of a 28 day cycle. Subject to evaluation of adverse events and tolerability, this may be deescalated to 3mg orally daily 21 of 28 days in a second cohort of up to 6 subjects. If either dose proves tolerable, the study will proceed to the phase II portion, and enroll up to 15 HIV positive and 10 HIV negative subjects. Antitumor activity will be assessed using modified ACTG KS response criteria in parallel with quality of life assessment. Key correlative studies include evaluation of immune responses including T cell numbers and activation in peripheral blood and tumor tissue and KSHV specific T-cell responses; HIV and KSHV activity and associated cytokines; and the first exploration of effects of pomalidomide pharmacokinetics when administered with common antiretroviral agents. Progress: The study opened to accrual in January 2012. The phase I portion is complete with no DLTs at the dose of 5mg 21 of 28 days. Phase II has accrued 11 subjects (4 HIV negative, 7 HIV positive) at this dose. Clinical trial information: NCT01495598.
Aspirin in the prevention of colorectal cancer recurrence.
Authors: Nimisha Kumari, Hiren A. Mandaliya, Tiffany Evans, Patrick McElduff, Christopher Oldmeadow, Fiona Lee Day
Journal: Journal of Clinical Oncology (2017)

578 Background: Aspirin use reduces the incidence of colorectal adenomas, and of colorectal cancer (CRC) in patients with hereditary non-polyposis colorectal cancer. There is limited data on the effect of aspirin in the secondary prevention of CRC, currently the subject of multiple prospective randomized trials. We aimed to test the hypothesis that aspirin reduces disease recurrence in patients diagnosed with early CRC at a high volume, single institution. Methods: A retrospective analysis was conducted of all patients (pts) treated with at least one cycle of adjuvant chemotherapy for stage II or III CRC over a 5yr period (2009–13). Patients with synchronous CRC were excluded. Aspirin use at the onset of adjuvant chemotherapy was sourced from the universal electronic recording of concomitant medications. Kaplan-Meier curves and the log-rank test were used to compare crude relapse free survival (RFS) between pts who were using aspirin to those who were not. Propensity score analyses was used to balance the groups according to potentially confounding variables: tumor site (colon vs rectum), tumor stage (II vs III), and adjuvant chemotherapy (oxaliplatin-based vs no oxaliplatin). The propensity scores were estimated through a multivariable logistic regression model, and a Cox proportional hazards model used to assess the effect of aspirin use on RFS in the sample weighted according to the inverse probability of receiving aspirin. Results: A cohort of 231 pts met eligibility criteria; median age 64yr; 50% colon, 50% rectal; 19% stage II, 81% stage III; 35% received oxaliplatin; 13% (n=31) were using aspirin and 26% of pts (n=61) developed CRC recurrence in median follow-up of 2.9yr. Unadjusted RFS was not significantly different for those using aspirin (log rank p value 0.88). There was good overlap in propensity scores for the two groups. The hazard ratio for RFS with aspirin use from the weighted Cox regression model was 1.2 (95% CI 0.62-2.29), indicating no statistically significant effect of aspirin on CRC relapse. Conclusions: In this single institution series, we did not find evidence that aspirin use at onset of chemotherapy had an effect on CRC relapse free survival. These results do not exclude an aspirin effect that is modest or restricted to select CRC subgroups.
Blockade of the PI3K-alpha isoform to inhibit myeloma cells.
Authors: Andreas Guenther, Renate Burger, Wolfram Klapper, Matthias Staudinger, Martin Gramatzki
Journal: Journal of Clinical Oncology (2014)

e19573 Background: Both, the phosphoinositide-3 kinase (PI3K)/AKT pathway as well as its downstream target, the mToR (mammalian target of rapamycin) kinase, are essential for the growth and survival of malignant plasma cells. PI3K exists in four isotypes (α - δ), which role is not defined in multiple myeloma (MM). Therefore, we evaluated systematically the anti-myeloma activity of BYL719, an inhibitor newly developed by Novartis Pharma and highly selective for the PI3Kα isoform. The activity of BYL719 was compared with other inhibitors of the PI3K/AKT/mToR signaling network. Methods: An MTS based growth assay with six human malignant plasma cell lines and two non-myeloma cell lines was used to measure growth inhibition of BYL719 in comparison to other inhibitors, namely the pan-PI3K inhibitors Ly294002 and BKM120, the dual PI3K/mToR inhibitor BEZ235, and the allosteric mToR inhibitors rapamycin and everolimus. Western blot analysis was used to confirm inhibitor activity and specificity. In addition, combinations of PI3K and mToR inhibitors were evaluated for antagonistic/synergistic activity using the CalcuSynTM (Biosoft) software. Results: The selective PI3Kα inhibitor BYL719 inhibited myeloma cell growth at a low dose level (IC50 < 10 µM in 5/6 cell lines), whereas non-MM cell lines were not affected. The pan-PI3K inhibitors showed comparable activity in all MM cell lines. BYL719 blocked phosphorylation of AKT in all tested MM cell lines including the resistant U266. Of particular note, whenever rapamycin was combined with a PI3K inhibitor, synergistic growth inhibition was seen. Conclusions: Here, in myeloma cells the PI3Kα isoform is reported to be the main activator of the AKT pathway and being essential for the growth of myeloma cells. The blockade of PI3Kα by reagents such as BYL719 appear to be particular advantageous for further development. In contrast, pan-PI3K inhibitors showed broader activity possibly acting on other targets than AKT. Allosteric mToR inhibitors, already active in early clinical trials in MM patients may provide interesting combination partners for PI3K-inhibitors.
Patulin, a Mycotoxin, Has Potent Cytotoxic Activity on Actue Lymphoblastic Leukemia and Induce Apoptosis through Intrinsic and Extrinsic Pathways.
Authors: Fengrong Wang, Ebeneier David, Sagar Lonial, Martha Arellano, Hanna J. Khoury, Amelia Langston, Mary Jo Lechowicz, Ned Waller
Journal: Blood (2007)
Milestone survival (MS): An alternative survival endpoint in cancer immunotherapies.
Authors: Tai-Tsang Chen
Journal: Journal of Clinical Oncology (2015)

e20004 Background: The presence of the unique survival kinetics and characteristics such as long-term survival and delayed clinical effect in immune checkpoint inhibitors could result in prolongation of study duration and loss of the power in study designs based on the proportional hazards assumption. MS, defined as the Kaplan-Meier survival probability at a prespecified time point, was proposed as an alternative survival endpoint in study designs that involve this new class of agents. The performance of MS was evaluated relative to that of the conventional overall survival (OS) endpoint based on the log-rank test. Methods: An example under the assumption of an overall hazard ratio of 0.75 was provided to illustrate the use of MS at 2 years based on Monte Carlo simulations. A group sequential design was first implemented to design studies under scenarios with various combinations of long-term survival and delayed clinical effects. The timings of the analyses obtained from these conventional designs were used as benchmarks to estimate the powers of the 2-year MS at the interim and final analyses, respectively. Results: At the final analysis, the statistical power of MS was approximately 80%, compared with 90% using OS when there was no delayed clinical effect. Powers were comparable between two endpoints when both long-term survival and delayed clinical effect were present. At the interim analysis, MS was the least powerful when the proportional hazards assumption held. The power at interim analysis was higher for MS when the study exhibited both long-term survival and delayed clinical effect. Conclusions: An alternative survival endpoint of MS was proposed to accelerate the drug development process while mitigating the long-term survival and delayed clinical effect introduced by immune checkpoint inhibitors, such as ipilimumab. This simulation study showed the endpoint of MS possessed higher interim power when both phenomena were present with overall study power comparable with OS. The proposed MS is an endpoint that is worth considering for late-stage drug development with immune checkpoint inhibitors.
NEOSCAN: Phase II trial of neoadjuvant chemotherapy for resectable lung cancers with switch to chemo alternative in <sup>18</sup>F-FDG PET nonresponders.
Authors: Mark G. Kris, Matthew David Hellmann, Jarushka Naidoo, Mark Dunphy, Camelia S. Sima, Robert J. Downey, William D. Travis, Christopher G. Azzoli, Jamie E. Chaft
Journal: Journal of Clinical Oncology (2014)

7515 Background: Perioperative chemotherapy improves survival in pts with resectable lung cancers. Administering chemotherapy prior to surgery enables assessment of response and opportunity to switch non-responding pts to potentially more effective regimens. Response measured by PET correlates better than CT with clinical outcomes. This trial assessed PET-guided neoadjuvant chemotherapy, assigning pts with suboptimal PET response after 2 cycles of platinum-based therapy to alternative “switch” chemotherapy. Methods: We enrolled pts with clinical stage IB-IIIA NSCLCs (primary tumor >2 cm and SUVmax≥4.5) deemed to be resectable by a thoracic surgeon. All pts had a pretreatment PET. Pts received 2 cycles of cisplatin (or carboplatin) + gemcitabine (squamous) or pemetrexed (adenocarcinoma/other), followed by repeat PET. If PET showed ≥35% decrease in SUVmax, pts continued on platinum-based therapy. Pts with suboptimal response (<35% decrease) were switched to vinorelbine + docetaxel q2 weeks (2 doses = 1 cycle). The primary endpoint was partial metabolic response after 2 cycles of “switch” therapy as assessed by PERCIST (SUVmax decrease ≥30% using the pre-switch scan as new baseline). We powered the study to detect a 30% response rate to “switch” chemotherapy (≥6 responses in ≤25 pts who received vinorelbine + docetaxel). Results: 32 pts were enrolled (7 gemcitabine, 25 pemetrexed). 21 (66%) had >35% decrease in SUVmax and continued platinum-based therapy. 11 (34%) had <35% decrease and switched therapy. The study met its primary endpoint when 6 of 9 pts (66%, 95% CI 35-88%) who received vinorelbine + docetaxel had a PERCIST partial metabolic response. 27 pts have been surgically explored with 23 (85%) R0 resections, including 7 of 7 who switched chemotherapy and were explored. There were no on-study deaths. Conclusions: Pts with resectable lung cancers who have a suboptimal PET response to histology-selected, platinum-doublet neoadjuvant chemotherapy can be effectively treated with vinorelbine and docetaxel followed by surgery. We now plan to correlate pathologic response in resected tumors with SUV change. Clinical trial information: NCT01443078.
MDCT and clinicopathologic characteristics of small bowel gastrointestinal stromal tumors (GISTs) in 102 patients: A single-institute experience.
Authors: Akshay Dwarka Baheti, Atul B. Shinagare, Ailbhe C O'Neill, Katherine Maragaret Krajewski, Jason L. Hornick, Suzanne George, Nikhil H. Ramaiya, Sree Harsha Tirumani
Journal: Journal of Clinical Oncology (2014)

10547 Background: SB is the 2nd most common site of GISTs and has worse prognosis than gastric GIST. We evaluated clinical presentation, pathology and imaging features of SB GIST. Methods: Imaging and clinicopathologic data of 102 pts (53M, 49F; mean age: 55 yrs; range: 19-83 yrs) with jejunal/ ileal GIST treated at our institute between 2002 and 2013 was reviewed. 2 radiologists in consensus reviewed imaging of treatment-naive primary in 41 pts and follow-up imaging in all pts. Results: 90/102 pts weresymptomatic at presentation (abdominal pain= 50, GI bleed= 40). Site of origin: jejunum= 64, ileum= 38. Risk stratification: low= 21; intermediate= 17; high= 64. Mean tumor size= 8.5 cm (range: 1-28 cm). On baseline CT (n= 41), tumors were predominantly well circumscribed and smooth/ mildly lobulated in contour. 22/41 tumors were exophytic, 16 had both exophytic and intraluminal components and 3 were intraluminal. 16/41 tumors were homogenous; 25 were heterogenous. Cystic/ necrotic areas (HU<20) were seen in 16/41 and calcification in 9. 14 homogenous (87%) and 16 heterogenous (64%) tumors had mitotic index ²5. CT demonstrated tumor-bowel fistula in 7/41, intraperitoneal rupture in 2 and bowel obstruction in 4. Amongst 102 total pts, metastases developed in 51 (27 at presentation), predominantly involving peritoneum and liver (refer table). 7/8 (87%) pts presenting with intraperitoneal rupture developed metastases. Metastases elsewhere were always associated with hepatic/ peritoneal metastases. At last follow-up, 28 pts were deceased (median survival 65 months, range: 22-179 months). Conclusions: SB GISTs were often symptomatic at presentation, high risk on pathology and had greater propensity for peritoneal metastases. On CT, they were predominantly large, well-circumscribed, exophytic tumors with or without cystic/ necrotic areas. Complications like rupture and bowel obstruction must be looked for. Metastases P without L L without P P+L Total Jejunum 8 7 16 31 Ileum 11 4 5 20 Abbreviations: L, liver; P, peritoneum.
Aromatase inhibitors, arthralgias, and exercise in breast cancer survivors.
Authors: Melinda Irwin, Brenda Cartmel, Elizabeth Ercolano, Martha Fiellin, Marianna Rothbard, Scott Capozza, Yang Zhou, Kathryn Schmitz, Jennifer A. Ligibel, Dawn L. Hershman, Tuhina Neogi, Cary P. Gross
Journal: Journal of Clinical Oncology (2012)

TPS669 Background: A substantial number of breast cancer survivors who are taking aromatase inhibitors (AIs) complain of side effects including arthralgias. Given the efficacy of AIs, it is essential that we identify approaches to mitigate arthralgias. We are conducting an NCI-funded trial is to examine the impact of a year-long exercise intervention in 180 breast cancer survivors taking an AI and experiencing at least mild arthralgias. Outcomes include severity of arthralgias, endocrine-related quality of life, % body fat, bone mass, and serum markers of inflammation. The purpose of this abstract is to present preliminary recruitment and adherence results. Methods: Women are being recruited via the Connecticut Tumor Registry and Rapid Case Ascertainment Shared Resource of Yale Cancer Center into the Hormones and Physical Exercise (HOPE) Study. Participants are randomly assigned to exercise (n = 90) or usual care (n = 90). The exercise intervention includes supervised resistance and unsupervised aerobic exercise sessions over 12 months. Data are collected at baseline, 3-, 6-, 9 and 12-months. Results: Study recruitment began in April 2010 and will continue through December 2012. As of January 1, 2012, we have received 1605 names of potentially eligible women. Of these 1605, 777 women are waiting to be screened (e.g., letter mailed to patient or on hold because recently diagnosed), 244 women could not be screened (e.g., unable to contact by phone), and 584 women have completed a telephone screening. Of the 584 women screened, 24% were ineligible because of discontinuing AIs because of arthralgias or chose not to take AIs primarily because of this potential side effect; another 36% were ineligible for various reasons; 24% were not interested; 11% were randomized (n = 65 women); and 5% are undergoing baseline visits (n = 29). On average, women are 62 yrs old and have been taking an AI for 1.8 yrs. Twenty-three women have completed the trial, with high exercise adherence rates (attendance to supervised sessions = 82% ). Conclusions: A growing number of women are choosing to not take AIs or are discontinuing AIs because of side effects. Our study may prove beneficial for the growing number of women diagnosed with hormone receptor-positive breast cancer each year.
Association of CpG island methylator phenotype (CIMP) with inferior progression-free survival with anti-EGFR monoclonal antibody therapy in metastatic colorectal cancer.
Authors: Michael Sangmin Lee, Michael J. Overman, Dipen M. Maru, Zhi-Qin Jiang, Shanequa Manuel, Cathy Eng, Bryan K. Kee, David R. Fogelman, Chris R. Garrett, Shailesh M Advani, Eduardo Vilar Sanchez, Imad Shureiqi, Robert A. Wolff, Stanley R. Hamilton, Scott Kopetz
Journal: Journal of Clinical Oncology (2014)

3633 Background: Deranged epigenetic regulation is thought to play an important role in pathogenesis and behavior of metastatic colorectal cancer (mCRC). The CpG island methylator phenotype (CIMP) is associated with distinct tumor biology, which may have differential sensitivity to targeted drug therapy. We hypothesized that methylation status affects susceptibility to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs). Methods: 195 mCRC patients initially tested as KRAS wild-type had tumor tissue successfully tested for CIMP status via bisulfite pyrosequencing and PCR amplification of MINT1, MINT2, and MINT31 loci and promoter sequences of p14, p16, and hMLH1. Next generation sequencing for KRAS, BRAF, and NRAS mutations was done. The duration of the first anti-EGFR mAb treatment and reason for cessation was retrospectively determined, and log-rank test was used for comparisons of progression-free survival (PFS). Cox regression analysis was performed. Results: 162 patients received therapy that included an anti-EGFR mAb: 24% CIMP-high (≥40% of tested sequences methylated), 40% CIMP-low, and 25% CIMP-none. Median PFS was 2.8 mo, 6.5 mo, and 6.5 mo respectively (p=0.0005 by log-rank test). On Cox regression analysis, CIMP-high was significantly associated with decreased PFS (HR 2.4, p=0.0002 on univariate analysis). CIMP-high status was associated with inferior PFS in the subgroup of patients known to be BRAF wild-type (p=0.03), and in the subgroup of known BRAF wild-type/NRAS wild-type patients (p=0.03). After excluding the 11 patients who received anti-EGFR mAb therapy first-line, CIMP-high status remained significantly associated with inferior PFS in the known BRAF wild-type and the known BRAF wild-type/NRAS wild-type subpopulations. Conclusions: CIMP-high methylation status is associated with shorter PFS on treatment with anti-EGFR mAb therapies, even among patients with BRAF and NRAS wild-type tumors.