tbuckley/cabot-search huggingface dataset:
Aspirin use and mortality in women with stage I-III breast cancer: A population-based study.
Authors: Thomas Ian Barron, Linda Sharp, Kathleen Bennett, Kala Visvanathan
Journal: Journal of Clinical Oncology (2012)

521 Background: Recent observational studies have associated aspirin (ASP) use with large reductions in breast cancer (BC) mortality. However, these studies have provided limited information on dose or duration of ASP use, key issues relevant to translation of the results into clinical practice. Methods: Linked National Cancer Registry Ireland and prescription refill data (General Medical Services Ireland, GMS) were used to identify women aged 50-80 with incident stage I-III BC (2001-2006). ASP use was defined as high or low by the median number of ASP days’ supply (85 days) in the 90 days pre-diagnosis. Full capture of ASP use is expected as the GMS provides all medications, including ASP, without charge. Hazard ratios (HR) with 95% confidence intervals (CI) for ASP use and (i) all-cause and (ii) BC-specific mortality were estimated using Cox proportional hazards models adjusted for age, stage, grade, ER, PR, HER-2 status, comorbidity and other drug exposures. Analyses were stratified by tumor stage and nodal status. Results: 2714 women with stage I-III BC were identified (median follow-up = 3.3 years), of whom 642 (23.7%) used ASP in the 90 days pre diagnosis. High and low ASP exposure groups were strongly predictive of post-diagnosis ASP exposure levels (High: mean post diagnosis exposure duration – 83% of follow-up; dose – 75mg/day in 91% of women. Low: mean post-diagnosis exposure duration – 58% of follow-up; dose – 75mg/day in 80% of women). Women with any ASP use had a non-significant reduction in all-cause (HR 0.85 95%CI 0.68, 1.06) and BC-specific (HR 0.86 95%CI 0.65, 1.15) mortality, compared to ASP unexposed women. However, in the dose response analysis high ASP exposure was associated with a significant reduction in all-cause (HR 0.70 95% CI 0.51, 0.95) and BC-specific (HR 0.63 95% CI 0.42, 0.96) mortality. No reduction was observed for low ASP exposure. The benefits of ASP exposure were greater in early stage, node negative disease. Conclusions: Only high ASP exposure was associated with a significant reduction in all cause and BC-specific mortality. These findings may explain inconsistent results from previous studies. Our findings can inform future clinical trials.
Imaging metastatic prostate cancer with <sup>18</sup>F-DCFBC PET/CT (DCFBC) and <sup>18</sup>F-NaF PET/CT (NaF).
Authors: Farhad Fakhrejahani, Maria Liza Lindenberg, Ethan S. Bargvall, Esther Mena, Baris Turkbey, Stephen Adler, James L. Gulley, Ravi Amrit Madan, Martin G. Pomper, William L. Dahut, Peter L. Choyke
Journal: Journal of Clinical Oncology (2017)

231 Background: Conventional imaging of advanced prostate cancer (computerized tomography and nuclear bone scintigraphy) is limited and indicates a need for a more specific molecular imaging probe. DCFBC is a radiolabeled PET agent that binds with high affinity to prostate specific membrane antigen (PSMA), which is overexpressed in almost all prostate cancers and through whole-body non-invasive functional imaging, may provide new information on the expression of PSMA. We compare the uptake of DCFBC in bone with respect to NaF PET/CT in metastatic prostate cancer patients. DCFBC has added capability to detect soft tissue metastasis whereas NaF is confined to secondary effects of bone disease. Methods: Subjects with known or suspected prostate cancer metastasis underwent DCFBC PET/CT imaging performed at 1 hour and 2 hours after IV bolus injection of 8 mCi of DCFBC. Patients also underwent a whole body NaF PET/CT scan within 3 weeks of DCFBC PET/CT to assess for bone metastases. Patients received 3 mCi of NaF IV bolus and then were imaged 1hour post injection. PSA levels and antiandrogen therapy status were obtained at the time of DCFBC imaging. Results: Fifteen patients have been preliminarily analyzed. PSA ranged from &lt; .01 to 4379 ng/mL. NaF identified bone lesions in 10 patients but matching focal DCFBC uptake was only seen in 3 patients. DCFBC additionally showed lymph node metastasis in 1of these 3 patient. There were 5 patients without focal abnormal bone uptake on NaF or DCFBC. In this group, 4 of 5 patients had focal DCFBC uptake in lymph nodes or soft tissue lesions. Ten patients were on some form of androgen deprivation therapy (ADT). For those on ADT, 7 of 10 patients had positive findings on NaF, compared to 2 of 10 patients on DCFBC. Conclusions: DCFBC uptake in bone metastasis does not routinely correspond to focal NaF uptake which could be due to distinct mechanisms of tracer uptake and tumor biology. There is an inverse association in focal bone findings when comparing each tracer on antiandrogen therapy. Through whole-body non-invasive functional imaging and further study, DCFBC may prove useful in characterizing prostate cancer based on PSMA expression. Clinical trial information: NCT02190279.
Pharmacokinetic study of a combination chemo-endocrine treatment of paclitaxel and toremifene
Authors: T. Saeki, A. Okita, K. Aogi, T. Kakishita, R. Okita, N. Taira, S. Takashima, K. Fujita, K. Nishikawa
Journal: Journal of Clinical Oncology (2007)

13017 Background: The mechanism of paclitaxel (PXL) resistance has been investigated. P-glycoprotein (P-gp) on cell membrane could be an important target for improving efficacy of PXL. Toremifene (TOR) may moderate P-gp-related drug resistance in vitro. To determine safety and efficacy of PXL and TOR, we conducted a pharmacokinetic study for a combination chemo-endocrine treatment of PXL plus TOR for metastatic breast cancer. Methods: Patients with metastatic breast cancer, who were previously treated with a standard chemotherapy without PXL, were eligible. Patients received PXL 80 mg/m 2 (i.v.) weekly on days 1, 8, and 15 in a cycle. Concurrently, toremifene 120mg/body (p.o.) was given dairy from day 1–28 in a cycle. For pharmacokinetic study, single agent of PXL was initially administrated on day 1, 8, and 15. From day 18, TOR 120mg/body was given dairy. On day 22, PXL administration in second cycle was skipped. On day 32, blood samples were collected from the patients received PXL 80 mg/m 2 + TOR 120 mg/day/body. Samples were analyzed by HPLC (Unisil Q 5CN). Response was evaluated by WHO criteria and adverse events were evaluated by NCI•CTC Ver.2. Results: Nineteen patients were enrolled. Out of 19, 15 patients had measurable disease, and 1 partial response, 8 stable disease, and 6 progressive disease were observed. The addition of TOR caused in no specific adverse events more than grade 3 and toxic profile in combination was similar that in PXL monotherapy. Pharmacokinetic profile of PXL was similar with/without TOR. In addition, Cmax of TOR was 1.85±0.71 mg/mL. Tmax was 2.9±1.8 hr were observed. AUC 0–8 of TOR was not affected in the presence of PXL. AUC 0- 8 of TOR-1, metabolite of TOR, also demonstrated the similar pharmacokinetic profile. Pharmacokinetic parameters of PXL did not reveal intra-patient variability in previously treated metastatic breast cancer patients. Conclusions: Pharmacokinetic profile in a combination of PXL and TOR was similar that in PXL monotherapy. The addition of TOR to PXL for previously treated metastatic breast cancer patients might be safety. No significant financial relationships to disclose.
Allogeneic partially HLA-matched dendritic cells (DC) as a vaccine in metastatic renal cell cancer (mRCC): Final analysis of a clinical phase I/II study.
Authors: Anne Flörcken, Joachim Kopp, Kamran Movassaghi, Antje van Lessen, Anna Takvorian, Constanze Schönemann, Korinna Jöhrens, Markus Möbs, Birgit Sawitzki, Bernd Dörken, Antonio Pezzutto, Jörg Westermann
Journal: Journal of Clinical Oncology (2012)

e15053 Background: Despite novel kinase inhibitors, prognosis of metastatic RCC remains poor and new experimental approaches are warranted. Our aim was to evaluate a DC-based vaccine, which exploits alloreactivity as a means to amplify specific anti-tumor immune responses. Methods: Allogeneic, partially HLA-matched DC were generated in our GMP facility. DC were loaded with autologous tumor lysate. 8 patients with progressive mRCC were included, 7 patients were immunized repetitively with 10 7 DC s.c. over 20 weeks. Low-dose IL-2 (3 Mio U s.c. qd) was used concomitantly. Endpoints of the study were feasibility, safety, immunological and clinical responses. T cell responses against HLA-A2-restricted RCC-associated antigens were evaluated by proliferation assays, ELISpot and cytokine bead array (CBA). T cell repertoire was analysed by T cell receptor γ and –β PCR. Results: Vaccination was feasible and safe, no treatment-related grade 3/4 toxicity or clinically relevant autoimmunity was observed. No objective responses were observed, however, 2/7 patients showed stable disease, one a minimal clinical response. The mean TTP was 24.6 weeks (range 5 to 96). Delayed-type hypersensitivity was detected in 3/7 and HLA antibodies were induced in 3/7 patients. In 3/7 patients T cell responses against RCC-associated antigens such as TYMS, G250, vimentin, surviving and cyclin-D1 were induced by vaccination. These antigen-specific T cells showed a predominant TH1-cytokine profile. Interestingly, a clonally expanded T cell population could be detected by γ- and –β PCR in one patient with both a minimal clinical response and a T cell response. This clone is currently persisting for more than 80 months, its specificity is under investigation. Conclusions: Vaccination with allogeneic tumor-lysate-loaded DC was feasible, safe and was able to induce TH1-polarized immune responses against RCC-associated antigens. Tumor vaccination might be a promising approach in minimal residual disease, possibly in combination with antibodies against CTLA-4 or PD-1.
Genotype characterization and prognosis of unknown primary melanoma patients with nodal metastases.
Authors: Aleksandra Gos, Caroline Robert, Monika Jurkowska, Nyam Kamsu-Kom, Wanda Michej, Arkadiusz Jeziorski, Christiane A. Voit, Joachim Roewert-Huber, Janusz A Siedlecki, Alexander Christopher Jonathan Van Akkooi, Alexander M. Eggermont, Piotr Rutkowski
Journal: Journal of Clinical Oncology (2012)

e19022 Background: Melanoma of unknown primary site (MUP) is unique, not completely understood entity with nodal metastases as the most common clinical manifestation. The aim of this multicentric study was to assess genetic alterations in MUP with clinically detected nodal metastases in terms of clinicopathological features and prognosis. Methods: We analyzed contemporary series of 37 MUP patients (median age 51 years) after therapeutic lymphadenectomy - LND (period: 1996-2010, 20 – axillary, 16 - inguinal, 1 – other basin) not treated with BRAF inhibitors and performed molecular characterization of BRAF/NRAS mutational status in nodal metastases using direct sequencing of respective coding sequences. Median follow-up time was 37 months. Results: BRAF mutations were detected in 23 (63%) cases (21 V600E - 91%, 2 others - 9%), and mutually exclusive NRAS mutations in 3 (8%) cases (Q61K, Q61R, Q13R). Presence of BRAF mutation correlated with younger age of patients (median 47 vs 60 years for BRAF+ vs. BRAF-, p&lt;0.05). 3-year overall survival (OS) was 45%, median – 23 months (from date of lymph node dissection). We have not found any difference in terms of OS between BRAF mutated- and wild-type melanomas (p=0.99). Conclusions: This unique, comprehensive study on molecular characterization of MUP with nodal involvement stage showed that MUPs have similar molecular features as sporadic non-chronic-sun-damaged melanomas. BRAF mutational status has no prognostic value in this group of patients, what may have potential implications for adjuvant therapy.
Risk factors of lymph node metastasis in undifferentiated early gastric cancers.
Authors: Il Kim, DaeYoung Cheung, Jin Il Kim, Jae J. Kim
Journal: Journal of Clinical Oncology (2017)

171 Background: The aims of this retrospective study were to analyze risk factors of lymph node metastasis undifferentiated-type early gastric cancer (UD-type EGC) and to select the suitable patient for endoscopic resection. Methods: We analyzed 368 patients who had undergone gastrectomy with lymphadenectomy for UD-type EGC between November 2001 and July 2016 at the Yeouido St. Mary’s Hospital. Using clinicopathological factors of patient age, size, an endoscopic macroscopic tumor form, ulceration, depth, histology, lymphatic involvement (LI) and venous involvement (VI), LNM risk was examined and stratified by univariate analysis and multivariate analysis. Results: Of the 368 patients, the lymph node metastases rate in patients with EGC was 48 patients (13%). 204 (55 %) had mucosal cancers and 164 (45 %) had submucosal cancers. Univariate analysis revealed &gt; 60 age, &gt; 2 cm, submucosal(sm), poorly cohesive carcinoma as significant prognostic factors. On multivariate analysis, &gt; 60 age (odd ratio , 2.20; 95% confidence interval, 1.19~4.06), submucosal(odd ratio , 9.38; 95% confidence interval, 4.08~21.56), poorly cohesive carcinoma (odd ratio, 0.33; 95% confidence interval, 0.12~0.86) were independent risk factors for lymph node involvement. Conclusions: LNM-related factors in undiff-EGC were age, depth and pathology. We proposed that risk factors for metastases should be considered when choosing surgery for EGC.
Pathway redundancy and feedback loop as drivers of nonresponse in colorectal cancer treatments.
Authors: Hee Cheol Kim, Phillip Sangwook Kim, Jeeyun Lee, Joon Oh Park, Tani Ann T. Lee, Xinjun Liu, Se Hoon Park, Anne Kuller, Sharat Singh, Won Ki Kang, Young Suk Park
Journal: Journal of Clinical Oncology (2013)

e14626 Background: There is urgent need for rational therapy selection based on functional-pathway characterization to achieve significantly improved clinical outcome. Methods: 207 CRC patients were evaluated for &gt;100 signal transduction proteins. Receptor tyrosine kinases (RTKs, i.e. ErbBs, FGFRs, VEGFRs, cMET, IGF1R, etc) and non-RTKs (Src, FAK, etc) as well as Jak/Stat along with AKT and MAPK pathway proteins were analyzed for their level of expression and activation utilizing Collaborative Enzyme Enhanced Reactive (CEER) immunoarray. In addition to pathway profiling, samples were also molecularly characterized for 14 different mutations within the KRAS, BRAF and PIK3CA oncogenes. Results: Both ErbB/VEGFR driven and ErbB/VEGFR-independent signal transduction activation patterns were observed in the CRC patients with complex redundant pathway circuitry. Phosphorylated RTKs led to downstream AKT and MAPK pathway activation. Various mutations in KRAS, PIK3CA and BRAF were found in 42%, 11% and 4% of CRC patients, respectively. KRAS G12D and G13D mutations were the most frequent mutations. Percent of mutant alleles per input DNA increased in matching metastatic tumors when compared to the primary tumors. While downstream signal transduction via AKT and MAPK pathways were similar in both wild-type and mutant tumors, we observed higher levels of potential compensating non-ErbB driven RTK expression/activation in KRAS mutant patients. A significant pathway redundancy was detected in most tumors. Furthermore, pathway diversity in tumors with identical mutational background was evident in this analysis. Conclusions: CEER-based pathway analysis adds value towards understanding of CRC tumor¡&amp;hibar;s potential response under various clinical scenarios. The comprehensive characterization of pathway redundancy allows for rational selection of a combination of targeted agents. A combination of Erbitux with anti-angiogenic therapy may provide most benefit for patients with concomitant EGFR and VEGFR2 activation. Based on pathway circuitry determined by CEER, clinicians can optimize clinical decisions in selecting more effective therapies that target relevant pathway proteins.
Results of the CARMA study to investigate catumaxomab therapy for ascites related to peritoneal carcinomatosis in clinical practice.
Authors: Christian M. Kurbacher, Jalid Sehouli, Manfred Welslau, G.-F. Tempelhoff, J. Kufahl, Christian Marth, Helmut Oettle, Barbara Schmalfeldt, Elisabeth Urban, Volker Kunzmann
Journal: Journal of Clinical Oncology (2013)

TPS3119^ Background: The trifunctional antibody CATU (catumaxomab) is approved in the EU for intraperitoneal (IP) treatment of malignant ascites (MA) in patients (pts) with EpCAM-positive carcinomas. Clinical data for CATU are based on 2 phase III and several phase I/II trials. However, the routine use of CATU has not been evaluated systematically. Therefore, a prospective observational study (CARMA) was started in 2010 investigating the administration of CATU in a total of 160 pts with MA under routine conditions. Participating centers were hospitals and oncologic practices in Germany and Austria. Hereby, we report on the results of the 2 nd interim CARMA analysis. Methods: This analysis included 103 pts with MA due to EpCAM-positive carcinomas: ovarian, n=37; gastric, n=13; pancreatic, n=10; colorectal, n=6, miscellaneous, n=37. Pts were treated with CATU at a routine setting at 4 increasing dosages over a 2-week interval. The primary endpoint was puncture-free interval (PFI), secondary endpoints included safety and overall survival (OS). Results: The study population mainly comprised pts with advanced-stage disease. In 65% distant metastases were present. Therapy was given in 24 hospitals (73 %) and 9 outpatient facilities (27 %). Pts suffered from typical MA related symptoms such as abdominal swelling (77%), pain (56%), dyspnea (27%), anorexia (31%), constipation (13%). In 67 pts (65%), CATU was given as planned, 36 pts (35%) received &lt;4 infusions. Most frequent adverse events (AE) were fever (20%), nausea (14%) and diarrhea (6%).The median PFI was 57 days (d), the median OS was 100 d. For the subgroups ovar/non-ovar, a median PFI of 93/41 d and a median OS of 115/72 d was observed. Conclusion: CARMA represents the first systematic evaluation of CATU therapy given for MA under routine conditions. In accordance to previous prospective trials, the presented 2 nd interim-analysis was able to demonstrate a clinically meaningful benefit of CATU, particularly impressive in ovarian cancer pts. CATU showed an acceptable safety profile, thus allowing for treatment at an outpatient setting in an adequately selected group of pts. The final CARMA analysis after including 160 pts is thus eagerly awaited. Clinical trial information: DRKS00000458.
Tamoxifen therapy for breast cancer and its relation to the prognosis and histopathology in subsequent endometrial cancer
Authors: C. Lasset, V. Bonadona, H. Mignotte, C. Bailly, I. Treilleux, V. Becette, J. Anjou, A. Bremond, F. Chauvin
Journal: Journal of Clinical Oncology (2004)

1016 Background: Tamoxifen-associated endometrial cancers may have poor prognosis but few data are available. We examined whether exposure to tamoxifen at defined steps of endometrial carcinogenesis could be associated with poor-prognosis tumours Methods: From a hospital-based case-control study*, 115 women with endometrial cancer after breast cancer were selected for pathological review. The delay between tamoxifen initiation and diagnosis of endometrial cancer was define as early- (delay <=5 years) and late- (delay >5 years) onset tumours. Results: The 5-year endometrial cancer-specific (ECS)-survival rate was worse in tamoxifen users for >5 years (55% vs 84% for 2–5 years, 86% for <2 years and 97% in non users, p<0.001). Tamoxifen use >5 years was independently linked to a lower survival rate (Cox model relative risk 7.9, p=0.03) and was associated with a high frequency of grade >=2 tumours (75.0% vs 44.8% for 2–5 years, 33.3% for <2 years and 21% in non users, p=0.05). Among tamoxifen users for 2–5 years, late onset tumours had poorer prognosis than early onset tumours (5-year ECS-survival rate 60.8% vs 95.0%, p=0.02 Late onset tumours in tamoxifen users for 2–5 years and tumours in users for >5 years had similar higher rates of adverse features (non endometrioid histology: 35.7% and 20%; grade >=2: 66.7% and 75%). Conclusions: Late onset tumours in women treated with tamoxifen for more than 2 years have poor outcome, due to frequent high grade of malignancy. The poor prognosis of tamoxifen-associated endometrial cancer might be due to exposure to tamoxifen during the early steps of endometrial carcinogenesis rather than to the duration of the treatment. As early exposure to tamoxifen could induce aggressive tumours, many women treated with tamoxifen for no more than five years may die from endometrial cancer. Long-term evaluation of the risk-benefit ratio of tamoxifen in chemoprevention trials clearly remains essential. * Mignotte H, Lasset C et al. Int J Cancer. 1998; 76:325–30. No significant financial relationships to disclose.
Impact of circulating tumor cell (CTC) nucleus size on outcomes with abiraterone acetate (AA) therapy in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: David Michael Gill, Neeraj Agarwal, Andrew W. Hahn, Eric Johnson, Austin Poole, Emma Carroll, Kenneth M. Boucher, Mohamed E. Salama, Archana M. Agarwal
Journal: Journal of Clinical Oncology (2017)

253 Background: CTC enumeration but not CTC morphology has been reported to predict outcomes to treatment in men with mCRPC. Recently Chen JF et. al (Cancer, 2015) showed an association with nuclear size and incidence of visceral disease in metastatic prostate cancer. In this study, we investigate the impact of CTC nucleus size on outcomes in men treated with AA for mCRPC. Methods: In a cohort of men with mCRPC treated with first-line AA, who had CTCs identified by CellSearch (CS) analysis prior to initiating treatment, we retrospectively quantified the nuclear size of CTCs by ImageJ/Fiji 1.46 software and correlated with progression free survival (PFS) on AA. We analyzed with univariate in addition to pre-specified multivariable analysis adjusted for Gleason score and baseline log PSA to assess independent predictive value of CTC nuclear size on PFS. Median PFS was calculated by Kaplan-Meier analysis and p-values were determined from Cox proportional hazards model. Results: 22 men treated with AA for mCRPC were included. Median nucleus size was 23.8 µm. Patients were divided in to 2 cohorts: small nuclear cohort (CTC nucleus size &lt; 23.8 µm) vs large nuclear cohort (CTC nucleus size ≥23.8 µm). There was a non-significant trend towards worsened PFS (5.8 versus 6.8 months) in the larger nuclear size arm (Table). Conclusions: In this cohort of men with CRPC treated with AA, there is a non-significant trend towards decreased PFS associated with larger CTC nucleus size. Data are hypothesis generating and require further interrogation in a larger cohort. [Table: see text]