bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II trial of the multitargeted kinase inhibitor lenvatinib (E7080) in advanced medullary thyroid cancer (MTC).
Authors: Schlumberger Martin , Jarzab Barbara , Cabanillas Maria E. , Robinson Bruce , Pacini Furio , Ball Douglas Wilmot , McCaffrey Judith C , Newbold Kate , Allison Roger , Martins Renato , Licitra Lisa F. , Shah Manisha H. , Bodenner Donald , Elisei Rossella , Burmeister Lynn A. , Funahashi Yasuhiro , Sellecchia Rita , Andresen Corina , O'Brien James P. , Sherman Steven I. 
Published: March 2020

5591 Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In phase I studies of lenvatinib partial responses (PR) were observed in thyroid as well as melanoma, endometrial, and renal cancers. Methods: Patients (pts) with unresectable MTC and disease progression demonstrated by RECIST during the prior 12 months were enrolled. Pts may have received prior VEGFR targeted therapy. Pts were treated with a starting dose of lenvatinib 24 mg once daily in 28 day cycles until disease progression or development of unmanageable toxicities. Primary end point was Response Rate (RR) by RECIST. Tumor genetic analysis and circulating cytokine and angiogenic factors (CAF) analysis were performed. Results: 59 pts were enrolled (med age: 52; Male: 63%;) and are evaluable for response. 54% of pts required dose reduction for management of toxicity, and 22% were withdrawn from therapy due to toxicity. The most common treatment-related adverse events were proteinuria 58% (Gr3: 2%), diarrhea 56% (Gr3: 5%), hypertension 48% (Gr3: 7%), fatigue 44% (Gr3: 5%), decreased appetite 41% (Gr3: 5%), nausea 34% (Gr3: 0), and weight decreased 32% (Gr3: 3%). No Gr4 events were reported for these event categories. Confirmed PRs were observed in 21pts (RR: 36%, 95% CI: 24-49) based on independent imaging review (IIR) and 29 pts (RR: 49%, 95% CI: 36-62) based on investigator assessment. For pts who received prior VEGFR-directed treatment (n=26) RR=35% (IIR); with no prior VEGFR-directed treatment (n=33) RR=36 % (IIR). Median PFS by IRR is 9.0 mo (95% CI: 7.0-) (based on minimum 8 mo. f/u, 46% events observed). There was no clear difference in treatment response between RET-mutant (RET-mu) and RET-wild type (RET-wt) patients. Low baseline levels of ANG2, sTie-2, HGF and IL-8 were associated with greater tumor shrinkage and prolonged PFS whereas high baseline levels of VEGF and sVEGFR3 were associated with greater tumor shrinkage. Conclusions: Lenvatinib administered orally at a dose of 24 mg once daily to patients with MTC is associated with manageable toxicity and a RR of 36%, identifying lenvatinib as a promising new potential therapeutic agent for treating patients affected with this disease.
Final results of a phase II study of sorafenib in combination with carboplatin and paclitaxel in patients with metastatic or recurrent squamous cell cancer of the head and neck (SCCHN).
Authors: Blumenschein George R. , Glisson Bonnie S. , Lu Charles , Sabichi Anita Lyn , Ginsberg Lawrence E. , Bartos Claudia I. , Feng Lei , Tran Hai T. , El-Naggar Adel K. , Lippman Scott Michael , Kies Merrill S. 
Published: March 2020

5592 Background: Cytotoxic chemotherapy (CT) is the current standard treatment for metastatic/recurrent SCCHN. The prognosis for these patients (PTS) is poor with a median progression free survival (PFS) of 4 months with CT. Survival in PTS with SCCHN may correlate inversely with the number of angiogenic growth factors secreted. Sorafenib is a potent inhibitor of c-Raf, b-Raf, VEGFR-1/2/3 and PDGFR-β. To investigate the hypothesis that a multi-targeted TKI added to chemotherapy would improve outcomes in patients with metastatic/recurrent SCCHN, we performed a phase II trial of paclitaxel and carboplatin and sorafenib (PCS). Methods: PTS were required to have ECOG PS 0-1, measurable disease, controlled blood pressure, and may have received one regimen of induction, concomitant or adjuvant CT, but not CT for recurrent/metastatic disease. Sites of primary disease excluded nasopharynx and paranasal sinus. Treatment consisted P 200mg/m2 and C AUC 6 intravenously on day 1 followed by S 400 mg orally bid (days 2-19) in every 3-week cycles. Primary endpoint was PFS, targeting median PFS of 6 months (M). Secondary endpoints include overall survival (OS), response rate (RR), exploratory biomarkers, and toxicity. Results: Forty-eight PTS with SCCHN were enrolled with 44 PTS evaluable for PFS and response using RECIST. Median age: 56 years (22-79 years), 89% male, median ECOG PS 1. Median follow-up was 24.1 M. RR was 55% (n=24), disease control rate was 84% (n=37), median PFS was 8.51 M (95% CI: 5.98 ~ 13 months), and median OS was 22.6 M (95% CI: 13.1 - NA months). Grade ³3 treatment related toxicities included hand-foot syndrome (n=10), neutropenia (n=5), pain (n=6), elevated lipase (n=4), elevated amylase (n=3), anemia (n=3), fatigue (n=2), hypertension (n=2), neuropathy (n=2), febrile neutropenia (n=2), and thrombocytopenia (n=2). Conclusions: The combination of PCS was well tolerated and had encouraging activity in recurrent/metastatic SCCHN. Blood-based and tissue biomarkers are being analyzed. Final outcomes, toxicity, and correlative biomarker data will be reported.
Contralateral parotid volume as an objective marker for adaptive radiotherapy in head and neck cancer.
Authors: Gagnon Patrick James , Simeonova Anna , Fuss Martin , Weintraub Sheri , Thomas Charles R. , Holland John M 
Published: March 2020

5596^ Background: Deformable image registration simplifies the process of adaptive radiotherapy and allows for sophisticated dosimetric analyses of anatomic changes. Lacking is an objective measurement that could reliably predict for undesirable dosimetric changes during a course of radiotherapy. We analyzed daily changes in contralateral parotid volume and correlated these changes to mean dose delivered to the parotid gland over a course of radiotherapy in four patients. Methods: Daily cone-beam CT (CBCT) scans of four patients were imported into the MIM Maestro software. The simulation CT scan was registered to 35 daily CBCT’s per patient using a sequence of rigid and deformable registrations. Parotid contours were resampled and a deformed reconstruction of the planning CT was exported to the Eclipse treatment planning software. The CT reconstructions were extended superiorly and inferiorly and the original fluence map was re-computed on the reconstructions with the isocenter at daily treatment position. Mean dose percent change and mean volume percent change were calculated for all CBCT’s and averaged across all patients. Average mean dose percent change was plotted against average mean volume change and evaluated with simple regression analysis. Results: A mean of 31 CBCT’s per patient were evaluated. Contralateral parotid volume percent changes for all patients were -31%, -40%, -40%, and -22% with a mean percent change of -33%. Mean dose percent changes were 25%, 35%, 19%, and 25% with a mean percent change of 26% and a mean absolute dose increase to the parotids of 6.8 Gy. Simple regression analysis identified a coefficient of determination (R2) of 0.23 where the independent variable is volume percent change and the dependent variable is mean dose percent change. Conclusions: Daily or weekly volume assessment of critical volumes is feasible utilizing deformable image registration and CBCT. Our data suggests there may be a correlation between parotid volume changes and increases in mean parotid dose though no causality is inferred. This relationship could be useful as a simple objective volumetric threshold measurement to prompt adaptive re-planning and warrants further investigation.
Effect of MDV3100, an androgen receptor signaling inhibitor, on tumor growth of estrogen and androgen receptor-positive (ER+/AR+) breast cancer xenografts.
Authors: Elias Anthony D. , Cochrane Dawn R. , Jacobsen Britta M. , Cittelly Diana M. , Howe Erin N. , Jean Annie , Spoelstra Nicole S. , Protter Andrew A , Richer Jennifer K. 
Published: March 2020

564 Background: The androgen receptor (AR) is detected by immunohistochemistry in approximately 75% of all invasive breast cancer; with ~88% of ER+ tumors expressing AR. Potent inhibition of AR activity could be a therapeutic strategy in ER+/AR+ breast cancer. MDV3100 is an androgen receptor signaling inhibitor (ARSI), which inhibits AR activity via three mechanisms: inhibition of androgen binding to AR, inhibition of AR nuclear translocation, and inhibition of nuclear AR-DNA binding. MDV3100 has demonstrated an overall survival benefit in men with post-docetaxel prostate cancer. Methods: Two ER+/AR+ breast cancer cell lines, MCF7 and BCK4 (recently derived from a pleurocentesis), were used to assess the proliferative effect of dihydrotestosterone (DHT) and estradiol (E2). The efficacy of MDV3100 at blocking DHT-mediated proliferation was compared to bicalutamide in ER+/AR+ breast cancer cells. MCF7 xenograft studies were performed to determine if MDV3100 can affect DHT or E2 mediated proliferation in vivo. Results: Both bicalutamide and MDV3100 inhibited DHT-mediated proliferation of ER+/AR+ cell lines. Although MDV3100 binds AR very effectively and does not bind ER, it also uniquely inhibited E2-mediated proliferation, while bicalutamide slightly enhanced E2 mediated proliferation. Results presented here demonstrate that MDV3100 inhibited E2-stimulated tumor growth of MCF7 mammary xenografts as effectively as tamoxifen. Conclusions: MDV3100 blocked both DHT- and E2-mediated growth of breast cancer cells, whereas bicalutamide enhanced E2-mediated proliferation. MDV3100 may have unique therapeutic utility in patients with AR+ breast cancer, regardless of ER status. Funding: DOD Breast Cancer Program Idea Award BC074403, Avon Foundation for Women, and University of Colorado Cancer Center pilot project funds to JKR.
ERβ mRNA expression in ERα-negative and triple-negative breast cancers.
Authors: Choi Young , Kim Hadong , Kim Tae-Hoon 
Published: March 2020

574 Background: ERα is the main prognostic and therapeutic marker in breast cancer (BC). About 30% of BC cases are negative for ER (ERα-) and do not benefit from antiestrogen therapy (TAM). We aim to study ER-beta (ERβ) expression in ERα- and triple negative (TN) cancers to explore alternate pathway of treatment in this cohort. Methods: We studied 67 ERα- BC cases including 44 TN together with 74 ERα +BC cases obtained from patients aged 29 to 97 years old between 2003 and 2010. The histology included 110 intraductal, 12 medullary and 19 other types. 78 cases were grade 3, 52 were grade 2, and 11 were grade 1. RNA was extracted from FFPE and mRNA levels of ERβ isoform and ERα were determined by real-time quantitative reverse transcription PCR. IHC stains were done on TMA the sections for ERα, PR, Her-2, Ki-67, CK5/6 and Cyclin D1. Results: ERβ isoforms were highly expressed in ERα-, TN, basal-like and HER2 type BC cases. ERβ2 was the major ERβ variant expressed. Ki-67 proliferating cells (>20% nuclear staining) were mostly in ERα- rather than ERα+ cases (69.0% vs. 31.0%) as were cyclin D1- cells (82.2% vs. 17.8%). On the other hand, in ERα+ BC, ERα mRNA expression was consistently high and upregulated, and ERβ, low and down regulated, and the ratio of ERα+ to ERβ+ ranged from 3 to 100. ERβ1, 2 and 5 were co-expressed with ERα in 56%, 63%, and 30% of cases, respectively. Overall, ERβ mRNA levels did not show any significant correlation with age, tumor size, lymph node status and histological grades. Conclusions: ERβ-dependent proliferating tumor cells may render them more sensitive to TAM, and increase the effectiveness of TAM and its metabolites in ERα- and TN cases. Increased overall survival after adjuvant TAM ERα-BC may be directly related to ERβ over-expression. ERβ isoform is potential selective therapeutic target in a sub-cohort of ERα- BC. Additionally, when ERβ and ERα are co-expressed, ERβ appears to play a distinct role from its action in ERα- BC. [Table: see text]
Assessment of method of breast cancer detection and Oncotype DX recurrence score.
Authors: Kelly Ciara Marie , Parker Imelda , McCaffrey John , Crown John , O'Connor Miriam , McGee Sharon F. , Pusztai Lajos , Kelly Catherine M. 
Published: March 2020

581 Background: Data indicate that screen-detected (SD) cancers show more favourable pathological characteristics and have a better prognosis compared to symptomatic or interval cancers (SY). These findings can be partly explained by length time and lead time biases. OncotypeDX recurrence score (RS) provides prognostic information independent of traditional clinicopathological variables and provides a robust measure of tumour proliferation. The objective of this study was to determine whether the RS would vary depending on the method of detection (MOD) in patients with lymph node-negative, ER-positive, HER-2 negative breast cancer (BC). Methods: We included patients with ER-positive, lymph node-negative and HER2-negative BC who underwent OncotypeDX testing as part of routine care or a clinical trial. We retrospectively reviewed patient charts and extracted information on MOD (SD versus SY), clinicopathological variables and RS. Chi-squared test was used to test for differences between categorical variables and MOD. Analysis of variance (ANOVA) was used to investigate the relationship between RS and MOD and clinicopathological variables. Results: We identified 596 patients from 4 academic hospitals (Mater University Hospital n= 98 (16%), St Vincent’s Hospital n= 161 (27%), Waterford Regional Hospital n= 27 (4%) and University of Texas, MD Anderson Cancer Center n= 310 (52%)). There were 359 (60 %) SD- detected and 237 (40%) SY-detected breast cancers. Clinicopathological variables were similar for age at diagnosis (56 versus 52 years), tumour size (16mm versus 18mm), grade (63% versus 61% grade 2; 15% versus 15% grade I; 21% versus 24% grade 3) and LVI (18% versus 18%) for SY compared to SD, respectively. The number of patients in each group with low (51% versus 50%), intermediate (41% each) or high (8% versus 9%) RS was similar in the SD compared to SY groups, respectively. There was a statistically significant association between RS and tumour grade (P=<0.001) and lymphovascular invasion (P=<0.001). We did not observe a statistically significant association between RS and MOD (P=0.086). Conclusions: In patients with clinically intermediate breast cancer sent for OncotypeDX testing we found no association between RS and MOD.
The role of Ki-67 in molecular breast cancer classification.
Authors: Stathopoulos George , Malamos Nikolaos , Markopoulos Christos , Polychronis Athanasios , Rigatos Sotirios , Yannopoulou A , Kaparelou Maria , Armakolas Athanasios 
Published: March 2020

583 Background: The Ki-67 antigen was identified the involvement in early steps of polymerase I-dependent ribosomal RNA synthesis. Although it seems that the protein has an important function in cell division, its exact role is still obscure and there is little published work on its overall function. The aim of the present study is to evaluate the contribution of Ki-67 level in respect of tumor recurrence in molecular classified groups of breast cancer patients. Methods: Breast cancer tumor samples were examined for histological confirmation and for estrogen and progesterone receptors, c-erb-B2 expression, proliferation with Grade and Ki-67. Ki-67 was divided in percentage levels, up to 20 and higher than 20%. Immunohistochemistry and Fluorescence in situ hybridization is described for the results of ER, PR, c-erb-B2, Ki-67 biomarkers. Formaldehyde – fixed breast samples were paraffin wax embedded and processed for paraffin sections. The primary antibodies used were: The monoclinal antibody ID5 (M7047, Dakocytomation, Carpinteria, CA) for the detection of ER, the monoclonal anti-PR antibody 636 was used. For the detection of Ki-67 we used monoclonal mouse anti-human Ki-67 MIB-1. The patients molecular classification was Luminal A, Luminal B, Her-2 subtype and basal cell (triple negative). Results: 847 breast cancer patients were recruited. 291 were group as Luminal A, 228 as Luminal B, 221 Her-2 subtype and 107 triple negative. Follow-up was from 3 years to 15 years since diagnosis. It was found that in Luminal A patients, none had Ki-67 higher than 20% and the recurrence was in 10.65%. In Luminal B, the Ki-67 was higher than 20% in 61% of the patients and recurrence 23.68%. In Her-2 subtype >20% Ki-67 was 78.94%, recurrence 17.19%. In triple negative > 20% Ki-67 was in 68.75% and recurrence in 29.90% of the patients. Conclusions: The data presented here indicate that Ki-67 level may be considered as one of valuable biomarkers in breast cancer patients process and recurrence.
Relapse rate after adjuvant trastuzumab in the northeast of Italy: Preliminary data from a multicenter observational study in a clinical setting.
Authors: Mustacchi Giorgio , Molino Annamaria , Fiorio Elena , Brunello Antonella , Zagonel Vittorina , Ferro Antonella , Caldara Alessia , Iop Aldo , Bonura Salvatore , Stefani Micaela , Bernardi Daniele 
Published: March 2020

586 Background: Relapse Rate (RR) after adjuvant trastuzumab (AT) reported in clinical trials is between 15 and 21%. Information on RR and clinical behaviour of HER2-POS metastatic disease after AT outside clinical trials is limited. At ASCO Meeting 2010 RR was reported 8% (Abs 1080) to 10% (Abs 684), with a Survival Post Progression (SPP) of 8.8 and 5.7 months, respectively. It is useful to increase informations about metastatic HER2-POS disease after AT, outside clinical trials. Methods: HER2-POS consecutive cases treated with AT in 6 Hospitals of North East Italy were anonymously collected and merged. The following data were analyzed: Stage, ER/PgR Status, Chemotherapy regimens (CHT) , follow up, RR, Disease Free Survival (DFS), Overall Survival (OS) and SPP. Results: The number of patients was 413, median age 55 (24-84). Anatomic Stage was I in 39.7%, II in 40,3%, III in 24.4%. ER/PgR neg cases were 164 (41.6%). Given CHT were Anthra-based 33.4% and Anthra-Taxane 54.5%. At a mean follow up of 35 months (7-115) RR was 10.8% (45 cases), with a mean DFS of 23.8 months (3.2-74). Among relapsed patients, 37/45 (82.2%) had ER/PgR neg tumors. One patient died NED for CHF and 22 for metastatic disease, with a mean OS of 37.1 months (10.2-87.9). Mean SPP was 17.8 months. According to DFS <12 mos , >12<24 and >24, mean OS was 31.3, 31.7 and 56.12(p=0.03) months; SPP was 24.2, 14.4 and 17.8 months, respectively. Conclusions: In our experience RR after AT is lower than in published Phase III clinical trials. ER/PgR neg status seems a negative prognostic factor (82.2% in the relapsed population vs 41.6% overall). OS is similar for patients relapsed within 24 months but SPP is 10 months longer in very early relapses. Relapse after 2 years is correlated with a long OS (nearly 5 years), with SPP shorter vs early relapse (17.8 vs 24.2 months). Our preliminary results suggest different disease behaviors in relapsed HER2-POS Breast Cancer after AT, with different DFS and SPP, suggesting a different effect of further therapies. Considering the small RR, the study target accrual is proceeding to collect up to more than 1000 AT treated patients, including post-progression treatments, not available at the moment.
Endocrine therapy in early breast cancer: Encouraging observations in a nontrial setting.
Authors: Dent Susan Faye , Campbell Michelle M. , Crawley Freya , Clemons Mark J. , Song Xinni 
Published: March 2020

587 Background: Poor adherence to adjuvant endocrine therapy (ET) in women with hormone receptor positive (HR +) early breast cancer (EBC) is well documented. Given the availability of multiple ET strategies [aromatase inhibitor (AI) upfront, tamoxifen (TAM) to AI, AI after 5 years TAM], we evaluated the delivery of ET in a non-trial setting. Methods: Post-menopausal women with HR + EBC treated with ET (that included an AI) at The Ottawa Hospital Cancer Center between 01/99 and 12/06 were included. Data was retrospectively collected and included: demographics, choice/duration of ET, adherence and toxicities. Results: In 626 patients (pts), median age 59 years (r: 30-92) with stage I (195 pts; 31 %), stage II (339 pts; 54 %) and stage III (88 pts; 14 %) EBC. Treatment strategies included: AI (s) only (251 pts; 40 %); TAM followed by AI (s) (323 pts; 51.6 %); AI (s) followed by TAM (16 pts; 2.6 %); TAM-AI (s)-TAM (24 pts; 3.8 %) and unknown (12 pts; 1.9 %). Prescribed AI therapy (upfront or sequential) was discontinued in 39 % of cases mainly due to toxicity (62.5 %) after median of 6, 9, or 12 months (ms) on exemestane, anastrazole and letrozole respectively. Common toxicities included: arthralgias (40.6 %), hot flushes (34 %), fatigue (25 %), myalgias (24.7 %) and osteoporosis (22.5%). In cases (177) where AI therapy was discontinued due to toxicity: 98 received no further ET, 29 TAM and 50 another AI. The majority of pts received at least 5 years of ET (79 %; median duration 64 ms; r 1-156 ms) and 376 pts (60 %) completed at least 5 years of AI therapy (median duration 59 ms; r: 1-124 ms). 9.9 % of pts are still receiving ET. Conclusions: This is one of the first non-clinical trial studies to demonstrate, that despite poor adherence to initial ET, the majority of women are able to complete five years of treatment (79 %). These results are encouraging and reflect the practical use of mutilple endorcrine strategies that have been shown to be efficacious in this pt population.
Regional variation in Medicare spending and survival among older adults with advanced cancer.
Authors: Brooks Gabriel , Li Ling , Sharma Dhruv B , Schrag Deborah 
Published: March 2020

6003 Background: There is substantial regional variation in medical spending in the United States. Whether this variation extends to spending for cancer care and is associated with cancer survival outcomes is unknown. Methods: Patients aged 65 and older with incident advanced cancer were identified from the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database. Advanced cancers included lung (stage IIIB/IV), pancreas (stage III/IV) colorectal, breast and prostate (stage IV). Medicare spending from 2 months pre-diagnosis until death or 12 months post-diagnosis was totaled in 2010 USD for Medicare-enrolled advanced cancer patients from 80 hospital referral regions (HRR’s). HRRs were then ranked by mean composite 14-month spending and grouped into quintiles. The hazard ratio for death was assessed in each disease cohort for the comparison between the quintiles with lowest (Q1, referent) and highest (Q5) composite spending. Results: Mean composite 14-month spending ranged from $143,870 to $303,902 in HRR’s with the lowest and highest spending (Mason City, IA and Los Angeles, CA). As shown in the table, increased spending was associated with decreased risk of death for lung, colorectal and pancreas cancer but not for prostate or breast cancer. Conclusions: There is substantial regional variation in Medicare spending for patients with advanced cancer. This variation is associated with modest differences in risk of death between the lowest and highest quintiles of spending for lung, colorectal and pancreas cancer. [Table: see text]