bluuebunny/crossref_metadata_2025_split huggingface dataset:
External validation of a nomogram predicting overall survival (OS) of women with uterine leiomyosarcoma (ULMS).
Authors: Iasonos Alexia , Keung Emily , Zivanovic Oliver , Mancari Rosanna , Peiretti Michele , Nucci Marisa , George Suzanne , Colombo Nicoletta , Carinelli Silvestro , Hensley Martee Leigh , Raut Chandrajit P. 
Published: March 2020

5090 Background: A nomogram for predicting OS of women with ULMS was developed , given the poor prognostic performance of FIGO and AJCC staging systems. We aimed to determine the validity of the ULMS nomogram using independent, external cohorts. Methods: The ULMS nomogram incorporates 7 clinical characteristics: age at diagnosis, tumor size, grade, involvement of cervix, locoregional metastases (direct extrauterine spread, locoregional lymph node), distant metastases, and mitotic index (per 10 HPF) to predict OS following primary surgery. Two independent cohorts from sarcoma centers (1 US, 1 Europe) were included. Eligible women were treated at the institutions (1994-2010) and had undergone hysterectomy. Women with locally advanced or metastatic disease who underwent more extensive surgery were included if the primary tumor (uterus) was resected. Women who previously underwent resection of the primary tumor or recurrences at other institutions were included if they received followup care at 1 of the centers. Women who presented with unresectable disease who never underwent surgery and those with insufficient information on any of the nomogram variables were excluded. Results: 187 women with ULMS were identified who met the above criteria (median age 51 yrs, median tumor size 9 cm, median mitotic index 20). Tumors were generally high grade (88%), FIGO stage I-II (61%) without cervical involvement (93%) and without locoregional (77%) or distant metastases (83%). Median and 5-yr OS rates were 4.5 (95% CI 3.2-5.3) yrs and 46%, respectively; 65 women (35%) were alive at last follow up. The nomogram concordance index was 0.67(SE=0.02) which was as high as the concordance index from the initial cohort used for nomogram development. The concordance between actual OS and nomogram predictions suggests excellent calibration of the nomogram in the validation cohort. Predictions were within 1% of actual 5-yr OS rates, except for the patients with a 5-yr OS rate of greater than 0.68. Conclusions: The ULMS nomogram was externally validated and can be generalized to independent cohorts. The nomogram provides a more individualized and accurate estimation of OS of women diagnosed with ULMS following primary surgery.
Phase II trial on cisplatin-doxorubicin hydrochloride-paclitaxel (TAP) combination as neoadjuvant chemotherapy (NACT) for locally advanced cervical adenocarcinoma (LACA).
Authors: Raspagliesi Francesco , Ramondino Stefano , Zanaboni Flavia , Ditto Antonino , Solima Eugenio , Grijuela Barbara , Spatti Gian Battista , Gabbanini Massimo , Mancini Maria , Martinelli Fabio , Amaya De Carrillo Carla , Fontanelli Rosanna , Lorusso Domenica 
Published: March 2020

5096 Background: NACT followed by surgery is a different therapeutic approach to locally advanced cervical cancer that seems to offer specific advantages over chemoradiation such as potential activity against distant micrometastases, a debulking effect improving subsequent surgical outcome, less toxicity, and an easier management of salvage therapy. This phase II trial was designed to evaluate the toxicity and activity of NACT with TAP in patients with LACA. Methods: Patients (pts) with FIGO stage IB2 (9 pts)- II (21 pts) uterine adenocarcinoma were treated with cisplatin 70 mg/mq, doxorubicin hydrochloride 45 mg/mq and paclitaxel 150 mg/mq day 1 every 21 days for 3 cycles. Eight pts (26.6%) presented with positive lymphnodes ( +LY) at diagnosis (5 pelvic and 3 pelvic+paraortic). After the last cycle of chemotherapy patients underwent radical surgery with lymphnode dissection. Clinical responses to chemotherapy was evaluated according to Recist criteria. Pathological response was classified as no residual tumor (pCR), residual disease with <3 mm stromal invasion (pR1) or residual disease with >3 mm stromal invasion (pR2). Due to the slow accrual the trial was closed before the target population of 45 pts was reached. Results: Between 2003 to 2010, 30 women were enrolled. Two complete clinical responses (6.7%), 21 partial responses (70%) and 7 stabilizations of disease (23.3%) were registered. All the patients underwent radical surgery and were assessable for pathologic responses. Five patients (16.6%) achieved a pCR , 8 (26.6 %) a pR1 response; 17 patients (56.7%) a pR2 response. At pathological assessment 10 pts (33.3%) presented with +LY (7 pelvic, 1 paraortic, 2 pelvic+paraortic). At a median follow up of 45 months progression free survival and overall survival were 37 months (95% CI 1-98) and 45 months (95% CI 9-101+) respectively. Hematologic toxicity was the most relevant side effect with 13 pts (43 %) reporting grade 3-4 neutropenia. Conclusions: The TAP combination seems to be feasible with an acceptable toxicity profile and a promising response rate for the treatment of LACA. The effect of NACT on lymphnodes status warrant further investigation.
Analysis of somatic mutation in miRNAs and miRNA regulation-related genes in gynecological cancers: New frameshift mutation of TNRC6A found in endometrial cancer.
Authors: Mei Qi , Yang Yang , Honisch Ellen , Yu Shi Ying , Janni Johann Wolfgang , Niederacher Dieter 
Published: March 2020

5097 Background: Micro RNAs (miRNAs) are small non-coding RNAs which plays an important role in tumorigenesis and mutation of a miRNA gene or miRNA regulation-related gene may cause butterfly effect on alteration of global gene expression.In order to investigate this hypothesis,high resolution melting analysis (HRM) and denaturing high-performance liquid chromatography (DHPLC) were used to screen 20 miRNA genes and 6 miRNA regulation-related genes for mutations in gynecologic cancers. Methods: In this study,182 DNA samples from breast cancer tumors,42 from ovrian cancers and 28 from endometrial cancers were obtained.18 human cancer cell lines were also included.We used HRM and/or DHPLC to screen mutations of these genes in human cancer cell lines and tumor tissues. All samples with curves that differed in shape compared to wild-type were directly sequenced for confirmation.Secondary structures for the wild-type and variant primary precursor of miRNA sequences obtained from sequencing were predicted using RNAfold software.Western blot and immunohistochemistry were used to evaluate the related protein change in cancer cell line and tumor tissues. Results: Polymorphisms of these genes were very frequently observed in gynecologic cancers.Two rare variants were found in the primary precursor sequences of mir-200c and mir-142 gene.Moreover,a novel frameshift mutation( c.3547_3548insA) in TNRC6A gene was found in two endometrial cacner cell lines (RL95-2 and Hec-1A) and endometrial cancers (1/28).Western blot and immunohistochemistry showed loss of expression of TNRC6A protein in the endometrial cacner cell lines and endometrial cancers with this mutation. Conclusions: Two rare novel variants in 20 miRNA genes and a novel frameshift mutation in TNRC6A gene were identified in gynecologic cancers.Oue data indicate that mutations in TNRC6A gene may contribute to the cancer development and might be a potential new therapeutic target in endometrial cacner.
Randomized trial of marker-directed versus standard schedule zoledronic acid for bone metastases from breast cancer.
Authors: Coleman Robert Edward , Wright Jonathan , Houston Stephen , Agrawal Rajiv , Purohit Om Pra-Kash , Hayward Larry , Simmonds Peter , Waterhouse Anna , Marshall Helen ,   BISMARK Investigators
Published: March 2020

511 Background: Zoledronic acid (ZOL) reduces skeletal morbidity associated with metastatic bone disease by 30-50%. Current recommendations are for indefinite administration of intravenous 3-4 weekly (w) ZOL 4mg. Over recent years it has become clear that the risk of skeletal morbidity is related to the rate of bone resorption. We have compared a marker directed schedule of ZOL (M-ZOL), using measurements of urinary n-telopeptide of type I collagen (NTX), to a standard treatment schedule (S-ZOL) in patients with bone metastases from breast cancer. Methods: The primary endpoint was skeletal related events (SRE). A non-inferiority study was designed with 80% power and (one-sided) 5% alpha to demonstrate that M-ZOL retained 67% of the efficacy of S-ZOL. This required 1500 patients, assuming a SRE rate of 0.7/year. Following minimisation for known prognostic factors, patients were randomised to receive S-ZOL 3-4 w or M-ZOL (15-16w; 8-9 w or 3-4w if NTX levels were <50, 50-100, >100 nmol/mmol creatinine respectively), with the schedule adjusted according to NTX measured every 16 weeks. The study duration was 24 months. Results: Due to lower than expected recruitment, the study closed in 2009 following recruitment of 289 patients. 90% of patients had received >4 cycles of ZOL or pamidronate prior to randomisation. The median number of ZOL infusions administered to S-ZOL patients was >2x that received on M-ZOL. 46 (32%) S-ZOL and 55 (38%) M-ZOL patients experienced an SRE. The numbers of SRE were 94 and 138 in the S-ZOL and M-ZOL arms, with the excess in SRE being largely due to more patients on M-ZOL experiencing ≥2 SRE. Multivariate analysis adjusting for key minimisation factors and baseline NTX for all SRE showed a hazard ratio for M-ZOL vs. S-ZOL of 1.41 (90%CI 0.98-2.02, p=.12). NTX levels were significantly higher at all time points in the M-ZOL treated patients. Osteonecrosis of the jaw was uncommon with 3 cases with S-ZOL and 1 with M-ZOL. Conclusions: The study is underpowered to demonstrate non-inferiority in SRE outcome between the treatment strategies. However, the results suggest that the adjustment of ZOL schedule based on NTX values alone may represent sub-optimal management.
Genetic variants associated with toxicity-related discontinuation of adjuvant aromatase inhibitor (AI) therapy.
Authors: Henry Norah Lynn , Skaar Todd C. , Dantzer Jessica , Li Lang , Nguyen Anne T , Rae James M. , Desta Zeruesenay , Oesterreich Steffi , Philips Santosh , Carpenter Janet S , Storniolo Anna Maria , Stearns Vered , Hayes Daniel F. , Flockhart David A. ,   Consortium on Breast Cancer Pharmacogenomics
Published: March 2020

525 Background: Discontinuation of adjuvant AI therapy due to intolerable symptoms occurs in up to 30% of patients. Predictors of which patients will be unable to tolerate these medications have not been defined. We hypothesized that inherited variants in candidate genes are associated with treatment discontinuation because of AI-associated toxicity. Methods: We prospectively evaluated reasons for treatment discontinuation in women with hormone receptor positive breast cancer initiating adjuvant AI through a multicenter, prospective, randomized clinical trial of exemestane (exe) versus letrozole (let). Using multiple genetic models, we evaluated potential associations between 136 single nucleotide polymorphisms (SNP) in 24 candidate genes, selected a priori, primarily with roles in estrogen metabolism and signaling, and discontinuation of AI therapy because of toxicity. To account for multiple comparisons, statistical significance was defined as p<0.0003. Results: Of the 467 enrolled patients who had available germ line DNA, 152 (33%) discontinued AI therapy because of toxicity. After adjusting for multiple covariates, multivariable analyses revealed that two inherited genetic variants in ESR1, which encodes estrogen receptor (ER) alpha, and one in CYP19A1 were associated with increased risk of discontinuation of AI therapy because of toxicity (Table). A variant in NCOR1 (ER co-repressor) was associated with decreased risk of discontinuation of letrozole because of toxicity. Conclusions: Variants in genes involved in estrogen metabolism and signaling may be associated with toxicity of AI therapy. [Table: see text]
Impact of adjuvant trastuzumab on outcomes of HER2-positive breast cancer patients treated with HER2-targeted therapy in the metastatic setting.
Authors: Murthy Rashmi Krishna , Varma Ankur , Mishra Priyankana , Hess Kenneth R. , Young Elliana J. , Murray James L. , Koenig Kimberly Higginbotham , Green Marjorie C. , Moulder Stacy L. , Melhem-Bertrandt Amal , Booser Daniel J. , Valero Vicente , Hortobagyi Gabriel N. , Esteva Francisco J. 
Published: March 2020

527 Background: Trastuzumab (T) was approved for the adjuvant treatment of women with early-stage, HER-2 overexpressing (HER2+) breast cancer in 2006. There are limited data outlining the outcomes of patients with HER2+ breast cancer who receive adjuvant T-based therapy and then receive T and/or lapatinib in the metastatic setting. Methods: We identified 540 patients with HER2+ breast cancer treated with T or lapatinib as part of their first-line treatment for metastatic disease from 01/1997 to 11/2011. HER-2 positivity was assessed by immunohistochemistry (score, 3+) or fluorescence in situ hybridization (HER2/CEP17 ratio ≥ 2). We excluded 17 patients from this analysis because they were either lost to follow-up or received less than 2 cycles of therapy at the institution. Statistical analyses were performed using the chi-square test to compare proportions between groups and the Cox proportional hazards regression analysis to compare survival times and estimate the corresponding hazard ratio with 95% confidence interval. Results: Of the 523 patients eligible for analysis, 76 patients had received T in the adjuvant setting and 447 had not. In the group who did not receive adjuvant T, 48% (213/447) of patients achieved a complete or partial response (CR/PR), whereas only 13% (14/76) achieved a CR/PR in the adjuvant T group (P<.0001). After adjustment for age, disease-free interval, post-menopausal status, stage at presentation, ER/PR status, and nuclear grade, the odds ratio was 0.27 (CI 0.13 - 0.56, p = 0.0004). Overall survival from first evidence of metastasis was significantly longer in the group who did not receive adjuvant T (39 months vs. 24 months, HR = 1.8, 95% CI 1.3-2.4). For OS, the adjusted hazard ratio was 1.5 (CI 1.04 - 2.1, p = 0.029). Age, DFI and stage were also significant predictors of OS. Conclusions: Patients with HER2+ metastatic breast cancer who were T naive, had a higher response rate (CR/PR) to front line HER2 targeted therapy and a longer OS compared to patients with metastatic HER2+ breast cancer who received T in the adjuvant setting. These findings highlight the importance of recognizing a pre-treated population and calls for further research in this area.
Phase Ib study of open-label AMG 386 plus paclitaxel (P) and trastuzumab (T) or capecitabine (C) and lapatinib (L) in patients (pts) with HER2+ locally recurrent or metastatic breast cancer (MBC).
Authors: Wildiers Hans , Goncalves Anthony , Kemeny Margaret , Swart Rachel Elizabeth , Freyer Gilles , Nanayakkara Nuwan , Wu Benjamin , Pickett-Gies Cheryl Ann , Kaufman Peter Andrew 
Published: March 2020

529 Background: AMG 386, an investigational peptibody, reduces tumor angiogenesis by blocking interaction of angiopoietins 1 and 2 with the Tie2 receptor. This interim analysis evaluates the tolerability and efficacy of AMG 386 + P/T or C/L in HER2+ MBC. Methods: In part 1, pts in cohorts A1 and A3 (no prior 1st-line MBC T or L ) received AMG 386 IV QW plus P 80 mg/m2 IV QW and T 8 mg/kg loading dose, then 6 mg/kg Q3W; pts in cohorts B1 and B3 (history of failed 1st-line MBC T treatment; no prior L or C) received AMG 386 IV QW plus C 1000 mg/m2 PO Q12 hrs, days 1-14 Q21D and L 1250 mg PO QD. A1 and B1 received AMG 386 at 10 mg/kg; A3 and B3 received AMG 386 at 30 mg/kg. In part 2, cohorts were expanded to n = 20 if ≤ 1 of 6 or ≤ 2 of 9 pts had dose-limiting toxicities (DLTs). Primary endpoints were adverse events (AEs) and DLTs; secondary endpoints included efficacy and pharmacokinetics (PK). Interim results from A1, A3, and B1 will be presented. Results: 46 pts were enrolled at interim analysis; all received ≥ 1 dose of study treatment (A1, A3, B1; n = 20, 6, 20). The median follow-up for A1, A3, and B1 was 39.6, 22.7, and 31.3 wks. Across cohorts, there was 1 DLT in A1. AEs > 50% were peripheral edema, diarrhea, fatigue and alopecia in A1 and A3 combined, and diarrhea, nausea, palmar-plantar erythrodysaesthesia syndrome (PPES), and peripheral edema in B1. AEs grade ≥3 occurring in > 2 pts were peripheral neuropathy, peripheral sensory neuropathy, dyspnea (n = 5, 4, 3, respectively, in A1 and A3 combined); PPES, diarrhea, and neutropenia (n = 6, 5, 3, respectively, in B1). Objective response rates were 80% in A1, 50% in A3, and 50% in B1. Median (95% CI) progression-free survival was 14.5 mo (6.8-20.5) in A1 and 10.1 mo (3.7-14.7) in B1. Median duration of response (DOR) was 12.6 mo (4.3-20.2) in A1 and 8.5 mo (4.1-not evaluable) in B1. PFS and DOR were not yet evaluable in A3. No changes were apparent in any PK parameters in these combinations relative to within study or historical monotherapy PK data. Conclusions: In this ongoing phase 1b study of pts with HER2+ MBC, interim results suggest that adding AMG 386 to P/T or C/L is tolerable and has antitumor activity. Updated data will be presented.
Phase IB/II study of the HSP90 inhibitor AUY922, in combination with trastuzumab, in patients with HER2+ advanced breast cancer.
Authors: Kong Anthony , Rea Daniel , Ahmed Samreen , Beck J. Thaddeus , López López Rafael , Biganzoli Laura , Armstrong Anne , Aglietta Massimo , Alba Emilio , Campone Mario , Akimov Mikhail , Matano Alessandro , Lefebvre Caroline , Lee Soo-Chin 
Published: March 2020

530 Background: AUY922 is a novel HSP90 inhibitor that causes degradation of oncogenic proteins. A Phase I study in advanced solid tumors gave a recommended Phase II dose (RP2D) of 70 mg/m2. In the Phase II part of the study, single-agent AUY922 showed preliminary activity in HER2+ metastatic breast cancer (mBC) (Schröder et al ASCO 2011). This Phase Ib/II study assessed safety and efficacy of AUY922 + trastuzumab (T) in pts with T-refractory HER2+ advanced/mBC. Methods: Pts with HER2+ BC (ECOG PS ≤1) who progressed on 1–2 prior anti-HER2 regimens with at least 1 T-containing regimen, received weekly AUY922 (55 or 70 mg/m2, IV) + T (2 mg/kg) in a 28-day cycle. The Phase Ib primary objective was to define a MTD/RP2D of AUY922 combined with T using an adaptive Bayesian logistic regression model. The Phase II primary objective is to evaluate preliminary antitumor activity at this dose (ORR). Secondary objectives included evaluation of PK, safety and preliminary efficacy (PFS, OS). Results: In the Phase Ib part (11 pts) there was 1 DLT (Grade [Gr] 3 diarrhea), and the full standard single dose of AUY922 was recommended for use in combination with T. As of 11th January 2012, 31 HER2+ BC pts (median age 51 years [range 29–71]; 84% invasive ductal carcinoma; 52% estrogen receptor-positive; 81% had received ≥2 prior antineoplastic regimens) received AUY922 at 55 mg/m2 (n=5) or 70 mg/m2 (n=26) + T. The most common study drug-related AEs (all Gr) were diarrhea (25 [81%] pts), visual AEs (e.g. vision blurred, visual impairment, photopsia) (25 [81%] pts), and nausea (11 [35%] pts). Gr 3/4 AEs were rare; most frequently diarrhea and visual impairment (both 6%). Treatment was ongoing for 13 (37%) pts at the cutoff date. Preliminary Phase II best overall response data (RECIST, investigator assessed) was available for 22 pts at AUY922 70 mg/m2. Any partial responses were reported in 5/22 (23%) pts. Conclusions: The data suggests AUY922 + T is well tolerated. Common AEs were considered manageable, and eye disorders were reversible with treatment interruption, dose reduction or discontinuation. The combination of AUY922 + T is active in pts with HER2+ mBC who progressed on T-based therapy, and the regimen warrants further investigation.
A randomized phase II study (VEG108838) of lapatanib plus pazopanib (L+P) versus lapatanib (L) in patients with ErbB2+ inflammatory breast cancer (IBC).
Authors: Cristofanilli Massimo , Johnston Stephen R. D. , Manikhas Alexey , Gomez Henry Leonidas , Gladkov Oleg , Shao Zhimin , Safina Sufia , Rubin Stephen D. , Ranganathan Sulabha , Lata Suman , Trudeau Maureen E. 
Published: March 2020

531 Background: ErbB2 amplification is frequently reported in IBC and there is evidence of positive association between ErbB2 and VEGF expression. We evaluated the combination of anti ErbB2 and VEGF therapy in ErbB2+ IBC. Methods: We conducted a multicenter, randomized clinical trial for patients (pts) with relapsed ErbB2+ IBC. Cohort 1: Pts stratified (prior trastuzumab; cutaneous disease only vs systemic) and randomized 1:1 to receive L 1500 mg + placebo or L 1500 mg + P 800 mg, QD. Due to high incidence of Grade 3/4 diarrhea in pts treated with L 1500 mg+ P 800 mg in another study, Cohort 1 was closed after 76 pts randomized. Cohort 2 (87 pts ): Pts were stratified (prior trastuzumab) and randomized 5:5:2 to receive L 1500 mg + placebo or L 1000 mg + P 400 mg (double-blind) or P 800 mg (open-label), respectively, QD. Treatment continued until PD, unacceptable toxicity or death. Primary endpoint was ORR. Secondary endpoints included PFS, OS, and safety. Results: Cohort 1: 76 pts were randomized and treated: L, n=38; L+P, n=38. ORR was 29% for the L arm, and 45% for the L+P arm. Median PFS was 16.1 and 14.3 wks, respectively, for the L and L+P arms. The most frequent Grade ≥3 AEs were diarrhea (0% vs 18%) vomiting (0% vs 8%), ALT increased (0% vs 8%), neutropenia (3% vs 13%), and bilirubin increased (0% vs 5%). Dose reductions due to AE were 3% and 21% and dose interruptions due to AE were 11% and 55% in the L and L+P arms, respectively. Cohort 2: 88 pts were randomized (87 treated): L, n=36; P, n=14; L+P, n=38. The ORR was 47%, 31%, and 58% for the L, P, and L+P arms, respectively. Median PFS was 16.0, 11.4, and 16.0 wks for the L, P, and L+P arms, respectively. The most frequent Grade ≥3 AEs were ALT increased (0%, 0%, 21%), AST increased (0%, 0%, 18%), diarrhea (3%, 8%, 8%), and fatigue (3%, 8%, 8%). Dose reductions due to AE occurred in 0%, 0%, and 13% of pts and dose interruptions due to AE occurred in 22%, 23%, and 39% of pts in the L, P, and L+P arms, respectively. Conclusions: This prospective, randomized study confirmed the clinical activity of lapatinib single agent in metastatic ErbB2+ IBC. Furthermore, we demonstrated increased toxicity associated with the combination without a clinically meaningful improvement in efficacy.