bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maintenance erlotinib (E) following first-line treatment with docetaxel, carboplatin and erlotinib in patients with ovarian carcinoma
Authors: Vasey P. A. , Paul J. , Rustin G. , Wilson R. , Guastalla J. , Pujade-Lauraine E. , Gore M. , Gabra H. , Carty K. , Kaye S. ,   The Scottish Gyn Cancer Trials Group
Published: March 2020

5560 Background: We previously reported on the feasibility of a combination of erlotinib (E; a HER1/EGFR tyrosine-kinase inhibitor) with platinum and taxane chemotherapy (Agarwal et al, Ann Oncol 2004) and reported that almost 1/3rd patients (pts) stopped E during treatment due to toxicities which included intolerable rash, diarrhea and neutropenic sepsis. This update reports on those pts who then received E at 150mg daily as maintenance treatment. Methods: 48 pts initially received docetaxel (75 mg/m2) and carboplatin (AUC 5) following surgery q21d for 6 cycles in combination with daily oral E (50–100 mg) in dose-escalating cohorts. After 6 cycles, pts could continue with E alone (150mg/d) until progression. Results: 27 pts (56%) continued E beyond chemotherapy for a median of 8.6 months (mo) (range 2.3–32.5 mos), and 23/27 were escalated as planned to daily. Subsequently, 12/27 (44%) pts had their dose either reduced or interrupted for toxicity, which was cutaneous in 10/12 (83%) pts. However, the incidence of = grade 2 toxicity was low apart from alopecia (24%), rash (18%) and fatigue (15%). During follow-up (36 mo) 22/27 (81%) pts stopped E due to progressive disease and 3/27 (11%) stopped E due to cutaneous toxicity. Only 2/27 (7%) pts continue to receive E without evidence of progression, both at doses less than 150mg, again due to cutaneous toxicity. Pts receiving maintenance E had a median progression-free survival of 14.8 mo (95% CI 12.6–17.1 mo) and median overall survival 37.0 mo (95% ci 31.6–42.4 mo); for all pts these figures were 12.5 mo (95% CI 9.1–15.9 mo) respectively, and 37.0 mo (95% ci 27.3–46.7 mo). Conclusions: Maintenance E at 150mg daily following initial treatment with E plus docetaxel-carboplatin for ovarian carcinoma is associated with cutaneous toxicity which limits the dose and duration of treatment in a proportion of pts. The potential benefit of this approach can only be addressed in a randomized trial, and this is now underway under the auspices of the EORTC. A parallel translational study will examine the possibility that patients most likely to benefit can be predicted by molecular tumor analysis. [Table: see text]
Phase I trial of PTK787/ZK222584 (PTK/ZK) in combination with carboplatin (C) and paclitaxel (T) in platinum-sensitive recurrent epithelial ovarian (EOC), fallopian tube (FT), or primary peritoneal (PPC) cancers
Authors: Juretzka M. M. , Aghajanian C. , Hensley M. L. , Tew W. P. , Spriggs D. , Konner J. , Chiang A. C. , Pezzulli S. , Kim M. , Sabbatini P. 
Published: March 2020

5564 Background: Targeting vascular endothelial growth factor (VEGF) in patients (pts) with ovarian cancer achieves objective responses. PTK/ZK is an orally active angiogenesis inhibitor which blocks all known VEGF receptor and platelet-derived growth factor receptor tyrosine kinases. A previous study administered PTK/ZK only on days 3–21 of C and T cycle based on pre-clinical data suggesting PTK/ZK increases T levels (PROC ASCO # 5042, 2005), and recent data supports bid dosing (JCO 18:1–10, 2005). Methods: In this open label, single institution phase I study, pts with platinum sensitive recurrent EOC, FT, or PPC were treated with C and T every 21 days with increasing continuous daily doses of PTK/ZK (250 mg to 1,250mg with bid dosing). Primary endpoints were safety and maximum tolerated dose (MTD). Pharmacokinetic (PK) analysis is planned to describe C and T pharmacokinetics when combined with PTK/ZK. Results: To date, 14 pts with median age 61 (range 45–73) have been enrolled on the first 3 dose levels, including 13 EOC and 1 PPC. All patients were evaluable for toxicity and 8 were evaluable for investigator assessed response. MTD has not been reached. Febrile neutropenia was dose limiting toxicity requiring expansion at levels II and III. PK analysis is ongoing. To date, best responses are: 4 (PR), 3 (SD) and 1 (POD). Other G III toxicity included: C hypersensitivity reaction (1, gr 3), hyperglycemia (4, gr 3), hypertension (1, gr 3), diarrhea (1, gr 3), and elevated liver function tests (1, gr 3). Conclusion: PTK/ZK can be administered continuously in combination with standard doses of C and T using bid dosing. MTD is not yet reached and accrual is ongoing. PK data and MTD will be presented. Supported by Novartis and Bayer Schering Pharma. [Table: see text] No significant financial relationships to disclose.
Microtubule-regulatory phosphoproteins and NER system are involved in platinum and paclitaxel-based chemotherapy resistance in ovarian cancer
Authors: Nadal R. , Romero M. L. , Ojeda B. , Gallardo A. , Rodríguez M. , Boguñà I. , Gich I. , Prat J. , Barnadas A. 
Published: March 2020

5567 Background: The treatment of ovarian cancer is hindered by intrinsic resistance to platinum and paclitaxel-based chemotherapy (CT). Nucleotide excision repair system plays a central role in DNA repair and is related with resistance to platinum compounds. Excision repair cross-complementation 1 (ERCC1) and 3 (ERCC3) genes confer a differential sensitivity to CT. OP18/stathmin and mDIA are involved in regulation of microtubules dynamics and may represent a mechanism of resistance to paclitaxel. Both mechanisms have been recently investigated in ovarian cancer (OC). Methods: Formalin and paraffin-embedded tissues obtained from 33 patients with advanced OC were retrospectively collected to investigate ERCC1, ERCC3, OP18, and mDIA mRNA levels by quantitative RT- PCR. All patients received a median of 6 cycles platinum based CT in combination with taxanes. Median age was 62 years. Tumors were classified: 52% serous, 9% endometrioid, 27% clear cell, and 12% poorly differentiated carcinomas. FIGO stage: 4 (12%) stage II, 19 (58%) stage III, and 10 (30%) stage IV. 12 chemoresistant tumors (time to recurrence (TTR) < 6 months) and 21 chemosensitive tumors (TTR = 6 months) were analyzed. Median follow-up was 31 months. Results: An increase in mRNA levels was consistently observed in the chemoresistent group: 1.9-fold increased in ERCC1 and 1.6-fold increased in ERCC3. Both genes exhibited comparable expression levels. Statistically significant differences on ERCC1 and ERCC3 mRNA levels were encountered when chemoresistant and chemosensitive tumors were compared (p=0.01 and p= 0.03, respectively). Statistically differences on OP18 mRNA levels were found when chemoresistant and chemosensitive tumors were compared (p=0.05). No differences in mDIA mRNA levels were encountered. Conclusions: Our results suggest that determination of ERCC1-ERCC3 before chemotherapy is potentially useful to predict the effectiveness of platinum-based therapy. Microtubule drug resistance in OC may be associated with altered OP18/stathmin expression. Novel treatment approaches based on molecular markers could be useful predictors of response and could identify targets for therapeutic strategies. Further studies are required. No significant financial relationships to disclose.
Prediction of response to chemotherapy by ERCC1 immunohistochemistry and ERCC1 polymorphism in ovarian cancer
Authors: Steffensen K. D. , Waldstrøm M. , Jeppesen U. , Brandslund I. , Jakobsen A. , University of Southern Denmark G. 
Published: March 2020

5568 Background: The response of tumor cells to platinum-based drugs involves DNA repair mechanisms. Platinum-DNA adducts are repaired by nucleotide excision repair (NER) enzymes that recognize the DNA damage and excise the platinum-DNA adducts from the injured DNA strand. Excision repair cross-complementation group 1 (ERCC1) is one of the genes that encode the proteins of the NER complex and several studies have linked ERCC1 to platinum resistance in cell lines and in human cancers. Cells with a high repair capacity, e.g. high level of ERCC1 expression may therefore be resistant to platinum-based chemotherapy, and conversely, polymorphisms within encoding DNA repair enzymes or low repair capacity may confer sensitivity. A common single nucleotide polymorphism (SNP) of ERCC1 at codon 118 have been proposed to impair ERCC1 translation and reduce ERCC1 protein expression and consequently influence the response to platinum based chemotherapy. The aim of this study was to evaluate ERCC1 expression and ERCC1 118 polymorphism in epithelial ovarian cancer and the potential association with response to platinum-based chemotherapy. Methods: Formalin-fixed, paraffin-embedded tissue sections from 159 patients with epithelial ovarian cancer, FIGO stage IIb-IV, were used for immunohistochemistry (monoclonal mouse antibody, clone 8F1, Neomarkers). ERCC1 codon 118 SNP genotyping was performed by real time PCR, Taqman SNP genotyping assay. Results: ERCC1 protein overexpression was found in 37.7 % of the tumors. The response rate (normalization of CA125 during platinum-based chemotherapy) was 63.6 % (35/55) in patients with ERCC1-negative tumors compared to only 35.6 % (16/45) in patients with ERCC1-positive tumors. (p = 0.0052, χ2). Furthermore increasing immunohistochemical score (H-score) was associated with poorer response to chemotherapy. (p = 0.0006, Spearman`s). The T/T genotype (44 %) showed better response to chemotherapy than C/C + C/T (15 % + 41 %) variants (p=0.042). Conclusions: Patients with ERCC1-negative tumors appear to have significantly better response to platinumbased chemotherapy compared to patients with ERCC1-positive tumors. In addition the TT genotype seems to be favorable towards better response to platinum-based chemotherapy. No significant financial relationships to disclose.
Comparison of the cost per distant disease-free year gained for upfront letrozole or anastrozole, or switched exemestane compared to tamoxifen for early breast cancer in hormone receptor-positive postmenopausal women: The UK perspective
Authors: Karnon J. , di Trapani F. , Kaura S. 
Published: March 2020

557 Background: Due to subsequent poor prognosis, prevention of distant recurrence (DR) is a primary aim of adjuvant hormonal therapy for early breast cancer. Compared to 5 years TAM in hormone receptor positive (HR+) postmenopausal women, DR relative risks are 0.73 (95% CI 0.6 - 0.88) for 5 years letrozole (LET), 0.84 (95% CI 0.7 - 1.0) for 5 years anastrozole (ANA), 0.73 (95% CI 0.59 - 0.9) for 2–3yrs exemestane after 2–3 years (EXE/TAM). This analysis evaluates the incremental cost per distant disease free year gained from a UK NHS perspective of LET, ANA, EXE/TAM versus 5 years TAM using the same health economic model. Methods: A Markov model described pathways through relevant health states over the remaining lifetime of a cohort of HR+ women aged 61 yrs. Probabilities of breast cancer events (contralateral; locoregional; soft tissue, bone, and visceral metastases) adverse events (endometrial cancer, hip and other fractures, cardiovascular disease, thromboembolic events, and arthralgia) were based on the latest early breast cancer overview, published results of the BIG 1–98, ATAC, and IES trials, and UK population-based studies as appropriate. Conservatively, no carry-over effect was assumed for the AIs after therapy discontinuation. Costs (2005 UK£) of breast-cancer care were obtained from a primary costing study in Scotland, and treatment costs for AEs were obtained from published studies. Costs and DR-free years were discounted at 3.5% annually. Results: The mean durations of DDFS were estimated to be 12.81, 12.66, 12.57, and 12.35 years for LET, ANA, TAM/EXE, and TAM, respectively. The incremental cost per distant disease free year gained of LET vs TAM is £10,379 (95% CI £5,286-£17,818), of ANA vs TAM is £11,428 (95% CI £5,071- £48,856), and of TAM/EXE vs TAM alone is £11,020 (95% CI £4,820-£36,947). Conclusion: Compared to 5 years TAM, adjuvant treatment of postmenopausal HR+ women with an AI is a cost-effective use of UK NHS resources. Based on the mean results, LET appears to be the most cost-effective of the three AIs, despite its higher acquisition cost compared to ANA in the UK, though the confidence intervals are wide. [Table: see text]
Trabectedin (T) in relapsed advanced ovarian cancer (ROC): A pooled analysis of three phase II studies
Authors: McMeekin S. , del Campo J. M. , Colombo N. , Krasner C. , Roszak A. , Braly P. , Ciuleanu T. E. , Lebedinsky C. , Izquierdo M. A. , Sessa C. 
Published: March 2020

5579 Introduction: Trabectedin is a DNA minor groove binding drug with a distinct MoA under development in sarcoma, prostate, breast and ROC. We have performed a pooled analysis of efficacy and tolerability of all phase II trials with T as 2nd - 3rd line in ROC. Methods: Three Trabectedin schedules were investigated: two every 3weeks (q3w; A: 1.3 mg/m2 3-h or B: 1.5 mg/m2 24-h) and one weekly (C: 0.58 mg/m2 3-h ×3 q4w). Endpoints were response rate (RR), time to progression (TTP), response duration (RD) and safety. 294 patients from 3 phase II (one randomized A vs B) trials were included: 108 were resistant (R) and 186 sensitive (S) to last platinum, based on progression-free interval <6 months or longer.Results: Overall RR and median TTP were 8% and 2.1mo in R and 34% and 5.8 mo in S patients. Median RD was 5.8 m. Schedules A & B q3w showed significant better RR (33% vs 16%, p=<0.0001) and median TTP (5.8 vs 2.8 m, p=0.0001) than the weekly schedule C. No efficacy difference was seen between 3-h and 24-h q3wk. In patients with = 2 prior platinum-based regimens, RR (R:7% and S:37%) and median TTP (R: 2.5 m and S:6.3 m) were similar than patients with only 1 prior platinum [RR (R:9%; S:33%) and TTP (R: 2 m; S: 5.5 m)]. 1,404 cycles were delivered [median A: 5(1–23), B: 5(1–19), C: 3(1–22)], with similar dose intensity (mg/m2/wk) across regimens (0.38, 0.42, 0.39). Most common drug-related AEs of any grade by cycle were (A, B, C) fatigue: 38, 35, 63% and vomiting: 16, 27, 21%. Grade 3/4 lab abnormalities were non-cumulative neutropenia: 21, 28, 1% and ALT increase: 32, 26, 3%. Low incidence of febrile neutropenia, neurotoxicity, stomatitis and alopecia was seen regardless of schedule. Conclusions: Trabectedin as single agent has shown clinical activity in both R and, particularly in S ROC. Activity was fully retained in patients with =2 prior platinum lines. Trabectedin q3w schedules (with no difference between 3 and 24-h) showed higher efficacy than T weekly. Toxicities were manageable and non-cumulative. Trabectedin is a promising new drug for the treatment of ROC and is under evaluation in a phase III trial. No significant financial relationships to disclose.
Adjuvant (adj) bevacizumab (B) plus dose-dense (dd) doxorubicin/cyclophosphamide (AC) followed by nanoparticle albumin- bound paclitaxel (nab-p) in early stage breast cancer (BC) patients (pts): Cardiac safety
Authors: Dickler M. N. , Traina T. , Panageas K. , Steingart R. , Dang C. , Fornier M. , Sugarman S. , Norton L. , Hudis C. , Rugo H. 
Published: March 2020

567 Background: Dose dense, q2 wk AC-paclitaxel (T) is superior to q3 wk therapy (Rx) (Citron, JCO 2003). The risk of congestive heart failure (CHF) with ddAC-T is not increased at <1%. In MBC, B improves PFS when added to T (Miller, SABCS 2005). It is unclear if doxorubicin plus B increases risk of CHF. Hence, we are testing the cardiac safety of ddAC-nab-p with concurrent B as adj therapy. Based upon the accepted cardiac event (CE) rate of ≤4% in trials with adj trastuzumab (an agent with known cardiac toxicity), we designed this study with similar monitoring & tolerability thresholds. The primary endpoint is cardiac safety, defined as discontinuation of B due to cardiac death from LV dysfunction or symptomatic CHF (dyspnea and LVEF<50%). Secondary endpoints: toxicity, disease-free & overall survival. Methods: Eligible pts have resected HER2(-) BC and normal LVEF. Rx consists of q2wk AC (60/600 mg/m2) ×4 then nab-p (260 mg/m2) x4 with pegfilgrastim on Day 2 plus B for one year (10mg/kg IV q2wk ×8 with chemoRx then B 15mg/kg q3wk); radiation & endocrine Rx per standard of care. MUGA obtained at baseline & mos. 2, 6, 9, 18. Pts with significant asymptomatic ↓LVEF during Rx may have B held per protocol. These pts are not counted as CEs but will have long-term cardiac monitoring. Accrual goal is 75 pts. If ≥3 CE (∼4.7%) or >1 cardiac death from LV dysfunction, B + ddAC-nab-p will not be considered safe. Results: 44 pts have enrolled, median (med) age 46.5 yrs (33–67). 28 pts have baseline & month 2 LVEF data: med baseline LVEF 68% (61–82), med LVEF at mo. 2 after ddAC+B 68% (53–75); 1 pt had an 18 point asymptomatic drop to 53% - B held but reinitiated in 4 wks with repeat LVEF 63%. 12 pts completed nab-p+B but none have reached the 6 mo. MUGA. Rx-related Gr 3/4 toxicity: neutropenia gr4 (6.8%), diarrhea gr3 (2.3%), hypertension gr3 (2.3%), neuropathy gr 3 (2.3%), fatigue gr 3 (2.3%), mucositis gr 3 (2.3%). 4 pts have withdrawn from study Rx, but only 1 due to toxicity including gr3 fatigue, mucositis & neuropathy. Conclusions: No LV dysfunction has been observed with B + ddAC-nab-p; this trial is on-going. Long-term follow-up and analysis of troponin, renin and circulating endothelial & tumor cells are planned. No significant financial relationships to disclose.
How well do standard prognostic criteria predict oncotype DX (ODX) scores?
Authors: Kamal A. H. , Loprinzi C. L. , Reynolds C. , Dueck A. C. , Geiger X. J. , Ingle J. N. , Carlson R. W. , Hobday T. J. , Winer E. P. , Perez E. A. , Goetz M. P. 
Published: March 2020

576 Background: In node-negative, ER + breast cancer, gene expression profiling can identify level of risk and, in the case of ODX, may also identify pts with a higher chance of benefiting from adjuvant chemotherapy. Because the gene profile in ODX includes an assessment of ER, HER2, and proliferation, we hypothesized that clinicians using standardized criteria could discriminate risk (high versus low/intermediate) as specified by ODX. Methods: We identified Mayo Clinic patients with node-negative, ER + breast cancer, for whom ODX scores were available. Tumor slides were reviewed by an expert breast pathologist to confirm tumor size, histology, and tumor grade. Both ER and PR were quantitated; HER-2 was determined by IHC (FISH, if 2+). These clinical cases were presented to six academic oncologists, blinded to the ODX score, to predict ODX risk (low, intermediate, or high) and give their recommendation for chemotherapy (CTX) (yes/no). Afterwards, they were presented with the same cases with the actual ODX score, to give recommendations regarding CTX. Results: ODX scores in tumors from 31 patients were low in 18 pts, intermediate in 10 pts, and high in 3 pts. Concordance between predicted and actual ODX scores being low/intermediate vs high exceeded 87% for each oncologist. The most frequent discrepancies were actual low scores predicted as intermediate (31/80 discordant) and actual intermediate scores predicted as low (29/80 discordant). Overall agreement of predicted scores (high vs low/intermediate) among the oncologists was substantial (kappa=0.75, p<0.0001). CTX recommendations following provision of the ODX scores changed on average 18.2% (range 12.9%-25.8%) of the time, with slightly fewer changing for, versus against, a CTX recommendation. Conclusions: Our findings suggest that the proper evaluation and interpretation of traditional prognostic criteria will identify most node negative, ER + patients at high risk of recurrence (as predicted by ODX) but poorly discriminate low versus intermediate risk. The provision of ODX data changed the recommendation for CTX in approximately 20% of cases. No significant financial relationships to disclose.
Adjuvant therapy for early stage breast cancer (EBC): Distant disease-free survival (DDFS) as a predictor of overall survival (OS)
Authors: Melisko M. , Lin A. , Rugo H. 
Published: March 2020

583 Background: OS advantages are often difficult to demonstrate in trials evaluating treatment for EBC, as this requires long follow-up (FU) and large trials. Results are also confounded by factors such as further treatment. DFS, the primary endpoint in many adjuvant trials, is not a consistent predictor of OS and lack of standard definitions renders its interpretation difficult. A better, quicker endpoint is needed as a surrogate for OS. Distant metastases (DM), the most common type of recurrence, are responsible for the initial peak of relapse seen at 2 years post surgery and are associated with the highest risk of death compared to locoregional and contralateral events. DDFS may be a better short-term OS predictor. Methods: The impact of common adjuvant therapies (chemotherapy [CT], tamoxifen [TAM], and aromatase inhibitors [AIs]) on DM risk and OS was examined. Results: CT trials show that improvements in DDFS often precede subsequent improvements in OS. In NSABP B14, TAM significantly improved DDFS at 4 years and OS at 10 years. In ATAC and BIG 1–98, over half of EBC recurrences are DM, but OS differences are limited by short FU. BIG 1–98 showed a significant reduction in DM risk with letrozole versus TAM, but ATAC showed no significant reduction in DM risk with anastrozole in hormone receptor-positive patients. The reason for this difference is unclear. IES initially showed a significant reduction in DM risk, which was later followed by a borderline significant OS benefit in estrogen receptor-positive/unknown patients, favoring exemestane. Conclusion: Data from several adjuvant trials show that improvements in DDFS often precede significant improvements in OS. AIs show superiority over TAM in reducing DM risk (IES, BIG 1–98). DDFS may be a better, more achievable endpoint than OS for women with EBC and could quicken the development of future adjuvant breast cancer therapies. [Table: see text] No significant financial relationships to disclose.
Adjuvant LH-RH agonists for premenopausal early breast cancer: A meta-analysis of randomized clinical trials (RCTs) exploring the magnitude of the disease-free and overall survival (DFS/OS) benefit
Authors: Carlini P. , Bria E. , Cuppone F. , Papaldo P. , Nisticò C. , Fabi A. , Ruggeri E. M. , Terzoli E. , Cognetti F. , Giannarelli D. 
Published: March 2020

592 Background: LH-RH agonists are considered as a milestone for adjuvant treatment for premenopausal early breast cancer patients (pts). All RCTs in which ovarian ablation (OA) with/without tamoxifen (TAM) and/or chemotherapy (CT) was compared with tamoxifen (TAM) and/or chemotherapy (CT) were pooled to estimate the magnitude of the benefit in both DFS and OS. Methods: A literature-based meta-analysis was accomplished, and event-based relative risk ratios (RRs) with 95% confidence interval (CI) were derived. A fixed- (FEM) and a random-effect (REM) model according to the inverse variance and heterogeneity (Het) test were applied as well. Absolute benefits (AB) and the number of pts needed to treat (NNT) were calculated. A sensitivity analysis to test for effect robustness in 4 sub-populations (OA/OS vs CT; OA/OS + CT vs CT; OA + TAM vs CT; OA + TAM vs observation) was accomplished. Results: Fifteen RCTs were gathered (12,545 pts); one RCT did not report the OS result. Results are depicted in the table . Conclusions: Although differences across RCTs exist in median follow-up time (as demonstrated by heterogeneity), OA seems to significantly improve DFS when combined with CT over CT alone, when combined with TAM versus CT alone and when combined with TAM versus observation. Actually, these DFS benefits do not translate into an OS benefit, with the exception of the last subgroup. [Table: see text] No significant financial relationships to disclose.