bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of adjuvant gemcitabine plus docetaxel (GD) for completely resected stage I-IV high grade uterine leiomyosarcoma (HGuLMS)
Authors: Hensley M. L. , Larkin J. , Ishill N. , Abu-Rustum N. , Sabbatini P. , Konner J. , Tew W. , Spriggs D. , Aghajanian C. A. 
Published: March 2020

5591 Background: Patients (pts) with completely resected stage I-IV HGuLMS are at high risk for recurrence, with reported 2-year progression-free survival ranging from 19–30% (Dinh, Gyn Onc 2004; Major, Cancer 1993). No adjuvant treatment has been shown to improve survival, although prospective data are limited. GD achieves objective responses in metastatic uLMS. We sought to determine whether 4 cycles GD given after complete resection of stage I-IV HGuLMS would yield a 2-year PFS of at least 40%, in order to determine whether GD was worth pursuing as an adjuvant strategy in a randomized trial. Methods: Eligible pts with completely resected HGuLMS within 8 weeks of surgery, no prior GD, no evidence of disease on post-resection CT, KPS = 80, and adequate organ function were treated with G 900 mg/m2 over 90 minutes days 1 and 8 + D 75 mg/m2 d8, with GCSF or pegfilgrastim, every 3 weeks for 4 cycles. CT was performed at baseline, after cycle 4, and every 3 months. Progression defined as new evidence of disease on CT. Results: 25 pts (median age 49, range 37–73) enrolled; 23 evaluable (1-never treated, 1-ineligible). Grade 3 related toxicities were: neutropenia (2/23) 8.7%, febrile neutropenia (2/23) 8.7%, anemia (2/23) 8.7%, thrombocytopenia (1/23) 4.3%, diarrhea (1/23) 4.3%, hyperglycemia (2/23) 8.7%, pulmonary (2/23) 8.7%; there were no ≥ grade 4 toxicities. With median follow-up of 29 months (range 0.5 to 45 months) for all pts, PFS at 2 y and 3 y is 45%, and median OS is not yet reached. For the 18 pts with stage I or II uLMS 2-y and 3-y PFS is 58%, and median PFS is 38 months (95%C.I. 6 months to not yet reached). Sites of first recurrence were: lung only-3/23 (13%); pelvis only-5/23 (22%); both-5 (22%). Treatment of recurrence was at physician discretion and included resection, resection plus pelvic radiation, and/or chemotherapy. Conclusions: Pts treated with post-resection GD for stage I-IV HGuLMS had 2-y and 3-y PFS that appears superior to historical rates of PFS. Incorporation of GD into a randomized trial of adjuvant chemotherapy vs adjuvant pelvic radiation for resected stage I and II uLMS is planned. No significant financial relationships to disclose.
Erlotinib (E), cisplatin (C) and radiotherapy (RT) for patients with locally advanced squamous cell cervical cancer—A phase I trial
Authors: Rodrigues A. N. , do Carmo C. C. , Viegas C. , Erlich F. , Lima R. , Martins R. , Hercenhorn D. , Fontão K. , Small I. A. , Ferreira C. M. 
Published: March 2020

5592 Background: Pre-clinical data indicates that inhibition of epidermal growth factor receptor (EGFR) potentiates the effect of RT. This phase I trial aimed to determine the maximal tolerated dose (MTD) of erlotinib, an oral EGFR tyrosine kinase inhibitor, when administered concurrently with standard chemoradiation (CRT) for cervical cancer. Methods: In a modified Fibonacci design, three cohorts of three patients received escalating doses of E (50/100/150 mg) one week before and combined with C (40 mg/m2, weekly, 5 cycles) and RT (external beam RT - 4,500 cGy in 25 fractions, followed by 4 fractions/600 cGy/weekly of brachytherapy). Eligibility criteria included histologically proven squamous cell cervical carcinoma, stage IIB to IIIB; no prior therapy; ECOG PS <3 and adequate end-organ functions. Patients were allowed four additional weeks of toxicity observation after CRT + E before proceeding to the next cohort. Frozen tissue for molecular studies was collected before treatment. Results: Between 12/04 and 8/06, 15 patients were enrolled, 3 at dose level (DL) 50 mg, 4 at DL 100mg and 6 at DL 150 mg. Patients presented median age 47 (36–59), stage IIB (46,2%) and IIIB (53,8%). Overall E+CRT was well tolerated; 3 patients did not complete the planned schedule.One patient at DL 100mg withdrew informed consent due to grade 2 rash; at DL150mg one patient presented Raynaud’s Syndrome and had C interrupted and one patient presented grade 4 hepatotoxicity. The latter was interpreted as DLT and 3 additional patients were included in this cohort. No further grade 4 toxicity occured. Grade 3 toxicity occurred in 33% of the cases, being diarrhea in 3 patients, rash in 2 patients and leukopenia in 1 patient.It shoud be highlighted that E+CRT did not lead to limiting in-field toxicity (radiodermitis, rash or diarrhea). Within the 12 patients who received through E+CRT, median duration of treatment and follow-up was 70 (67–80) days and 9.5 (3–23) months, respectively. The phase II of this trial is ongoing. Conclusions: The MTD has been defined as 150 mg. This is the first report of a combination of erlotinib, cisplatin and pelvic RT. The addition of E to standard CRT does not appear to increase in-field or systemic toxicities. No significant financial relationships to disclose.
Clear cell endometrial cancer patients have an increased risk of venous thrombotic events
Authors: Garrett L. , Lee L. M. , Oliva E. , Horowitz N. , Duska L. 
Published: March 2020

5597 Objective: To document the rate of clinically significant venous thromboembolism (VTE) in patients with clear cell carcinoma of the endometrium (CCC-E). Methods: Institutional review board (IRB) permission was obtained for retrospective record review. The pathology database at our institution located cases of CCCs over the time period 1994–2004. Controls with high grade endometrial cancers were matched for stage, age and date of diagnosis. All patients underwent surgical staging with gynecologic oncology staff surgeons and all patients received VTE prophylaxis peri-operatively. Records were reviewed and data were collected regarding patient age, tumor stage, body mass index, surgical procedure, adjuvant therapy, survival, and presence of VTE. All pathology was reviewed at the MGH. Results: Thirty-nine cases of CCC-E were identified. Complete clinical data were available for 29 cases. Age ranged from 38–85 (mean 64.6) years. 35% of patients had stage I tumors, 10% stage II, 27.5% stage III, and 27.5% had stage IV tumors. 58 age and stage matched controls were selected. The majority were grade 3 endometrioid cancers (50%) with the remainder being serous (35%), mixed histology (7%), carcinosarcoma (5%), and undifferentiated carcinoma (3%). The majority of the control patients had a higher BMI than the case patients. Overall there were 18 VTE events, 10 (34.5%) in those with CCC-E and 8 (13.8%) controls p = 0.046. A higher proportion of VTE occurred in those with stage III/IV disease (n=16) as compared to those with early stage (n =2) p =0.01. When considering the timing of VTE, the VTE observed in those with CCC-E occurred at presentation or with disease recurrence (8 vs 1) while nearly all VTE in the control group occurred in the postoperative period. (7 vs 2). This was statistically significant p =0.01 Conclusion: Patients with CCC-E are at increased risk of VTE compared to patients with other high- risk endometrial cancers. This is particularly true for those with advanced stage disease. Presentation with a VTE and postmenopausal bleeding should raise the suspicion for CCC-E. Likewise, in those with known CCC-E development of a VTE may be a harbinger of recurrence. Consideration should be given to extended prophylaxis in patients with CCC-E to prevent VTE. No significant financial relationships to disclose.
A detailed analysis of the risk factors influencing local and distant breast cancer recurrence during adjuvant endocrine therapy
Authors: Houghton J. 
Published: March 2020

562 Background: The ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC; ISRCTN18233230 ) trial compared the efficacy and safety of 5 years’ anastrozole, tamoxifen, or combination as adjuvant therapy for 9366 postmenopausal women with early invasive breast cancer. Here, risk factors influencing local and distant recurrences during the trial, independent of trial treatment, are assessed. Methods: The influence of standard baseline factors such as hormone receptor status, nodal involvement, tumor size, grade and age were evaluated on both local and distant recurrence rates. The use of other treatments (adjuvant chemotherapy, radiotherapy) and surgical status (mastectomy and axillary surgery) were also included. In addition, weight, body mass index, hysterectomy and prior hormone- replacement therapy were added. Cox models were used to analyze events by prognostic factors, and subsequently adjusted by country, before the production of confirmatory models. Results: For both local and distant recurrence, the highest risk correlated with poorer tumor differentiation, larger tumor size, increased nodal involvement and a negative hormone receptor status (see table ). While surgical status also affected the risk of developing a recurrence, previous treatments were less important, but residence in the USA showed a significant advantage. No association was seen with hysterectomy or weight for any recurrence. Conclusions: Although the pattern of risk varied for local and distant recurrence, tumor grade, size, and nodal involvement were the strongest risk factors for both. In comparison, the impact of previous treatments on hazard risk was lower. These data from a large international clinical trial confirm that women with less differentiated or larger tumors, and those with involved nodes, are at an increased risk of recurrence. [Table: see text] [Table: see text]
YB-1 expression and effectiveness of different dose-intensification strategies in high-risk breast cancer: Five-year follow-up results of prospective randomized WSG-AM-01 trial
Authors: Gluz O. , Kates R. , Schmitt M. , Mengele K. , Royer H. , Mohrmann S. , Ting E. , Diallo-Danebrock R. , Kiechle-Bahat M. , Nitz U. , Harbeck N. 
Published: March 2020

563 Background: Y-box binding protein (YB-1), known as oncogenic transcription factor, is associated with up-regulation of MDR1, alters p53 function, and induces growth of an aggressive phenotype. In high-risk breast cancer, the prospective randomized WSG-AM-01 trial has reported significantly better event-free (EFS) and overall survival (OS) for tandem high-dose (HD) vs. dose-dense (DD) chemotherapy, especially in basal-like und HER2 subgroups. The present study examines the interaction of a drug resistant phenotype induced by YB-1 within the WSG-AM-01 collective at 5-year follow-up. Methods: 236 tumors (116 HD/120 DD) of 403 randomized patients (60%) were available for construction of tissue microarrays and determination of molecular classification by k-clustering of expression of 34 protein markers. Immunostaining of YB-1 by specific peptide antibody was scored semiquatitatively by intensity. Associations of YB-1 staining with other protein expression factors were studied by Pearson correlations. Univariate survival was estimated by Kaplan-Meier analysis and tested by log rank statistics. Multivariate survival modeling was performed by a generalized Cox model, with linear proportional hazards terms in the first block and time-varying interactions in the second block. Results: At a median follow-up of 61.7 months, the WSG-AM-01 confirms a significant EFS and OS benefit for HD in HRBC. In 60% of tumors, there was strong YB-1 expression. YB-1 was significantly associated with several proliferation and drug resistance markers, such as p53, EGFR, S6 and with basal-like/Her2 subtypes.YB-1 expression was highly predictive for response to HD: both EFS (HR=0.29, p=0.001) and OS (HR=0.16, p=0.0001) were significantly improved by HD compared to DD for YB-1 positive tumors; these favorable time-varying hazard ratios signify decreases in early (≤3 years) relapses and deaths, respectively. Conclusions: Among all investigated markers, only YB-1 expression was significantly associated by time- varying interaction analysis with efficacy of HD. The results suggest YB-1 as a potential stratification criterion for future trials as well as a target for treatment of drug resistant HRBC. No significant financial relationships to disclose.
Second interims analysis of the ARA Plus study: Breast Cancer (BC) adjuvant chemotherapy (CT) with and without darbepoetin- alpha, analysis of serious adverse events
Authors: Ziegler K. , Warm M. , Oberhoff C. , Reimer T. , Mohrmann S. , Schumacher C. , Gluz O. , Nitz U. , Zuna I. , Werner F. 
Published: March 2020

564 Background: TAC is one of the most effective regimens. It‘s associated with higher frequency of anemia and chemotherapy-induced neutropenia (CIN). The erythropoiesis stimulating factor (ESF) support of chemotherapy, its complications and survival effect remain unclear. Erythropoetins do prevent chemotherapy-associated anemia (CAA) and subsequent fatigue syndrome but their potential influence on survival is still unclear. One aim of this analysis is to investigate the correlation between CT, growth factor support and toxicity (SAE‘s). Methods: This ARA Plus phase III trial compare chemotherapy ±ARA in breast cancer patients >18 years old, with positive lymph nodes and with M0 disease. Pts get six cycles of of 5-fluoro-uracile 500mg/m2, epirubicine 100mg/m2 and cyclophosphamide 500mg/m2, (FEC, Bonneterre), 3-weekly or six cycles of docetaxcel 75mg/m2, adriamycin 50mg/m2 and cyclophosphamide 500mg/m2, (TAC, BCIRG) and are randomized to ARA 500μg q3w if Hb<13 g/dl or standard support care. Here arte the results. of SAE‘S. Results: A total of 756 pts (373 + ARA/383 -ARA) from 53 sites were enrolled since January 2004, there are 1234 pts. planned up to January 2008. 185 serious adverse events (SAE) are reported. Of these 185 SAE’s 100 (54%) had an ARA-therapy. Most frequent SAE’s were: leucopenia, febrile neutropenia, thrombosis and infections. In 9 (31%) out of the 29 febrile neuropenia SAE’s, ARA was given. 30 thromboses were reported (23+ARA/7-ARA s.) but only 10 at the verty time ARA was given. In 31 severe infections 16 (51,6%; n.s.) were reported in patients receiving ARA Therapy. From 43 patients with intestinal SAE‘s like Diarrhea/Mucositis/Nausea to 30 pts. (69,8 %) ARA eas given. Conclusions: The combination of CT and ARA is safe concerning febrile neutropenia and furthermore appears to be protective factor of this SAE when combined with TAC. There seem to be more SAE‘s concerning thrombosis and intestinal difficulties.These results allow to hypothesize that ARA therapy is associated with higher toxicity concerning thrombosis which could make the use of heparin necessary but on the other side it shows significant reduced neutropenia. No significant financial relationships to disclose.
Cell-cycle complete response after neoadjuvant letrozole predicts superior relapse-free and overall survival: Long-term follow- up of the letrozole P024 study
Authors: Ellis M. J. , Tao Y. , Bhatnagar A. S. , Ross H. Chaudri , Evans D. , Miller W. R. , Eiermann W. 
Published: March 2020

570 Background: The P024 study was a double blind randomized endocrine therapy trial that compared 16 weeks of letrozole 2.5 mg daily (LET) with tamoxifen 20 mg daily (TAM). LET proved to be more effective than TAM in terms of tumor response and rates of breast conservation therapy (1). Biomarker studies also indicated that LET was a more effective anti-proliferative agent, with greater declines in Ki67 values (2). However, in the P024 trial patients experienced a very low rate of pathological complete response (pCR). We have therefore proposed that a cell-cycle complete response (CCCR - in which tumor cell Ki67 staining is 1% or less in the surgical specimen) may be an alternative to pCR because CCCR indicates that the endocrine therapy was maximally effective in causing cell-cycle arrest. In initial studies we had already shown that CCCR is more common with LET than TAM (3), and also there was a strong association between the absence of a CCCR and the presence of HER2 gene amplification (4). In this study we examined the relationships between CCCR and relapse-free and overall survival. Methods: Per protocol, patients were followed yearly for breast cancer relapse, all cause mortality and breast cancer specific mortality. Relapse-free and breast cancer specific survival was examined according to CCCR status after patients had been followed for five years on adjuvant TAM. Results: Patients who received neoadjuvant LET and whose tumors exhibited a CCCR had superior relapse-free (log rank P=0.0077) and breast cancer specific survival (P=0.0006). Patients who received TAM with a CCCR had superior RFS (P=0.0224) but not breast cancer specific survival. Conclusions: This study supports the conclusion that CCCR may be a clinically useful measurement for patients who undergo neoadjuvant LET. The value of CCCR after neoadjuvant TAM is less clear. A prospective trial that incorporates information on CCCR into clinical decision making regarding adjuvant chemotherapy may be appropriate. 1. Ann Oncol 12, 1527–32 (2001) 2. Cancer Res 63, 6523–31 (2003). 3. J Steroid Biochem Mol Biol 95, 91–5 (2005). 4. J Clin Oncol 24, 3019–25 (2006). No significant financial relationships to disclose.
Genomic heritage of sentinel lymph node metastases: Implications for clinical management of breast cancer patients
Authors: Ellsworth D. L. , Ellsworth R. E. , Becker T. E. , Deyarmin B. , Patney H. L. , Hooke J. A. , Shriver C. D. 
Published: March 2020

571 Background: Sentinel lymph node (SLN) biopsy status is a key prognostic factor for breast cancer patients. Sentinel nodes are believed to receive early disseminating cells from the primary tumor, but little is known about the origin of metastases colonizing the sentinel nodes. We used allelic imbalance (AI) to examine genomic relationships among metastases in the sentinel and non-sentinel axillary lymph nodes from complete axillary dissections in 15 patients with lymph node positive breast cancer. Methods: Sentinel nodes were localized by standard scintigraphic and gamma probe techniques using 1.0 mCi technetium-99m sulfur colloid. Pathologically positive nodes were identified by H&E histology and immunohistochemistry. Primary breast tumors and metastases in sentinel and axillary nodes were isolated by laser microdissection. AI was assessed at 26 chromosomal regions and used to examine the timing and molecular mechanisms of metastatic spread to the sentinel and axillary nodes. Results: Overall AI frequencies were significantly higher (p<0.05) in primary breast tumors compared to lymph node metastases. A high level of discordance was observed in patterns and frequencies of AI events between metastases in the sentinel and non-sentinel axillary nodes. Phylogenetic analyses showed that 1) multiple genetically-divergent lineages of metastatic cells independently colonize the lymph nodes; 2) some lymph node metastases appeared to acquire metastatic potential early in tumorigenesis, while other metastases evolved later; and 3) importantly, lineages colonizing the sentinel nodes appeared to originate at different times and to progress by different molecular mechanisms. Conclusions: Genomic diversity and timing of metastatic nodal spread may be important factors in determining outcomes of breast cancer patients. Metastases colonizing the sentinel nodes appear to arise at different times during disease progression and may not be descendants of progenitor cells that colonize the lymph nodes early in tumorigenesis. Metastatic growth in the sentinel nodes thus may be a consequence of stimulating factors from the primary tumor that affect proliferation of previously disseminated cells rather than the timing of metastatic spread. No significant financial relationships to disclose.
Endocrine effects of letrozole + triptoreline compared to tamoxifen + triptoreline as adjuvant treatment of premenopausal patients with early breast cancer
Authors: Rossi E. , Esposito G. , Rella F. Di , Gravina A. , Landi G. , Nuzzo F. , Pacilio C. , Monaco K. , Piccirillo M. , de Matteis A. 
Published: March 2020

578 Background: Few data have been reported on endocrine effects of combining LHRH-analogues with aromatase inhibitors (AI) in premenopausal patients. However, promising data in postmenopausal patients make this information interesting in view of extending adjuvant AI to premenopausal patients. We are conducting a phase 3 trial (Hormonal adjuvant treatment bone effects (HOBOE)) comparing tamoxifen (Tam), letrozole (L) and L + zoledronate (Z) for the effect on bone mineral density at 1 year. Postmenopausal and premenopausal patients are eligible, the latter also receiving monthly triptorelin (Tr). Methods: This analysis is limited to 76 premenopausal patients with early endocrine-responsive breast cancer, 28 treated with Tam+Tr and 48 with L+Tr±Z, assuming that Z has no endocrine effects. Serum 17-β-estradiol, FSH, LH, Δ4-androstenedione, testosterone, dehydroepiandrosterone-solphate, progesterone, ACTH and cortisol are measured at baseline and after 6 months of treatment. We compared, for each hormone, 6-month values between treatment groups by applying Exact Wilcoxon-Mann-Whitney test. Results: Baseline values for all the hormones were comparable between treatment groups. At 6 months, statistically significant differences were found for estradiol, FSH, LH and cortisol (see table , with median and range values by treatment group). No differences were found in plasma levels of testosterone, progesterone, ACTH, androstenedione, and dehydroepiandrosterone between the two groups. Conclusions: These data support that letrozole compared to tamoxifen, in combination with triptorelin, induces a more intense estrogen suppression also in premenopausal patients. Such evidence makes reasonable the hypothesis that the higher efficacy of letrozole versus tamoxifen shown in postmenopausal patients could be confirmed also in premenopausal patients. [Table: see text] No significant financial relationships to disclose.