bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognosic value of lower uterine segment involvement in high-grade endometrial cancers.
Authors: Gehrig Paola A. , Clark Leslie Horn , Franasiak Jason , Bae-Jump Victoria Lin , Ko Emily 
Published: March 2020

5092 Background: To determine the relationship of lower uterine segment (LUS) involvement and clinical-pathologic outcomes in high grade endometrial cancers (EC). Although LUS and prognosis has been previously reported in the literature, the results have been conflicting and limited to early stage cases without focus upon the highest risk histologies. Methods: A single-institution retrospective cohort analysis of all grade 3 EC from Jan 2005- Sept 2010 was performed. Clinical-pathologic data were abstracted. LUS status was determined based on permanent-section pathology. Statistical analyses were performed using univariate and bivariate analyses with t-tests, X2, and log-rank tests. Multivariate regressions were performed by cox modeling. Two sided p-values<0.05 were considered significant. Results: Of 329 cases, 52% were LUS+. Mean age was 66.1(SD 10.8) and BMI 31.7(SD 8.3). The majority were Caucasian (63.2%) and 30.1% were African-American (AA). Most women (80.2%) were overweight or obese, 58.7% had hypertension, and 22.5% were diabetic. Most women had stage I disease (54.8%), but 8.6% had stage II disease, and 36.6% had stage III-IV disease. Histologic subtypes included 32.2% endometrioid, 47.4% serous/clear cell, and 17% carcinosarcoma. Thirty-nine percent had > 50% myometrial invasion (MI) and 43.2% had LVSI. Most of the women (80.8%) underwent retroperitoneal node dissection (77.9% pelvic, 70.0% periaortic). Mean follow-up time was 24.5 months (range 0.13, 73.3). Age, HTN, and DM did not differ by LUS status. Statistically significant factors associated with LUS positivity included race AA (38.3 v 26.5%), obesity (57.5 v 46.7%), serous/clear cell (65.7 v 53.8%), LVSI (56.2 v 30.5%), deep MI (52.1 v 25.3%), and positive nodes (42.4 v 12.7%). LUS+ was significantly associated with an increased rate of recurrence (HR 2.3, CI 1.16-4.47, p =0.02) after adjusting for obesity, deep MI, LVSI, nodal status, stage, serous/clear cell histology, and adjuvant therapy. Conclusions: Lower uterine segment was independently associated with an increased rate of recurrence in high grade EC. This should be confirmed in prospective endometrial trials to see if this remains an independent predictor of recurrence.
Phase II trial of robotic stereotactic radiosurgery (SBRT) in patients with recurrent gynecologic malignancies.
Authors: Kunos Charles , Brindle James , Adams Ramon , DeBernardo Robert 
Published: March 2020

5102 Background: Ablative radiation dose delivered by a robotic SBRT platform has shown progression-free survival benefit in two limited case series among patients with recurrent gynecological malignancies. The therapeutic impact of SBRT on disease progression (PD) was evaluated in the recurrent setting in this phase II trial. Methods: Fifty patients with recurrent and measurable gynecologic malignancy were treated with SBRT. The cohort included patients with recurrent ovarian (n =25), endometrial (n =14), cervical (n =9), or vulvar (n =2) cancer, 1 prior chemotherapy or radiation regimen, and GOG performance status 0, 1, 2. Patients underwent image-guided SBRT in 3 daily doses of 800 cGy = 2400 cGy. SBRT planning target volumes were determined by both the radiation and gynecologic oncologist using non-contrasted CT and 18F-FDG PET/CT overlays. The primary endpoints were 6-month clinical benefit rate (# complete response + # partial response + # stable disease without PD [by RECIST v1.0] / 50), and less than 30-day posttherapy toxicity. Results: Between July 2009 and September 2011, 50 patients were enrolled and have a median posttherapy follow-up of 9 months. At 3 months, 50% (n=25) had complete response, 46% (n=23) had partial response, and 4% (n=2) had stable disease in SBRT-targeted lesions. Twenty-six patients (52%) have had non-SBRT target PD and 18 (36%) have died of PD. Of the 50 patients, 33 had a PD-free interval of at least 6 months, for an overall clinical benefit rate of 66%. Less than 30-day posttherapy SBRT-related toxicities were grade 2 fatigue (n =9 [18%]), grade 2 nausea (n =3[6%], grade 3 nephropathy (n =2[4%]), and grade 4 hyperbilirubinemia (n =1[2%]). Conclusions: This is the first phase II clinical trial of SBRT showing a clinically relevant benefit of ablative radiation in the setting of recurrent gynecological disease. Despite excellent control of targeted lesions with minimal toxicity, non-SBRT target PD rates are high, spurring interest for future SBRT-chemotherapy clinical trials.
Validation of the predictive value of modeled HCG residual production “P” in low-risk gestational trophoblastic neoplasia (GTN) patients treated in GOG-174 phase III trial.
Authors: You Benoit , Deng Wei , Oza Amit M. , Osborne Raymond 
Published: March 2020

5110 Background: In low-risk GTN, chemotherapy is changed according to serum hCG levels. We previously showed mathematical modeling of hCG kinetics provides a parameter production “P”, a useful early predictor of methotrexate (MTX) resistance (You et al; Ann Oncol 2010; ASCO and ISSTD 2011). We applied this approach to patient cohort of GOG-174 trial, in which weekly MTX (Arm 1) was compared to dactinomycin (Arm 2). Methods: Database (210 patients, including 78 with resistance) was split into 2 sets. A 126 patient Model Set was initially used to adjust model parameters. Patient hCG kinetics from day7 to day50 were fit with NONMEM™ program to: “[hCG(time)] = hCG0i * exp(–k*time) + P”; where P is residual hCG tumor production, hCG0i is the initial hCG level, and k is the rate constant. Three putative P-based classifiers of resistance were assessed using ROC analyses. Then an 84 patient Test Set with blinded-resistance status was used to assess the validity of predictions. The primary endpoint was treatment resistance defined as relapse and/or lack of hCG normalization. Results: Due to initial surge in 14% patients, hCG kinetic modeling was started on day7. Individual hCG decline profiles of Model Set patients were modeled. There was no impact of treatment arm on variability of kinetic parameter estimates. The best P cut-offs to discriminate resistant vs. sensitive patients were 7.7 in Arm 1 and 74.0 in Arm 2. They were combined to define 2 predictive groups with low vs. high risks of resistance (ROC AUC = 0.82; Se = 93.8%; Sp = 70.5%). The model was then applied to Test Set patient cohort. The predictive value of P-based predictive groups regarding resistance was reproducible (ROC AUC = 0.81; Se = 88.9% (95% CI: 70.8%-97.7%); Sp = 73.1% (95% CI: 60.0%-84.4%)). Both P and treatment arm were associated with resistance using multivariate logistic regression tests. Predictive value of P was less accurate in dactinomycin arm. Conclusions: The early predictive value of the modeled kinetic parameter P regarding resistance appears promising in GOG-174 study, especially in MTX arm. This is the second positive evaluation of this procedure study. Prospective validation is warranted.
Reduction in Ki-67 in benign breast tissue of high-risk premenopausal women with the SERM acolbifene.
Authors: Fabian Carol J. , Kimler Bruce F. , Zalles Carola M. , Petroff Brian K. , Metheny Trina , Phillips Teresa A. , Echalier Ben R. , Bailey Howard Harry , Cornelison Terri L 
Published: March 2020

520 Background: Selective Estrogen Receptor Modulators (SERMs) are approved for reduction of risk for breast cancer; however, uptake and use is limited. We conducted a pilot study of a 4th generation SERM to determine tolerability and effect on tissue biomarkers in healthy women at high risk for development of breast cancer. Methods: Premenopausal women at elevated risk for breast cancer were screened by random periareolar fine needle aspiration (RPFNA) performed during the follicular phase of the menstrual cycle. Women were eligible if breast epithelial cells exhibited evidence of cytologic hyperplasia with or without atypia, as well as Ki-67 ≥2% by immunocytochemistry. Following 6-8 months of open-label acolbifene (20 mg/d), the RPFNA was repeated. The primary endpoint was modulation of the proportion of cells that expressed Ki-67. Body composition (DEXA), pelvic sonography, mammographic breast density, and serum levels of IGF-1/IGFBP3 and several bioavailable hormones were assessed pre and post intervention. Results: 76 women were screened by RPFNA, with 25 eligible and enrolled in the intervention over a 9 month period. All 25 (7 on oral contraceptives) subjects completed the study, had a second RPFNA, and were evaluable. Median Ki-67 at baseline was 4.6% (range 2.4 – 21.9%) and off study 1.4% (range 0 – 6.6%); median change was a reduction of 3.0% (range -20.2% to +2.8%; decreased in 23, increased in 2) or a relative reduction of 77%. The end-of-study Ki-67 was significantly less than baseline (p<0.001, 2-tailed Wilcoxon test). There were no statistically significant changes in cytomorphology over this short intervention period. There was a marginal effect on breast density (16 decreased; 8 increased; p=0.067). Adverse events were minimal with greatest grade of 3 reported by 2 subjects, grade 2 by 7 subjects, and grade 1 by 11 subjects. No serious adverse event was reported and no subject discontinued the study due to an AE. Conclusions: Based on preliminary evaluation showing favorable modulation of proliferation and minimal adverse events, further investigation of acolbifene, a fourth generation SERM, as a breast cancer chemoprevention agent for premenopausal women appears warranted. Supported by NO1-CN-35135.
Mucin-1 protein and mRNA expression in breast cancer: Predictive value for therapy response and survival after neoadjuvant chemotherapy.
Authors: Sinn Bruno Valentin , Von Minckwitz Gunter , Denkert Carsten , Eidtmann Holger , Darb-Esfahani Silvia , Belau Antje , Kronenwett Ralf , Holzhausen Hans-Juergen , Mehta Keyur , Loibl Sibylle 
Published: March 2020

522 Background: Mucin-1 (MUC1) is expressed in normal epithelial cells and in breast cancer. Immunotherapeutic agents targeting MUC1 are currently tested in clinical trials. Methods: We evaluated the frequency of MUC1 expression by immunohistochemistry (IHC; n = 691) and quantitative RT-PCR (qRT-PCR; n = 286) in formalin-fixed paraffin-embedded (FFPE) pre-treatment biopsies from patients of the GeparTrio trial (NCT 00544765). mRNA levels were analyzed as a continuous variable, a distribution-based cut-off was chosen for IHC data. The predictive value for therapy response and survival after neoadjuvant anthracycline/taxane-based chemotherapy (CTX) was evaluated. Results: MUC1 was detectable by IHC in 95%. qRT-PCR covered a dynamic range of 3 orders of magnitude. IHC and mRNA data were correlated (p < 0.001). MUC1 was detected in higher quantities in HR+ tumors (p < 0.001), the lowest levels were found in HR-/HER2- tumors (p < 0.001). High MUC1 protein and mRNA expression were associated with lower probability of pathologic complete response (pCR) in the overall population (p < 0.001) and in HR+ (p = 0.004 and < 0.001), HER2- (p < 0.001) and HR+/HER2- tumors (p < 0.001). In multivariable logistic regression, MUC1 was independently predictive (high MUC1 protein: odds ratio (OR) 0.464, 95% CI 0.300 – 0.719, p = 0.001; MUC1 mRNA (per 20-dCT unit): OR 0.673, CI 0.546 – 0.829, p < 0.001). MUC1 protein and mRNA expression were associated with longer patient survival in the overall population (p = 0.03 and < 0.001) and in HER2- tumors (p = 0.005 and < 0.001). MUC1 mRNA was also prognostic in HR+ (p < 0.001) and HR+/HER2- tumors (p = 0.001). In multivariable analysis, protein and mRNA expression were independently prognostic (high MUC1 protein: hazard ratio (HR) 0.388, CI 0.166 – 0.907, p = 0.029; MUC1 mRNA per 20-dCT unit: HR 0.763, CI 0.595 – 0.909, p = 0.005). Conclusions: MUC1 is frequently expressed in breast cancer and detectable by IHC and qRT-PCR from FFPE tissue. Despite its association with HR+ status, it provides independent predictive information for therapy response and survival after neoadjuvant CTX. In clinical immunotherapy trials, MUC1 expression may serve as a predictive marker.
ACE inhibitors and angiotensin receptor blockers use and breast cancer outcomes in patients treated with neoadjuvant systemic chemotherapy.
Authors: Chae Young Kwang , Brown Erika N. , Lei Xiudong , Melhem-Bertrandt Amal , Giordano Sharon Hermes , Litton Jennifer Keating , Hortobagyi Gabriel N. , Gonzalez-Angulo Ana M. , Chavez-Mac Gregor Mariana 
Published: March 2020

537 Background: There is a growing body of evidence to suggest that ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) might have anti-tumor properties. We investigated whether the use of ACEI/ARBs during chemotherapy affects the clinical outcomes of breast cancer patients receiving taxane and anthracycline-based neoadjuvant chemotherapy. Methods: We included in this analysis 1449 patients with diagnosis of invasive primary breast cancer diagnosed at the MD Anderson Cancer Center between 1995 and 2007 who underwent neoadjuvant chemotherapy. Of them, 160 (11%) patients were identified by review of their medical record, as ACEI/ARBs users. We compared pathologic complete response (pCR) rates, relapse-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) between ACEI/ARB users and non-users. pCR was defined as no evidence of invasive carcinoma in the breast and axillary lymph nodes at the time of surgery. Descriptive statistics and Cox proportional hazards model were used in the analyses. Results: There was no difference in the pCR rates between ACEI/ARB users (16%) versus non-users (18.1%) (p=0.50). After adjustment for important demographic and clinical characteristics, no significant differences between ACEI/ARB users and nonusers were observed in RFS (HR=0.81; 95% CI=0.54-1.21; P=0.30), DSS (HR=0.83; 95% CI=0.52-1.31; P=0.42), or OS (HR=0.91; 95% CI =0.61-1.37; P=0.66). In a subgroup analysis among ARB users, the 5-year RFS was 82% vs 71% in ACEI/ARB non-users (P=0.03). In the multivariable analysis, ARB use was also associated with a decreased risk of recurrence (HR=0.35; 95% CI=0.14-0.86; P=0.02). However, no statistically significant differences in DSS or OS were seen. Conclusions: No differences in pCR and survival outcomes were seen between ACEI/ARB users and non-users among breast cancer patients receiving neoadjuvant chemotherapy. ARB use may be associated with improved RFS. Further research is needed to validate this finding.
Impact of the EndoPredict-clin score on risk stratification in ER-positive, HER2-negative breast cancer after considering clinical guidelines.
Authors: Filipits Martin , Dubsky Peter Christian , Rudas Margaretha , Brase Jan C. , Kronenwett Ralf , Weber Karsten E. , Petry Christoph , Schmidt Marcus , Luisser Irmard , Klug Evelyn , Gnant Michael 
Published: March 2020

542 Background: Many ER-positive, HER2-negative breast cancer patients are treated by adjuvant chemotherapy according to current clinical guidelines. We retrospectively assessed whether the combined gene expression/ clinicopathological EndoPredict-clin (EPclin) score improved the accuracy of risk classification in addition to considering clinical guidelines. Methods: Three clinical breast cancer guidelines (National Comprehensive Cancer Center Network (NCCN), German S3 and St. Gallen 2011), and the EPclin score - assessed by quantitative RT-PCR in formalin-fixed paraffin-embedded tissue - were used to assign risk groups in 1,702 ER-positive, HER2-negative breast cancer patients from two randomized phase III trials (Austrian Breast and Colorectal Cancer Study Group 6 and 8) treated with endocrine therapy only. Results: Although all analyzed clinical guidelines identified a low-risk group with improved metastasis-free survival, the overwhelming majority of all patients (81-94%) were classified as intermediate / high risk. In contrast to that, the EPclin classified only 37% of all patients as high risk and that stratification resulted in the best separation between low and high risk groups (p < 0.001, HR = 5.11 (3.48-7.51). Consequently, the majority of all patients deemed intermediate / high risk by the clinical guidelines was re-classified as low risk by the EPclin score. Kaplan Meier analyses demonstrated that the re-classified subgroups (47 to 57% of all patients) had an excellent 10-year metastasis-free survival of 95% comparable to the clinical assigned low-risk groups although encompassing a higher proportion of the trial patients. Conclusions: The EPclin score predicted distant recurrence more accurately than all three clinical guidelines and is especially useful to reclassify patients considered as intermediate / high risk by the guidelines. The data suggests that the EPclin score provides clinically useful prognostic information beyond common clinical guidelines and can be used to accurately identify the clinically relevant group of patients who are adequately and sufficiently treated with adjuvant endocrine therapy alone.
Interpathologists discrepancies in Ki67 assessment in the PACS01 trial: An independent prognosis factor.
Authors: Penault-Llorca Frederique Madeleine , Goubar Aicha , Raoelfils Ines , Sagan Christine , Lacroix-Triki Magali , Denoux Yves , Verrielle Veronique , Jacquemier Jocelyne , Martin Anne-Laure , Roche Henri , Andre Fabrice 
Published: March 2020

543 Background: Several reports suggest an inter-observer variability in Ki67 assessment. Nevertheless, there is no large study that evaluates the rate of discrepancies, together with their impact. Methods: Ki67 expression was assessed on 663 samples from patients with ER-positive breast cancers included in the PACS01 trial (Roche, J Clin Oncol, 2006). Ki67 staining was done using MiB1 antibody (Dako, Copenhagen, Denmark, Dilution 1:250). Prognostic and predictive values have been reported previously (Penault-Llorca, J Clin Oncol, 2009). A second central review was done by a senior breast pathologist from a French Cancer center. A discrepancy was defined as either a false positive or false negative result. Cut-off for positivity was defined at 15% according to data from Cheang et al (JNCI, 2009). Results: The rate of discrepancy was correlated with the percentage of stained tumor cells. A 10% discrepancy rate between the 2 pathologists was observed when the first pathologist reported <10% tumor cells stained. Same low rate of discrepancy (10%) was observed if more than 30% cancer cells were stained according to the first assessment. At the opposite, discrepancy rates were 47%, 45%, 22%, 34% when the first pathologist reported 10-15%, 15-20%, 20-25% and 25-30% tumor cells stained. Overall, 36% of the patients presented a grade II tumor together with Ki67 <10% or >30%. We then evaluated the impact of discrepancy in terms of prognosis. Patients presenting a concordant result between the two pathologists showed a better outcome as compared to patients presenting a discrepancy, independently to the percentage of tumor stained (p=0.05, patients with concordant Ki67 ranged between 10-30% versus those with one reader <10% and the other one >10%-<30%). Conclusions: Discrepancy rates between pathologists are acceptable when Ki67 is either <10% or >30%. A Ki67 ranged between 10 and 30% could define a grey zone in which Ki67 should be reported with caution or be double checked by another pathologist. Survival analysis suggested that inter-observer discrepancies could act a prognostic factor. Such finding could reflect underlying intra-tumor heterogeneity.
A phase II, randomized trial (CONCERT-1) of chemoradiotherapy (CRT) with or without panitumumab (pmab) in patients (pts) with unresected, locally advanced squamous cell carcinoma of the head and neck (LASCCHN).
Authors: Giralt Jordi , Fortin Andre , Mesia Ricard , Minn Heikki , Henke Michael , Yunes Ancona Alejandro , Cmelak Anthony , Markowitz Avi B. , Hotte Sebastien J. , Singh Simron , Chan Anthony T. C. , Merlano Marco Carlo , Zhang Alicia , Oliner Kelly S. , Vanderwalde Ari M. 
Published: March 2020

5502 Background: Pmab is a fully human monoclonal antibody against the epidermal growth factor receptor. We evaluated the safety and efficacy in pts receiving CRT alone or CRT plus pmab (PCRT) as 1st‑line treatment of LASCCHN (sponsored and funded by Amgen Inc.). Methods: Pts with stage III, IVA, or IVB previously untreated LASCCHN of all sites excluding the nasopharynx were randomized 2:3 to open-label CRT or PCRT. CRT included cisplatin 100 mg/m2 for 3 cycles during standard fractionation radiotherapy (RT). PCRT included pmab 9.0 mg/kg + cisplatin 75 mg/m2, both administered with RT as in the CRT arm. The primary endpoint was local regional control (LRC) rate at 2 years; key secondary endpoints included PFS, OS, and safety. Preplanned HPV subset analysis, as determined by p16 immunohistochemistry, was performed on available samples. Results: Of 150 treated pts (87 pts PCRT, 63 pts CRT), 87% were men; median (range) age was 57 (39-77) years; ECOG PS 0: 68%. Of 99 pts with tumor evaluable for HPV, 42% were HPV+. Overall, the 2-year LRC rate (95% CI) was 61% (50%-71%) for PCRT and 68% (54%-78%) for CRT. PFS events occurred in 40% of the PCRT and 35% of CRT arm (HR [95% CI] 1.15 [0.68-1.96]; p=0.61). Death occurred in 36% of the PCRT arm vs 24% of the CRT arm (HR [95% Cl] for OS 1.63 [0.88-3.02]; p=0.12). Disease progression was the cause of death in 22% of PCRT pts and 10% of CRT pts. There were no differences in outcome by tumor HPV status. No difference in fatal adverse events (AEs) was seen between arms. Grade 3+ AEs occurred in 85% vs 68% of pts (PCRT vs CRT). Differences in grade 3+ toxicity between treatment arms (PCRT, CRT) were most pronounced for mucosal inflammation (55%, 24%), radiation skin injury (28%, 13%), dysphagia (40%, 27%), and rash (11%, 0%). RT delays of >10 days occurred in 16% of the PCRT arm and 3% of the CRT arm. Median cisplatin cumulative dose received was 223.1 mg/m2 in the PCRT arm and 296.9 mg/m2 in the CRT arm, reflective of differences in planned dose. Conclusions: The addition of pmab to CRT did not show an increase in efficacy and was associated with increased toxicity. Further results of HPV biomarker analysis will be presented.