bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mismatch repair deficiency as a predictor of adjuvant radiotherapy response in endometrioid endometrial carcinoma.
Authors: Kommoss Stefan , Reijnen Casper , Küsters-Vandevelde Heidi V.N. , Prinsen Clemens , Leon Massuger , Snijders Marc P.M.L. , Brucker Sara , Wallwiener Diethelm , Kwon Janice S , McAlpine Jessica N. , Pijnenborg Johanna M.A. 
Published: May 2019

5586 Background: Adjuvant radiotherapy improves progression-free survival in intermediate and high-risk endometrial cancer. However, so far there is no evidence of improved overall or disease-specific survival after adjuvant radiotherapy. There is accumulating evidence that MMR proteins are involved in DNA repair following radiotherapy. We investigated the predictive value of MMR status in terms of survival benefit after adjuvant radiotherapy in patients with stage IB/II, grade 3 endometrioid endometrial cancer (EEC). Methods: A retrospective multicenter cohort study was performed to compare patients with histopathologically confirmed stage IB/II grade 3 EEC with and without adjuvant radiotherapy. Patients were classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identifying ECs as either MMR-deficient, POLE, p53abn or p53wt. Multivariable Cox regression analysis explored associations between patient characteristics, adjuvant treatment and outcome. Results: A total of 128 patients were analyzed, including 57 patients (43.0%) with MMR-deficient EECs. Baseline characteristics were comparable, except a higher proportion of MMR-deficient EECs were stage II (36.8% vs. 15.5%, p = 0.006). Eighty-two patients (64.1%) received adjuvant radiotherapy (external beam [n = 55], vaginal brachytherapy [n = 27]). In multivariate analysis, adjuvant radiotherapy was independently associated with improved disease-specific survival in patients with MMR-deficient EECs (hazard ratio 0.19, 95%-CI 0.05 - 0.77), but not in patients with MMR-proficient EECs (hazard ratio 0.92, 95%-CI 0.37 - 2.31). Conclusions: Adjuvant radiotherapy improved disease-specific survival in patients with MMR-deficient EECs, but not in those with MMR-proficient EECs. This study demonstrates the predictive ability of MMR IHC to identify women who likely have increased benefit from radiotherapy.
Impact of non-compliance with guidelines in early type 1 endometrial cancers management, study from FRANCOGYN group.
Authors: Costaz Hélène , Bendifallah Sofiane , Raimond Emilie , Jankowski Clémentine , Dridi Sabrina , Lavoué Vincent , Collinet Pierre , Ouldamer Lobna , Touboul Cyril , Bricou Alexandre , Padeano Marie-Martine , Loustalot Catherine , Graesslin Olivier , Ballester Marcos , Coutant Charles 
Published: May 2019

5587 Background: To standardize surgical practices, ESMO-ESGO-ESTRO consensus conference published in 2016 new guidelines on the management of endometrial cancer. The main objective of this study was to evaluate the impact of non-compliance with current surgical guidelines on disease-free survival and overall survival. Methods: 852 patients with presumptive stage I and II type 1 endometrial cancer were included in a multicenter retrospective study, conducted between January 2000 and November 2015. The main objective of this study was to evaluate the impact of non-compliance with current surgical recommendations on overall survival and disease-free survival. Results: Our study shows that 34.3% of patients (n = 292) did not benefit from optimal surgical treatment. These patients did not have a lombo-aortic lymphadenectomy (LAL) and were at high risk of recurrence. There is a significant difference in disease-free survival in favor of patients undergoing surgery according to the recommendations, (Hazard Ratio (HR): 0.37 (Confidence interval (95% CI): 0.26-0.54), p < 0.001). In multivariate analysis, optimal surgical procedure performance is an independent factor for disease-free survival with HR at 2.04 (95% CI: 1.14-3.68), p = 0.01. There is a significant difference in overall survival in favor of patients undergoing surgery according to the recommendations, (HR: 0.31 (95% CI): 0.19-0.49), p < 0.001. In multivariate analysis, there is a trend toward significance with HR: 2.24 (95% CI: 1-5.05), p = 0.05. Older patients, patients with a larger BMI, patients with no indication of LAL at the preoperative ESMO classification, and no node involvement in are factors contributing to the decision of not to perform a LAL: p < 0.001, p = 0.03, p < 0.001 and p < 0.001 respectively. Conclusions: This study shows that patients with early type 1 endometrial cancer have improved recurrence-free survival and a statistical trend for an increased overall survival when recommended surgery is performed. Despite the current context of therapeutic de-escalation, we must strive to achieve the recommended optimal surgery, even if it requires secondary surgical revision, to avoid underestimation of patients with a poorer prognosis. To improve endometrial cancers management, amelioration of the preoperative assessment by increasing the sensitivity of emboli detection should be considered.
The prognostic significance of white adipose tissue inflammation in advanced-stage, high-grade, and serous endometrial cancers.
Authors: Broach Vance , Iyengar Neil M. , Zhou Xi K. , Wang Hanhan , Giri Dilip D. , Williams Samantha , Abu-Rustum Nadeem , Rubinstein Maria M , Dannenberg Andrew J. , Makker Vicky 
Published: May 2019

5589 Background: Obesity is associated with worse outcomes in endometrial cancer, but the underlying mechanisms are poorly understood. In other obesity-related cancers, white adipose tissue inflammation (WATi) is an independent predictor of shortened cancer-specific survival. We hypothesized that WATi occurs in patients with endometrial cancers and is a prognostic marker of shortened survival. Methods: We conducted a retrospective cohort study in which patients with stage III or IV grade 3 endometrioid (G3) or serous endometrial cancer were included. Eligible subjects had archived omental and/or peri-nodal adipose tissue available. WATi was detected by the presence of dead/dying adipocytes surrounded by CD68+ macrophages forming a crown-like structure (CLS). Clinicopathologic data were abstracted from medical records. For association with WATi, Wilcoxon rank sum test was used for continuous variables, Fisher’s exact test for categorical variables. Log rank test was used to assess the association of WATi and survival. Results: A total of 95 patients who underwent debulking surgery from 2001–2017 were included (median age, 67 years; range, 33-86 years). Of these, 51 (54%) had WATi. The presence of WATi was unaffected by race, tumor histology or stage. Patients with WATi had a higher median body mass index (BMI) than those without WATi (32.17 and 27.33 kg/m2, respectively; P < 0.001) and were more likely to be obese (P = 0.01). Patients with the most severe WATi (n = 20) had shorter progression-free survival (PFS) and a trend suggesting shorter overall survival (OS) than those patients with less severe or no WATi (n = 75) (median PFS 15.8 vs 59.2 months, respectively, P = 0.001; median OS 33.9 vs 59.4 months, respectively, P = 0.059). Conclusions: Visceral adipose inflammation is prevalent in obese patients with advanced G3 and serous endometrial cancer. Severe inflammation was associated with significantly worse PFS.
p53 and p16 expression profiles reveal three prognostically relevant subgroups in vulvar cancer: A TMA based study by the AGO-CaRE-translational study group.
Authors: Woelber Linn Lena , Prieske Katharina , Eulenburg Christine , de Gregorio Nikolaus , Klapdor Rüdiger , Kalder Matthias , Braicu Elena Ioana , Fuerst Sophie , Klar Maximillian , Strauss Hans-Georg , Mehlhorn Grit , Meier Werner , Ignatov Atanas , Mustea Alexander , Jueckstock Julia Kathrin , Schmidt Georg , Bauerschlag Dirk , Hellriegel Martin , Mahner Sven , Burandt Eike 
Published: May 2019

5592 Background: Currently, there are two major pathways for tumorigenesis of vulvar squamous cell carcinoma (VSCC) – an HPV-dependent with p16 overexpression as a surrogate for HPV-associated transformation and an HPV-independent route linked to lichen sclerosus, characterized by p53 mutation. A possible correlation of HPV dependency with a favourable prognosis has been proposed. Methods: The AGO CaRE-1 study is a retrospective survey of pts with primary VSCC FIGO stage ≥1B (UICC-TNM version 6) treated at 29 gynecologic cancer centers in Germany 1998-2008 (n = 1,618). For this CaRE-translational sub-study available FFPE tissue was collected centrally (n = 648). A tissue micro array (TMA) was constructed; p16 and p53 expression was determined by immunohistochemistry (IHC). HPV status and subtype were analyzed by PCR. Results: p16 IHC was interpretable in 550 TMA spots and considered positive in 166/550 (30.2%). HPV DNA was detected in 78.4% of the p16+ tumors, with HPV 16 being the most common subtype (88.3%) . Pts with p16+ tumors were younger at diagnosis (63 vs. 70 yrs for p16- tumors; p = 0 < 0.01) and showed lower rates of lymph-node involvement (29.0% vs. 39.7%; p = 0.021). p53 IHC was interpretable in 597 spots, 187/597 (31.3%) were considered positive. Pts with p53+ tumors were older at first diagnosis (71 vs. 66 yrs; p = 0.001 for p53- tumors) and showed lymph-node involvement more often (43.3% vs. 31.1%; p = 0.007). There was a relevant number of tumors with neither p16 nor p53 overexpression (221/535); while co-expression of p53 and p16 was rare (12/535). For survival analyses, three groups were defined: p53+ (n = 163), p16+/p53- (n = 151) and p16-/p53- (n = 221). 2-y-disease-free (DFS) and overall survival (OS) rates were significantly different between the groups: DFS: p53+ 47.0%; p16-/p53- 53% and p16+/p53- 65.5% (p < 0.001); OS: 70.4%, 72.6% and 82.7% (p = 0.003), respectively. Adjustment for age and nodal status showed consistent p16 and p53 effects regarding DFS. Conclusions: p16 overexpression is associated with an improved prognosis in VSCC while p53 positivity is linked to an adverse outcome. Our data provide evidence of a clinically relevant third subgroup of VSCC with a p53-/p16- phenotype showing an intermediate prognosis that needs to be further characterized.
Evaluation of survival by ADCC status: Subgroup analysis of SB3 (Trastuzumab Biosimilar) and reference trastuzumab in patients with HER2-positive early breast cancer at three-year follow-up.
Authors: Pivot Xavier , Pegram Mark D. , Cortes Javier , Lüftner Diana , Lyman Gary H. , Curigliano Giuseppe , Bondarenko Igor , Yoon Ye Chan , Kim Younsoo , Lim Jae Yun 
Published: May 2019

580 Background: SB3 is an approved biosimilar of reference trastuzumab (TRZ). At additional 2-year follow-up after completing neoadjuvant and adjuvant treatment, there was a difference in event-free survival (EFS), but no difference in overall survival (OS) between SB3 and TRZ. Upon monitoring quality attributes of TRZ, a marked downward shift in antibody-dependent cell-mediated cytotoxicity activities (ADCC) was observed in TRZ lots with expiry dates from Aug 2018 to Dec 2019. Some of the lots were used in the Phase III study. This is a post-hoc analysis of EFS and OS by ADCC status from a 3-year follow-up to investigate the difference in EFS between SB3 and TRZ. Methods: After completion of neoadjuvant and adjuvant therapy in patients with HER2 positive early breast cancer, patients from selected countries participated in a 5-year follow-up study (NCT02771795). Within the TRZ group, patients exposed to at least one shifted ADCC lot and those never exposed to shifted ADCC lot during neoadjuvant period were considered as “Exposed” and “Unexposed,” respectively. EFS and OS after 3-year follow-up was analyzed by ADCC status in the long-term follow-up set. Results: 367 patients (SB3, N = 186; TRZ, N = 181) were enrolled in the follow-up study. Within TRZ, 55 patients were Unexposed and 126 patients were Exposed. At a median follow-up duration of 40.8 months in SB3 and 40.5 months in TRZ, 3-year EFS rates were 92.5% in SB3, 94.5% in Unexposed, and 82.5% in Exposed and OS rates were 97.0%, 100%, and 90.6%, respectively. Exposed was associated with decreased EFS compared to Unexposed (HR 0.14, 95% CI 0.04-0.51, p= 0.003). There was a trend of decreased OS in Exposed compared to Unexposed, however, there was no significant difference (HR 0.14, 95% CI 0.02-1.15, p= 0.068). Between SB3 and Unexposed, no difference was observed in EFS (HR 1.06, 95% CI 0.33-3.44, p= 0.923), or OS (HR 0.54, 95% CI 0.05-5.44, p= 0.600). Conclusions: Within the TRZ group, Exposed showed significantly lower EFS compared to Unexposed, and a similar trend was observed in OS with no statistical significance. Between SB3 and Unexposed, no significant difference in EFS or OS was observed. Clinical trial information: NCT02771795.
Delineating longitudinal patterns of response to neoadjuvant systemic therapy (NAST) in triple-negative breast cancer (TNBC): Profiling results from a randomized, TNBC enrolling trial to confirm molecular profiling improves survival (ARTEMIS; NCT02276443).
Authors: Seth Sahil , Huo Lei , Rauch Gaiane M , Adrada Beatriz E , Piwnica-Worms Helen , Thompson Alastair Mark , Mittendorf Elizabeth A. , Litton Jennifer Keating , Symmans William Fraser , Draetta Giulio Francesco , Futreal Andrew , Moulder Stacy L. , Chang Jeff 
Published: May 2019

586 Background: The heterogeneity of TNBC results in varied responses to NAST: 30-40% of patients (pts) have pathologic complete response (pCR) with excellent prognosis. Those with residual disease, have a much higher risk of recurrence. Longitudinal profiling assesses biologic response to NAST and mechanisms of resistance. Methods: Pts with stage I-III TNBC began a planned 4 cycles of Adriamycin-based chemo (AC). Biopsies were performed pre (mandatory) and post (optional) AC. Volumetric change by ultrasound (VUS) at completion of AC (or progression) was calculated. Pts with sensitive disease received subsequent taxane-based (T) therapy. Pts with insensitive disease were offered phase II trials. Pathologic response was assessed at surgical resection in 47 pts. Matched samples, pre and post AC (N = 48 pts) underwent transcriptomic and genomic profiling. Samples were classified into six previously identified ARTEMIS subtypes of TNBC (ART-Type). Immune deconvolution and estimation was performed using RNA-Seq profiles. Differential pathway-level analysis was performed comparing pre and post AC samples. Results: There was heterogeneity in response to AC with 4 predominate patterns of biologic response (Table). In 48% of cases the ART-Type of the tumor switched after AC, with androgen receptor like (LAR) and immune modulatory (IM) showing greatest stability. Tumors with enrichment in EMT or those with no significant dysregulation after AC (Groups C + D) were associated with less immune modulation and lower rates of pCR compared to those with depleted EMT (A and B) (8.7% vs 45.8%, p = 0.0078). Conclusions: Molecular profiling of longitudinal TNBC samples reveals distinct response patterns in tumors and their micro-environments upon treatment with AC. These patterns were indicative of pathologic response in this cohort; however, they require validation in a separate cohort. Clinical trial information: NCT02276443. [Table: see text]
A neutrophil to lymphocyte ratio is predictive of response to neoadjuvant HER2-targeted therapies in the patients with HER2-positive breast cancer.
Authors: Bae Soong June , Yoon Chang-Ik , Park So Eun , Cha Chi Hwan , Kim Dooreh , Lee Janghee , Ahn Sung Gwe , Park Hyung Seok , Cho Youngup , Jeong Joon 
Published: May 2019

587 Background: The neutrophil to lymphocyte ratio (NLR) has been reported that is associated with response to treatment and prognosis in breast cancer, but its role is unclear in HER2 positive breast cancer. In this study, the relevance of NLR for treatment efficacy was analyzed in HER2 positive breast cancer patients underwent neoadjuvant therapy. Methods: Pre-treatment NLR was assessed in 546 HER2 positive breast cancer patients divided into three groups according to neoadjuvant treatment regimens: i) chemotherapy alone, ii) chemotherapy plus trastuzumab, and iii) chemotherapy plus trastuzumab and pertuzumab. The cutoff value of NLR was defined as 2.75. We evaluated the correlation of NLR with pathologic complete response (pCR) rate to neoadjuvant treatment regimen. Results: Of all patients, 422 (77.3%) patients were classified as low NLR group (NLR < 2.75) and 124 (22.7%) patients as high NLR group (NLR≥2.75). In the low NLR group, a pCR was achieved in 59 (25.7%) of 230 patients with chemotherapy alone, 69 (57.5%) of 120 patients with chemotherapy plus trastuzumab, and 47 (65.3%) of 72 patients with chemotherapy plus trastuzumab and pertuzumab ( P< 0.001). In the high NLR group, a pCR was achieved 13 (18.8%) of 69 patients with chemotherapy alone, 5 (20.0%) of 25 patients with chemotherapy plus trastuzumab, and 18 (60.0%) of 30 patients with chemotherapy plus trastuzumab and pertuzumab in the high NLR group ( P< 0.001). The pCR rate of chemotherapy plus trastuzumab and chemotherapy plus trastuzumab and pertuzumab was similar, but higher than chemotherapy alone in patients with low NLR. However, only chemotherapy plus trastuzumab and pertuzumab showed high pCR rate compared to chemotherapy alone and chemotherapy plus trastuzumab in patients with high NLR, regardless of hormone receptor status. The elevated NLR was an independent predictor of low pCR rate in patients with chemotherapy plus trastuzumab (OR 0.18, 95% CI, 0.07 to 0.52; P= 0.002), but not in those with chemotherapy alone (OR 0.67; 95% CI, 0.34 to 1.32; P= 0.248; Pinteraction= 0.041) and chemotherapy plus trastuzumab and pertuzumab (OR 0.80; 95% CI, 0.33 to 1.92; P= 0.614; Pinteraction= 0.031). Conclusions: This study identified a possibility of NLR as an easily accessible predictive marker to guide neoadjuvant HER2 target therapy in HER2 positive early breast cancer. Further study with other cohort is needed for validation.
Evaluation of predictive biomarkers for AR therapy and to identify the LAR subtype of TNBC.
Authors: Seth Sahil , Crespo James , Huo Lei , Thompson Alastair Mark , Mittendorf Elizabeth A. , Hess Kenneth R. , Litton Jennifer Keating , Rauch Gaiane M , Adrada Beatriz E , Damodaran Senthil , Candelaria Rosalind P , Arun Banu , Yang Wei Tse , Santiago Lumarie , Murthy Rashmi Krishna , Sahin Aysegul A. , Symmans William Fraser , Moulder Stacy L. , Ueno Naoto T. , Lim Bora 
Published: May 2019

595 Background: Androgen-receptor-like (LAR) triple-negative breast cancer (TNBC) is a subtype identified using Vanderbilt’s molecular signature. LAR subtype has the lowest pCR rate for NACT among all TNBC subtypes (10% vs. 28% for TNBC in general). We launched a clinical trial to determine the effectiveness of enzalutamide and paclitaxel (ZT) in improving this poor chemo. response in the neoadjuvant setting for pts with anthracycline-refractory, androgen receptor (AR)+ TNBC (NCT02689427). However, we do not yet have a robust predictive biomarker to detect an activated AR pathway and have not seen a robust correlation between molecular LAR subtype and AR IHC staining intensity. Methods: Molecular profiling and immunohistochemical analysis of key biomarkers (LAR, Ki67, and vimentin) was performed for all pts enrolled in A Randomized triple negative breast cancer enrolling Trial to Confirm Molecular Profiling Improves Survival (ARTEMIS; NCT02276443). Patients receive 4 cycles of AC, followed by an experimental arm or standard taxane, tailored using nuclear IHC staining. IHC staining of ≥30% AR+ was used as a threshold for selection for enzalutamide combination arm. We evaluated the concordance between LAR-subtype using molecular profiling vs % AR+ cells via IHC. Results: As part of the clinical trial, tumors with ≥30% AR+ cells were classified as LAR. In addition, we used RNA profiling to assign Vanderbilt subtype scores, resulting in classification of 15 tumors as LAR+. We observed a significant correlation (r=0.75) between LAR score and %AR+ cells, with 13 of 15 LAR tumors having ≥30% AR+ cells. Among patients with high % of AR+ tumor cells, 11 received enzalutamide, with 43% (3/7) having responses (pCR or RCB-I). Conclusions: Comparison on numerical scores for Vanderbilt subtype and IHC scores suggests ≥30% AR+ IHC staining as the threshold (ppv=0.65, npv=0.98, Table) to identify the molecular LAR subtype. We observed a trend where response rate was higher in patients with ≥ AR+ IHC scores treated with enzalutamide; however, these results need confirmation in a larger cohort of patients. Clinical trial information: NCT02689427, NCT02276443. [Table: see text]
TPExtreme randomized trial: TPEx versus Extreme regimen in 1st line recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).
Authors: Guigay Joel , Fayette Jerome , Mesia Ricard , Lafond Cedrik , Saada-Bouzid Esma , Geoffrois Lionnel , Martin Laurent , Cupissol Didier , Capitain Olivier , Castanie Helene , Vansteene Damien , Schafhausen Philippe , Dubos Arvis Catherine , Even Caroline , Sire Christian , Delhommeau Melissa , Michel Cecile , Bourhis Jean , Keilholz Ulrich , Auperin Anne ,   GORTEC - AIO Studien gGmbH - TTCC - H&N Unicancer
Published: May 2019

6002 Background: After promising results from the GORTEC TPEx phase II trial, the role of taxane instead of 5FU in 1st-line R/M HNSCC chemotherapy (CT) remained to be confirmed by comparing TPEx to the reference EXTREME regimen. Methods: Randomized (1:1), open-label trial. Main inclusion criteria were R/M HNSCC not suitable for locoregional treatment, age 18-70 years, PS <2, creatinine clearance >60ml/min, prior cisplatin <300 mg/m². Reference EXTREME regimen (arm A: 6 cycles every 3 weeks (Q3W) of 5FU–cisplatin-cetuximab (cetux) followed by weekly cetux maintenance) was compared to TPEx regimen (arm B: 4 cycles Q3W of docetaxel 75mg/m²–cisplatin 75mg/m²- cetux 250mg/m² with mandatory G-CSF support followed by every 2W cetux 500mg/m² maintenance). The primary endpoint was Overall Survival (OS). To detect a hazard ratio (HR) of 0.72 (median OS increase from 10.1 to 14.0 months (mo) with 88% power, 2-sided significance level of 0.05, 374 deaths were required. 540 patients (pts) were planned to enroll. Results: 539 pts were enrolled in 37 mo. Median age was 60 years, 93% were smokers, 40% had oropharyngeal tumor (p16 or HPV DNA was done in 85%, positive in 28%). In arm A, 44% of pts received all CT cycles vs 72% in arm B. Delays in administration were more frequent in arm A (27% vs 10%). Cisplatin was more frequently switched to carboplatin in arm A (34% vs 9%). Toxicity was lower in arm B: 34% pts had grade ≥4 adverse events during CT in arm B vs 50% in arm A (p<0.001). Less pts in arm A started maintenance than in arm B (53% vs 73%). At time of analysis, the median follow-up duration was 30 mo and 406 pts had died. OS was not significantly different between arms: HR=0.87 (95%CI: 0.71-1.05), p=0.15. Median OS was 13.4 mo in arm A vs 14.5 in arm B. 2-year OS rate was 21.0% in arm A vs 28.6% in arm B. Conclusions: This large randomized trial confirmed the encouraging survival results of the TPEx regimen observed in the first phase II. OS in both arms was higher than observed in previous randomized CT or immunotherapy combination trials. Despite lack of significant OS increase, taxane based TPEx regimen appears to be a new option in 1st line R/M HNSCC, with a shorter time on CT and significantly lower toxicity than the EXTREME regimen. Clinical trial information: NCT02268695.