bluuebunny/crossref_metadata_2025 huggingface dataset:
How long have we got? The accuracy of physicians’ estimates and scenarios for survival time in 898 women with recurrent ovarian cancer (ROC).
Authors: Roncolato Felicia , O'Connell Rachel , Joly Florence , Lanceley Anne , Hilpert Felix , Okamoto Aikou , Aotani Eriko , Pignata Sandro , Donnellan Paul P. , Oza Amit M. , Avall-Lundqvist Elisabeth , Berek Jonathan S. , Sehouli Jalid , Ledermann Jonathan A. , Berton-Rigaud Dominique , Kiely Belinda Emma , Friedlander Michael , Stockler Martin R. ,   ANZGOG and GCIG Symptom Benefit Group
Published: May 2019

5549

Background: Predicting, formulating, and communicating prognosis in women with ROC is difficult. Best-case, worst-case, and typical scenarios for survival time based on simple multiples of an individual’s expected survival time (EST) estimated by their oncologist have proven accurate and useful in a range of advanced cancers. We sought the accuracy and prognostic significance of such estimates in the GCIG Symptom Benefit Study: a multinational, prospective cohort study of women with ROC (platinum resistant and potentially platinum sensitive ROC who have had more than 2 lines of chemotherapy). Methods: Oncologists estimated EST at baseline for each woman they recruited to the GCIG Symptom Benefit Study in 11 countries. We hypothesised a priori that oncologists’ estimates of EST would be unbiased (equal proportions [approximately 50%] of women living longer versus shorter than their EST), imprecise ( < 33% living within 0.75 to 1.33 times their EST), and provide accurate scenarios for survival time (approximately 10% dying within ¼ of their EST, 10% living longer than 3 times their EST, and 50% living from half to double their EST). We also hypothesised that oncologists’ estimates of EST would be independently significant predictors of survival in a multivariable Cox model adjusting for prognostic factors established in previous studies. Results: Oncologists’ individualised estimates of EST in 898 women with ROC were unbiased (55% of women lived longer than their EST) and imprecise (23% lived within 0.75 to 1.33 times their EST). Scenarios for survival time based on oncologists’ estimates of EST were remarkably accurate: 7% of women died within ¼ of their EST, 13% lived longer than 3 times their EST, and 53% lived from half to double their EST. The median EST was 12 months (range 3-70), and median observed was 12.7 months. Oncologists’ estimates of EST were independently significant predictors of overall survival (HR 0.96, CI 0.94-0.98, p < 0.0001) in Cox models accounting for previously established prognostic factors. Conclusions: Oncologists’ estimates of EST were unbiased, imprecise, and independently significant predictors of survival time. Best-case, worst-case and typical scenarios based on simple multiples of EST were remarkably accurate, and provide a useful approach for predicting, formulating, and explaining prognosis in women with recurrent ovarian cancer. Clinical trial information: ACTRN: 12607000603415.
Patient preferences for maintenance PARP therapy in ovarian cancer treatment.
Authors: Havrilesky Laura Jean , Lim Stephanie , Yang Jui-Chen , Lorenzo Amelia , Ehrisman Jessie A , Secord Angeles Alvarez , Johnson Reed , Reed Shelby D.
Published: May 2019

5558

Background: Maintenance therapy with PARP inhibitors has become prevalent in treating ovarian cancer. However, the preferences of women with ovarian cancer regarding the risks, side effects and benefits afforded by maintenance therapies are largely unstudied. Methods: A discrete choice experiment was designed to elicit the preferences of women with ovarian cancer regarding 6 attributes (levels presented in parentheses) relevant to the decision for maintenance PARP inhibitor therapy versus surveillance: (1) overall survival (36, 38, 42 months); (2) progression-free survival (15, 17, 21 months); (3) nausea (none, mild, moderate); (4) fatigue (none, mild, moderate); (5) probability of death from myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML) (0%, 1%, 5%, 10%); and (6) monthly out-of-pocket cost ($0, $50, $500, $1,000). Educational material was provided, with embedded questions to test respondents’ understanding. Participants chose between 2 variable clinical scenarios and a constant scenario representing a treatment break, with multiple iterations. Random-parameters logit regression was applied to model participants’ choices as a function of attribute levels. Results: Of 150 women with ovarian cancer recruited, 95 were eligible and completed the survey. The mean age was 62, 48% had recurrent ovarian cancer, and 13% were currently taking a PARP. Participants always significantly preferred better clinical outcomes to worse (except between 0% and 1% risk of MDS/AML), preferred low out-of-pocket cost, and disliked the idea of a treatment break. Participants valued overall survival most (average importance weight 25 out of 100 total), followed by monthly out-of-pocket cost (24), risk of death from MDS/AML (18), nausea (15), PFS (10) and fatigue (8). On average, participants would tolerate a 2% additional risk of MDS/AML in exchange for 2 additional months of PFS and 7% additional risk of MDS/AML in exchange for 6 additional months of PFS. Conclusions: Women with ovarian cancer are willing to accept the side effects of PARP maintenance therapy and a higher than clinically observed risk of MDS/AML in exchange for clinically observed levels of improvement in PFS.
Survival and clinical outcomes of ovarian cancer patients enrolled in phase I clinical trials.
Authors: Corr Bradley , Moroney Marisa , Sheeder Jeanelle , Sawyer Brandon , Eckhardt S. Gail , Behbakht Kian , Diamond Jennifer Robinson
Published: May 2019

5559

Background: Ovarian cancer patients who enroll in Phase I clinical trials are typically platinum resistant, heavily pretreated patients with a poor prognosis. Historically, clinical benefit of Phase I trials in this patient population has been uncertain. We assessed prognostic factors and survival in women with recurrent, previously treated ovarian cancer who enrolled in Phase I clinical trials. Methods: We performed a retrospective analysis of all ovarian cancer patients who were treated on Phase I clinical trials from 2008 through 2018 at the University of Colorado Cancer Center. Patient characteristics, treatment-related toxicities and survival data were assessed. Descriptive statistics and Cox proportional hazards models were utilized to identify risk factors associated with survival time. Results: A total of 132 individual patients were treated on Phase I clinical trials. Patients had a median age of 59 years (range 33-88) with a median of 5.5 (range 1-13) previous chemotherapy lines. 53/132 (40%) of patients were treated on multiple Phase I trials with a median of 1 (range 0-5) prior Phase 1 clinical trial enrollments. All patients had an ECOG performance status of 0 or 1. Overall response rate (defined as complete or partial response) was 9% and disease control rate (defined as complete or partial response or stable disease as best response) was 33%. Median overall survival (OS) was 11.5 months (95% CI: 9.3-13.7). Two patients died on trial due to progression of disease while no patients died due to treatment-related toxicity. In multivariate analysis, independent risk factors predicting shorter survival were elevated CA-125 (HR 2.8; 95% CI: 1.6-5.2) and albumin < 3.5 g/dL (HR 2.5; 95% CI: 1.65-3.79). BMI > 25 predicted longer survival (HR 0.65; 95% CI: 0.44-0.96). Conclusions: Phase I clinical trials for heavily pretreated ovarian cancer patients are safe by a standard of no patients experiencing toxicity-related deaths in our study. They are clinically efficacious with patients experiencing OS of 11.5 months, which is comparable to existing approved therapies. Elevated CA-125 and low albumin levels predict shorter survival, while BMI > 25 predicts longer survival. Phase I clinical trial options should be considered for all heavily pretreated ovarian cancer patients if available to them.
Effect of estrogen and progesterone receptor expression on progression-free and overall survival outcomes in low-grade serous ovarian cancer.
Authors: Llaurado Fernandez Marta , Dawson Amy , Kim Hannah , Lam Nicole , Bruce Maegan , Russell Holly , Hoenisch Joshua , Provencher Diane M. , Nourmoussavi Melica , Gilks Cyril Blake , Lee Cheng-Han , Kobel Martin , Wong Nelson , Scott Stephanie , Dimattia Gabriel , Mes-Masson Anne-Marie , Carey Mark Stafford
Published: May 2019

5560

Background: Research on ER/PR receptor function in low-grade serous ovarian cancer (LGSC) and the determinants of response to treatment are lacking. A recent study (Sehouli et al.,2018) described ER/PR immunohistochemistry (IHC) cut-points that distinguished PFS. Thus, we report on a group of patients with ER/PR expression by IHC in tumor samples of patients with LGSC and used this information to evaluate survival outcomes. Methods: Clinical information and FFPE sections were obtained from the Canadian Ovarian Experimental Unified Resource (COEUR). Tissue microarray (TMA) sections were stained for ER/PR using standard IHC techniques (MK). 50 stage 3 and 5 stage 4 patients were analyzed. ER/PR expression was scored using a simple scoring system ( < 1% cells staining, 1-50%, and ≥ 50%) and Allred scoring. We compared Kaplan-Meier (KM) survival (PFS and OS) curves using Log rank testing and Cox regression was used to model predictive/prognostic factors. A p-value of 0.05 was considered significant. Results: The mean age of the population was 49.5 years (SD;13.7). Ninety percent of patients were treated by surgery followed by platinum-based chemotherapy (PBC). Simple scoring did not discriminate outcomes as well for ER levels. PR Allred score ( < 2, vs 2- < 6 vs ≥6) clearly discriminated KM curves for PFS (p = 0.036) and OS (p = 0.01). For Allred ER score ( < 7 vs.7- < 8 vs 8) did not distinguish PFS (p = 0.4) but notably most patients received PBC after surgery. ER Allred score significantly distinguished OS (p = 0.008). Significant factors on Cox regression for PFS were residuum (p = 0.008;95%CI:1.2-3.1) and PR (p = 0.05;95%CI:0.39-0.99), whereas for OS ER(p = 0.01:95%CI:0.2-0.8) and residuum (p = 0.04;95%CI:1-2.8). Conclusions: ER/PR expression by Allred scoring was associated with PFS and OS. Patients will benefit from much needed research on ER/PR prediction/prognosis in LGSC. This work can inform clinical trials selection/stratification and patient selection for endocrine treatment.
Real life efficacy and safety data of bevacizumab-based front line treatment in advance or metastatic ovarian cancer patients: Focus on patients with malignant ascites—A phase IV study.
Authors: Nikolaou Michail , Ziras Nikolaos , Athanasiadis Ilias , Ardavanis Alexandros , Vaslamatzis Michael , Kentepozidis Nikolaos K. , Makrantonakis Paris , Christopoulou Athina , Michalaki Vasiliki , Polyzos Aristidis , Emmanouilides Christos E. , Vardakis Nikolaos , Kotsakis Athanasios , Georgoulias Vassilis
Published: May 2019

5562

Background: The standard of care for Epithelial Ovarian cancer (EOC) is the combination of a taxane plus a platinum compound (TC) whereas the addition of bevacizumab (bev) to this regimen (TC-bev) has been shown to improve the PFS. Patients (pts) with ascites have more aggressive disease and less overall survival. The aim of the study was to evaluate the safety of the TC/bev regimen in the real life clinical practice. Methods: A multi-center observational study, approved by the ethics committees of the participating centers, including 314 pts with stage III/IV EOC, was conducted (11.2011-06.2014) in Greece. Two independent cohorts, with similar clinico-pathologic characteristics, were treated with front-line TC (n = 109) or TC/bev (n = 205) according to the physician’s choice. 83 (40.5%) and 40 (36.7%) in the TC/bev and TC groups presented with ascites. Results: Disease control was achieved in 90.7% and in 78.9% of patients treated with TC/bev and TC, respectively (p = 0.003). Pts with ascites treated with TC/bev experienced a better overall response rate (ORR) (68.7% Vs 55%) and less progression disease (PD) compared to patients receiving TC (13.2% Vs 30.8%). The median PFS in all pts was 21.5mo and 12.4mo (p < 0.001) and median PFS in ascites pts was 18.1mo and 10.3mo in the TC/bev and TC cohort , respectively (p < 0.001). The median OS was not reached in the TC/bev group and it was 36.9mo in the TC group, ( p = 0.059) while in the ascites pts also has not reached and it is 22.5m, respectively ( p = 0.023). The 3 year survival rate in all pts was 59.4% and 50.4% and in ascites pts was 55.3% and 30% in the TC/bev and TC respectively. Neutropenia was the most common grade 3/4 adverse event in 16.6% and 9.1% in TC/bev- and TC- treated patients ( p = 0.072) with no other adverse events > 5%. Conclusions: These real life data demonstrate that the combination of TC/bev represents an active and well tolerated regimen offering survival benefit in patients with stage III/IV EOC and especially in patients with ascites. Additional larger prospective studies are required to confirm these observations. Clinical trial information: NCT01982500.
Everolimus plus letrozole treatment of recurrent gynecologic cancers.
Authors: Miller Kenneth David , Min Frederick , Barter James , Hughes Corilynn , Kalnitskaya Lyudmila , Bell-Farrell Wanda , Lalagari Sujana , Solis Alexis , Phelps Jeanne , Wade Christine , Tangrea Michael , Feldman Marvin J.
Published: May 2019

5567

Background: Hormonal therapy has limited activity in gynecologic (Gyn) cancer treatment. mTOR inhibitors plus aromatase inhibitors (AI's) improve the response rate and response duration in breast cancer patients. We studied this combination in heavily pre-treated women having estrogen receptor positive (ER+) Gyn cancers. Methods: This phase II study combines everolimus and letrozole for ER+ Gyn cancers with disease progression following primary and salvage chemotherapy. 19 patients participated (Ovary-10, Endometrium-7, and Primary Peritoneal Cancer-2). The mean age was 64, prior lines of therapy ranged from 2-7, and median time from diagnosis to study entry was 67 months (m) (range 10-348m). Results: There were no complete responders, but 7 of 19 (37%) patients treated had clinical benefit, with 1 PR and 6 with stable disease. In responding patients, the earliest time to best response was 2m and the median time to progression was 5m (range 5-40+m). The mean number of treatment cycles was 11. Toxicities: The most common adverse events were: hyperglycemia, rash, stomatitis, fatigue, and anemia. 7 patients required dose reductions, and 2 discontinued study drugs due to pneumonitis. The therapy was generally well tolerated in both women < 65 and > 65 years old. Toxicities were less common with reduced everolimus doses. Conclusions: Recurrent Gyn cancers become refractory to chemotherapy. We tested the combination of everolimus plus letrozole in heavily pretreated patients with ER + recurrent disease. 1 patient had a PR and 6 had stable disease with a range of 5-40+m. This oral regimen was generally well tolerated and allowed time without IV chemotherapy, while providing clinical benefit to patients with refractory ER+ Gyn cancers.
Elucidation of PARP inhibitor activity in BRCAwt recurrent ovarian cancer by hrr mutational gene profile analysis.
Authors: Mirza Mansoor Raza , Feng Bin , Shan Ming , Sun Kaiming , Yalcin Ilkar , Coleman Kevin , Thress Kenneth S. , Hazard Sebastien , Wang Jing Y. , Matulonis Ursula A.
Published: May 2019

5568

Background: Niraparib is an oral, selective poly(ADP-ribose) polymerase inhibitor (PARPi) approved for maintenance treatment of BRCA mutated ( BRCAmut) and BRCA wild-type ( BRCAwt) recurrent ovarian cancer patients (pts) who are in response to platinum-based chemotherapy. In the non-germline BRCA mutated (non-g BRCAmut) cohort of the ENGOT-OV16/NOVA trial, clinical benefit with niraparib vs placebo was seen in pts regardless of their Myriad myChoice HRD test status ( BRCAmut and homologous recombination deficiency [HRD] score), with a hazard ratio (HR) of 0.38 in HRD-positive (HRDpos) and 0.58 in HRD-negative (HRDneg) pts. To determine if treatment benefit in HRDneg pts may result from mutations in other homologous recombination repair ( HRR) genes, we examined the relationship between progression-free survival and other HRR gene mutations in the NOVA non-gBRCAmut cohort. Methods: A retrospective, exploratory biomarker analysis was conducted using all available tumor samples from 331 pts enrolled in the NOVA non-g BRCAmut cohort. Mutation status of HRR genes was evaluated using a 43-gene NGS assay (Myriad Genetics), including BRCA1/2 and 16 additional HRR genes. Results: In this exploratory analysis of the NOVA non-g BRCAmut cohort, niraparib demonstrated clinical benefit in pts with somatic BRCA mutation (HR, 0.27) and in BRCAwt pts (HR, 0.47). In addition, BRCAwt pts with other HRR gene mutations also derived benefit from niraparib (HR, 0.31), as did BRCAwt/ HRRwt pts (HR, 0.49). When BRCAwt/ HRRwt pts were categorized by HRD score, clinical benefit was also observed in both HRDpos and HRDneg pts, with HRs of 0.33 and 0.60, respectively. These results suggest that, although these biomarkers have good positive predictive value, they are not good negative predictors for niraparib benefit in this indication. Conclusions: This retrospective, exploratory analysis of the ENGOT-OV16/NOVA non-g BRCAmut cohort suggests that although pts with somatic BRCA mutation and other HRR mutations benefit from niraparib treatment, clinical benefit is also seen in HRDneg pts without HRR mutations, perhaps related to other genomic, epigenetic, or functional alterations within ovarian tumors yet to be defined.
Correlation of surgeon radiology assessment with laparoscopic scoring in patients with advanced-stage ovarian cancer.
Authors: Fleming Nicole D. , Westin Shannon Neville , Meyer Larissa , Rauh-Hain Jose Alejandro , Shafer Aaron , Onstad Michaela , Cobb Lauren Patterson , Bevers Michael W. , Burzawa Jennifer K. , Zand Behrouz , Fellman Bryan M. , Jazaeri Amir A. , Levenback Charles F. , Coleman Robert L. , Soliman Pamela T. , Sood Anil K
Published: May 2019

5570

Background: To determine the correlation between surgeon radiology assessment and laparoscopic scoring in patients with newly diagnosed advanced stage ovarian cancer. Methods: Following IRB approval, 14 gynecologic oncologists from a single institution performed a blinded review of radiology imaging from 20 patients with advanced stage ovarian cancer. All patients previously underwent laparoscopic scoring assessment to determine primary resectability at tumor reductive surgery (TRS) using a validated scoring method from April 2013 to December 2017. The patients with predictive index value (PIV) scores < 8 were offered primary surgery and those with a score ≥8 received neoadjuvant chemotherapy (NACT). Surgeons viewed contrasted CT imaging reports and images from all patients in a blinded fashion and recorded PIV scores using the same validated scoring method. Linear mixed models were conducted to calculate the correlation between radiology and laparoscopic score for each surgeon and as a group. Once the model was fit, the inter-class correlation (ICC) and 95% confidence interval was calculated. Results: Radiology review was performed on 20 patients with advanced stage ovarian cancer who underwent laparoscopic scoring assessment. Most patients had stage IIIC disease (85%) and median laparoscopic score was 9 (range 0-14). Surgeon faculty rank included Assistant Professor (n = 5), Associate Professor (n = 4), and Professor (n = 5). Median surgeon experience during the study period with laparoscopic assessment was 13 cases (range 1-28) and TRS was 22.5 cases (range 2-48). The kappa inter-rater agreement was -0.017 (95% CI 0.023 to -0.005) indicating low inter-rater agreement between radiology review and actual laparoscopic score. The ICC in this model was 0.06 (0.02-0.21) indicating that surgeons do not score the same across all the images. When using a clinical cutoff of PIV of 8, the probability of agreement between radiology and actual laparoscopic score was 0.56 (95% CI: 0.49-0.73). Number of laparoscopic cases, TRS cases, or faculty rank was not significantly associated with agreement. Conclusions: Surgeon radiology review did not correlate highly with actual laparoscopic scoring assessment findings in patients with advanced stage ovarian cancer. 44% of patients in our study may have been inadequately triaged by radiology review alone, which may have led to suboptimal TRS. Our study highlights the utility of laparoscopic scoring assessment to determine resectability over radiology assessment alone in ovarian cancer.
Real-world data analysis of ovarian cancer (OC) maintenance utilization among maintenance eligible patients.
Authors: Garofalo David , Aydin Ebru , Labrador Monica , Webster Jennifer , Brown Greg , Donaldson Joseph , Gierman Hinco Jasper , Varughese Prateesh , Malik Ash , Scott Jeffrey A.
Published: May 2019

5579

Background: Approximately 1% of US women will be diagnosed with epithelial OC during their lifetime. OC patients who achieve a response to platinum-based chemotherapy may benefit from maintenance therapy, with the goal of inducing a lasting remission or extending the time interval before progression without any deleterious impact on quality of life1. This analysis, based on real world data sourced from US community oncology practices, was designed to assess the current utilization of maintenance therapy among maintenance eligible patients. Methods: This analysis utilized the Integra Data Exchange (DTX) database, a deidentified data source from community oncology practice systems (EMR, practice management, paid claims). This retrospective study included 3,629 OC patients with at least two visits between 7/16/16 and 4/16/18. 398 patients who completed 2nd line or later platinum-based chemotherapy for 4-9 cycles and/or had a complete/partial response between 1/1/17 and 7/31/18 were included. Potential maintenance therapy options were monotherapy of PARP inhibitors, bevacizumab, and non-platinum-chemotherapy agents. Rate of maintenance therapy after platinum-based treatment was assessed. Results: Our real-world analysis found that 49% of 398 maintenance eligible patients received maintenance therapy at least once following response to 2nd line or later platinum chemotherapy. Among those that received maintenance, 46% received PARPi, 28% bevacizumab, and 26% non-platinum chemotherapy. Further, 56% of women with BRCA mutations received maintenance treatment, compared with 49% of women without BRCA mutations. Conclusions: Though there are several options available, 51% of OC women studied who could potentially benefit from maintenance treatment did not receive maintenance. Only 56% of BRCA mutation carriers were targeted for maintenance in the real world. Among patients that receive maintenance therapy following 2nd line or later platinum chemotherapy 46% received a PARPi based regimen. 1) Quality of life in patients with recurrent ovarian cancer treated with niraparib versus placebo (ENGOT-OV16/NOVA): results from a double-blind, phase 3, randomized controlled trial. Lancet Oncol. 2018 Aug;19(8).
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.