bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical utilization of Breast Cancer Index (BCI) for late recurrence risk assessment and prediction of extended endocrine therapy (EET) benefit in early stage HR+ breast cancer.
Authors: Mahtani Reshma L. , Gadi Vijayakrishna K. , Operana Theresa N. , Soifer Harris S , Schroeder Brock , Schnabel Catherine A. , Schwartzberg Lee Steven
Published: September 2018

551

Background: Randomized trials demonstrated a modest (3-5%) absolute benefit from EET in patients (pts) with early stage HR+ breast cancer (BC), but also a risk of toxicities. BCI is a validated gene expression-based assay that provides 2 results: BCI Prognostic, based on the algorithmic combination of HoxB13/IL17BR (H/I ratio) and a set of proliferation-based genes, reports individualized risk of late distant recurrence (DR); BCI Predictive, based on H/I alone, reports a prediction of high vs low likelihood of benefit from EET. The objective of this study was to assess clinical and pathologic patient characteristics, prognostic and predictive assay results, and physician testing patterns in >14,000 clinical cases. Methods: The BCI Clinical Database for Correlative Studies is a de-identified database developed under an IRB approved protocol that contains >50 clinicopathologic and molecular variables from cases submitted for BCI in clinical practice. Clinicopathologic variables were abstracted from pathology reports, and were available for a subset of cases. Results: Across all pts (N=14,463), median age was 58.2y (range: 23-92y; 73.9% ≥50y). The majority were Stage I (47.3% IA, 3.5% IB, 29.1% IIA, 14.1% IIB, 6% III). Cases were 29%, 51%, and 20% Grade 1, 2, and 3, respectively. Most pts were ER+/PR+ (87.7%) or ER+/PR- (11.3%); 11.3% were HER2+. The majority of cases (55.7%) were ordered 4-6y postdiagnosis, with 23.1% >6y, 14.4% between 1-4y, and 6.8% <1y postdiagnosis. In LN- pts (n=3395), BCI Prognostic identified 50.6% as low risk for late DR vs 49.4% as high risk, while BCI Predictive (H/I) classified 41.0% as high vs 59.0% as low likelihood of benefit. In LN+ pts tested with the BCIN+ Prognostic algorithm (BCI + size/grade, n=818), 77.3% were classified as high risk vs 22.7% as low risk, while BCI Predictive (H/I) classified 44.6% and 55.4% as high vs low likelihood of benefit. Conclusions: Findings from this large cohort characterize utilization of BCI in clinical practice for pts with early-stage, HR+ BC. BCI stratification of pts with high risk and high likelihood of benefit from EET may facilitate selection of pts for prolonged regimens.
The prognostic value of tumor residuals indicated by surgeon, by radiology or an integrated approach by surgeons' assessment and pre-chemotherapy CT-scan in patients with advanced ovarian cancer: An exploratory analysis of the AGO Study led Intergroup trial AGO-OVAR 12.
Authors: Heitz Florian , Harter Philipp , Avall-Lundqvist Elisabeth , Reuss Alexander , Pautier Patricia , Cormio Gennaro , Colombo Nicoletta , Hell Johanna , Vergote Ignace , Poveda Andres , Ottevanger P. B. , Hanker Lars Christian , Leminen Arto Olavi , Alexandre Jerome , Canzler Ulrich , Sehouli Jalid , Herrstedt Jorn , Fiane Bent , Merger Michael , Du Bois Andreas
Published: September 2018

5521

Background: Post-OP TR is a strong prognostic factor in AOC; the best prognosis is observed after complete resection (TR0). TR assessment is performed at the end of the surgery and may be exposed to personal bias. Pre-Chemo CT may improve post-OP assessment, however, it may also be prone to findings by post-OP tumor re-growth, tissue repair or scarring. Methods: Pts with FIGO IIB-IV AOC recruited into the double-blind randomized frontline AGO-OVAR12 trial were scheduled for baseline CT before the 1st chemo cycle. SA and RA of TR were compared. Additionally, a measurement of TR integrating both approaches were assessed (IA). For this IA information of surgical and path reports were reviewed by two of the authors. Results: 1355 pts had complete data for all 3 assessment methods. Of 689 pts with TR0 in SA, 497 (72%) and 539 (78%) had also TR0 pre-Chemo (RA and IA), but showed TR>0 in 192 (28%) and 150 pts (22%), respectively. Pts with SA defined TR0 had a similar median PFS of 27.6 mos compared to TR0 defined by RA (27.8 mos) and IA (28.9 mos). Pts with concordant TR0 (SA/ IA and SA/ RA) had a median PFS of 28.9 mos. In contrast, pts with discordant SA TR0 - RA TR>0 or SA TR0 - IA TR>0 showed inferior median PFS of 19.2 mos (HR: 1.89, 95%CI: 1.48-2.40; p<0.0001) and 16.9 mos (HR: 2.02, 95% CI: 1.57- 2.59; p<0.0001), respectively. Pts with concordant TR>0 had an even lower median PFS of 13.5 (SA and IA) and 12.9 mos (SA and RA). PFS of the experimental therapy or placebo dependent if SA, RA or IA were used, will be presented. Conclusions: Pre-Chemo CT provides information separating the group of pts with post-OP TR0 in pts with TR0 and pts with TR> 0 pre-Chemo. The latter group showed PFS values in between those with surgically assessed post-OP TR0 and those with post-OP TR> 0, forming a third prognostic group. Detailed analysis should evaluate to what extend tumor biology, surgical bias, or imperfect imaging contribute to the discrepancies. Integrating all this may lead to better definition of prognostic groups and the need for specific treatment strategies.
Association of T cell responses after vaccination with HPV16 long peptides for late stage cervical cancer with prolonged survival.
Authors: Gerritsen Winald R. , Melief Cornelis Joseph , Welters Marij , Vergote Ignace , Kroep Judith R. , Kenter Gemma , Ottevanger Nelleke , Tjalma Wiebren Age , Denys Hannelore , van Poelgeest Mariette IE , Nijman Hans , Reyners An K.L , Velu Thierry J. , Goffin Frederic , Lalisang Roy Iqbal , Stead Richard B. , Blumenstein Brent A. , van der Burg Sjoerd
Published: September 2018

5525

Background: Therapeutic vaccination with HPV type 16 synthetic long peptides (HPV16-SLP) results in T cell–mediated regression of HPV16-induced premalignant lesions but fails to install effective immunity in patients with advanced HPV16-positive cervical cancer. We showed that HPV16-SLP vaccination in mice and in patients with advanced cervical cancer patients fosters robust HPV16-specific T cell responses, when combined with chemotherapy (Welters et al. Sci. Transl. Med., 2016). Methods: We have now completed a chemo-immunotherapy study in 70 patients with late stage HPV16+ cervical cancer (clinical trials.gov NCT02128126). Three HPV16-SLP vaccine doses were given 2 weeks after the second, third and fourth cycle of standard chemotherapy (carboplatin, AUC 6; paclitaxel 175 mg/ m2). Cohorts of 12 patients each were vaccinated with each of 4 dose levels (20, 40, 100 and 300 µg/ per peptide) of 13 overlapping HPV16 synthetic long peptides (HPV16-SLP) together covering the length of the 2 E6 and E7 proteins. Two additional cohorts of 6 patients each were vaccinated with the most promising doses of 40 and 100 µg/ peptide. Results: Robust vaccine-induced HPV16-specific T cell responses as assessed by interferon-γ Elispot were observed and were sustained until at least 30 days after the 6th cycle of chemotherapy. In addition the chemotherapy augmented recall responses to microbial antigens. Such robust T cell responses were not noted in previous trials when similar patients were vaccinated without timing of vaccination during chemotherapy. A marked and significant positive correlation was observed between the strength of the vaccine-induced immune response and overall survival. No such correlation was observed between the strength of the T cell response against common recall antigens and survival. In addition a remarkably high proportion of patients survived beyond 2 years after the start of therapy. Conclusions: The results suggest that survival duration is directly related to the strength of the vaccine-induced HPV16-specific T cell response and is not due to generally better immuno-competence. Clinical trial information: NCT 02128126.
3D HDR intracavitary brachytherapy combined with complementary applicator-guided external beam radiotherapy for 338 patients with stage IIB-IIIB uterine cervical cancer: A single-center phase II prospective study with long-term follow-up.
Authors: Lang Jin Yi , Fan Zixuan , Xu Peng , Feng Mei , Wang Weidong
Published: September 2018

5530

Background: For uterine cervical cancer (UCC) patients with asymmetric parametric lesions, 3D HDR-intracavitary brachytherapy (HDR-ICBT) could not cover all the lesions, resulting in residual lesion and treatment failure. To settle this problem, a novel treatment modal of 3D HDR-ICBT combined with complementary applicator-guided external beam radiotherapy (EBRT) was used for UCC patients with stage IIB-IIIB in present study. Methods: Between June 2010 and June 2015, 338 patients with locally advanced cervical cancer (International Federation of Gynecology and Obstetrics stage IIB-IIIB) were treated with concurrent chemoradiotherapy. Imaged guided IMRT was used for external beam radiotherapy, 45Gy/25f. The chemotherapy was weekly cisplatin (40mg/m2). Four fractions of 3D HDR-ICBT combined with complementary applicator-guided external beam radiotherapy were used. The prescribed dose for HR-CTV and IR-CTV was 7Gy (D90) and 5Gy (D90). Dose constraints for organs at risk were D2cc <70 Gy for rectum, and D2cc<90 Gy for bladder in terms of equivalent total dose in 2 Gy fractions as GEC-ESTRO recommendations. Results: Median follow-up was 64 months (11–71 months). The D90 of GTV, HR-CTV, and IR-CTV in all cases were 93.4 (85.1-107.8) Gy, 86.4 (79.9-91.3) Gy and 72.3 (70.8-75.2) Gy, respectively. The D2CC of bladder, rectum and sigmoid were 74.3Gy、65.5Gy and 64.1Gy, respectively. 5-year LRC, DFS, and OS was 90.8%, 84.1% and 80.8%, respectively. Treatment was well tolerated. The grade ≥3 genitourinary and gastrointestinal acute and late toxicities were 2.1% and 5.2%, respectively. Conclusions: The combination of HDR-ICBT with an applicator-guided IMRT is feasible for uterine cervical cancer patients with asymmetric parametric lesions. Further study is needed to determine whether this treatment modal could be used to replace the invasive interstitial brachytherapy (ISBT) in the cases of locally advanced cervical cancer where HR-CTV coverage cannot be obtained with ICBT.
Overall survival and updated progression-free survival results from a randomized phase 2 trial comparing the combination of olaparib and cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.
Authors: Liu Joyce F. , Barry William Thomas , Birrer Michael J. , Lee Jung-min , Buckanovich Ronald J. , Fleming Gini F. , Rimel Bj , Buss Mary K. , Nattam Sreenivasa R. , Hurteau Jean , Luo Weixiu , Farooq Sarah , Whalen Christin , Kohn Elise C. , Ivy S. Percy , Matulonis Ursula A.
Published: September 2018

5535

Background: We previously reported that the combination of cediranib (ced) and olaparib (olap) improved progression-free survival (PFS) and overall response rates (ORR) in women with recurrent platinum-sensitive (plat-sens) high-grade serous (HGS) or BRCA-related ovarian cancer (OvCa) (NCT 01116648). We conducted an updated PFS and overall survival (OS) analysis. Methods: Patients (pts) across 9 centers were randomized 1:1 in this Ph 2 open label study to Olap (olap 400 mg capsules BID) or Ced/Olap (olap 200 mg capsules BID; ced 30 mg daily), stratified by BRCA status and prior anti-angiogenic therapy. Eligibility included pts with recurrent plat-sens HGS or BRCA-related OvCa. Pts had measurable disease by RECIST 1.1, PS 0 or 1, and the ability to take POs. No prior anti-angiogenics in the recurrent setting or prior PARP inhibitor was allowed. PFS was defined as time from randomization to radiographic progression or death. OS was defined as time from randomization to death. Results: Pts were enrolled from Oct 2011 to Jun 2013: 46 to Olap, 44 to Ced/Olap. 48 pts were known BRCA carriers (25 Olap; 23 Ced/Olap). As of Dec 21, 2016, 67 pts had a PFS event, and 52 pts had an OS event. Updated median PFS was 8.2 mos for Olap and 16.5 mos for Ced/Olap (HR 0.50, 95% CI 0.30-0.83, p=0.007). Median OS was 33.3 mos for Olap and 44.2 mos for Ced/Olap (HR 0.64, 95% CI 0.36-1.11, p=0.11). Within known germline BRCA mut carriers, updated PFS was 16.5 vs 16.4 mos (HR 0.75, p=0.42), and OS was 40.1 vs 44.2 mos (HR 0.79, p=0.55) for Olap and Ced/Olap, respectively. In pts without known germline BRCA mut, updated PFS was 5.7 vs 23.7 mos (HR 0.32, p=0.002), and OS was 23.0 vs 37.8 mos (HR 0.48, p=0.074). Conclusions: Updated PFS results consistently demonstrated that Ced/Olap significantly extended PFS compared to Olap in the overall population of women with plat-sens OvCa. In this Phase 2 study not powered to detect OS diferences, there was a trend towards OS improvement with Ced/Olap, particularly in pts without a known germline BRCA mutation. Results from ongoing studies of this oral combination in OvCa are of clinical interest. Clinical trial information: NCT 01116648.
Somatic mutations in homologous recombination pathway genes in ovarian cancer.
Authors: Aghajanian Carol , DeLair Deborah , Grisham Rachel N. , Hensley Martee Leigh , Konner Jason A. , Makker Vicky , O'Cearbhaill Roisin Eilish , Sabbatini Paul , Soumerai Tara , Snyder Charen Alexandra , Spriggs David R. , Soslow Robert A. , Tew William P. , Zamarin Dmitriy , Robson Mark E. , Berger Michael F. , Solit David B. , Hyman David Michael , Cadoo Karen Anne
Published: September 2018

5545

Background: 15% of patients with OC have a germline BRCA 1 / 2 mut & 6% of OC have a somatic BRCA 1/ 2 mut. Inhibitors of poly ADP ribose polymerase (PARPi) are approved in this setting. Data is evolving as to activity of PARPi in BRCA wild type OC with somatic homologous recombination (HR) gene deficiency. We sought to determine the prevalence of somatic alterations in HR genes in an unselected cohort of epithelial OC of any histologic type. Methods: From 03/2014-10/2016 patients consented to an IRB approved protocol for tumor-normal sequencing, via a custom next-generation sequencing panel (MSK-IMPACT) with return of results for tumor mut only. Muts in 14 HR genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, MRE11, NBN, PALB2, PTEN, RAD51D, RAD51C) and p53were assessed. Statistics were analyzed using GraphPad Prism v. 6. Results: 260 tumors were sequenced; 156 (60%) high grade serous (HGS), 34 (13%) low grade serous (LGS), 34 (13%) clear cell, 10 (4%) mucinous, 8 (3%) endometrioid, 18 (7%) mixed/other histology. 151 (97%) of HGS and 24 (23%) of the remaining tumors harbored p53 mut. 48 (18%) somatic HR mut were identified. (Table 1) 26 HGS (17%) tumors and 22 (21%) of the remaining tumors harbored a HR gene mut (HGS vs other histology, p=0.4). Notably, 8 (24%) of clear cell cancers demonstrated HR gene muts (vs HGS, p=0.3). 18 (38%) of the identified muts in the overall cohort were in BRCA 1/2. There were no somatic HR gene muts identified in the mucinous OC, which were characterized by frequent p53 (90%) and KRAS(60%) muts. Conclusions: In this cohort of OC, 17% of tumors harbor somatic HR gene muts. The prevalence of HR somatic muts was similar in HGS vs other histologies, with the exception of mucinous OC. BRCA1/2 muts predominated, however 60% of identified muts were in other genes. Accrual is ongoing to increase histologic cohort sizes. Broad HR gene somatic mutational profiling may identify a wider cohort of OC patients with potential to benefit from PARPi therapy. [Table: see text]
Shared decision-making in ovarian cancer.
Authors: Wenzel Lari B. , Mukamel Dana B , Osann Kathryn , Sparks Lisa , Havrilesky Laura Jean , Wright Alexi A. , Walker Joan L. , Robison Katina , Alvarez Ronald David , Van Le Linda , Wakabayashi Mark Tsuneo , Randall Leslie M. , Wahi Aditi , Hsieh Susie , Lipscomb Joseph , Cohn David E.
Published: September 2018

5549

Background: The value of shared decision-making in ovarian cancer is relatively unexplored. The goal of this study was to test a new decision aid, Patient Centered Outcome Aid (PCOA), that facilitates shared decision-making and helps ovarian cancer patients assimilate information and identify quality of life (QOL), toxicity and survival trade-offs between IP/IV therapy and IV therapy alone, based on their preferences and personal clinical characteristics. Methods: Participants were randomized to either PCOA (N=64) or usual care (N=59). Patient characteristics, QOL and shared decision-making data were collected at baseline and treatment initiation. Primary outcomes included satisfaction with treatment decision and decisional regret. Comparisons were made using t-tests and multivariate methods, adjusting for patient covariates. Multivariate linear models were used to investigate predictors of the primary outcomes. Results: Although satisfaction and decisional regret did not differ significantly by arm at any time point, the majority of PCOA patients indicated that the aid helped them understand treatment options and side effects. Notably, low shared decision-making and low QOL, were significant predictors of low satisfaction at treatment initiation (multiple r=0.76), six months (multiple r=0.48) and nine months (r=0.58). They were also significant predictors of decisional regret (multiple r=0.48 and 0.36 at 6 and 9 months). Patient covariates including age, stage, treatment and neoadjuvant status were not associated with differences in satisfaction or decisional regret. Conclusions: There were no clinically meaningful differences in satisfaction with the treatment decision, or decisional regret between the study arms. The absence of a difference may reflect the high degree of shared decision-making in both arms and greater disease severity in PCOA patients, who were more likely to report low baseline QOL and declining QOL over time. Both shared decision-making and quality of life were robust, independent predictors of satisfaction with the treatment decision over time. This implies that women who perceive themselves as less engaged in the decision process, and report poor QOL may benefit from a decision aid, in addition to physician counseling. Clinical trial information: NCT02259699.
Bevacizumab, eribulin, and oxaliplatin in patients with platinum-resistant ovarian carcinomas: A phase II study with biomarker analysis.
Authors: Takano Masashi , Kouta Hiroko , Kudoh Kazuya , Kita Tsunekazu , Yoshikawa Tomoyuki , Kikuchi Ryoko , Matsuura Hiroko , Miyamoto Morikazu , Goto Tomoko , Furuya Kenichi , Kikuchi Yoshihiro
Published: September 2018

5550

Background: Eribulin is a candidate for paclitaxel-refractory breast cancers, and Bevacizumab (B) is known to enhance efficacy of anti-cancer agents in ovarian cancers. A phase II study to evaluate weekly administration of B with eribulin and oxaliplatin (EriOX) in patients with platinum-resistant and refractory ovarian carcinomas (PR-ROC) was performed. Methods: Eligible patients were as follows: (a) ECOG PS = 0~2 (b) histologically confirmed epithelial ovarian cancer (c) diagnosed as platinum-resistant ovarian cancer (d) written informed consent. Patients were treated with weekly-B-EriOX consisting of B (2mg/kg), eribulin (1mg/m2) and oxaliplatin (30mg/m2), three weeks on and on week off, q4weeks. The study was conducted using two-stage design of Simon (type I error = 0.05, power = 0.9, true response rate = 25%). Biomarker analyses including serum VEGF, BNP, p53, IL-6, and Her-2 were also conducted. Results: A total of 34 patients were enrolled in the present study: 13 cases in the first-stage, and additional 21 cases in the second-stage. There were 3 responders (≧2) in the first-stage, and the protocol was proceeded to the second-stage. Median age of the patient was 58.5 years (range: 35-76), and median number of previous regimen was 4 (range: 2-9). Overall, two patients (6%) had a complete response (CR), 8 patients (24%) had a partial remission (PR) and 16 patients (47%) had a stable disease (SD). The response rate and clinical benefit rate (CR+PR+SD) were 29% and 76%, respectively. Median progression-free survival was 4 months (range: 1-27+). Hematological adverse effects (AE) with grade 3/4 were observed in 4 patients (11%). Non-hematological AE greater than grade2 was observed in one case: hypo albuminemia and edema, which were manageable and tolerable. As there were 10 responders (≧6), the protocol was considered for additional investigation. The Patients with elevated serum mutated p53 / IL-6 showed lower response and worse prognoses. Conclusions: Weekly B and EriOX administration was considered for additional investigation for patients with PR-ROC. Serum mutated p53 protein and/or IL-6 could be biomarkers in PR-ROC patients treated with weekly B and EriOX.
Panitumumab in platinum-sensitive epithelial ovarian cancer patients with KRAS wild-type: The PROVE-study, a phase II randomized multicenter study of the North-Eastern German Society of Gynaecologic Oncology.
Authors: Chekerov Radoslav , Klare Peter , Krabisch Petra , Potenberg Jochem , Heinrich Georg , Mueller Lothar , Kurbacher Christian M. , Grischke Eva-Maria , Braicu Elena Ioana , Wimberger Pauline , Sehouli Jalid
Published: September 2018

5558

Background: For ovarian cancer (OC) patients with platinum-sensitive recurrence the addition of new biologic agents to chemotherapy may improve survival. Panitumumab is a fully human monoclonal antibody specific to the epidermal growth factor receptor (EGFR). The purpose of this trial was to investigate the therapeutic efficacy of panitumumab in the combination with carboplatin-based chemotherapy in relation to the respective standard combination in patients with a KRAS wildtype with platinum-sensitive recurrent ovarian cancer (NCT01388621). Methods: Major eligibility criteria were pretreated platinum-sensitive epithelial ovarian/ fallopian/ peritoneal cancer and no more than 2 prior treatments for this disease. Only patients with measurable disease or elevated CA125 and with KRAS wild type were eligible. Patients were treated with Carboplatin AUC4/Gemcitabine 1000 mg/m² or Carboplatin AUC5/PLD 40 mg/m² and randomized to panitumumab 6 mg/kg day 1 and day 15, every 3 or 4 weeks. Tumor assessment was performed at baseline and at every third cycle according to CT-scan and CA-125 criteria. Results: In this multi-institutional phase II trial 102 patients were randomized and 96 enrolled for the final analysis. Progression-free survival in the intention-to-treat population (N=96) was 9.5 vs. 10.7 months (HR 0.829, 95%CI of 8.5-11.6 months vs 8.5-13.1 months) for the experimental vs. standard arm, p=0.45. Data of overall survival are not jet evaluable. The most common treatment related grade 3+ toxicities included hematologic toxicity (54%), skin reactions (18%) and gastrointestinal events (16%). Conclusions: The addition of panitumumab to platinum-based chemotherapy for recurrent ovarian cancer does not influence efficacy and progression-free survival in platinum sensitive patients, while no new additional toxicity aspects for panitumumab were evaluated. Clinical trial information: NCT01388621.
ENGAGE: Evaluation of a streamlined oncologist-led BRCA mutation (BRCAm) testing and counselling model for patients with ovarian cancer.
Authors: Colombo Nicoletta , Scambia Giovanni , Chalas Eva , Huang Gloria S. , Pignata Sandro , Fiorica James , Van Le Linda , Ghamande Sharad A. , Gonzalez Santiago Santiago , Bover Isabel , Suárez Begoña Graña , Green Andrew Emmons , Huot-Marchand Philippe , Bourhis Yann , Karve Sudeep , Blakeley Christopher
Published: September 2018

5559

Background: Short BRCAm testing turnaround times (TAT) are crucial to making timely treatment decisions for patients (pts) with ovarian cancer. ENGAGE (NCT02406235; D0816R00006) evaluated a streamlined, oncologist-led germline BRCAm testing model, piloted by the Institute of Cancer Research and the Royal Marsden Hospital, London, UK. Results presented are from the final analysis (data cut-off: 30 Sep 2016). Methods: This prospective, observational study enrolled pts with ovarian cancer across sites in the US (n = 11), Italy (n = 8) and Spain (n = 7). Oncologists and nurses at participating sites were trained on genetic counselling techniques relating to BRCAm testing. Primary endpoints were BRCAm testing TAT (time from initial counselling to the provision of test results or post- BRCAm test counselling [whichever occurred latest]); pts’ satisfaction with the oncogenetic testing model, evaluated using pre- and post- BRCAm testing surveys; and clinicians’ opinion on the value of this new testing pathway, evaluated using a post- BRCAm testing survey. Results: For the 700 evaluable pts enrolled (US = 317; EU = 383), pre- BRCAm testing counselling was carried out by either an oncologist (40.7%) or clinical staff (nurse or research coordinator; 59.3%) in the US, and only by oncologists in the EU. The median overall TAT was 9.1 weeks (all pts), with 12.0 weeks in Spain, 20.4 weeks in Italy (17.4 weeks EU median) and 4.1 weeks in the US. The differences were mainly due to the time from BRCAm testing to obtaining the test results. Satisfaction with the overall counselling was high amongst pts, with a mean dimension score rating of 3.8/4 (where 4.0 = highest satisfaction). 93.6% of pts were happy to have received genetic testing as part of an existing oncologist appointment, and more than 80% of oncologists were satisfied with the screening process, agreeing that it was an efficient use of their time. Conclusions: The ENGAGE study results show that a streamlined oncologist-led BRCAm testing model can offer reduced TAT and high levels of satisfaction amongst pts and clinicians. The success of this model is enhanced by access to a BRCAm testing facility, from which results can be obtained quickly. Clinical trial information: NCT02406235; D0816R00006.
Ki67 as a prognostic factor in low grade serous ovarian cancer (LGSOC): A retrospective analysis of the Tumor Bank Ovarian Cancer (TOC).
Authors: Sehouli Jalid , Plett Helmut , Richter Rolf , Denkert Carsten , Darb-Esfahani Silvia , Chekerov Radoslav , Schmitt Wolfgang D , Grabowski J.P. , Taube Eliane T , Braicu Elena Ioana
Published: September 2018

5562

Background: LGSOC is a rare and distinct entity characterized by younger age, lower response to chemotherapy and better clinical outcome. Aim of this study was to evaluate the impact of Ki67, estrogen and progesterone receptors (ER and PR) on platinum response and survival in primary LGSOC patients. Methods: 80 primary LGSOC patients with available FFPEs were identified within TOC. The histology was confirmed at a second histological evaluation. For Ki67 analysis conventional immunohistochemical staining was performed with the Mib-1 clone on Ventana. Slides were explored with a light microscope camera. A representative field for Ki-67 evaluation was selected, in case of heterogeneous staining a hot spot was chosen. The software classified detected cells into non-tumor, negative and positive cells. When necessary, a correction of tumor and non-tumor areas was performed by an experienced pathologist. The counted cells ranged between 175 and 2398. Overall the method allows a precise, continuous and standardized means to quantify Ki-67. ER and PR status was determined on scanned IHC TMA slides. ER and PR positive tumors were defined if the percentage of stained tumor cells was at least 10%. Statistical analysis was performed using IBM SPSS Statistics. Results: Median age at diagnosis was 56 years (range: 20-81), 81.3% of patients presented in advanced stage and 96.3% received platinum based chemotherapy. Ki67 median value was 5.09 (IQR: 1.56-10.5). 93.1% and 47.9% of the patients showed ER and PR positive tumors, respectively. Median overall survival (OS) was 45.5 months (range: 0.1-182.8). Our analysis showed that platinum free interval (PFI) was significant longer in patients with lower Ki67 (p = 0.006). Higher proliferation rates were significant associated with poorer progression free (p = 0.011, HR = 1.039, 95%CI: 1.009-1.070) and OS rates (p = 0.001, HR = 1.059, 95%CI: 1.025-1.095). No differences in clinical outcome were seen in patients with different ER and PR status. Conclusions: This is the first study showing that higher Ki67 values correlate with shorter PFI and poorer survival rates in LGSOC, underlying the heterogeneous character of this disease.
Are symptoms of ovarian cancer evident: A retrospective analysis of claims data to determine prior symptoms to diagnosis.
Authors: Langabeer Denise Manon , Ganduglia Cazaban Cecilia , Swartz Michael D , Krause Trudy
Published: September 2018

5565

Background: There are no standard of care screening methods for ovarian cancer. Over sixty percent (60%) of ovarian cancer cases are found at Stage III and IV, which ultimately impacts a woman’s survival rate. The purpose of this study is to determine if specific symptoms are evident prior to diagnosis of ovarian cancer. Methods: A retrospective analysis of health insurance claims between 2008 through 2013 from a commercial payer was performed based on the following eligibility criteria: 1) women diagnosed with ovarian cancer, 2) at the time of diagnosis, 24 years of age or older, 3) enrolled in healthcare plan for a period of 24 months or more prior to diagnosis, and 4) resident in the state of Texas. Symptoms were identified based on ICD-9 diagnosis codes and categorized specific to pain, abdominal and pelvis, digestive, and bladder and were evaluated at minimum of six months prior to diagnosis. ICD9 codes are used for this analysis as the data is limited to years before the change to ICD10. Results: Baseline data of 3,641 women diagnosed with ovarian cancer were identified and were associated with 927,528 claims specific to the symptoms. The age of women diagnosed with cancer ranged between 24 and 88 (mean=52; SD: 0.1833). Nearly 70% of women were treated for one or more symptoms prior to diagnosis. The symptoms women experienced the most were associated with abdomen and pelvis at 60%. Pain, digestive, and bladder ranged between 20% and 30%. Conclusions: This research is intended to further explore whether symptoms are evident in women diagnosed with this disease, and if so, how long and how frequent did the symptoms occur prior to diagnosis. Additionally, a review of combination of symptoms is explored. This research is intended to provide a better understanding of the disease as well as support that women may need to be referred to an oncologist earlier for further evaluation should reoccurring symptoms present.
Evaluating the repertoire of immune checkpoint markers expressed on peripheral and ascites CD8+ T cells in ovarian cancer.
Authors: Gaillard Stephanie , Dumbauld Chelsae , Bilewski Alyssa , Ehrisman Jessie A , Secord Angeles Alvarez , Havrilesky Laura Jean , Berchuck Andrew , Weinhold Kent , Chan Cliburn , Yi John
Published: September 2018

5571

Background: Understanding the immune checkpoint marker repertoire can facilitate development of therapeutic strategies to improve efficacy of immune-based therapies. We used a novel high-dimensional flow cytometry panel to determine co-expression patterns of immune checkpoint markers and effector function of CD8+ T cells from peripheral blood and ascites of patients newly diagnosed with ovarian cancer. Methods: Peripheral blood and ascites samples were collected from patients with epithelial ovarian cancer (n=8). Cells isolated from peripheral blood and ascites were used for immune profiling by multiparameter flow cytometry of 5 inhibitory receptors (PD-1, LAG-3, TIM-3, TIGIT, and BTLA) on CD8+ T cells, along with 4 functional parameters (production of each of the following: TNF-α, IFN-γ, IL-2, and upregulation of CD107a). A complementary multiplex analysis on plasma and ascites fluid was performed to quantify 14 soluble checkpoint markers. Results: The concentrations of soluble PD-1, TIM-3, LAG-3, CTLA-4, BTLA, IDO, and CD137 were increased in ascites fluid compared to plasma from patients with ovarian cancer. Ascites CD8+ T cells co-express higher levels of inhibitory receptors than peripheral CD8+ T cells. In total, CD8+ T cells in ascites retained the ability to produce effector functions at levels similar to peripheral blood. However, IFN-γ production was retained in PD-1 only expressing CD8+ T cells and decreased in CD8+ T cells co-expressing multiple receptors. Conclusions: High-dimensional flow cytometry allowed for the phenotypic and functional characterization of CD8+ T cells from ovarian cancer patients. The profile of receptor co-expression was distinct in peripheral blood compared to ascites. Collectively, our study suggests that co-expression of factors beyond PD-1 influences CD8+ T cell activity. Thus blocking PD-1 and PD-L1 alone may not be sufficient for CD8+ T cells expressing multiple inhibitory receptors.
Incidence of secondary myelodysplastic syndrome and acute myeloid leukemia in patients with ovarian and breast cancer in real-world setting in the U.S.
Authors: Fulcher Nicole , Shenolikar Rahul A. , Durden Emily , Moore Kathleen N.
Published: September 2018

5574

Background: Limited real-world data are available on cancer patients withsecondary malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) caused by use of certain chemotherapeutic agents that interfere with DNA. This study assessedthe incidence of secondary MDS and AML in patients (pts) with ovarian cancer (OC) or breast cancer (BC), including subcohorts tested for BRCA mutations and those exposed to DNA damaging therapy. Methods: Adult females with OC or BC between 1/1/2000 and 6/30/2014 (first observed diagnosis of OC or BC = index date) were identified from the MarketScan Commercial and Medicare claims databases. Patients had ≥12 months of pre- and ≥1 month of post-index continuous health plan enrollment. The incidence of MDS and AML (per 1000 person-years [PY]) was assessed using ICD-9 codes over a variable-length post-index period for each cancer cohort and separately for pts with BRCA testing and those exposed to DNA damaging therapy. Results: The study identified 23,862 OC pts (mean [SD] follow-up: 35.8 [31.4] months), and 281,473 BC pts (mean [SD] follow-up: 46.0 [37.2] months). Among OC pts, 10.9% had BRCA testing (OC- BRCA) and 56.6% had exposure to DNA damaging therapy (OC-DNA); 12.9% of BC pts were BRCA tested (BC- BRCA) and 28.1% had exposure to DNA damaging therapy (BC-DNA). The incidence of MDS and AML expressed as cases per 1,000 PY in the OC cohort was 0.51 (0.2%) and 0.39 (0.1%); in OC- BRCA pts, 0.62 and 0.25; and in OC-DNA pts, 0.68 and 0.41. In the BC cohort, the incidence of MDS and AML was 0.33 (0.1%) and 0.19 (0.1%); in BC- BRCA pts, 0.07 and 0.15; and in BC-DNA pts, 0.60 and 0.50. Conclusions: In addition to providing background rates in OC and BC pts, these data suggest that the incidence of MDS and AML in OC and BC pts was higher in patient subcohorts exposed to DNA damaging agents than in the overall cohort.
Impact of beta blocker medication on survival outcome of ovarian cancer: A nationwide population-based cohort study.
Authors: Park Jeong-Yeol , Baek Min-Hyun , Park Young-Han , Kim Dae-Yeon , Suh Dae-Shik , Kim Jong-Hyeok , Kim Yong-Man , Kim Young-Tak , Nam Joo-Hyun
Published: September 2018

5578

Background: In experimental studies, adrenergic hormones are involved in tumorigenesis of ovarian cancer and its progression. We investigated the impact of beta adrenergic blocker on survival outcome of ovarian cancer since few studies have investigated its relevance. Methods: Data of Korean National Health Insurance Service was analyzed (n = 866). We analyzed the impact of beta blocker on survival outcome of ovarian cancer according to the duration on medication and age groups of patients. Cox proportional hazards regression was used to analyze hazard ratios (HR) for all-cause mortality with 95% confidence intervals (CI) adjusting for confounding factors. Results: Median years of follow-up was 5.98 and 6.71 for non-users and users, respectively. Among the 866 patients, 206 (23.8%) were users and 660 (76.2%) were non-users. In total, there was no survival difference between the 2 groups. But, when patietns were grouped according to the duration of medication, patients with longer duration of medication (≥1 year) showed better survival outcome (adjusted HR 0.305 [95% CI: 0.187-0.500], P < 0.001). Also, beta blocker use in patients with > 60 years showed better survival compared to younger patients (adjusted HR 0.579 [95% CI: 0.408-0.822], P = 0.002). In patients with > 60 years, medication longer than 720 days was associated with better survival outcome (adjusted HR 0.267 [95% CI: 0.140-0.511], P < 0.001). Both selective and non-selective beta blocker showed identical survival benefit in these settings without difference between each other. Conclusions: Beta blocker medication was associated with favorable survival outcome in ovarian cancer, especially when used in older patients and in long term duration.
Exploratory phase II evaluation of cabozantinib in recurrent/metastatic uterine carcinosarcoma (CS): A study of the Princess Margaret, Chicago, and California phase II consortia.
Authors: Mandilaras Victoria , Dhani Neesha C. , Tan Qian , Jain Angela , Johnston Carolyn , Hirte Hal W. , Tonkin Katia Sonia , Cristea Mihaela C. , Matsuo Koji , Butler Marcus O. , Lheureux Stephanie , Burnier Julia V. , Wang Lisa , Mehta Anjali , Wright John Joseph , Oza Amit M.
Published: September 2018

5587

Background: Carcinosarcoma (CS) is a rare ( < 5%) aggressive subtype of endometrial cancer (EC). Patients (pts) with progression on platinum-based chemotherapy (CTX) have limited options, there is no standard 2ndline treatment and median progression-free survival (PFS) is < 2months (mt), 6-mt PFS less than 20%. Limited molecular data on CS aligns with epithelial EC, providing rationale for evaluating similar strategies such as targeting MET and angiogenesis. Cabozantinib (cabo) is multi-targeted tyrosine kinase inhibitor against MET, VEGFR, TIE2, RET, AXL and KIT. Methods: PHL-86 (NCI#9322/NCT01935934) is a multi-centre, non-randomized, phase II trial of cabo (60 mg oral daily dose on a 28-day cycle) in EC pts recurring within a year of adjuvant CTX or with progression after 1stline of CTX for metastatic disease. Pts with rare histology including CS, were enrolled in an exploratory cohort. Activity of interest for further evaluation was defined as 4 responses (either partial response [PR] or 12-wk PFS) out of 10 pts of a given histotype. CT scans were performed after cycle 3 and every 2 cycles thereafter. Results: From 2013 to 2016, 32 pts were treated in the exploratory cohort, 19 pts with CS. Median age was 66 years (range 25-75); prior treatment included CTX (17: 1 line, 6: 2 lines) and/or radiation (11). Fifteen pts were evaluable for response, with 1 PR (7%) and 8 pts with 12-wk PFS (53%). Median PFS was 3 mt (95% CI: 2.7 – 4.6) with estimated 6-mt PFS of 13% (2 to 33%). Toxicity evaluation is available for 19 pts. Common events were fatigue and GI upset. Most frequent > Grade3 toxicities were hypertension (5), anemia (4), diarrhea (2). Four pts had GI fistula (2) or perforation (2). Mutation profiling in archival tissue showed TP53 (73%), PIK3CA (40%), KRAS (27%), PTEN(13%) with > 1 mutation present in 14/15 pts analyzed. The 1 pt with no somatic mutations had a PR (31% decrease) on cabo (PFS 6.7mt). Conclusions: Cabo in CS cohort met the predefined endpoint for further evaluation and compares favourably with other agents in this poor prognosis disease. Larger studies are required to define depth and durability of response and identify relevant biomarkers. Clinical trial information: NCT01935934.
Contemporary breast conservation patient outcomes for ductal carcinoma in situ and margins < 2 mm.
Authors: Tadros Audree , Smith Benjamin D. , Shen Yu , Lin Heather Y. , Krishnamurthy Savitri , Lucci Anthony , Barcenas Carlos Hernando , Hwang Rosa F. , Rauch Gaiane , Santiago Lumarie , Strom Eric A , DeSnyder Sarah Marie , Yang Wei Tse , Black Dalliah MaShon , Albarracin Constance T. , Chavez-Mac Gregor Mariana , Hunt Kelly , Kuerer Henry Mark
Published: September 2018

559

Background: Recent national consensus guidelines regarding optimal margin width for the management of DCIS have been published; however, controversy remains for managing margins <2mm. The relationship between margin width and locoregional recurrence (LRR) was determined in a contemporary cohort of patients. Methods: 1504 patients with DCIS undergoing definitive breast conserving surgery from 1996 to 2010 were analyzed for clinical and pathologic characteristics from a prospectively managed comprehensive academic cancer center database. Cox proportional hazard models were used to examine the relationship between margin width (<2mm or ≥2mm) and LRR by adjuvant radiation therapy (RT). Patients with positive margins (n=11) were excluded. Results: Overall, 3.4% of patients had a LRR at a median follow-up of 8.7 years. Univariate analysis of age, family history, grade, tumor size, comedonecrosis, RT, adjuvant hormonal therapy, ER status, and margin width found younger age (< 40 yr, p=0.02), no RT (n=299, p=0.005), and margin width <2mm(n=138, p=0.005) to be associated with LRR. The association between margin width and LRR differed by adjuvant radiation therapy status (p=0.02 for the interaction). There was no statistical significant difference in LRR for patients with margins <2mm vs ≥2 mm who received RT, (10-year LRR 6.0% vs 3.2%, respectively; HR 1.5, 95% CI 0.5-4.2, p=0.48). For patients who did not receive RT (n=299), those with margins < 2 mm were significantly more likely to develop a LRR than those with margins ≥2mm (10-year LRR 35.7% vs. 4.6%, respectively; HR 7.2, 95%CI 2.6-19.4, p=0.0001). Conclusions: In patients with <2mm margins receiving adjuvant radiation therapy, there is no difference in locoregional recurrence when compared to patients with ≥2mm margins. Additional surgery for wider margins of resection are not routinely justified in this group of patients but should be obtained for patients with <2mm margins who forego radiotherapy.
The combination of preoperative computed tomography lymphography and intraoperative fluorescence imaging navigation for sentinel lymph node biopsy of early breast cancer patients.
Authors: Abe Hajime , Teramoto Atsuko , Yamasaki Keiichi , Yoneda Kohri , Ogawa Masao , Kawasaki Masayasu , Kameyama Masao
Published: September 2018

567

Background: This study investigated a usefulness of the combination of fluorescence imaging and computed tomography lymphography (CTLG) for sentinel lymph node biopsy (SLN) biopsy of early breast cancer patients. Methods: Between January 2013 and August 2016, 350 breast cancer patients without clinical evidence of lymph node metastasis were treated. Preoperaitve CTLG was performed using 64-row multidetector CT injected contrast agent. The contrasted lymph route and SLN were identified in reconstructed three-dimensional imaging. The SLN spot was indicated by CT laser light navigator system. We established typical pattern of the lymphography: stain defect of SLN, stagnation of lymphatic route for preoperative diagnosis of metastatic SLN. Intraoperative fluorescence images were obtained using the fluorescence imaging system (pde-neo). After dye mixed indocyanine green and indigocarmin was injected, lymphatic route was observed with fluorescence images. SLN biopsy was performed referring to the point by axillary compression technique by plastic device. Results: The median age of the 350 patients was 59 (range 28 – 90) years old. CTLG could visualize lymphatic route and accurately identify SLN in 336 (96.0 %) and 343 (98.0 %) cases, respectively, whereas fluorescence imaging identified successfully lymphatic route and SLN in all patients. Lymphatic routes of CTLG were completely consistent with those of fluorescence imaging. The number of SLN identified by CTLG was significantly lower than that by fluorescence imaging (1.1 vs. 1.6, p<0.01). Fifty of 350 patients had metastatic SLN pathologically, and 11 of them had micrometastases of SLNs. The accuracy for metastatic diagnosis of SLN using CTLG without micrometastasis was 84.1 %, sensitivity was 82.1 % and specificity was 84.3 %. The positive predictive value was 40.5 % and negative predictive value was 97.3 %. Conclusions: This combined navigation method of fluorescence imaging and CTLG revealed more easy and effective to detect SLN than fluorescence imaging alone. In addition, the information from CTLG would be helpful for the preoperative diagnosis of SLN metastasis.
Hypofractionated, normofractionated and intraoperative breast irradiation: Long term cosmetic outcome based on photographic evaluation.
Authors: Ellethy Tarek , Welzel Grit , Sperk Elena , Neumaier Christian , Tuschy Benjamin , Berlit Sebastian , Ehmann Michael , Sütterlin Marc , Wenz Frederik K. , Abo-Madyan Yasser
Published: September 2018

568

Background: Photographic documentation of breast changes after breast radiotherapy (RT) is a helpful tool to both subjectively and objectively evaluate cosmesis. The aim of this study was to evaluate cosmesis in breast cancer patients after receiving hypofractionated whole breast RT (HF-WBRT), normofractionated (NF-WBRT), intraoperative RT (IORT) or combined WBRT/IORT. Methods: After excluding cases with missing or inadequate photos from three prospective clinical trials, KOSIMA, TARGIT-A & TARGIT-E, 155 and 205 cases were included in a subjective analysis while 132 and 185 cases were included in an objective analysis postoperatively and after 2 years respectively. Subjective evaluation was done by 9 observers using the Harvard scale. Objective evaluation was done by assessing percentage breast retraction (pBRA). Based on the treatment received, patients were divided into 5 groups: 1. HF-WBRT 40/2,67 Gy ± Boost, 2. NF-WBRT 50/2 Gy ± Boost, 3. NF-WBRT 56/2 Gy, 4. IORT 20 Gy, 5. IORT 20 Gy+WBRT 46/2 Gy. Results: Subjectively, the rate of excellent-good cosmesis was 92% postoperatively and 84% after 2 years while objectively it was around 56% at both time points. At 2 years, no significant difference was observed between the 5 treatment groups with the subjective excellent-good cosmesis being 82%, 80%, 92%, 83%, 85% (p = 0.546) and objective being 56%, 61%, 52%, 53%, 50% (p = 0.883) in groups 1-5 respectively. Factors possibly affecting cosmesis at 2 years were examined. No significant difference was observed with age, smoking, BMI, chemotherapy, hormone therapy or type of axillary surgery. Significantly better cosmesis was observed with upper outer tumor location compared to other quadrants (p < 0.0001) also with a ratio of excised/total breast volume under 20% (p < 0.0294). Conclusions: Cosmetic outcome after hypofractionated and IORT was similar to normofractionated breast RT. After 2 years of treatment, cosmetic deterioration remained acceptable, overall < 10%. Tumor location and excised breast volume were the only factors significantly affecting cosmetic outcome.