bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of DNA repair deficiency signature on outcomes in triple negative breast cancer (TNBC) patients treated with AC chemotherapy (SWOG S9313).
Authors: Sharma Priyanka , Barlow William E. , Godwin Andrew K. , Knight Laura A , Walker Steven M. , Kennedy Richard D. , Badve Sunil S. , Gokmen-Polar Yesim , Pathak Harsh B , Isakova Kamilla , Linden Hannah M. , Tripathy Debu , Hortobagyi Gabriel N. , Hayes Daniel F. 
Published: September 2018

529 Background: Biomarkers of response and resistance to adjuvant chemotherapy for TNBC are needed. Deficiency in DNA damage response (DDR) and repair pathways have been reported in TNBC and may impact response to chemotherapy. Aims: To investigate DNA damage response deficiency (DDRD) molecular signature, BRCA1mRNA expression and Tumor Infiltrating Lymphocytes (TILs) as prognostic markers in TNBC patients treated with adjuvant AC on S9313. Methods: S9313 accrued 3125 early stage BC patients to two alternative schedules of AC with no difference in outcomes between the two arms. We identified 425 (14%) patients with centrally determined TNBC with tissue availability. DDRD signature (44 gene signature, Almac Inc.) and BRCA1expression (NanoString nCounter) were performed on RNA isolated from pre-treatment FFPE tumor tissue. DDRD score was classified in quartiles. TILs evaluation was performed using previously described criteria. Markers were tested for prognostic effect on DFS and OS using Cox regression model with adjustment for randomized treatment assignment. Results: For 425 TNBC patients median age: 45 yrs, and 5 year DFS and OS = 74% and 82%, respectively. DDRD signature was successfully evaluated in 89.6% (381/425) but only 267 (62.8%) met 60% tumor content criterion for inclusion. DDRD score quartiles were associated with DFS (5 year DFS 59% & 82% in the lowest & highest quartiles respectively, p = 0.0005) and OS (5 year OS 74% and 86% in lowest and highest quartiles respectively, p = 0.008). BRCA1 expression and TILs were successfully determined in 78% and 99% samples, respectively. BRCA1expression was not associated with DFS. TILs were associated with DFS (10% increase HR = 0.88; 95% CI 0.79-0.97; p = 0.016) and OS (HR = 0.84; 95% CI 0.74-0.94; p = 0.0005). DDRD score and TILs were highly correlated (Pearson = 0.62). In multivariate model of DFS including TILs and DDRD quartiles, only DDRD remains significant (p = 0.018). Conclusions: DDRD signature was prognostic in TNBC patients treated with AC chemotherapy and has the potential to be used as a selection criterion to identify TNBC patients whose prognosis is sufficiently poor to justify evaluation of alternative treatment.
Prognostic value of histopathology, stromal tumor infiltrating lymphocytes (sTILs) and adjuvant chemotherapy (AdjCT) in early stage triple negative breast cancer (TNBC).
Authors: Leon-Ferre Roberto Antonio , Polley Mei-Yin , Liu Heshan , Gilbert Judith A. , Cafourek Victoria , Hillman David W. , Elkhanany Ahmed , Akinhanmi Margaret , Negron Vivian , Boughey Judy Caroline , Liu Minetta C. , Ingle James N. , Kalari Krishna R. , Couch Fergus , Visscher Daniel W. , Goetz Matthew P. 
Published: September 2018

533 Background: Current guidelines define TNBC as complete absence of estrogen (ER) and progesterone receptor (PR), without HER2 amplification. However, the prognostic impact of clinical and histopathological factors, sTILs, and AdjCT in TNBC meeting these strict criteria is unknown. Methods: From a cohort of 9985 women who underwent upfront surgery for M0 breast cancer (BC) at Mayo Clinic Rochester from 1985-2012, 1159 pts with ER negative or low (≤10%) BC were identified for central ER/PR/HER2 staining and HER2 FISH (IHC2+ only) to select those with TNBC by modern definitions. Cox proportional hazards models were used to assess the impact of clinicopathological variables on invasive disease-free (IDFS) and overall survival (OS). Results: Tumors from 605 pts (median age 56.3 yrs) met criteria for TNBC (ER < 1%, PR < 1% and HER2 0, 1 or 2+ and FISH negative). 51% were T1, 65% N0, 88% grade 3, and 75% had Ki67 > 15%. Histologically, 39% were anaplastic, 26% invasive ductal, 16% medullary, 8% metaplastic, 6% apocrine and 5% others. Median sTILs was 20% (0-90%). 55% pts received AdjCT [21% anthracycline (A), 19% A + taxane, and 15% other]. Median follow-up for IDFS and OS were 7.4 and 10.6 yrs, respectively. Multivariate analyses demonstrated that higher N stage (p < 0.01), lower sTILs (p = 0.01) and no AdjCT (p < 0.01) were independently associated with worse IDFS and OS. Histology (medullary subtype) was associated with better IDFS in univariate (HR 0.56, 95% CI, 0.35-0.89) but not in multivariate analyses, once sTILs were accounted for. Among systemically untreated pts (n = 182), higher N (p < 0.01) and lower sTILs (p = 0.04) were associated with worse IDFS. For systemically untreated T1N0 pts (n = 111), the 5-yr IDFS was 70% (95% CI, 61-81) [T1a: 83% (95% CI, 63-100), T1b: 68% (95% CI, 52-88) and T1c: 67% (95% CI, 55-83)], compared to 78% (95% CI, 68-84) for T1N0 pts treated with AdjCT. Conclusions: In TNBC pts, N stage, sTILs and receipt of AdjCT were independently prognostic for IDFS and OS. sTILs remained prognostic for IDFS in systemically untreated TNBC. In N0 TNBC, the risk of recurrence or death was substantial in the absence of chemotherapy, even for those with T1 tumors.
Adjustments in relative dose intensity (RDI) for FECD chemotherapy in breast cancer: A population analysis.
Authors: Veitch Zachary William Neil , Khan Omar Farooq , Tilley Derek , Xanthoula Kostaras , Tang Patricia A. , King Karen M. , Lupichuk Sasha M. 
Published: September 2018

547 Background: Reductions in RDI of adjuvant chemotherapy for breast cancer (BC) has been associated with inferior survival. However, earlier studies may be confounded by uncharacterized BC subtype(s) (TNBC, HER2+) and non-taxane chemotherapy regimens (CMF, AC). This retrospective study evaluates survival (DFS/OS) outcomes for patients receiving RDI reductions for FECD adjuvant chemotherapy in Alberta, Canada. Methods: Patients with stage I-III, ER +/-, HER2- BC receiving adjuvant FECD chemotherapy from 2007-2014 were identified using the Alberta Cancer Registry. RDI of individual chemotherapeutics (cycle 1-6) were recorded. Average RDI was stratified by <85% vs ≥85% of total dose. Subgroup analysis for early (cycle 1-3) versus late (cycle 4-6) RDI reductions were evaluated. Events (recurrence/death) from any cause were identified. Results: FECD patients (n=1304) receiving an average RDI <85% (range 25-84%) compared to ≥85% demonstrated a significant decline in DFS (79% vs 85%; p<0.01) and OS (82% vs 89%; p<0.01). Early reductions (any) compared to no reduction in RDI were correlated with inferior DFS (77% vs 86%; p<0.01) and OS (79% vs 90%; p<0.01). Late reductions in RDI did not affect DFS/OS. Proportions of TNBC were non-significant for comparative cohorts. Significantly more N0 and N1-3 patients were seen in the any and no early reduction cohort respectively. Conclusions: In high risk BC patients, average RDI <85% is correlated with reduced DFS/OS for FECD. Early (FEC) compared with late (docetaxel) reductions in RDI are correlated with inferior survival. This data suggests that where possible, total (<85%) and early (FEC) dose reductions should be avoided in patients receiving adjuvant FEC-D chemotherapy. [Table: see text]
Toxicity of extended adjuvant aromatase inhibitors therapy in postmenopausal breast cancer patients: A systematic review and meta-analysis.
Authors: Goldvaser Hadar , Ribnikar Domen , Barnes Tristan Alexandra , Cescon David W. , Ocana Alberto , Amir Eitan 
Published: September 2018

549 Background: Aromatase inhibitors (AI) are a gold standard adjuvant endocrine therapy for postmenopausal women with breast cancer. A number of randomized trials (RCTs) have reported modest improvements in breast cancer outcomes from extending treatment with AI beyond the initial 5 years after diagnosis. However, less in known about the toxicity of extended AI compared with no therapy. Methods: We conducted a systematic review of MEDLINE to identify RCTs that compared extended AI to placebo or no treatment. The search was supplemented by a review of abstracts from the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meetings between 2013 and 2016. Odds ratios (ORs), 95% confidence intervals (CI), absolute risks, and the number needed to harm (NNH) associated with one adverse event were computed for prespecified safety and tolerability outcomes including cardiovascular disease, bone fractures, second cancers (excluding new breast cancer), treatment discontinuation due to adverse events and death without recurrence. Results: Seven trials comprising 16349 patients met the inclusion criteria. Longer treatment with AI was associated with increased odds of cardiovascular disease (OR = 1.18, 95% CI 1.00-1.40, P=0.05; NNH = 122) and bone fractures (OR = 1.34, 95% CI 1.16 - 1.55, P < 0.001; NNH = 72). Compared to control, longer AI therapy was associated with a higher odds of treatment discontinuation due to adverse events (OR = 1.45, 95% CI 1.25 - 1.68, P < 0.001; NNH = 20). Longer AI therapy did not influence the odds of second cancers (OR = 0.93, 95% CI 0.73-1.18, P = 0.56). There was a numerical excess of death without recurrence with longer AI therapy, but this was not statistically significant (OR = 1.11, 95% CI 0.9 - 1.36, P = 0.34). Conclusions: Longer durations of AI use are associated with increased cardiovascular events and bone fracture. There is a numerical, but non-statistically significant excess of deaths without breast cancer recurrence among patients receiving longer AI therapy. These data should be taken into account when considering extended adjuvant AI therapy for breast cancer patients.
Disparities in multigene signature testing and its impact on adjuvant therapy in early stage breast cancer.
Authors: Jones Maris S. , Goldfarb Melanie , Wang Mansen , Ho Emily 
Published: September 2018

550 Background: Commercially available prognostic multigene signature tests (PMT) have been available for over a decade to guide adjuvant therapy in early stage breast cancer. This study explores persistent disparities in the availability of PMT and how results influence the use of adjuvant therapy. Methods: Females > 18 years of age with newly diagnosed, primary, Stage I-III, ER positive, HER2-neu negative breast cancer that did not receive neoadjuvant therapy between 2006-2014 were captured from the National Cancer Database (NCDB) participant user file. Univariate and multivariate analyses identified factors associated with utilization of PMT as well as receipt of adjuvant chemotherapy for patients with PMT risk stratification. Results: Of 574,921 eligible females, 130,297 (22.66%) received PMT. Almost all patients that had PMT had pathologically negative (pN0 = 83%) or 1-3 positive LNs (pN1 = 16%). Controlling for tumor features, patients least likely to have PMT were of lower socioeconomic status, uninsured, not White non-Hispanic, < 40 or > 70 years of age, and treated at community hospitals or in the Western region (all p < 0.001). Very few patients with PMT results actually received adjuvant chemotherapy (0.64% of 92,235). Of this small group, younger patients (ages 18-49) those with less education (OR = 1.37, 95%CI:1.07-1.76), positive lymph nodes, and larger tumors (OR = 1.62, 95%CI:1.37-1.91) were more likely to receive adjuvant chemotherapy whereas patients with PR positive tumors (OR = 0.33, 95%CI:0.18-0.60) and those treated at academic facilities (OR = 0.81, 95%CI:0.68-0.96) were less likely to receive adjuvant chemotherapy after controlling for competing factors. Intermediate (OR = 5.34, 95%CI: 4.42-6.45) or high risk (OR = 32.65, 95%CI: 25.74-41.43) PMT scores had the greatest impact on receipt of adjuvant chemotherapy regardless of nodal status. Conclusions: Common socioeconomic and racial/ethnic disparities exist for PMT testing, though inappropriate use (high T or N stage) was minimal. Since PMT results strongly influenced recommendation of adjuvant therapy, decreasing disparities and making PMT available to all patients that are deciding on adjuvant therapy should be a priority.
An open-label, multicohort, phase I/II study of nivolumab in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in recurrent or metastatic (R/M) cervical, vaginal, and vulvar cancers.
Authors: Hollebecque Antoine , Meyer Tim , Moore Kathleen N. , Machiels Jean-Pascal H. , De Greve Jacques , López-Picazo José María , Oaknin Ana , Kerger Joseph N. , Boni Valentina , Evans T.R. Jeffry , Kristeleit Rebecca Sophie , Rao Shangbang , Soumaoro Ibrahima , Cao Z. Alexander , Topalian Suzanne Louise 
Published: September 2018

5504 Background: Treatment options for cervical, vaginal, and vulvar (GYN) cancers are limited after first-line therapy. Human papillomavirus (HPV) infection is associated with squamous cell carcinomas of the cervix (≥90%) and vulva/vagina (40–70%), and may elicit an immune reaction. Programmed death (PD)-1 and its major ligand PD-L1 are expressed in GYN cancers and inhibit immune responses. Nivolumab disrupts PD-1–mediated signaling, restoring antitumor immunity. Methods: In CheckMate 358 (NCT02488759), an ongoing multicohort study of 5 virus-associated cancers, PD-L1–unselected adults with R/M GYN cancers, ECOG PS 0–1, and ≤2 prior systemic therapies for R/M disease were eligible to receive nivolumab 240 mg every 2 weeks until progression or unacceptable toxicity. Primary endpoints were objective response rate (ORR) and safety; secondary endpoints were duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Results: Of 24 treated patients (pts), 19 had cervical and 5 had vaginal or vulvar cancer; median age was 51 y. At a median follow-up of 31 wks (range: 6–38), ORR was 20.8% (Table), and disease control rate (ORR + SD) was 70.8%. All responses were in pts with cervical cancer (ORR, 26.3%) and were observed regardless of PD-L1 or HPV status or number of prior R/M therapies. Median PFS was 5.5 mo (95% CI: 3.5, NR); median OS was NR. Conclusions: Nivolumab demonstrated encouraging clinical activity in pts with cervical cancer and a manageable safety profile in virus-associated GYN cancers, supporting further evaluation in these pts. Updated clinical and biomarker data to be presented. Clinical trial information: NCT02488759. [Table: see text]
Pembrolizumab in patients (pts) with PD-L1–positive (PD-L1+) advanced ovarian cancer: Updated analysis of KEYNOTE-028.
Authors: Varga Andrea , Piha-Paul Sarina Anne , Ott Patrick Alexander , Mehnert Janice M. , Berton-Rigaud Dominique , Morosky Anne , Zhao Guo Qing , Rangwala Reshma A. , Matei Daniela 
Published: September 2018

5513 Background: Overexpression of the PD-1 ligand PD-L1 has been demonstrated in ovarian cancer and may hinder an effective antitumor immune response. A preliminary analysis of the ovarian cancer cohort of the KEYNOTE-028 study (NCT02054806) suggested that the PD-1 inhibitor pembrolizumab has promising antitumor activity in pts with PD-L1+advanced ovarian cancer. An updated analysis of the ovarian cancer cohort based on 15.5 months of follow-up is presented. Methods: Key eligibility criteria for the ovarian cohort of this nonrandomized, multicohort phase Ib trial were advanced ovarian epithelial, fallopian tube, or primary peritoneal carcinoma; failure of prior therapy; PD-L1 positivity defined as membranous staining on ≥1% of tumor and associated inflammatory cells or positive staining in stroma; and ECOG PS 0/1. Pembrolizumab (10 mg/kg every 2 wk) was given for ≤2 y or until confirmed progression/unacceptable toxicity. Response was assessed per RECIST v1.1 by investigators every 8 wk for the first 6 mo and every 12 wk thereafter. Primary end points were safety, tolerability, and confirmed ORR. Results: 26 pts (median age, 57.5 y) were enrolled; 61.5% were white, 38.5% received ≥5 therapies for recurrent/metastatic disease, and 53.8% received prior neoadjuvant/adjuvant therapies. As of the October 10, 2016, data cutoff, the median follow-up duration was 15.5 mo (range, 2.4-30.8 mo). 1 pt had a complete response and 2 had partial responses; 6 pts had stable disease as best response. ORR was 11.5% (95% CI, 2.4%-30.2%). Tumor reduction was observed in 6/26 (23.1%); all 3 patients who responded completed 2 years of treatment. Median duration of response was not reached (range, 24.9+ to 26.5+ mo). Median (95% CI) PFS and OS were 1.9 mo (1.8-3.2 mo) and 13.1 mo (6.7-17.5 mo) respectively. Treatment-related AEs occurred in 73.1% of pts, and the most common were arthralgia (19.2%), nausea (15.4%), pruritus (15.4%), rash (11.5%), and diarrhea (11.5%). 1 patient had a grade 3 drug-related adverse event (transaminase increased). Conclusions: With 15.5 mo of follow-up, pembrolizumab continued to be well tolerated and demonstrated durable antitumor activity in pts with advanced ovarian cancer. Clinical trial information: NCT02054806.
Aromatase inhibitor maintenance therapy in high grade advanced ovarian cancer to delay first recurrence.
Authors: Knipprath-Mészáros Alexandra Maria , Vetter Marcus , Montavon Celine , Vigo Francesco , Schoetzau Andreas , Heinzelmann-Schwarz Viola A. ,   Gynecological Cancer Centre, University Hospital Basel
Published: September 2018

5515 Background: Ovarian cancer (OC) is mostly diagnosed as G3 serous advanced stage disease with survival of only 20% in 5 years. Maintenance therapy after 1st line chemotherapy is increasingly used, particularly with Bevacizumab or PARP inhibitors. However, the effect of antihormonal treatment in breast cancer but also in relapsed gynecological cancers has been shown. Also in low grade OC, data are highly supportive of antihormonal treatment. In a previous study of ours, also high grade serous cancers express high amounts of estrogen receptor (ER). The aim of this study was to analyze whether a maintenance antihormonal therapy in advanced OC adds a benefit in relation to the time of recurrence. Methods: All newly diagnosed G3 FIGO III/IV OC cases at our Hospital were assessed prospectively for ER expression. Patients with positive ER status (> 10%) were treated as maintenance therapy with Letrozol 2.5mg 1x/d or not. Progression free survival was recorded and analyzed according to Kaplan-Meier. Patients with macroscopic residual disease post surgery receiving Bevacizumab maintenance treatment were also included. Results: We identified 51 patients with G3 serous OC FIGO III/IV expressing ER. Hereby, 24 patients received and 27 patients did not receive Letrozol after adjuvant chemotherapy. Time to progression ranged from 4 to 121 months. The use of Letrozol was associated with a significant prolonged progression free interval. After 12 months, only 65% of women in the control group vs 84% in the Letrozol group were progression-free. After 24 months, the effect was even stronger (46% in the control group vs 74% with Letrozol (p= 0.02)). Within the subgroup of patients with residual disease treated with Bevacizumab a similar effect was seen with 41% of patients progression free after 12 months vs 89% when taking Letrozol in addition to Bevacizumab. Conclusions: The use of Letrozol as a maintenance therapy after the 1st line treatment in G3 advanced stage serous OC patients was associated with a longer recurrence free interval in our cohort. These findings warrant a randomized controlled trial comparing all existing maintenance regimen as this might have a major influence on cost development in OC treatment.
Efficacy of niraparib on progression-free survival (PFS) in patients (pts) with recurrent ovarian cancer (OC) with partial response (PR) to the last platinum-based chemotherapy.
Authors: Mirza Mansoor Raza , Monk Bradley J. , Gil-Martin Marta , Gilbert Lucy , Canzler Ulrich , Follana Philippe , Waters Justin S. , Kridelka Frederic , Levy Tally , Benigno Benedict B. , Woie Kathrine , Provencher Diane M. , Lueck Hans-Joachim , Casado Herraez Antonio , Lesoin Anne , Buscema Joseph , Hellman Kristina , Rimel Bj , Hazard Sebastien , Matulonis Ursula A. ,   For the ENGOT-OV16/NOVA Investigators
Published: September 2018

5517 Background: Therapeutic paradigms for recurrent OC vary by geography. Maintenance following response to platinum-based chemotherapy (Plat) is standard in Europe, whereas in the US maintenance is considered following complete response (CR) vs treatment for partial response (PR). Niraparib is a highly selective PARP 1/2 inhibitor (PARPi). In preclinical studies it concentrates in the tumor relative to plasma, delivering > 90% durable PARP inhibition and antitumor effects. Niraparib demonstrated significantly longer PFS vs placebo (P) in pts with recurrent OC following a CR or PR to Plat in the randomized, controlled, double-blind phase 3 ENGOT-OV16/NOVA trial. Methods: Pts with recurrent OC, no prior PARPi use, ≥2 prior courses of Plat, and response to most recent Plat were eligible. Pts were assigned to 1 of 2 cohorts on the basis of g BRCA testing (g BRCAmut or non-g BRCAmut) and randomized 2:1 within each cohort to niraparib 300 mg or P qd until progressive disease (PD). Randomization occurred up to 8 weeks after last dose of the most recent Plat. Pts were stratified by time to progression after penultimate Plat (6 to < 12 months or ≥12 months), prior use of bevacizumab (yes/no), and response to most recent Plat (CR or PR). PFS was measured from time of randomization to death or earliest PD as assessed by independent review committee. Results: 49% of pts (niraparib: 67/138; P: 32/65) in the g BRCAmut and ~49% of pts (niraparib: 117/234 [50%]; P: 56/116 [48%]) in the non-g BRCAmut cohorts entered NOVA with a PR following their most recent Plat. At time of unblinding, 30 (45%) niraparib and 23 (72%) P pts in the g BRCAmut and 65 (56%) niraparib and 45 (80%) P pts in the non-g BRCAmut cohorts had PFS events. PFS hazard ratios (95% CI) were 0.24 (0.131–0.441) in g BRCAmut and 0.35 (0.230–0.532) in non-g BRCAmut cohorts for pts who had a PR to their most recent platinum regimen. This compared favorably to the overall NOVA study results, where PFS hazard ratios (95% CI) were 0.27 (0.173–0.410) in g BRCAmut and 0.45 (0.338–0.607) in non-g BRCAmut cohorts. Conclusions: Niraparib treatment provided significant benefit to pts with recurrent OC who achieved a PR following Plat. Clinical trial information: NCT01847274.