bluuebunny/crossref_metadata_2025_split huggingface dataset:
MONARCH 2: Subgroup analysis of patients receiving abemaciclib + fulvestrant as first- and second-line therapy for HR+, HER2- advanced breast cancer.
Authors: Neven Patrick , Johnston Stephen R. D. , Toi Masakazu , Sohn Joohyuk , Inoue Kenichi , Pivot Xavier , Burdaeva Olga Nikolaevna , Okera Meena , Masuda Norikazu , Koh Han A. , Grischke Eva-Maria , Conte Pier Franco , Lu Yi , Haddad Nadine , Hurt Karla , Kaufman Peter A. , Llombart-Cussac Antonio , Sledge George W. 
Published: May 2020

1061 Background: In MONARCH 2 (M2), abemaciclib (A), an oral selective cyclin dependent kinase 4 & 6 inhibitor, + fulvestrant (F) demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) compared to placebo (P) + F in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC). Numerically more pronounced PFS & OS improvement was noted in subgroups (Sub) with visceral (V) disease and primary endocrine resistance. Here we report efficacy data for M2 with respect to 1L and 2L Sub (last line of endocrine therapy [ET] in (neo)adjuvant and metastatic setting, respectively). Methods: M2 (NCT02107703) was a global, randomized, double-blind Phase 3 trial of A+ F (N = 446) or P + F (N = 223) in women with ET resistant (ETR) HR+, HER2- ABC regardless of menopausal status. Patients (pts) were stratified by site of metastasis (V, bone-only, or other) and resistance to prior ET (primary vs secondary). Exploratory Sub analyses of PFS and OS were conducted among pts in the ITT population with 1L vs 2L. Hazard ratios (HR) were estimated using Cox models with a test of interactions of Sub with treatment performed. Results: At data cut-off (June 20th, 2019), the effect of A + F vs P + F was consistent across 1L (N = 265/133) and 2L (N = 170/86) Sub, with no statistically significant interaction for PFS (p = 0.341) or OS (p = 0.265). For 1L pts, improvements in PFS (HR: 0.57; 95% CI:0.45, 0.73) and OS (HR: 0.85; 95% CI:0.64, 1.14) were observed. Similar efficacy results were observed for 2L pts (PFS: HR: 0.48; [95% CI: 0.36, 0.64]; OS HR: 0.66 [95% CI: 0.46, 0.94]). The numerically largest effects in the 1L population were noted in pts with less favorable prognostic factors such as primary ETR (PFS: HR 0.40 [95% CI: 0.26, 0.63]; OS: HR 0.58 [95% CI:0.35, 0.97]) and V disease (PFS: HR 0.54 [95% CI: 0.39, 0.73]; OS: HR 0.82 [95% CI: 0.57, 1.17]). Conclusions: The statistically significant benefit observed in the M2 study was observed across 1L and 2L patients. In 1L patients (A+F Arm), improvements were observed for PFS and OS with the most pronounced effects noted in patients with less favorable prognostic factors. Clinical trial information: NCT02107703 .
A phase II study of rh-endostatin in combination with chemotherapy in human epidermal growth factor receptor 2 (HER-2) negative advanced breast cancer (ABC).
Authors: Huang Yuan , Zheng Ya-bing , Cao Wen-Ming , Chen Zhan-hong , Fu Jianfei , Li Gang , Jia Wang Xiao 
Published: May 2020

1071 Background: There is an urgent need to improve the efficacy of chemotherapy for HER-2 negative patients (pts) who lack anti-HER-2 therapies. Rh-Endostatin (endostar), a recombinant human endostatin, is a potent inhibitor of angiogenesis. This single-arm multicenter phase 2 study was designed to assess the efficacy and safety of endostar combined with chemotherapy in HER-2 negative ABC. Methods: Eligible pts had HER-2 negative inoperable locoregionally recurrent or metastatic breast cancer and an ECOG PS of 0 or 1. Pts with either measurable or nonmeasurable disease were eligible. Endostar (15 mg/m2, continuous infusion, day 1-7) plus chemotherapy were administered every 21 days until disease progression, intolerable toxicity or other reasons. Chemotherapy regimens were selected by investigators based on clinical decision. Primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) and adverse events (AEs). Results: From August 2016 to December 2019, 40 female pts were enrolled in 3 centers. The median age was 52. Ten pts were previously untreated and 30 pts had at least 1 line of chemotherapy for advanced disease. 31 pts were triple negative BC (TNBC) and 9 pts were hormonal receptor positive (HR+). Platinum combined with paclitaxel or gemcitabine were administered with endostar in 55% of pts. Others received paclitaxel or gemcitabine combined with endostar. 12 pts achieved a best response of partial response (PR) and 13 pts had stable disease (SD). Among 30 pts with measurable disease, ORR was 40% and DCR was 83%. The ORR for patients treated as the first-line therapy was 75% while as the second line or beyond was 27%. For TNBC and HR+ BC pts, the ORR was 46% and 17% respectively. Median PFS was not reached after a median follow-up of 7.6 months. The most common Grade 3/4 AEs observed during this study were neutropenia (10%), leukopenia (10%) and thrombocytopenia (5%). Conclusions: Endostar combined with chemotherapy was effective and well tolerated for the treatment of HER-2 negative ABC, especially TNBC. Its efficacy and safety could be further studied in randomized trials. Clinical trial information: NCT03907098 .
Preliminary safety and efficacy of GX-I7, a long-acting interleukin-7, in combination with pembrolizumab in patients with refractory or recurrent metastatic triple negative breast cancer (mTNBC): Dose escalation period of Phase Ib/II study (KEYNOTE-899).
Authors: Sohn Joohyuk , Park Kyong Hwa , Ahn Hee Kyung , Lee Keun Seok , Kim Jee Hyun , Kim Sung-Bae , Lee Kyoung Eun , Kim Jee Hung , Yang Se Hwan , Le Ngocdiep T. , Kim Jiwon , Heo MinKyu , Woo Jung-Won , Sung Young Chul , Im Young Hyuck 
Published: May 2020

1072 Background: Pembrolizumab monotherapy did not significantly improve OS as 2nd and 3rd-lines treatment for mTNBC compared to standard chemotherapy in phase III study (KEYNOTE-119) leading to high unmet needs of effective treatment. Recent studies showed that higher lymphocyte count is an independent factor which correlates with better response to checkpoint blockade in cancer patients. GX-I7, a long-acting interleukin-7, could potentially provide synergistic anti-tumor efficacy with pembrolizumab by increasing number of T cells both in tumor microenvironment (TME) and peripheral blood (PB). Methods: This is an open-label, phase Ib/II study in patients with refractory or recurrent TNBC who failed from standard chemotherapy in the metastatic setting, with ≤3rd-lines of previous chemotherapy. The dose escalation phase adopted the 3+3 design. The GX-I7 doses were administered IM q9w or q12w, with or without cyclophosphamide pre-conditioning depending on the allocation, and in combination with pembrolizumab 200 mg IV q3w. The objectives were dose limiting toxicities (DLTs), safety, pharmacodynamic markers including lymphocyte increase and RP2D. Results: As of January 30, 2020, GX-I7 and pembrolizumab were exposed to 24 patients (median age 46.0 years [29-75], ECOG PS 1 [58.3%], median cycle no. 3 [1-9]). Treatment was discontinued in 13 (54.2%), majority due to PD and 11 patients are ongoing. No DLTs were reported in all dose groups. Treatment related AEs occurred in 91.7% of patients with grade 1-2 and 9.1% with grade 3 (no grade 4). Common AEs were injection site reaction (39.0%) and fever (13.0%), which were easily managed. Grade 3 toxicity were AST/ALT elevation and infusion related reaction, reported from 1 patient each (4.2%). GX-I7 induced dose-dependent lymphocyte proliferation in PB, with approximately 4-folds increase in high doses. 17 patients were evaluable; confirmed objective responses from ongoing patients included one partial response (5.9%), 2 stable disease (11.8%) and 1 durable unconfirmed PD (5.9%). Conclusions: GX-I7 in combination with pembrolizumab was well tolerated, with no DLTs reported. There was no apparent increase of immune-related AEs with the addition of GX-I7. Pharmacodynamics data support proof of mechanism and it warrants further clinical studies. Clinical trial information: NCT03752723 .
Dual anti-CTLA-4 and anti-PD-1 blockade in metaplastic carcinoma of the breast: Dart (SWOG S1609, Cohort 36).
Authors: Adams Sylvia , Othus Megan , Patel Sandip Pravin , Chae Young Kwang , Miller Kathy , Chugh Rashmi , Schuetze Scott , Sharon Elad , Korde Larissa A. , Gray Robert James , Mayerson Edward , Plets Melissa , Kurzrock Razelle 
Published: May 2020

1073 Background: Immune checkpoint blockade, specifically anti-CTLA-4 and anti-PD-1-directed approaches, has improved outcomes in various tumors and is being tested in SWOG S1609 in rare solid tumors (DART=Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors). Metaplastic breast cancer (MpBC) is a rare subtype of breast cancer with poor response to cytotoxics and median survival of < 1 year for metastatic disease. A MpBC stratum was added based on promising activity of immunotherapy in a patient with MpBC (Adams, npj Breast Cancer 2017). Here, we report the MpBC cohort of S1609 DART. Methods: In this prospective, open-label, multicenter phase II trial patients received ipilimumab (1mg/kg q6 weeks) plus nivolumab (240mg intravenously every 2 weeks). Eligibility for cohort 36 required histologically confirmed MpBC, measurable disease, and ECOG PS 0-2. Prior anti-CTLA4 or anti-PD-1/PD-L1 treatment (but not both) was permitted as well as treated brain metastases. The primary endpoint was overall response rate (ORR, confirmed CR, PR) by RECIST v1.1; 2 or more responses in 16 patients was considered a success. Secondary endpoints: toxicity (CTCAE v4.0), PFS and ORR by immune-related RECIST (iRECIST), overall survival (OS). Biomarker analyses are ongoing. Results: Nineteen patients were registered to the cohort and seventeen eligible patients received therapy. The median age was 60 (range 26-85), most tumors were high grade, triple negative and had a high ki67 (median 87%), median prior therapy = 2 lines. The ORR was 12% (RECIST 1.1) and 18% (iRECIST), with ongoing responses at 23, 18 and 11 months, respectively; SD was seen in 24%, none > 6 months (Table). Median OS was 12 months. AEs were observed in 11 patients (65%), with 3 patients (18%) having Grade 3/4 AEs and 1 patient with a fatal AE (myocarditis). The most common toxicities were LFT abnormalities and fatigue. Conclusions: Cohort 36 met its primary endpoint: ipilimumab plus nivolumab was clinically active in advanced MpBC, with durable responses observed in 3/17 patients. Further investigation of this combination is warranted. Clinical trial information: NCT02834013 . [Table: see text]
Translational relevance of androgen receptor immunohistochemistry scoring systems for data harmonization in triple negative breast cancer (TNBC).
Authors: Mufti Suhail Sayeed , Lalkota Bhanu Prakash , BN Tejaswini , Varayathu Hrishi , Sarathy Vinu , Puii Lalnun , Sangi Lalram , Thomas Beulah Elsa , Hazarika Diganta , Thungappa Satheesh Chiradoni , Bj Sriniivas , Patil Shekar , Naik Radheshyam , Ajaikumar Basavalinga Sadasivaiah 
Published: May 2020

1078 Background: Androgen receptor (AR) expressing triple negative breast cancer (TNBC) is a sub-set of TNBC with an evolving prognostic and predictive behaviour. AR immunohistochemical threshold for positivity has not been standardized and a wide range of cut-offs have been used across studies ( > 0% to 75%). In this study we explored AR immunohistochemistry thresholds in relation to disease free survival (DFS) and clinical outcomes in non-metastatic TNBC using the Allred and H-Score systems. Increasing interest in AR as a therapeutic target for TNBC and the use of digital tissue image analysis makes it important to standardize AR immunohistochemistry reporting. Methods: 100 FFPE (formalin-fixed paraffin-embedded) tumour blocks were retrieved for non-metastatic TNBCs diagnosed between January 2015 and May 2017 and immunostained using AR441 (IgG1) mouse monoclonal antibody. Clinical follow-up ranged from 59 to 31 months and DFS was calculated. Cut-off scores were explored using Evaluate Cutpoints ( R maxstat package) and X-tile software. The score with maximum split in DFS (based on log-rank statistics and lowest p-value) was chosen as the cut-off. Descriptive and survival statistics was performed. Results: The median age was 51 (SD 11.262; range 28 to 82) years. Using Evaluate Cutpoints ≥3 was found as the threshold for AR by Allred Score. 36% cases were AR positive using Allred score (HR 0.508; CI 0.234 - 1.11; p-value 0.08). Using Evaluate Cutpoints ≥30 was found as the threshold for AR by H-Score (HR 0.624, CI 0.306 - 1.27; p-value 0.19). 35% cases were AR positive using H-Score. X-tile analysis also found the cut-offs as ≥3 and ≥30 for Allred and H-Score respectively (p < 0.05). A significant correlation was seen between the two scoring systems (Pearson Correlation 0.935; p < 0.01). A significantly higher number of grade III TNBCs were AR negative (n = 55/76) compared to grade II (n = 9/24) (p = 0.002). Cut-off for Ki67 was 75 (HR 1.61, CI 0.85-3.04, p-value 0.141) with a significantly higher number of AR negatives in the Ki67≥75 group (21/26; p < 0.05). The overall median DFS was 51.9 months. There was no significant difference in DFS for the AR negative (median: 47.4 months; mean: 39.39 months) and AR positive (Median survival not reached; mean: 41.3 months) groups(p = 0.23). Conclusions: AR immunohistochemistry cut-offs using the Allred (≥3) and H-Score (≥30) are close to the ones used for ER/PR immunohistochemistry as per ASCO/CAP guidelines, making a strong case for universal application of these systems for harmonization of AR data.
Clinical predictors of long-term response to capecitabine in metastatic breast cancer (MBC).
Authors: Kelly Deirdre , Lupichuk Sasha M. , Bedard Philippe L. , King Karen , Cescon David W. , Veitch Zachary William Neil 
Published: May 2020

1088 Background: Select patients (pts) with metastatic breast cancer (MBC) treated with capecitabine (cape) experience long-term disease control. We aimed to evaluate the clinical and biological predictors of long-term response. Methods: Pts receiving cape monotherapy for breast cancer from 01/2006 to 01/2016 at Princess Margaret Cancer Centre in Toronto, Canada (N = 352) or Alberta, Canada (N = 798) were identified through central pharmacy records. A median time-to-progression (MTTP) 3-fold higher (19.3 months) than those seen in published studies for patients treated with cape monotherapy at 1000mg/m2 was applied to select for pts with long-term response. MBC pts meeting these criteria were identified through chart review, with collection of clinical, pathological, and survival outcomes in addition to oncologist assessed (o) best response (eg: oCR, oPR, oSD) by radiology report review. Descriptive statistics, Kaplan-Meier and Cox-regressions were applied. Results: Overall, 41 (4%) pts met long-term response criteria. Median age of the study cohort was 62 (range 40-80), with 39% metastatic at diagnosis and 76% post-menopausal. At initiation of cape, a majority of pts were HR positive (85%), with an LDH < ULN (56%), and had bone (83%) or visceral (63%) metastases. Only 1 (2%) patient was HER2+. In the metastatic setting, most patients were chemotherapy-naive (83%) and had received 0-1 lines of hormonal therapy (61%). Median treatment duration with cape was 2.2 years (range 1.7-5.7) with 37% of pts having ≥40 cycles (range 22-94). Visceral (49%), bone (34%), and lymph nodes (24%) were the most common sites of progression, with 41% requiring 1 dose reduction and 27% requiring 2 dose reductions of cape. Overall response rate was 56% (oCR = 2%, oPR = 54%) with 44% having oSD as best response. Median follow-up was 6.8 years (95%CI: 5.5-8.2). Median PFS was 2.3 years (2.0-2.6), with a median OS of 3.8 years (2.9-4.6). 5 patients (12%) remained alive at data-cutoff, and 1 (2%) remained on treatment after 94 cycles of cape. Conclusions: Clinical features associated with long-term response on cape include HR positive, HER2 negative postmenopausal patients with bone predominant metastasis who have received 0-2 lines of prior hormone therapy and 0-1 lines of chemotherapy in the metastatic setting. This is the largest reported analysis of MBC patients with prolonged responses to cape. In the absence of randomized controlled trials; real-world evidence could aid clinicians in the optimal patient selection for treatment with cape.
Veliparib (V) monotherapy (monoTx) following combination therapy with V + carboplatin/paclitaxel (CP) in patients with gBRCA-associated advanced breast cancer: Exploratory results from BROCADE3.
Authors: Han Hyo S. , Arun Banu , Kaufman Bella , Wildiers Hans , Friedlander Michael , Ayoub Jean-Pierre M. , Puhalla Shannon L , Bach Bruce Allen , Dudley Matthew , Kundu Madan Gopal , Maag David , Ratajczak Christine , Dieras Veronique 
Published: May 2020

1091 Background: In BROCADE3 (NCT02163694), addition of PARP inhibitor V to CP resulted in improved progression-free survival (PFS) (HR 0.71 [95% CI 0.57−0.88], p=0.002) in patients (pts) with advanced HER2-negative breast cancer and g BRCA1/2 mutation. A subset of pts transitioned to V/placebo (PL) monoTx at an intensified dose/schedule after CP discontinuation prior to progression (investigator discretion). Here, we evaluate the impact of this transition on efficacy and safety. Methods: Pts were randomized 2:1 to CP with V (n=337) or PL (n=172). V (120 mg po BID) or PL was given on Days (D) −2 to 5, C (AUC 6) on D1, and P (80 mg/m2) on D1, 8, and 15 (21-day cycles). Pts who transitioned to monoTx received V/PL 300-400mg BID daily until progression. A Cox model with a time varying covariate indicating transition from V/PL with CP to V/PL monoTx was fit to estimate treatment effect during combination and monoTx phases. PFS by cycles of CP prior to monoTx and AEs during monoTx are summarized. Results: A subgroup of 136 (40%) and 58 (34%) pts on the V and PL arms, respectively, received monoTx. When a Cox model with a time-varying covariate was fit for PFS (per investigator), the nominal P-value for treatment by covariate interaction was 0.038. The HRs (95% CI) for V vs PL during combination therapy and monoTx were 0.81 (0.62–1.06) and 0.49 (0.33–0.73). The Table summarizes PFS by cycles of C and/or P prior to monoTx. Common AEs (>20% of pts) during V or PL monoTx were nausea (52%/10%), fatigue (23%/12%), headache (21%/17%), and diarrhea (21%/9%). Seizures (2.2%/0%) were reported during monoTx. Rates of cytopenias for V or PL monoTx were: anemia 12%/14%; neutropenia 13%/12%; and thrombocytopenia 10%/5%. Conclusions: These analyses suggest that pts treated with V + CP derive benefit from both combination therapy as well as V monoTx after CP discontinuation. Pts receiving V monoTx after ≤ 6 cycles of VCP experienced a similar benefit to those who transitioned to monoTx after 7–12 cycles of VCP, suggesting that V maintenance therapy may be suitable following a limited duration of combination therapy. Clinical trial information: NCT02163694 . [Table: see text]
Comparison of the cell-free DNA genomics in patients with metastatic breast cancer (MBC) who develop brain metastases versus those without brain metastases.
Authors: Vidula Neelima , Niemierko Andrzej , Hesler Katherine , Isakoff Steven J. , Juric Dejan , Spring Laura , Mulvey Therese Marie , Younger Jerry , Moy Beverly , Ellisen Leif W. , Bardia Aditya 
Published: May 2020

1094 Background: The genomics of patients with metastatic breast cancer (MBC) who develop brain metastases (BM) is not well understood given the difficulty in obtaining brain tumor for genotyping. We compared tumor genotyping results via cell-free DNA (cfDNA) collected at MBC diagnosis in patients who developed BM after MBC diagnosis with those who did not develop BM (non-BM). Methods: Patients at an academic institution who had cfDNA testing (Guardant 360/Next generation sequencing, 73 gene assay) at MBC diagnosis between 1/2016-12/2017, with ≥ 6 months of follow-up post testing, were identified. A chart review was done to identify tumor subtype, demographics, cfDNA results, and development of BM at or after MBC diagnosis. Pearson’s chi-squared and Wilcoxon rank sum tests were used to determine differences in clinical and cfDNA characteristics in BM vs. non-BM (p<0.05 for statistical significance). Results: CfDNA results were available for 49 patients, of whom 13 (27%) developed BM (4 with BM at MBC diagnosis). The median time to BM development was 11 months. While patients with BM were younger at MBC diagnosis than non-BM (median age BM 53 vs. non-BM 61, p=0.05), they had similar subtype (BM vs. non-BM: HR+/HER2- 62% vs. 69%, HER2+ 8% vs. 14%, TNBC 23% vs. 17%, unknown 8% vs. 0%, p=0.3), de-novo vs. recurrent disease (BM vs. non-BM: de-novo 8% vs. 14%, recurrent 92% vs. 86%, p=0.6), and visceral disease (BM vs. non-BM: 77% vs. 56%, p=0.2) distributions. All patients with BM had ≥1 detectable cfDNA mutation vs. 88% of non-BM. While the median mutant allele frequency of the most common mutation was similar in BM vs. non-BM (2.4% vs. 3.7%, p=0.5), the mutation pattern varied. Patients with BM more often had mutations in BRCA1 (15% vs. 3%, p=0.1), APC (15% vs. 0%, p=0.02), and CDKN2A (15% vs. 0%, p=0.02), compared to non-BM. In 4 patients with BM at MBC diagnosis, mutations in APC (50%), CDKN2A (50%), and BRCA 1/2 (25%) were noted; 1 had coexisting APC and BRCA1/2 mutations and another had coexisting APC and CDKN2A mutations. Conclusions: Patients with MBC who develop BM may have different cfDNA genomics, particularly BRCA1, APC, and CDKN2A mutations. Further research is needed to determine the predictive value of cfDNA at MBC diagnosis in the identification of patients at higher risk of developing BM. [Table: see text]