bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic risk prediction of aromatase inhibitor-related arthralgias (AIA) in breast cancer (BC) patients using a novel analytical algorithm (NAA).
Authors: Reinbolt Raquel E. , Sonis Stephen T. , Timmers Cynthia Dawn , Fernández-Martínez Juan Luis , deAndrés-Galiana Enrique J. , Hashemi Sepehr , Miller Karin , Ramaswamy Bhuvaneswari , Wesolowski Robert , Noonan Anne M. , Dewani Shabana Jaynul , Williams Nicole Olivia , Sardesai Sagar D. , Pilarski Robert , Lustberg Maryam B. 
Published: September 2018

10102 Background: Many BC patients treated with aromatase inhibitors (AIs) develop AIA; 20% have symptoms severe enough to effect treatment compliance. Results of candidate gene studies to identify AIA risk are limited in scope. In this case-controlled study, we evaluated the potential of a NAA to predict AIA using germline single nucleotide polymorphism (SNP) data obtained prior to treatment initiation. Methods: Systematic chart review of 700 AI-treated patients with stage I-III BC between 2003-2012 identified asymptomatic patients (n = 39) and those with clinically significant AIA resulting in AI termination or therapy switch (n = 123). Germline DNA was obtained from peripheral blood cells and SNP genotyping performed using the Affymetrix UK BioBank Axiom Array to yield 695,277 SNPs. The identity of the cluster of SNPs that most closely defined AIA risk was discovered using an NAA that sequentially combined statistical filtering and a machine learning algorithm. NCBI PhenGenI and Ensemble databases were used to define gene attribution of the 200 most discriminating SNPs. Phenotype, pathway, and ontologic analyses assessed functional and mechanistic validity. Results: Cases and controls were similar in demographic characteristics. A cluster of 70 SNPs, correlated to 57 genes (accounting for linkage disequilibrium), was identified. This SNP group predicted AIA occurrence with a maximum accuracy of 75.93%. Strong associations with arthralgia, breast cancer, and estrogen phenotypes were seen in 19/57 genes (33%) and were functionally and ontologically consistent. Conclusions: Using a NAA, we identified a 70 SNP cluster that predicted AIA risk with fair accuracy. Phenotype, functional, and pathway analysis of attributed genes was consistent with clinical phenotypes. This study is the first to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias. An ongoing prospective companion study will be used to validate and to expand upon results.
A prospective randomized controlled trial of hydrating nail solution for prevention or treatment of onycholysis in breast cancer patients who received neoadjuvant/adjuvant docetaxel chemotherapy.
Authors: Kim Ji-Yeon , Ok Oh-Nam , Seo Jeong Ju , Lee Soo-Hyeon , Ahn Jin Seok , Park Yeon Hee 
Published: September 2018

10108 Background: Onycholysis and other nail toxicities occur in approximately 20-30% of breast cancer(BC) patients receiving docetaxel(D) chemotherapy. Onycholysis, the separation of the nail plate from nail bed, is also often associated with painful paronychia decreasing patients’ the efficacy of a hydrating nail solution (EVONAIL solution, Evaux Laboratories, France) for the prevention and treatment of D-induced onycholysis and nail toxicities. Methods: This study is a prospective randomized controlled study of hydrating nail solution for prevention or treatment of onycholysis in patients with BC receiving neo/adjuvant 3-weekly D after doxorubicin plus cyclophosphamide. In experimental arm, each patient painted hydrating nail solution on nails and periungual areas once a day till developing onycholysis grade 2 or more. After Gr 2 onycholysis development, patients painted EVONAIL twice a day regardless of treatment arms. The primary endpoint is the incidence of onycholysis Gr 2 or more and recovery rate from Gr2 onycholysis. The secondary endpoints include: the incidence of all grade onycholysis; duration from first docetaxel treatment until onycholysis symptom appearance; degree of pain from nail toxicities; the incidence of other nail toxicities. Results: Since Aug 2015 to May 2016, 103 patients were enrolled and completed this study (Experimental arm(E) : 51, control arm(C): 52). Of 103 patients, 25 cases of Gr1 and 22 of Gr2 onycholysis were observed (Gr1 and 2(n,(%)) : 8(15.7%) and 7(13.7%) in E, 17(32.7%) and 15(21.4%)in C, respectively). Hydrating nail solution resulted in statistically significant reduction of Gr2 onycholysis compared to C (HR = 0.39, 95% CI 0.16, 0.96; P = 0.041) and all grade onycholysis decreased in experimental arm with statistical significance (HR = 0.37, 95% CI 0.20-0.69, P = 0.002). However, the effect of onycholysis treatment was not observed. Conclusions: Hydrating nail solution significantly reduced the incidence of D induced onycholysis in BC patients (NCT02670603). Clinical trial information: NCT02670603.
Chemotherapy induced nausea and vomiting in breast cancer treated with antiemetic prophylaxis as recommended by the ASCO antiemesis guidelines.
Authors: Copher Ronda , Knoth Russell L. , Magee Glenn , Misir Soamnauth , McBride Ali 
Published: September 2018

10109 Background: Current ASCO Antiemesis Guidelines recommend triple antiemetic therapy (a 5HT3RA, an NK1, and dexamethasone) to prevent chemotherapy (CT) induced nausea and vomiting (CINV) in patients undergoing highly emetogenic chemotherapy (HEC). This study evaluated whether this regimen resulted in reduced rates of CINV in patients diagnosed with breast cancer (BC) and initiated on HEC. The primary outcomes of interest were rates of acute and delayed CINV in patients whose antiemesis prophylaxis was or was not in accordance with the ASCO guideline (i.e., Per-guideline vs. Non-Guideline). Costs of treating CINV were also calculated. Methods: Patients were identified in the Premier Healthcare database, a complete geographically diverse census of inpatients and hospital-based outpatients. Adults treated for BC with HEC during the years 2012-14 were identified and stratified based on their antiemesis prophylaxis. Rates of acute (day of CT) and delayed CINV (days 2-7 post CT) were calculated following initiation of HEC. CINV was defined by ICD9 codes for nausea and vomiting or volume depletion/dehydration or use of a rescue antiemetic. Rates of CINV and health care costs were then compared between the two cohorts. Results: A total of 8,388 patients were included in the analysis. Of these, 5,447 (65%) had treatment Per-Guideline and 2,941 (35%) were Non-Guideline. For acute CINV, Per-Guideline patients had a significantly lower rate of CINV when compared to Non-Guideline patients (1.7% vs. 3.2%, respectively, p < .001). Similarly, in delayed CINV Per-Guideline patients had significantly lower rates of CINV when compared to Non-Guideline patients (15.4% vs. 19.1%, p < .001). Patients who experienced CINV also had significantly greater total health care costs versus those without CINV ($32,199 vs. $20,163, respectively, p < .001). Conclusions: The results showed adherence to the ASCO Antiemesis Guidelines led to lower rates of CINV and lower costs. Although defining CINV by claims may tell an incomplete story, this study suggests that following the ASCO Antiemesis Guidelines may help both patients and payers of health care costs.
Trastuzumab-related subclinical cardiotoxicity in patients with early stage HER2-positive breast cancer: A retrospective single-center cohort study.
Authors: Aseyev Olexiy , Rushton-Marovac Moira , Crawley Freya L. , Johnson Christopher , Dent Susan Faye 
Published: September 2018

10123 Background: Trastuzumab-based therapy (TT) is standard treatment for HER2-positive breast cancer (HBC). Subclinical cardiotoxicity (SCTx), defined as asymptomatic decline in left ventricular ejection fraction (LVEF) > 10% to < 50%, has been reported in up to 30 % of HBC patients (pts) receiving TT. Objectives included: determine prevalence of SCTx; associated risk factors (RF); and completion rates of TT in pts with HBC referred to a cardio-oncology clinic (COC). Methods: HBC patients receiving TT referred to the Ottawa Hospital COC were included. Demographics, TNM staging, performance status, stage, cardio-vascular (CV) RF (history of heart disease, hypertension, smoking, dyslipidemia, and diabetes), cardiac medications (CM) (ACE-inhibitors, beta-blockers), baseline LVEF, previous cancer therapy, baseline anthracycline exposure, previous radiation therapy (RT) (including mediastinal RT) were collected. LVEF was evaluated by ECHO or MUGA. Rate of successful completion of TT among pts with SCTx was determined. Risk ratio (RR) and logistic regression analysis was performed. Results: 240/408 BC pts referred to the COC (2008-2016) had HBC and 163/240 (68%) were referred with SCTx while on TT. 139/163 (85 %) pts with SCTx recovered after COC assessment: 77/163 (47%) pts were prescribed CMs. A significantly higher proportion of recovery was observed in pts who did not require CM (0.92 vs 0.78, p = 0.012; RR = 0.85, 95%CI:0.74-0.91). A total of 129/163 (79%) pts who experienced SCTx finished a full course of TT. Regression analysis found baseline LVEF, diabetes, and diastolic blood pressure as significant RFs for SCTx. There were no independent predictors for recovery after asymptomatic drop in LVEF while on TT. Diabetes (OR:2.97, 95%CI:1.3-6.8) and left chest wall RT (OR:2.4, 95%CI:1.1-5.6) significantly increased risk of permanent TT interruption in pts with asymptomatic drop in LVEF. Conclusions: The majority of HBC pts who experience SCTx can safely complete a full course of TT; many without use of CMs. While CV RFs were associated with increased risk of SCTx, this did not impact CV recovery after asymptomatic drops in LVEF.
Circulating PD-L1 (programmed death-ligand 1) and outcomes in a HER2-positive metastatic breast cancer cohort treated with first-line trastuzumab.
Authors: Ali Ayesha , Krecko Laura , Leitzel Kim , Ali Suhail M. , Drabick Joseph J. , Halstead E Scott , Nagabhairu Vinod , Marks Eric , Polimera Hyma Vani , Richardson Angelique Ellerbee , Evans Robert , Spiegel Howard , Köstler Wolfgang , Esteva Francisco J. , Lipton Allan 
Published: September 2018

1024 Background: Recently the immune checkpoint inhibitors (ICIs) have demonstrated efficacy across a wide variety of cancers, but have been less effective in breast cancer. PD-L1 (B7-H1, CD274) is a ligand produced by many tumor cells and some immune cells, and suppresses the T cell immune response. This allows tumor cells to escape immune detection. PD-L1 is used as a companion tumor tissue IHC biomarker for patient selection for some of the FDA-approved ICIs (pembrolizumab), but not for others (nivolumab, atezolizumab). Circulating PD-L1 has been detected in multiple myeloma, renal, lung, and gastric cancer, but not in breast cancer. Here we correlated serum PD-L1 levels with outcome in a HER2-positive metastatic breast cancer cohort treated with trastuzumab. Methods: Pretreatment serum was obtained from 63 metastatic breast cancer patients before starting first-line trastuzumab-containing therapy. A novel ELLA microfluidic channel immunoassay platform (ProteinSimple, San Jose, CA) was employed to quantitate serum PD-L1. Serum PD-L1 levels were analyzed using continuous, quartile, and dichotomous (25%, median, and 75%) cutpoints. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Results: On a continuous basis, patients with higher serum PD-L1 had a significantly reduced PFS (p = 0.045) and overall survival OS (p = 0.004) compared to patients with lower serum PD-L1 levels. Patients with the higher quartiles of serum PD-L1 also trended to have reduced PFS (0.11) and significantly reduced OS (p = 0.015) compared to the lower quartiles of serum PD-L1. Finally, using either the 25th or 75th percentile of serum PD-L1 as dichotomous cutpoint, patients with higher serum PD-L1 had significantly reduced OS (p = 0.04). Conclusions: Higher circulating PD-L1 levels were prognostic for reduced PFS and OS in HER2-positive metastatic breast cancer patients treated with first-line trastuzumab. Circulating PD-L1 deserves further study for prognostic and predictive biomarker utility in larger trials of immune checkpoint inhibitors and other immunotherapies in breast and other cancers. AA, LK contributed equally.
TBCRC 036: Window of opportunity clinical trial reveals adaptive kinome reprogramming in single and combination HER2-targeting in breast cancer (BrCa).
Authors: Angus Steven P , Stuhlmiller Timothy , Sciaky Noah , Chen Xin , Naim Rashid , Tanioka Maki , Gallagher Kristalyn K. , Forero Andres , Krop Ian E. , Thompson Alastair Mark , Murthy Rashmi Krishna , He Xiaping , Perou Charles M. , Earp Shelton , Carey Lisa A. , Johnson Gary L. 
Published: September 2018

1027 Background: HER2 targeting is challenging due to heterogeneity in response and resistance. Adaptive kinome reprogramming (AKRP) is a resistance mechanism to kinase-targeted therapy (Rx) in TNBC ( Cancer Discovery2017). We studied AKRP in HER2+ BrCa by comparing transcriptome and kinome profiles before and after Rx with FDA-approved anti-HER2 drugs and combinations: trastuzumab (T), pertuzumab (P), T+P, or T+ lapatinib (T+L). Profiling was by RNA sequencing (RNAseq) and multiplexed inhibitor beads coupled with mass spectrometry (MIB/MS). MIB affinity-purification selectively enriches the functional kinome ( > 250 kinases per sample) for identification/quantification by MS. Methods: Eligible patients (pts) had biopsy then randomization to: T (8 mg/kg iv), P (840 mg iv), T+P (same doses), or T+L (8mg/kg iv x1, 1000 mg po/d) 7 days before breast surgery. RNAseq and MIB/MS on paired pre- and post-Rx samples were analyzed using DESeq2 (comparison of mean difference in log2fold change (post/pre)) and MaxQuant (kinome response profiling) software. Results: Of 23 evaluable pts, we obtained informative paired RNAseq data in 13 (5 T, 3 P, 3 T+P, 2 T+L), and identified distinct expression responses (padj≤0.05) between Rx arms, such as FGFR4 increase in P vs T or T+P. All samples had HER2 enrichment by RNAseq. Kinome response profiling from 11 pts (3 T, 3 P, 4 T+P, 2 T+L) revealed consistent increases in MIB binding (abundance a/o activity) of several tyrosine kinases regardless of Rx, including immune-related kinases SYK, IRAK4, FGR, and FES. Other kinases, such as p90Rsk and GSK3B, exhibited increased binding in response to T and T+P, but not P alone. While not quantifiable in every sample due to detection limits, HER2 inhibition was observed by loss of MIB binding in select post-Rx versus pre-Rx comparisons. Conclusions: HER2 inhibition upregulates and activates specific receptor tyrosine kinases in tumor cells as well as alterations that may reflect changes in the immune compartment. HER2+ BrCa exhibit plasticity, characterized by distinct expression and kinome profile changes within 1 week of initiating Rx, and reprogramming in both immune responses and BrCa cells. Clinical trial information: NCT01875666.
Survival by HER2 receptor status in stage IV breast cancer: SEER 2010-2012.
Authors: Thomas Alexandra , Khan Seema Ahsan , Lynch Charles , Schroeder Mary Chen 
Published: September 2018

1032 Background: Therapeutic advances have altered the course of once highly lethal HER2+ breast cancer (BC). We report survival in a recent population-based cohort by HER2 status, overall, and within hormone receptor(HR)+ BC. Methods: Surveillance, Epidemiology, and End Results Program data were queried to identify women diagnosed 2010-2012 with Stage IV BC as first cancer. Patients were grouped by HER2 and HR status. Kaplan Meier estimates of 3-yr observed survival (OS) were compared with log-rank tests. A multivariate cox model was fitted for the HER2+ cohort. Results: 3-yr OS for HER2+(any HR), HR+/HER- and triple-negative (TN) BC was 52.3%, 48.4% and 16.0% respectively (p<0.01 HER2+(any HR) vs TNBC; p=0.20 HER2+(any HR) vs HR+/HER2-). Across registries, OS for HER2+(any HR) BC ranged from 29.2% to 61.7% (p=0.05). On Cox model, survival in HER2+(any HR) BC was associated with age 50+ (Hazard ratio (HR) 1.84, 95% CI 1.45-2.34), HR+ status (HR 0.70, 0.58-0.84), high histologic grade (HR 1.30, 0.58-0.84), surgery (HR 0.40, 0.33-0.49), separated marital status (HR 1.72, 1.4-2.13), year 2012 (HR 0.81, 0.64-1.04), and registry (varies by reference group). For HR+ BC, OS also differed by HER2 status: 55.3% for HR+/HER+ and 48.4% for HR+/HER2- (p<0.01). 3-yr OS by HER2 status for women presenting with HR+ BC is shown (Table). Conclusions: Survival in de novo Stage IV HER2+ BC in the United States exceeds that in HER2- BC, with median survival >3 yrs. Survival was significantly better for HR+/HER+ BC than HR+/HER- BC. Disparate OS in HER2+ BC suggest opportunities may remain to fully realize advances in HER2-directed therapy. Given recent therapeutic advances, the trend of HER2+ survival gains from 2010 to 2012 will likely continue. [Table: see text]
Assessment of ESR1 and ERBB2 mutations in estrogen receptor positive (ER+) metastatic breast cancers (MBC).
Authors: Basu Gargi D. , White Tracey , LoBello Janine R , Kurdoglu Ahmet , Trent Jeffrey M. , Halbert Matthew J , Royce Thomas , O'Shaughnessy Joyce 
Published: September 2018

1040 Background: Mutations (mut) in ESR1 have been reported in ER+ breast cancers (BC) as an acquired resistance mut to aromatase inhibitor (AI) therapy. Acquired ERBB2 mut have also been reported in MBC patients (pts) that cause activated ERBB2 signaling. The emergence of acquired secondary mut presents challenges in effective treatment approaches. Methods: Comprehensive genomic profiling was performed on 83 BC samples with 48 metastatic; 34 primary samples. Targeted next-generation sequencing was performed on 562 cancer associated genes in paired tumor and blood DNA (germline) samples. Results: ESR1-mut were found in 23%(11/48) of ER+ MBC tissues with no mut detected in primary ER+ BCs. Mutations-D538G, Y537S and E380Q in the ligand binding domain of ER were the most common alterations, found in 54.5%, 18% and 18% of ESR1 mut samples, respectively. An ER+ HER2- liver biopsy obtained after 20 mos on AI + everolimus had ESR1-D538G and TSC2 structural event. Protein array showed high expression of androgen receptor (AR) and p-AR and activation of ERBB1/2/3, p-SRC and p-4EBP1 in this sample. Further, a functionally uncharacterized ESR1 mut was found in ER+, HER2+ and a triple negative MBC tissue (the primary BC had been ER+). Mut in PI3K pathway (PIK3CA, ARID1A, TSC1/2, PTEN) were present in 8/11 samples with ESR1 mut. Activating mut in ERBB2 were found in 3/83 samples; all 3 were in ER+ MBC samples with one case harboring mut in both ERBB2 and ESR1 (E380Q – uncertain degree of constitutive activity). Interestingly, a BC sample with ER+ HER2- liver met harbored both ERBB2 (V777L) and ERBB3 (E928G) mut; this pt responded well to trastuzumab/pertuzumab (HP) therapy. A pt with ER+ HER2-ERBB2- L755S mut met to gallbladder found after 7 mos on letrozole/palbociclib therapy responded well to HP and T-DM1 therapy. All 3 ERBB2-mut cancers had a CDH1 frameshift mut suggesting enrichment in pretreated lobular MBCs (Ross J. CCR, 2013). Conclusions: This study shows a 23% and 6% ESR1 and ERBB2 mut rate in MBC samples. No ESR1 and ERBB2 mut were present in primary BC samples. Our findings suggest that pts with lobular MBC should be monitored for acquired ERBB2 mut, and that ERBB2 mut may not arise in BCs which harbor known constitutively active ESR1 mut.
Efficacy and safety in elderly patient subsets across studies investigating endocrine monotherapy versus combination therapy in patients with HR+/HER2−advanced breast cancer.
Authors: Freedman Rachel A. , Tolaney Sara M. 
Published: September 2018

1045 Background: Combination of endocrine therapy and targeted agents in 1st and 2nd-line therapy prolong progression-free survival (PFS) in patients with hormone receptor–positive (HR+), HER2 − advanced breast cancer (ABC). However, a greater risk of adverse events (AEs) and a greater possibility of drug-drug interaction, associated with combination therapy, present challenges in older patients. Methods: This study reviewed PFS and safety data in age-stratified subsets from Phase II or III clinical trials comparing endocrine monotherapy vs combinations of endocrine or targeted therapy in patients with HR+, HER2−ABC. Results: Among 9 identified studies, combination therapy that included ribociclib, palbociclib, and everolimus significantly reduced risk of disease progression vs monotherapy in older and younger patient subsets (Table). For combination therapy that included ribociclib or palbociclib, frequency of discontinuations due to AEs was similar between the subsets; more frequent discontinuations due to AEs were noted in the ≥70-year subset with everolimus. Conclusions: Combination endocrine therapies involving CDK4/6 or mTOR inhibitors have similar efficacy but vary in tolerability among older and younger patients with HR+, HER2− ABC. [Table: see text]
Characteristics of disease activity able to identify risk categories and probability to respond to first-line endocrine therapy (ET) in HR+ve/HER2-ve metastatic breast cancer (MBC) patients (pts): Dream or reality? Evaluation of a composite risk score in a subgroup population of the GIM 13-AMBRA study.
Authors: Mustacchi Giorgio , Cazzaniga Marina Elena , Giordano Monica , Garrone Ornella , Beano Alessandra , Del Mastro Lucia , Livi Lorenzo , Iezzi Laura , Michelotti Andrea , Turletti Anna , Riccardi Ferdinando , De Laurentiis Michele , Marchetti Paolo , Biganzoli Laura , Montemurro Filippo , Romagnoli Emanuela , De Placido Sabino , Pronzato Paolo ,   On Behalf of GIM 13-AMBRA Study Group
Published: September 2018

1049 Background: The appropriate choice of 1st-line therapy in HR+ve/HER2-ve MBC pts is becoming more complicated since the data of front-line Fulvestrant and CDK 4/6 Inhibitors have been released. In the absence of predictive biomarkers of tumor response, one possible option is the recently proposed “composite score” (Schmid, ESMO 2016), composed by visceral tumor burden (VTB) and Disease-Free-Interval (DFI) to identify risk categories and the probability of response to ET or chemotherapy (CHT). Aim of the present analysis is to describe the choices of 1st-line treatment and the response rate, according to the mentioned score in a population of HR+/HER2-ve MBC. Methods: We used data of the HR+ve pts of the AMBRA study, a longitudinal cohort study, describing the choice of first and subsequent lines of treatment in HER2-ve MBC pts (SABCS 2016 P5-15-07 & P5-14-09). Using median DFI and VTB three categories of risk have been identified: Low (DFI > 24 months & VTB-), Intermediate (DFI £ 24 months & VTB- or DFI > 24 months & VTB+) and High (DFI £ 24 months & VTB+). This analysis describes the choices of 1st-line therapy and relative response rate according to these risk categories. Results: So far, 791/1500 pts have been registered into the AMBRA study, 673 of them (85%) with HR+ MBC and 659 (83.3%) are evaluable for this analysis. Risk categories and response to therapy are detailed in the table below. Conclusions: No conclusion can be done regarding the “High Risk” group because of the low number of pts treated with ET alone. Regarding the “Low” and “Intermediate” risk categories, we can conclude that the proposed “composite risk score” doesn’t seem to discriminate MBC patients who could be treated with ET alone or with a more aggressive treatment, at least in terms of response rate. [Table: see text]