bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of T- and B-cell receptor repertoires with molecular subtypes and outcome in HER2+ breast cancer: An analysis of the NeoALTTO clinical trial.
Authors: Rediti Mattia , Venet David , Rothe Francoise , Qing Tao , Maetens Marion , Bradbury Ian , Izquierdo Miguel A. , Di Cosimo Serena , Hilbers Florentine , Bajji Mohammed , Harbeck Nadia , Untch Michael , Liu Minetta C. , Saura Cristina , Huober Jens Bodo , Nuciforo Paolo , Salgado Roberto , Loi Sherene , Pusztai Lajos , Sotiriou Christos 
Published: May 2020

511 Background: Clinicopathological and molecular features, including estrogen receptor (ER) status and PAM50 subtypes, have shown an association with immunogenicity and tumor-infiltrating lymphocyte (TIL) levels in breast cancer (BC). To investigate the complexity of the immune response in HER2+ BC, we explored the association of T- and B-cell receptor (TCR and BCR) repertoires with clinicopathological characteristics, PAM50 subtypes and outcome in the NeoALTTO phase III trial. Methods: RNA sequencing (RNAseq) data from baseline tumor biopsies were available for 254 out of the 455 patients enrolled. TCR and BCR repertoires were extracted from RNAseq data using the MiXCR software. Repertoire and diversity measures (read counts, number of clones, evenness, Gini index, Shannon entropy, length of the complementarity-determining region 3 [CDR3], top and second top clone proportions) were estimated. PAM50 subtypes were computed from RNAseq data. Univariate and multivariate (adjusted for clinicopathological characteristics, TIL levels dichotomized using the median value of 12.5% and treatment arm) Cox proportional hazard models were used for survival analysis, while logistic regressions were used for pathological complete response (pCR), defined as ypT0/is. All results reported had a false discovery rate (FDR) <0.05. Results: Higher BCR read counts, number of clones and Gini index were significantly associated with ER-negative as well as grade 3 tumors. Among the PAM50 subtypes, HER2-enriched (HER2-E) showed significantly higher BCR read counts, number of clones and Gini index along with lower evenness compared to luminal A and B, as well as higher length of CDR3 than luminal A. Of note, basal-like showed similar BCR diversity measures to HER2-E. No significant differences were noted for TCR diversity measures. In multivariate analyses, neither TCR nor BCR features were associated with pCR, while BCR evenness (HR 1.5; 95%CI 1.1-2.1) and Gini index (HR 0.66; 95%CI 0.5-0.88) were associated with event-free survival. Conclusions: BCR repertoire measures suggest a clonal expansion in HER2-E and basal-like PAM50 subtypes. Furthermore, the implementation of BCR-derived biomarkers can help to identify patients with an improved clinical outcome after neoadjuvant anti-HER2 treatment. Our findings highlight the heterogeneity of the immune response within HER2+ BC and provide support for biomarker-driven treatment strategies including immunotherapy in this BC subtype. Further validation is required. Clinical trial information: NCT00553358 .
Value of clinical treatment score post-5 years (CTS5) for late relapse risk assessment in patients with early-stage HER2+ breast cancer (BC) in the north central cancer treatment group (NCCTG) N9831 (Alliance) trial.
Authors: Pai Tanmayi , Gil Angelica , Ma Yaohua , Li Zhuo , Advani Pooja , Moreno-Aspitia Alvaro , Colon-Otero Gerardo , Perez Edith A. , Thompson E Aubrey , Chumsri Saranya 
Published: May 2020

529 Background: Multiple prognostic models exist to predict late relapse risk in early stage hormone receptor-positive (HR+) breast cancer (BC). The CTS5 is one such model that has been validated in HR+ HER2-negative BC. The value of this model in HR+ HER2+ has not been established. Here, we assessed CTS5 in patients (pts) with early stage HER2+ BC treated in the NCCTG N9831 (Alliance) trial. Methods: Pts with stage I-III HER2+ HR+ BC who survived ≥ 5 years were included. The online CTS5 calculator was used to determine CTS5 score and risk group (low, intermediate, and high) based on age, tumor size, grade, and number of involved nodes. Kaplan-Meier (KM) estimates, Cox regression models, and C index were used for analysis. Results: From 3,130 pts, 1,204 pts met the criteria and were included. Median age was 49 (22-79) years and median tumor size was 2.4 (0.1-12) cm. 63.6% had grade 3 tumors, 33.6% grade 2, and 2.8% grade 1. Median follow up was 10.89 (5.01-15.32) years. Based on CTS5, 821 (68.2%) pts were classified as high risk, 289 (24%) as intermediate risk, and 94 (7.8%) as low risk. Overall, using univariate Cox regression analysis, there was no statistically significant difference in recurrence free survival (RFS) among pts with intermediate vs. low (HR 0.47 95%CI 0.18-1.22, p = 0.12) and high vs. low (HR1.23 95%CI0.57-2.67, p = 0.6) with the C index of 0.58. Among pts who received concurrent trastuzumab (H) with HR+ BC, there was also no statistical difference in RFS between high vs. low (HR 0.68 95%CI0.24-1.97, p = 0.48) with the C index of 0.55. Paradoxically, pts with intermediate risk had better RFS than low risk (HR 0.18 95%CI0.03-0.97, p = 0.05). As a continuous variable, there is also no significant improvement in RFS per 1 unit increase in CTS5 score (HR 1.19 95%CI 0.73-1.96, p = 0.49) with the C index of 0.54. After 5 years, 7.06% (n = 30/425) of HR+ pts treated with concurrent H recurred. Conclusions: The CTS5 model is not prognostic in pts with early stage HR+ HER2+ BC receiving adjuvant H. While most HR+ HER2+ pts are classified as high risk by CTS5, the recurrence between years 5-10 was low in pts who received adjuvant H. This study highlights the need to develop a new predictive model for risk of late relapse in this specific group of pts to enable clinicians to determine which pts would benefit from extended adjuvant endocrine therapy. Support: BCRF-19-161, U10CA180821, Genentech. https://acknowledgments.alliancefound.org Clinical trial information: NCT00005970 .
Phase II study of adjuvant endocrine therapy with CDK 4/6 inhibitor, ribociclib, for localized ER+/HER2- breast cancer (LEADER).
Authors: Spring Laura , Griffin Colleen , Isakoff Steven J. , Moy Beverly , Wander Seth Andrew , Shin Jennifer , Abraham Elizabeth , Habin Karleen , Patel Jaymin M. , Comander Amy H. , Mulvey Therese Marie , Bardia Aditya 
Published: May 2020

531 Background: Given the success of CDK 4/6 inhibitors for ER+/HER2- metastatic breast cancer, there is much interest in exploring these agents in early breast cancer to potentially reduce recurrence risk. However, tolerability and adherence are important considerations in the adjuvant setting. We evaluated the tolerability and adherence of adjuvant endocrine therapy with the CDK 4/6 inhibitor, ribociclib, in two different schedules, in a prospective phase II clinical trial. Methods: Eligible patients were those with localized stage I-III ER+ (≥ 10%), HER2- breast cancer who had completed surgery and were on adjuvant endocrine therapy with at least one year or more of treatment remaining. Patients were randomized to receive continuous ribociclib (400 mg daily of 28-day cycle; arm 1) or intermittent ribociclib (600 mg daily on days 1-21 of 28-day cycle; arm 2) for one year, in addition to an aromatase inhibitor (plus GnRH agonist if premenopausal). Toxicities were evaluated using CTCAE version 4.03. Adherence was monitored by review of patient diaries and pill count. Results: Of the 81 patients enrolled, 24 discontinued early. The table shows the current status of the patients based on treatment arm (data cut-off as of 1/31/20; updated results will be presented at meeting). A total of 8 serious adverse events (AEs) have occurred thus far: grade 3 transaminitis (1), grade 4 transaminitis (3), grade 3 colitis (1), grade 3 infection (2), and grade 4 lymphopenia (1). The most common grade 3 or greater AEs leading to study discontinuation thus far were transaminitis (8.6%), neutropenia (2.5%), and fatigue (2.5%). No patients discontinued early due to prolonged QTc. Adherence results will be reported at the meeting. Conclusions: Interim results demonstrate that while serious AEs with one year of adjuvant ribociclib are low, a number of patients discontinued adjuvant CDK 4/6 inhibitor. Tolerability and adherence patterns will need to be carefully considered with CDK 4/6 inhibitors in the adjuvant setting. Clinical trial information: NCT03285412 . [Table: see text]
Real-world analysis of clinical and economic impact of 21-gene recurrence score (RS) testing in early-stage breast cancer (ESBC) in Ireland.
Authors: McSorley Lynda M , Al Rahbi Fathiya , Tharmabala Mehala , Evoy Denis , Geraghty James G. , Prichard Ruth , Rothwell Jane , McCartan Damian , McDermott Enda , Keane Maccon M. , Kennedy John , O'Reilly Seamus , Millen Steve , Crown John , Smyth Lillian Mary , Kelly Catherine Margaret , Quinn Cecily , Walshe Janice Maria 
Published: May 2020

540 Background: Treatment of hormone receptor positive (HR+) ESBC is evolving. The use of chemotherapy (CT) is declining with use of the 21-gene RS assay. This validated tool predicts the likelihood of adjuvant CT benefit in HR+ ESBC. Results from the TAILOR-x study suggest up to 70% of HR+ node negative ESBC patients (pts) may avoid CT with RS ≤25. Our objectives were to assess the clinical and economic impact of RS testing on treatment decisions using real-world data. Methods: From October 2011 to February 2019, a retrospective, cross-sectional observational study was conducted of HR+ node negative ESBC pts who had RS testing in Ireland. A survey of Irish breast medical oncologists provided the assumption for the decision impact analysis that grade (G) 1 pts would not receive CT pre RS testing and G2/3 pts would receive CT. Using TAILOR-x results, pts were classified low risk (RS ≤ 25) and high risk (RS > 25). Data was collected via electronic patient records. Descriptive statistics were used. Cost data was obtained via the National Healthcare Pricing Regulatory Authority. The economic analysis was adjusted for changing treatment and assay costs over the study period. Results: 963pts were identified. Mean age 56 years. Mean tumour size 1.87cm. 114 (11.8%), 636(66%), 211(22%), 2(0.2%) pts had G1, G2, G3 and unknown G respectively (resp). 797pts (82.8%) had low RS, 159 (16.5%) had high RS, and 7pts(0.7%) unknown RS. 251pts(26%) were aged < 51 at diagnosis. Of these, 45(17.9%), 145(57.8%), 58(23%), 3(1.2) had G1, G2, G3 and unknown G resp. 208pts(82.9%) had RS ≤ 25, 39pts(15.5%) had RS > 25 and 4pts(1.6%) unknown RS. In the RS ≤ 25 group, 111pts(44%) had RS 0-15, 59(23.5%) had RS16-20, and 38(15.1%) had RS21-25. Post RS testing 595pts(61.8%) had a change in CT decision; 586 changed to hormone therapy (HT) alone, and 9 from HT to CT. In total, 227pts(23.5%) received CT, and 3pts(0.3%) declined. Of pts treated with CT; 9(4%) had RS 0-15, 89(39.2%) had RS16-25, 129(56.8%) had RS > 25. The most common CT regimen was docetaxel and cyclophosphamide(TC), administered to 121pts(53%). RS assay use achieved a 69% change in treatment decision among G2/3 pts and a net 61% reduction in CT use. This resulted in savings of over €4 million in treatment costs. Deducting the assay cost, net savings of over one million euro was achieved. Conclusions: Ireland was the first public healthcare system to approve reimbursement for RS testing. Over the 8 year period of the study, a net 61% reduction in CT use in Irish pts with HR+ ESBC was achieved with conservative net savings of over €1,000,000.
The comprehensive methylation landscape of metastatic castration-resistant prostate cancer (mCRPC) identifies new phenotypic subtypes: Results from the West Coast Prostate Cancer Dream Team (WCDT).
Authors: Small Eric Jay , Zhao Shuang , Chen William S. , Li Haolong , Foye Adam , Sjöström Martin , Hua Jun Jie , Aggarwal Rahul Raj , Alumkal Joshi J. , Beer Tomasz M. , Gleave Martin , Rettig Matthew , Witte Owen , Lara Primo , Chinnaiyan Arul , Maher Chris , Quigley David A. , Feng Felix Y 
Published: May 2020

5507 Background: While recent studies have delineated the genomic landscape of mCRPC, its epigenomic landscape has not been as well characterized. The goal of this study was to define the comprehensive methylation landscape of mCRPC. Methods: mCRPC patients (pts) underwent a metastasis biopsy as part of a multi-institutional study (NCT02432001). Deep whole-genome bisulfite sequencing (mean depth 46x) was performed on fresh frozen tissue from 100 mCRPC patients; data was paired with deep whole-genome and transcriptome sequencing from the same samples. Unbiased hierarchical clustering of the mCRPC methylome was undertaken, and the survival of patients in each cluster was calculated using the Kaplan Meier method. Results: Unbiased hierarchical clustering revealed several distinct subtypes. 22% of mCRPC samples exhibited a novel epigenomic subtype associated with hyper-methylation. This hypermethylated (HM) cluster was significantly associated with somatic mutations in genes known to be involved in methylation, eg TET2 and DNMT3B, as well as in genes in which mutations have been associated with hyper-methylation in other cancer types ( IDH1 in glioblastoma and BRAF in colon cancer). mCRPC survival was 56.1 mos in pts with HM cancers compared to 35.6 mos in non-HM (p = .055). Methylome clustering also identified a unique cluster comprised of all patients with treatment-induced small cell/neuroendocrine cancer, a subtype previously associated with poor survival. Conclusions: This integrated study of whole-genome, whole methylome and whole-transcriptome sequencing provides the first comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer, and has identified at least two distinct subtypes. The clinical and therapeutic implications of methylation subtypes should be explored in future studies. Clinical trial information: NCT02432001 .
Prostate cancer relative survival by stage and race/ethnicity, United States, 2001 to 2015.
Authors: Siegel David A , O'Neil Mary Elizabeth , Richards Thomas B , Dowling Nicole F , Weir Hannah K 
Published: May 2020

5509 Background: Prostate cancer is the most common cancer diagnosed and the second leading cause of cancer-related deaths among U.S. men. Incidence rates for distant stage cancer increased during 2010–2014, and survival at all stages was lower for black men than white men. We examined temporal changes in survival by race/ethnicity. Methods: Five-year relative survival (RS) (cancer survival in the absence of other causes of death) was calculated for men with prostate cancer aged ≥40 years using National Program of Cancer Registries data (93% U.S. population coverage). Cancers were diagnosed during 2001–2015 with follow-up through 2015. RS was estimated by race/ethnicity (non-Hispanic white, non-Hispanic black, and Hispanic), stage, and year (2001–2007 and 2008–2015). Differences were determined by non-overlapping 95% confidence intervals (CI). Results: During 2001–2015, 2,234,233 cases were recorded. Five-year RS was 100% for localized disease in all race/ethnicities and time periods. Overall, RS improved from 29.0% (95% CI, 28.5–29.5) to 31.3% (30.8–31.9) for distant stage and 83.4% (83.0–83.8) to 84.7% (84.2–85.1) for unknown stage. For regional stage, RS improved for white men (table). For distant stage, RS was highest for black and Hispanic men. For unknown stage, RS was highest for white and Hispanic men. Conclusions: RS improved for regional, distant, and unknown stage, but disparities by race/ethnicity persist. The disparity between black and white men for distant stage reversed compared to past studies. Further investigation of diagnosis patterns and clinical characteristics of men with distant and unknown stage cancer could inform interventions to address disparities in outcomes. [Table: see text]
Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Fizazi Karim , Shore Neal D. , Tammela Teuvo , Ulys Albertas , Vjaters Egils , Polyakov Sergey , Jievaltas Mindaugas , Luz Murilo , Alekseev Boris , Kuss Iris , Le Berre Marie-Aude , Petrenciuc Oana , Snapir Amir , Sarapohja Toni , Smith Matthew Raymond 
Published: May 2020

5514 Background: DARO is a structurally distinct androgen receptor inhibitor with a favorable safety profile, approved for treating men with nmCRPC after demonstrating significantly prolonged metastasis-free survival, compared with placebo (PBO), in the phase III ARAMIS trial: median 40.4 vs 18.4 months, respectively (HR 0.41; 95% CI 0.34–0.50; P<0.0001). We report final analyses of OS and prospectively collected, patient-relevant secondary endpoints, and updated safety results. Methods: 1509 patients (pts) with nmCRPC were randomized 2:1 to DARO 600 mg twice daily (n=955) or PBO (n=554) while continuing ADT. Secondary endpoints included OS, and times to pain progression, first cytotoxic chemotherapy, and first symptomatic skeletal event. The OS analysis was planned to occur after approximately 240 deaths. Secondary endpoints were evaluated in a hierarchical order. Results: Final analysis was conducted after 254 deaths were observed (15.5% of DARO and 19.1% of PBO patients). After unblinding at the primary analysis, 170 pts crossed over from PBO to DARO. DARO showed a statistically significant OS benefit corresponding to a 31% reduction in the risk of death compared with placebo. All other secondary endpoints were significantly prolonged by DARO (Table), regardless of the effect of crossover and subsequent therapies on survival benefit. Incidences of treatment-emergent adverse events (AEs) with ≥5% frequency were generally comparable between DARO and PBO, similar to the safety profile observed at the primary analysis. Incidences of AEs of interest (including falls, CNS effects, and hypertension) were not increased with DARO compared with PBO when adjusted for treatment exposure. AEs in the crossover group were consistent with those for the DARO treatment arm. Conclusions: DARO showed a statistically significant OS benefit for men with nmCRPC. In addition, DARO delayed onset of cancer-related symptoms and subsequent chemotherapy, compared with PBO. With extended follow-up, safety and tolerability were favorable and consistent with the primary ARAMIS analysis (Fizazi et al, N Engl J Med 2019;380:1235-46). Clinical trial information: NCT02200614 .[Table: see text]
Final survival results from SPARTAN, a phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Small Eric Jay , Saad Fred , Chowdhury Simon , Oudard Stephane , Hadaschik Boris A. , Graff Julie N , Olmos David , Mainwaring Paul N. , Lee Ji Youl , Uemura Hiroji , De Porre Peter , Smith Andressa , Brookman-May Sabine Doris , Li Susan , Zhang Ke , Rooney Oliver Brendan , Lopez-Gitlitz Angela , Smith Matthew Raymond 
Published: May 2020

5516 Background: SPARTAN evaluated APA vs PBO in pts with nmCRPC and a prostate-specific antigen doubling time of ≤ 10 mo receiving androgen deprivation therapy (ADT). At primary end point analysis of metastasis-free survival (MFS), APA significantly improved median MFS by 2 yrs, as well as time to metastasis, progression-free survival, and time to symptomatic progression vs PBO (Smith, et al. NEJM 2018); overall survival (OS) results were immature. SPARTAN was unblinded upon meeting the primary end point; pts still on PBO were allowed to cross over to APA. Final survival results are reported herein. Methods: 1207 nmCRPC pts were randomized 2:1 to APA (240 mg QD) or PBO plus ongoing ADT. At progression, pts could receive open-label sponsor-provided abiraterone acetate + prednisone. After the primary efficacy end point (MFS) was met, 76 PBO pts (19%) crossed over to APA. OS and time to cytotoxic chemotherapy (TTCx) were tested by group sequential testing procedure with O’Brien-Fleming (OBF)-type alpha spending function. Time-to-event end points were analyzed by Kaplan-Meier method and Cox model. A sensitivity analysis for OS, accounting for crossover using a naïve censoring approach, was conducted. Results: With follow-up of 52.0 mo, 428 (of 427 required) OS events had occurred. Median treatment duration: APA, 32.9 mo; PBO, 11.5 mo. Median OS was significantly longer with APA + ADT vs PBO + ADT (73.9 vs 59.9 mo), (hazard ratio [HR], 0.784, Table). APA significantly lengthened TTCx (HR, 0.629). Discontinuation rates (APA vs PBO) due to progressive disease were 42.7% vs 73.9%, and due to adverse events (AE) 15.2% vs 8.4%. Safety was consistent with previous reports; grade 3/4 treatment-emergent (TE) AEs of special interest were rash 5.2%, fractures 4.9%, falls 2.7%, ischemic heart disease 2.6%, hypothyroidism 0%, and seizures 0%. 1 TEAE leading to death (myocardial infarction) was considered potentially APA related. Conclusions: In pts with nmCRPC, APA + ADT significantly improved OS compared with PBO + ADT, with median OS > 6 yr in the APA + ADT group and 14 mo improvement over PBO + ADT. Benefit from APA was observed despite a 19% crossover from PBO. The safety profile of APA was consistent with prior interim analyses. Clinical trial information: NCT01946204 . [Table: see text]