bluuebunny/crossref_metadata_2025_split huggingface dataset:
Post radical prostatectomy (RP) PSA outcomes following 6 vs 18 months of perioperative androgen deprivation therapy (ADT) in men with localized high risk prostate cancer (LHRPC): Results of Part 2 of a randomized phase 2 trial.
Authors: McKay Rana R. , Xie Wanling , Yang Xiaoyu , Rathkopf Dana E. , Laudone Vincent Paul , Bubley Glenn , Einstein David Johnson , Chang Peter , Wagner Andrew , Kane Christopher J. , Parsons J. Kellogg , Preston Mark A. , Kilbridge Kerry L. , Chang Steven Lee , Choudhury Atish Dipankar , Trinh Quoc-Dien , Pomerantz Mark , Kibel Adam S. , Taplin Mary Ellen 
Published: June 2023

5095 Background: Patients with LHRPC have an increased risk of relapse following RP. We previously reported on Part 1 of a phase 2 trial testing neoadjuvant apalutamide, leuprolide, and abiraterone acetate plus prednisone (ALAAP) or leuprolide and abiraterone plus prednisone (LAP) for 6 months followed by RP (McKay, J Urol, 2021). We demonstrated favorable pathologic responses (tumor <5 mm) at RP in 20.3% of patients (n=24/118). Herein, we report the results of Part 2 testing adjuvant ALAAP (NCT02903368). Methods: Eligible patients had a Gleason score ≥4+3, PSA >20 ng/mL, or T3 disease (by DRE or MRI) and lymph nodes <20 mm. At Part 2, patients were randomized 1:1 to ALAAP for 12 months (Arm 2A) or observation (Arm 2B), stratified by neoadjuvant therapy and pathologic T stage (<ypT3 or ≥ypT3). The primary endpoint was biochemical progression-free survival (bPFS) at 3 years post-RP. bPFS was defined as the time from randomization to progression (PSA ≥ 0.2 ng/mL, local/distant disease on CT/MRI or bone scan, or receipt of post-RP therapy or radiation for rising PSA) or death. The Kaplan-Meier estimate of bPFS at 3 years was compared between arms using a Chi-square test (Klein, Stat Med, 2007). Secondary endpoints included safety and time to testosterone recovery (>200 ng/dL). Results: Overall, 82/118 (69%) of patients enrolled to Part 1 were randomized to Part 2. Median follow-up was 47 months post-RP. Patient preference was the main reason for non-randomization in Part 2. In the intent-to-treat analysis, the 3-year bPFS estimate was 80% (95% CI:65-90%) for Arm 2A and 72% (95% CI:56-84%) for Arm 2B, which was not statistically significant (2-sided p=0.39). Patients who achieved pathologic responses (n=14) had longer bPFS than non-responders (log-rank test two-sided p=0.03; 3-year bPFS 100% vs 72%). In per-protocol population, of 36 patients receiving Arm 2A treatment with available data, 83% had testosterone recovery and median time to recovery from therapy end was 8.7 months. For patients on observation (n=42), 95% had testosterone recovery, and median time to recovery from RP was 4.0 months. No new safety signals were observed. Conclusions: Neoadjuvant ADT in LHRPC resulted in favorable pathologic responses and 3-year bPFS in a subset of patients. As 30% of patients declined an additional 12 months of adjuvant treatment, the study was underpowered to detect a difference between 6 months vs. 18 months of treatment. Subsequent analyses will evaluate predictors of improved bPFS. Clinical trial information: NCT02903368 . [Table: see text]
ECOG-ACRIN E2197: Comparison of HER2 gene expression by RT-PCR across all HER2 immunohistochemistry groups with recurrence analysis.
Authors: Can Nhu Thuy , Bennett John , Flannery Cynthia A. , Bailey Helen , Goldstein Lori J. , Davidson Nancy E. , Sparano Joseph A. , Baehner Frederick L. , Badve Sunil S. 
Published: June 2023

515 Background: Accurate assessment of HER2-low [immunohistochemical (IHC) score of 1+ or 2+ and in-situ hybridization negative] breast cancer is clinically relevant following DESTINY-Breast04. In hormone receptor positive breast cancers, Oncotype DX assay Recurrence Score results are widely used to guide adjuvant chemotherapy selection, and standardized quantitative HER2 mRNA reference-normalized expression levels by RT-PCR are included in patient reports. Previously, a high degree of concordance between central IHC and quantitative HER2 by RT-PCR was demonstrated in E2197. Here, we compare quantitative HER2 gene expression using Oncotype DX assay within all IHC subgroups and risk of recurrence in E2197. Methods: Data analyzed were from a case-control sample from E2197 (no adjuvant anti-HER2 therapy) of 755 patients. Central IHC for HER2 used duplicate 1.0 mm microarrays (HercepTest, Dako) and scored per 2007 ASCO/CAP guidelines. Based on quantitative reference-normalized RT-PCR measures of HER2 expression, cases were assigned: positive ≥11.5 units, equivocal ≥10.7 to <11.5 units, and negative <10.7 units (1 unit increase represents ~2-fold increase in RNA). Spearman’s rank correlation was used to measure strength of association between the 2 methods. Cox proportional hazards regression was used to evaluate the association between quantitative HER2 expression and recurrence (defined as invasive breast cancer in local, regional, or distant sites). Analyses were weighted to account for study design. Results: 48% were IHC 0, 11% were IHC 1+, 23% were IHC 2+, and 18% were IHC 3+. 85% were HER2 negative, 3% equivocal, and 11% positive by RT-PCR. While there was moderately strong correlation between HER2 IHC and HER2 gene expression by RT-PCR [Spearman’s rho: 0.63 (95% CI: 0.59, 0.67); p<0.001], there were wide and overlapping ranges of HER2 gene expression across all IHC categories with almost identical medians and inter-quartile ranges for HER2 IHC 1+ and 2+ (n=248; see table). An exploratory analysis showed 86% of IHC 0, 97% of IHC 1+, and 99% of IHC 2+ had HER2 >8 units. After controlling for baseline clinicopathologic features (age, hormone receptor status, grade, size, and nodal status), continuous quantitative HER2 expression was associated with time to recurrence in HER2 IHC 0 to 2+ [HR 1.17 per 1-unit increase in HER2 (95% CI 1.01, 1.35; p=0.036)]. Conclusions: There was a wide range of quantitative HER2 gene expression using Oncotype DX assay across all IHC categories; continuous HER2 expression is independently associated with recurrence. Quantitative HER2 expression may be useful for identification of HER2-low breast cancer. Further studies are needed. [Table: see text]
Differential benefit of capecitabine-based chemotherapy among TNBC subtypes in the context of the CBCSG010 study.
Authors: Li Junjie , Wu Wenya , Yang Yunsong , Yang Wentao , Zhimin Shao 
Published: June 2023

528 Background: Our previous study classified TNBCs into four mRNA subtypes, provided additional insights into TNBC heterogeneity and potential therapeutic options. Then we conducted a phase Ib/II subtyping-based and genomic biomarker-guided umbrella trial (FUTURE, NCT03805399 ), demonstrated the clinical benefit of subtyping-based targeted therapy for refractory metastatic TNBC. Here, we further evaluate the prognosis and predictive value of molecular classification in early TNBC in CBCSG010 trial (NCT01642771), which is a prospective, randomized phase III trial confirmed adding capecitabine to anthracycline-taxane-based adjuvant chemotherapy significantly improved survival in TNBC. Methods: Tumor tissues and pathological sections were retrospectively collected. Immunohistochemical (IHC) staining and hematoxylin and eosin (HE) staining were performed on paraffin-embedded sections to conduct TNBC IHC subtype staining. RNA-sequencing were performed to characterize the intrinsic molecular features of TNBC microenvironment. Results: 585 patients enrolled in the CBCSG010 trial, 450 patients had pathological sections, among which 207 patients achieved successfully stained sections. PDL1, CD8 and stromal tumor infiltrating lymphocytes (sTILs) were chosen for identified TNBC Immune enriched phenotype. Patients with ≥20% positive tumor cell proportion score (TPS) of PDL1, ≥10% positive cells of CD8, and ≥10% positive sTILs were significantly associated with better 5y-DFS (disease-free survival). Among Immune enriched TNBC, kaplan-Meier curves showed that DFS rates were 96.4% and 73.7% in the capecitabine and control groups. Transcriptome data was used to picture the immune microenvironment landscape, showed that “immune-hot” patients (immune cells or immune genes enriched) were more likely to benefit from capecitabine treatment. Conclusions: TNBC subtypes is significantly associated with DFS, with Immune enriched phenotype achieving the best outcome, and “immune-hot” patients are more likely to benefit from adjuvant capecitabine. Designing future clinical trials adding immunotherapy in adjuvant treatment of TNBC might base on molecular features.
Disease-free survival (DFS) as a surrogate for overall survival (OS) in patients (pts) with HR+/HER2− early breast cancer (EBC): A correlation analysis.
Authors: Untch Michael , Pérol David , Mayer Erica L. , Cortes Javier , Nusch Arnd , Cameron David A. , Barrios Carlos , Delea Thomas E. , Romero Salas Tonatiuh , Kalra Manik , Gupta Rhea , Pathak Purnima , Fasching Peter A. 
Published: June 2023

535 Background: DFS has been widely adopted as a clinically meaningful primary endpoint in EBC trials in place of OS, which needs extensive follow-up to observe sufficient events and fails to assess survival benefit early. However, a rigorous validation of DFS as a surrogate endpoint for OS is required for each given setting. The objective of this analysis was to evaluate DFS as surrogate for OS in the adjuvant treatment of HR+/HER2− EBC. Methods: A systematic literature review (SLR) was conducted using biomedical literature databases (ie, Embase, PubMed, and Medline [from database inception to January 2023]) and key conferences to identify published studies in EBC. The eligibility criteria for the SLR were RCTs that included ≥80% of adult pts with HR+/HER2− EBC and assessing different treatment options (ie, cyclin-dependent kinase 4/6 inhibitors [CDK4/6i], endocrine therapies [ET], and chemotherapies [CT]). Studies were considered for correlation analysis if hazard ratios (HRs) were reported for both DFS and OS. The analysis excluded observational studies and trials with immature OS data. Spearman rank correlation (rs) and weighted linear regression analyses (measured by coefficient of determination [R2]) were performed to evaluate the correlation between HRs for OS and DFS. Considering heterogeneity, multiple scenario analyses were conducted. Surrogate threshold effect (STE) was also estimated; STE is defined as the maximum value of the HR for DFS that needs to be observed in a trial to ensure the possibility of concluding that a significant effect on OS occurred. Correlation was also assessed using pt-level data from the FACE trial (letrozole vs anastrozole in postmenopausal pts with HR+/HER2− EBC) to validate findings of the trial-level analysis. Results: A total of 14 RCTs (N = 31,668) were included (CDK4/6, 2; ET, 7; CT, 5). Trial-level analysis showed that rs between OS and DFS was 0.81 (95% CI, 0.56-0.94), which when weighted by variance was 0.81. Regression analysis showed that 84% of the variability in OS was explained by DFS (R2 = 0.84). A meta-regression model estimated an STE of 0.82 for HR of DFS, which can be leveraged to validate the surrogacy based on the DFS estimated from a future trial. Analysis of pt-level data from the FACE trial demonstrated a correlation between DFS and OS (rs = 0.75). Additionally, correlation coefficients estimated by the Pearson method and iterative imputation were 0.83 and 0.89, respectively. Conclusions: Both trial-level and pt-level analyses demonstrate a positive correlation between DFS and OS. These results support the use of DFS as a reliable surrogate endpoint for OS in HR+/HER2− EBC trials to give an early access to innovative therapies.
Real-world outcomes with adjuvant nonsteroidal aromatase inhibitors (NSAIs) vs tamoxifen (TAM) in patients with hormone receptor−positive/human epidermal growth factor receptor 2−negative (HR+/HER2−) early breast cancer (EBC): A US database analysis.
Authors: Graff Stephanie L. , Tolaney Sara M. , Hart Lowell L. , Razavi Pedram , Fasching Peter A. , Janni Wolfgang , Schwartzberg Lee S. , Lanoue Brad , Romero Salas Tonatiuh , Khakwani Aamir , McDermott Courtney , Pathak Purnima , O'Shaughnessy Joyce 
Published: June 2023

542 Background: Randomized controlled trial (RCT) meta-analysis data have shown a significantly greater disease-free survival (DFS) benefit with aromatase inhibitors than TAM in patients with HR+/HER2− EBC. Here we compare real-world outcomes in patients with HR+/HER2− EBC who received adjuvant endocrine therapy (ET) with NSAIs or TAM. Methods: This was a retrospective analysis of ConcertAI’s deidentified electronic medical records data set of patients treated at US academic and community oncology clinics from January 1, 1995 to April 30, 2021. The cohort included patients with stage II-III (if IIIB or IIIC, confirmation was required on residual tumor status) HR+/HER2− EBC who underwent surgery and initiated adjuvant ET (excluding those who switched classes of ET); ovarian function suppression (OFS) was permitted. Menopausal status was determined using age (≥ 50 years) as a proxy for undocumented status. Invasive DFS (IDFS; risk of disease recurrence, death, or second primary tumor), distant DFS (DDFS; risk of distant recurrence, death, or second primary tumor), and overall survival (OS; risk of death) were assessed and defined as the time interval between start of ET and first event. Multivariate Cox regression analyses were performed, adjusting for age, stage, Charlson Comorbidity Index, and prior adjuvant or neoadjuvant chemotherapy for the ET cohort. Results: Of the total 3133 patients analyzed, 2507 were included in this analysis (NSAI ± OFS, n = 1854; TAM ± OFS, n = 653). Among these patients, the median (range) age was 59.5 (22.8-86.6) years, 25.4% were premenopausal, and 56.2% had tumor node involvement. The mean (SD) time to ET discontinuation was 46.2 (35.9) months overall and was similar between the NSAI and TAM cohorts. Reasons for ET discontinuation were undocumented or missing from the database for 76.8% of patients. Multivariate Cox regression analyses suggested a significant risk reduction with NSAIs vs TAM, with a 17% reduction in risk of an IDFS event (hazard ratio [HR], 0.83 [95% CI, 0.69-0.98]) and an 18% reduction in risk of a DDFS event (HR, 0.82 [95% CI, 0.69-0.98]). Although there were few events, OS analysis suggested a numerical trend favoring NSAIs over TAM, with a 12% reduction in risk of death (HR, 0.88 [95% CI, 0.69-1.13]). Conclusions: This real-world data analysis revealed a reduction in risk of IDFS and DDFS events with adjuvant NSAIs vs TAM in patients with HR+/HER2− EBC. Collectively, RCT and real-world data demonstrate greater benefit with adjuvant NSAIs vs TAM with respect to risk of recurrence in this patient population.
The worldwide impact of HER2-targeted treatments in women with breast cancer: An epidemiological modeling study.
Authors: Press David J. , Arnold Melina , Hansen Svenn 
Published: June 2023

543 Background: HER2-targeted therapies (trastuzumab, pertuzumab, and T-DM1) have revolutionized the treatment and epidemiological landscape of HER2+ breast cancer, resulting in population-level increases in survival and decreases in disease recurrence. The aim of this epidemiological modeling study was to quantify the estimated global impact of HER2-targeted therapies, by estimating the number of women diagnosed with HER2+ early breast cancer (eBC) who have avoided (or will avoid) metastatic disease recurrence following treatment. Methods: We used data and projections from cancer registries, observational studies, clinical trials, and drug sales volumes (ie, utilization) to create annual country-level synthetic cohorts of patients diagnosed with HER2+ eBC, for the years 2004-2033 in 185 countries. The real-world uptake of HER2-targeted treatments and treatment flow was estimated in the main scenario. The impact of chemotherapy alone was estimated in the counterfactual scenario, assuming 100% chemotherapy worldwide. The occurrence of distant recurrences was modeled in both scenarios using weighted transitional probability averages based on invasive disease-free survival curves from clinical trials. Results: In total, during the 3-decade study period, we predicted that 11.9 million (M) women would be diagnosed with HER2+ eBC, out of which 7.5M were estimated to be treated with HER2-targeted therapies in a real-world uptake scenario. In the counterfactual scenario with only chemotherapy available, a total of 2.9M women were estimated to experience a metastatic disease recurrence, compared to only 2.1M women in the base scenario of predicted real-world uptake of HER2+ targeted therapies. This corresponds to a reduction of 26% or 768,000 women who may avoid metastatic recurrence since the introduction of HER2-targeted therapies (Table). Conclusions: HER2+ targeted therapies have substantially improved breast cancer outcomes and continue to contribute to the reduction in breast cancer recurrence rates. Further research may elucidate treatment-related reductions in costs to society as a result of population-level improvements in disease outcomes for breast cancer survivors. Given the expected rise in the burden of breast cancer globally, therapeutic advances and increased treatment utilization may further accelerate global patient benefit. [Table: see text]
Additional prognostic value of the BCT score in patients with ER+HER2- breast cancer receiving 21-gene assay–guided adjuvant treatments.
Authors: Ahn Sung Gwe , Kook Yoonwon , Lee Sae Byul , Lee Eun-Gyeong , Yu Jonghan , Lee Young-Won , Kim Yeon Jin , Woo Sang Uk 
Published: June 2023

548 Background: In early estrogen receptor (ER)+HER2- breast cancer, a 21-gene expression assay-guided decision-making for adjuvant treatments has been widely utilized as a standard-of-care. The GenesWell BCT is a multigene assay that is designed to predict the risk of distant recurrence (DR) in patients with ER+HER2- breast cancer. This assay consists of nine genes, which are used to generate a risk score that can help guide treatment decisions. We addressed an additional value of the GenesWell Breast Cancer Test (BCT) score using the cohort of ER+HER2- breast cancer patients receiving a 21-gene assay-guided adjuvant treatments, focusing the chemotherapy untreated subset with low 21-gene recurrence score (RS). Methods: This multicentre, observational follow-up study was done in 4 academic institutions in South Korea. Patients with ER+HER2- breast cancer who received RS-guided adjuvant treatments were enrolled. A total of 705 patients were included. Of these, the rate of women with node-positive disease was 21.6% (152/705), and the rate of women with younger than 50 years old was 61.4% (433/705). The BCT score was obtained using the specimens which were previously analyzed for RS. The primary endpoint was recurrence-free survival (RFS), and the secondary endpoint was distant recurrence-free survival (DRFS). Results: Among the 705 patients, the RS assigned 110 (15.6%) as high risk (≥26), whereas the BCT score assigned 239 (33.9%) as high risk (≥4). The agreement between two tests was noted in 494 (70.1%); concordances were made in 69 for high and in 425 for low, respectively. At a median follow up of 85 months, 80 had tumor recurrences, 38 had distant recurrences, and the 7-year RFS was 90.0% (95% CI, 87.6%-92.5%). In the 595 patients with low RS, 556 (93.4%) did not receive adjuvant chemotherapy. Within the 556 chemotherapy-untreated patients with low RS, the RFS differed significantly according to the BCT score ( p= .014); the 7-year RFS was 92.9% in the BCT-low, while it was 85.7% in the BCT-high. Within the group, the BCT score was demonstrated as an independent prognostic factor for both RFS and DRFS adjustment of tumor size, nodal stage, and histologic grade. In addition, the RFS of the low-BCT score group was superior to that of the high-BCT group in either women younger than 50 years of age with an RS of 21 to 25 or all women with an RS of 21 to 25. Conclusions: We found that the BCT score was useful in stratifying the risk of relapse in chemotherapy-untreated patients with a low recurrence score (RS). This indicates that the BCT score could provide additional clinical value in identifying patients with a long-term risk of relapse, particularly in young women with an RS of 21 to 25.
KEYNOTE-826: Final overall survival results from a randomized, double-blind, phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer.
Authors: Monk Bradley J. , Colombo Nicoletta , Tewari Krishnansu Sujata , Dubot Coraline , Caceres M. Valeria , Hasegawa Kosei , Shapira-Frommer Ronnie , Salman Pamela , Yañez Eduardo , Gumus Mahmut , Olivera Hurtado de Mendoza Mivael , Samouëlian Vanessa , Castonguay Vincent , Arkhipov Alexander , Tekin Cumhur , Li Kan , Keefe Stephen Michael , Lorusso Domenica 
Published: June 2023

5500 Background: The first interim analysis of KEYNOTE-826 (NCT03635567) showed that first-line pembrolizumab (pembro) + chemotherapy (chemo) provided statistically significant and clinically meaningful improvements in OS and PFS vs placebo (pbo) + chemo in patients (pts) with recurrent, persistent, or metastatic cervical cancer across all prespecified populations (PD-L1 combined positive score [CPS] ≥1, all-comer, and CPS ≥10). Here, we present the protocol-specified final OS analysis results of KEYNOTE-826. Methods: Eligible adults with persistent, recurrent, or metastatic cervical cancer not previously treated with systemic chemo (prior radiosensitizing chemo allowed) and not amenable to curative treatment (surgery or radiation) were randomized 1:1 to pembro 200 mg or placebo Q3W for up to 35 cycles + chemo (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5), ± bev 15 mg/kg. Pts were stratified by metastatic status at diagnosis (yes/no), planned bev use (yes/no), and PD-L1 CPS (<1, 1 to <10, or ≥10). Dual primary end points were OS and PFS per RECIST v1.1 assessed by investigator review, each tested sequentially in the PD-L1 CPS ≥1, all-comer, and CPS ≥10 populations. Results: From Nov 2018 to Jan 2020, 617 patients were randomized (pembro + chemo, n = 308 [63.6% with bev]; pbo + chemo, n = 309 [62.5% with bev]); 548 (88.8%) pts had PD-L1 CPS ≥1 and 317 (51.4%) had CPS ≥10. At the Oct 3, 2022 data cutoff, median follow-up was 39.1 mo. Pembro + chemo significantly improved OS and PFS in the CPS ≥1, all-comer, and CPS ≥10 populations (Table). The pembro + chemo benefit was seen regardless of bev use. Grade ≥3 AE incidence was 82.4% in the pembro + chemo arm and 75.4% in the placebo + chemo arm. The most common grade ≥3 AEs were anemia (30.3% vs 27.8%), neutropenia (12.4% vs 9.7%), and hypertension (10.4% vs 11.7%). Conclusions: The addition of pembro to chemo ± bev significantly reduced the risk of death by 40% in the PD-L1 CPS ≥1 population, by 37% in the all-comer population, and by 42% in the CPS ≥10 population, and had a manageable safety profile. These data are consistent with the earlier results and provide further support for pembro + chemo ± bev as a new standard of care for first-line treatment of persistent, recurrent, or metastatic cervical cancer. Clinical trial information: NCT03635567 . [Table: see text]