bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of 2,000 patients presenting to a multidisciplinary prostate cancer clinic in the United Kingdom.
Authors: Rudd Pandora , Hines John , Watkins Eleanor , Powles Thomas , Tipples Karen
Published: May 2019

5077

Background: Multidisciplinary clinics (MDCs) involving both oncologists and urologists are recommended for managing radical prostate cancer patients. The effectiveness of MDCs in arriving at best treatment decisions is unknown. We analysed patient characteristics and management decisions over 8 years in a MDC at Bart’s Hospital, London. Methods: Clinical data were collected in real time and analysed retrospectively, including demographics, tumour stage and grade, D’amico risk group, treatment choice and first clinician seen. We compared variables in 1000 consecutive patients presenting between 2011-2015 (cohort A) to 1000 patients presenting 2016-18 (cohort B) to investigate trends over time. Results: 2000 patients were included, age 65.2 ± 8.6 years and 65.9 ± 9.1 years (p=0.08), with presenting PSA 9.0 (6.3-14.4) and 9.2 (6.4-15.0) ng/ml (p=0.36), in cohort A and B respectively. Disease severity and initial treatment decision are shown in the table. In low risk disease, 126 (75%) patients had active surveillance in cohort A, and 158 (90%) in cohort B (p=0.0003). In high risk disease, 202 (59%) patients had radiotherapy compared to 194 (50%) in cohort B (p=0.011). In cohort B, 127 (39%) patients seeing oncology first had radiotherapy compared to 143 (25%) patients who saw urology first (p<0.0001). 76 (23%) and 154 (27%) patients had surgery, that saw oncology and urology first, respectively (p=0.11). Conclusions: In 2000 patients presenting to a prostate MDC over 8 years, active surveillance in low risk disease increased, radiotherapy in high risk disease reduced, and the proportion undergoing surgery was unchanged. The initial clinician seen influenced treatment choice; having both specialists in the same consultation may improve consistency of treatment decisions. Disease severity and treatment choice before and after 2016. [Table: see text]
Patient-reported outcomes (PROs) in NRG oncology/NSABP B-39/RTOG 0413: A randomized phase III study of conventional whole breast irradiation (WBI) versus partial breast irradiation (PBI) in stage 0, I, or II breast cancer.
Authors: Ganz Patricia A. , Cecchini Reena S. , White Julia R. , Vicini Frank , Julian Thomas B. , Arthur Douglas W , Rabinovitch Rachel , Kuske Robert R. , Parda David S. , Scheier Michael , Winter Kathryn A. , Paik Soonmyung , Kuerer Henry Mark , Vallow Laura , Pierce Lori J. , Mamounas Eleftherios P. , Costantino Joseph P. , McCormick Beryl , Curran Walter John , Wolmark Norman
Published: May 2019

508

Background: PBI is an alternative to WBI, with potentially greater therapy (tx) compliance, and better integration with chemotherapy (CTX). NSABP B-39/RTOG 0413 clinical outcome results from 2018 did not show equivalence of PBI to WBI in local tumor control; PBI was statistically inferior, but with clinically small differences. PBI may be an acceptable alternative to WBI for some women. Understanding cosmesis and quality of life (QOL) treatment outcomes is important. Methods: B-39/0413 included a prospective QOL substudy with PRO evaluation of breast cancer treatment outcomes (cosmesis, function, pain) and fatigue using BCTOS and SF-36 vitality scales. Secondary QOL parameters included treatment related symptoms, perceived convenience of care, and the BPI pain scale. The study sample was stratified by CTX or not, as CTX is given before WBI but after PBI. PRO assessments occurred before randomization, the last day of adjuvant tx [CTX or radiation], 4 wks later, and 6, 12, 24, and 36 mo later. Primary aims included comparisons of change in fatigue from baseline to end of tx and equivalency of change in cosmesis from baseline to 36 mo for PBI v WBI. Separate analyses were done for CTX and non-CTX pts, controlling for axillary dissection. Each comparison used α=0.0125. Planned sample size was 964. Results: From 3-23-05 to 5-27-09, 975 pts were enrolled in the PRO study; 950 had follow-up data. 504 did not receive CTX and 446 received CTX. In non-CTX pts, PBI had less fatigue (p=0.011) and did not meet criteria for cosmesis equivalence (97.5% CI, -0.02 to 0.22; ∆=0.20). In CTX pts, PBI had worse fatigue (p=0.011) and equivalent cosmesis to WBI (97.5% CI, -0.09 to 0.21; ∆=0.24). In both groups, PBI pts reported less pain at end of tx. In non-CTX pts, PBI had more pain at 36 mo but in CTX pts, there was no difference. Convenience of care and treatment related symptom outcomes will be presented. Conclusions: In non-CTX pts, PBI is more convenient with less fatigue and slightly poorer cosmesis at 36 mo. Cosmesis was equivalent at 36 mo in CTX pts. Support: U10CA180868, -180822, UG1CA189867. Clinical trial information: NCT00103181.
IMRT pelvic radiotherapy with simultaneous integrated boost in high-risk prostate cancer: Results after 10 years.
Authors: Ekanger Christian , Dahl Olav
Published: May 2019

5084

Background: To report 10 year results after image guided intensity-modulated radiotherapy (IMRT) with hypofractionated simultaneous integrated boost (SIB) in high-risk prostate cancer. Methods: Between 2007 and 2009, 97 patients with an estimated risk of lymph node metastases above 15% (Roach equation) were prospectively included in a phase II study. Patients were treated with 2-2.7 Gy to the prostate, vesicula seminalis and elective pelvic field in 25 fractions over 5 weeks with androgen deprivation therapy for 2 years. Toxicity was scored according to RTOG criteria and biochemical free survival (BFS) using the Phoenix definition. Patients were divided into three groups; very high-risk patients (VHR) according to NCCN 2015 criteria (n=50), high-risk patients (HR) (n=32), and patients with N+ disease and/or pretreatment s-PSA ≥100 (n=15). Differences were examined using Kaplan Meier estimates with log rank test. Results: Ten year BFS in the entire cohort was 63%. Metastasis-free survival (MFS) was 77% and prostate-cancer-specific-survival (PCSS) 88%. Overall survival (OS) was 69% and local failure rate was 11%. VHR vs. HR subgroups had significant different BFS; 58% vs 84% (p=0.01) respectively. MFS and PCSS in the VHR group compared to the HR group was 78% vs 91% (p=0.108) and 86% vs 97% (p=0.157) respectively. Patients with N+ and/or PSA>100 had worse outcome compared to the HR/VHR groups, but not all had treatment failure. BFS was 33% vs 68% (p=0.001), MFS 47% vs 83% (p=0.000) and PCSS 73 % vs 90% (p=0.04), respectively. Patients who reached a PSA nadir value below 0.1 (n=80) had significant better outcomes, with PCSS 93% vs 65% (p= 0.001) and BFS 74% vs 12% (p=0.000), respectively. Acute gr 2 GI and GU toxicity was observed in 27% and 40%, gr 3 GI and GU toxicity in 1% and 3%. Late gr 2 GI and GU toxicity at 3 years appeared in 3% and 4% with no gr 3 toxicity. Conclusions: High-risk prostate cancer patients treated with IMRT with SIB obtained favorable outcomes with few serious side effects. There were significant better results in the HR versus the VHR group, both better than the N+/PSA≥100 group.
Differential impact of endocrine therapy (ET) and chemotherapy (CT) on quality of life (QoL) of 4,262 breast cancer (BC) survivors: A prospective patient-reported outcomes (PRO) analysis.
Authors: Ferreira Arlindo R. , Di Meglio Antonio , Pistilli Barbara , Gbenou Arnauld S. , El-Mouhebb Mayssam , Everhard Sibille , Coutant Charles , Cottu Paul-Henri , Lerebours Florence , Petit Thierry , Dalenc Florence , Rouanet Philippe , Arnaud Antoine , Martin Anne-Laure , Ganz Patricia A. , Partridge Ann H. , Delaloge Suzette , Michiels Stefan , Andre Fabrice , Luis Ines Maria Vaz Duarte
Published: May 2019

512

Background: We recently witnessed a trend to de-escalate CT and escalate ET in adjuvant BC treatment (tx). However, there has been limited prior research investigating the differential impact on QoL of tx classes. We aimed to test the impact of CT and ET on QoL PROs 2 yrs after diagnosis (dx). Methods: CANTO (NCT01993498) is a multicenter prospective longitudinal study of stage I-III BC pts that characterizes long-term toxicities of BC tx. For this analysis we included 4262 pts recruited from 2012-14. QoL was extensively evaluated using the EORTC QLQ C30 and BR23. Linear regression modeling was performed, adjusting for demographic and clinical factors, with use of CT and/or ET as independent variables. Analyses were stratified by menopausal status due to different tx patterns and sequelae of CT. Results: Median age at dx was 56 yrs, 63% of pts were post (PostM) and 37% premenopausal (PreM), 80% had Charlson score 0, 91% stage I-II. 26% received mastectomy, 52% CT (preM 68%, postM 44%; 86% anthracycline+taxane) and 82% ET (preM 89% tamoxifen; postM 88% aromatase inhibitor). 32% preM pts had menses 1 year after ET initiation. Overall, QoL deteriorates 2 yrs after dx. ET negatively impacts more QoL domains than CT at 2 yrs. Also, young age, smoking, income, aggressive local tx and physiological distress are often associated with low QoL. In the stratified analyses, in postM pts, mostly ET (not CT) is associated with deteriorated QoL. In contrast, in preM pts, mostly CT (not ET) is associated with deteriorated QoL. Table shows eg of associations. Conclusions: In a large prospective cohort of BC survivors, detrimental QoL 2 yrs after dx is mostly associated with ET; however, negative effects of CT persist on preM. This differential effect on QOL should be considered when choosing optimal adjuvant therapy and appropriate selection of pts for ET escalation should be a research priority. [Table: see text]
Avoiding peg-filgrastim (Peg-F) prophylaxis during the paclitaxel (T) portion of the dose-dense (DD) doxorubicin-cyclophosphamide (AC)-T regimen: A prospective study.
Authors: Barroso-Sousa Romualdo , Luis Ines Maria Vaz Duarte , Di Meglio Antonio , Hu Jiani , Rees Rebecca , Sinclair Natalie Faye , Milisits Lindsey , Leone Jose Pablo , Constantine Michael , Faggen Meredith Gail , Briccetti Frederick , Block Caroline Cole , Partridge Ann H. , Burstein Harold J. , Waks Adrienne Gropper , Trippa Lorenzo , Tolaney Sara M. , Hassett Michael J. , Winer Eric P. , Lin Nancy U.
Published: May 2019

517

Background: Use of growth factors (GF) adds considerable expense and some toxicity to adjuvant breast cancer chemotherapy. We tested the feasibility and safety of omitting routine GF use during the T portion of DD AC-T. Methods: This is a prospective, single-arm study in which patients (pts) who completed 4 cycles of DD-AC proceeded to DD-T 175 mg/m2 every two weeks (wks) without routine GF (NCT02698891). Key inclusion: age≤ 65, ECOG PS≤1, absolute neutrophil count (ANC) ≥1500/mm3, and no febrile neutropenia (FN) during DD-AC. Criteria to treat for T included ANC ≥1000/mm3. Peg-F was given only if pts had FN in a prior cycle, or at investigator discretion if infection or treatment delay > 1 wk. Once Peg-F was given, pts received it in all future cycles. The primary endpoint was the rate of T completion ≤ 7 wks from cycle 1 day 1 (C1D1) to C4D1. Secondary endpoints included total use of Peg-F, rates of hematologic toxicity and FN, reasons for dose modification or hold. If ≥85% of pts completed T on time, the regimen would be considered feasible. If the true on-time completion rate is 75%, the chance the regimen would be declared infeasible is 91%, and if it is 85% the chance that the regimen is falsely declared infeasible is 10% (power = 0.899). ≥100/125 pts had to complete T on time for the regimen to be deemed successful. Results: Among 127 pts enrolled, 125 received ≥1 dose of protocol therapy and are included in the analysis. Median age at registration was 46 (range 21-65). Median C1D1 ANC was 7500/mm3 (range 1500-20500). 112 (90%) (95% CI 83-94%) pts completed DD-T ≤ 7 wks, and 3 (2%) completed within > 7 wks (2 due to neutropenia); 10 (8%) did not complete all cycles of T. Omission of Peg-F was not causally related to non-completion of T in any pts. The most common reasons for dose reduction or delays were non-hematologic. One pt had FN but was able to complete T on time. Eight (6.4%) pts received Peg-F during the trial. Conclusions: Omission of routine GF use during DD-T according to a pre-specified algorithm appears safe, feasible, and was associated with a 95.7% reduction in use of Peg-F, relative to the current standard of care. Additional analyses including cost implications are ongoing. Clinical trial information: NCT02698891.
Adjuvant endocrine monotherapy (ET) versus adjuvant breast radiation (RT) alone in healthy older women with stage I, estrogen receptor-positive (ER+) breast cancer: An analysis of the National Cancer Database (NCDB).
Authors: Bui Anthony H. , Chadha Manjeet , Shao Theresa H. , Gerber Naamit K. , Cate Sarah P. , Boolbol Susan K. , Zubizarreta Nicole J.
Published: May 2019

519

Background: The NCCN guidelines state that breast RT may be omitted in patients > 70 years of age with ER+, clinically node-negative, T1 breast cancer (BC) who receive adjuvant ET. Available data on older patients notes that local relapses are the most frequent site of failure, and distant relapse rates are low. The side effects of ET are not inconsequential and negatively affect QOL. The objectives of this study are to examine clinical outcomes including overall survival (OS) in women ≥70 years of age treated by lumpectomy(L)+ET and L+RT in the NCDB. Methods: The 2004-2013 NCDB includes 76,431 women ≥70 years with ER+ stage I BC who underwent L, and had a minimum one year follow up. Women who received no adjuvant therapy, both ET+RT, or any chemotherapy were excluded. To limit the analysis to healthy women, we excluded subjects with a Charlson comorbidity index > 0. We identified 24,572 patients who received either adjuvant ET monotherapy or adjuvant RT alone. Among these, 46% (11,313) received ET and 54% (13,259) breast RT. Overall median follow up was 57 months (range: 12-143 months). Analysis of OS between the 2 treatment groups was performed using Kaplan-Meier statistics and Cox proportional hazards regression; propensity weighting was used to balance covariates across the 2 treatment groups. Results: After propensity weighting, demographic covariates including age, race, insurance, and facility type were balanced between the 2 treatment groups. The median OS for ET was 125.9 months (95% CI 120.1-131.8), and 127.2 months for RT (95% CI 124.5-131.7) (p < 0.0001). The weighted hazard of death was 11.7% less in women receiving RT compared to ET (HR 0.883, 95% CI 0.834-0.936, p < 0.0001). Conclusions: To our knowledge, this is the first large study comparing RT and ET monotherapy in healthy older women with stage I, ER+ BC. The OS with RT alone is not inferior to ET alone, and in this study population is noted to be better. While this analysis has various limitations not dissimilar from other NCDB database studies, our observations are encouraging and warrant further research with prospective studies.
Low-fat dietary pattern and long-term breast cancer incidence and mortality: The Women’s Health Initiative randomized clinical trial.
Authors: Chlebowski Rowan T. , Aragaki Aaron K , Anderson Garnet L , Pan Kathy , Neuhouser Marian L , Manson JoAnn E , Thomson Cynthia A. , Mossavar-Rahmani Yasmin , Lane Dorothy , Johnson Karen , Wactawski-Wende Jean , Linda Snetselaar , Rohan Thomas E , Luo Juhua , Barac Ana , Prentice Ross L
Published: May 2019

520

Background: Observational studies of dietary fat intake and breast cancer have inconsistent findings. To address this issue, the Women’s Health Initiative (WHI) Dietary Modification (DM) clinical trial assessed a low-fat dietary pattern influence on breast cancer incidence and outcome. Methods: The WHI DM trial is a randomized, controlled clinical trial conducted at 40 US centers, where 48,835 postmenopausal women, aged 50-79 years, with no previous breast cancer and dietary fat intake ≥32% of total energy, were randomly assigned, from 1993-1998, to a usual diet comparison group (60%) or dietary intervention group (40%) with goals to reduce fat intake to 20% of energy and increase vegetables, fruit, and grain intake. This study is registered as: NCT00000611. Results: The dietary intervention significantly reduced fat intake; increased fruit, vegetable and grain intake with modest weight loss (3%) (all P< 0.001). During 8.5 years of dietary intervention, there were 8% fewer breast cancers and deaths from breast cancer were somewhat lower in the intervention group but the rates were not significantly different. However, deaths after breast cancer (breast cancer followed by death from any cause) were significantly reduced in the intervention group, both during intervention (hazard ratio [HR] 0·65 95% confidence interval [CI] 0·45-0·95) and through 16.1 year (median) cumulative follow-up. Now, after long- term, cumulative 19.6 year (median) follow-up, with 3,374 incident breast cancers, the significant reduction in deaths after breast cancer continued (with 1,011 deaths, HR 0·85 95% CI 0·74-0·96) and a significant reduction in deaths from breast cancer (breast cancer followed by death attributed to the breast cancer) emerged (with 383 deaths, HR 0·79 95% CI 0·64-0·97). Conclusions: Adoption of a low-fat dietary pattern associated with increased vegetable, fruit, and grain intake, demonstrably achievable by many, significantly reduced the risk of death from breast cancer in postmenopausal women. To our review, these findings provide the first randomized clinical trial evidence that a dietary change can reduce a postmenopausal woman’s risk of dying from breast cancer. Clinical trial information: NCT00000611.
Do all patients with HER2-positive breast cancer require one year of adjuvant trastuzumab?: A systematic review and meta-analysis.
Authors: Stewart Paul , Blanchette Phillip S. , Shah Prakesh S , Ye Xiang Y , Boldt R Gabriel , Fernandes Ricardo , Vandenberg Theodore A. , Raphael Jacques
Published: May 2019

522

Background: One year of adjuvant trastuzumab (T) remains the standard treatment for patients with HER2 positive breast cancer. Results from randomized trials with diverse non-inferiority margins comparing one year to a shorter duration of adjuvant T were not consistent, particularly with the PERSEPHONE and the final PHARE and Short-HER trials’ results. Our objective was to conduct a systematic review and meta-analysis of randomized trials in patients with HER2 positive breast cancer to assess whether a shorter duration of adjuvant T was non-inferior to one year of treatment. Methods: PubMed, EMBASE and The Cochrane Library were searched for eligible randomized trials. Hazard ratios (HR) for disease free and overall survival (DFS, OS) were weighted using generic inverse variance and pooled in a meta-analysis using random-effects models. The median of non-inferiority margins derived from each trial was calculated to set a non-inferiority margin of 1.29 for the pooled analysis. Subgroup analyses compared survival outcomes by estrogen receptor (ER) status, nodal status, length and timing of trastuzumab treatment. Results: Data of 11,376 patients from 5 trials were analyzed. A shorter duration of T was non-inferior to one year of therapy for DFS (HR 1.13, 95%CI 1.03-1.24) but worse for OS (HR 1.16, 95%CI 1.01-1.32). In addition, the non-inferiority for DFS was met for patients with ER positive disease (HR 1.1, 95%CI 0.95-1.28) and patients treated with 6 months (HR 1.09, 95%CI 0.98-1.22) or sequential T (HR 0.97, 95%CI 0.75-1.27). Conversely, the non-inferiority for DFS was not met for patients with ER negative disease (HR 1.22, 95%CI 1.06-1.41), patients treated with 9 weeks (HR 1.26, 95%CI 1.02-1.55) or concomitant T (HR 1.25, 95%CI 1.07-1.45) and patients with node negative (HR 1.12, 95% 0.93-1.35) or positive (HR 1.16, 95%CI 0.99-1.36) disease. Conclusions: Within the limitations of the available data and the different non-inferiority margins used in randomized trials, a shorter duration of adjuvant T is non-inferior to one year of therapy for DFS in patients with HER2 positive breast cancer, particularly in patients with ER positive disease. Further trials with appropriately chosen non-inferiority margins are needed to confirm the optimal duration of T in patients with low-risk disease.
Simulation modeling of the effects of adjuvant chemotherapy in early-stage breast cancer.
Authors: Jayasekera Jinani , Schechter Clyde B. , Sparano Joseph A. , Isaacs Claudine , Gray Robert James , Cadham Christopher , Mandelblatt Jeanne S.
Published: May 2019

526

Background: The recent Trial Assigning Individualized Options for Treatment (TAILORx) was practice changing. However, several important questions remain unanswered about therapy for women with early stage, hormone receptor positive (HR+), HER2- breast cancers, including chemotherapy effects by age and different Oncotype recurrence score (RS) cut-points, and longer follow-up. We developed a simulation model to extend the trial results to begin to fill these gaps. Methods: We developed a simulation model using an empirical Bayesian approach to simulate women eligible for the TAILORx trial. The joint distributions of patient and tumor characteristics were derived from de-identified TAILORx data. The remaining inputs used data independent of the trial, including SEER, the Oxford Overview, and other trials. TAILORx was simulated to examine the effects of chemotherapy (+ hormonal Rx) vs. hormonal Rx alone on distant recurrence-free survival (DRFS) at 9- and 20-years by age (≤50 and >50 years) and RS (11-25 and 16-25). We also evaluated the effects of chemotherapy in women with RS 26-30. Hazard ratios (HR) were determined using Cox regressions and DRFS by treatment were derived from Kaplan-Meier curves. We report the mean results from 1000 trial simulations, where each simulation randomly sampled values for each parameter from their observed joint distribution. Finally, the original trial was replicated for model validation. Results: The model closely replicated actual trial results. Sample sizes ranged from 7000-10000. The model estimated that chemotherapy improved DFRS in women aged ≤50 with RS 16-25 (Table). The 20-year event rates remained low in the 11-25 category. Among women with RS 26-30, HR for no chemo vs. chemo was 1.38 (95% CI:1.18-1.58). Conclusions: Simulation suggests that chemotherapy may reduce distant recurrence in younger women at different cut points between 11-25. Simulation modeling may be useful to translate trial results to broader population subgroups than those possible to test in RCTs. Nine-year distant recurrence-free survival by chemotherapy. [Table: see text]
Prognostic value of a new clinical-genomic model to predict 10-year risk of recurrence in patients with operable breast cancer.
Authors: Lei Lei , Huang Tzu-Ting , Chen Andre Ching-Hsuan , Lu Tzu-Pin , Cheng Skye Hung-Chun
Published: May 2019

530

Background: Searching for a specific biomarker to predict long-term risk of recurrence for all breast cancer subtypes is challenging. DGM-CM6 (Distant Genetic Model-Clinical variable Model 6) is a new clinical-genomic prognostic model developed from the 18-gene panel which was reported previously. This study aims to validate the long-term prognostic value of this new model in all subtypes of operable breast cancer patients. Methods: We included 752 operable breast cancer patients with stage I-III in all subtypes treated in a Cancer Center from 2005 to 2014 as the internal validation (IV) cohort. The median follow-up was 94.1 months. Meanwhile, Affymetrix U133P2 (n = 1139) data obtained from GEO (GSE9195/16391/17907/19615/20711/21653/42568, EMTAB365) were collected as the external validation (EV) dataset. The prognostic effect of DGM-CM6 was then evaluated by uni- and multivariate analyses. The low- and high-risk patients ( < 33 or ≥ 33 as cut-off value) classified by DGM-CM6 were evaluated by the 10-year distant relapse-free interval (DRFI), relapse-free interval (RFI), relapse-free survival (RFS) and distant relapse-free survival (DRFS), respectively. We further compared the predictive performance between DGM-CM6/DGM and PAM50-ROR score in our IV dataset. Results: In the IV dataset, DGM-CM6 was proved to be an independent prognostic factor by multivariate analysis with hazard ratios of 3.1 (1.6-6.0) for RFS (P = 0.0009) and 3.2 (1.6-6.3) for DRFS (P = 0.0009). Significant differences were observed between low- and high-risk groups with 10-year RFI (94.0% vs. 83.5%, P < 0.0001), RFS (90.0% vs. 80.5%, P = 0.0003), DRFI (94.1% vs. 85.0%, P < 0.0001), and DRFS (90.1% vs. 81.9%, P = 0.0004), respectively. The prognostic value of RFS was convinced in the EV dataset (HR = 1.34, P = 0.00052) by the DGM only. According to C-index estimate analysis, DGM appeared to have better performance comparing with PAM50 ROR score in prediction of long-term DR, DRFS, RFI, and RFS in N0 patients (C index for distant recurrence: 0.582 by DGM, 0.528 by ROR). Conclusions: DGM-CM6 could be a new long-term prognostic model to be applied in all subtypes of operable breast cancer patients. Further validation in a large scale of clinical trials is needed.
Abandonment trajectories of conventionally fractionated adjuvant radiotherapy in breast cancer care.
Authors: Xu Xiao , Soulos Pamela R. , Herrin Jeph , Wang Shi-Yi , Pollack Craig Evan , Evans Suzanne B. , Gross Cary Philip , Yu James B.
Published: May 2019

531

Background: Hypofractionated radiotherapy is the recommended approach for adjuvant breast cancer care. Yet physicians have been slow to abandon conventionally fractionated radiotherapy (CFRT). We examined distinct trajectories of abandoning CFRT among physician patient-sharing peer groups and the associated cost implications. Methods: Using 2011-2014 national Medicare claims, we constructed peer groups of physicians (radiation and medical oncologists, surgeons, and primary care physicians) who cared for women with breast cancer. Women ≥66 years of age who underwent lumpectomy plus adjuvant radiotherapy were included. Peer groups represented physicians who frequently shared patients with one another. For each peer group, we calculated risk-adjusted rate of CFRT use in 2011-2012 (T1) and 2013-2014 (T2) after accounting for patient risk factors. Based on these utilization rates and a latent growth curve analysis, we identified distinct trajectories of abandoning CFRT among peer groups and estimated their cost implications from the Medicare perspective. Results: The 215 physician peer groups (caring for 16,988 patients) exhibited four distinct trajectories of CFRT use: 1) persistent high use (mean adjusted utilization: T1 = 94.3%, T2 = 90.6%); 2) decreased high use (T1 = 81.3%, T2 = 65.3%); 3) decreased medium use (T1 = 60.1%, T2 = 44.0%); and 4) decreased low use (T1 = 31.6%, T2 = 23.6%). They accounted for 33.0%, 35.3%, 25.6% and 6.0% of the peer groups, respectively. Compared to “persistent high use” of CFRT, peer groups with “decreased high use” and “decreased medium use” of CFRT had a smaller proportion of patients receiving radiotherapy at free-standing (vs. hospital-based) facilities (adjusted odds ratio = 0.89, p = 0.01; and 0.78, p < 0.01; respectively). Accelerating abandonment of CFRT in the three higher utilization trajectories to “decreased low use” for the 2011-2014 patient cohort could save Medicare $342.7 million (95% confidence interval: $232.2-$457.6 million). Conclusions: Physician peer groups had distinct trajectories in abandoning CFRT exhibiting different baseline levels and rates of change in utilization. Efforts to reduce overuse of CFRT could generate substantial savings.
Breast Cancer Index and risk stratification in luminal subtypes: A trans-ATAC study.
Authors: Sestak Ivana , Zhang Yi , Schnabel Catherine A. , Cuzick Jack M. , Dowsett Mitchell
Published: May 2019

534

Background: The Breast Cancer Index (BCI) is a gene-expression based signature that provides prognostic information for overall (0-10 years) and late (5-10 years) distant recurrence (DR) and prediction of extended endocrine benefit in hormone receptor positive (HR+) early stage breast cancer. The current analysis aims to further characterize, correlate and compare the prognostic performance of BCI in luminal subtypes based on immunohistochemical classification. Methods: 670 postmenopausal women with HR+, LN- disease from the TransATAC cohort were included in this analysis. Luminal A-like tumors (LumA) were identified as those with ER+ and/or PR+ and HER2 -, and Ki67 < 20% by IHC. All other tumors were classified as Luminal B-like (LumB) for this analysis. Primary endpoint was DR. Cox regression models were used to examine BCI prognostic performance according to luminal subtype, adjusting for the clinicopathological model Clinical Treatment Score (CTS). Results: 452 (67.5%) patients were classified as LumA and 218 (32.5%) as LumB. BCI was highly prognostic in LumA cancers (adjusted HR = 1.57 (1.23-1.96), P < 0.001, ΔLR-χ2= 14.09), but not in LumB tumors (adjusted HR = 1.20 (0.94-1.52, P = 0.14, ΔLR-χ2= 2.23). In LumA, 10-year DR risks in BCI intermediate and high risk groups were very similar (25.6% (16.4-38.6) and 25.3% (13.5-44.3), respectively) and significantly different from BCI low (3.9% (2.1-7.0); HR = 7.47 (3.50-15.96) and HR = 8.13 (3.27-20.23), respectively). In LumB, 10-year DR risks in BCI low and BCI intermediate risk groups (13.8% (6.8-26.9) and 14.6% (8.3-24.9), respectively) were very similar and significantly lower than for the BCI high (29.1% (20.0-41.1)). Lum subtyping was only prognostic in the BCI low risk group (LumA vs. LumB: HR = 4.27 (1.65-11.02)) but not in the other two BCI risk groups. Conclusions: BCI provided significant prognostic information in Lum A subtype. These results show that BCI intermediate and high risk had similar risk of DR in LumA tumors, while shared similarly low risk of DR as BCI-low in LumB tumors. Further evaluation is needed to elucidate the distinct mechanisms underlying each classification system.
Adjuvant chemotherapy in small node-negative triple-negative breast cancer (TNBC).
Authors: Steenbruggen Tessa Gerjanne , Van Ramshorst Mette S. , van Werkhoven Erik , Dezentjé Vincent O. , Siesling Sabine , Linn Sabine C. , Sonke Gabe S.
Published: May 2019

536

Background: International guidelines differ in their recommendation for adjuvant chemotherapy in small node negative TNBC. We evaluated associations of chemotherapy with long-term outcome in a large population-based TNBC cohort. Methods: All patients diagnosed with pT1N0M0 TNBC between 2005 and 2015 were identified from the Netherlands Cancer Registry. Patient, tumor and therapy characteristics were recorded. Date and cause of death were obtained from Statistics Netherlands. We used multivariable cox regression models to evaluate associations of chemotherapy with overall survival (OS) and breast-cancer specific survival (BCSS), adjusted for baseline characteristics. Subgroup analyses were performed by tumor size and grade. Results: We identified 4393 patients: 284 with T1a, 924 with T1b, and 3185 with T1c tumors. Chemotherapy was administered in 53% of patients: 6% with T1a, 17% with T1b and 67% with T1c. Chemotherapy use increased over time and varied by geographic region. Patients receiving chemotherapy were younger, had larger tumors, higher tumor grade, and more often isolated tumor cells (itc) in the lymph nodes. At a median follow-up of 7 years (IQR 5-10 years), 611 patients had died, of whom 287 due to breast cancer. Chemotherapy was associated with improved OS in the whole group (adjusted hazard ratio [aHR] 0.55; 95% CI 0.44–0.69), in the pT1c subgroup (aHR 0.53, 95% CI 0.41-0.67), and in grade 3 tumors (aHR 0.50, 95% CI 0.39-0.65). Associations were not significant for pT1ab or grade 1-2 tumors (table). Findings for BCSS were in line with OS results (table). To illustrate the absolute difference we estimated 10-year OS and BCSS for a 60-year old woman with a pT1cN0(itc+) grade 3 TNBC. The predicted 10-year OS was 67% with chemotherapy and 49% without; predictions for 10-year BCSS were 80% and 66%, respectively. Conclusions: Adjuvant chemotherapy is associated with higher OS and BCSS in small node negative TNBC. Benefit is most evident in grade 3 tumors and tumors > 1cm and not evident in tumors ≤1cm and grade 1-2.[Table: see text]
Eflapegrastim, a novel and potent long-acting GCSF for reducing chemotherapy-induced neutropenia: Integrated results from two phase III trials in breast cancer patients.
Authors: Schwartzberg Lee S. , Bhat Gajanan , Bharadwaj Jayaram S. , Hlalah Osama , Restrepo Alvaro , Mehmi Inderjit , Chawla Shanta , Cobb Patrick Wayne
Published: May 2019

539

Background: Eflapegrastim (E) is a novel long-acting GCSF comprised of recombinant human GCSF covalently linked to human IgG4 Fc fragment via a PEG linker (MW, 72 kDa). E showed increased potency vs pegfilgrastim (P) in preclinical and Phase I and II trials. Two identically designed Phase III pivotal trials (NCT02643420, NCT02953340) were conducted globally with a fixed dose of 13.2 mg E containing 3.6 mg GCSF to evaluate E vs P (6 mg) in pts receiving chemotherapy for early-stage breast cancer. Methods: Each open-label trial randomized pts 1:1 to a single subcutaneous dose of E 13.2 mg/0.6 mL or P 6 mg/0.6 mL on Day 2 of each of four 21-day cycles following Day 1 adj/neoadj docetaxel 75 mg/m2 + cyclophosphamide 600mg/m2 (TC). The primary endpoint was to demonstrate E non-inferiority (NI) to P as measured by mean duration of severe neutropenia (DSN) in Cycle 1. Results: A total 643 intent-to-treat pts (314 E/329 P) with median age 60 yrs (24–88) were enrolled. Cycle 1 mean (SD) DSN was 0.24 (0.581) vs 0.36 (0.789) days for E and P, confirming NI (p < .0001) and suggesting statistical superiority (p < .029). DSN NI was also shown across cycles 2–4. Among subgroups, including elderly (≥65 yrs) and overweight ( > 75kg) pts, DSN was reduced for E vs P. In Cycle 1, E showed an absolute risk reduction for severe neutropenia of 6.5% vs P (27.1% relative risk reduction, p < .043). Neutropenic complications (hospitalization and/or anti-infective use) were 2.9% and 4.0% for E and P (p = ns). Incidence of FN was low for both E and P, 1.6% vs 1.8% in Cycle 1 and 3.2% vs 3.0% overall. ANC profiles showed sustained increased levels for E vs P in the recovery phase across all cycles. Safety profiles were similar for E and P, including primarily for expected hematologic AEs and for bone pain and other musculoskeletal pain. Conclusions: These integrated pivotal trial results confirm a similar safety profile and non-inferiority in reducing neutropenic risk for E at a lower GCSF dose vs P. The data also suggests the potential for increased potency of E to deliver improved clinical benefit, a possibility that warrants further clinical trials. Clinical trial information: NCT02643420, NCT02953340.
Effects of Non-Linear or Linear Aerobic Training (AT) Dosing Regimens on Impaired Cardiovascular (CV) Function in Patients with Operable Breast Cancer: A Randomized Controlled Trial (RCT).
Authors: Scott Jessica , Thomas Samantha M. , Herndon James Emmett , Peppercorn Jeffrey M. , Douglas Pamela S. , Khouri Michel , Dang Chau T. , Yu Anthony Francis , Catalina Diane , Ciolino Cristi , Capaci Catherine , Michalski Meghan , Eves Neil Derek , Jones Lee
Published: May 2019

541

Background: Breast cancer therapy causes marked impairments in CV function predisposing to elevated risk of CV morbidity. We investigated the effects of two AT dosing regimens on CV function in post-treatment patients with operable breast cancer. Methods: In a three-arm, parallel-group RCT, 174 post-menopausal patients (2.8 years post primary adjuvant therapy) with impaired age/sex-matched peak oxygen consumption (VO2peak) were randomized to: (1) conventional linear AT (uniform dose-intensity / session), (2) nonlinear AT (variable dose-intensity / session), or (3) stretching (attention control). AT consisted of 64 supervised treadmill walking sessions delivered four times weekly at either ~70% VO2peak for 40 mins/session (linear) or 55% to 100% VO2peak for 20-45 mins/session (nonlinear) for 16 consecutive weeks. Stretching was matched to AT on the basis of location, frequency, duration, and treatment length. The primary end point was change in VO2peak. Secondary end points were other markers of CV risk profile (biochemical CV risk profile, cardiac function, body composition), patient-reported outcomes (PROs), tolerability (e.g., relative dose intensity), and safety. All analyses followed the intention-to-treat principle. Results: Rates of lost-to-follow were < 10% in all arms. Relative dose intensity of AT was 73% ± 27% and 80% ± 21% in linear and nonlinear arms, respectively. No serious adverse events were observed. In adjusted analysis, compared to control, VO2peak (ml O2.kg-1.min-1) increased 0.7 (± 0.3) ml O2.kg-1.min-1 (p = 0.06) and 0.8 (± 0.4) ml O2.kg-1.min-1 (p = 0.02) in linear and nonlinear AT, respectively. Rates of VO2peak improvement greater than the technical error of measurement (i.e., ≥1.32ml O2.kg-1.min-1) were 33% and 39% in linear and nonlinear AT (p = 0.03), respectively. Both AT regimens were associated with improvements in several secondary CV end points but only nonlinear AT improved PROs compared with control (all p’s < 0.05). There were no differences between the two AT regimens. Conclusion: AT significantly improves CV function and PROs in post-treatment breast cancer patients. The efficacy-tolerability ratio favors the non-linear regimen over the conventional linear prescription approach. Clinical trial information: NCT01186367.
PAM50 HER2-enriched subtype as an independent prognostic factor in early-stage HER2+ breast cancer following adjuvant chemotherapy plus trastuzumab in the ShortHER trial.
Authors: Conte Pier Franco , Griguolo Gaia , Dieci Maria Vittoria , Bisagni Giancarlo , Brandes Alba Ariela , Frassoldati Antonio , Cavanna Luigi , Musolino Antonino , Giotta Francesco , Rimanti Anita , Garrone Ornella , Galvan Patricia , Brasó Maristany Fara , Orvieto Enrico , Urso Loredana , Maiorana Antonino , Balduzzi Sara , D'Amico Roberto , Guarneri Valentina , Prat Aleix
Published: May 2019

544

Background: We investigated the prognostic role of the PAM50 HER2-enriched (HER2-E) subtype in HER2+ early breast cancer enrolled in the randomized Phase III ShortHER trial. Methods: The ShortHER study randomized 1254 HER2+ early breast cancer patients to receive 9 weeks vs 1 year of adjuvant trastuzumab combined with chemotherapy. Gene expression measured using nCounter platform was available for 438 surgical samples. Intrinsic subtyping was determined using the research-based PAM50 predictor. Metastasis-free survival (MFS) was calculated from randomization to distant disease recurrence or death (median follow up 72 months). Uni- and multi-variable analysis were performed using Cox models. Results: PAM50 subtype distribution was: HER2-E 53% (N = 233), Luminal A 20% (N = 87), Luminal B 10% (N = 43), Normal-like 11% (N = 48) and Basal-like 6% (N = 27). HER2-E subtype was associated with hormone receptor-negative status (p < 0.001) and TILs ≥20% (p < 0.001), but not with stage and age ( < or ≥60 yrs). HER2-E subtype was associated with worse MFS vs other PAM50 subtypes overall (HR 2.78, p = 0.001), in the short (HR 2.24, p = 0.046), and in the long arm (HR 4.04, p = 0.011). Multivariable Cox model confirmed the independent prognostic value of HER2-E subtype (Table). HER2-E subtype added significant prognostic value on top of clinicopathological variables (Likelihood ratio test p < 0.001). Conclusions: HER2-E intrinsic subtype is an independent prognostic factor for HER2+ early breast cancer patients treated with adjuvant chemotherapy and trastuzumab. Integration of PAM50 subtype in prognostic algorithms can help refine risk stratification. These findings warrant independent validation. Clinical trial information: NCT00629278. [Table: see text]
The prognostic role of progesterone receptor in patients with rapidly proliferating, hormone receptor-positive early breast cancer.
Authors: Bravaccini Sara , Bronte Giuseppe , Scarpi Emanuela , Ravaioli Sara , Tumedei Maria Maddalena , Maltoni Roberta , Puccetti Maurizio , Mangia Anita , Amadori Dino , Rocca Andrea
Published: May 2019

545

Background: The prognostic role of progesterone receptor (PgR) in highly proliferating early breast cancer (BC) is not well established. We retrospectively explored this biomarker in a cohort of patients with highly proliferating tumors enrolled in a phase III trial of adjuvant therapy. Methods: 1066 patients with N- or 1-3 N+ BC were randomized to receive: epirubicin followed by CMF, CMF followed by epirubicin, or CMF alone. Rapidly proliferating tumors were defined by thymidine labeling index (TLI) > 3% or histological grade 3 or S-phase > 10% or Ki67 > 20%. We analyze the subgroup of 466 patients with hormone receptor (HR)-positive tumors treated with sequential epirubicin/CMF regimens followed by tamoxifen and for whom immunohistochemical assessments of estrogen receptor (ER), PgR, HER2 and Ki67 were available. Disease-free (DFS) and overall survival (OS) curves were built with the Kaplan–Meier estimator and compared by logrank test and Cox regression models. Results: PgR expression was significantly associated with ER expression, HER2 status, age and menopausal status, but not with Ki67, tumor size and nodal status. PgR cutoff values of 10% and 20% were chosen based on a Receiver Operating Characteristics analysis and the literature data. DFS and OS figures at 5 and 10 years, as well as the relative hazard ratios, according to the different PgR cutoff values, are reported in the table. Conclusions: Our results confirm the prognostic relevance of PgR expression in a cohort of patients with highly proliferating, HR-positive early BC treated with adjuvant chemotherapy and endocrine therapy. [Table: see text]
Patterns of systemic treatment utilization in ER+/PgR+/HER2+, early-stage breast cancer (BC): An analysis of the National Cancer Database.
Authors: Nahleh Zeina A. , Hobbs Brian , Elimimian Elizabeth , Wei Wei (Auston) , Gupta Annie , Blake Cassann N.
Published: May 2019

547

Background: The preferences and trends of treatment utilization of adjuvant endocrine therapy (ET) versus chemotherapy (CH) for small node-negative triple positive (TP) BC are unclear. We sought to determine these preferences and assess the impact on outcome. Methods: This is a retrospective study from the National Cancer Database including patients with TP stage I BC, 2004-2015. Treatment selection was evaluated for association with patient clinical and demographic characteristics using logistic regression. Overall survival (OS) was estimated using the Kaplan-Meier method and compared among patient and treatment cohorts by log-rank test and Cox regression. Results: Of 37,777 patients analyzed, 79% were White (Non-Hispanics), 10% African Americans, and 5% Hispanic/Latinos. 57% were 50-70 years old. 86% received adjuvant endocrine therapy versus 14% CH first. Around 40 % of all patients received anti-Her2 therapy. Patients younger than 70 years, with male BC, diagnosed with poorly differentiated BC, African Americans and Hispanics were more likely to be treated with chemotherapy. OS rate at 5-year was 92.3% (95% CI: 0.918-0.928). In multivariate analysis for patients with survival data, an increased rate of death was associated with: treatment in community versus academic/research centers, CH first versus ET, no treatment with anti-Her2 therapy, government versus private /no insurance, Native American ethnicity. A slight but statistically significant reduction in the in the risk of death at 5 years was evident for patients receiving anti-Her2 therapy plus ET therapy, 5-year OS 93.5% (CI: 89.2-98%), when compared to patients receiving anti-Her2 therapy plus CH 92.7 % (CI: 89.4-96). Conclusions: This study provides real world data of common practices in the US . The majority of patients with node negative Stage I, ER+/PR+/Her2+ BC received adjuvant ET and anti-Her2 therapy, not chemotherapy. These patients had a similar to slightly improved 5 year- survival when compared to anti-Her2 therapy plus CH, supporting the use ET plus anti-Her2 therapy in this setting. Future studies should focus on better selecting patients with hormone receptor positive and Her 2 + early stage BC who would benefit from adjuvant CH. Disparity in outcome also warrants further evaluation. [Table: see text]
Prognostic value of PD-L1 gene expression with Recurrence Score and 70-gene signature in patients with ER+/HER2- early breast cancer.
Authors: Zerdes Ioannis , Sifakis Emmanouil G. , Tobin Nicholas , Bergh Jonas C. S. , Matikas Alexios , Foukakis Theodoros
Published: May 2019

550

Background: We have previously demonstrated that PD-L1 mRNA expression can serve as prognostic biomarker in breast cancer (BC). In ER+/HER2- BC, RS and 70-gene signature are used to predict the risk of recurrence and benefit from chemotherapy. Methods: Discovery cohort (cohort 1) included 302 patients diagnosed with primary ER+/HER2- BC (1997-2005) in Stockholm health care region. Gene expression profiling has been performed using DNA microarrays (GSE48091) while information regarding tumor characteristics, treatment and follow-up have been obtained. TCGA’s dataset including 590 ER+/HER2- patients, was used as validation cohort (cohort 2). Kaplan–Meier estimates and Cox regression univariate/multivariable analyses were performed using breast cancer-specific survival(BCSS) and progression-free interval (PFI) as endpoints in cohorts 1 and 2, respectively. Gene signature scores were calculated using the R genefu package. Likelihood ratio (LR) tests and concordance indices (c-indices) were used to assess each score’s added prognostic value. Results: PD-L1 mRNA expression (treated as a continuous variable) was independently associated with better BCSS in cohort 1 (HR = 0.72; 95% CI = 0.58-0.90;p = 0.003) and with better PFI in cohort 2 (HR = 0.67; 95% CI = 0.50-0.90; p = 0.008) in the multivariable analysis. PD-L1 provided significant additional prognostic information beyond that of both RS alone (LR-Δχ2= 9.6; p = 0.002 and LR-Δχ2= 9.7; p = 0.002, in cohorts 1 and 2, respectively), and 70-gene signature score alone (LR-Δχ2= 10.4; p = 0.001 and LR-Δχ2= 9.2; p = 0.002 in cohort 1 and 2, respectively). C-indices for PD-L1 + RS vs RS were 0.65 vs 0.60 (cohort 1) and 0.66 vs 0.60 (cohort 2), and for PD-L1 + 70-gene vs 70-gene were 0.65 vs 0.59 (cohort 1) and 0.64 vs 0.54 (cohort 2), respectively. Conclusions: PD-L1 gene expression was correlated with better outcomes and can provide added prognostic value to RS and 70-gene signature scores in ER+/HER2- BC.