bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): Updated analyses from PALOMA-3.
Authors: Cristofanilli Massimo , Rugo Hope S. , Im Seock-Ah , Slamon Dennis J. , Harbeck Nadia , Bondarenko Igor , Masuda Norikazu , Colleoni Marco , DeMichele Angela , Loi Sherene , Iwata Hiroji , O'Leary Ben , Bananis Eustratios , Liu Yuan , Huang Xin , Kim Sindy , Lechuga Mariajose , Turner Nicholas C. 
Published: June 2021

1000 Background: In PALOMA-3, a randomized, double-blind, placebo-controlled, phase 3 study, PAL+FUL significantly prolonged progression-free survival (PFS) compared with placebo (PBO) + FUL (1-sided P<0.0001). The final protocol-specified OS analysis, which was conducted with a median follow-up of 44.8 months (mo), showed improved OS with PAL+FUL vs PBO+FUL (median OS, 34.9 vs 28.0 mo; hazard ratio, 0.814 [95% CI, 0.644–1.029]; 1-sided P=0.0429). Here, we report the results from an OS analysis with a longer median follow-up of 73.3 mo. Methods: A total of 521 patients (pts) with HR+/HER2– ABC who had progressed on prior endocrine therapy were randomized 2:1 to PAL (125 mg/d orally, 3/1 week schedule) + FUL (500 mg intramuscular injection) or PBO+FUL. Investigator-assessed PFS was the primary endpoint; OS was a key secondary endpoint. An ad hoc OS analysis was performed when 393 events (75% of the total population) were observed. Circulating tumor DNA (ctDNA) analysis was conducted among pts who consented for this study. Results: Improvement in OS continues to be observed with longer follow-up, with a hazard ratio of 0.806 (95% CI, 0.654–0.994; 1-sided nominal P=0.0221). The 5-year OS rate was 23.3% (95% CI, 18.7–28.2) with PAL+FUL and 16.8% (95% CI, 11.2–23.3) with PBO+FUL. Favorable OS with PAL+FUL vs PBO+FUL was observed in most subgroups except among pts who were endocrine resistant or had prior chemotherapy for ABC. No new safety signals were identified. Eighteen pts remain on study treatment, including 15 (4.3%) on PAL+FUL and 3 (1.7%) on PBO+FUL. A post-study cyclin-dependent kinase 4/6 inhibitor was received by 20 pts (7.5%) in the PAL+FUL arm and 32 pts (22.2%) in the PBO+FUL arm. ctDNA analyses of tumor mutation profiles (ie, ESR1, PIK3CA, RB1) at the end of treatment and their effect on OS will also be presented. Conclusions: The clinically meaningful improvement in OS with PAL+FUL was maintained with >6 years of median follow-up in pts with HR+/HER2– ABC who had progressed on prior endocrine treatment. Pfizer (NCT01942135) Clinical trial information: NCT01942135 .[Table: see text]
Clinical impact of molecular tumor profiling in pediatric, adolescent, and young adult patients with extra-cranial solid malignancies: An interim report from the GAIN/iCat2 study.
Authors: Church Alanna J. , Corson Laura , Kao Pei-Chi , Imamovic-Tuco Alma , Kang Wenjun , Pinto Navin R. , Maese Luke , Laetsch Theodore Willis , Kim AeRang , Colace Susan , Macy Margaret E , Applebaum Mark A. , Bagatell Rochelle , Sabnis Amit J. , Weiser Daniel , Glade Bender Julia Lynne , Volchenboum Samuel Louis , DuBois Steven G. , London Wendy B. , Janeway Katherine A. 
Published: June 2021

10005 Background: Next generation sequencing (NGS) assays are now a standard part of clinical care for many adult solid cancers. The significance of molecular tumor profiling for the care of children with cancer is not well understood.We aimed to determine the clinical impact of identifying genomic alterations by NGS for young patients with relapsed, refractory, or high-risk extracranial solid tumors. Methods: We report on the first 389 participants in a prospective cohort study enrolling patients at 12 institutions with extracranial solid tumors diagnosed at age 30 years or less. Targeted DNA NGS was performed on one or more tumor samples from each patient. Selected patients also had tumors subjected to RNA sequencing. Test results were returned to the treating oncologist and follow-up treatment and response data were collected.Identified genomic alterations were classified according to evidence of impact on diagnosis, prognosis or response to targeted therapy matched to an identified alteration (matched targeted therapy, MTT) using established guidelines. Response to MTT was determined and reported as a response if either there was radiographic response according to RECIST or the duration of therapy was > 4 months. Results: Molecular tumor profiling (MTP) was successful in 345 (89%) patients (mean age 11 years at diagnosis; 65% with sarcoma). Two hundred and ninety-nine patients with MTP results (87%) had one or more alterations of clinical significance. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 208 (60%), 51 (15%) and 240 (70%) patients, respectively. Of the 240 patients with tumors harboring genomic alterations designated as having therapeutic impact, 23 (11%) had Tier 1 molecular findings. 205 patients were eligible to receive MTT based on having a molecular alteration with therapeutic significance and sufficient follow-up; 31 of these patients (15%) received MTT. Seven patients (23%) receiving MTT responded, 6 of these were kinase fusions. All of the responders received targeted therapy matched to a fusion and 78% of diagnostically significant alterations were fusions. Conclusions: Molecular tumor profiling has a significant impact on diagnosis and treatment recommendations for young patients with extracranial solid tumors. These results emphasize the importance of fusion detection for patients with sarcomas and rare tumors. Clinical trial information: NCT02520713.
Safety and activity of single-agent giredestrant (GDC-9545) from a phase Ia/b study in patients (pts) with estrogen receptor-positive (ER+), HER2-negative locally advanced/metastatic breast cancer (LA/mBC).
Authors: Jhaveri Komal L. , Boni Valentina , Sohn Joohyuk , Villanueva-Vásquez Rafael , Bardia Aditya , Schmid Peter , Lim Elgene , Patel Jaymin M. , Perez-Fidalgo Jose Alejandro , Loi Sherene , Im Seock-Ah , Kshirsagar Smita , Gates Mary R. , Bond John , Eng-Wong Jennifer , Chang Ching-Wei , Turner Nicholas C. , Lopez Miranda Elena , García-Estévez Laura , Bellet Meritxell 
Published: June 2021

1017 Background: Targeting ER activity and/or E synthesis is a mainstay of ER+ BC treatment, but many pts relapse during/after adjuvant endocrine therapy (ET) or develop resistance via ESR1 mutations that drive E-independent transcription and proliferation. Most tumors remain ER signaling-dependent and pts may respond to second-/third-line ET after disease progression (PD) on prior therapies (Di Leo 2010; Baselga 2012). Giredestrant, a highly potent, nonsteroidal oral selective ER degrader, achieves robust ER occupancy, is active despite ESR1 mutations, and was well tolerated ± palbociclib with encouraging antitumor activity in the nonrandomized, open-label, dose-escalation and -expansion, phase Ia/b GO39932 study (NCT03332797; Jhaveri 2019; Lim 2020). We present updated interim data from the dose-escalation and -expansion single-agent giredestrant cohorts. Methods: Pts had ≤2 prior therapies in the LA/mBC setting with disease recurrence/PD while being treated with adjuvant ET for ≥24 mo and/or ET in the LA/mBC setting, and derived a clinical benefit (CB) from therapy (tumor response/stable disease [SD] ≥6 mo). Pts received 10, 30, 90/100, or 250 mg PO giredestrant QD on D1–28 of each 28-day cycle. Pts were postmenopausal (medical menopause on LHRH agonists was allowed with ≥100 mg giredestrant). Results: Clinical cutoff: Jul 31, 2020; median prior therapy lines in the LA/mBC setting: 1; mean dose intensity: 98%. Safety/activity: see the table below. No adverse events (AEs) led to study drug withdrawal. No dose-limiting toxicities (DLTs) occurred; maximum tolerated dose was not reached. Most common AEs in 107 pts: fatigue (22; 21%), arthralgia (18; 17%), and nausea (17; 16%); largely grade 1/2. Related grade 3 AEs were infrequent (5; 5%); none were grade 4/5 per investigator assessment (grade 5 duodenal perforation occurred with 90/100 mg after stopping giredestrant due to PD). 8 (7%) had bradycardia (none with 10 mg or the 30 mg phase 3 dose; all grade 1 except one grade 2 at 250 mg; no treatment interruptions/dose reductions were required). Objective responses and CB were observed at all doses. Conclusions: Single-agent giredestrant was well tolerated at all doses, with no DLTs. AEs were generally low grade and in keeping with expected AEs for ETs. Clinical activity was observed at all doses. Updated data, including biomarker and correlative data, will be presented. Clinical trial information: NCT03332797 .[Table: see text]
Phase I/II study of H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer.
Authors: Hamilton Erika P. , Wang Judy S. , Pluard Timothy J. , Johnston Stephen R. D. , Morikawa Aki , Dees Elizabeth Claire , Jones Robert Hugh , Haley Barbara B. , Armstrong Anne Caroline , Cohen Adam Louis , Munster Pamela N. , Wright Gail Lynn Shaw , Kayali Fadi , Korpal Manav , Xiao Jianjun Alan , Long Jenny , Destenaves Benoit , Gao Lei , Gualberto Antonio , Juric Dejan 
Published: June 2021

1018 Background: H3B-6545, a selective, small molecule covalent antagonist of ERα demonstrated preclinical and preliminary clinical activity against ER+ breast cancer (Hamilton EP, SABCS, 2020). This study evaluated the activity and tolerability of H3B-6545 in patients (pts) with metastatic ER+, HER2-, breast cancer refractory to endocrine therapy. Methods: Patients received H3B-6545 once daily at the recommended phase II dose of 450 mg. The primary objective of the phase II is to estimate the objective response rate (ORR), progression-free survival (PFS), clinical benefit rate (CBR) and secondary objectives include safety. Results: 83 pts were treated with 450 mg in the phase II part of the trial. Additionally, 11 pts were treated with 450 mg in the phase I part of the trial and are included in this analysis. Median age was 62 years (range: 38 to 87 years), 81% had liver and/or lung metastases, and the median number of prior therapies for metastatic disease was 3 (range: 1 to 8). Prior CDK4/6 inhibitors, aromatase inhibitors, fulvestrant, and chemotherapy were received by 85%, 80%, 72%, and 50% of the pts, respectively. 58 pts (62%) had detectable ESR1 mutations in liquid biopsies, including 10 (11%) and 19 pts (20%) who had clonal Y537S and clonal D538G mutation, respectively. As of January 29, 2021, grade (gr) 2 or higher adverse events (AE) reported in ≥10% were anemia (19%), fatigue (16%), nausea (17%), and diarrhea (12%). Laboratory gr 2 or higher abnormalities reported in ≥10% pts were creatinine clearance decrease (38%), hemoglobin decrease (37%), bilirubin increase (12%), ALT increase (14%), AST increase (13%), and creatinine increase (11%). AE of gr 1 sinus bradycardia (asymptomatic) was reported in 34% and gr 2 (symptomatic, no intervention needed) was reported in 5%. Gr 2 and 3 QTcF prolongation were reported in 2 and 3 pts, respectively. There were no treatment-related deaths. Efficacy estimates are presented in the table below. Responses were observed in heavily pretreated pts, pts with visceral metastases and in pts who received prior fulvestrant, CDK4/6 inhibitor, and/or chemotherapy in the metastatic setting. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients. Clinical activity was observed in pts with ESR1 mutations. Clinical trial information: NCT03250676 .[Table: see text]
Efficacy of enobosarm, a selective androgen receptor (AR) targeting agent, correlates with the degree of AR positivity in advanced AR+/estrogen receptor (ER)+ breast cancer in an international phase 2 clinical study.
Authors: Palmieri Carlo , Linden Hannah M. , Birrell Stephen , Lim Elgene , Schwartzberg Lee S. , Rugo Hope S. , Cobb Patrick Wayne , Jain Kirti , Vogel Charles L. , O'Shaughnessy Joyce , Johnston Stephen R. D. , Getzenberg Robert H. , Barnette K. Gary , Steiner Mitchell S. , Brufsky Adam , Overmoyer Beth 
Published: June 2021

1020 Background: The AR is expressed in up to 90% of ER+ breast cancer where it acts as a tumor suppressor. Historically, therapy with synthetic androgens had efficacy, but virilizing side effects and toxicity limited their use. Enobosarm is a selective AR activating agent that does not cause masculinization and has positive attributes such as promotion of bone and improvement of physical function. In a phase 2 study, correlation between the degree of AR staining and antitumor activity in AR+/ER+ patients with metastatic breast cancer (MBC) was examined. Methods: A phase 2, open label, parallel design randomized study was conducted in 136 patients to evaluate the efficacy and safety of enobosarm in heavily pretreated women with AR+/ER+ MBC. Patients were randomized to 9 mg (n=72) or 18 mg (n=64) of oral daily enobosarm. AR expression (%AR nuclei staining) in breast cancer samples was determined centrally by immunohistochemistry. The correlation between %AR staining and clinical outcomes was examined with a focus on the 9mg dose, selected for the phase 3 study and the optimal %AR staining established. Results: Tumor objective outcomes correlated with percent AR staining (Table). Further, using a 40% AR staining cutoff in patients with measurable disease, the clinical benefit rate (CBR) for ≥40% AR is 80% and <40% is 18% (p<0.0001). Best objective tumor response (BOR) in patients with ≥40% AR is 48% and <40% is 0% (p<0.0001). At ≥40% AR, median radiographic progression free survival (rPFS) is 5.47 and mean is 7.15 months vs <40% AR where the median rPFS is 2.72 and mean is 2.7 months. Similar %AR staining correlation was observed in the 18mg cohort. Enobosarm treatment was well tolerated with significant positive effects on quality of life measurements. Conclusions: Enobosarm is a novel oral selective AR activating agent in which a higher % AR staining correlates with a greater antitumor activity. By targeting and activating AR, enobosarm may represent a new hormone treatment approach for AR+/ER+ MBC. The phase 3, ARTEST trial will commence in early 2021 and randomize patients with AR+/ER+/HER2- heavily treated MBC that have progressed on a non-steroidal aromatase inhibitor, fulvestrant and CDK 4/6 inhibitor to receive enobosarm or standard endocrine therapy. Clinical trial information: NCT02463032 .[Table: see text]
Prevalence of HER2 low in breast cancer subtypes using the VENTANA anti-HER2/neu (4B5) assay.
Authors: Scott Marietta , Vandenberghe Michel Erminio , Scorer Paul , Boothman Anne-Marie , Barker Craig 
Published: June 2021

1021 Background: Breast cancer patients with HER2 low expression by immunohistochemistry (IHC), defined as IHC1+ or IHC2+ without gene amplification (ISH-) do not respond to conventional anti-HER2 therapies such as trastuzumab or pertuzumab. The HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) showed efficacy in late line HER2-overexpressing patients, with some responses in patients with low HER2 expression. Two of the market leading IHC IVDs are Dako Herceptest and Ventana 4B5. T-DXd is being investigated in HER2 low patients as determined by the VENTANA anti-HER2/neu (4B5) assay in the phase III DESTINY-Breast04 study. There is a paucity of information on prevalence of IHC1+/2+ in different breast cancer subtypes, which this study aims to address. Methods: HER2 status was calculated from 3750 consecutive primary or metastatic breast cancer patient samples successfully stained using the 4B5 assay and scored locally according to ASCO/CAP 2018 guidelines. Samples were obtained from 3 anatomic pathology labs that support networks of US community hospitals. 500 additional breast cancer samples, pre-selected to include a range of IHC staining (concordance cohort), were stained with both 4B5 and HercepTest (Dako/Agilent) and scored (IHC0, IHC1+, IHC2+, IHC3+) at a central laboratory. Results: Prevalence of HER2 categories in 3750 consecutive breast cancer samples is presented in the table below. >50% of estrogen-receptor positive (ER+ve) and progesterone receptor positive (PR+ve) subtypes are HER2 low. In the 500 sample concordance cohort, 28.0% were IHC1+/2+ using the 4B5 assay compared with 11.6% using HercepTest. HercepTest identified IHC1+/2+ staining in 21.6% [95%CI:15.1,29.4] of the patients classified as IHC1+/2+ by 4B5. 98.3% [95%CI: 96.2, 99.5] of samples IHC0 by 4B5 were also IHC0 by Herceptest. Conclusions: HER2 IHC1+/2+ (ISH-) by Ventana 4B5 represent a significant proportion of breast cancer patients and more than 50% of ER+ve and PR+ve subtypes. The 4B5 assay classed several patients as IHC1+/2+ that are IHC0 by Herceptest, but almost all patients IHC0 by 4B5 were also IHC0 by Herceptest.[Table: see text]
A retrospective study of characteristics and survival in patients with breast cancer brain metastases classified by subtype using NCI SEER registry.
Authors: Devanaboyina Monika , Bailey Morgan Marie , Hamouda Danae M. 
Published: June 2021

1031 Background: Breast cancer brain metastasis (BCBM) de novo is associated with the worst prognosis among all types of metastases in breast cancer (BC). Analysis of factors associated with BCBM stratified by subtype of BC could lead to earlier identification of metastasis. Methods: 1,268 patients with BCBM at the time of BC diagnosis and known clinical subtype (580 HR+/HER2-, 225 HR+/HER2+, 176 HR-/HER2+, and 287 HR-/HER2-) who were ≥ 20 years of age from 2010 to 2017 were identified using the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program 18 registry. Baseline characteristics and survival were analyzed using Chi-Square and Kaplan-Meier methods. Results: Patients with HR-/HER2+ BC were the most likely to present with BCBM, compared to all BC patients (prevalence of 13.9% vs. 4.7%; p<0.001). Further analysis demonstrated that HER2+ patients had an odds ratio of presenting with BCBM of 2.52 (95% CI: 2.24-2.84) compared to HER2- patients. Interestingly, in patients ages 20-39 with HR-/HER2+ BC, higher rates of brain metastases are noted within the BCBM group compared to all HR-/HER2+ breast cancer cases (28% vs. 7.6%; p<0.001). The same trend is seen within the HR-/HER2+ African American population, with those in the BCBM group experiencing higher rates of brain metastases compared to all BC cases with the same subtype (14.3% vs. 5.9%; p<0.001). Upon exploring insurance demographics, uninsured patients with HR-/HER2+ BCBM had much higher rates of brain metastases compared to all HR-/HER2+ BC cases (14.8% vs 6.4%; p=0.001). When examining TNM status, significant associations were noted between brain metastases and increased tumor and nodal status. Patients with T4 or N3 status with HR-/HER2+ BCBM exhibited much higher rates of metastasis compared to all BC cases with the same subtype (p<0.001). Analysis of survival outcomes showed a median overall survival of 12 months for patients with HR-/HER2+ BCBM. The results displayed in the table below show that HR-/HER2- BCBM patients had the lowest 5-year percent survival, while HR+/HER2+ BCBM patients had the highest 5-year survival. Conclusions: This SEER database study provides insight into the demographics, clinical variables, and outcomes for BC clinical subtypes, specifically HR-/HER2+, from 2010 to 2017 in the United States. HR-/HER2+ breast cancer patients within the noted high-risk populations should be made aware of the increased rates of brain metastases compared to the general BC population, as earlier identification of brain metastases within the HR-/HER2+ cohort could improve patient survival.[Table: see text]
Concordance of HER2+ status by IHC/ISH and ERBB2 status by NGS in a real-world clinicogenomic database and analysis of outcomes in patients (pts) with metastatic breast cancer (mBC).
Authors: Cho-Phan Cheryl D. , Snider Jeremy , Zhang Liangliang , McGregor Kimberly , Schrock Alexa Betzig , Castellanos Emily 
Published: June 2021

1036 Background: HER2 overexpression/amplification measured by IHC or ISH is a predictive biomarker for HER2-targeted therapies. Next-generation sequencing (NGS) can identify ERBB2 amplification (amp) and mutations. We examined clinical characteristics, NGS testing patterns, and outcomes of pts treated with 1L HER2 therapy with HER2+ mBC based on ERBB2 amp status using a real-world (RW) clinico-genomic database (CGDB). Methods: Pts with mBC (HER2+ by IHC and/or ISH) treated with 1L HER2 therapy who had undergone NGS and were treated within the Flatiron Health (FH) network were eligible. Clinical characteristics and HER2 testing results were obtained via technology-enabled abstraction of clinician notes and radiology/pathology reports and linked to genomic data from Foundation Medicine (FMI) in the nationwide (US-based), de-identified FH-FMI CGDB. Demographic, clinical and genomic characteristics were summarized and stratified by concordance between HER2+ (IHC 3+ or ISH amp+) and ERBB2amp+ status [copy number (CN) ≥ 5]. NGS testing patterns and 1L HER2 therapy were characterized and stratified by concordance status. Concordance was assessed based on contemporaneous timing of paired test specimen collection dates (FMI NGS ≤ 30 days of HER2+ status). RW overall survival (rwOS) stratified by HER2+/ ERBB2 amp concordance was estimated with Kaplan-Meier analysis and adjusted Cox proportional hazards models. Results: Among 268 eligible pts, HER2+/ ERBB2amp+ concordance was 66% (176/268); concordance among contemporaneous paired specimens was 73% (106/145). Demographic and clinical features were overall well-balanced with most pts treated at community sites [94%, (252/268)]; the discordant (HER2+/ ERBB2amp-) group (95/268) had more pts with hormone receptor positive disease (73% vs 62%). Concordance by assay type varied; IHC+ only, IHC+/ISH+, and ISH+ only agreement was 72% (95/132), 76% (26/34) and 52% (50/96), respectively. A higher proportion of discordance (35% vs 19%) was seen in pts treated at community vs. academic sites. Median rwOS was 32.9 months (IQR 25.9-38.9) among concordant (HER2+/ ERBB2amp+) and 15.5 months (IQR 8.9-30.1) among discordant (HER2+/ ERBB2amp-) pts, aHR = 0.71 [95% CI: 0.48-1.03; p = 0.073]. Conclusions: Among RW pts with HER2+ mBC receiving 1L HER2 therapy, discordance between ERBB2amp and IHC/ISH HER2 testing methods was observed. Pts with tumors HER2+ by IHC and/or ISH but negative for ERBB2amp had a trend towards worse rwOS following receipt of HER2 therapy compared to concordant cases. Contemporaneous timing of specimen collection was associated with greater concordance. Future analyses on the additive value of ERBB2 CN as a predictive marker, and assessing factors that may affect discordance such as intratumor HER2 heterogeneity, tumor content, and biopsy site are warranted.